Priority Medicines for Europe and the World 2013 Update. Background Paper 7 - Cross-cutting themes

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1 Priority Medicines for Europe and the World 2013 Update Background Paper 7 - Cross-cutting themes BP Priority medicines for children BP Priority medicines for women BP Priority medicines for elderly BP Pharmacogenomics and stratified medicine

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3 Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by MGP Zuidgeest, MJC Willemen and JN van den Anker Background Paper 7.1 Priority Medicines for Children By Verica Ivanovska 1,2, Aukje K. Mantel-Teeuwisse 1, Liset Van Dijk 3 May 10, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands 2 University Goce Delcev, Stip, Macedonia 3 Netherlands Institute for Health Services Research (NIVEL), Utrecht, the Netherlands This Background Paper was commissioned by the WHO Collaborating Centre for Pharmaceutical Policy and Regulation ( This work was financially supported by the Dutch Ministry of Health, Welfare and Sport.

4 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Table of contents Executive summary and key research points Introduction Demographics and diseases faced by children Childhood mortality Childhood morbidity Asthma in children Diabetes in children Mental diseases in children Infectious diseases in children General use of medicines in children Conclusions Product related issues in children Paediatric age-appropriate dosing and formulations New oral paediatric formulations Novel paediatric drug devices Taste and palatability of paediatric dosage forms Use of excipients in paediatric dosage forms Clinical evidence on impact of paediatric pharmaceutical development WHO activities towards better medicines for children Conclusions Regulatory aspects related to children Implementation of the EU paediatric legal framework Achievements of the EU Paediatric Regulation Patients participation in the development of paediatric medicines Conclusions The usage environment Off-label and unlicensed use of medicines in children Medicines use in children for specific diseases Use of antibiotics in children Use of psychotropic medicines in children Use of medicines in preterm newborns Use of medicines in children in hospitals Use of medicines in children in developing and transitional countries Adherence to treatment in children

5 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 5.6 Availability of information on (off-label) paediatric medicines and its dissemination to health workers and patients Identified gaps and recommendations for research and policy References Annex 7.1.1: Infant mortality rates in Europe in Annex 7.1.2: Regional causes of childhood deaths in Annex 7.1.3: Developmental Changes in Physiology in Children Annex 7.1.4: EMA Matrix routes of administration/dosage form vs. age Annex 7.1.5: Novel drug formulations for children Annex 7.1.6: Novel drug devices for children Annex 7.1.7: Paediatric products prequalified up to Annex 7.1.8: List of centrally authorised medicinal products for which the therapeutic indication was extended or amended to the paediatric population Annex 7.1.9: List of medicinal products and companies that have benefited from the 6-month extension of the supplementary protection certificate Annex : Funded off-patent medicine projects (start up to 1 January 2010) and agreed PIPs, if available Annex : Therapeutic needs in the paediatric population according to the survey of all paediatric uses (EMA/794083/2009) and projects addressing the needs Annex : Projects on use of paediatric medicines funded by the Sixth and Seventh Framework Programme (FP6, FP7), excluding off-patent funded projects, presented in Annex Annex : WHO/INRUD prescribing indicators by health facility ownership Annex : WHO/INRUD prescribing indicators by prescriber type

6 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Executive summary and key research points Children are entitled to safe, efficacious, and age-appropriate medicines. However, the provision of optimal medicines for children is limited by the lack of commercial incentives, a dearth of clinical trials on paediatric medicines, delays in licensing medicines for children, and the absence of suitable formulations for children. Children are not small adults, but rather a vulnerable population with specific needs resulting from their changing physiology, who make up a heterogeneous patient group with a scope of diseases different than those of adults, and for whom there is a scarcity of data on appropriate medicines delivery and use. Therefore, these needs are discussed in detail in this background paper; the challenges and opportunities for improvement and further research are also identified. Demographics and diseases faced by children Children in Europe represent 20% of the total population and child mortality rates are low in the European Union. Worldwide under-five mortality steadily declined, from 10.4 million in 2004 to 6.9 million in 2011, but it remains a significant and inequitable problem. Children suffer from a different range of diseases than adults, as some diseases only occur in children, while others occur in both adults and children, but with different pathophysiology, severity, course, and response to treatment across the life span. Asthma is the most common chronic childhood disease in Europe, affecting 5 20% of schoolaged children in Europe. It is assumed that the recent decrease in the prevalence of asthma may correspond with improved environmental control measures. The childhood type 1 diabetes incidence rate continues to rise across Europe by 3-4% per year, and the risk of type 2 diabetes in adolescents is increasing due to overweight and obesity. Mental disorders are increasingly important causes of ill health and disability in children and adolescents, but the recent broadening of age ranges and the scope of diseases has led to debates on the medicalisation of certain conditions. Despite the increasing prevalence of chronic diseases, infectious diseases remain the most common cause of illness in children in the developing world and a predominant cause of childhood mortality in these countries. A study on paediatric drug utilisation in Europe (TEDDY) illustrated that anti-infectives, dermatological and respiratory drugs were the most frequently used medicines in children. Product related issues in children The 2004 Priority Medicines Report called for public investments to reverse the insufficient funding for research on children-specific medicine formulations. An effective paediatric therapy requires medicines adjusted to a child s body development, medicines-related toxicity, and the taste preferences of children. To meet these requirements, it may be necessary to develop age-appropriate medicines with strengths and dosage forms suitable for each paediatric subpopulation using the medicine. Liquid formulations used to be considered the most suitable form for children under six years of age. In 2008, a WHO expert forum proposed a global paradigm shift towards solid oral dosage forms for paediatric medicines, and solid, oral, flexible dosage forms (orodispersible tablets and tablets for oral liquid preparation) became the recommended 7.1-4

7 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children paediatric dosage forms. For oral medicines with precise dose measurements, a new flexible platform technology was proposed to produce multiparticulate solids (mini-tablets and spherical granules - pellets) and dosage forms that are dispersible into liquids or that can be mixed with food. The advantages of novel, solid dosage forms are their dose flexibility for different patient ages and weights, and their easier administration in younger children. Following recent studies on mini-tablets, the age at which young children can safely swallow orally administered solid forms is decreasing. With the development of orally disintegrating mini-tablets, there are more promising results for infants younger than two years of age. Recently various innovative, oral, solid dosage forms and drug devices for paediatric use have become commercially available or are under development. These developments should be accompanied by studies on price implications and access to innovative products, children s preferences and adherence to different dosage forms, safe excipients for children, and new routes of administration (mainly for neonates). The industry should implement the acquired knowledge about more suitable formulations for paediatric use. Regulatory aspects related to children The European Union adopted the Paediatric Regulation in 2007 to support the development and administration of appropriate paediatric medicines and to improve the information available on their use. The Regulation combines requirements for paediatric drug development (paediatric investigation plans - PIPs) with incentives for the pharmaceutical industry to test medicines in children (extension of the supplementary protection certificate - SPC and Paediatric Use Marketing Authorisation - PUMA). The long-term aim of the Paediatric Regulation is to achieve the goal of an integrated approach to the development of paediatric medicines in the overall medicines development area. Nevertheless, paediatric therapeutic areas addressed by the industry since 2007 seem more aligned with adult drug development than to indicated unmet public health needs of children (paediatric oncology, pain, neonatal morbidity). In addition, the awarding of SPC extensions to paediatric medicines may increase public expenditures for healthcare and have cost implications for the public purse. Such effects have to be identified and negotiated according to the available budgets. The fact that only one PUMA has been granted since 2008 indicates that it may not be an adequate incentive to the industry for the development of off-patent drugs. As a response, a priority list of studies into off-patent paediatric medicines has been produced by EMA to serve as a basis for EU public sector research funding. As a complementary measure that addresses the lack of paediatric clinical trials for off-patent medicines, existing patient records on the use of off-label medicines could be systematically collected and evaluated to contribute towards more evidence-based medicines use. Off-label medicines are those prescribed outside their authorised indications with respect to age, dosage, indication or route. The paediatric usage environment Based on an EMA survey published in 2010, 45-60% of all medicines given to children in the EU were used outside their marketing authorisation (off-label), especially in neonates, patients with serious conditions and those in intensive care units. The most frequently used off-label and unlicensed medicines in children were the anti-arrhythmics, anti-hypertensives, proton pump inhibitors, H2-receptor antagonists, anti-asthmatics, and antidepressants. Preterm neonates were the most vulnerable patient group, as they were exposed to a high 7.1-5

8 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children numbers of medicines (mostly unlicensed or off-label), at a higher risk for adverse drug reactions, and without information on safety and efficacy in preterms available in the Summary of Product Characteristics (SmPC). Inappropriate antibiotic prescribing for children was common in Europe, with marked differences between Northern and Southern Europe as well as difference within countries being seen. Of particular concern was the issue of prescribing antibiotics for viral infections because of the problem of antibiotic resistance. Antimicrobials were also among the most commonly prescribed drugs in hospitals. The European Surveillance of Antimicrobial Consumption (ESAC) study in paediatric units in 2008 revealed that a third of paediatric patients were on antimicrobials, with a high proportion of them receiving antimicrobial combinations. The targets for quality improvement included the excessive use of antimicrobial combinations, high proportion of parenteral antimicrobials, and long surgical prophylaxis times. Psychotropic prescribing has risen in European children in the last decade. The most widely used drug subclasses have been the selective serotonin reuptake inhibitor antidepressants and the atypical antipsychotics. Some of the worrisome aspects of this increased use are the lack of well investigated psychotropic medicines, their side-effects (especially long-term effects), and the increase in children and adolescents receiving these medications. Similarly, the irrational use of medications has posed significant challenges for most common childhood diseases (pneumonia, diarrhoea, and malaria) in resource poor settings. A WHO systematic global review of interventions to improve paediatric treatments suggested that the most effective interventions were multifaceted and took place at the system level, as opposed to the individual prescriber level. As definitive data on dosing, efficacy and safety of medicines used in children are seldom demonstrated in paediatric trials, concerted efforts are needed to produce universally accpeted dosing recommendations in children, derived from an integrated analysis of pharmacokinetic and pharmacodynamic data, specific disease factors and developmental growth. This is particularly relevant to the frequent off-label use of paediatric medicines, which lacks the adequate information about possible indications, dosing regimens, dose adjustments, and how they should be administered. Some recent initiatives to improve information dissemination on medicines use in children included the new websites Paediatric Medicines in the Netherlands, Medicines for children in the United Kingdom, the British National Formulary for Children and the WHO Model Formulary for Children. Nonetheless, it should be explored whether the existing information with precise outcome elements within the electronic patient-based system can be utilised to improve the prescribing and utilisation of medicines in children in daily clinical practice. In summary, the following key research priorities for children have been identified: Collection of data on disease burden and medicines use in children across Europe Use of data on disease burden, prevalence and incidence, as well as medicine use in children collected at country level to allow for inter-country comparisons and comprehensive EU analysis of trends and variations over time 7.1-6

9 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Improvement of the methodological quality of data collection and provision of EU support for more multinational collaborative studies of medicines use in children Further research into development of age-appropriate medicines Further research on (younger) children's ability to swallow solid oral formulations Study on children s preferences and adherence to different dosage forms Development of new routes of administration, such as oral-transmusosal (buccal strips), intra-nasal and trans-dermal routes (including needs in neonates) More research into safe use of excipients for children, and data sharing within the research community Need for additional pharmacological data on optimal dosing, efficacy and safety of medicines in children Study effects of development of age-appropriate medications and paediatric regulations Study the impact of different paediatric formulations on patients outcomes Stimulate research on alternative methodological approaches to classical clinical trials to facilitate and optimize clinical trials in children Monitor effects of the development of age-appropriate medications and their introduction on the national markets (increased public expenditure, poor quality products with reference to labelling and packaging) Increase efficiency of the Paediatric Regulation with a focus on real paediatric needs Indicate clinical trials on certain priority medicines with significant therapeutic benefits in children (including neonates) Evaluate new EU Pharmacovigilance Regulation s potential added value in providing safety and efficacy data on off-label-medicines use in children Improve (information on) rational use of paediatric medicines Collect existing individual (electronic) patient records to produce evidence on safety and efficacy of off-label medicines use in children Collect data to measure medicines use in children and assess the effectiveness of interventions to improve treatments Evaluate the impact of adherence-promoting interventions in children Evaluate how healthcare professionals obtain information to treat children in daily practice Evaluate the impact of new information sources on medicines use in children, on better use of medicines and on improved adherence to treatments

10 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 1. Introduction Paediatric patients have specific needs that may not be covered in other parts of the Priority Medicines for Europe and the World 2013 report, since children suffer from a different range of diseases than adults. They are a heterogeneous patient group with developmental, physiological, and psychological differences between age groups and from adults. The provision of optimal medicines for children is limited by various barriers that include insufficient research in children, delays in licensing medicines for children, inadequate development of appropriate formulations for children, and knowledge deficiencies that would enable optimal prescribing. This background paper provides an update on the activities undertaken to provide optimal medicines for children since the previous version of the report published in It identifies knowledge gaps related to children and discusses potential areas for further research, identifying issues that need more attention and analysis in the future. 2. Demographics and diseases faced by children In this section, we will concentrate on childhood mortality, as well as the diseases that are most prevalent in children. We will provide an overview of their trends over time, identify novel insights that have been gained since 2004, and discuss the strategies needed to decrease disease burden in childhood. This section complements Background Paper 5 of the report on general demography, and various parts of Chapter 6 that cover additional childhood conditions (neonatal morbidity, infectious diseases and pneumonia, childhood cancers, orphan diseases, etc.). Nevertheless, we do not intend to provide a full overview of research gaps in the management of specific childhood diseases. Additionally, patterns of general medicines use are studied to provide data about the suboptimal use of medicines, uncover undesirable prescribing practices in childhood diseases, and inform decisions on the prioritisation of research. 2.1 Childhood mortality Most children and adolescents in the European Union enjoy a high standard of health and well-being. The paediatric population (0-18 years) represents about 100 million people or 20% of the total population. The crude birth rates have increased modestly from 10.4 in 2004 to 10.7 births per inhabitants in 2010, with 5.4 million children having been born in , 2 The child mortality rates are low in the European Union. The average EU mortality rates in the first year of life declined from 5.1 deaths in 2004 to 4.2 deaths in Annex shows that the rates ranged from three deaths per live births in most Nordic countries, Portugal, Slovenia, and the Czech Republic, up to 9.4 and 9.8 deaths per live births in Bulgaria and Romania respectively, and 13.6 deaths in Turkey. 3 An infant`s risk of dying in Europe is greatest during the first four weeks of life. According to the statistics, two-thirds of 7.1-8

11 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children neonatal deaths in the first year of life occurred due to prematurity, congenital abnormalities and birth asphyxia. 3 In the WHO European region, children died before the age of five in As shown in Annex 7.1.2, half of them were neonatal deaths (49%), related to preterm birth or intrapartum complications, congenital anomalies, neonatal disorders, sepsis, or meningitis. 4 Other common causes for death in children under age five were pneumonia, injuries, diarrhoea, and undefined disorders. 4 Worldwide, under-five mortality has steadily declined from 10.4 million in 2004 to 6.9 million in The most significant causes of death in children under the age of five worldwide were pneumonia, preterm birth complications, diarrhoeal diseases, child birth complications, and, malaria. About 40% of children younger than five years of age died during the neonatal period due to preterm birth complications, birth sepsis, and asphyxia. 4 (Figure 7.1.1) In older age groups, infectious diseases, HIV and tuberculosis, injuries, and some cancers predominated, although overall mortality was lower. 5,6 During adolescence, the leading causes of death were accidents, suicide, violence, pregnancy related complications, communicable diseases (tuberculosis, meningitis, and HIV/AIDS), and non-communicable diseases (diabetes and cancer). 7 Figure 7.1.1: Global causes of childhood deaths in 2010 Source: Liu L, Johnson HL, Cousens S, et al, for the Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since Lancet 2012; 379: Childhood morbidity Children suffer from a different range of diseases than adults. Firstly, some diseases such as prematurity, congenital abnormalities, respiratory distress, certain leukaemias, or genetic conditions like phenylketonuria only occur in children. The diagnosis, prevention and treatment of these conditions cannot be adequately investigated without studying children

12 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Secondly, other conditions, such as influenza, asthma, mental health problems, certain cancers, and forms of arthritis, occur in both adults and children, but their pathophysiology, severity, course, and response to treatment may differ across the life span. Thus, treatments that are safe and effective for adults may be dangerous or ineffective for children. Furthermore, certain diseases like asthma and psychiatric disorders may start in childhood and continue into adult life, so effective treatment at an early stage of the disease may be beneficial. Also, lifestyles started in childhood may lead to chronic diseases later (e.g. hypertension, obesity, diabetes mellitus, asthma, and mental diseases). Therefore, research in children is necessary to establish the causes and natural history of diseases and to enable the employment of primary prevention strategies to counter risk factors and behaviours in childhood and adolescence Asthma in children Asthma is the most common chronic childhood disease in Europe, affecting 5 20% of schoolaged children in Europe. 9 Its prevalence varies widely across Europe, with a rate up to ten times higher being reported in Western Europe than in Eastern Europe, possibly due to different exposure to respiratory infections, pollution and diet. 10 On the other hand, underfive morbidity rates are not known because most surveys, including the International Study of Asthma and Allergies in Childhood (ISAAC; ), have not studied this age group. 11 The underlying reasons are the difficulties in making a confident diagnosis of asthma and the variability of wheezy phenotypes in very young children. 12 The global ISAAC research has been discontinued, but new evidence coming from high-prevalence European countries showed that childhood asthma rates increased steadily for several decades and then levelled off, or even declined. In a study of six to nine year-old Irish children, the asthma prevalence remained stable at 21.7% in 2002 and 23.5% in Moreover, a respiratory health survey of primary school children in England showed a significant decrease in the prevalence of asthma, wheezing, and allergies between 1998 (29.8%) and 2006 (19.4%), coinciding with improved environmental control measures in the area. 14 Asthma affects lung growth in children, which is a determinant of lung function in adult life, so optimal treatment is of major concern for long-term prognosis. 15, 16 In recent years, several efforts have been made to provide a uniform definition of asthma severity, and to improve knowledge about its pathophysiology, prevention, diagnosis, treatment, and monitoring. 12,17 In 2007, a project funded by the EU's Sixth Framework Programme (GABRIEL) succeeded in identifying new genetic markers that raise the risk of asthma in infancy. 18 However, given the heterogeneity of asthma, the identification of its diverse childhood phenotypes, including those that develop into adult asthma, still remains. The identification of these diverse phenotypes will further contribute to a more personalised patient approach Diabetes in children According to the European diabetes registry, EURODIAB, the type 1 childhood diabetes incidence rate continues to rise across Europe by 3-4% per year. During the period of incidence rates varied from 5.8 per in the Republic of Macedonia to 36.6 per in the Stockholm area of Sweden. The evidence pointed to an interplay between genes and environmental factors (e.g. lifestyle, diet, virus infections), which may differ between populations. 20 Between 2005 and 2020, EURODIAB research has estimated a doubling of new cases of diabetes in children under five years of age and an increase of the prevalence in the

13 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children under 15-year-olds by 70%. The most striking changes over time are expected in central and eastern European countries with currently lower incidence rates, 21 presumably due to improvements in their case detection and detrimental changes in their lifestyle habits. Type 1 diabetes is the most prominent form of diabetes seen in childhood, especially in children under 10-years-old. However the trend towards overweight and obesity is driving the development of type 2 diabetes in youths, particularly after the onset of adolescence Mental diseases in children Mental disorders are increasingly recognised as a significant causes of ill health and disability in children and adolescents globally, including Europe. 23 Research has shown that mental health is the largest contributor to the burden of disease in young people aged years (45%), clearly ahead of unintentional injuries (12%) and infectious and parasitic diseases (10%). 7 In Europe, the prevalence of mental illness prior to 2004 was 8-23% in the child and adolescent population. 24 For the 2010 study on mental and neurological disorders in the EU, the European Brain Council broadened the age range and scope of diseases studied, including childhood and adolescence brain disorders. According to the age-specific data, an estimated 3 million children suffered from attention-deficit hyperactivity disorders and hyperkinetic disorders, 0.6 million from pervasive developmental disorders (e.g. autism, Asperger's syndrome), and 2.1 million from conduct disorders. 25 Similarly, bipolar disorder has been progressively more often diagnosed in children, despite the previous psychiatric consensus that manic-depressive illness rarely has its onset before adolescence. 26 The total disease burden of paediatric mental health diseases has not yet been fully elucidated because of the many complexities involved, in terms of defining diagnostic categories and health measurements in children. It is a well-established fact that many of the mental disorders seen in children can be precursors of much more disabling disorders in later life. 27 On the other hand, the increased prevalence rates led to debates on the medicalization of certain conditions, the diagnostic validity and the true size of mental disorders. 28, Infectious diseases in children Despite improved living conditions and health care (e.g. use of antibiotics and vaccines), infectious diseases remain the most common cause of illness in children in the developing world and are a predominant cause of childhood mortality in these countries. 4 In the category of infectious diseases, the most serious are acute respiratory diseases (including pneumonia and influenza), HIV/AIDS, diarrhoea, tuberculosis, malaria, and measles. 4 Even though the prevalence and burden of infectious diseases is much lower in Europe 4, their public health effects extend beyond direct disability and death. Increased global mobility can lead to an increased risk of epidemics, while the irrational use of medicines can contribute to the emergence of antimicrobial and multidrug resistance, further complicating the management of subsequent infections. Thus, new and re-emerging infectious diseases present a global health concern, which necessitates investments in effective surveillance networks and targeted prevention and intervention strategies. For more information on infectious diseases and resistance, see the background paper on antimicrobial resistance (6.1)

14 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 2.3 General use of medicines in children A literature review ( ) on drug utilisation in paediatric outpatients found only a few countries involved in research (mostly from Europe and North America) and large differences between studies with regards to data source, sample size, and age range. The drug utilisation prevalence rate was higher in preschool children and lower in older children. 30 More than half of the children (51-70%) in outpatient care received at least one medication. Each child treated received, on average, between 1.3 and 5.3 prescriptions, and 60% of children received an average of three drug prescriptions in a one-year period. Antibiotics were the most frequently prescribed drugs (20 33% of all prescriptions), followed by anti-asthmatics (10 25%). 30 Patterns of paediatric drug utilisation in Europe were specifically studied using three population based databases from Italy, the United Kingdom and the Netherlands for the period The analysis revealed that prescription rates were highest for children less than two years of age, and they were higher in the United Kingdom and Italy when compared to the Netherlands in each of the age groups. Furthermore, certain gender patterns were observed with more prescriptions being written for girls than for boys after the age of ten, as opposed to the pattern seen in the younger age groups. The user prevalence rates for the year 2005 showed that anti-infective, dermatological, and respiratory drugs were in the high-use group for all age categories, whereas cardiovascular and anti-neoplastic drugs were in the low-use group, corresponding to the childhood morbidity rates. 31 (Figure 7.1.2) Figure 7.1.2: Year prevalence of drug use (per 1000 person years) by age (<2, 2-11, 12-18), country, and anatomical class for most prevalently used drug classes (data for Italy excluded age category 12-18) he Source: Sturkenboom MC, Verhamme KM, Nicolosi A, et al; TEDDY European Network of Excellence. Drug use in children: cohort study in three European countries. BMJ 2008;337:a This general drug use overview, based on multiple European paediatric populations, was conducted for the TEDDY (Task Force in Europe for Drug Development for the Young) project, co-funded by the European Commission within the Sixth Framework Programme ( ). 32 Lamentably, no similar initiative in the paediatric field, including a wider range of countries and more recent data, has been supported with EU funding

15 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 2.4 Conclusions Addressing the gaps and identifying future priorities for paediatric medicines requires information on burden of diseases and use of medicines in children. Data routinely collected at national or local levels can prove to be a valuable source for inter-country comparisons and comprehensive EU analysis of trends and variations over time. Although individual countries and research communities may study particular aspects of childhood diseases and maintain prescription databases, the process of data gathering and analysis at the EU level is not very common. The lack of systematic and continuous monitoring in all EU countries and the heterogeneity between studies make comparative evaluations difficult or incomplete. Therefore, the methodological quality of data collection should be improved, and more multinational collaborative studies should be performed with EU support. 3. Product related issues in children It is well established that children are not small adults, but rather distinct entities with regards to pharmacotherapy. First, they differ from adults with regards to their body development, their medicines related toxicity and their taste preferences. 33 As a result, an effective paediatric therapy requires medicines adjusted to the needs of children. Second, children are a heterogeneous patient group that may need age-appropriate medicines suitable for each paediatric subpopulation. These two important factors affecting drug delivery in children require novel formulations with dose flexibility and also medical devices for easier administration of paediatric medicines, as discussed in this section. 3.1 Paediatric age-appropriate dosing and formulations Children are different from adults in many respects, including their body development, pharmacokinetics and pharmacodynamics. Infants have slower gastrointestinal, but faster intramuscular (IM) absorption, limited protein binding and immature enzymes. 34 Their livers are immature and may not metabolise drugs as rapidly as expected; their kidneys are also small and immature. Drug distribution is also different because a neonate s body contains 80% water (adult proportion is 55 60%), and the water is distributed more into the extracellular than into the intracellular space when compared to adults. Furthermore, children have larger liver/body and brain/body weight ratios and higher blood brain barrier permeability, and small infants often have a two to three times longer half-life for elimination of medicines than adults, requiring lower doses of medicines. Consequently, even when a medicine has a known effect in adults, a linear dose-per-kg correlation often does not hold true with regards to small children, as shown in Annex ,35 Given the information above, it is clear that paediatric dosage regimens cannot simply be extrapolated from adult data, as an effective therapy requires medicines adapted to the needs of children. In addition, the knowledge on optimal dosing for efficacy and safety is very important for deciding on the appropriateness of a formulation. It is vital to consider the criticality of the dose (i.e. steep dose/pharmacodynamics response curve, narrow therapeutic window) and the dosing regimen (i.e. dose calculation, dose titration, flexibility of dosing)

16 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children The purpose of good paediatric formulations is to achieve safe and accurate dose administration, reduce the risks of medication errors and enhance medication compliance. 37 Selection of appropriate formulations should be based on a case-by-case basis, including the age, size, condition of the child (e.g. critical illness, concomitant medication, ability to swallow dose), usage environment, and the expected duration of the therapy. 38 Further basic criteria for paediatric medicines include: sufficient bioavailability minimal dosage frequency safe excipients minimum impact on lifestyle good taste acceptance socio-cultural acceptability clear product information 39 The development of suitable paediatric medicines is a complex task with a range of technical challenges, such as: diversity of children accuracy of dosing with lower paediatric doses and volumes inability to swallow solid dosage forms taste masking in oral forms stability and unsafe excipients needle phobia and small veins for parenteral forms, etc. 39 Body size and weight increase up to twentyfold from birth to adulthood, and the magnitude of doses administered throughout childhood can vary a hundredfold. Plus, the ability to take medicines (i.e. cognitive and motor skills, dependence on caregivers) and dosage form preferences differ greatly across the age spectrum. 38 Accordingly, it may be necessary to develop age-appropriate medicines with strengths and dosage forms suitable for each paediatric subpopulation using the medicine. 38 Table and the EMA Matrix (Annex 7.1.4) illustrate suitable dosing and dosage forms as a function of the child s age

17 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Table Change in magnitude of dose and the ability to cope with dosage forms BNFC 1 age-based dosing guidelines for Paracetamol Age Baby Dose mg 1 year mg 6 years mg 12 years mg Adolescent g Change in ability to cope with dosage forms Age Dosage forms Baby drops 1 year liquid, melts 6 years liquid, tablets, melts 12 years tablets Adolescent tablets/capsules 1 British National Formulary for Children 2006 Source: Nunn T. Presentation: Age-appropriate formulations paediatric needs. EMA Workshop on Paediatric Formulations II 8 November Accessed April 29, New oral paediatric formulations In general, oral formulations are preferred for long-term use in children, whereas parenteral administration is likely to remain the first choice during the neonatal period and for emergency cases. Alternative routes of administration under investigation include transdermal (for constant blood levels), or the less invasive buccal, nasal and pulmonary drug delivery systems. 38 Tablets have not been ideal dosage forms for all paediatric patients due to difficulties in swallowing and in the division of the tablet dose based on weight. Thus, liquid formulations used to be considered the most suitable for children less than six years of age 3838, despite their major disadvantages such as chemical, physical or microbial instability, taste issues, and lack of controlled release properties. 41 In 2008, a WHO expert forum proposed a paradigm shift towards solid, oral dosage forms for paediatric medicines, in view of stability problems with liquid formulations in different climate zones and the high costs of their transportation and storage. 42 Oral, solid flexible dosage forms, such as orodispersible tablets, and/or tablets used to prepare oral liquid preparation suitable for younger age groups became the recommended paediatric dosage forms for global use. 42 The following year, Coartem Dispersible was the first dispersible artemisinin-combination therapy for children (5-35 kg) launched in Africa by Novartis and the Medicines for Malaria Venture. 43 A clinical study in Tanzania confirmed a high cure rate of 97.8% with the pleasant tasting suspension, comparable to that of the bitter Coartem tablet (98.5%). 44 For oral medicines requiring precise dose measurement, a new flexible platform technology was proposed to produce multiparticulate solids (mini-tablets and spherical granules

18 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children pellets) and dosage forms dispersible into liquids or to be mixed with food. 42 Since then, various innovative oral, solid dosage forms for paediatric use, such as multiparticulate and flexible dispersible solids, have been commercially available or are under development. (Table and Annex for branded products). 43,45 Table 7.1.2:Novel oral drug formulations for children Multiparticulates Flexible dispersible formulations Other oral preparations Granules Dispersible tablets Chewable tablets Sprinkles Oral lyophilistaes Gummy bears Pellets Orally disintegrating tablets lozenges Chewing gum Mini-tablets Oral strips / Buccal wafers Medicated lollipop (melt-away lozenge with applicator) Orally disintegrating mini-tablets (experimental) Sources: Stoltenberg I, Winzerburg G, Breitkreutz J. Solid oral forms for children formulations, excipients and acceptance issues. Journal of Applied Therapeutic Research, 2010; 7(4): Breitkreutz J. Nach der EU-Reform. Arzneiformen für Kinder. Pharm. Unserer Zeit 2009;38: The advantages of these novel, solid dosage forms over the conventional ones are not only in their dose flexibility for different patient ages and weights, but also in their ease of administration in younger children. 46 For a while, there have been concerns and uncertainties about the age at which young children can safely swallow orally administered tablets and capsules. It is generally accepted that the age at which children can swallow intact tablets or capsules is highly dependent on the individuals and the training and the support they receive from healthcare professionals and caregivers. 36 The matrix combining different age groups, routes of administration and dosage forms, developed by EMA (Annex 7.1.4), reflects on the variability in children s ability to swallow solid dosage forms. EMA considers tablets as potentially acceptable from the age of three. 36 Studies have reported tablet use in three year-old children for the treatment of long-term illnesses. 47 However, in 2009 the acceptability of and the ability to swallow these innovative mini-tablets (3 mm in diameter) was explored in children aged two to five years. Forty-six per cent of the children aged two years, and up to 86% of the five-year-old children swallowed the minitablets; no children choked or aspirated the mini-tablets. To improve the acceptability of mini-tablets by parents, suitable dosing devices that automatically count a variable number of mini-tablets or electronic dispensers were suggested. 48 A recent exploratory study illustrated a high acceptance and ability of children aged years to swallow uncoated drug-free mini-tablets (2 mm in diameter) compared with a sweet testing syrup. 49 (Figure 7.1.3) The study is currently being repeated with a larger cohort to confirm safety and to explore whether the observed chewing before swallowing has an impact on the usability of uncoated mini-tablets. Its results may convince the EMA to consider uncoated 2 mm mini-tablets for children aged six months in its new guidelines

19 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Figure 7.1.3: Children s ability to completely swallow mini-tablets and glucose syrup (n=10 children per age group; mean ± 95% CI). Source: Spomer N, Klingmann, Stoltenberg I, et al. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch Dis Child 2012;97: There are more promising results coming for infants younger than two years with the development of orally disintegrating mini-tablets (ODMTs) a novel, solid oral dosage form that combines mini-tablets and fast-dissolving dosage forms. A 1 mg ODMT was produced as a novel paediatric medicine using the diuretic hydrochlorothiazide. The aim was to offer a suitable therapeutic option for very young children, as only tablets and capsules of 12.5 mg are available on the market. The ODMT was manufactured with safe excipients and it has passed all required laboratory tests. Further investigations, with regard to taste masking, dissolution, advanced suitable dosing systems, and acceptability still have to be performed. 50 The innovations regarding paediatric formulations remain to be implemented by the industry during the process of the development of medicines for paediatric use. The new technologies must be applied outside the academic setting, in particular where dosing flexibility, taste masking and administration flexibility is needed. 3.3 Novel paediatric drug devices Some of the obstacles and limitations in ensuring the delivery of a correct dose born by currently available paediatric formulations can be overcome by new technologies. Over 100 patents have been filed for novel paediatric dosing devices in order to ensure the accurate and consistent administration of paediatric formulations. 39 The majority of these patents relate to the delivery of liquids to very small children orally, such as modified feeding bottles, modified pacifiers and teats with the required dose of medicine placed in a reservoir. 39 Also, the dose sipping technology, consisting of a straw with film-coated micro

20 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children pellets ingested in a liquid of choice, has been developed to improve the problem related to the palatability of oral solution. The manufacturer s internal studies showed an improved adherence in children, but compatibility studies with the drink are still required Table 7.1.3:Novel drug devices for children Novel dosing instruments for oral liquids Teat/Pacifier with reservoir Single-use spoon filled with medicine Dropper tube Dose sipping technology - straw with taste Solid dosage pen Coated particles for oral administration Coated particles on dosage spoon Coated particles in suspension Coated particles in tablets for preparing a suspension Coated particles on dosage spoon Needle-free injection devices Jet injectors (drive small droplets through the skin by high pressure) Microstructured transdermal systems for intradermal vaccines Novel devices for inhalation therapy Nebuliser with spacer/valved holding chamber and face mask Nebulisers with a vibrating mesh technology for aerosol generation Nebuliser with an electronic unit Dry powder inhalers Sources: Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Exp Opin Drug Deliv 2007; 4: Walsh J,Bickmann D, Breitkreutz J, Chariot-Goulet M, on behalf of the European Paediatric Formulation Initiative (EuPFI). Delivery devices for the administration of paediatric formulations: Overview of current practice, challenges and recent developments. International Journal of Pharmaceutics 2011;415: Table and Annex listing branded products, provide an overview of currently available paediatric administration devices for the parenteral, oral, and inhaled administration of paediatric formulations. However, although many paediatric drug delivery devices have been developed, some of which may offer tangible patient benefits, there appears to be very few available on the current market. This is likely due to their high costs, as many novel technologies are protected by patents, and to the (un)willingness of health insurance bodies to reimburse for the use of these devices Taste and palatability of paediatric dosage forms Paediatric dosage forms must also be designed to ensure patient compliance, either by having a minimal impact on lifestyle or by having an appropriate appearance (colour and palatability) especially for oral liquids and powders. 52 It is often difficult to assess the taste attributes of the drug formulation, particularly in younger children who are not capable of

21 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children expressing their taste sensations and mouth feelings adequately. In addition, taste masking of certain solid paediatric dosage forms, such as chewable tablets or fast dissolving preparations (e.g. orodispersible tablets and films), can be particularly challenging, especially for high solubility drugs that dissolve rapidly in the mouth. 52 Some paediatric formulations take into account the individual taste preferences of the child. Examples include Children s Tylenol with Flavor Creator, where sachets of different flavouring agents can be added to the liquid prior to administration. A similar concept is that of the FLAVORx system, which consists of various flavours that can be added to oral medications to improve palatability, and that has been used in Thai AIDS patients to increase adherence with antiretroviral medicines. 53 The limitation of this approach is that the compatibility of the flavours with the medication is often unknown, potentially impacting formulation stability. 53 Another example is the previously mentioned dose sipping technology using a drinking straw with taste-masked granules. 52 Alternative approaches to facilitating taste masking of paediatric solid preparations include the coating of a drug substance prior to incorporation into formulations or the film-coating of small dosage forms such as pellets or mini-tablets. It is essential that all taste masking approaches are guided by the specific safety considerations of paediatric drug development Use of excipients in paediatric dosage forms One critical element in the development of paediatric formulations is the selection and use of excipients, as their safety in paediatric subpopulations is often unknown. As a result of age differences, there are elevated toxicological risks in young children for some excipients, such as ethanol, propylene glycol, benzyl alcohol, polysorbate, parabens, etc. (Table 7.1.4) in their metabolism and elimination as compared to adults. 39 In 2011, the FDA issued a drug safety communication and changed the drug label of Kaletra (lopinavir/ritonavir) because of some serious health problems that arose in premature newborns related to the propylene glycol contained in the oral solution. 54 In 2012, the EMA issued a concept paper to get input from the public on revisions to its excipient guidelines on labelling and packaging in order to include safety concerns for paediatric populations and pregnant women, since the current 2003 guidelines do not address these safety issues. 55 Table 7.1.4: Excipients with elevated toxicological risks for the paediatric population (preterm and term neonates, infants less than 6 months of age Excipient Administration Adverse reaction Benzyl alcohol Oral, parenteral Neurotoxicity, metabolic acidosis Ethanol Oral, parenteral Neurotoxicity Polyethylene glycol Parenteral Metabolic acidosis Polysorbate 20 and 80 Parenteral Lives and kidney failure Propylene glycol Oral, parenteral Seizures, neurotoxicity, hyperosmolarity Source: Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Exp Opin Drug Deliv 2007; 4:

22 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Even though the demand for paediatric data on the safety of excipients has grown considerably, there is very limited paediatric excipient safety data, and it is distributed throughout many sources. 56 As a result, the EU and the United States Paediatric Formulation Initiatives are creating a Database of Safety and Toxicity of Excipients for Paediatrics (STEP) to incorporate this safety data into a single comprehensive and readily accessible database. This repository of excipient information (e.g. dose information, pharmacokinetics (PK)) is expected to provide a basis for screening and selecting excipients for use in paediatric product development and further accelerate product-specific safety and toxicity studies. The first prototype version database was launched in To support the task of safe use of medicines in children, there is an urgent need for concerted action toward obtaining the missing data on safety of excipients for paediatric use. While the companies are responsible for providing data on safety of excipients in paediatric medicines, EU programmes are also needed to fund related research activities and fill this information gap. 3.6 Clinical evidence on impact of paediatric pharmaceutical development Despite all the research on novel paediatric products, the literature suggests limited clinical evidence to support pharmaceutical development programmes in children. A recent systematic review identified 94 articles on oral medicines for use in children and adolescents that reported the effects of three pharmaceutical technologic aspects (formulation and dosage form; route and frequency of administration; and packaging, administration device, and user instruction) on six patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and adherence). The majority of the studies (90%) were conducted on children aged 2 to 12 years, which can be explained by a lack of clinical trials in neonates and infants, as a result of the limited market potential of products for this population. Only two publications were of good methodologic quality, suggesting that paediatric pharmaceutical development studies may need more suitable instruments to measure their methodological quality, as randomized controlled and double blind trials might not be always appropriate. Table demonstrates that side effects, tolerability and administration errors received limited attention, resulting in no evidence being available to substantiate that improved formulations lead to fewer side effects. 57 Based on the study findings, the authors encouraged an agreement on taxonomy of pharmaceutical technological aspects and patient-related outcomes, and the creation of a global database with literature on the development of paediatric pharmaceuticals to promote research in these neglected areas

23 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Table 7.1.5: Impact of pharmaceutical technologic aspects on patient-related outcomes parameters. Patient-Related Outcomes Parameter Formulation and Dosage Form (n=85) Pharmaceutical Technologic aspect Route and Frequency of Administration (n=77) Packaging, Adminstration Device, and User Instruction (n=14) All Assessments (n=176) * Patient acceptance 38 (45) ** 5 (6) 1 (7) 44 (25) Patient preference 19 (22) 4 (5) 0 23 (13) Adherence 11 (13) 15 (19) 6 (43) 32 (18) Clinical efficacy 8 (9) 31 (40) 2 (14) 41 (23) Side effects and tolerability 8 (9) 22 (29) 0 30 (17) Administration errors 1 (1) 0 5 (36) 6 (3) * Two investigations assessed >1 pharmaceutical technologic aspect. ** Data are number (%) of assessments Source: van Riet-Nales DA, Schobben AF, Egberts TC, Rademaker CM. Effects of the pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes. Clin Ther 2010;32(5): WHO activities towards better medicines for children To address the lack of child-specific medicines, the Member States of the World Health Organization (WHO) passed a resolution on Better Medicines for Children WHA during the 2007 World Health Assembly. The resolution mandates the WHO to explore ways to promote more research and development into paediatric medicines and to improve knowledge on the quality, effectiveness and safety of these medicines. Following this breakthrough event, the WHO commenced work on a number of activities to improve the availability of better medicines for children. In December 2007 the WHO launched its initiative Make medicines child size 58 in order to raise awareness and to accelerate action in order to meet the need for improved availability and access to childspecific medicines. The same year, the WHO Subcommittee on Selection and Use of Essential Medicines developed the first Model List of Essential Medicines for Children, 59 and has been revising and updating it every two years to include missing essential medicines for children, using evidence-based clinical guidelines. The list was developed to serve as a reference for countries in developing national lists according to their specific public health priorities and to ensure that child-specific medicines are developed and delivered to the intended patient groups. As a follow up, the WHO Model Formulary for Children was created in 2010 to provide independent prescriber information on dosage and treatment guidance for medicines based on the WHO Model List of Essential Medicines for Children. The publication Sources and Prices of Selected Medicines for Children 60, produced annually by UNICEF and the WHO, identifies the sources and prices for selected products used in the treatment of childhood diseases and contributes to the effort to increase access to appropriate medicines. As part of the Better Medicines for Children Project, funded by the Bill and Melinda Gates Foundation, the WHO has also helped in the foundation of an international regulatory working group (Paediatric Medicines Regulatory Network) 61, responsible for reviewing

24 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children existing regulatory standards and enhancing the availability of quality medicines for children by facilitating communication, collaboration, and regulatory coordination across the areas of manufacturing, licensing, and research. The Paediatric Medicines Regulators Network recently contributed to the development of the Guidance on Assessing Clinical Trials in Children, as well as the important documents Development of paediatric medicines: points to consider in formulation 46 and a review on extemporaneous or compounded formulations. Simultaneously, the WHO International Clinical Trials Registry Platform (ICTRP) launched the Clinical Trials in Children website, 62 with the aim of improving research transparency and making it easier to access accurate, up-to-date and understandable information relevant to the conducting of clinical trials in children. In 2012, the list of Priority life-saving medicines for mothers and children was updated, 63 highlighting the most important medicines for mothers and children that should be readily available throughout health systems. The list was compiled according to the global burden of disease and is based on evidence of efficacy and safety. Medicines were selected from the Model List of Essential Medicines and are included in current WHO treatment guidelines. Medicines for pneumonia, diarrhoea, malaria, neonatal sepsis, HIV/AIDS, and vitamin A deficiency are included on the priority list for children under five. Treatments for palliative care and pain for all children are included as well. Additionally, the WHO Prequalification of Medicines Programme has been prequalifying new products specially designed to treat HIV/AIDS in children, 64 which is considered to be one of the priority paediatric treatment areas (Annex 7.1.7). The product prequalification represents a considerable advance in making user-friendly formulations that improve efficacy of treatment available. Overall, the WHO has made progress on several fronts: essential tools, such as treatment guidelines and information on the use of essential medicines have been developed and published; relevant professional groups have been engaged; and key studies have been initiated. Further research and development for appropriate formulations, such as fixed-dose combination products, is expected to be directed towards paediatric tuberculosis treatment and treatment of HIV in young infants. 3.8 Conclusions Much progress has been made in the development of age-appropriate paediatric formulations, especially those for oral administration. The current formulation research has been directed towards mini-tablets, chewable and dispersible tablets for younger children. Nevertheless, the ongoing research into the ability of children to swallow medication needs to be accompanied by studies on children s preferences and adherence to different dosage forms. In addition, new routes of administration such as oral-transmusosal (buccal strips), intra-nasal, and trans-dermal routes (for neonates mainly) are ripe for future developments and research. In neonates, particular caution is needed for these forms in terms of optimal use and dosing

25 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children More research into alternative safe excipients for children is also expected, given the safety and toxicity concerns of some excipients in paediatric formulations. Yet, it is also essential to incorporate the available knowledge on excipients, generated through individual research, into a single and public repository. It would be helpful in avoiding a duplication of efforts, and encourage further discovery and innovation. Despite all the technologic progress, the published clinical evidence on the impact of different paediatric formulations on patients outcomes is still limited. This research should be central in order to support pharmaceutical development of paediatric medicines. 4. Regulatory aspects related to children For years, the lack of information about the safety, efficacy and dosing data of paediatric medicines, as well as the lack of child-appropriate formulations resulted in the unsatisfactory treatment of paediatric patients. Healthcare professionals were left with no alternative but to use off-label and unauthorised products with their associated risks of inefficacy or adverse reactions (see Section 5 of this background paper). The lack of suitable, authorised medicinal products to treat conditions in children can be best explained by the fact that frequently pharmaceutical companies did not carry out the necessary research and development to adapt medicines to the needs of children. The underlying reason being that medicine development for paediatric patients is accompanied by numerous challenges for pharmaceutical companies, such as the diversity of children in different age groups, the consent and recruitment process or the ethical implications. Over the past decades, regulatory legislations for drug development in paediatric patients were passed worldwide to support the development and administration of appropriate paediatric medicines (see also Background Paper 8.2 Regulatory incentives for innovation ). Progress is being made by combining requirements for paediatric drug development with market incentives for the pharmaceutical industry to (at least partly) cover the additional investment needed for testing drugs in children. 4.1 Implementation of the EU paediatric legal framework Following the successful example of the United States paediatric initiative, the European Union adopted the Paediatric Regulation 65 in 2007, with its main provisions coming into effect in 2008 and The regulation aims to improve the health of children in Europe by increasing research, development and the authorisation of medicines for paediatric use. 66 Its policy objectives are as follows: to facilitate the development and accessibility of medicines for use in children to ensure that medicinal products used to treat children are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population to improve the information available on the use of medicines in the various paediatric populations. 66 One key measure of the regulation is the creation of the Paediatric Committee (PDCO), a committee of scientific experts within EMA, whose principal task is to assess paediatric investigation plans (PIP) submitted by the pharmaceutical industry. A PIP is a development

26 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children plan which contains full details of the timing and the measures proposed to demonstrate the quality, safety and efficacy of the medicines in specified paediatric subsets. An approved PIP must always be demonstrated at the time of the marketing authorisation (MA) application for new products. This is also true for authorised products where new indications, new pharmaceutical forms and new routes are sought. A system of waivers and deferrals has been introduced to ensure that the requirements do not delay the authorisation of medicines in adults. 66 A waiver of the paediatric development can be granted for all (a full waiver) or subsets (a partial waiver) of the paediatric population on the basis of the lack of efficacy or safety of the medicine, when the disease or condition only occur in adults, or when the medicine does not have significant therapeutic benefit over existing therapies. A deferral allows postponing the initiation and/or the completion of the PIP measures to ensure that research is conducted only when it is safe and ethical and does not delay or block the marketing authorisation for adults. The PIP requirements do not apply to generics. For medicines not yet authorised or still covered by intellectual property rights (IPRs), the regulation established rewards and incentives, such as a six month extension of the supplementary protection certificate (SPC), including adult use. In the case of orphan medicinal products, the incentive is the extension of market exclusivity (12 years instead of 10, see also Background Paper 6.19). 66 However, the additional market exclusivity granted for paediatric medicines may delay generic entry and have price implications. In the case of authorised products no longer covered by IPRs, whose manufacturer voluntarily apply for a MA in children, the regulation establishes a new type of marketing authorisation, the Paediatric Use Marketing Authorisation (PUMA), which provides data protection for a ten-year period. PUMA is granted to off-patent medicines adjusted exclusively for use in children to stimulate innovation in treating childhood diseases. It is, however, weaker than patent protection and does not guarantee market exclusivity, as competitors could carry out their own research and development on the same active substance, if they judge the market to be large enough. 66 To generate studies on off-patent medicines the regulation provides an opportunity to access ad hoc European funds for research and development through the EU Seventh Research Framework Programme (FP7). 66 Other PDCO specific functions include establishing an inventory of specific needs for paediatric medicinal products and the giving of free scientific input into the development of any documents related to achieving the regulation s objectives. 66 In accordance with the Paediatric Regulation, the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) was set up in 2009 as a network of 38 national research networks, investigators and centres with expertise in performing clinical studies in children. 67 The objectives of the European network include coordinating studies relating to paediatric medicinal products, building up the necessary scientific and administrative competences at a European level, and avoiding unnecessary duplication of studies and testing in the paediatric population. There is no specific funding provided through the regulation for this European network. The network also works at an international level with the World Health Organization through the EMA s membership in the Paediatric Medicines Regulators Network (PmNR) and with the U.S. FDA through the EMA s existing interaction on paediatric medicines. The Enpr-EMA still does not cover all

27 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children paediatric therapeutic areas and needs to foster further research in paediatric cardiology, gastroenterology, diabetes, and neonatology. 67 There is also public access to information about trials using a paediatric population, including those that have been temporarily halted or prematurely terminated, via the EU Clinical Trials Register 68, launched in 2011, which is also a WHO Registry Network data provider. 4.2 Achievements of the EU Paediatric Regulation The intended long-term impact of the Paediatric Regulation is the integration of paediatric development in the overall area of medicine development. Therefore, the regulation demands that each new compound is systematically evaluated during the research and development (R&D) process for its potential use in children. Its key measures (PDCO, PIP) set norms and standards for the suitable design of paediatric clinical trials in order to ensure the development of safe, efficacious, and age-appropriate paediatric medicines. 69 As a result, some companies have consulted with investigators during the development process, creating beneficial links between the industry and the research community. However, the paediatric requirements may also put an increased administrative burden on the industry. Moreover, many may see the compliance with PIP requirements as a fulfilment of regulatory obligations rather than as an establishment of a complete and independent R&D programme. 70 Based on EudraCT data, the number of clinical trials with children in the European Union was stable over time during the period with an average of 350 trials per year being conducted, with the number of trials in all populations declining by about 6% per year. (Table 7.1.6) One of the innovations introduced in paediatric research was the inclusion of younger children in clinical trials for cholesterol-lowering and anti-hypertensive medicines, juvenile idiopathic arthritis, diabetes mellitus, and haemophilia A and B. 69 To facilitate clinical trials in children or reduce the need for investigation in this vulnerable and limited population, it is important to encourage alternative methodological approaches to classical clinical trials, such as modelling and simulation techniques. The Paediatric Regulation may contribute towards greater transparency in clinical trials by preventing unnecessary trials, since the protocol-related information for registered trials is made publicly available through EudraCT. 69 Since 2008, approximately 70% of all PIPs evaluated by the PDCO proposed or required development of indications for the whole or some subsets of the paediatric population. This indicates an increase in the development of medicines for children, as only approximately 30% of medicines applied for and obtained a paediatric indication before the EU Paediatric Regulation came into force. 69 Nevertheless, therapeutic areas addressed by PIPs and agreed by PDCO primarily cover those diseases that affect adults and children similarly (e.g. endocrinology, gynaecology and fertility, metabolism, infectious diseases, oncology, cardiovascular diseases). Lamentably, the impact of the regulation on high priority and unmet therapeutic paediatric needs, including rare diseases or diseases that occur only in children (e.g. paediatric oncology, pain, neonatal morbidity), is not encouraging. 69 Only about 25% of all agreed PIPs were submitted exclusively for the therapeutic area of neonatology despite their having the highest need for medicine development. This indicates that paediatric development is significantly dependent on the adult development of

28 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children medicines, and thereby market oriented, and it does not correspond to unmet paediatric needs. Table 7.1.6:Paediatric clinical trials by year of authorisation (or, if not available, by year of protocol uploaded into EudraCT) Paediatric trials (number) Paediatric trial that are part of an agreed ** PIP* (number) Proportion of paediatric trials that are 0% 0% 0% 1% 3% 6% 19% part of an agreed PIP among paediatric trials* Total number of trials (adults and/or children Proportion of paediatric trials among all trials 7.6% 8.0% 7.4% 7.6% 9.1% 9.4% 9.9% * This partial information requires sponsors using a Clinical Trial Application form that was available from November 2009 only, for use with version 8 of EudraCT available from ** Number of paediatric trials uploaded into EudraCT by 3 April 2012 for authorisation in EudraCT Data Warehouse using pre-defined query on 3 April 2012 and counting the first authorised trial only, in case of more than one Member State. As National Competent Authorities of Member States upload data into EudraCT irrespective of the study population, the year of authorisation is a better indicator of the initiation than the year of upload. Source: European Medicines Agency. Draft 5-year Report to the European Commission: General report on the experience acquired as a result of the application of the Paediatric Regulation. 8 July 2012 EMA/428172/ Between 2008 and 2012, 29 PIPs were completed in compliance with the PDCO decisions, which led to 24 new paediatric indications and seven new pharmaceutical forms appropriate for children. Centralized authorisations for paediatric use were obtained for 34 new medicines (Table 7.1.7), and 38 new paediatric indications, as variations of 33 already authorized medicines (Annex 7.1.8). In addition, 14 centrally authorized products had either a new pharmaceutical form, a new route of administration, or a new strength authorized for paediatric use. 69 Rewards were obtained for 12 medicines; supplementary protection certificate (SPC) extensions for 11 medicines (Annex 7.1.9), and one PUMA exclusivity was provided for the midazolam paediatric oromucosal form. 69 As far as incentives are concerned, the value of a six-month extension of the SPC can vary widely. It can be economically significant, and even excessive, especially in the case of blockbusters, leading to unnecessary additional costs for consumers. Here, the introduction of a cap system for super profits may be necessary to control the cost implications for the healthcare systems. 70 Many health workers may even prefer to use off-label medicines with the same active ingredient at a lower cost for children. The cost implication of the access to improved medicines is put in context of the drug development expenditures and the costs related to off label use and lack of available medicines

29 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Table 7.1.8: Medicinal products with initial marketing authorisation including a paediatric indication Year of European Commission Decision No. in year Requirement to fulfil Paediatric Regulation at first authorisation Indication is paediatric-only or mixed (adult and paediatric) Active substance(s) Trade Name ( ) No Mixed Retapamulin Altargo No Mixed Nelarabine Atriance No Mixed Human papillomavirus Cervarix vaccine [types 16 and 18] No Mixed Hydroxocobalamin Cyanokit No Mixed Idursulfase Elaprase No Mixed Gadoversetamide Optimark No Mixed Betaine anhydrous Cystadane No Paediatric-only Stiripentol Diacomit No Paediatric-only Mecarsermin Increlex No Mixed Rufinamide Inovelon No Mixed Hydroxycarbamide Siklos No Mixed Human normal immunoglobulin (ivig) Flebogamma DIF No Mixed Fluticason fuorate Avamys No Mixed Human normal Privigen immunoglobulin No Mixed Lacosamide Vimpat No Mixed Micafungin Mycamine No Mixed Sapropterin Kuvan No Mixed Sugammadex Bridion No Paediatric-only Tocofersonal d-alpha Vedrop tocopheryl polyethylene glycol succinate No Mixed Mifamurtide Mepact No Mixed Rilonacept Arcalyst No Mixed Tacrolimus Modigraf Yes Paediatric-only Pneumococcal Synfiorix polysaccharide conjugate vaccine (absorbed) Yes Mixed Canakinumab Ilaris (PIP not yet completed) Yes Paediatric-only Pneumococcal polysaccharide conjugate vaccine (13-valent, absorbed) Prevenar 13 (PIP not yet completed)

30 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Yes Mixed Meningococcal group a, c, w135 and 7 conjugate vaccine Menveo (PIP completed) Yes Mixed Velaglucerase alfa Vpriv (PIP not yet completed) Yes* Paediatric-only Influenza vaccine (live attenuated nasal) Fluenz (Waiver) Yes Mixed C1 inhibitor, human Cinryze (PIP not yet completed) Yes Mixed Dihydroartemisinin/ piperaquine phosphate Eurartesim (PIP not yet completed) Yes (PUMA) Paediatric-only Midazolam Buccolam (PIP completed) Yes** Mixed Everolimus Votubia (PIP not yet completed) Yes** Mixed Tobramycin TOBI Podhaler (PIP not yet completed) Yes Mixed Nomegestrol/ estradiol IOA, Zoely (PIP completed) * The PDCO opinion had granted a waiver for the full paediatric population. ** This was a new marketing authorisation for an orphan designated condition of a medicinal product that was already authorised in the EU for non-orphan designated condition(s). PUMA = Paediatric use marketing authorisation. Source: European Medicines Agency. Draft five-year Report to the European Commission: General report on the experience acquired as a result of the application of the Paediatric Regulation. 8 July 2012 EMA/428172/ The fact that to date only one PUMA has been granted demonstrates that in practice the incentive of 10 years of data exclusivity has not been an attractive option to the industry. This concept does not seem financially viable to companies, as the target population for a PUMA is too small. Plus, national reimbursement rules may not offer rewards great enough to make up for the costs of off-patent medicines. It is also questionable as to whether generic companies that hold authorisations for off-patent products have the necessary resources to invest in additional research. In addition, it has to be evaluated as to whether PUMA granted products have therapeutic benefit over existing treatments. As an illustration, the French National Authority for Health rated the midazolam paediatric oromucosal solution (Buccolam ) as representing only a minor therapeutic advance for paediatric seizure treatment

31 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children In order to identify gaps in paediatric treatments, a survey of all paediatric uses was undertaken in the EU in The objective was to produce an inventory of specific therapeutic needs for off-patent paediatric medicines. 72 The list includes 16 active substances/classes for the following paediatric therapeutic areas: pulmonology/respiratory diseases, psychiatry, dermatology, and endocrinology. 69 (Annex 7.1.9) The Paediatric Regulation contains a provision for community funding for research into offpatent paediatric medicines. The funding is provided through the EU Framework Programmes for Research and Technological Development to cover the development of offpatent medicinal products by submitting PUMAs to PDCO. To ensure that funds are directed into research on medicines with the highest need in children in Europe, the PDCO adopted the priority list of off-patent products for which studies were required in January The list includes specific recommendations on areas where data and studies were lacking, covering potentially all therapeutic areas and age groups (Cardiology, psychiatry, endocrinology, gastroenterology, haematology, immunology, infections, intensive care, metabolism, neonatology, nephrology, neurology, oncology, pain, pneumology and rheumatology). The list now serves as the basis for the EU Seventh Framework Programme (FP7) community funding for research into off-patent medicines. Annex displays a list of 15 funded projects and two investigator-driven clinical trials for off-patent medicines (total value of 75 million). 69 As illustrated, a number of PIPs have been submitted by academia and SMEs and agreed with the PDCO with the view to apply for a PUMA. In addition, Annex presents the remainder of the projects on the use of paediatric medicines, which were funded by the Sixth and Seventh Framework Programme (FP6, FP7). 74 Also, five EU countries introduced specific national paediatric research incentives to support paediatric medicines development (Belgium, Finland, France, Malta, Spain, United Kingdom). 69 Complementary, to address the unmet needs of paediatric medicines, EMA has published a range of lists 75 covering specific substances within several therapeutic areas (anaesthesiology, anti-infectious therapy, cardiovascular diseases, chemotherapy, diabetes, epilepsy, gastroenterology, immunology, migraine, nephrology, obstructive lung disease, pain, psychiatry, rheumatology). The lists cover substances where off label use in children is significant and where data on pharmacokinetics, dosing, efficacy and safety in children is highly needed. The inventory is currently under revision, taking into account the EMA survey of all paediatric uses of medicines in Europe. 72 Five years after the implementation of the Paediatric Regulation, paediatric therapeutic areas addressed by the industry seem more aligned with adult drug development than to the indicated unmet public health needs of children (paediatric oncology, pain, neonatal morbidity). Taking into consideration the lack of financial interest from the industry for the PUMA incentive, collecting and analysing existing knowledge on off-label use of medicines in children and disseminating the information among health practitioners could prove more sustainable (see Section 5 of this background paper). The introduction of a new paediatric product (resulting from this EU regulation) on the market has to be accompanied by adequate regulatory, political and financial decisions at the national levels. Some undesirable issues that may have arisen from a deficient handling of a paediatric marketing authorisation are illustrated by the case of Cozaar oral suspension. It is a paediatric form of the antihypertensive drug losartan that was given a six-month

32 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children extension to its market exclusivity in France. 71 (Table 7.1.8) It has resulted in higher healthcare spending in France than if a generic had been used, while the product is unsuitably packaged, difficult to obtain, not reimbursable, and not the standard treatment for children with hypertension. 71 Table 7.1.8: Undesirable outcomes of the introduction of a new paediatric product on the market, an example of Cozaar oral suspension Name of the Medicine Paediatric Regulation reward Therapeutic use Packaging and labelling Availability Price implications Cozaar oral suspension, paediatric form of the antihypertensive drug losartan Six-months extension to its market exclusivity in France, including nonpaediatric indications Hypertension, but not standard treatment for hypertension in children Suspension not ready to use Not labelled properly Poor quality packaging prone to dosing mistakes (diluting) Difficult to obtain from retail pharmacies via wholesalers Company did not ask for inclusion in the French reimbursement list Expensive, out-of-pocket expenditure High profitability for the company * * According to figures from the French national health insurance fund for salaried workers (Cnamts) on reimbursement requests in France during 2009, reimbursements for losartan (excluding the losartan + hydrochlorothiazide combination) over a 6-month period totalled 27 million euros. Source: Prescrire. Who Benefits from the European Paediatric Regulation? Response to the European Commission s public consultation on the lessons learnt from the first 5 years of application of the Paediatric Regulation. Paris, Patients participation in the development of paediatric medicines In addition to the active participation of two patients representatives (families) since 2008 at PDCO, in 2011 the EMA initiated an innovative project to facilitate the direct participation of children and young people in the PDCO activities. The objective is to involve children and young people across a wide age range, disease groups, different Member States and cultural groups to provide a new age-appropriate dimension to the scientific aspects of the PIP evaluation process. Some of the proposed areas for consultation are as follows: evaluation of individual PIPs; definition of significant therapeutic needs according to therapeutic areas; clinical assessments used as endpoints; invasiveness, frequency and duration of tests; preferences for clinical trial design features: randomisation, placebo, frequency of visits, duration of study, number of tests, and medicines of choice; acceptability of route of administrations; and acceptability of formulations / preferred formulation type / palatability / frequency of dosing / container closure systems and other packaging issue. The Concept paper on the involvement of children and young people at the Paediatric Committee (PDCO) was released in September 2012 for public review, and the expected

33 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children date for adoption of the outcome is January For more information on stakeholder involvement, please see Background Paper Chapter Conclusions Overall, the Paediatric Regulation has put a framework and structure in place to encourage an integrated approach to the development of paediatric medicines. As a result, a systematic evaluation of each new compound to identify paediatric needs and potential value for children, has been embedded into the research and development (R&D) process. Its requirements and incentives system have produced initial results, addressing some of the complexities associated with paediatric studies and stimulating the paediatric research over time. The number of EU clinical trials with paediatric populations was stable during , and some innovations were introduced in clinical trials, such as the inclusion of younger children in certain circumstances. Alternative methodological approaches to classical clinical trials should be encouraged to facilitate clinical trials in children or reduce the need for investigation in this vulnerable and limited population. That includes the modelling and simulation approaches, as well as extrapolation, which depends on basic knowledge on specific diseases in children, such as pathophysiology, biomarkers and pharmacodynamic end-points. The Paediatric Regulation led to an authorisation of a number of new paediatric indications and new pharmaceutical forms, routes of administration, or strengths for paediatric use. However, the current therapeutic areas covered by PIPs seem to be more in alignment with adult drug development than with the unmet public health needs in children. Moreover, it may be expected that the reward of six-month SPC extension may increase public expenditures and have cost implications for the public purse. A recent example has shown that a deficient market approval of a new paediatric product at national level may result in unsafe due to inadequate packaging and labelling. It is therefore, essential that regulatory authorities have robust approval systems in place, including active systems to detect and act on effects, resulting from the introduction of new paediatric products on the market. The fact that only one PUMA (with limited therapeutic benefit) was granted, indicates that this reward may not be an adequate incentive to the industry for investments in off-patent drug research. This might be linked to reimbursement rules that may not recognize PUMA and thus attach little value to old medicines, even if they include new age-appropriate formulations. Where little industry interest has been expected, the EU Paediatric Regulation includes provisions for public sector research funding for off-patent medicines, and number of projects have been already initiated by academia and SMEs. Accordingly, the collaboration and active involvement of all stakeholders (governments, regulatory authorities, research institutions, pharmaceutical industry, and healthcare facilities) prove to be vital to effectively address off-label use of medicines in children. As an alternative to clinical trials in children, it may be necessary for healthcare professionals to systematically monitor the use of off-label medicines in paediatric clinical practice and share patient records to produce robust safety and efficacy data. It is also expected that the new EU Pharmacovigilance Regulation will support the evidencebased use of off-label medicines in children, because it includes both marketed and unlicensed/off label medicines. Hence, it is important to evaluate the added value of this promising regulation with respect to children

34 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children To ensure that children s priority therapeutic needs are met, the Paediatric Committee has been producing lists on unmet needs. Complementary, medicines with paediatric indications have to represent tangible progress with significant therapeutic benefits in paediatric treatment areas. A similar situation was previously observed in the US, when pharmaceutical companies did not willingly focus their paediatric R&D efforts on the priority needs of children. Consequently, a Best Pharmaceuticals for Children Act (BPCA) 77 was adopted in 2007 to allow the FDA to demand clinical trials on certain medicines (even with pre-specified trial design), based on an annual list of needs and priorities in paediatric medicines published by the FDA and the National Institute of Health (NIH). 5. The usage environment This section discusses the common problem of off-label and unlicensed use of medicines in children, as well as the appropriateness of medicines used for some specific childhood diseases, in different healthcare settings, and at different national income levels. Furthermore, this section addresses important issues related to the availability of information on medicines used in children and the challenges associated with adherence to treatment. 5.1 Off-label and unlicensed use of medicines in children Children have been commonly considered therapeutic orphans because the majority of medicines on the market have not been studied in the paediatric population, nor have they been approved by regulatory authorities for use in children. It has been estimated that only a third of all authorised medicines approved by the European Medicines Agency over the period were licensed for use in paediatric patients. The main constraints to the development of paediatric drugs are ethical concerns, economic barriers, and logistical and technical issues. 76 As a result, many medicinal products are not available in formulations suitable for administration in paediatric patients. This often leaves no alternative for the prescriber other than to use adult medicines as off-label (medicines prescribed outside their authorised indications with respect to age, dosage, indication or route) or unlicensed medicines (modified formulations, extemporaneous preparations, imported or used medicines before the authorisation license is granted, or chemicals used for therapeutic purposes). 78 An EMA survey published in 2010 explored unlicensed and off-label use of medicines in children based on data from 20 EU and two non-eu countries covering 50% of the total population in Europe. 72 Overall, the analysis revealed that 45 to 60% of all medicines used for children were used outside their marketing authorisation. Higher rates were reported in the premature (up to 90% of medicines) and term neonates, as well as in patients with serious conditions and those in intensive care units. The most frequently used off-label and unlicensed medicines belong to the following therapeutic classes: antiarrhythmics antihypertensives (renin-angiotensin inhibitors, beta blockers) proton pump inhibitors H2-receptor antagonists antiasthmatics

35 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptakeinhibitors, tricyclic antidepressants). Adolescents, mainly in Scandinavia, used high rates of off-label oral contraceptives. Off-label antimicrobials (e.g. macrolides, beta lactamines, plus beta-lactamase inhibitors and carbapenems) and corticosteroids (dexamethasone) were used extensively in very young children. The analysis of dosage forms showed that both oral and parenteral formulations were used off-label and unlicensed. Hospitalised children, as well as outpatients, were frequently treated with off-label medicines, and (preterm) neonates had the highest unmet therapeutic needs. There were discrepancies across individual countries in the use of unapproved medicines due to differences in data collection methods, prescribing habits and a medicine s regulatory status (approved or not, in all or some subsets). For that reason, it should be a requirement that approved products be made available in all Member States. Likewise, regulatory action is needed to address the general lack of paediatric labelling in the Summary of Product Characteristics, and in order to foster the harmonisation of information on product labels (e.g. between different manufacturers of the same generic medicines, or different pharmaceutical forms and administration routes of the same medicine). Using medicines that are not licensed means that there is limited available evidence or reporting on its safety, quality and efficacy and a potentially increased risk of adverse drug reactions (ADRs). 79 In 2004, the EMA reported an increased incidence of, seriousness in, and underreporting of adverse paediatric drug reactions related to off-label and unlicensed use of medicines. 80 The ADRs in children have been dominated by anti-infectives, anti-asthmatic, and gastrointestinal ADRs, reflecting the most common diseases in children; but central nervous system ADRs have been equally common. 80 Despite the risks of harm, off-label use of medicines has become an accepted standard of medical practice, particularly in paediatric intensive care units, where approved medicines are scarce. 81,82,83 Denying the use of off-label medicines capable of providing benefits could be considered unethical in a given clinical context, especially for life-threatening or severe chronic illnesses (e.g. cancer therapy, epinephrine, albuterol, dopamine). Experts and health authorities have acknowledged that off-label drug use can be medically appropriate, if the benefits outweigh the potential risks. 84,85,86 Given the lack of age-appropriate doses and formulations, healthcare professionals may change a medicine s administration route, or manipulate adult dosage forms (e.g. segmenting tablets and suppositories, cutting patches, dispersing open capsules, or crushed tablets in water, liquid, or food). These practices may affect a medicine s stability and bioavailability, and lead to considerable inaccuracies in dose delivery, causing overdoses (potential toxicity) or under-doses (potential inefficacy). 87 Dose calculation involves a systematic examination of both the available evidence on safety and efficacy and the seriousness of the condition being treated. Ideally, the evidence should be from a clinical trial and should also include information regarding the minimum effective dose. Unfortunately, for many conditions in paediatric patients, this detailed information is not available. 86 Although the paediatric regulation imposes special attention to dose selection in paediatric clinical trials and evaluation of effective and safe doses in children, paediatric trials remain

36 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children difficult to accomplish. As children may often not be subject to dose-finding studies, empirical scaling from adults to children continues to be the mainstream method for dose selection in children. This implies paediatric dosing calculations by adult data extrapolation, based on the child s gestational and postnatal age, clinical condition, weight, and/or body surface area. 88 All these approaches have disadvantages, determined by differences in paediatric physiological development or pharmacodynamic and pharmacokinetic characteristics, such as variability due to age, gender, body composition, functionality of liver and kidneys and maturation of enzymatic systems throughout the life span from neonates to adults. This increases the risk of toxicity due to lack of understanding of the ontogeny of metabolic pathways, as for example in neonates and toddlers, or poor efficacy due to suboptimal dosing. 88 Ideally, children's dose calculations should be based on dose scaling in paediatric trials, or at least on established paediatric dosage reference texts and formularies (British National Formulary for children BNFc 89 and the WHO Model Formulary for Children 90 ), even though these guidelines rely on dosing recommendations from clinical experience and off-label use rather than on randomized clinical trials. 90 For resource limited settings, the WHO recommends simplified dosing regimens for HIV and malaria treatments using a weightbased formula to predict body-surface area. 91 Because any off-label or unlicensed product manipulation includes dose calculations, their use has great potential of introducing dosing errors. This is most likely the case in younger children, or in neonatal intensive care units, because their weights change rapidly, and the appropriate dosing becomes particularly difficult. 92 Hence, it is often a real challenge to prevent medical errors and to improve patient safety in the paediatric setting. 93 In western healthcare systems, electronic prescribing systems are considered to be potentially helpful tools for reducing prescribing error rates and even death rates in paediatric patients. 94 But, as prescribing for children is different in comparison to adults, the systems require child-tailored solutions (integrated dose checking and obligatory entry fields for indications to check off-label use), as a well as clinical pharmacy interventions to check administration routes and dosing. 94 More importantly, it can be argued that since off-label use of medicines in children is such a common practice, it already relies on sufficient data. Yet, existing electronic patient-level registries have not been routinely used to explore the efficiency and effectiveness of off-label use in children in a systematic manner. To produce evidence for appropriate evidence-based off label use it is important to have precise outcome elements within these electronic systems to generate sufficient data on dose, efficacy and safety for off-patent medicines. Hopefully, the expanded availability and use of electronic medical records will soon allow researchers to link clinical treatments and outcomes with off-label medication prescribing trends in order to elucidate the implications of off-label use of medicines in children. (See the Background Paper Chapter 8.4 Real life data and learning from practice to advance innovation for more information.) 5.2 Medicines use in children for specific diseases Our focus is on the use of medicines for childhood conditions that are considered to be the most relevant to public health and that have the highest medical needs in children. The

37 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children studies on medicines use in children presented below address the issue of the rational use of medicines, which requires that patients receive appropriate medications (safe and effective) for their clinical conditions, in doses and formulations suitable to their personal requirements, for adequate periods of time, and at the lowest cost to their families and communities Use of antibiotics in children The majority of drug utilisation studies highlight the high rates of outpatient antibiotic prescribing in paediatric populations. Of particular concern is the issue of prescribing antibiotics for infections with predominantly viral aetiologies (e.g. most upper respiratory infections, diarrhoea) because of the problems with antibiotic resistance. 96,97 The inappropriate prescribing of antibiotics for children is common in Europe, with marked differences being seen between Northern and Southern Europe. This variation is caused not only by differences in patient populations, but also by differences in prescribing patterns based on differences in prescribers and patients attitudes toward antibiotics, as well as cultural and social factors and health-care systems. 98,99 Previous studies have even demonstrated considerable variations in antibiotic use in all of the neonatal intensive care units (NICUs) in one single country the Netherlands, a country that is characterised by relatively low antibiotic utilisation rates in the EU context. All the while, the recommended treatment guidelines for neonatal infections within these NICUs were similar. Such incountry variations might be explained by the emergence of resistant microorganisms in one particular NICU requiring the consequent use of a broad range of different antibiotics, and the influence of different antibiotic stewardship on the prescription of antibiotics in a NICU. 100 Correspondingly, a recent United States study shows high rates of systemic antibiotics use that account for one-quarter of all the prescriptions dispensed to the paediatric population. Encouragingly, the study demonstrates a 14 per cent decrease in paediatric antibiotics utilisation rates from 2002 through It demonstrated the positive results of the numerous national initiatives launched to promote the appropriate use of antibiotics, particularly for acute respiratory tract infections, and acute otitis media. 101 Urgent interventions for improved antibiotic use include implementation of antibiotic stewardship programmes; uniformity in antibiotic policies, including uniformity in dosage recommendations; educational programmes; surveillance systems; identification of children at risk for antibiotic resistant bacteria colonization; and the linkage of antibiotic usage data to antimicrobial resistance data. 102 For more information on antimicrobial use, see Background Paper Chapter Use of psychotropic medicines in children Depression and other psychiatric disorders in paediatric patients can have significant consequences if not appropriately treated. Still, there have been ongoing debates on the augmented use of psychotropic medicines in children, as well as their safety and efficacy. Psychotropic prescribing has risen in both European and American children in the last decade, with greater annual prevalence in the USA due to differences in psychiatric practices, health service systems and financing and cultural beliefs. 103 The selective serotonin reuptake inhibitor (SSRI) antidepressants and the atypical antipsychotics have been the most widely used drug subclasses. Yet, psychotropic medicines

38 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children used in bipolar disorder and attention deficit hyperactivity disorder, for instance, show fair short-term risk-benefit ratios and poor long-term benefits, and they still have not been properly evaluated for paediatric use. In the past few years, clinicians have recognised the side effects of these medications, including metabolic syndrome and diabetes. Concerns about the lack of well investigated psychotropic medicines, their side-effects, and the increase in children and adolescents receiving these medications, have been raised at all levels parents, clinicians, researchers, the lay press, and government officials. 104 One of the biggest worries has been that widely used antidepressant drugs might be associated with an increased risk of suicidality in paediatric patients. Although the findings of drug-induced suicidality, based on adverse event reporting in paediatric patients during short-term treatment with antidepressant drugs, seem to be robust, an overall interpretation of this finding and its implications for clinical practice are less clear, as it may result from greater reporting of suicidal thoughts and behaviours in these patients. The established boxed warning on the risk of suicidality is important in alerting patients and their families to the safety risk and in encouraging prescribers to balance this risk with clinical need and closely monitor patients. 105 The lack of well investigated psychotropic medication for children is serious because it is inappropriate to extrapolate from adults due to the still developing paediatric brain and central nervous system during adolescence. This field remains relatively unresearched at the moment Use of medicines in preterm newborns The preterm birth prevalence rate has been increasing in Europe over the last 10 years, reaching 7% of all life births in Although their survival rates have improved, preterm infants are at greater risk for health complications in later life, such as cerebral palsy, respiratory illnesses, sensorial and motor disabilities, and learning and behavioural disorders (see Background Paper Chapter 6.23 for more detailed information on neonatal conditions). 107 The problem of newborn survival has received greater global attention lately, with the UN campaign Every Woman, Every Child being launched to prevent preterm births and improve the survival and outcome of premature babies. 108,109,110 Despite the fact that (preterm) neonates belong to the most vulnerable population, data on drug utilisation in neonatal intensive care units are limited. Preterm neonates are often multi-morbid, in need of intensive and complex medical care, exposed to a high number of drugs (mostly unlicensed or off-label), and at higher risk of adverse drug reactions. 111,112 A German study in a neonatal intensive care unit (NICU) specialised in pre-term neonates confirmed the complexity of treatment strategies and the polypharmacy patterns as preterms received an average of eleven different medicines. Contrary to drug utilisation patterns in other newborns, the most frequently prescribed medications for preterms were systemic use anti-infectives, and central nervous system and respiratory system drugs. 113 All very preterm infants received at least one unlicensed or off-label medicine, with no information available on their safety and efficacy in preterms in the Summary of Product Characteristics (SmPC). In this context, the cardiovascular drugs, including diuretics and anaesthetics/analgesics were of major concern. 113 Similarly, a recent Estonian hospital study described extensive pharmacotherapy in (preterm) neonates, frequent use of off-label and unlicensed medicines

39 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children and large differences in the neonatal information provided by different sources (BNFc, Micromedex and the Estonian SPC). 114 Moreover, a United Kingdom study found potentially harmful substances and excipients (e.g. ethanol, propylene glycol) in the liquid medicines used in a NICU. During treatment, preterm newborns were regularly exposed to 20 different excipients that have the potential to cause nerve damage, including ethanol and propylene glycol chemicals. The level of the recommended maximum intake of sorbitol was also exceeded in the patients when it was calculated according to the baby s weight. 115 The European regulatory authorities have recognised this problem and some of the drugs frequently given to very preterm infants, such as midazolam, fentanyl, dobutamine, or hydrochlorothiazide, were included in their list of priority off-patent drugs. 73 The lack of data on safety and efficacy leads to uncertainties in (preterm) neonatal drug therapy, so more information is urgently needed for optimal use of medicines prescribed in neonates. Randomised controlled trials have conventionally been regarded as the golden rule for data collection, but they might be impractical and unethical in neonates because of difficulties with randomisation or recruitment. Thus, it seems more appropriate to use the vast amount of clinical data that already exists in electronic medical records in order to improve the knowledge of safety and efficacy related to the use of medicines in preterm neonates. Another concern is the lack of appropriate formulations for preterm newborns, especially for injection antibiotics (e.g. gentamicin), that are often misadministered due to low dosing. Therefore, innovations like pre-packaged doses and needle-free technology are needed. 5.3 Use of medicines in children in hospitals Recent research has provided new data on the use of medicines in the hospital sector, an area generally characterized by a lack of knowledge and transparency. A multicentre study (ADVISE) was conducted on paediatric general medical wards in two European (United Kingdom, Germany) and three non-european (Malaysia, Australia and Hong Kong) hospitals in On average, the children received three medicines during their hospitalization, with antibacterials for systemic use, analgesics, and drugs for obstructive airway diseases being the medicines most frequently prescribed to the cohorts. 116 A study conducted at a large university hospital in Germany showed that while antibacterials for systemic use were prescribed most frequently, their use decreased between 1999 and 2008, whereas exposure to analgesics and anti-inflammatory drugs increased. 117 Antimicrobials are among the most commonly prescribed drugs in hospitals; therefore, in 2008 the European Surveillance for Antibiotic Consumption (ESAC) project performed a study in the paediatric units of 32 hospitals from 21 European countries. It revealed that a third of all paediatric patients were on antimicrobials, with a high proportion of them receiving antimicrobial combinations. The ESAC study identified the following targets for quality improvements of antimicrobial use in children: reducing the excessive use of antimicrobial combinations, high proportion of parenteral antimicrobials, and the long surgical prophylaxis times. 118 A recent, large United States study showed serious polypharmacy in paediatric inpatients as a considerable fraction of them were exposed to five or more medicines, especially those patients with rare conditions. 119 Drug exposures were more prevalent in those children who

40 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children were older than one year and in children s hospitals. The most frequently used drugs and therapeutic agents included intravenous fluids, narcotics, antipyretics and analgesics, antiinfective agents, anaesthetic agents, gastrointestinal drugs, and medicines prescribed as part of a newborn s routine care Use of medicines in children in developing and transitional countries Similarly, the irrational use of medications poses significant challenges in resource poor settings. A WHO systematic review from 2007 assessed the progress and impact of interventions that have been undertaken to improve the treatment of childhood illness in developing countries. 120 The report indicated that regardless of the numerous national and international efforts, suboptimal treatment patterns of acute childhood diseases continued over the past 20 years. There has been improvement in the treatment of acute diarrhoea, reflected by an increased use of oral rehydration salts (ORS) and a decreased use of antidiarrheals and antibiotics. Optimal pneumonia treatment with appropriate antibiotics remained the same over time (80% of patients), while inappropriate use of antibiotics to treat viral upper respiratory tract infections (URTI) increased steadily, and malaria treatment with appropriate antimalarials deteriorated. 120 The use of medicines in the public sector was substantially better than in the private sector, but there were longer consultation times, better labelling, and better patient knowledge of dosing in the private sector. (Annex ) Prescribing by the paramedical and nursing staff was similar to that of doctors for the common childhood diseases treated in health facilities. 120 (Annex ) The review suggests that the most effective interventions are multifaceted; target specific behaviours and assess local barriers to changing the behaviours; and take place at the system level, as opposed to the individual prescriber level. Effective intervention packages include educational materials, interactive lectures, educational outreach visits, audits and feedback, reminders, use of opinion leaders, policy changes, and the implementation of clinical protocols. (Figure 7.1.4) In 2009, a systematic review examined interventions for changing physician prescribing practices and improving child health with regards to paediatric asthma, antibiotic prescription, treatment of malaria, and diarrheal disease. 121 Interventions focusing on structural changes in the design of current practices (e.g., implementation of a new asthma clinical pathway, an asthma peer leader with organization change, or restrictions on antibiotic use in a neonatal unit, etc.) were more successful than interventions focused on individual provider change (e.g., an educational conference for providers, or distribution of clinical practice guidelines to physicians). 121 As expected, multi-faceted interventions tended to be more successful than single interventions. 121 Many industrialised countries have adopted activities to promote the more appropriate use of medicines, but it seems that their impacts have rarely been thoroughly evaluated. The WHO systematic review demonstrates that systematically collected and evaluated evidence provides a valuable opportunity for measuring medicine use within health systems and for testing the effectiveness of interventions to improve the use of medicines. Such studies are therefore also warranted in Europe

41 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Figure 7.1.4: Median reported percentage change across all prescribing outcomes for welldesigned paediatric prescribing improvement interventions, by type of intervention. Source: World Health Organization. Medicines use in primary care in developing and transitional countries: Fact book summarizing results from studies reported between 1990 and WHO/EMP/MAR/ Adherence to treatment in children Poor compliance to medical regimens may have serious consequences for paediatric patients in terms of their health outcomes. Non-adherence may compromise the efficacy of drug regimens, thus diminishing the desired treatment goal, or may lead to changes in treatment regimens or dosages and an increase in toxicity, unnecessary investigations, and treatment costs. Estimates of non-compliance in children and adolescents (40-75%) are greater than in adults, particularly in adolescents. 122,123,124 Many factors affect medication adherence and in most cases there are multiple causes. Factors affecting adherence may be related to illness and treatment regimens; characteristics of an individual child, including its age, race, socioeconomic status, developmental level, and psychopathology; and characteristics of the family system in which the child lives. 125,126,127 Importantly, children need appropriate parental and professional support in taking control of their medication and treatment. 125,126,127 (Table 7.1.9) A survey in the Netherlands in a multicultural population of children with asthma indicated that adherence to inhaled corticosteroids in children was a particular problem amongst ethnic minority patients, but further studies were recommended to clarify the causal mechanism

42 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Table 7.1.9: Important factors and considerations for adherence to treatment in children Reasons and barriers for non-adherence with medicines in children The demands of daily schedules of activities, stress, and family dynamics Parents' lack of understanding about the diagnosis, concerns about drug therapy effectiveness, and fears about medication side effects Age, socioeconomic status, race, and family factors Language barriers and low health literacy Considerations for improved adherence with medicines in children The triangle of communication between health professionals, parents, and children The medication regimen should be tailored to the child and family's lifestyle and daily routine, taking into account the frequency and timing of administration Consideration should be given to the palatability and formulations of medications prescribed for young children Reinforcement of instructions by pharmacists or nurses, medication technique training (e.g., inhaler, injection, or dropper use) Sources: Gardiner P, Dvorkin L, Promoting Medication Adherence in Children American Family Physician Accessed April 29, Matsui D. Current Issues in Pediatric Medication Adherence. Pediatr Drugs 2007; 9 (5): There has been limited research on the most effective methods for improving adherence to recommended treatment in children. 129 Methods that have proven to be successful in improving adherence in children were, as is also the case in adults, usually multifactorial and include: educational programmes, including information on the disease; explaining the purpose and potential benefits of the recommended medication; behavioural programmes that reward good compliance; and good supportive relationships and therapeutic alliances between patient and health professionals that include effective communication. Simplified regimens (with minimum effect on lifestyle) and palatable medications with age-appropriate formulations and delivery mechanisms may enhance the ability of paediatric patients to adhere to their medicines ,126,127 (Table 7.1.9) In addition, pharmaceutical companies have been developing innovative, child-friendly preparations appropriate for administration to infants and young children in terms of taste, formulation, and route of administration. But, the effects of newer formulations, such as effervescent and chewable dosage forms, granules and sprinkles, and the novel delivery system (Sip-Technology, that provides ready, easy-to-use, pre-measured dose of medication in a straw) are largely untested with regards to medication adherence, as previously stated in section 3 of this background paper. Although there is no consensus as to what is the best approach to promote adherence with therapy, attention should be given to determining what barriers exist and trying to overcome them by involving children and their parents in the treatment planning process. It has even been suggested that perhaps perfect adherence is an ideal that will never be achieved, and that maybe the focus should be on determining how much adherence is enough to achieve the therapeutic goal. Further research in this direction is encouraged

43 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 5.6 Availability of information on (off-label) paediatric medicines and its dissemination to health workers and patients One implication of the frequent, off-label use of paediatric medicines is the lack of adequate information about their possible indications, dosing regimens, dose adjustments, and administration. This information is neither included in the Summary of Product Characteristics (SmPC) for health-care professionals, nor in the patient information leaflets from the manufacturers or the media information resources for patients and their families/caregivers. Historically, the lack of adequate information on paediatric medicines has been attributed to deficient scientific evidence to prescribe medicines in children, but nowadays there are also delays in updating the SmPCs with recently generated data. In order to provide better information on the use of medicines in children, the Paediatric Regulation has included an instrument for collecting existing paediatric studies. The Regulation has obliged companies holding data on the safety or efficacy of authorized medicines in children, as well as newly generated paediatric data, to submit those studies to the competent authorities, so that data can be assessed and authorized product information amended. 66 Since 2008 more than study reports on medicinal products have been submitted to the competent authorities, revealing the large amount of existing paediatric information available at company level. These study reports are being assessed by the authorities, resulting in the publishing of assessment reports on 140 active substances, and recommending changes to the SmPC for authorized products. However, marketing authorisation holders have not progressed much in updating the SmPC, so little of those new data have been systematically included in the SmPC. 69 There have been recent improvements regarding information dissemination on medicine use in children for both healthcare workers and the public. The website Paediatric Medicines in the Netherlands 130 is a multidisciplinary knowledge network initiated by the Dutch Knowledge Centre for Pharmacotherapy in Children (NKFK) and supported by the Ministry of Health, Welfare and Sport. The NKFK focuses primarily on improving the provision of information on the use of medicines in children to health professionals. Furthermore, the British National Formulary for Children 89 and the WHO Model Formulary for Children 90 provide dosage information for medicines used off-label in children. Patient information for unlicensed and off-label medicines is also available on the website Medicines for children, which consists of medicine information leaflets and provides opportunities for interactions between professionals and the public. These encouraging developments should be supported by complementary research further exploring how healthcare professionals obtain their information to adequately treat children in daily practice and how this information becomes updated on a regular basis. In addition, more should be invested in evaluating the impact of existing information on medicine use in children to improve clinical practice and the adherence to treatments in children

44 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 6. Identified gaps and recommendations for research and policy Since 2004, numerous activities have been undertaken to support the development and administration of appropriate paediatric medicines and to improve the information available on their use. As a result, a legal EU framework has been put into place to encourage paediatric research, and various innovative, age-appropriate formulations, and drug devices for paediatric use have followed. Despite rapid technological advances and emerging networks for collaborations and expertise, we identified the following knowledge gaps and areas that need strengthening and/or future research in the area of medicine use in children. Collection of data on disease burden and medicine use in children across Europe In order to understand the burden of childhood diseases in the EU and set priorities, the collection of data on disease prevalence rates, and the use of medicines in children at a country level would allow inter-country comparisons and EU analysis of trends and variations over time. The main challenges for a complete and comprehensive evaluation are the lack of systematic and continuous monitoring in all EU countries and the disparity between studies. Therefore, the methodological quality of data collection should be improved and more multinational collaborative studies should be performed with EU support. Further research into development of age-appropriate medicines In recent years, much progress has been made in the development of age-appropriate novel, oral formulations with dose flexibility (mini-tablets, chewable, and orodispersible tablets for younger children, and dosage forms dispersible into liquids or mixed with food) and medical devices for easier administration of paediatric medicines. The ongoing research on the ability of children to swallow solid oral forms needs to be accompanied by studies on children s preferences and adherence to different dosage forms. In addition, new routes of administration, such as oral-transmusosal (buccal strips), intra-nasal and transdermal routes (for neonates mainly), are ripe for future development and research. In neonates, particular caution should is needed for these forms in terms of optimal use and dosing. Given the safety and toxicity concerns of some excipients in paediatric formulations, more research is needed into alternative safe alternatives for children. It is also important to incorporate the available knowledge on excipients into a single, public repository to avoid a duplication of efforts and to encourage further discovery and innovation. Study effects of development of age-appropriate medications and paediatric regulations Irrespective of all technological developments, there is limited evidence on the impact of pharmaceutical formulations, routes, and dosage forms on patient-related outcomes (e.g. clinical efficacy, side effects and tolerability, and patient preference, acceptance, and adherence). This research should be central to the support of the pharmaceutical development of paediatric medicines with clear clinical advantages. In addition, although many novel formulations and paediatric drug delivery devices have been developed, very few appear to be available on the market. This is most likely due to the

45 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children high costs of patent protection and the (un)willingness of health insurance bodies to reimburse for these new items. Therefore, current formulation research should also be accompanied by studies on price implications and access to innovative products that have tangible therapeutic benefit. Moreover, some paediatric medicines awarded six-month SPC extensions have cost implications and may increase public health expenditures. It is therefore essential that regulatory authorities have active systems in place to detect and act upon, resulting from the introduction of new paediatric products on the market. Increase efficiency of the Paediatric Regulation with a focus on real paediatric needs The Paediatric Regulation aims to achieve an integrated approach to the development of paediatric medicines in the overall medicine development area. However, current PIPS and their therapeutic areas covered by the industry seem to be more in alignment with adult drug development than with unmet public health needs in children (e.g. paediatric oncology, pain, neonatal morbidity). As a response, the Paediatric Committee has been producing lists on unmet therapeutic needs in children to identify priority research areas. This activity should be complemented by proactive demands for clinical trials on priority medicines with significant therapeutic benefits in children. In addition, alternative methodological approaches to classical clinical trials should be encouraged to facilitate and optimize clinical trials in children, and potentially also reduce the need for (or size of) clinical trials in this vulnerable and limited population. Research in this field should be stimulated. The new EU Pharmacovigilance Regulation may have potential added value in providing safety and efficacy data on off-label-medicine use in children, which should be evaluated. Improve (information on) rational use of paediatric medicines Various studies on medicine use trends and patterns in children indicate that more efforts are needed to guarantee the rational use of medicines, especially antibiotics, psychotropic medicines, medicines for neonates, and medicines used in hospitals. Effective interventions that are multifaceted and that take place at the system level must be considered in order improve the use of medicines. In addition, data should be systematically collected and evaluated to measure and to test the effectiveness of interventions in improving medicine use. The off-label use of medicines has become an accepted standard of paediatric medical practice, particularly in areas where approved medicines are scarce. But, due to the lack of clinical trials using children, the available evidence on safety, quality, and efficacy and the knowledge of the potential risks of adverse drug reactions with off-label medicines used in children is limited. On the other hand, existing, electronic, anonymised, patient-level registries have not been used to explore the efficiency and effectiveness of off-label use in children. It is therefore essential to systematically collect and use the real life data on offlabel or unlicensed medicine use in children to produce the evidence. Hopefully, the expanded availability and use of electronic medical records will soon allow researchers to link clinical treatments and outcomes with off-label medication prescribing trends and elucidate the implications of their use in children

46 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children There has also been limited evidence on the most effective methods for improving adherence to recommended treatments in children. More research is needed to identify adherencepromoting interventions in children, and to evaluate their impact. Recent improvements in information dissemination on medicine use in children for both healthcare workers and the public include the creation of websites ( Paediatric Medicines in the Netherlands and Medicines for Children in the United Kingdom), the BNFc and the WHO Model Formulary for Children. Complementary research should follow up on this to evaluate how healthcare professionals obtain information to treat children in daily practice and to evaluate what impact new information resources have on the use of medicines and adherence to treatment in children. References 1 European Commission Eurostat. Crude birth rate. Tables, graphs and maps interface Available at: Accessed May 2, European Commission Eurostat Ageing in the European Union: where exactly? Available at: EN.PDF. Accessed May 2, European Commission and the Organisation for Economic Co-operation. Health at a Glance: Europe OECD Publishing, Available at: Accessed May 2, Liu L, Johnson HL, Cousens S, et al, for the Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since Lancet 2012; 379: United Nations Inter-agency Group for Child Mortality Estimation (IGME). Levels & Trends in Child Mortality Report UNICEF, WHO, WB, UNDP. New York, Available at: ortality%20report% pdf. Accessed May 2, Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study Lancet 2012; 380: Gore FM, Bloem PJN, Patton GC, et al. Global burden of disease in young people aged years: a systematic analysis Lancet 2011;377: Darnton-Hill I, Nishida C, James WPT. A life course approach to diet, nutrition and the prevention of chronic diseases Public Health Nutrition 2004: 7(1A),

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52 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Accessed May 2, Senate and House of Representatives of the United States of America in Congress assembled. Food and Drug Administration Amendments Act of ; Available at M pdf. Accessed May 2, Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ. 2000;320: Choonara I Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf. 2002;25(1): European Medicines Agency. Evidence of harm from off-label or unlicensed medicines in children. EMEA. EMEA/126327/2004. Available at: Accessed May 2, Shah SS, Hall M, Goodman DM, MDet al. Off Label Drug Use in Hospitalized Children, Arch Pediatr Adolesc Med 2007, Cuzzolin L Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin. Drug Saf. 2006; 5(5): Pandolfini C, Bonati M. A literature review on off-label drug use in children Eur J Pediatr 2005; 164: American Academy of Pediatrics Committee on Drugs. Uses of Drugs Not Described in the Package Insert (Off-Label Uses), Pediatrics 2002; 110(1). 85 MHRA, UK. Off-label or unlicensed use of medicines: prescribers responsibilities, Drug Safety Update, Available at: Accessed May 2, Bonati M, Pandolfini C. Off-label drug use in children should be rational. Arch Dis Child September 2011;96(9): Sammons H, Conroy S. How do we ensure safe prescribing for children? Arch Dis Child 2008;93: Bartelink IH, Rademaker CMA, Schobben AFAM, van den Anker JN. Guidelines on Paediatric Dosing on the Basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokinet 2006; 45(11): British National Formulary. Available at: Accessed May 2, World Health Organization, WHO model formulary for children World Health Organization, Geneva Available at: Accessed May 2,

53 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 91 World Health Organization. Technical consultation on the use of pharmacokinetic analyses for paediatric medicine development. Geneva, Switzerland, May Available at: Accessed May 2, Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in pediatric inpaients. JAMA 2001, 283 (16): Miller M, Robinson, K, et al. Medication errors in paediatric care: a systematic review of epidemiology and an evaluation of evidence supporting reduction strategy recommendations. Quality and Safety in Health Care 2007;16: Maat B, Au YS, Bollen CW, et al. Clinical pharmacy interventions in paediatric electronic prescriptions. Arch Dis Child Nov World Health Organization. The Rational Use of Drugs. Report of the Conference of Experts. Geneva: World Health Organization; Available at: Accessed May 2, Finkelstein JA, Metlay JP, Davis RL, et al. Antimicrobial use in defined populations of infants and young children. Arch Pediatr Adolesc Med 2000;154: Resi D, Milandri M, Moro ML. Antibiotic prescriptions in children. J Antimicrob Chemother 2003;52: Rossignoli A, Clavenna A, Bonati M. Antibiotic prescription and prevalence rate in the outpatient paediatric population: analysis of surveys published during Eur J Clin Pharmacol 2007;63: LusiniG, Lapi F, Benocci S, Vannacci A, et al. Antibiotic prescribing in paediatric populations: a comparison between Viareggio, Italy and Funen, Denmark European Journal of Public Health 2009;19(4): Liem TBY, Krediet TG, Fleer A, et all. Variation in antibiotic use in neonatal intensive care units in the Netherlands. J Antimicrob Chemother 2010;65: Chai MG, Governale L, McMahon AW, Trinidad JP, Staffa J. Trends of Outpatient Prescription Drug Utilization in US Children, Pediatrics 2012;130; World Health Organization. The evolving threat of antimicrobial resistance Options for action. Geneva, Available at: Accessed May 2, Zito JM, Safer DJ, de Jong-van den Berg LTW, et al. A three-country comparison of psychotropic medication prevalence in youth Child and Adolescent Psychiatry and Mental Health 2008, 2: Kuehn BM. Studies Shed Light on Risks and Trends in Pediatric Antipsychotic Prescribing. JAMA 2010;303 (19): Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry, 2006; 63:

54 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children 106 Blakemore SJ, Choudhury S. Development of the adolescent brain: implications for executive function and social cognition. Journal of Child Psychology and Psychiatry 2006;47(3): Liu, L., Johnson, H.L., Cousens, S., Perin, J., Scott, S., et al. Global, regional, and national causes of child mortality in : an updated systematic analysis. The Lancet, 2012;379: Editorial A timely arrival for Born Too Soon. The Lancet 2012; 380(9855): March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on Preterm Birth. Eds CP Howson, MV Kinney, JE Lawn. World Health Organization. Geneva, Available at: Accessed May 3, WHO. Priority life-saving medicines for women and children WHO/EMP/MAR/ Available at: Accessed May 2, Kumar P, Walker JK, Hurt KM, Bennett KM, Grosshans N, Fotis MA. Medication use in the neonatal intensive care unit: current patterns and off-label use of parenteral medications. J Pediatr 2008;152: Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 2006; 117: Neubert A, Lukas K, Leis T, Dormann H, Brune K, Rasher W. Drug utilization on a preterm and neonatal intensive care unit in Germany: a prospective, cohort based analysis. Eur J Clin Pharmacol 2010;66: Lass j, Käär R, Jõgi K, et al. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol 2011;67: Whittaker A, Currie AE, Turner MA, et al. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F236 F Rashed AN, Wong ICK, Cranswick N, et al. Risk factors associated with adverse drug reactions in hospitalised children: international multicentre study. Eur J Clin Pharmacol 2012; 68: Oehme A, Rashed AN, Hefele B, Wong et al. Adverse Drug Reactions in Hospitalised Children in Germany Are Decreasing: Results of a Nine Year Cohort-Based Comparison. PLOS ONE 2012; 7(9): Amadeo B, Zarb P, Muller A, Drapier N, Vankerckhoven V, Rogues AM, et al. European Surveillance of Antibiotic Consumption (ESAC) point prevalence survey 2008: paediatric antimicrobial prescribing in 32 hospitals of 21 European countries. J Antimicrob Chemother 2010 Oct;65(10): Feudtner C, Dai D, Hexem KR, et al. Prevalence of Polypharmacy Exposure Among Hospitalized Children in the United States. Arch Pediatr Adolesc Med. 2012;166(1): World Health Organization. Medicines use in primary care in developing and transitional countries: Fact book summarizing results from studies reported between 1990 and

55 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children WHO/EMP/MAR/ WHO Geneva, Available at: Accessed May 2, Cabana MD, Coffman JM, Bekmezian A et al. Analysis of published trials examining methods to change provider prescribing behaviour and child health outcomes; Available at: Accessed May 2, Stevenson FA, Cox K, Britten N, Dundar Y. A systematic review of the research on communication between patients and health care professionals about medicines: the consequences for concordance. Health Expect 2004 Sep;7(3): Hampson S, Skinner TC, Hart J, et al. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review. Health Technology Assessment 2001;5: Carter S, Taylor D, Levenson R. A question of choice-compliance in medicine taking. A preliminary review. 2nd ed. London: Medicines Partnership; Gardiner P, Dvorkin L, Promoting Medication Adherence in Children American Family Physician. 2006; Available at: Accessed May 2, Matsui D. Current Issues in Pediatric Medication Adherence. Pediatr Drugs 2007; 9 (5): Dawood OT, Ibrahim MIM, Palaian S. Medication compliance among children. World J Pediatr, Vol 6 No 3. August 15, Vasbinder, E, Dahhan, N, Wolf, B, et al. The association of ethnicity with electronically measured adherence to inhaled corticosteroids in children. European Journal of Clinical Pharmacology: World Health Organization. Adherence to long-term therapies: Evidence for action. WHO Geneva, Available at: Accessed May 2, Nederlands Kenniscentrum Farmacotherapie bij Kinderen. Kinderformularium. Available at: Accessed May 2,

56 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annexes Annex 7.1.1: Infant mortality rates in Europe in 2010 Annex 7.1.2: Regional causes of childhood deaths in 2010 Annex 7.1.3: Annex 7.1.4: Annex 7.1.5: Annex 7.1.6: Developmental Changes in Physiology in Children EMA Matrix routes of administration/dosage form vs. age Novel drug formulations for children Novel drug devices for children Annex 7.1.7: Paediatric products prequalified up to 2012 Annex 7.1.8: List of centrally authorised medicinal products for which the therapeutic indication was extended or amended to the paediatric population. Annex 7.1.9: List of medicinal products and companies that have benefited from the 6- month extension of the supplementary protection certificate. Annex : Annex : Annex : Annex : Annex : Funded off-patent medicine projects (start up to 1 January 2010) and agreed PIPs, if available. Therapeutic needs in the paediatric population according to the survey of all paediatric uses (EMA/794083/2009) and projects addressing the needs Projects on use of paediatric medicines funded by the Sixth and Seventh Framework Programme (FP6, FP7), excluding off-patent funded projects, presented in Annex WHO/INRUD prescribing indicators by health facility ownership WHO/INRUD prescribing indicators by prescriber type

57 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.1: Infant mortality rates in Europe in 2010 Source: European Commission and the Organisation for Economic Co-operation. Health at a Glance: Europe OECD Publishing, Accessed May 2,

58 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.2: Regional causes of childhood deaths in 2010 Source: Liu L, Johnson HL, Cousens S, et al, for the Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since Lancet 2012; 379:

59 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.3: Developmental Changes in Physiology in Children Source: Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental Pharmacology drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:

60 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.4: EMA Matrix routes of administration/dosage form versus age (1 not applicable, 2 applicable with problems, 3 probably applicable, but not preferred, 4 good applicability, 5 best and preferred applicability) Source: European Medicines Agency. Reflection Paper on Formulations of Choice for the Paediatric Population (EMEA/CHMP/PEG/194810/ 2005)

61 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.5: Novel drug formulations for children Dosage form Brand product (manufacturer) Multiparticulates Granules / Sprinkles / Pellets Mini-tablets Pankreatin Kreon (Kali-Chemi Pharma), artesunate and mefloquine granules - Artequin Pediatric (Mepha), methylphenidate granules Medikinet (Medice) Pankreatin - Pankreatan (Novartis) Cholspasminase (Merck) Enzym-Lefax (Bayer) Cotazym (UCB), Methylphenidate controlled release Ritalin pellets (Sandoz) Concerta trilayer (J&JPRD) Flexible dispersible formulations Dispersible tablets Oral lyophilisates Orally disintegrating tablets- lozenges Oral strips / Buccal wafers Chewable tablets Chewing gums Medicated lollipop Orally disintegrating mini-tablets ACT-Coartem Dispersible (Novartis,MMV) Sinupret Liquitabs (Bionorica) Cetirizine - Zyrtec (Duncan) Sodium fluoride - Fluoretten (Sanofi-Aventis) Dextromethorphan, acetaminophen - Triaminic (Novartis) Ondansetro - Setofilm (Applied Pharma Research & Labtec & Monosol Rx) Magnesium hydroxide gummy bears-pedia Lax (Fleet) Montelukast sodium Singulair (MSD) Dimenhydrinate - Superpep (Hermes) Fentanyl citrate - Actiq (Cephalon) Hydrochlorothiazide-Ludiflash, Sodium stearylfumarate - Pruv (JRS) Sources: Stoltenberg I, Winzerburg G, Breitkreutz J. Solid oral forms for children formulations, excipients and acceptance issues. Journal of Applied Therapeutic Research, 2010; 7(4): Breitkreutz J. Nach der EU-Reform. Arzneiformen für Kinder. Pharm. Unserer Zeit 2009;38:

62 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.6: Novel drug devices for children Dosage form Brand product (manufacturer) Novel dosing instruments for oral liquids Teat/Pacifier with reservoir Single-use spoon filled with medicine Dropper tube Dose sipping technology straw with taste Solid dosage pen Coated particles for oral administration Coated particles in suspension Coated particles in tablets for preparing suspension Coated particles on dosage spoon Needle-free injection devices Nystatin suspension, Mykundex (Bioglan) Diphenhydramin solution,benadriltm (Pfizer) Codeine drops (Stella / Abbott) Clarithromycin micropellets Clarosip (Grünenthal GmbH) Carvedilol, salutas and metoprolol tartrate, microsinused as model drugs Clarytromycin (Abbott) Roxithromycin (Infectopharm) Pre-dosed azithromycin spoon (Sandoz) Jet injectors Subcutaneous administration of insulin, vaccines, growth hormone Saizen Microstructured transdermal systems for intradermal vaccines Novel devices for inhalation therapy (Bioject and Serono) Nebuliser with spacer/valved holding chamber and face mask Nebulisers with a vibrating mesh technology for aerosol generation Nebuliser with an electronic unit Dry powder inhalers For antibiotics e.g. tobramycine, Pari Boy - electric nebuliser with compressor and face mask, AeroChamber Plus (VHC) Ventolair Autohaler for beclomethasone dipropionate Flutide Diskus 50 with fluticasone propionate, (GSK) Inhalation-driven multidose dry powder inhaler with micronized budesonide (AstraZeneka), Pulmicort Resules with micronised budesonide suspension for inhalation Sources: Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Exp Opin Drug Deliv 2007; 4: Walsh J,Bickmann D, Breitkreutz J, Chariot-Goulet M, on behalf of the European Paediatric Formulation Initiative (EuPFI). Delivery devices for the administration of paediatric formulations: Overview of current practice, challenges and recent developments. International Journal of Pharmaceutics 2011;415: Annex 7.1.7: Paediatric products prequalified up to 2012 Abacavir (as sulfate) 60 mg Lamivudine/Nevirapine/Stavudine 60 mg/100 mg/12 mg Lamivudine/Nevirapine/Stavudine 30 mg/50 mg/6 mg Lamivudine/Nevirapine/Zidovudine 30 mg/50 mg/60 mg

63 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Isoniazid/Pyrazinamide/Rifampicin 30 mg/150 mg/60 mg Artemether/Lumefantrine 20 mg/120 mg Lamivudine 30 mg - Dispersible tablets Lamivudine 30 mg Tablets Zidovudine 100 mg - Tablets Isoniazid/Rifampicin 60 mg/60 mg - Dispersible tablets Abacavir (as sulfate)/lamivudine 60 mg/30 mg Tablets Nevirapine 50 mg/5 ml - Oral suspension Lopinavir/Ritonavir 100 mg/25 mg - Tablets Abacavir (as sulfate)/lamivudine/zidovudine 60 mg/30 mg/60 mg - Tablets Lamivudine/Zidovudine 30 mg/60 mg - Tablets Source: World Health Organization. Prequalification Programme, A United Nations Programme managed by WHO. 2011; Available at: Accessed May 2,

64 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.8: List of centrally authorised medicinal products for which the therapeutic indication was extended or amended to the paediatric population

65 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

66 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

67 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

68 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

69 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Source: European Medicines Agency with its Paediatric Committee. 5-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation. EMA/428172/ ; Available at: Accessed May 2,

70 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex 7.1.9: List of medicinal products and companies that have benefited from the 6-month extension of the supplementary protection certificate

71 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

72 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

73 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

74 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

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76 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children

77 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Source: European Medicines Agency with its Paediatric Committee. 5-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation. EMA/428172/ ; Available at: Accessed May 2,

78 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex : Funded off-patent medicine projects (start up to 1 January 2010) and agreed PIPs, if available

79 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Source: European Medicines Agency with its Paediatric Committee. 5-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation. EMA/428172/ ; Available at: Accessed May 2, Information available on the website page: and Accessed May 3,

80 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex : Therapeutic needs in the paediatric population according to the survey of all paediatric uses (EMA/794083/2009) and projects addressing the needs

81 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Source: European Medicines Agency with its Paediatric Committee. 5-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation. EMA/428172/ ; Available at: Accessed May 2,

82 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex : Projects on use of paediatric medicines funded by the Sixth and Seventh Framework Programme (FP6, FP7), excluding off-patent funded projects, presented in Annex No Project name Period Objective FP6 1 PRIOMEDCHILD EUROSTEC KIDSCANCERKINOME CHILDHOPE TEDDY FP7 1 DIRECT GRIP CUREHLH RESPECT PHARMACHILD PANCARESURFUP STOP ADDUCE ENCCA Coordination of research on priority medicines for children Soft tissue engineering for congenital birth defects in children: new treatment modalities for spina bifida, urogenital and abdominal wall defects Selecting and validating drug targets from the human kinome for high risk paediatric cancers Chimaeric T-cells for the treatment of paediatric cancers Optimise paediatric use of current drugs and promote the development of new drugs, by incorporating pharmacogenetic applications and implementing guidance/tools to perform paediatric research. Disseminate research funded by EC for improving treatment options for children suffering from cancer Coordinate knowledge management efforts and integrate existing research capacity for development and safe use of medicine in children, work closely with families to provide children with safe and effective medicines. Establish earlier diagnosis, learn about pathophysiology, and develop less toxic treatments for the rare disease haemophagocytic lymphohistiocytosis Clarify expectations and needs of children and families to participation in clinical trials, empower and motivate children in future clinical trials research. Study pharmacovigilance for adverse effects in childhood arthritis from treatment with immune modulatory drugs Collect data on long-term complications of cancer treatments, create European cohort for early identification and management of complications to improve health and quality of life and maximise use of health services Assess and monitoring of Medication-Related Suicidality in children and adolescents in three paediatric observational trials (risperidone in conduct disorder; fluoxetine in depression, and montelukast in bronchial asthma) Investigate long-term adverse effects of methylphenidate on growth, neurological system, psychiatric states and cardiovascular system in children and adults Establish European network for cancer research in children and adolescents, define research strategy facilitate clinical trials to introduce the new generation of biologically targeted drugs Source: European Commission. CORDIS (Community Research and Development Information Centre) European R&D Projects funded under FP6 and FP. Accessed May 2,

83 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex : WHO/INRUD prescribing indicators by health facility ownership WHO- World Health Organization, INRUD - International Network for the Rational Use of Drugs EML Essential Medicines List Source: World Health Organization. Medicines use in primary care in developing and transitional countries: Fact book summarizing results from studies reported between 1990 and WHO/EMP/MAR/ WHO Geneva, Available at: Accessed May 2,

84 Update on 2004 Background Paper, BP 7.1 Priority Medicines for Children Annex : WHO/INRUD prescribing indicators by prescriber type WHO - World Health Organization, INRUD - International Network for the Rational Use of Drugs EML Essential Medicines List Source: World Health Organization. Medicines use in primary care in developing and transitional countries: Fact book summarizing results from studies reported between 1990 and WHO/EMP/MAR/ WHO Geneva, Available at: Accessed May 2,

85 Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by MJC Willemen, FFT Ververs and HGM Leufkens Background Paper 7.2 Priority Medicines for Women By Justine M.Z. van Tongeren, Laurien A. Rook, Aukje K. Mantel-Teeuwisse Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands May 10, 2013 This Background Paper was commissioned by the WHO Collaborating Centre for Pharmaceutical Policy and Regulation ( This work was financially supported by the Dutch Ministry of Health, Welfare and Sport.

86 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table of Contents Executive summary and key research points Introduction Demographics and trends in medicines use General demographics of women s health Trends in the use of medicines Product related issues in women New medicines for women registered since Contraceptives: innovations and unmet needs Pain management in childbirth Regulatory aspects related to women Inclusion of women in clinical trials Birth defects and pregnancy registries Pregnancy prevention programmes (PPPs) Medicines use during lactation The usage environment Underutilisation of medicines in women Gender gap in drug dosing Access to emergency contraceptives Conclusion References Annexes Annex Pain management methods for women in childbirth Annex Elements of pregnancy prevention programmes of different medicines

87 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Executive summary and key research points Female health, and especially maternal health, has been one of the top priorities for health decision makers and health researchers over the past decades. Women not only use specific medicines related to (post)reproduction and pregnancy, but they also differ from men in their overall medicine use, pharmacokinetics, and pharmacodynamics. The 2004 Priority Medicines Report highlighted the knowledge and research gaps that existed with regards to female medicinal treatment, despite the particular attention being paid to women. This background paper follows on from and updates the 2004 Background Paper, discusses challenges and opportunities for improvement, and provides recommendations for further research. Demographics and trends in medicine use Global female life expectancy at birth increased from 61.2 years in 1970 to 73.3 years in 2010, and life expectancy is, on average, five years higher in women than in men. Fertility rates have decreased dramatically over the past 30 years, with the fertility rate in the European Union (1.59 births per woman in 2010) being lower than the global average (2.45 births per woman in 2010). In 2009, the mean age of women at first childbirth in the EU increased to 29.6 years. Maternal mortality has worldwide declined to 210 deaths per live births, but remains an area of concern. Low- and middle-income countries account for 99% of these deaths and large differences are noted between countries and regions. Within the EU, 1.2 million induced abortions are reported annually. This corresponds to 10.3 abortions per women, aged 15 to 49 years. The World Bank estimated that worldwide the proportion of women aged years using contraceptives increased from 58.1% in 1990 to 62.2% in 2010, but this progress has slowed down considerably. Particularly in certain regions, e.g. sub-saharan Africa, the unmet need for contraception is high. The two most popular forms of contraception are oral contraceptives (28%) and the male condom as single method (17%), with the copper intrauterine device (5%), and other forms of hormonal contraception, e.g. implants and patches, being less popular. Hormone replacement therapy (HRT) was widely used for treatment of menopausal symptoms, but its use declined considerably after the publication of two trials showing the harmful long-term effects of HRT in postmenopausal women over the age of 60 years. Product related issues in women New medicines have been developed and registered for several key conditions that only occur in or have a higher prevalence in women: for breast cancer, for the prevention of cervical cancer (HPV vaccine), for infertility, and for osteoporosis. In addition, new contraceptives (new active substances and new formulations) have been authorised and more products are under development. These new products may satisfy the ongoing need for efficacious, safe and convenient forms of contraception; however, the suitability of a contraceptive also depends on a woman s health condition. Important conditions to consider are, for example, lactation, epilepsy, diabetes mellitus, and mental illness. In order to increase the use of a suitable and effective form of contraception, providing adequate counselling is also much needed. However, current levels of counselling and aids do not 7.2-3

88 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women seem fully adequate, and there remains a need to improve knowledge and attitudes towards contraceptives, which will ideally lead to fewer unintended pregnancies. Such measures should be further explored and evaluated. Lack of knowledge by both health care professionals and women also seems to play a significant role in the existing burden of pain during labour, which also warrants further study. Regulatory aspects related to women Women have been under-represented in clinical trials but some improvements have been observed in recent years. The most recent FDA data ( ) show that the participation of women in late phase clinical trials was, on average, 44%. Of the new drug applications, 74% included exploratory or confirmative gender-specific efficacy and safety analyses. In early phase clinical trials, the participation of women was slightly lower. In 2005, the European Medicines Agency concluded that there was no need for separate guidelines to ensure that gender specific effects are investigated. The exclusion of pregnant women from virtually all clinical trials leads to a situation in which there is little information on the safety of medicines in pregnancy; 97.7% of medicines approved by the FDA between 2000 and 2010 have an undetermined teratogenic risk, and data on the benefits and risks of use in pregnancy are absent in 73.3% of medicines. Furthermore, despite the recommendation against the use of drugs in the absence of a pregnancy safety profile, at least one prescription medication is used by half of pregnant women. An important method for collecting pregnancy safety data is the use of birth defect or pregnancy registries. International birth defect registries are very large and their data are less prone to regional bias due to their international nature. The major disadvantage is that most of the data are collected retrospectively; therefore, the information on pregnancy exposures is limited and varies greatly. These disadvantages have been overcome with the more recent development of pregnancy registries; but challenges still remain, including, among others, variations in strategies and definitions, which hampers the pooling of data, and the lack of power to detect small increases in risks. Moreover, more attention should be paid to the effects of paternal medicine use, the longterm effects of medicine use during pregnancy (such as fertility and behavioural problems), the effects of medicine use on fertility and very early spontaneous abortion, and opportunities to collect data on medicine use during lactation. Finally, it is crucial to clearly communicate the available information on teratogenic risks. Pregnancy Prevention Programmes (PPPs) have been developed and implemented to manage the potential risks of medicines that should be avoided during pregnancy, because the benefits of use in women do not outweigh the risks for the foetus. Currently, PPPs exist for seven medicines that are licensed in the EU. The first PPP was developed in 1988 for isotretinoin and it has been updated several times over the past years. Despite increased vigilance, pregnancies still occur in women using isotretinoin ( per 1000 women of childbearing potential using this medicine in the EU). These programmes have been criticised for this failure, for reducing access, and for ethical reasons. In order to resolve problems concerning adherence, effectiveness, and the additional burden to both patients and health care providers, it is crucial that each element of current and future PPPs is carefully evaluated by its users. The fundamentals of a PPP have to, therefore, be defined

89 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women The use of medicines in women Gender differences in health related indicators have been identified and often show a strong bias against women. A recent study focusing on gender differences in medicine use demonstrated that women with cardiovascular disease were less likely to take antiplatelet drugs (19.8% versus 32.8%), β blockers (17.4% versus 23.9%), ACE inhibitors or angiotensin receptor blockers (16.0% versus 24.6%), and statins (10.5% versus 23.8%). Other studies, however, have shown that although gender differences may occur, there is no consistent bias towards women. Some cases have shown that, in certain settings, disease areas and/or age categories, men were more disadvantaged with respect to medicine prescribing than women. These results highlight the need for continuous monitoring of gender-specific treatment patterns. The recent zolpidem case in the United States highlighted the fact that a medicine s benefitrisk balance may be gender-specific: women eliminate zolpidem slower from their bodies than do men, which may lead to an increased risk of adverse drug events. Pharmacokinetics and pharmacodynamics are determined by physiological processes, which differ between women and men in numerous ways. Gender based dosing differences are rare since pharmacokinetic differences, as reported in clinical trials, are often considered not clinically relevant. Gender effects can, however, be caused by differences in pharmacokinetics and pharmacodynamics, and it is therefore desirable that there be sufficient information on both. Effective models to determine these effects for medicines that have been on the market for long periods of time, as well should be developed. The use of emergency contraception (EC) finally warrants further attention. Currently, ECs are registered in 149 countries and are available without a prescription in 64 countries, of which six countries (Canada, Norway, Sweden, the Netherlands, India and Bangladesh) allow direct access `over the counter. There has been no decrease in unintended pregnancies despite a change in prescription status in many countries. A lack of knowledge in both women and health care providers is a current barrier to the use of emergency contraception. Schools, pharmacists, and doctors should be educated to inform women about emergency contraceptives, yet it still remains to identify and involve other information sources in the counselling process. The further determination of the influence of other factors on EC use is still needed, and measures to modify these influences should be researched. In summary, the following key research priorities for women have been identified: Use existing (real life) data to its full potential Use of existing data and the development of (innovative) methodological approaches for better use of these data should be explored. Existing data will most likely provide more insight into gender-specific benefit-risk profiles of medicines, and also those related to dosing, and gender-specific underutilisation of medicines. Alignment with similar initiatives for the improved use of existing data in elderly and children is recommended. Pregnancy registries should be further strengthened, and collaborations between these registries, e.g. in a research network, should be stimulated. Attention should be paid to the effects of paternal medicine use, the long-term effects of medicine use during pregnancy (such as fertility and behavioural problems), 7.2-5

90 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women effects on fertility and very early spontaneous abortion, and opportunities to collect data on medicine use during lactation. Strengthen informed decision making by women Improve knowledge and attitudes toward (emergency) contraceptives by stimulating better education of women, doctors and pharmacists Develop and evaluate improved patient counselling and aids, especially for young women and women with co-morbidities Assess the impact of strategies to achieve better knowledge levels, also with regards to important health outcomes such as unintended pregnancies (for contraception) and the burden of pain during labour (for pain management) More research is needed to establish how the risks of parental drug use can be effectively communicated to patients and health care professionals and to assess the effects of communication on their behaviour. Fundamentals of PPPs should be discussed with all stakeholders and further alignment of PPPs for different products should be explored. Adequate parameters to evaluate PPPs need to be determined in order to monitor their (future) effectiveness, burden and adherence to these PPPs

91 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women 1. Introduction Female health, and especially maternal health, has been one of the top priorities for health decision makers and health researchers over the past few decades. Millennium Development Goal 5 (MDG5) is, for example, dedicated to the improvement of maternal health, and target 5B is to achieve universal access to reproductive health by On average, when it comes to the use of medicines, women use more than men, starting as early as the age of ten. 2 The 2004 Priority Medicines for Europe and the World report concluded that, despite particular attention being paid to women, and therefore surprisingly, gaps existed in knowledge and research related to female medicinal treatment. The inclusion of women in clinical trials, appropriate risk management strategies to monitor the long-term effects of female medicine therapies, and the collection of data on birth defects and susceptible exposures at an international level were identified as key priorities for research. 3 This background paper follows on from and updates the 2004 Background Paper, which covered the following four areas: 1. Reproduction control (pharmacological contraceptives) 2. Female subfertility 3. Pregnancy and lactation, including birth defects and teratogenicity 4. Post-reproduction hormones (e.g. hormone replacement therapy) This updated background paper addresses the four original areas, but as a cross-cutting paper focuses on general issues related to the special needs of women as well. As such, this paper complements the other background papers of this report; cross references to the other background papers are provided wherever this was deemed useful. The background paper starts with an overview of general demographics and medicine use in women. Section 3 describes the developments in product related issues, such as the range of contraceptive methods and opportunities for the management of pain during labour, whereas Section 4 focuses on regulatory aspects in women, including the top priorities as identified in In Section 5, topics related to medicine use in women in daily medical practice are presented. Finally, remaining and new knowledge gaps, as well as implications for future research, are discussed in Section 6; an overview of the items and subjects related to women that need more attention in the near future is also given. 2. Demographics and trends in medicines use This section describes the general demographics of women s health and trends in the use of medicines, covering the areas of reproductive control including emergency contraception, female subfertility, and post-reproduction hormones. For more detailed information on general demographics, the reader is kindly referred to the background paper to Chapter 5 of the 2013 Priority Medicines report

92 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women 2.1 General demographics of women s health Over the past few decades levels of mortality have been changing and overall life expectancy has increased continuously. Global female life expectancy at birth increased from 61.2 years in 1970 to 73.3 years in The global male life expectancy at birth is lower and increased from 56.4 years in 1970 to 67.5 years in The greater increase in the female life expectancy widened the gap between the sexes from 4.8 years in 1970 to 5.7 years in Life expectancy has increased for all age groups of both sexes over the past four decades. In 2010, Japanese women had the highest global life expectancy at birth of 85.9 years. In 2010, female life expectancy in Western Europe, Central Europe and Eastern Europe was 83.2, 79.2, and 74.9 years respectively. The lowest life expectancy for women at birth can be found in countries such as Haiti (43.6 years), the Central African Republic (49.3 years), Lesotho (50.7 years), and Swaziland (51.4 years). 4 The female life expectancy at birth in 2010 per country is shown in Figure Substantial improvements (more than a 20 year increase from 1970 to 2010) in female life expectancy at birth occurred in the Maldives, Bangladesh, Bhutan, Iran, Peru, Guatemala, and Oman. Life expectancy at birth declined from one to seven years in Zimbabwe and Lesotho, due mainly to the HIV/AIDs pandemic. 4 The percentage decline in death rates from 1970 to 2010 was over 60% for both sexes in the age group up to nine years. In the age group of years, female death rates generally declined by 40-50%. Within this group, the decline of the age group of years was lower and most likely due to the rise of HIV/AIDS. The percentage decline in mortality for women aged years ranged from 40% to 43%. The decline in mortality in men was lower than for females in all age groups. 4 Globally total fertility rates (defined as the number of children that would be born to a woman if she were to live to the end of her childbearing years and bear children in accordance with current age-specific fertility rates) have dropped from 4.73 births per woman in 1970 to 2.45 births per woman in The fertility rate in the European Union was lower than the global average at 1.59 births per woman in The global adolescent fertility rate was births per women aged years in The adolescent fertility rate in the European Union was much lower at births per women in Within the entire EU the mean age of women at first childbirth increased from 28.0 years in 1998 to 29.6 years in Prevalent causes of death differ between sexes, age groups, and global regions. Sex differences are evident within the age range of years, with injuries being more prevalent in men and maternal causes, approximately 10.7% of total deaths in 2010, making a significant contribution to death in women. 8 Globally, the leading cause of death in women aged years (the reproductive age) is HIV/AIDS, followed by cardiovascular disease, maternal disorders, self-harm, tuberculosis, breast and cervical cancer, digestive diseases, and cirrhosis. 8 In post-menopausal women, the leading non-communicable diseases are the main causes of death, in particular cardiovascular disease and neoplasms

93 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure Female life expectancy at birth in 2010 Source: Wang H et al. Age-specific and sex-specific mortality in 187 countries, : a systematic analysis for the Global Burden of Disease Study Lancet, 2012; 380(9859): One of the United Nations (UN) Millennium Development Goals aims to reduce the maternal mortality ratio and achieve universal access to reproductive health by Causes of maternal death are, for example, unsafe abortion, (postpartum) haemorrhage, sepsis, hypertensive disorders during pregnancy, obstructed labour, and other causes. Maternal death rates differ per global region and are particularly high in Southern, Eastern, Western and Central sub-saharan Africa, and Oceania. 9 This is shown in Figure The World Bank estimates that the global maternal mortality ratio (the number of women who die during pregnancy and childbirth) was 210 deaths per live births in In 1990, the global maternal mortality ratio was 400 deaths per live births. Low- and middle-income countries account for 99% of the global maternal deaths, and the maternal mortality ratio in these regions (240 deaths per live births) was 15 times higher than in the developed regions (16 deaths per live births). 10 When an unwanted pregnancy occurs the pregnancy can be aborted. However, it is essential for the woman s health that this is done in a safe manner (i.e. in accordance with the current WHO standards), as an unsafe abortion can result in severe morbidity and death. 11 In 2008, approximately one in five pregnancies ended in an induced abortion worldwide. Of all induced abortions, an estimated 22.2 million were safe and 21.6 million were considered unsafe. Induced abortions occur in all regions of the world, but almost all (98%) unsafe abortions take place in low- and middle-income countries. 11,12 In the developed world, 6% of all abortions are unsafe, compared with 56% in low- and middle-income countries

94 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure 7.2.2: Death rates (per deaths) due to maternal disorders in year old women per global region. Source: Global Burden of Disease 2010 database. Visualisation of GBD 2010 patterns by broad cause group. Picture created by Laurien Rook. Set parameters: 2010, Female, Rate, Deaths, All ages (data for maternal disorders limited to years old), Maternal disorders, Region Available at Accessed April 15, Another reproductive health issue is the inability to conceive a child. In 2010, global primary infertility (defined as the absence of a live birth for women who desire a child and have been in a union for at least five years, during which they have not used any contraceptives) and secondary infertility (defined as the absence of a live birth for women who desire a child and have been in a union for at least five years since their last live birth, during which they have not used any contraceptives) were estimated at 1.9% and 10.5%, respectively. The absolute number of couples affected globally by infertility in 2010 was approximately 48.5 million. Primary infertility prevalence is higher among younger women, 2.7% in women aged years versus 1.7% in women aged years. The prevalence of secondary infertility increases sharply with age, 2.6% in women aged years versus 27.1% in women aged years. The prevalence of infertility was highest in South Asia, sub-saharan Africa, North Africa/Middle East, Central/Eastern Europe, and Central Asia Trends in the use of medicines Part of the Millennium Development Goal 5 is to increase access to contraceptives. Contraceptives are crucial for family planning and could improve maternal health and

95 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women reduce the number of maternal deaths. 14 The risk of maternal mortality is highest for adolescent girls and increases with each pregnancy. 15 The World Bank estimates that the global contraceptive prevalence (the percentage of women (aged 15-49) who are practicing, or whose sexual partners are practicing, any form of contraception) increased from 58.1% in 1990 to 62.2% in A large survey of women of reproductive age (15-49 years) in 14 European countries (Spain, Italy, United Kingdom, France, Germany, Sweden, Denmark, Norway, the Czech Republic, Austria, Estonia, Latvia, Lithuania and the Russian Federation) revealed that between 21-30% of these women did not use any form of contraception. The most popular forms of contraception used were oral contraceptives (OCs, `the pill ) by 28% of women, followed by the male condom as single method (17%), the copper intrauterine device (5%), and the progestin-releasing intrauterine system (3%). Other forms of hormonal contraception, i.e. implants, patches, injectables, and the vaginal ring, were less popular, and each form was used by 1% of women respectively. 17 The use of contraceptives by women has increased since the 1990s, but this progress has slowed down considerably. The use of contraceptives remains low in sub-saharan Africa and Oceania. The unmet need for contraception is high in sub-saharan Africa in particular. One in four women, aged years and in a marriage or a union, expressed a desire to use contraceptives, but had no access to them. 14 Globally, approximately 215 million women would prefer to delay or avoid childbearing, but cannot due to a lack access to safe and effective contraception. 15 Less research is available on the prevalence of emergency contraception use in Europe. A survey among 754 southern Italian women (average age 19.5 years) indicated that 16% had previously used hormonal emergency contraception, and three per cent had used it more than once. 18 A Spanish study of women (median age 26 years) seeking abortion showed that 16% of these women had occasionally resorted to emergency contraception. 19 Survey data from a United States national database showed that 10% of women had ever used emergency contraception. 20 Within the EU, induced abortion is not legal in Ireland and Malta, and Poland has very restrictive access to induced abortion. Annually, 1.2 million induced abortions are reported in the EU, corresponding to 10.3 abortions per women aged years. The lowest prevalence of induced abortions occurred in Germany and Greece (6/1 000 women of reproductive age); and Belgium, the Netherlands and Portugal (7.5/1 000 women of reproductive age). Estonia, Romania and Bulgaria had the highest prevalence of induced abortions (20 or more per women of reproductive age). No data on the method of abortion, e.g. medical (induced by pharmaceuticals such as mifepristone in combination with misoprostol) and surgical, were provided. 7 Data from the U.S. Centers for Disease Control and Prevention (CDC) indicate that approximately 15% of all abortions in the United States are medical abortions. 21 Assisted reproductive technologies (ART) are an important part of infertility treatment. Data on percentages of ART births per national births were collected within the EU in The highest percentages were seen in Denmark (4.1%), Slovenia (3.6%), Belgium (3.3%), Finland (3.3%), Sweden (3.3%), and the Netherlands (2.4%). The lowest rates were seen in Italy (1.0%), Estonia (0.9%), and Malta (0.54%). 7 Other data on trends in the use of ART are lacking. Hormone replacement therapy (HRT: e.g. oestrogens with or without progestagens) were widely used for the treatment of menopausal symptoms, but are no longer in use as a first

96 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women line therapy due to the increased risk of cardiovascular diseases, cerebrovascular accidents, venous thrombo-embolism, dementia, and breast cancer in the relatively older group of patients included in the trials (those over 60 years). 22 A Dutch study in 2005 showed that the prevalence of HRT prescribing decreased after the publication of two trials showing the harmful long-term effects of HRT. In 2000, HRTs were prescribed to 107 users per women aged 45 to 69 years, which decreased to 87 users per women in this age category after the publication. 23 A second study in the Netherlands showed that a prescription for HRT as the treatment of choice for menopausal symptoms decreased from 37% in 2002 to 4% in 2004, which was then however followed by an increase in 2006 (13.5%). 24 A recent study in the USA showed a similar decrease in the use of HRT. In the period from , use of HRT was reported by 22.4% of women aged 40 years and older. The prevalence dropped to 11.9% in and was followed by a further decrease to 4.7% in More recently, the International Menopause Society and the North American Menopause Society have stressed that re-analyses of the older studies by women s age showed a more favourable benefit-risk balance in patients aged years Product related issues in women Many new medicines for women, including new contraceptive methods, have come onto the market since Despite the still increasing range of contraceptive methods, opportunities for improvement exist related to products, as well as to the making of (informed) choices. The management of pain during labour, for which different methods and formulations exist, is also covered in this section. 3.1 New medicines for women registered since 2004 An overview of medicines for women that have been registered with the European Medicines Agency (EMA) since the previous report in 2004 is presented in Table The overview includes medicines for conditions that only occur or have a higher prevalence in women. Breast and cervical cancer The development of medicines for breast cancer and cervical cancer is important since these types of cancer are among the leading causes of death in women worldwide (see also the background paper belonging to Chapter 6.5 on Cancer). 27 Breast cancer (along with other types of cancer) is seen more and more as a group of distinct diseases with subtypes, and these subtypes can, in the case of breast cancer, contain specific growth receptors, such as oestrogen- and HER2-receptors. 28 Medicines that block these specific growth receptors can and have been designed, such as fulvestrant, which is an oestrogen-receptor blocker, for example. 29 The identification of biomarkers in subtypes of diseases allows for the design of more specific and successful treatments

97 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Contraception and fertility The benefits of effective contraception speak for themselves. The registration of Zoely adds another choice to the spectrum of contraceptives. This product consists of nomegestrol acetate and estradiol. Nomegestrol has such potent effects on the endometrium, that the lighter oestrogen estradiol can be used without losing cycle control. Estradiol may increase coagulation factors less than ethinylestradiol, the oestrogen that is used more often in oral contraceptives. However, the (absence of a) relationship with thrombosis, remains to be determined for estradiol. 30 The new emergency contraception ulipristal acetate provides the convenience of using a tablet instead of having an intrauterine device placed when intercourse has taken place four to five days earlier. The other emergency contraception pill levonorgestrel is only effective up to three days after intercourse, although new data suggest that it may be effective up to five days after intercourse. 31 The need to control the ability to become pregnant is as strong as the need for effective contraception. Infertility can cause a deep sense of failure. 32 Medicines to treat infertility like Pergoveris (follitropin alfa and lutropin alfa) and Elonva (corifollitropin), registered in 2007 and 2010 respectively, have the advantage that the number of injections required for treatments can be reduced. Pergoveris is a combination of two medicines that were already registered, while Elonva is a longer acting follicle stimulating hormone (FSH) analogue. Table 7.2.1:Medicines for women registered at the EMA since previous Priority Medicines report in Medicine ( ) Date of registration Indication Additional requirements Neoplasms - benign and malignant tumors Halaven (eribulin) March 2011 Advanced/metastatic breast cancer Tyverb (lapatinib) June 2008 HER2-positive breast cancer Two previous treatments for advanced cancer including an anthracycline and taxane unless these were not suitable Combined with capecitabine in advanced or metastatic cancer after treatment including an anthracycline and taxane and following treatment with trastuzumab Combined with an aromatase inhibitor in post-menopausal women that have metastatic cancer Abraxane (paclitaxel) January 2008 Metastatic breast cancer Previous treatment includes an anthracycline Faslodex (fulvestrant) March 2004 Oestrogen-receptorpositive Postmenopausal women advanced/metastatic breast cancer Previous anti-oestrogen treatment Avastin (bevacizumab) January 2005 Metastatic breast cancer Breast cancer: combined with paclitaxel or capecitabine First occurrence of or advanced epithelial cancer of the ovary, cancer of the fallopian tube or peritoneum Ovary/fallopian tube/peritoneum cancer: combined with carboplatin and gemcitabine

98 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Esmya (ulipristal acetate) February 2012 Treatment of moderatesevere symptoms of uterine fibroids Premenopausal women Gardasil vaccine - also known as Silgard (human papilloma virus vaccine) September 2006 Prevention of precancerous lesions in the genital area, cancer of the cervix and external genital warts caused by certain types of human papillomavirus Contraception / fertility Zoely (nomogestrol/estradiol) EllaOne (ulipristal acetate) July 2011 May 2009 Contraception Emergency contraception Elonva (corifollitropin) January 2010 Fertility treatment to Pergoveris (follitropin alfa and lutropin alfa) June 2007 stimulate the development of more than one mature egg at a time in the ovaries Fertility treatment to develop a follicle Use within 120 hours of unprotected sex or contraceptive failure Combined with a gonadrotrophinreleasing hormone antagonist Postmenopausal osteoporosis Prolia (denosumab) February 2010 Osteoporosis Vantavo/Fosavance/ Adrovance (alendronic Vantavo March 2010 Osteoporosis Women are at risk of low vitamin D levels acid and colecalciferol) Fosavance August 2005 Adrovance January 2007 Conbriza (bazedoxifene) April 2009 Osteoporosis Protelos/Osseor (strontium ranelate) September 2004 Osteoporosis Other conditions highly prevalent in women Benlysta (belimumab) July 2011 Lupus erythematosus (SLE) Yentreve (duloxetine) August 2004 Stress urinary incontinence Kentera (oxybutynin) June 2004 Urge incontinence, increased urinary frequency and urgency Positive autoantibody test Highly active disease despite standard treatment Overactive bladder

99 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Postmenopausal osteoporosis The prevalence of postmenopausal osteoporosis is 34%. The incidence and economic burden of osteoporosis-related fractures (including male osteoporosis) in the United States are estimated to be 2 million fractures at a cost of 17 billion US dollar for 2005 and is even projected to be 150% higher in These numbers emphasise the need for an adequate treatment of osteoporosis. Among the medicines that have been registered with the EMA for postmenopausal osteoporosis are medicines with a mode of action that is different from existing treatments for osteoporosis. Currently, bisphosphonates are considered to be the most cost-effective; 34 however, they can frequently cause serious side effects, such as esophagitis 35 and osteonecrosis of the jaw. 36,37 When these or other harmful side effects occur, medicines with other modes of action (e.g. strontium ranelate or denosumab) may offer a possible solution. 38, Contraceptives: innovations and unmet needs Current data indicate that in 2006 half of all pregnancies in the USA were unintended. 40 It was estimated in 2001 that half of all unintended pregnancies occurred in women using contraceptives. 41 Only 10% of unintended pregnancies during contraceptive use are caused by method failure; the remaining 90% are caused by inconsistent or incorrect method use. An important factor in inconsistent use is the lack of complete satisfaction with the method used for contraception. 42 Factors leading to discontinuities are cultural factors, misconceptions about safety, and fear of side effects. 43 Measures to influence these factors can be categorized into product specific measures and measures that improve knowledge and attitudes toward contraceptives. Table 7.2.2: Characteristics of new contraception products under development in clinical studies. Substance Administration form Potential benefits Oestradiol or estetrol Oral tablet (oestradiol and estetrol) Vaginal ring (oestradiol) Transdermal gel Ulipristal acetate Oral tablet Vaginal ring Nestorone Implant Vaginal ring Transdermal spray Transdermal gel Use of these oestrogens may reduce risk of venous thromboembolism and other side effects due to a reduced influence on haemostasis, lipids and carbohydrate metabolism compared to ethinylestradiol. 44,45 The gel is a new administration form that may be more user-friendly. 46 This progesterone receptor modulator has convenient amenorrhoeic effects. 43,47 Nestorone has no effect on infants when it is used by the mother because it is extensively metabolized when orally administered. 48,49 Nestorone has no effects on lactation 49 and may have neuro-protective effects. 50 Sprays and gels are new administration forms that may be more user-friendly. Levonorgestrel + tenofovir Vaginal Prevents both pregnancies and HIV transmission. 43 Source: Sitruk-Ware R et al. Contraception technology: past, present and future. Contraception 2013; 87(3):

100 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Product specific measures include (1) improvement of safety, (2) improvement of efficacy, (3) improvement of convenience, and (4) maximizing secondary benefits. Secondary benefits that may occur in some of the currently available contraceptives are reducing (risks of developing) menstrual bleeding, acne, fracture risks, certain types of cancer and iron deficiency, for example. 43,,51 Products that may have better safety and efficacy profiles and that are more convenient to use are under development. These favourable properties may be achieved by using newer hormones and/or newer administration forms. Examples of products under development are presented in Table The contraceptive effects of these new products are promising, but safety profiles need to be carefully evaluated as safety remains a sensitive subject. Just recently, the safety of Diane - 35 (containing cyproterone acetate and ethinylestradiol) and its generic equivalents have come under scrutiny due to an analysis of existing data from the French national pharmacovigilance database, which include reports of venous and arterial thromboembolism. The French National Agency for Medicines and Health Products Safety (ANSM) has proposed the suspension of the marketing authorisation for Diane - 35and its generics for a period of three months and the European Medicines Agency s Pharmacovigilance Risk Assessment Committee (EMA s PRAC) formally started a safety review of Diane - 35 and its generic equivalents as a reaction to ANSM s proposal. 52 The suitability of a contraceptive may depend on the health condition a woman. For example, lactating women cannot use oestrogens because this interferes with breastfeeding. A number of comorbidities/risk factors prompt the use or avoidance of specific contraception methods (Table 7.2.3). A study of women with epilepsy showed that 47% of the women used ineffective contraception methods. Of the 21 women using normally effective hormonal measures, six concomitantly used anti-epileptics that can reduce contraceptive efficacy by inducing the metabolism of the hormones. Moreover, half of the pregnancies that had occurred were unplanned. 53 In another study, women with diabetes were less likely to have received documented contraceptive counselling, prescriptions, or services than women without chronic conditions. Women with diabetes were more likely to have undergone sterilization, but were less likely to have received effective contraceptives such as intrauterine devices. 54 These examples stress the fact that there is a need for more contraceptive counselling, the provision of additional options, and further use of effective contraception in women with comorbidities. Women obtain information on contraception from healthcare professionals (52-71%), the internet (13-39%), friends/family/partner (20-35%), articles/advertisements/books (9-23%), brochures in doctors waiting rooms (10-29%), and family planning organizations/clinics (1-17%). 55,56 Despite the wide use of reliable information sources, myths about side effects (e.g. mood swings) still exist. 56 Moreover, women do not associate long-acting reversible contraceptives (LARCs, e.g. intrauterine devices and implants) with the benefits that are recognized in other methods. While LARCs have shown to be more effective than contraceptive pills, patches, or rings 57, they are not often used in daily practice (see also Section 2.2). In the United States 8.5% of women using contraceptives reported using LARCs in In general, methods that are new to women raise concerns about potential side effects and other problems. 58 Therefore, it is necessary to better inform women and help them in choosing an effective contraceptive. Doctors have the most influence on a woman s choice of

101 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women contraceptive (59-78%), followed by their partner (14-24%). Partners should consequently be involved when women are obtaining information and receiving contraceptive counselling. A method that has been shown to help in the choice of an effective and suitable contraceptive is the use of a computer-based module. 55 Current counselling and aids, however, do not seem fully adequate, and there remains a need for additional measures to improve knowledge and attitudes towards contraceptives, which hopefully lead to fewer unintended pregnancies. Table 7.2.3: Methods to consider and to avoid for different comorbidities. Comorbidity or risk factor Methods to consider Methods to avoid Depression Combination OCPs; Depo-Provera (longacting injectable); Implanon (single-rod implantable device); Mirena (levonorgestrelcontaining intrauterine system); Nuvaring (ring); Ortho Evra (patch); progestin-only OCPs Diabetes mellitus with complications Depo-Provera ; Implanon ; Mirena ; progestin-only OCPs Epilepsy treated with medications that induce hepatic enzymes: Carbamazepine; lamotrigine*; oxcarbazepine; phenobarbital; phenytoin; primidone; topiramate (more than 200 mg per day) Epilepsy treated with medications that do not induce hepatic enzymes: Acetazolamide; benzodiazepines; ethosuximide; gabapentin; levetiracetam; pregabalin; tiagabine; valproic acid ; vigabatrin; zonisamide History of bariatric surgery (malabsorptive procedure) History of bariatric surgery (restrictive procedure) Depo-Provera ; Mirena Combination OCPs; Depo-Provera ; Implanon ; Mirena ; Nuvaring ; Ortho Evra ; progestin-only OCPs Depo-Provera ; Implanon ; Mirena ; Nuvaring ; Ortho Evra Combination OCPs; Depo-Provera ; Implanon ; Mirena ; Nuvaring ; Ortho Evra ; progestin-only OCPs History of VTE/pulmonary embolism Depo-Provera ; Implanon ; Mirena ; progestin-only OCPs Inflammatory bowel disease (mild) Combination OCPs; Depo-Provera ; Implanon ; Mirena ; Nuvaring ; Ortho Evra ; progestin-only OCPs Migraine headaches with aura Depo-Provera; Implanon; Mirena; progestinonly OCPs Poorly controlled hypertension Depo-Provera ; Implanon ; Mirena ; progestin-only OCPs Rheumatoid arthritis (in patients taking immunosuppressants) Combination OCPs; Implanon ; Mirena ; Nuvaring ; Ortho Evra ; progestin-only OCPs Smoking and age older than 35 years Depo-Provera ; Implanon ; Mirena ; progestin-only OCPs Combination OCPs; Nuvaring ; Ortho Evra Combination OCPs; Implanon ; Nuvaring ; Ortho Evra ; progestinonly OCPs Combination OCPs; progestin-only OCPs Combination OCPs; Nuvaring ; Ortho Evra Combination OCPs; Nuvaring ; Ortho Evra Combination OCPs; Nuvaring ; Ortho Evra Depo-Provera Combination OCPs; Nuvaring ; Ortho Evra Stroke Depo-Provera ; Implanon ; Mirena ; Combination OCPs;

102 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Comorbidity or risk factor Methods to consider Methods to avoid Systemic lupus erythematosus with antiphospholipid antibodies progestin-only OCPs Depo-Provera ; Implanon ; Mirena ; progestin-only OCPs Nuvaring ; Ortho Evra Combination OCPs; Nuvaring ; Ortho Evra OCP = oral contraceptive pill; VTE = venous thromboembolism. * Lamotrigine is not a typical enzyme-inducing antiepileptic, but it may reduce the concentration of progesterone. Combination OCPs may reduce concentrations of valproic acid and breakthrough seizures may occur. The risks of combination OCPs, Nuvaring, or Ortho Evra use may outweigh the benefits in women with inflammatory bowel disease who are at increased risk of VTE. The risks of Depo-Provera use may outweigh the benefits in women on long-term corticosteroid therapy with a history of or risk factors for non-traumatic fractures. Information from references 6, and 8 through 13. Source: Bonnema R, McNamara M, Spencer A. Contraception choices in women with underlying medical conditions. Am Fam Physician 2010;82(6): In conclusion, there is still a need for more efficacious and convenient contraceptives, and optimal safety is one of the greatest challenges in the development of contraceptives. Only time and extensive research can tell whether the products currently under development will bring better efficacy, safety, and convenience. Possibilities to improve knowledge on contraceptives and to increase the use of LARCs should be further explored. These recommendations are more stringent with regard to women with comorbidities, since contraceptive use and counselling lag behind in this group. When improvements in products and the making of an (informed) choice are achieved, a significant reduction in unintended pregnancies can be accomplished, which can contribute to Millennium Development Goal 5: improving maternal health. 1 Male contraceptives Men play an increasing role in family planning. The current contraceptive options for men are vasectomy and condoms. Vasectomy may not be completely reversible, which is the largest disadvantage of this contraceptive method. Condoms may not provide enough protection; 1% of women became pregnant within six months when using condoms consistently, while inconsistent used resulted in 7% of women becoming pregnant within six months. Nowadays men seem more willing to take hormonal contraceptives, 60,61 while at the same time the experience of women is that too much of the responsibility for preventing pregnancy lies with them. 62 The use of male contraceptives enhances gender equality by sharing the risks of contraception, as well as sharing the responsibility for the prevention of pregnancy. 63 Different strategies for male contraception have been examined. The elements of the ideal male contraceptive are presented in Table

103 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table 7.2.4: Elements of the ideal male contraceptive. Elements of the ideal male contraceptive Application independent of sexual act Acceptable to both partners No interference with libido, potency, or sexual activity No short- or long-term toxic side effects No impact on eventual offspring Rapid effectiveness and full reversibility Efficacy comparable to female methods Source: Nieschlag E. Male hormonal contraception. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology 2010(198): In order to prevent pregnancy, multiple targets for male contraception can be identified. Figure illustrates these targets and presents agents that can potentially influence those targets, thus preventing pregnancy. Non-hormonal methods have not (yet) been shown to be effective. 64 Anti-sperm vaccines (not displayed in Figure 7.2.3) are also suggested as male contraceptives. 65 However, the effects of the vaccines cannot be reversed. Their only advantage over vasectomy is that the vaccines do not require surgery. The only agents presented in Figure that have shown potential are steroids and GnRH analogues. The Cochrane Collaboration recently performed a systematic review on the effectiveness of male hormonal contraceptives. They concluded that the combination of a progestin (desogestrel, etonogestrel or levonorgestrel) with testosterone is the best option to achieve azoospermia (no detectable sperm). 64 A factor that limited the systematic review is that the trials used different definitions of oligozoospermia (diminished sperm counts). The best outcome measure is the occurrence of pregnancy, but oligozoospermia can be used as an intermediate outcome measure to determine effectiveness in smaller, shorter trials. Recommendations on oligozoospermia definitions and other factors in male contraception research are presented in Table

104 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure 7.2.3: Agents that act on the male reproductive system, thereby potentially preventing pregnancy, and their targets. Source: Cheng CY, Mruk D. Male contraception: Where do we go from here? Spermatogenesis 2011;1(4): Recently, the development of male hormonal contraceptives has been set back. A phase IIb trial determining the safety and efficacy of testosterone undecanoate combined with the progestin norethisterone enanthate was discontinued after the WHO review panel determined that the potential risks might outweigh the potential benefits. 67 Although the exact reasons for discontinuation remain unpublished, the discontinuation of such an important trial in the history of developing male hormonal contraception may have a detrimental effect on the future of male hormonal contraception

105 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table 7.2.5: Recommendations for male contraception studies 1. Phase 2 studies evaluating efficacy should use WHO sperm concentration parameters and the goal should be suppression to 1 million sperms per millilitre 2. After cessation of therapy, patients need to be followed until normal fertility is restored (criteria used is 20 million sperms per millilitre ) 3. Inclusion criteria must include men with sperm concentrations above 20 million per millilitre 4. Open-label, non-comparative contraceptive efficacy studies are acceptable if the primary end point is not susceptible to bias, e.g. pregnancy rate 5. For efficacy, two independent phase 3 trials for one year from suppression to less than one million per millilitre should include 200 men/couples per trial 6. For safety, new agents require studies in men for six months at the intended combination and dose, 100 men exposed for one year and 1500 men in phase 1-3 studies at a minimum 7. Long-term safety will be monitored by post-marketing surveillance 8. Laboratory data need to be performed under strict quality control Source: Nieschlag E. 10th Summit Meeting consensus: recommendations for regulatory approval for hormonal male contraception. October 22-23, Contraception 2007;75(3): Pain management in childbirth Childbirth pain is a complex and subjective experience. It has a sensory (physical) and an affective component and is determined by multiple factors. 70 Sensory factors include the position of both the infant and the mother, intensity of contractions, fatigue level, physical trauma, and whether or not this is a woman`s first birth. Examples of affective factors are prior experience, culture and ethnicity, fear, emotional support, and emotional trauma. 71,72 The perceptions of pain during childbirth vary from painless to the most excruciating pain of one s life. 72 The experience of intense pain can result in a positive memory based on a sense of accomplishment in having dealt with it, or it can cause trauma. 71 Although not clearly established in humans 73, endogenous opioids are produced during parturition in response to pain in rats. 74 Since women s experiences of pain sometimes result in trauma, endogenous opioid production seems to be insufficient in some cases, even if it does exist. It is therefore desirable to maximize this process and/or reduce the pain through other methods. The Cochrane Collaboration has recently published an overview of their systematic review of pain management for women in labour. 72 The results are summarized in Annex Some of the methods are based on pharmacological interventions, such as the widely used epidural analgesia. Other methods are based on the release of endogenous opioids, the suppression of neural activity, gaining (a sense of) control over one s body, or by gate control. The gate control theory suggests that stimulation of sensory touch nerve fibres (e.g. by massage) can inhibit the transmission of pain. Epidural, combined spinal epidural, and inhaled analgesia are regarded as effective in managing pain during labour, but can cause side effects. There was conflicting or limited evidence on the efficacy of hypnosis, immersion, relaxation techniques, acupuncture, massage/reflexology, non-opioids, and local anaesthetic nerve blockers. The lack of evidence on biofeedback, sterile water injections, aromatherapy, TENS, and opioids did not allow for a judgement of their efficacy to be made. 72 In general, more high quality trials are needed. One of the major problems addressed by the Cochrane Collaboration is that the outcome measures used in these studies differ. The outcome measures used in the Cochrane s

106 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women overview that were agreed upon after widespread consultations should be used in future research to enable the pooling of results of similar studies. It is important to evaluate the extent to which women still experience pain during labour. Problems can be caused by the insufficient efficacy of current pain management methods, the availability of these methods and/or a lack of knowledge by both health care professionals and women. When the magnitude of the burden and its causes are assessed, a strategy to minimize the burden should be designed and implemented. 4. Regulatory aspects related to women The major gaps related to medicine use in women that were identified in the 2004 report were related to regulatory aspects. The report concluded that `There are still various gaps in knowledge and research related to female drug treatment that have been identified. These include (1) females are frequently excluded from clinical trials and other types of medical research because of complexity issues related to reproduction and hormone cycles; (2) most typical female drug therapies are long-term (e.g. oral contraceptives, hormone replacement therapies, psychotropics, etc.) and are in need of sound risk management systems for long duration drug exposures; (3) since the thalidomide disaster, medication safety in pregnancy is a well-known concern, but this area is still under-funded and poorly developed, i.e. in terms of availability of appropriate (multinational) data on birth defects and susceptible exposures, methodology and classification systems. The present section provides an overview of regulatory developments and research since 2004, and identifies ongoing knowledge gaps and areas for improvement that warrant further research and funding. 4.1 Inclusion of women in clinical trials Women have been underrepresented in clinical trials for decades. There are several reasons to exclude women from clinical trials. As discussed earlier in the 2004 Background Paper, there is a need to protect foetuses from potential harmful medicinal effects. The Food and Drug Administration s (FDA s) 1977 `General Considerations for the Clinical Evaluation of Drugs guideline prohibited the participation of women of child bearing potential in phase 1 and early phase 2 studies, even when they used effective contraception. 75 This restriction was lifted after the adoption of the FDA s 1993 `Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. 76 Apart from the need to protect women, the exclusion of women of child bearing potential is also caused by the fear of liability should birth defects occur during (accidental) pregnancy. Another reason for excluding women from clinical trials is that a homogeneous population (limited to men) can decrease the sample size to detect a significant treatment effect. Heterogeneity is not only caused by differences between men and women, but also by large(r) inter-individual differences between women. A woman s reproductive life cycle phase and (concomitant) hormonal effects are great contributors to these differences. 77,

107 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure 7.2.4: Percentage of New Drug Applications including gender analysis. Source: Otugo O, Poon R, Copeland V, Khanijow K, Umarjee S, Chinn L, et al. Survey of the Presentation of Sex Analysis in the FDA Review of Efficacy and Safety Clinical Data of New Molecular Entity Drugs and Biologics Approved From 2007 to ; Available at: pdf. Accessed February 6, After the FDA s 1993 `Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs came into effect, the Office of Women s Health (OWH) was established in The mission of this office is to protect and advance the health of women through policy, science, and outreach, to advocate for the participation of women in clinical trials, and sex, gender, and subpopulation analyses. 80 Amongst other research, the OWH has funded different studies that assessed the inclusion of women in clinical trials. Their most recent study addressing this subject assessed the inclusion of women in late phase trials for medicines that were approved by the FDA during the period The participation of women was on average 44%. Of the new drug applications, 74% included exploratory or confirmative gender specific efficacy and safety analyses (see Figure for trend over time). 79 The FDA analysed the inclusion of women by scrutinizing early phase clinical trial data that were submitted to the FDA during the period Of these trials, 34.1% still enrolled only male participants. Overall, 30.6% of the enrolled participants were female (see Figure for trend over time). In studies enrolling both male and female patients, 38.8% were female. 81 Figure 7.2.5: Proportion of female participants in phase 1 trials by year trial began. Source: Pinnow E, Sharma P, Parekh A, Gevorkian N, Uhl K. Increasing participation of women in early phase clinical trials approved by the FDA. Womens Health Issues 2009;19(2):

108 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women In 2005, the European Medicines Agency (EMA) reviewed whether there was a need for a separate guideline to ensure that gender specific effects are investigated sufficiently. The EMA concluded that there were sufficient recommendations in the International Conference on Harmonisation (ICH) guidelines, and that women were being adequately represented in trials. In particular, ICH guidelines M4E and E3 require adequate demographic (including gender) characterization, analysis and assessment of the patient population. In general, either gender specific subgroup analyses or pharmacokinetics/ pharmacodynamics analyses were performed. In studies where such analyses were absent, a lack of power probably played an important role. Even though women were still underrepresented in early phase studies, the EMA decided that there was no need for a separate guideline. 82 Several facts emphasise the need for gender analyses in clinical studies. Numerous conditions are more prevalent in women, such as certain types of cancer 83, lupus 84, anxiety disorders 85, non-allergic asthma, 86 and goitre 87. Women may eliminate medicines differently (see Section 5.2), and they also have adverse drug reactions more often. 88 As stated earlier, women are very complex and their hormonal/reproductive state can be of great influence on their response to medicines. Treating individuals based on their specific characteristics is, in fact, personalized medicine (also called stratified medicine). To obtain information for specific subgroups, the `classic methodology for clinical research would require an increase in sample size to retain statistical power, thus bringing higher costs and the slowing down of research. Therefore, alignment with methodological approaches in stratified medicine (see Background Paper Chapter 7.4) may be possible. In conclusion, there still is a need for more information on medicinal effects in women. Opportunities in this field are (1) the evaluation of the inclusion of women in early phase trials and, if necessary, inclusion of women being mandated by regulatory agencies, and (2) innovations in research methodologies. The latter should result in more efficient development and evaluation of medicines, leading to stratified medicine and therefore better treatment in women. 4.2 Birth defects and pregnancy registries The thalidomide affair brought awareness to the potential harmful effects of medicines in pregnancy. In order to prevent future tragedies of that magnitude, legislation was developed to ensure stricter regulation of medicines. Guidelines state that pregnant women should be excluded from studies, except when the medication is intended for use during pregnancy. 89,90 Consequently, there is little information on the safety of medicines in pregnancy; 97.7% of medicines approved by the FDA between 2000 and 2010 have an undetermined teratogenic risk and data on the risks and benefits in pregnancy are absent in 73.3% of medicines. 91 Although medicines with an unknown or dangerous pregnancy safety profile are generally not recommended in pregnancy, they are still used in a few situations. For example, chronic medical conditions such as epilepsy, HIV/AIDS, and asthma require ongoing medication to protect the mother, as well as the foetus. Some medical conditions (e.g. migraine, depression, hypertension, gestational diabetes) can also develop or exacerbate during pregnancy requiring medical treatment. Furthermore, women might not even be aware of their pregnancy and accidentally expose the foetus to drugs. In the USA, half of the pregnancies in 2006 were unintended. 92 This poses a great risk, since major congenital malformations (MCMs) are often caused by exposure during the first trimester, in which the organs are

109 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women formed. Despite the recommendation against the use of drugs in the absence of a pregnancy safety profile, drugs are often used by pregnant women, with half of pregnant women using at least one prescription medication during pregnancy. 93,94 Table 7.2.6: Examples of results from international birth defect registries Study Birth defect register Drug Van Beynum Jentink EUROCAT EUROCAT Periconceptional folic acid reduces congenital heart diseases Valproic acid in the first trimester is associated with spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly and craniosynostosis Lisi ICBDSR Barbiturates are associated with orofacial clefts and multimalformations Blood glucose lowering drugs (excluding insulins) are associated with multi-malformations Carboxamides are associated with orofacial clefts and spina bifida Benzodiazepines are associated with orofacial clefts Bakker EUROCAT Paroxetine in early pregnancy is associated with atrium septum defects Dolk EUROCAT Lamotrigine in the first trimester is not associated with an increased risk of isolated orofacial clefts relative to other malformations Both the FDA s `Guidance for Industry Establishing Pregnancy Exposure Registries and European Medicinal Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) s `Guideline on the Exposure to Medicinal Products During Pregnancy: Need for Post-Authorisation Data address the need for data on the safety of drugs in pregnancy. 90,100 An important method for collecting pregnancy safety data is the use of registries. International birth defect registries such as the European Surveillance of Congenital Anomalies (EUROCAT) and the International Clearing House for Birth Defects Surveillance and Research (ICBDSR) have certain advantages. These registries are very large and data are less prone to regional bias due to their international nature. The great disadvantage is that most of the data are collected retrospectively, and the information on pregnancy exposures is therefore limited and of great variance. 101 Examples of results from these international birth defect registries are displayed in Table Hence, the FDA s guideline advise and sometimes oblige marketing authorisation holders (MAHs) as a condition for approval the establishment of pregnancy registries when pregnancy risk information is needed. Pregnancy registries collect data prospectively, which diminishes recall bias and yields structured data. 96 There are several ways to set up a pregnancy registry. In the Scandinavian countries, the entire birth population is recorded in pregnancy registries. 102 Other pregnancy registries may collect information on all medication use for a certain illness such as the epilepsy pregnancy registries (European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP 103 ), on one drug (e.g. the Cymbalta Pregnancy Registry 104 ), or on several

110 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women drugs (e.g. the Sumatriptan and Naratriptan Pregnancy Registry 105 ), and they can be initiated by academia, teratology information organisations, or MAHs. 95 Recently, the WHO Pregnancy Registry Protocol was established in order to provide evidence on the safety of medicines in settings with limited resources such as in low- and middle-income countries. 106 Each pregnancy registry setting comes with its own set of pros, cons and subsequent uncertainties. However, there is potential for improving the collection of pregnancy safety information. For example, there are several epileptic pregnancy registries that all use their own protocol to include patients and collect data. Because of these different strategies and definitions, their data cannot easily be pooled. 107 One of the great limitations of pregnancy registries is the lack of power to detect small or moderate increases in risks. 102,108 This makes the ability to combine all existing data essential. Regulatory authorities can play an important role in this process by stimulating existing pregnancy registries to work together and by encouraging new initiatives to join existing registries, instead of starting on their own. Options stimulating the participation of more patients should also be explored. Additionally, regulatory authorities could influence the inclusion criteria. For example, a minimum age of 18 years should not be an inclusion criterion since safety data on pregnancies in people under the age of 18 years is just as important. Also, pregnancy registries should not be limited to, for example, the USA, but should also be carried out in other countries, providing that a good comparator group can be established. These measures should shorten the time needed to determine the pregnancy risk of drugs that have an undetermined risk at time of approval, which has been shockingly long; 27 (95% CI 26-28) years on average. 91 EUROmediCAT is a new, large pharmacovigilance system in Europe (2011). One of its objectives is to develop an efficient system for drug safety evaluation by combining EUROCAT data with existing healthcare databases. This new type of large-scale data collection could provide extensive information. 109 Since most of the pregnancy registries cover new medications and chronic illnesses, perhaps this pharmacovigilance system could close another gap in drug safety in pregnancy by researching the effects of other drugs that are often used in women of childbearing age. In addition, better use of real life data (see Chapter 8.4) may provide additional opportunities in this research area. Three other areas remain to be explored. Maternal drug use is a large contributor to exposure, but exposure through semen, as happens when the father is using medication, can also play a role in fertility and pregnancy safety. Drugs can potentially have effects on the quantity and quality of semen, as well as direct effects on the foetus when the drug is excreted in seminal fluid. 110 The highly teratogenic thalidomide is found in paternal sperm, 111 therefore, conditions for male patients treated with thalidomide are mentioned in the pregnancy prevention programme (PPP) for thalidomide. 112 Despite this role for men in preventing thalidomide exposed pregnancies, there is hardly any data on pregnancy safety with regards to paternal drug use. A second area that should be explored concerns the longterm effects of drug exposure that cannot be determined in infancy, such as the case with fertility and behavioural problems. A follow up years after pregnancy is generally considered unfeasible; consequently other ways of determining these potential effects should be investigated. Finally, drug effects on fertility and very early spontaneous abortions are difficult to detect. Very early spontaneous abortions probably occur more often than expected 113 and could be mistaken for menstruation. Potential drug effects are therefore not likely to be detected through existing sources of post-authorisation pregnancy data (e.g. case

111 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women reports/series, birth defect and pregnancy registries, randomised controlled trials, and cohort and case control studies) since these data are collected in women with an existing pregnancy and who have knowledge of it. Different research strategies, as for example coupling prescription data to birth rates, should be explored. It has been suggested that fear of pregnancy risks has led to unnecessary pregnancy terminations. 114,115 It is therefore crucial to clearly communicate the information available on pregnancy risk. EMA CHMP s `Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: from Data to Labelling provides guidance on how to present available data in the EMA s Summary of Product Characteristics. Similarly, the FDA has proposed major revisions to prescription drug labelling to better inform health care professionals (HCPs) and patients. 116 The current FDA labels are highly criticised because they are considered to be incomplete, misleading and difficult to interpret and use by HCPs. 115 More research is necessary to study this issue and to assess the effects of communication on prescriber and patient behaviour. 4.3 Pregnancy prevention programmes (PPPs) In order to achieve and retain market authorisation for a medicine, it is essential that a positive benefit-risk balance is established and maintained throughout the entire drug life cycle. To maximise and maintain this benefit-risk balance, a Risk Management Plan (RMP) is part of the marketing authorisation application in the EU. 117 Similarly, the FDA can require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers. 118 The benefits of certain medicines in pregnant women are not considered to outweigh the risks for the foetus. This is the case for medicines that have shown or are expected (based on preclinical study results) to cause malformations in humans. In order to let people benefit from the therapeutic effects yet prevent malformations, Pregnancy Prevention Programmes (PPPs) have been developed and included in RMPs and REMSs. PPPs usually include different kinds of measures to ensure that a) pregnant women are not exposed to (potentially) highly teratogenic medicines, and b) women of child-bearing potential do not get pregnant during medicinal therapy with these agents. PPPs for isotretinoin The first PPP was developed in 1988 by the manufacturer Roche for oral isotretinoin and has been updated several times over the years; see Table for an overview of the changes in the United States. Despite the well-intended changes, the programme has been criticised. For example, the strictest programme (ipledge) has led to fewer isotretinoin treatments. A possible explanation might be that isotretinoin is currently given more frequently in the case of severe acne instead of in mild/moderate acne cases. Other, more alarming, explanations might be that patients perceive the medicine as being dangerous due to all the prescribing conditions and therefore refuse therapy, or that ipledge reduces access to isotretinoin due to the strict conditions and great administrative burden. 119 Furthermore, the current design of ipledge raises ethical questions; can, for example, ipledge make decisions for women based on a woman s potential to become pregnant or their presumed sexual activity? This could be considered as a deprivation of a woman s decision-making ability. 120 Lastly, a study has shown that ipledge does not reduce the number of pregnancies when compared to its predecessor SMART

112 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table 7.2.7: Overview of the history of isotretinoin (Accutane) risk management approaches. Risk management approach Original Warning (1982) Revised Warning (1983) PPP b (1988) SMART c (2001) ipledge (2006) Warning on label X X X X X Red label stickers to pharmacies X X X X Avoid Pregnancy icon X X X Patient consent form X X X Required pregnancy test prior to start of treatment a X X X Required selection of two forms of birth control a X X X Required two pregnancy tests prior to start of X X treatment a Pharmacists required to give medication guide with prescription Required use of qualification stickers by registered prescribers a Required monthly pregnancy tests a Required registration in database by patients, prescribers, pharmacists and wholesalers ax Qualifying questions for patients Monthly identification of contraceptive methods by patients and doctors X X X X X X X X a: As noted on prescription package insert; b: Pregnancy Prevention Program; c: System to Manage Accutane- Related Teratogenicity Source: Schonfeld T, Amoura NJ, Kratochvil C. ipledge allegiance to the pill: evaluation of year 1 of a birth defect prevention and monitoring system. The Journal of Law, Medicine 2009;37(1): In Europe, the isotretinoin PPPs were harmonised in 2003 because there were multiple PPPs due to the authorisation of various generic formulations. 122 Despite the harmonisation and additional measures, a total of 143 pregnancies were exposed to isotretinoin in 16 member states since the implementation of the harmonised PPP. 123 A systematic review demonstrated that there was poor compliance with the PPP and that the pregnancy incidence is still per women of childbearing age using isotretinoin. 124 The isotretinoin PPPs do not seem to accomplish their goal. However, before changing the PPPs again, the fundamentals of the PPPs should be discussed with all the involved stakeholders: prescribers, pharmacists, MAHs, regulatory agencies, and patients. Adequate parameters to evaluate the current PPPs need to be determined since these are currently considered to be absent. 121 The different stakeholders have offered a number of suggestions to make the PPPs more effective. These proposals should also be discussed with all the involved stakeholders, including patients (see also Background Paper Chapter 8.5). Interesting proposals are summarised in Table

113 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table 7.2.8: Proposals for improving Pregnancy Prevention Programmes. Proposals for improving PPPs Better communication and collaboration among all the stakeholders Implementation in healthcare professional software More involvement of all the stakeholders in every part of the PPP development process, including the development of information/working material More awareness among patients and professionals PPPs should be part of healthcare professional education or part of post-graduate trainings A clear website with all the information for patients and healthcare professionals together Development of an app for mobile phones containing information on the pregnancy risks, different kinds of contraception, and reminders for pregnancy testing/oral contraception intake Development of medicines containing the medicine of interest and oral contraceptives Stimulation of the use of long-term contraceptives such as vaginal rings, implants, injections and intrauterine devices Sources: Crijns I, Mantel Teeuwisse A, Bloemberg R, Pinas E, Straus S, de Jong-van den Berg L. Healthcare professional surveys to investigate the implementation of the isotretinoin Pregnancy Prevention Programme: a descriptive study. Expert Opinion on Drug Safety 2013;12(1): Altroconsumo. The case of ISOTRETINOIN compliance with the Pregnancy Prevention Programme in EU. 2011; Available at: ontentid=wc &mid=wc0b01ac058009a3dc. Accessed January 19, Mee S. Isotretinoin: Review of the Pregnancy Prevention Programme. 2011; Available at: Accessed January 19, Other issues related to PPPs PPPs for different medicines share common elements. An overview of the elements of the various PPPs is presented in Annex Harmonisation of the different medicines could avoid confusion and should be explored in the near future. 128 The blueprint for a final, universal PPP composed by all stakeholders could be included in a regulatory guideline. In conclusion, current PPPs have yet to resolve problems concerning adherence, effectiveness, and the additional burden to both patient and health care providers. In order to properly address and resolve these issues, it is crucial that each element of current and future PPPs is carefully evaluated by its users. The fundamentals of a PPP have to be defined. Only then, and with the involvement of all stakeholders, can a new, possibly universal, PPP be designed. 4.4 Medicines use during lactation Breastfeeding is the best strategy for infant feeding and nutrition due to a variety of health benefits. 129,130 However, these benefits can sometimes be countered by harmful effects from maternal medicine intake. A number of medicines are known to be excreted in breast milk, some of which can harm the infant. Just as in pregnancy, however, there are situations in which medicines have to be used during lactation. As stated in Section 4.2, women with certain chronic illnesses, such as epilepsy, need chronic medicinal therapy. Women may also

114 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women suffer from specific conditions occurring just after birth or at a later stage requiring medicinal therapy, such as caesarean wound pain or postnatal depression. 131 A study in the Netherlands found that 66% of all lactating women had used medicines, 132 while a Brazilian study reported 98%. 133 According to EMA s `Note for Guidance on General Considerations for Clinical Trials, they do not recommend that women who are lactating be excluded from studies, unlike the recommendation for pregnant women. 89 The pharmaceutical industry, however, does not seem eager to include lactating patients because of the potential risks. Therefore, there is still a lack of information on whether or not medicines or their metabolites are excreted into breast milk, and what their effects on infants are. As stated earlier in Section 4.2, the FDA has proposed major revisions for pregnancy and breastfeeding labelling. The FDA expects that their proposed labelling regulations will increase the data for pregnancy and breastfeeding, even without requiring these studies by regulation. 134 In 2009, the EMA `Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling came into effect, 135 which is similar to the FDA s proposed revisions. Since this guideline has already been in effect for a few years, its influence on the ongoing process of collecting lactation data should be determined. If the process of collecting lactation data is still insufficient, regulatory agencies should explore measures to improve the process. Table summarises three potential measures. Table 7.2.9: Possible regulatory measures to enhance the collection of lactation data Possible regulatory measures to enhance the collecting of lactation data Clinical studies Linking to pregnancy registries Lactation registries Clinical studies can be performed to collect the necessary data. The FDA released the `Guidance for Industry: Clinical Lactation Studies Study Design, Data Analysis, and Recommendations for Labeling draft guidelines in 2005, which contained different study designs and their considerations. 136 By modernising the guidance (e.g. the recommendations for labelling should be discarded since they are already in another proposal), the FDA could standardise data collection and oblige marketing authorisation holders (MAH s) to perform these clinical studies. The EMA could design a similar guideline and impose similar obligations on the MAH s. It is, however, unethical to expose infants to potentially harmful medicines in breastfeeding; therefore, clinical studies can only be used to determine the excretion of medicines and their metabolites in breast milk. Linking the process of collecting lactation data to pregnancy registries has the advantage that patients do not have to be actively recruited, since they are already enrolled in the pregnancy registry. Another advantage is that this method of data collecting in mother and infant is not unethical. However, when collecting lactation data in this way, effects of lactation on the infant can be confused with long-term effects of exposure to medicines during pregnancy

115 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women The last strategy is setting up lactation registries. Patients have to be actively recruited, which could slow down the data collection. The advantage of this approach is that only the effect of exposure via breast milk is determined. Lactation registries should be used for medicines for which the pregnancy risks have already been determined. If lactation registries are established, medicine labels/spc texts should contain a reference to these lactation registries. 5. The usage environment This section describes three pivotal issues related to medicine use in women in daily clinical practice. First, (potential) underutilisation of medicines in women is discussed. Second, the need for assessing gender gaps in drug dosing - emerging from pharmacokinetics and pharmacodynamics differences - recently (re)appeared after the FDA announced a recommendation for a lower dose of the insomnia drug zolpidem for women. Finally, access to emergency contraceptives remains an important topic that warrants attention. 5.1 Underutilisation of medicines in women Gender differences in health related indicators have been identified and often show a strong bias against women, especially in South Asian countries. 137,138 A key question, however, is if a gender gap exists in the pharmacological treatment of specific diseases among those eligible for treatment, i.e. those patients who have been adequately diagnosed and qualify for treatment according to treatment guidelines. The effect of gender on treatment with medicines is largely unknown because research that addresses this topic is scarce. In 2005, Baghdadi concluded that there was not enough evidence to assume that obstacles to care lead to underutilisation of medicines in women, but hypothesised that it seemed likely. 139 Recently, several studies have been published that focused on gender differences in medicine use. The large Prospective Urban Rural Epidemiological (PURE) study assessed the use of medicines for the secondary prevention of cardiovascular disease in adults from 628 urban and rural communities in various countries and across all income levels. 140 This study concluded that overall country-level factors, such as economic status, affected the use of medicines more than individual-level factors did, but women were less likely to take antiplatelet drugs (19.8% versus 32.8%), β blockers (17.4% versus 23.9%), ACE inhibitors or angiotensin receptor blockers (16.0% versus 24.6%), and statins (10.5% versus 23.8%) after coronary heart disease than men. Such differences may be related to multiple factors, like the patient s age, consequence of the disease, and a physician s risk perception, but other unknown factors may play a role as well. 141 Data from national health examination surveys conducted in Colombia, England, the Islamic Republic of Iran, Mexico, Scotland, Thailand, and the United States of America focusing on the management of blood glucose, hypertension, and cholesterol levels among patients with diabetes mellitus showed no uniform gender pattern. 142 In this study, once men were appropriately diagnosed, they were less likely to be treated and controlled (meeting treatment targets) in the Islamic Republic of Iran and Mexico; however, similar rates when compared to women were seen in Colombia, England, Scotland, and the United States, whereas women were less likely to be treated and controlled in Thailand. Evidence from 15 low- and middle-income countries confirmed that gender differences in the treatment of depression, diabetes and acute respiratory infections

116 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women were common. 143 Overall, only female patients with diabetes were treated less often than expected (p=0.02), but neither gender was favoured consistently across countries or age groups. No significant difference in the overall treatment of female and male patients with depression and acute respiratory infections was observed, again with variable patterns across countries and age groups. Similar variations have also been observed across HIV treatment centres in resource constrained settings with no gender differences in eight centres, overrepresentation of women based on treatment estimates in 13 centres, and underrepresentation in one centre in Uganda. 144 The above mentioned study results show that gender differences may occur, but that there is no consistent bias towards women. In some cases, in certain settings, disease areas and/or age categories, men were more disadvantaged with respect to medicine prescribing than women. These results highlight the need for continuous monitoring of gender-specific treatment patterns. More in-depth understanding of the underlying causes of gender-specific (under)utilisation of medicines is necessary in order to prevent unwarranted underuse of medicines in both women and men. 5.2 Gender gap in drug dosing On January , the FDA issued a safety communication regarding the dose of zolpidem for women. The FDA recommended a lower dose of zolpidem for women because of a risk of impaired alertness and drowsiness because women eliminate zolpidem slower from their body than do men. For men, a lower dose is not recommended per se, but should be considered. 145 This example illustrates a clear gender gap that can take decades before being determined. It is commonly known that women experience adverse drug reactions more often than men. 88 Three main factors contribute to this phenomenon (see Table ). The number of prescribed medicines is higher in women than in men, 146 and when multiple drugs are taken, these can interact with each other resulting in differences in pharmacokinetics and pharmacodynamics. Pharmacokinetics and pharmacodynamics are determined by physiological processes, and women and men differ physiologically from each other in numerous ways. The physiological differences involved in the actions of medicines will be discussed

117 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table : Factors contributing to the higher prevalence of adverse drug reactions in women. Reason for sex difference Pharmacological reason Pharmacological factors Women are overdosed Pharmacokinetics Sex difference in volume of distribution Sex difference in protein binding of drugs Sex difference in transport, phase 1, and phase 2 metabolism Women are more sensitive Pharmacodynamics Sex difference in drug targets: (i) receptor number (ii) receptor binding (iii) signal transduction following receptor binding Women are prescribed multiple medications Drug-drug interactions Drug-drug induced alterations Pharmacokinetics Pharmacodynamics Source: Soldin O, Chung S, Mattison D. Sex differences in drug disposition. J Biomed Biotechnol 2011;2011: LADMER (Liberation, Absorption, Distribution, Metabolism, Elimination, Response) describes the factors determining the effect of a medicine after it is administered. The first five (LADME) are factors determining pharmacokinetics, Response is essentially pharmacodynamics. LA: When a medicine is, for example, taken orally, the tablet or capsule first needs to release the active substance (liberation), which then has to dissolve before it can be absorbed. Dimensions and motility of the gastrointestinal tract, the bacterial flora, and secretions of enzymes and other substances influence the liberation and absorption steps. Gender differences in these factors are presented in Figure

118 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure Gender differences in gastrointestinal tract affecting liberation and absorption of medicines (M = males, F = females) Source: Freire A, Basit A, Choudhary R, Piong C, Merchant H. Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm 2011;415(1-2): D: After absorption, the medicine will be distributed through the body. Table presents the factors influencing distribution and the effects of pregnancy another factor strongly influencing the effect of a medicine and gender thereupon. M: Medicines are metabolised by a great variety of enzymes of which some are more active in women (e.g. cytochrome P450 3A subtypes) and others are more active in men (e.g. cytochrome P450 1A subtypes). 149 E: The most common routes for medicines to be eliminated from the body are via faeces and urine. Women have a lower renal clearance then men. 150 R: Pharmacodynamics are determined by the number of receptors the medicine targets, binding of the receptors by the medicine, and signal transduction following receptor binding; sex differences are known to exist

119 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Table : Parameters of distribution and the effects of gender and pregnancy hereon. Parameter Physiological difference Pharmacokinetic impact Plasma volume Pregnant F > M > F Decreased concentration in pregnancy Body mass index M > F Higher in men Average organ blood flow Pregnant F > M > F Higher in pregnant women Total body water M > pregnant F > F Decreased concentration Plasma proteins M = F > pregnant F a Free concentration increases in pregnancy Body fat Pregnant F > F > M Increase body burden of lipidsoluble drug in pregnant women Cardiac output M > pregnant F > F Increase rate of distribution in men a An exception is thyroxine binding protein, which increases by 50% in pregnancy F = females; M = males. Source: Soldin O, Mattison D. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009;48(3): The FDA reviewed 300 new drug applications between 1995 and 2000, of which 163 included a sex analysis. Despite a difference of over 40% in pharmacokinetics in 11 medicines, there were no sex based dose recommendations. 151 The FDA also analysed pharmacokinetics and dose differences in medicines approved in the period from September 2007 to August Of the 51 approved medicines, six did not report pharmacokinetic differences in men versus women, and 10 had at least one pharmacokinetic parameter that deviated more than 20% (see Figure 7.2.7). There were, however, no sex based dose adjustments, since the pharmacokinetic differences were considered not clinically relevant. 152 As stated in Section 4.1, in 2005 the EMA found that gender specific subgroup or pharmacokinetics/pharmacodynamics analyses were being performed in general

120 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Figure 7.2.7: Differences in pharmacokinetics between women and men in new medicines approved by the FDA in the period from September 2007 to August 2010 Source: Copeland C, Sahaiwalla C, Parekh A. Sex-Differences in Exposure for FDA Approved New Molecular Entities (NMEs) : Exposure Based Dosing in Subgroup Populations However, since gender effects can be caused by differences in pharmacokinetics and pharmacodynamics, it is desirable that there be sufficient information on both. This may result in differences in benefit-assessment between men and women, when taking both into account. Ideally, clinical research should, therefore, investigate both efficacy and safety for both genders for multiple dosage regimens and determine which pharmacokinetic/pharmacodynamic factors are involved in gender differences. This, however, is very costly. As an alternative, models should be developed to efficiently characterise gender differences with acceptable burden/costs also for evaluating gender effects of medicines that are already approved. These recommendations apply especially to medicines with a small therapeutic range. In conclusion, gender differences in the effects of medicines are a result of complex, multiple factors. Although there is regulatory attention to these differences, there is still a need for a complete picture of gender effects in medicines linked to their specific causes. Efficient models to determine these, also for medicines that have been on the market for long periods of time, should be developed. 5.3 Access to emergency contraceptives Half of all pregnancies are unintended in the United States. The proportion of unintended pregnancies increases with younger age: with 64% of pregnancies being unintended in women aged years, 82% in women aged years, and 98% in women less than 15 years. 92 Pregnancies bring health risks to the mother and can have detrimental effects, especially in younger women, on a woman s education and career. Moreover, teenage pregnancies are expensive; the national cost of teen childbearing in the United States was estimated at 10.9 billion US dollars in These problems can be reduced by abstinence, correctly using effective contraception during intercourse, and using emergency contraceptives (ECs) when the first two measures are not carried out or have failed. The use of adequate (hormonal) contraception and unmet needs are discussed in Section 3.2. This section focuses on access to EC

121 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women The availability of ECs has increased over the last few decades. In 2003, ECs were registered in 97 countries and were available without a prescription in pharmacies in 27 European, Asian, and African countries, and two states in the United States. 154 Currently, ECs are registered in 149 countries and are available without a prescription in 64 countries, of which six countries (Canada, Norway, Sweden, the Netherlands, India and Bangladesh) allow direct access `over the counter. 155,156 Prescribing in advance and/or not requiring a prescription increased the use of ECs, 157,158,159 but did not reduce the number of unintended pregnancies. 157,160,161 It is possible that the increase in EC use is mainly seen in women with a lower baseline risk (e.g. women that already use effective contraception). 162 The lack of a decrease in unintended pregnancies illustrates that `access does not only depend on the prescription status of EC pills, but also on other, more complicated factors. These factors are listed in Table Several concerns have been raised about the use of ECs without a prescription: 1. Opponents state that ECs work as abortifacients, which may be true for ulipristal acetate when used in an established pregnancy, 163 but not for the other widely used ECs. 164, Many religious groups object to any form of birth control. 3. Not requiring a prescription would make access to ECs too easy, leading to increased sexual risk taking and thus more sexually transmitted infections. 166 However, a large trial has proven that sexual behaviour, sexually transmitted infections, and non-emergency contraceptive use do not change when a prescription is not required for EC use. 157,167 Also, prescribing in advance neither affects sexually transmitted infections, sexual behaviour, nor the use of non-emergency contraceptives. 158,158,161 Table : Factors influencing the use of emergency contraception pills. Factors influencing the use of EC pills Money/insurance coverage Concerns about being judged by the doctors/pharmacist Rural versus urban areas Knowledge and attitude of women, doctors and pharmacists Age Language Ethnicity, culture, stigma Sources: Finer L, Zolna M. Unintended pregnancy in the United States: incidence and disparities, Contraception 2011;84(5): Free C, Lee R, Ogden J. Young women's accounts of factors influencing their use and non-use of emergency contraception: in-depth interview study. BMJ 2002;325(7377): International Consortium for Emergency Contraception. Emergency Contraception: How far have we come? What's new? What's next? 2011; Available at: Accessed April 15, Sampson O, Navarro S, Khan A, Hearst N, Raine T, Gold M, et al. Barriers to adolescents' getting emergency contraception through pharmacy access in California: differences by language and region. Perspect Sex Reprod Health 2009;41(2): Miller L. College student knowledge and attitudes toward emergency contraception. Contraception 2011;83(1):

122 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women One of the most important factors influencing EC use is knowledge. A United States study in 2008 showed that only 74% of college students had heard of ECs, while almost the same amount of students did not know the time frame in which ECs are effective. Only 15% knew that ECs was available on campus, and 60% did not know where to obtain it in the local community In another study, only half of women knew that ECs have no effects on future fertility. 172 Every woman should have basic knowledge on ECs, i.e. know the mode of action (prevention pregnancy instead of abortifacient), side effects/absence of permanent effects, when it should be taken, and how and where to obtain it. Useful sources of information could be schools or doctors. However, a study showed that only 26% of paediatric residents routinely provide information on ECs. During a contraception visit, only 56% would counsel women on ECs. 173 Another study showed that 37% of general practitioners provided information about ECs. Six months after a peer-led intervention with educational and reminder components, 80% of the general practitioners had counselled women about ECs. 174 Some doctors may never offer ECs, e.g. for religious reasons. 175 Measures to improve knowledge among women, especially young, should be researched. Younger women are better informed than older women, but use ECs less often. 176 A potential explanation is that individuals also judge themselves for needing ECs, and young women think that their risk on pregnancy is low Male pregnancy intentions are also related to the use of ECs; the strong desire of a man to avoid pregnancy is associated with higher EC use. 177 This underlines another important role for men in preventing pregnancy. Only when the reasons for not using ECs are understood, can a strategy to improve (young) women s knowledge on ECs be designed involving the participations of schools, doctors, and other potential sources of information. Pharmacists also play an important role in the provision of ECs; nonetheless, they can refuse to dispense ECs based on personal, moral, religious or ethical beliefs. According to some pharmacists, they do not even stock ECs due to a lack of demand. 178 This can be a big problem in rural areas where pharmacies are not widespread. 179 Studies have shown that knowledge of ECs needs improvement in this group of healthcare professionals. For example, a study from revealed that 18.9% of pharmacists in Iowa did not know how ECs worked, while 6.6% thought that ECs terminated pregnancies, and 11% thought that ECs were abortifacients. 178 Another study determined that 54% of pharmacists in Florida even thought that levonorgestrel was an abortifacient. 180 Since knowledge is related to dispensing by pharmacists, 180 it is necessary for pharmacists to receive training in order to improve their knowledge as well. In conclusion, there has been worldwide progress in the registration of ECs and the availability of ECs without a prescription. Current barriers for using ECs of which we only partially know how to reduce them are a lack of knowledge in both women and health care providers. Schools, pharmacists and doctors should be educated in order to inform women about ECs, yet other information sources remain to be identified and involved in the counselling process. The influence of other factors on EC use still needs to be further determined and measures to modify these influences should be researched

123 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women 6. Conclusion In the 2004 report, gaps and priorities for treatment in women were mainly identified in the area of regulation and (safety) monitoring of medicines in women. Since then, many activities have been undertaken to improve the situation and to support research and other work in this field. These activities and their results have been described in this background paper. Nevertheless, several knowledge gaps have not been (fully) resolved and a few new issues have emerged over the past few years. This section summarises and groups the identified knowledge gaps and the areas that need strengthening and/or future research to advance in the use of medicines in women. Access for women to certain medicines, especially contraceptives and emergency contraceptives, remains an area of concern in many parts of the world, but is outside the scope of the current background paper and its recommendations. Use existing (real life) data to their full potential Women are still underrepresented in clinical trials, although slight progress has been noted over the years, and regulatory agencies regularly monitor participation in trials. The need for gender analyses was underlined in January 2013 when the FDA announced a recommendation to lower the dose of a medicine that had been on the market for decades. It is questionable, however, whether stronger regulations and more (regulatory) requirements offer the best solution to obtaining the necessary data, as much of the needed knowledge pertains to `old medicines, as shown by the FDA dosing example. Therefore, use of existing data and the development of (innovative) methodological approaches for better use of these data should be further explored. These data should be able to provide more insight into gender-specific, benefit-risk profiles of medicines, also with relation to dosing and the gender-specific underutilisation of medicines. While the latter issue is of concern, with gender differences occurring, these are not consistently biased towards women. Alignment with similar initiatives for better use of existing data in elderly and children is recommended. The need for data on the safety of medicines has been addressed by regulatory authorities over the past years, and many pregnancy registries have been set up in addition to the already existing birth defect registries. Pregnancy registries should be further strengthened and collaborations between these registries, e.g. in a research network, should be stimulated. Attention should also be paid to the effects of paternal medicine use, the long-term effects of medicine use during pregnancy (such as fertility and behavioural problems), effects on fertility and very early spontaneous abortion, and opportunities to collect data on medicine use during lactation. Strengthen informed decision making among women Although there are many products for contraception are on the market, there is still a need for more efficacious, safe, and convenient contraceptives (including male contraceptives). Such products are currently under development. A major challenge lies in strengthening informed decision making among women when it comes to contraceptives and emergency contraceptives, but also when it comes to methods of pain relief during labour. Women and (especially in the case of emergency contraceptives) doctors and pharmacists need to be

124 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women better educated. Improving knowledge and attitudes towards contraceptives requires better counselling and aids, especially for young women and women with co-morbidities. Strategies to achieve a better level of knowledge and improve attitudes in the various areas need to be developed and evaluated on their impact, not only on the level of knowledge, but also on important health outcomes such as unintended pregnancy rates or the burden of pain during labour. More research is needed to establish how the risks of parental drug use can be effectively communicated to both patients and health care professionals, and to assess the effects of communication on their behaviour. Data have shown that pregnancy prevention programmes (PPPs) do not seem to accomplish their goal. Before changing PPPs, the fundamentals of PPPs should be discussed with all involved stakeholders and the further alignment of PPPs for different products should be explored. Adequate parameters to evaluate PPPs need to be determined in order to monitor their (future) effectiveness, burden and adherence to the PPPs. References 1 United Nations. Millennium development goals. 2013; Available at: Accessed February 21, Sturkenboom MCJM, Verhamme KMC, Nicolosi A, Murray M, Neubert A, Caudri D, et al. Drug use in children: cohort study in three European countries. BMJ 2008;337:a2245-a Kaplan W, Laing R. Priority Medicines for Europe and the World. 2004; Available at: Accessed April 15, Wang H, Dwyer Lindgren L, Lofgren K, Rajaratnam J, Marcus J, Levin Rector A, et al. Age-specific and sex-specific mortality in 187 countries, : a systematic analysis for the Global Burden of Disease Study Lancet 2012;380(9859): The World Bank. Fertility rate, total (births per woman). 2013; Available at: Accessed February 21, The World Bank. Adolescent fertility rate (births per 1,000 women ages 15-19). 2013; Available at: /indicator/sp.ado.tfrt/countries/1w-eu?display=graph. Accessed February 21, European Union. The reproductive health report: The state of sexual and reproductive health within the European Union. Eur J Contracept Reprod Health Care 2011;16 Suppl 1:S Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study Lancet 2012;380(9859): Global Burden of Disease 2010 database. Visualisation of GBD 2010 patterns by broad cause group. Picture created by Laurien Rook. Set parameters: 2010, Female, Rate, Deaths, All ages (data for maternal disorders limited to years old), Maternal disorders, Region. 2013; Available at:

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136 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women 169 International Consortium for Emergency Contraception. Emergency Contraception: How far have we come? What's new? What's next? 2011; Available at: Accessed April 15, Sampson O, Navarro S, Khan A, Hearst N, Raine T, Gold M, et al. Barriers to adolescents' getting emergency contraception through pharmacy access in California: differences by language and region. Perspect Sex Reprod Health 2009;41(2): Miller L. College student knowledge and attitudes toward emergency contraception. Contraception 2011;83(1): Schwarz E, Reeves M, Gerbert B, Gonzales R. Knowledge of and perceived access to emergency contraception at two urgent care clinics in California. Contraception 2007;75(3): Lim SW, Iheagwara KN, Legano L, Coupey SM. Emergency Contraception: Are Pediatric Residents Counseling and Prescribing to Teens? J Pediatr Adolesc Gynecol ;21(3): Sobota M, Warkol R, Gold M, Milan F, Schwarz E, Arnsten J, et al. An intervention to improve advance emergency contraceptive prescribing practices among academic primary care physicians. Contraception 2008;78(2): Lawrence R, Rasinski K, Yoon J, Curlin F. Obstetrician-gynecologist physicians' beliefs about emergency contraception: a national survey. Contraception 2010;82(4): Sorensen MB, Pedersen BL, Nyrnberg LE. Differences between users and non-users of emergency contraception after a recognized unprotected intercourse. Contraception 2000;62(1): Harper C, Minnis A, Padian N. Sexual partners and use of emergency contraception. Obstet Gynecol 2003;189(4): Mackin M, Clark K. Emergency contraception in Iowa pharmacies before and after over-the-counter approval. Public Health Nurs 2011;28(4): Devine K. The underutilization of emergency contraception. Am J Nurs 2012;112(4): Richman A, Daley E, Baldwin J, Kromrey J, O'Rourke K, Perrin K. The role of pharmacists and emergency contraception: Are pharmacists' perceptions of emergency contraception predictive of their dispensing practices? Contraception 2012;86(4):

137 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Annexes Annex Pain management methods for women in childbirth Efficacy Method Mode of administration (Proposed) mode of action Side effects (+/+-/?) Hypnosis Self-hypnosis: the mother induces, by focusing Suppression of neural activity +- Unknown Biofeedback Sterile water injections and relaxing, a state of subconsciousness that makes her less reactive to signals that she normally perceives when she is conscious Instruments tell the mother in which state physiological processes are in, such as muscle tension meters, skin temperature gauges and galvanic skin response sensors which assess the amount of sweating Intracutaneous or intradermal injections of sterile water in the skin over the sacrum Relaxation Changes in thoughts and emotions may result in changes of body functioning Release endogenous opioids Gate control Immersion in water Immersion of the body in a pool, tub or bath Induce sense of control Release of endogenous Aromatherapy (essential oils) opioids Water lets the women move more easily than on land, alleviating pain and optimizing the progress of labour Massage into skin or inhalation Release of sedative, stimulant and relaxing neurotransmitters Relaxation techniques Yoga, music, or audio therapy Relaxation by focusing and awareness of muscular tension? Unknown? Unknown +- Unknown? Unknown +- Unknown

138 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Acupuncture/ acupressure Massage, reflexology and other manual methods Transcutaneous Electrical Nerve Stimulation (TENS) Inhaled analgesia (nitrous oxide, isoflurane, enflurane, methoxyflurane) Opioids (pethidine, meptazinol, diamorphine, morphine, nalbuphine, fentanyl, remifentanil) Non-opioids (paracetamol, aspirin, hyoscine) Local anaesthetic nerve blocks Epidural analgesia (bupivacaine, ropivacaine, lidocaine/ lignocaine) Combined spinal-epidural analgesia (anaesthetic and/or opiate) Insertion of small needles into (acupuncture) or Release endogenous opioids +- Unknown pressing on (acupressure) specific points in hands, feet and ears Gate control Manipulation of body tissues (massage), Relaxation +- Unknown pressing on parts of the foot (reflexology) Gate control Improving blood flow and oxygenation of tissues Device that emits low voltage electrical impulses Induce sense of control? Local irritation is applied to the lower back, acupuncture points Release endogenous opioids or head Gate control Inhalation of analgesia intermittently or Suppression of neural activity + Effects of prolonged exposure on staff on fertility continuously, which may or me not be selfadministered Release endogenous opioids and pregnancy under supervision Drowsiness, hallucinations, vomiting, hyperventilation, tetany Intramuscular or intravenous Analgesia through activating? Impaired capacity to engage in decision making pharmacological pathways about care, sedation, hypoventilation, hypotension, prolonged labour, urine retention, nausea/vomiting, slowing of gastric emptying, reduced breastfeeding rates, itching Neonatal respiratory depression and hypothermia Oral Analgesia through activating +- There are seldom side effects during the short use pharmacological pathways of this type of medication Injection of local anaesthetic around the trunk of Local nerve blockade +- Sweating, tingling of lower limbs, bradycardia the pudendal nerve or alongside the vaginal infant portion of the cervix in the vaginal fornices Epidural administration of local anaesthetics by Central nerve blockade + Vasodilatation, hypotension, urine retention, bolus injection, continuous infusion or patientcontrolled shivering, fever, tinnitus, tremor, respiratory and pump cardiovascular depression, reduced motor function, infection, nerve root damage Combined spinal epidural into cerebral spinal Central nerve blockade + See opioids and epidural fluid as well as insertion of epidural catheter

139 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women Annex Elements of pregnancy prevention programmes of different medicines Active substance Thalidomide Lenalidomide Isotretinoin Acitretin Alitretinoin Bosentan Ambrisentan Contra-indication during pregnancy and for WCBP* unless following PPP Need for contraception for WCBP Negative pregnancy test for WCBP Advice on pregnancy prevention Precautions for male patients Blood donation during and for a certain period after Yes Yes Yes Yes Yes Yes Yes four weeks before therapy until four week after discontinuation. Combined oral contraceptives are not recommended because of increased risk of VTE in patients with Multiple Myeloma. Prior to therapy; monthly during therapy; four weeks after discontinuation four weeks before therapy until four week after discontinuation. Combined oral contraceptives are not recommended because of increased risk of VTE in patients with Multiple Myeloma. Prior to therapy; monthly during therapy; four weeks after discontinuation four weeks before therapy until four weeks after discontinuation. Additional barrier method is advised Prior to therapy; monthly during therapy; five weeks after discontinuation four weeks before therapy until four weeks after discontinuation. Additional barrier method is advised Prior to therapy; monthly during therapy; one to three monthly until two years after discontinuation four weeks before therapy until four weeks after discontinuation. Additional barrier method is advised Prior to therapy; monthly during therapy; five weeks after discontinuation Practice reliable contraception during treatment. Since hormonal contraceptive interact with bosentan, additional methods are advised Prior to therapy; monthly during therapy Yes Yes Yes Yes Yes Yes Yes The use of condoms since thalidomide is present in human semen During until one week following discontinuation The use of condoms since lenalidomide is present in human semen. During until one week following discontinuation Transmission via the male is considered negligible During until one month following discontinuation Transmission via the male is considered minimal (WCBP may not receive blood of patients treated with Transmission via the male is considered negligible During until one month following discontinuation None None Practice reliable contraception during treatment. Prior to therapy; monthly during therapy None None

140 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women treatment use Confirmation of understanding the risk and precautions and/or appropriate counselling has taken place Prescription restriction for WCBP Dispensing restrictions for WCBP Follow-up consults of WCBP Education material regarding PPP for: Treatment Initiation Forms Limited to four weeks. Continuation requires new prescription. Negative pregnancy test before initiation Should be filled within seven days after prescription** Prescribers Brochure Patients (WCBP and males) Brochure Patient Card Via patient card and checklist for physician Negative pregnancy test before initiation Prescribers Brochure Checklist Patients (WCBP and males) Brochure Patient Card Informed consent form Limited to 30 days. Negative pregnancy test before initiation or continuation. Should be filled within 7 days after prescription. acitretin) Limited to 30 days. Negative pregnancy test. Informed consent form Limited to 30 days. Negative pregnancy test before initiation or continuation. Should be filled within seven days after prescription. Each 28 days Each 28 days Each 28 days Prescribers Brochure Pharmacist Brochure All patients Brochure No Prescribers Brochure Pharmacist Brochure All patients Brochure Negative pregnancy test before initiation** Prescribers Brochure All patients Brochure Limited to 30 days. Negative pregnancy test before initiation Prescribers Brochure Pre-prescription checklist All patients Brochure SmPC referred to a educational programme or PPP SmPC section that provides information about PPP Referred to PPP and educational material Referred to PPP and educational material Referred to PPP and educational material No Referred to PPP and educational material No Patient reminder card Male partners of WCBP Brochure No and and

141 Update on 2004 Background Paper, BP 7.2 Priority Medicines for Women *WCBP = Women of childbearing potential Only included in the SmPC and not in Annex II Only included in Annex II and not in SmPC The SmPCs of acitretin-containing products authorised through DCP do refer to educational materials

142

143 Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by MJC Willemen, PAF Jansen en HGM Leufkens Background Paper 7.3 Priority Medicines for Elderly By Lisa Martial 1, Aukje K. Mantel-Teeuwisse 1, and Paul A.F. Jansen 2 5/21/ Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands 2 Department of Geriatric Medicine, Univeristy Medical Center Utrecht (UMCU), Utrecht, the Netherlands This Background Paper was commissioned by the WHO Collaborating Centre for Pharmaceutical Policy and Regulation ( This work was financially supported by the Dutch Ministry of Health, Welfare and Sport.

144 Update on 2004 Background Paper, BP 7.3 Elderly Table of contents Executive summary and key research points Introduction Demographics and diseases faced by elderly Ageing Osteoporosis Oncology Vascular Dementia Product related issues in elderly Changes in body function in elderly Product related problems Potential solutions and implications for research Regulatory aspects related to elderly Participation in clinical trials Information about elderly in product information and other information sources The usage environment Polypharmacy Adverse drug reactions Adherence Access to medicines Palliative care Integrated care Conclusion References Annexes Annex 7.3.1: Cancer prevalence by age at prevalence (US data ) Annex 7.3.2: Charter for the rights of older people in clinical trials

145 Update on 2004 Background Paper, BP 7.3 Elderly Executive summary and key research points This cross-cutting background paper addresses special needs in the treatment of elderly patients that may not be covered in other parts of the Priority Medicines for Europe and the World Report and depicts developments since the previous edition of this report in These specific needs are a result of changing physiology over the course of their lifetime, the spectrum of diseases that the elderly face, the fact that they are often left out of the drug development process, and that, in daily practice, medicine use in the elderly is complicated as a result of many factors, such as polypharmacy. People aged 60 and older are a growing part of both European and global communities. The proportion of the global population aged 60 and over will increase to more than 16% in In Europe, the growth of the elderly population is more pronounced. Demographics are further characterised by decreased fertility rates and increased life expectancy, with women living longer than men. The diversity of older people is one factor contributing to their complex health issues and care needs. This paper describes three common conditions in the elderly that were not (fully) covered in other background papers: osteoporosis (including falls), cancer, and vascular dementia. Fall prevention is of the utmost importance in the elderly to prevent adverse outcomes. Various fall prevention programs exist, but implementation, uptake of, and adherence to evidence-based fall prevention programs need further attention. As the population grows older, the incidence of cancer increases. The elderly are a heterogeneous population responding differently to chemotherapy. Whether geriatric co-morbidities can predict specific clinical outcomes in cancer patients, such as quality of life, treatment tolerance or survival, has not yet been clarified. A robust screening tool is therefore needed in order to facilitate treatment decisions and offer tailored care. Although most cases of dementias are mixed cases in which a vascular component plays an important role, research has focused on Alzheimer disease over the past decade. More research on vascular dementia is needed to assess its epidemiology, improve diagnosis, and identify (new) targets for treatment. For many reasons, the elderly may have difficulty taking medications. Tasks like opening packages, reading leaflet information and/or swallowing oral medication may be especially difficult. Some of these special needs have strong similarities with the needs of children. There is a call for the development of special geriatric formulations, and the example of paediatric adapted formulations could be a useful model here. When, in the near future, adapted formulations have been developed it will be necessary to study and evaluate how these products have influenced healthcare, and if they have indeed led to better health in the elderly. The elderly are still underrepresented in clinical trials, resulting in a lack of information about the safety and efficacy of medicines in this population. A consensus definition of frailty, as well as better tools to evaluate it, are needed, as these may enable the selection and inclusion of elderly in clinical trials. Besides, new approaches such as the improved use of existing data (e.g. electronic health records) may be valuable in obtaining (better) data on the effectiveness of medicines in the elderly. Finally, ways to translate the obtained information 7.3-3

146 Update on 2004 Background Paper, BP 7.3 Elderly from clinical trials into practical recommendations in the Summary of Product Characteristics and/or age specific recommendations in guidelines, should be further explored. Various improvements can be made in the medicine usage environment of the elderly. Polypharmacy, defined as taking multiple medicines for chronic use at the same time (usually more than 4 or 5 medicines), is very common in the elderly, and medication reviewing has become common practice in some countries. However, the benefits of medication reviewing are not fully proven yet; medication reviewing leads to more appropriate prescribing, but benefits on harder clinical outcomes, such as hospital admissions or mortality and their cost-effectiveness, need to be confirmed. The potentially facilitating role of computerized systems in this instance should be explored. Electronic solutions could make the reviewing less time consuming and could help the reviewer to systematically select patients that might benefit most from reviewing, but the added value of these solutions remains to be established. Adherence to medication regimes should be improved in the elderly. There is an important need for basic and applied research on interventions to assist patients in following the instructions on prescriptions for chronic medical disorders. Although this applies to the population as a whole, the elderly deserve special attention in this respect. Effective interventions may be quite complex and unsuitable for daily practice. More research into establishing the most (cost-)effective interventions is needed. Future emphasis should also be placed on the necessity to actively involve the patient in treatment decisions. It is unknown if inequity in access to medicines exists in the elderly. Research to establish this is needed, especially in light of the ongoing economic recession and subsequent policy measures that have been taken. Underuse and under-prescribing are, however, also present in this population. The relative absence of guidance on prescribing in the elderly population in clinical guidelines may contribute to this situation. Improvement might be possible through quick and extensive data sharing with the aid of computerized systems, although this is yet to be confirmed. Palliative care has become more important over the last few years and has been acknowledged as a serious part of healthcare. There is a need for further evaluation of the (cost-)effectiveness of interventions in the last phase of life. Still, many elderly near the end of life suffer from pain, hence improvements in pain management are needed. Identifying and resolving barriers to treatment with opioid medications is an important step forward, but for optimal treatment their effects need to be established. Further, polypharmacy is prevalent at the end of life, and medication review and simplification of drug regimes in this cohort have been called for. Finally, integration of care in elderly patients is essential, to prevent medication errors due to loss of information for example. The elderly dwell in different environments depending on their care needs and experience more transfers between care settings than other populations. Each transfer introduces the potential risk of unintentionally discontinuing medications or of represcribing medicines that were initially stopped. Effort is put on ensuring accurate medication taking in second-line care (hospitals) through medication reviewing of complete geriatric assessments for example, but little effort is put into the communication between first and second-line care. It seems beneficial for the older patient to be treated in an 7.3-4

147 Update on 2004 Background Paper, BP 7.3 Elderly environment that provides multidimensional, interdisciplinary care; how such care is organised needs further investigation. There is a trend toward the elderly living longer independently, but medication management is complex and many elderly have difficulties that may hamper accurate medication management. Tools to assess their ability to manage their medication at home have been developed, but still need further evaluation. The role of caregivers in medication management, including adherence, should be further explored, especially because at-home populations rely heavily on their support. ehealth might help to facilitate quick and easy information exchange between healthcare professionals, making it easier to communicate and provide integrated care. Until now, the fact that ehealth solutions lead to better health in the general population has not been proven. Therefore, the role of ehealth in this population warrants further investigation. In summary, the following key research priorities for elderly have been identified: Evaluation of the (cost-)effectiveness of ongoing programs and initiatives in the elderly with a focus on objective clinical outcomes: o Fall prevention programs o Medication reviewing o Interventions to improve adherence o Interventions in palliative care Development of a robust screening tool for oncology in order to establish which conditions are predictable for specific clinical outcomes of interest Development of adapted formulations for elderly adopting knowledge from paediatric formulations Assessment of tools that may improve participation of the elderly in clinical trials and new approaches to better use of real world data to establish effectiveness Translation of information about elderly into clinical guidelines and other sources of information for healthcare professionals that may guide better use of medicines and prevent under-prescribing Evaluation of the benefits of fast and extensive data sharing with the aid of computerized systems (role of ehealth) Integration of care and better self management for the elderly dwelling in different sites of care including their own homes; communication between health care professionals (especially at the interface of first and second line care), and medication management in the home situation need special attention

148 Update on 2004 Background Paper, BP 7.3 Elderly 1. Introduction In 2004 the Priority Medicines for Europe and the World report was published. It included Section 7.2 on pharmaceuticals and the elderly. This background paper continues from and updates the 2004 background paper. With the population ageing, the number of older people is increasing rapidly worldwide, introducing a growing burden on global health systems (see Background Paper 5). The elderly consume more medicines than any other population and deserve special attention. Elderly patients have specific needs that may not be covered in other parts of the Priority Medicines for Europe and the World report. These needs are a result of changing physiology over a lifespan, the spectrum of diseases that the elderly encounter, the fact that they are often overlooked during the drug development phase, and that in daily practice the use of medicines in the elderly is complicated as a result of various issues polypharmacy, for example that result in additional risks of severe harm. These issues require careful attention and analysis to guide future decision-making. This background paper addresses the special needs of the elderly. As such, this cross-cutting paper complements other background papers of this report, and cross references to other background papers are provided wherever relevant. In the present background paper, knowledge gaps, as well as implications for future research are discussed, giving an overview of the items and subjects related to the elderly that need more attention in the near future. 2. Demographics and diseases faced by the elderly This section focuses on demographics and several diseases that are specific to the elderly. For more general or detailed trends in demography the reader is referred to Background Paper 5 of this report. Many of the conditions that the elderly suffer from are described in the various components of chapter 6 of this report. In this section, we focus briefly, but in more detail, on three very common diseases in the elderly that require additional attention: osteoporosis (including falls), cancer, and vascular dementia. These conditions were all urgent issues that appeared prominently on the agendas of several international geriatric conferences, such as those of the European Union Geriatric Medicine Society (EUGMS), the International Association of Gerontology and Geriatrics (IAGG), the British Geriatrics Society, and the American Geriatrics Society. Although the importance of healthy ageing and prevention (including vaccination, if appropriate) is acknowledged, this is regarded as outside the scope of this present cross-cutting background paper. 2.1 Ageing People aged 60 and older are a growing part of both European and global communities (see Figure 7.3.1). In 2010, about 11% of the population worldwide was aged 60 and over. By the year 2030, this proportion will increase to more than 16%. In Europe, the growth of the elderly population is more pronounced. By the year 2030, forecasts say that the percentage of the population who will be aged 60 and over will be about 29%. 1, 2 While the overall trend is virtually the same in all countries, there is considerable variation between individual 7.3-6

149 Fertility rate Age % of total population % of total population Update on 2004 Background Paper, BP 7.3 Elderly countries, and between Europe and the rest of the world, with respect to the speed of these developments. 1 Figure 7.3.1: Population distribution in the world and Europe: recent history and coming decades. From: World Population Prospects, the 2010 revision database, UN Population division. World Europe Age groups Age groups Source: United Nations, Department of Economic and Social Affairs. Population Database UNDoEaSA Accessed May 13, Figure 7.3.2: upper: life expectancy over time; lower: fertility rate over time Life expectancy World More developed countries Less developed countries Least developed countries Year Fertility rate World More developed countries Less developed countries Least developed countries Year Source: UN population division. World Population Prospects, The 2002 revision database

150 Update on 2004 Background Paper, BP 7.3 Elderly Multiple factors contribute to the shift in population distribution. On one hand, life expectancy dramatically increased in the past century (see Figure 7.3.2, upper) due to a combination of improvements in both socio-economic and environmental conditions and in preventive (e.g. vaccines) and direct medical care. 4 On the other hand, fertility has decreased (as shown in Figure 7.3.2, lower). In more developed countries, fertility decreased below the replacement level. Furthermore, the baby-boom generation (born between 1946 and 1964) will reach the age of 70 in this and the next decade. These factors discussed in more detail in Background Paper 5 make the elderly population the fastest growing part of the total population. In addition, there is a trend towards the feminisation of the elderly population due to the differences in life expectancies between men and women. This difference is more pronounced in Eastern European countries, as shown in Figure Figure 7.3.3: European life expectancy rates for men and women [Source: WHO Pharmaceutical Country Project, 2011 Source: Development of Country Profiles and monitoring of the pharmaceutical situation in countries. WHO,

151 Update on 2004 Background Paper, BP 7.3 Elderly 2.2 Osteoporosis Epidemiology and burden of disease Osteoporosis is a disease characterised by a decrease in bone density resulting in an increased risk of fractures. Decreased bone formation by osteoblasts and the increased breakdown of bone by osteoclasts eventually lead to changes in the micro-architecture of the bone. 6 The prevalence of osteoporosis increases with age, and women are much more affected than men. The prevalence rises from 5% in women aged 50, up to 50% in women aged 85 years. In men, the prevalence ranges from 2.4% (50 years) up to 20% (85 years). 7 Osteoporosis is much more prevalent among Caucasian populations. 8 Due to the ageing and feminisation of the population, osteoporosis is becoming more prevalent. 8 Figure shows the projected number of osteoporotic hip fractures worldwide. These are projected to rise from 1.6 million in 1990 to 6.3 million in Figure 7.3.4: Projected number of osteoporosis fractures worldwide. Source: Internation Osteoporosis Foundation. Epidemiology, Home - Osteoporosis & Musculoskeletal Disorders - Osteoporosis - What is Osteoporosis? Most osteoporotic fractures occur in the hip, spine, or wrist, and cause considerable reductions in mobility and quality of life. 11 Most of these fractures require hospitalisation and are therefore associated with complications such as pneumonia or thrombo-embolism due to chronic immobilisation. 11 Hip and spine fractures are also associated with high mortality rates, increasing with age from 3% in people younger than 60 years and up to 51% for the very elderly (90+) within the first year after diagnosis of the fracture. 12 Osteoporotic fractures are associated with high costs from hospitalisation, rehabilitation, and (premature) transition to institutional care. One United States study estimated that the total expenditures in the United States due to osteoporotic fractures were 16.9 billion dollars in the 7.3-9

152 Update on 2004 Background Paper, BP 7.3 Elderly year Three quarters of these costs were attributable to care for women. 8 More than half (62.4%) of the expenditures for osteoporotic fractures could be attributed to inpatient care and more than one quarter (28.2%) to nursing home care. 13 With the ageing of the population, it is predicted that osteoporotic fractures will cost about 25 billion dollar in the year 2025, an increase of 50%. 8 Diagnosis Osteoporosis is often diagnosed once a patient presents with a fracture, although efforts are ongoing to increase diagnosis before fractures occur. The density of the bone mineral, expressed in a T-value, is a measure for the degree of osteoporosis. 11 A T-value less than -2.5 confirms the diagnosis of osteoporosis. 6 Therapy Non-pharmacologic treatment for osteoporosis consists of life style changes, more physical activity (weight bearing exercises), cessation of smoking, and decreased alcohol consumption. The addition of vitamin D to achieve sufficient serum levels is usually advised. Pharmacologic treatments consist of compounds to increase bone density through the formation of bone (anabolic compounds, such as parathyroid hormone) or to decrease the breakdown of bone (antiresorptives such as bisphosphonates). These current therapies are known to be effective. A Cochrane Review on the effect of 10 mgs of alendronate daily (a bisphosphonate) showed statistically significant effects for the secondary prevention of vertebral, combined non-vertebral, hip, and wrist fractures. Relative risk reductions for secondary prevention were 45%, 23%, 53%, and 50%, respectively. 14 For primary prevention, only a significant relative risk reduction in vertebral fractures was observed (45% reduction). In another Cochrane Review, a dose of 5 mgs of risedronate daily (another bisphosphonate) showed similar effects; a statistically significant and clinically relevant benefit in the secondary prevention of vertebral, non-vertebral, and hip fractures, but with no effects in primary prevention. 15 Etidronate seems to have less effect in reducing fractures. Four hundred mgs daily showed only clinical significant benefit in the secondary prevention of vertebral fractures according to a Cochrane Review. 16 The use of bisphosphonates are hindered by side effects such as oesophageal irritation and drug-drug/drug-food interactions. Administration of oral bisphosphonates can be tedious: they require ingestion on an empty stomach, and after administration, along with drinking a full glass of water, the patient needs to sit upright or stand for minutes. Novel insights During the last decade, research revealed the pathogenesis of osteoporosis through linkages with tissue, cellular and signalling processes in more detail. Due to increased knowledge of molecular and cellular principles, novel therapies are being developed. An example is denozumab, a human IgG2 monoclonal antibody that interferes with Nuclear Factor-Kappa B (NFKB), which is an essential signalling compound in the activation of osteoclasts. Likewise, odanacatib inhibits the protease cathepsin K, which plays a role in bone degradation. This compound is currently under investigation in phase 3 trials

153 Update on 2004 Background Paper, BP 7.3 Elderly Fall prevention programmes Although osteoporosis leads to increased fracture risk, falls are the predominant predictor of fractures. About a third of the people aged 65 or over fall each year. Several risk factors for falls have been investigated. It is estimated that accidental/environmental causes account for 31% of falls, followed by gait/balance disorders (17%), and dizziness/vertigo (13%). 17 The use of psychotropic medicines is also another important risk factor. About 10% of all falls result in fractures. 18 Therefore, various fall prevention programs have been developed. Different studies have shown that between 15 to 50% of the falls can be prevented with interventions. The interventions that have been developed and studied are mainly strength and balance training, reduction in the number of psychotropic medicines, or dietary supplementation with vitamin D and calcium. 19 A recent Cochrane Review (2012) assessed the effects of interventions designed to reduce falls in the elderly living in the community. They used two outcomes: rate ratios to compare rates of falls (falls per person per year) and risk of falling based on the number of people falling in each group. The study showed that group and home based exercise programs and home safety interventions significantly reduced the rate of falling (rate ratio, RaR) and risk of falling (RR), with a RaR of 0.71 and a RR of 0.81 for exercise programs, and RaR 0.81 and RR 0.88 for home safety interventions, respectively. Multifactorial approaches (in which participants receive more than one intervention based on an individual assessment) reduced the rate of falls, but not the risk of falls. Interventions that focus on psychotropic medications are of value; gradual withdrawal of psychotropic medication reduced the rate of falls and a prescribing modification program for primary care physicians reduced the risk of falling. The supplementation of vitamin D did not reduce falls. 18 In the future, the study recommended that effective programs should be better implemented into practice, e.g. translation of research into practice should be strengthened. Research should also focus on methods to deliver the evidence-based programs and methods for increasing the uptake of and adherence to these interventions by the elderly. 18 These recommendations are in line with the recently announced action plan of the European Innovation Partnership on Active and Healthy Ageing launched by the European Commission which presents the basis for the future work of this action group on fall prevention. 20 Six different objectives have been described including the promotion of a systematic approach to identifying individuals at higher risk for fall and harm of falls who will benefit from tailored intervention, and promotion of a systematic and coordinated approach to implementing evidence based strategies for the prevention and optimal management of falls and fractures, in order to reduce the associated physical, psychological, and functional disability. 2.3 Oncology The background paper belonging to chapter 6.5 (Cancer and Cancer Therapeutics: Opportunities to address pharmaceutical gaps) describes the developments over the period of 2004 to 2012 in cancer diagnoses and treatment and identifies gaps between current research and potential research issues that could make a difference. The elderly are not specifically addressed in that background paper. Therefore, the present paper focuses on important topics related to cancer treatment in elderly patients

154 Update on 2004 Background Paper, BP 7.3 Elderly Prevalence of cancer in elderly patients Cancer is highly prevalent in a relatively small proportion of the total population. In the United States, more than half of all new cancer diagnoses are in people older than 65, 21 and this population accounted for only 12.4% of the total United States population in This trend will probably be more pronounced in the coming years due to the aging of the population. Likewise, the burden of cancer in this portion of the population will increase in the future. 23 Annex shows the United States prevalence by cancer type and age at prevalence ( data). In absolute terms, all types of cancer are more prevalent in the elderly except for Hodgkin Lymphoma and acute lymphocytic leukaemia. The most prevalent types of cancer in the elderly are prostate cancer in males; breast cancer in females; colon and rectum cancer, melanoma of the skin, and lung and bronchus cancer. 21 Although trends in prevalence are generally similar for the older population versus the younger population, disease profiles and the natural course of the disease may differ between age groups, with slower disease progression in the older population. Participation of elderly cancer patients in clinical trials Despite the fact that the elderly account for the largest population group of cancer patients, their participation in clinical trials is low, see also Section 3. 24, 25 While 63% of United States cancer patients were 65 years and older, this age cohort comprised only 23% of oncology trial populations in Figure shows the percentage of United States cancer patients represented in National Cancer Institute sponsored clinical trials, divided by age group. Some trials have been designed to investigate the effects of therapies in elderly cancer patients, but failed due to insufficient participation. For example, the ACTION trial, designed to evaluate the effect of chemotherapy versus observation in oestrogen receptor (ER) negative/er weakly positive breast cancer in women over the age of 70. The investigators planned to include patients from 43 research centres, but after 10 months only 4 of the 41 eligible patients were randomised and the study was discontinued. 26 The CASA study, set up to investigate the role of pegylated liposomal doxorubicin as an adjuvant chemotherapy in women with breast cancer aged 66 or older, also closed early due to poor recruitment. 27 Recruitment seems to be the complicating factor; this might be due to the treatment preferences of the clinician and the reluctance of this group of patients to agree to participate in trials in which the treatment arms differ radically

155 Update on 2004 Background Paper, BP 7.3 Elderly Figure 7.3.5: Percentage of the estimated United States male and female cancer population represented in National Cancer Institute-sponsored cancer treatment clinical trials in (note the log scale on the y-axis) Source: Sateren WB, Trimble EL, Abrams J, Brawley O, Breen N, Ford L, et al. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 2002 Apr 15;20(8): A factor that specifically complicates clinical research in the older oncology patient is their heterogeneity in terms of comorbidity, physical reserves, disability, and geriatric conditions. 29 This applies to older patients in general; but, for example, with cancer, it means that is not easy to predict how these patients will respond to chemotherapy. To enhance our understanding of patient response in relation to frailty, uniform tools to define and assess frailty are needed. There is an urgent need for a consensus on the definition of frailty, which is currently defined as the concept of a state of decreased physiological reserves due to an accumulation of deficits in physiological systems leading to a decreased resistance to stressors. 29 A uniform tool to assess frailty, with enough specificity and selectivity, would aid in deciding which patients are too healthy or too sick to participate in clinical trials, 30 and would guide therapy as well. The need for a clear and operable definition of frailty is also recognized by the International Society of Geriatric Oncology in their report on the ten priorities concerning geriatric oncology, 31 as part of the action plan on the Prevention and early diagnosis of frailty and functional decline, both physical and cognitive, in older people of the European Innovation Partnership on Active and Healthy Ageing. 32 Comprehensive Geriatric Assessment The recommendations of the oncology treatment guidelines, designed for younger patients, cannot be extrapolated to serve an elderly patient. For example, a study by Hoeben et al. investigated the patient factors associated with receiving adjuvant chemotherapy, treatment tolerance and outcome in patients older than 75 years of age with colon cancer. This study highlighted the necessity of screening a geriatric oncology patient before starting chemotherapy. In only 3% of the cases, the dose was adjusted before starting, but in 57% of the patients receiving chemotherapy, at least one adaptation was made after starting the therapy, as shown in Table

156 Update on 2004 Background Paper, BP 7.3 Elderly Table 7.3.1: Type and prevalence of adaptation of chemotherapy for stage III colon cancer made after start with chemotherapy in elderly oncology patients. Type of adaptation % of Patients Type of chemotherapy 3 Dose 18 Time in between courses 23 Number of cycles 28 Total 57* *In some patients more than one adaptation was made Source: Hoeben KW, van Steenbergen LN, van de Wouw AJ, Rutten HJ, van Spronsen DJ, Janssen- Heijnen ML. Treatment and complications in elderly stage III colon cancer patients in the Netherlands. Ann Oncol 2012 Nov In an attempt to overcome this knowledge gap and to help guide treatment decisions, two features of geriatric medicine have been incorporated into geriatric oncology: frailty and the comprehensive geriatric assessment (CGA). 29 The CGA is a systematic procedure that assesses the health status of the elderly focusing on functional, somatic, and psychosocial domains. 29, 34 The CGA has proven to be beneficial for patients in general, as discussed in more detail in Section 5.6. A study evaluating the influence of a CGA on treatment decisions in 161 patients aged 75 or over and diagnosed with cancer showed that in 49% of patients the initially proposed chemotherapy dose was changed after the CGA. In 76% of all cases, the CGA led to a geriatric intervention, including management of nutrition (47%), polypharmacy (37%), depression (19%), and cognitive impairment (18%). These results show the capacity of a CGA to highlight treatment/diagnosis gaps and influence treatment decisions. In a similar study in 375 patients older than 70 with cancer, the CGA led to a change in the initial cancer treatment plan in nearly 21% of the patients; most patients switched from chemotherapy to supportive care. 35 To perform the CGA, a variety of tools are used in order to assess specific geriatric conditions, such as the Mini-Mental State Examination (MMSE) for cognition. A systematic review investigated the association between the CGA and clinically relevant outcomes such as mortality, treatment toxicity, or chemotherapy completion. Different geriatric conditions were predictive for specific outcomes; frailty was predictive for toxicity of chemotherapy, and cognitive impairment and activities of daily living impairment were predictive for chemotherapy completion. However, evidence for the various conditions is too inconsistent to allow the CGA to guide decision making. 36 Because the CGA is a time consuming process, patients are often preassessed with a quick screening tool to select them for the CGA or standard treatment. This is known as a 2-step method. 29,37 Different screening tools to perform the first step exist, but their predictive value in making a good pre-selection before the CGA, or even replacing the whole CGA is not sufficient. 29,37 A systematic review on the predictive value of seven frailty screening tools on the outcome of the CGA found no conclusive evidence for one of the tools; tools with the highest specificity lacked sensitivity and vice-versa. Several tools addressed only one or a few of the different geriatric domains, 29 which makes them less applicable for a general preselection. The evaluation of these rapid screening tools needs further research and evaluation

157 Update on 2004 Background Paper, BP 7.3 Elderly It has not yet been clarified which geriatric conditions, such as quality of life, treatment tolerance or survival, are predictive of a specific clinical outcome in cancer patients. A robust screening tool is therefore needed in order to facilitate treatment decisions and offer tailored care. As long as this is not available, a complete multi-disciplinary geriatric assessment might be beneficial for all geriatric oncology patients, 29 in order to avoid under- or overtreatment and prevent complications or adverse treatment outcomes Vascular dementia Most cases of dementia that occur in the elderly are related to Alzheimer disease (AD). Background Paper Chapter 6.11 extensively focuses on the developments in AD since Here, we would like to focus on the knowledge gap around vascular dementia (VD). In most cases of dementia, there is a vascular component, which underlines the mixed character of dementia. 39 Attention is often paid more to AD, while VD is of great importance as well. Valid epidemiological data on the (age-specific) prevalence and incidence of VD are lacking. Depending on the different screening methods used, data differ considerably. It is assumed, however, that the incidence of VD is underestimated. 40 VD is a term describing dementia resulting from vascular brain lesions. Pure VD seems to be rare, and differentiating between VD and mixed dementia is challenging. VD is heterogeneous in terms of pathogenesis, pathology, and clinical phenotype. Stroke seems to be a predisposing factor, but cognitive decline may develop slowly after stroke, and lesions may be visible, clouding the border between AD and VD. VD patients benefit to a much lesser extent from cholinesterase treatment, and concurrent AD may have contributed to the positive results shown in some trials. 40 Current treatments focus on the prevention of VD, which is driven by the prevention of stroke. Targets for modifying vascular risk factors are similar to the well-described risk factors for cardiovascular disease and include hypertension, dyslipidemia, diabetes mellitus, blood hyperviscosity, carotid artery and intracranial artery stenoses, smoking, overweight, and physical inactivity. 40 Much remains unclear about VD, including its epidemiology. As the aforementioned risk factors are the only etiological factors that can be prevented at present, and most of the cases of dementia are mixed, more research on VD is needed. 3. Product related issues in the elderly There are several factors interfering with drug delivery in the elderly and two of those will be discussed in this background paper. First, the elderly have a different body composition, and their altered body functions are associated with changes in the pharmacokinetics and the pharmacodynamics of medicines. Second, the elderly are more vulnerable to factors influencing the administration of medication, such as difficulties with opening packages, swallowing or understanding health information. The development of special formulations aimed at older populations may help to overcome these difficulties

158 Update on 2004 Background Paper, BP 7.3 Elderly 3.1 Changes in body function in elderly In older people body functions change, and almost all body systems alter in structure and/or function with increasing age. In a healthy elderly person, this change might not be an overt problem, but it may nevertheless be more difficult or take more time for an elderly person to recover from illness. It is also more likely for the elderly to be left with a permanent disability after illness. Changes in body function can influence the metabolism and/or excretion of medicines. Prescribers must be aware of the risk of altered body functions as it may cause unexpectedly higher or lower drug levels. This can result in preventable adverse drug reactions, or, conversely, in reduced therapeutic effectiveness. Table 7.3.2: Physiological changes in older people with direct relevance to drug handling. Altered function Implications Example of a drug Change in body composition: decreased proportion of body water, relatively increased proportion of body fat Small reduction in serum albumin Differences in drug partition leading to different serum levels, depending on the polarity of the drug. Serum levels of hydrophilic drugs are likely to increase and serum levels of fat-soluble drugs are likely to accumulate in body fat which could prolong their effect. Easy intoxication with highly proteinbound drugs Liphophilic medicines, e.g. benzodiazepines and morphine accumulate in fat and show longer t1/2. Hydrophilic medicines, e.g. aminoglycoside antibiotics, digoxin and lithium show higher serum levels and need a lower loading dose. Usually low clinical relevance, except for phenytoin Decreased liver size and blood flow Decreased renal function Higher bioavailability of hepatic metabolized drugs and lower bioavailability of some pro-drugs Decreased clearance in water-soluble drugs and glucuronized metabolites leading to higher serum levels Metoclopramide shows higher serum levels due to decreased first-pass metabolism. Aminoglycoside antibiotics, digoxin, lithium, with their small therapeutic window, cause serious adverse effect if they accumulate Sources: Crome P. What's different about older people. Toxicology 2003 Oct 1;192(1): Jansen P, Brouwers J. Clinical Pharmacology in Old Persons, Review Article. Scientifica With advancing age, the body composition alters, there is a reduction in body water and lean body mass anda relative increase in body fat. This can induce a different partition of a drug in the body. Polar drugs will have decreased distribution volumes, resulting in higher serum levels. Non-polar drugs will have increased partition volumes, thereby resulting in prolonged half-lives. Thus, it is important to understand drug properties to ensure accurate dosage and dosage regime, especially in drugs with a narrow therapeutic range. Many drugs are metabolised in the liver (first-pass metabolism), either to be excreted more easily or to be activated (pro-drugs). In elderly people, there is a reduced blood flow to the liver and the mass of the liver decreases. The implication thereof is that first-pass metabolism results in higher bioavailability for drugs that are metabolised for excretion. On the other hand, the bioavailability of pro-drugs will be decreased. 41,43 In the elderly, reduced renal

159 Update on 2004 Background Paper, BP 7.3 Elderly function is common. This kind of reduction decreases the clearance of mainly water-soluble drugs and glucoronized metabolites. Whether or not this becomes a problem is dependent on the toxicity and therapeutic range of the drug. 43 These and other changes in body compositions and their implications are shown in Table Product related problems It is necessary to improve the delivery of medicines for the elderly. To illustrate the need for special formulations or packages, a patient with Parkinson disease (PD) might function as an example. First, these patients have difficulties with opening (blister) packages. This is also the case in many elderly, as shown in a study by van Geffen et al. using an internet-based medicine problem reporting system. A total of 10% of the reported problems were practical issues, of which almost 60% were related to difficulties with opening packages. 44 A study by Atkin et al. showed that almost three quarters of their study population (120 elderly with a mean age of 81 years) could not split a tablet and more than half of them could not open child-proof packages. 45 Second, patients with PD have difficulties with swallowing medications, both because of their disease-associated dysphagia and because the capacity for swallowing decreases with age. 46 About 9% of people aged 65, and up to 28% of people aged 85 or over have swallowing issues. Not only PD but other diseases are also associated with dysphagia as a common comorbidity (e.g., Alzheimer Disease, stroke, various oncological conditions and diabetes). 47 Levodopa, used to treat the symptoms of PD, has a short half-life (t1/2 = 1-2 hours) requiring frequent dosing of up to eight times a day. 48 To improve the dosing scheme and to provide stable serum concentrations, controlled release tablets have been developed. The controlled release tablets are often bigger, which then introduce difficulties with actually swallowing the tablet. The elderly often use many medicines which makes it more difficult to take them all. Capsules have been found to be easier to swallow than coated tablets, and coated tablets easier than uncoated tablets. 46 Patient centred care, stimulated by regulatory authorities and provided by manufacturers, is needed for the elderly with swallowing problems and other product-related problems. 47 Third, the elderly are often subject to polypharmacy, and with the deterioration of cognitive function, organisation might be problematic. Leaflet information is not always suitable for the elderly patient due to small letter sizes, or their poor health literacy for example. A study revealed that two thirds of older Americans (over 60 years of age) have inadequate or marginal literacy skills, hampering their understanding of the information provided. 49 Due to the introduction of generics, the packaging of medications changes continuously, potentially leading to confusion for the patient. A study by Bakke et al. investigated if the standardisation of packaging improved accuracy of recognition and discrimination of the medicine packaged. In the older group, overall accuracy improved from 52% to 82% (p<0.0001) Potential solutions and implications for research One solution for the above mentioned problem of polypharmacy could be the use of fixed dose combinations (FDC). These have been developed in order to improve adherence and to decrease the amount of individual pills a patient needs to take. This is also known as substitution indication. Between 2008 and 2012, a total of 27 FDC procedures were

160 Update on 2004 Background Paper, BP 7.3 Elderly completed and accepted by the European Medicines Agency (EMA). Most combinations were anti-hypertensives, oral contraceptives, and bisphosphonates with vitamin D and/or calcium. 51 Another relatively new development is the cardiovascular polypill for the treatment of ischaemic heart disease (IHD). Several variations exist, but in principle this is a tablet containing a fixed number and doses of more than two medicines, targeting a set of diseases or risk factors frequently co-occurring in patients. The IHD polypill has been developed for cardiovascular risks and contains a combination of blood pressure lowering drug(s), a cholesterol lowering drug, and/or a platelet aggregation inhibitor. For more information about the polypill as a FDC, the reader is kindly referred to Background Paper 6.3 on IHD. Many of the difficulties that the elderly have with formulations are similar to the problems seen in the paediatric populations. Table shows the basic criteria for paediatric and geriatric drug formulations. There are some key steps in the development of the medicines with regards to these patient groups concerning bioavailability, acceptability and palatability, dose adaptation and administration, socio-cultural acceptability, and product information. Adaptation of the dose is needed in both subpopulations. This is feasible for liquid formulations, but for tablets it is not as easy. Some formulations have special coatings, or are formulated in such a way that splitting disturbs the desired absorption profile. When the compounds are toxic, mutagenic, or have very narrow therapeutic indices, splitting is not appropriate. The main problem with using liquids is the taste. Newer formulation techniques using multiparticulate systems, such as mini pallets, might be an option for dose adaptation. 52 Many of these newer techniques have been designed for children and are extensively discussed in Chapter 7.1 (Priority Medicines for Children). Table 7.3.3: Basic criteria for both paediatric and geriatric drug formulations. Sufficient bioavailability Safe excipients Palatable and/or acceptable properties Acceptable dose uniformity Easy and safe administration Socio-cultural acceptability Precise and clear product information Source: Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv 2007 Jan;4(1): The EMA has recognised the need for special formulations for the elderly, and established a Geriatric Expert Group that is currently investigating how to improve the situation. The agency wants to make sure that it takes the needs of the elderly into account during the development, approval, and use of medicines. In a document prepared for a two-day workshop session on Ensuring safe and effective medicines for an ageing population, attention was paid to topics related to drug formulations. The workshop brought together various stakeholders, including EU public bodies, regulators, academic researchers, patients, and healthcare professional representatives, as well as representatives from the pharmaceutical industry. The workshop highlighted the fact that poor formulations decrease

161 Update on 2004 Background Paper, BP 7.3 Elderly adherence, and there is no one-size-fits all solution; a number of factors need to be taken into consideration looking at the patient as a whole. 53 For the development of more appropriate formulations for the elderly, we should learn from what we already know, including how we have started developing specialised medicine formulations for paediatrics. In some aspects delivery and formulations problems may differ between these two populations, but in many other aspects they are similar. These differences and similarities need to be studied in more detail and it is time to take the first steps in this direction. When in the near future adapted formulations have been developed, it will be crucial to study and evaluate how these products have influenced healthcare, and if they have indeed led to better health for the elderly. 4. Regulatory aspects related to elderly 4.1 Participation in clinical trials Despite their large consumption of medicines, and the fact that up to almost half of the total pharmaceutical expenditures is spent on the elderly, 54,55,56 they are still underrepresented in clinical trials. 42,57,58 Figure shows the percentages of patients included in trials compared to the percentages treated with cardiovascular drugs, stratified by age. The very old and the elderly with multi-morbidities are particularly not often included in clinical trials. Several factors complicate their inclusion: fear of the researchers to include frail elder patients, hesitation of clinicians to randomise patients due to treatment preferences and use of existing medication, lack of patient consent to enrolment, and difficulties accessing the research centre might play a role. 57,58 Pharmaceutical (innovator) companies seek trial conditions leading to a high internal validity, in order to prove the beneficial effects of the new drug. Homogenous groups, without interfering factors such as multiple drug use and multimorbidity, increase this internal validity; therefore, exclusion criteria are the predominant factor hampering the participation of this population. Because elderly are heavy drug consumers, often with multiple morbidities and high disease reoccurrence rates, the opportunities to include them are low

162 Update on 2004 Background Paper, BP 7.3 Elderly Figure 7.3.6: Percentage of patients enrolled in clinical trials of cardiovascular drugs compared to the percentage of patients treated with this medicines. Source: Cerreta F, Eichler HG, Rasi G. Drug policy for an aging population--the European Medicines Agency's geriatric medicines strategy. N Engl J Med 2012 Nov 22;367(21): Exclusion criteria A 1997 study showed that 35% of the papers published between June 1996 and June 1997 in four high standard journals (n=409) excluded the elderly (older than 75 years of age) unjustifiably. 60 Another group reviewed studies admitted to a local research ethics committee during a period of seven months in They revealed that in over half of the studies relevant to the elderly (n=155), the age limit was unjustifiably set. 61 Another study in the USA compared the participation of different age groups in cancer clinical trials with the prevalence of cancer in these age groups. They found that patients with cancer aged 65 and over accounted for 25% in the trials, compared to a 63% prevalence in the United States population. 25 The situation seems to have not improved over recent years. A more recent study (2007) investigated the amount of numerous justifiable and unjustifiable exclusion criteria from randomised controlled trials (RCTs) published between 1994 and They selected 283 articles with a total of 2709 exclusion criteria. In 38.5% of the randomized clinical trials (RCTs) people aged 65 and over were excluded, and in 81.3% of the RCTs people with co-morbidities were excluded. A total of 54.1% of the trials had medication related exclusion criteria. The study categorised exclusion criteria as strongly justified, potentially justifiable, and poorly justifiable. As shown in Table 7.3.4, age (78.4%), medical co-morbidity (64.8%), and medication-related issues were common unjustifiable exclusion criteria. 58 Choosing stringent eligibility criteria increases the internal validity and therefore efficacy, but the results are not always easy to extrapolate to patients that represent the actual treatment population in clinical settings. As a result, effectiveness is not adequately measured in these RCTs

163 Update on 2004 Background Paper, BP 7.3 Elderly Table 7.3.4: Justification of exclusion criteria from JAMA No. (%) of Trials * Grading of individual exclusion criteria Total number of exclusions 2709 (100.0) Strongly justified 1275 (47.2) Potentially justified 430 (15.9) Poorly justified 1004 (37.1) At least 1 poorly justified exclusion criterion 238 (84.1) Category with poor justification Age 160 (78.4) Medical comorbidity 149 (64.8) Sex 70 (52.6) Females 69 (62.2) Males 1 (4.5) Medication-related 56 (36.6) Socioeconomic status 31 (79.5) Percentage of poorly justified exclusion criteria (80.6) (61.5) (29.3) (8.5) Exclusions per trial, mean (SD) 9.5 (6.1) * Unless otherwise indicated Source: Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA 2007 Mar 21;297(11): Role of authorities Regulatory authorities play an important role in the encouragement of the participation of the elderly in clinical trials. In 1989, The FDA issued the Guideline for the Study of Drugs Likely to be Used in Elderly, in order to regulate and promote the inclusion of the elderly in clinical trials, so that sufficient information could be gained about medicine use in the elderly. In 1993, the International Conference on Harmonisation (ICH) developed the ICH E7 guideline: Studies in Support of Special Populations: Geriatrics, which was adopted by the FDA, EMA and the Japanese regulatory authority (PMDA). In 2010, a Questions & Answers report was developed by the ICH in order to implement the ICH E7 guideline. The aim was to make some recommendations in order to improve the implementation of the existing guidelines. 62 Recently, different attempts have been made to increase the participation of the elderly in RCTs. The PREDICT group, a multi-disciplinary and multinational consortium of health care professionals, supported by the Seventh Framework program, developed a Charter in order to promote the participation of the elderly in clinical trials. 63,64 First, the consortium prepared a systematic review to establish whether the elderly had been inappropriately underrepresented in trials of treatments for specific conditions. They recognised barriers to and promoters of participation, from a professional and patient point-of-view. The outcomes of this review were the preparation basis for the second step where, with the use of 521 questionnaires, they gathered the views of experts in nine European countries and asked if the elderly were under-represented in clinical reviews, and if so, what could be done to

164 Update on 2004 Background Paper, BP 7.3 Elderly overcome this. A total of 71% of the professionals did not consider the regulations and present arrangements for the conduct of clinical trials to be satisfactory, while 60% felt that national or European regulations needs alteration. Based on this information, they finally developed the Charter for the Rights of Older People in Clinical Trials, 65,66 which was launched in February This Charter contains guidelines and statements about this topic (see Annex 7.3.1). The PREDICT group gained attention from regulatory agencies, which resulted in EMA establishing a Geriatric Expert Group. Geriatric Medicines Strategy At a regulatory level, attempts have been made to improve knowledge about drug use in the elderly. In 2011 the EMA launched their Geriatric Medicines Strategy and established a Geriatric Expert Group (GEG), which provides scientific advice to the CHMP (Committee for Medicinal Products for Human Use) and the agency secretariat on issues related to the elderly. The Geriatric Medicines Strategy has two main aims to ensure that medicines used by the elderly are appropriately researched and evaluated throughout the lifecycle of the product. Firstly, the strategy recognises the elderly as the main users of medicines and seeks to ensure that the development and evaluation of new medicines take into account specific safety and efficacy aspects related to ageing. Secondly, they wish to improve the availability of information for patients and prescribers on the use of medicines in this population, in order to improve safety. 59,67 The strategy has identified that the very elderly (older than 75 years of age), with their frailty, should especially receive more attention. This group uses a disproportionate amount of medicines and should be represented in clinical trials following existing guidelines. In 2011, GEG members proposed several instruments that, in their opinion, are the most appropriate (although not free from methodological limitations) for the characterisation of the frailty level of older people enrolled in a clinical trial, both at baseline and at study completion: the Short Physical Performance Battery 68 and the Study of Osteoporosis Fracture Index. 69,70 Parameters considered by the GEG members when making their choice included an instruments validation status, predictive value, ease, and breadth of use. Additionally, the GEG has identified a scale that it considers more appropriate for monitoring change in the frailty levels. The Geriatric Medicines Strategy promotes the investigation of population pharmacokinetics, or a specific pharmacokinetic study including the very elderly, in order to recommend dose regimens and identify patients at risk. For these studies modelling and simulation might be helpful. The establishment of the Geriatric Medicines Strategy has been warmly welcomed by the AGE Platform Europe, a network of 165 European organisations focusing on a wide range of policy areas that impact older and retired people. The platform has promised to closely monitor the implementation of this strategy. 71 A recent position statement from the American Geriatric Society addressed this subject again and proposed several possible approaches to address the lack of representation of elderly patients in clinical trials. They suggested policies that call for the inclusion of elderly in government supported research, or laws to ensure that all drugs are tested for their use in this population prior to prescription. The creation of incentives, like patent extensions, when

165 Update on 2004 Background Paper, BP 7.3 Elderly older adults are included in industry supported research, as has been implemented for paediatrics, or allowing Medicare coverage of healthcare costs during clinical trials was also suggested. The society also proposed close examination of exclusion criteria in each protocol in a clinical trial design to ensure that these are scientifically justified. Finally, the society wants to persuade healthcare workers to highlight the importance of clinical trial participation to their older patients, and encourage them to enrol in studies Information about the elderly in product information and other information sources Because of the under-representation of the elderly in clinical trials, medicines are often prescribed off-label in this patient group. Sometimes there is already enough scientific evidence to prescribe in the elderly, but, due to delays in regulatory procedures, the Summary of Product Characteristics (SPC) has not yet been updated. Preliminary results from a study that investigated the availability of information revealed that in the information transfer process, much information is lost. For 53 new medicines, a maximum of 19 items derived from the ICH E7 guideline for studies involving geriatric populations were scored per new medicine. A large proportion (79%) of the information specified in the ICH E7 guideline is provided by the pharmaceutical companies and is available in the EPAR (European Public Assessment Report), the scientific report made by the EMA with regard to the registration of the product. However, only 56% of this information is available in the SPC text. 73 There is apparently no uniform European or international source of information for the treatment of elderly patients in daily practice. Treatment guidelines appear to be more disease-driven than patient-centered, and specific guidance on the treatment of elderly patients is frequently lacking, which may cause not only overuse but also underuse of medicines in this population. Ongoing and much needed research focuses on how physicians obtain their information to adequately treat the elderly in daily practice and how this information is being updated on a regular basis, but data are not available yet. It is estimated that 55% of people aged 75 and over suffer from four or more chronic conditions. 74 Guidelines developed in order to offer evidence based care usually focus on a single condition. These guidelines do not consider the cumulative impact of treatment recommendations, nor do they help to prioritise treatments. Therefore, they are not generally applicable to the multi-morbid patient. 75 Several groups have investigated the extent to which national guidelines addressed patient co-morbidity. 75,76 A paper examining the application of NICE (National Institute of Health and Clinical Excellence) guidelines to people with multi-morbidity showed that the guidelines consider older patients to varying degrees. They investigated if the guidelines made notes on age, co-morbidity and patient-centred care. Most guidelines contained only some general statements on the elderly, e.g. the clinician should consider individual drug characteristics and prescribe age-adjusted doses of relevant medications. Multi-morbidity was inconsistently accounted for in guidelines, usually without detailed discussion. In their introduction, most guidelines emphasised the importance of patient-tailored care, without offering disease-specific recommendations to do so. The guideline giving the most extensive and specific recommendations was the depression guideline, in which age adjusted medication use, tailored care, cases of co-morbidity and issues addressing adherence were discussed. The paper gave some recommendations on improving guidelines in the future, as

166 Update on 2004 Background Paper, BP 7.3 Elderly shown in Table One recommendation that was given was the cross-referencing of guidelines when the recommendations are synergistic or contradictory, using an internetbased format. Here again, the need for specific and easy accessible information on medication use in the elderly population is highlighted. Pharmacists could play an important role as they are in a unique position to assess all prescribed medications and the strengthening of their role in this respect should therefore be further explored. Table 7.3.5: Recommendations for improving clinical guidelines Providing summarised and comparable information about the relative benefits and risks of different recommend treatments would help inform prioritisation in multimorbid patients Existing guidelines should explicitly cross-reference each other when recommendations are synergistic or contradictory, and identify high-risk interactions between recommend treatments and other commonly prescribed drugs. This may be done in a internet-based format Clinical guidelines should include a small number of specific patient case examples for common combinations of comorbidity seen in clinical practice Guidelines should note some specific advice for practitioners when treating older patients (e.g, drug doses of class) Concerted action is needed to increase the participation of older people in clinical trials. Source: Hughes LD, McMurdo ME, Guthrie B. Guidelines for people not for diseases: the challenges of applying UK clinical guidelines to people with multimorbidity. Age Ageing 2012 Aug Because there is a lack of knowledge about the safety and effectiveness of the use of medicines in the elderly, more clinically generated information should be collected in order to enhance the informed prescribing of medicines. For example, prescribers worldwide should be encouraged to report all adverse drug reactions related to their prescription in elderly. 77 This information should be collected and presented in such a way that it is available in an integrated format for all healthcare professionals, thus leading to more informed prescribing. 42,59,77 Besides the inclusion of an adequate number of elderly patients in clinical trials and the collection of relevant data during the post-marketing phase, new and innovative approaches are needed to ensure the assessment of the effectiveness of medicines in the elderly (see Chapter 8.4). 5. The usage environment Medicine use in daily practice is or may be complicated in elderly patients, especially because elderly patients are often treated for multiple morbidities; treating co-morbidities often leads to polypharmacy. In addition, a full understanding of complex patients is often lacking. This section discusses the problem of polypharmacy, including the increased risk of adverse drug reactions and (non-)adherence, and provides insights into screening tools and interventions to monitor and improve polypharmacy. Furthermore, this section addresses other cross-cutting themes related to medicine use in the elderly such as access to medicines, palliative or end-of-life care, and integration or continuity of care, which poses particular challenges, as the elderly frequently move between different healthcare settings when diseased

167 Update on 2004 Background Paper, BP 7.3 Elderly 5.1 Polypharmacy The first edition of the Priority Medicines for Europe and the World report (2004) already acknowledged that if one speaks about polypharmacy as 'using multiple medicines' it does not appoint polypharmacy as a bad event. The use of fewer medications does not necessarily mean better treatment for the patient, and neither does more medication use imply overtreatment; the focus should not be on the number of medications, but on appropriate prescribing. 78,79 The treatment and prevention of cardiovascular disease e.g. ischaemic heart disease, is a good example of appropriate polypharmacy. To obtain optimal pharmacotherapy, the use of several different drugs is often required (e.g. antiplatelet therapy, cholesterol-lowering drugs, and blood pressure lowering drugs). 80 For many physicians, appropriate prescribing is not that easy. To obtain optimal prescription, it is necessary for physicians to have a good understanding of the pathophysiology of the disease, the changes of pharmacology with increasing age, 42 and in drug pharmacology. Several studies have shown that inappropriate prescribing occurs frequently among the elderly and that it is often related to polypharmacy. 81,82,83 Recent literature shows that this is still the case. A cross-sectional study from 2012 with 302 frail elderly persons (above 75 years of age) admitted acutely to a hospital were screened for potentially inappropriate prescribing (PIM). PIM was significantly associated with polypharmacy (more than five daily medications; OR 1.9, 95% CI and p = 0.026). 84 Another study showed a relationship between under-prescribing and polypharmacy. Patients with five or more medications were more likely to be under-treated than patients with four medications or less (OR 4.8, 95% CI ). 85 Figure shows the estimated probability of under-treatment related to the number of drugs. Despite the advantages of polypharmacy in some specific cases, it is not favourable in all cases. If polypharmacy is seen as the 'administration of more medications than are clinically indicated', a negative event, which has to be avoided, occurs. In the elderly, it has been found that the percentage of medication prescribed without indication or a less than optimal indication ranges from between 55 and 59% of all prescriptions. 86,87 This kind of polypharmacy is problematic, especially in the elderly, because it unnecessarily increases the risks of adverse drug reactions, geriatric syndromes (like cognitive impairment and delirium) and healthcare costs. 88 A more recent study by Dedhiya investigated the incidence of PIM in the elderly living in nursing homes. They found a one-year incidence of 42.1%. The elderly using a PIM were more likely to be hospitalised OR = 1.27; (95% CI 1.10 to 1.46), and more likely to die OR 1.46 (95% CI 1.31 to 1.62)

168 Update on 2004 Background Paper, BP 7.3 Elderly Figure 7.3.7: Estimated probability of under-treatment related to the number of drugs. Source: Kuijpers MA, van Marum RJ, Egberts AC, Jansen PA. Relationship between polypharmacy and underprescribing. Br J Clin Pharmacol 2008 Jan;65(1): Another problem stems from the discontinuity of geriatric care. Many patients are treated by different physicians concurrently, who are often unaware of the other medications a patient is using, which have been prescribed by other doctors. In most countries, people do not have a regular pharmacist or a family doctor who can review all of a patient's medications. Moreover, many people use not only prescription medications, but they also use a large amount of 'over-the-counter' (OTC) products. These OTC medicines include not only things like NSAIDs and antihistamines, but also vitamins, minerals and herbals. Most patients do not realize that the OTC-medications they are using can also influence their therapy, by interacting with their prescribed medications, for example, or augmenting the effects or sideeffects of prescribed medications (e.g. NSAIDs and antihistamines). Because of this ignorance, most patients do not report the use of OTC medications. 90 A study from 2005 showed that less than 5% of the OTC drugs were reported on drug charts, while almost two thirds of inpatients used them. 91 A recent Danish study showed that 74% of the elderly (above 65 years of age) used OTC drugs not listed in the Danish online prescription report. Fifty per cent of patients taking OTC drugs were exposed to potential interactions. 92 Polypharmacy has received a lot of attention since the first edition of this report in Recent data confirm that the elderly still consume many medicines and will always do so by virtue of their complex health needs. From 1996 to 2006, the average amount of medicines prescribed to elderly in the United Kingdom almost doubled. 93 This patient group consumes an average of four to five prescription medicines and two over-the-counter medicines at any given time. 94 Moreover, among people aged 65 or over, 40% consume between five and nine medicines weekly, and 18% consume more than 10 medicines on a weekly basis. 95,96,97 Polypharmacy is still associated with drug interactions, adverse drug reactions, increased risk of hospital admissions, falls, lower adherence and higher costs. 98,

169 Update on 2004 Background Paper, BP 7.3 Elderly Screening tools To assess suboptimal (misuse, underuse and overuse) or inappropriate prescribing, different tools have been developed and validated. The explicit and implicit methods both assess suboptimal prescription. 100 The explicit method makes use of standard (check-)lists or tools and focuses on the disease state or specific medicines. Examples of these lists are the Beers Criteria 101,102, the STOPP (Screening Tool of Older Persons potentially inappropriate Prescriptions) criteria, and the START (Screening Tool to Alert doctors to Right, i.e. appropriate indicated Treatment) criteria. 103 These tools are quite rigid and do not take specific patient information into account. They specify inappropriate drug combinations or contraindications. In contrast, implicit methods take the individual state of the patient into account to assess the appropriateness of prescription, thereby providing an opportunity to conduct a complete and flexible assessment of the pharmacotherapy of the patient. 42 A validated tool that could help with the implicit method is the Medication Appropriateness Index (MAI). 104 The applicability of the MAI score is limited in clinical practice because it is time consuming. Another example of an implicit method, which may be easier to use in clinical practice, is the Prescribing Optimisation Method (POM) that has been developed by the Expertise Centre Pharmacotherapy in Old Persons (Ephor). 105 Interventions to improve polypharmacy Several different interventions have been developed in order to improve polypharmacy. These interventions include the education of healthcare professionals, medication review clinics, the promotion of generic prescribing, or computerized decision support systems. A systematic Cochrane Review investigated the effects of different interventions on polypharmacy in the elderly. The primary outcomes were the appropriateness of medications prescribed (with the Beers List or the MAI), the prevalence of appropriate medication (using START criteria), and hospital admissions. Ten studies were included, of which nine were multifaceted interventions of pharmaceutical care performed by a pharmacist collaborating with the physician, patient, and carer. One was a computerized decision support system (CDSS) provided to the general practitioners. Most of the studies examined the appropriateness of prescribing using the MAI score. Table shows the pooled data of the primary outcome, e.g. the mean reduction in the summated MAI score post intervention was (95% CI to -2.35). The review found evidence that pharmaceutical interventions increase appropriate prescribing; however, it could not find evidence for clinically significant improvements, such as hospital admissions or adverse drug reactions. 106 It should be noted, however, that the quality of the underlying evidence was classified as very low, which hampers the interpretation of the results. This could be due to the great heterogeneity of the studies

170 Update on 2004 Background Paper, BP 7.3 Elderly Table 7.3.6: Pharmaceutical care interventions versus usual care in older patients. Outcomes Illustrative comparative risks (95% CI) Relative Summated MAI score Follow-up 0 to 12 months Change in MAI score The change in the MAI Follow-up 0 to 3 months Number of Beer drugs per patient. The Beers criteria Follow-up 0 to 12 months Assumed risk Usual care The mean summated MAI score in the control groups was 1.44 The mean change in MAI in the control groups was 1.43 The mean number of Beer drugs per patient in de control groups was 0.23 Corresponding risk (95% CI) Pharmaceutical care The mean summated MAI score in the intervention groups was 3.88 lower (5.4 to 2.35 lower) The mean change in MAI score in the interventions groups was 3.81 higher (1.17 lower to 8.78 higher) The mean number of Beers drugs per patient in the intervention groups was 0.06 lower (0.16 lower to 0.04 higher) effect (95% CI) Number of Participants (studies) 965 (five studies) 424 (four studies) (three studies) Quality of the evidence (GRADE) Very low Very low Very low Source: Patterson SM, Hughes C, Kerse N, Cardwell CR, Bradley MC. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database Syst Rev 2012;5:CD Medication reviews A specific type of intervention to improve polypharmacy is the medication review. Medication reviewing is a structured evaluation and reconciliation of a patient s medications, which often leads to some interventions in order to improve pharmacotherapy. When done, these reviews are usually performed by pharmacists in both primary and secondary health care. 107 Knowing that only 50% of medications are taken as directed 108, this review may improve pharmacotherapy, especially when performed with the participation of the patient. Different groups investigated the effects of medication reviews on outcomes such as appropriate prescribing, medication adherence, ADRs (adverse drug reactions), hospital admissions, or death. 109,110,111,112,113 Medication reviewing has been established to increase appropriate prescribing with regards to the reduction of polypharmacy, more appropriate formulation, and the more appropriate choice of medicine. 1076,109,1109,1110,1132 Pharmacist led reviewing often leads to the implementation of recommendations made towards the physician. A 2001 study by Krska showed that in elderly patients reviewed at home, 82.7% of the pharmaceutical care issues (PCI) were wholly or partially solved after the three-months follow up, in contrast to the 41.2% of the patients receiving usual care. GPs agreed with 95.8% of the documented PCIs and accepted 87.3% of the actions to resolve them. 113 A 2006 study by Zemansky et al. measured the impact of pharmacist performed clinical medication reviewing on the number of changes in medication for the elderly living in care

171 Update on 2004 Background Paper, BP 7.3 Elderly homes. They showed that medication reviewing was associated with a significant increase in the number of drug changes per patients, with a mean of 3.1 for the intervention group versus 2.4 for regular GP care, p<0,0001. Their secondary outcomes, such as drug costs ( and per 28 days, p-value unknown), hospitalisations (means 0.2 and 0.3, p = 0.11), and deaths (51/331 and 48/330, p = 0.81) did not show any statistical significance for the intervention versus regular care, respectively. A total of 75.6% (565/747) of the recommendations made by pharmacists were accepted by the GPs; 76.6% of these (433/565) were actually implemented. 110 A 2008 systematic review and meta-analysis by Holland et al. investigated the effects of medication reviewing on hospitalisations and mortality in the elderly. They pooled data and found no significant effect on all-cause admissions, RR 0.99 (95% CI 0.87 to 1.14, p = 0.92) or mortality, RR 0.96 (0.82 to 1.13, p = 0.62). On the other hand, reviewing was associated with improved knowledge and adherence in elderly patients. 1121,114 Table shows the secondary outcomes of the systematic review. Until now, the positive effects of reviewing in the elderly such as more appropriate prescribing, a tendency toward improved adherence and improved knowledge that the patients have, have not been translated in positive effects on harder clinical outcomes such as decreased hospital admissions, improved quality of life, or reduced mortality. 98,106,1121 Some of the studies did not have enough power to detect the above mentioned clinical outcomes, while in some larger studies there seemed to be a diluting effect of involving more pharmacists and more patients. In the larger settings, it was not the highly trained pharmacist performing the medication reviews. Because the design of the studies investigating the effects of reviewing varied widely, with some of them lacking a description of the interventions performed as a consequence of the review, systematic evaluation is difficult. 115 Due to a lack of robust research in this area, it has not been established if medication reviewing in the elderly is cost-effective. 107,115 Trials evaluating the effects of reviewing measured different outcomes and did not always measure costs. 114 A review conducted on this topic concluded that, generally, the costs of the interventions were not greater than the benefits, although in some cases there was a cost reduction in terms of the savings on medication costs These savings could be due to more generic prescribing or to the deletion of unnecessary medication

172 Update on 2004 Background Paper, BP 7.3 Elderly Table 7.3.7: Secondary outcomes of a meta-analysis on the different effects of reviewing in the elderly. No. of trials reporting outcomes compared with control No. reporting a significant positive effect (%) No. reporting a non-significant positive effect (%) No reporting no effect (%) No reporting either a nonsignificant or a significant negative effect (%) Quality of life (33) 8 (66) 0 Patient satisfaction Drug-related problems 4 2 (50) 1 (25) 0 1 (25) 4 4 (100) Knowledge 11 6 (55) 2 (18) 3 (27) 0 Adherence 14 7 (50) 4 (29) 3 (21) 0 Adverse drug reactions Storage problems Unnecessary drugs 9 1 (11) 3 (33) 3 (33) 2 (22) 3 2 (66) 0 1 (33) (71) 2 (29) 0 0 Cost analysis* 14 4 (29) 6 (43) 2 (14) 2 (14) * Three studies reported some form of cost-effectiveness analysis Source: Holland R, Desborough J, Goodyer L, Hall S, Wright D, Loke YK. Does pharmacist-led medication review help to reduce hospital admissions and deaths in older people? A systematic review and meta-analysis. Br J Clin Pharmacol 2008 Mar;65(3): Implementation of reviewing in daily care Despite a lack of evidence on harder clinical outcomes, medication reviewing has been recommended and implemented by different authorities and pharmacist associations. The General Medicines Contract, which is the contract of the GPs with the primary health organisations United Kingdom wide, advises that patients who receive prescribed medicines undergo medication reviewing at least every 15 months. The reviews may be performed by the GP, the practice based pharmacist, or the practice-based nurse. 107 Community pharmacists in England and Wales perform medication use reviews (MURs) as part of their NHS contract. They must be accredited to perform this task, and their pharmacy must have a consultation area that fulfils the NHS standards of privacy. Nowadays, they are focusing on specific patients groups such as those on warfarin, asthma/copd patients, or patients recently discharged from the hospital. 107 In Australia, as an initiative of the Australian government, the GP, along with the preferred community pharmacist, reviews polypharmacy patients using a team approach; the GP s medication information is shared with the pharmacist, and the pharmacist performs the Home Medicines Reviews and reports back to the GP. 107,116 In the United States, pharmacists working for two collaborating non-governmental associations provide reviews as part of a Medication Therapy Management service, in order to optimise drug therapy. 117 In the Netherlands, an

173 Update on 2004 Background Paper, BP 7.3 Elderly interdisciplinary guideline for polypharmacy was implemented this year (2012). It states that for the elderly patients (65 years or over) using five or more medicines and having one or more risk factor such as non-adherence, impaired cognition, or a decreased renal function, a medication review should be performed every year. For the elderly living at home, this can be performed by the GP in collaboration with the community pharmacist. 118 In this interdisciplinary guideline, the STRIP-method (Systematic Tool to Reduce Inappropriate Prescribing) is recommended to perform the review. This method consists of five steps, as shown in Table Table 7.3.8: The five step STRIP-method in order to structure the medication review. 1 Structured history taking of the patient 2 Pharmacotherapeutic analysis (effectiveness, under treatment, drugs without indication, ADRs, interactions, dosages) 3 Development of treatment plan by physician and pharmacist 4 Discussion of the plan with the patient 5 Follow up and monitoring Sources: Jansen P, Brouwers J. Clinical Pharmacology in Old Persons, Review Article. Scientifica Nederlands Huisartsen Genootschap. Multidisciplinaire richtlijn Polyfarmacie bij ouderen, Thus, different countries are performing medication reviews as a routine practice. The initiative of this reviewing differs from purely governmental (United Kingdom) to nongovernmental (United States and The Netherlands), depending on how the healthcare service is designed. Other publications emphasize the importance of the participation of the patient in the review process. A review by Blenkinsopp et al. on medication reviewing notes that the full participation of the patient supports partnership in medicine taking, achieving a more appropriate outcome for that particular patient. 107 The STRIP method explicitly includes the patient; there is direct contact with the patient in steps 1 and Further research evaluating the different methods to perform medication reviewing, including the assessment of the added value of involving patients is warranted. The necessity of an increased role for Information and Communications Technology (ICT) Reviewing is extremely time consuming. A thorough screening, with the collection of all the data, the interviewing of the patient, and the interaction of the pharmacist with the prescriber, is estimated to take at least two hours. 118 This estimate will be different depending on which tasks are performed by which healthcare professional. In order to facilitate appropriate prescribing and conduct medication reviewing more efficiently, there is a need to improve the supporting role of electronic health records and use of ICT. Only when computerised systems are more connected and clinical information about the patient is shared, can reviewing be efficient and cost-effective. In some countries, such as the Netherlands, parts of the review process are incorporated into daily pharmaceutical care in the hospital setting. A CDSS (computerised decision support system) can be incorporated into a computerised physician order entry (CPOE). These systems give basic alerts about

174 Update on 2004 Background Paper, BP 7.3 Elderly drug-drug interactions or contraindications. Nowadays, with the so-called clinical rules, more advanced and appropriate advice can be generated to provide clinical guidance. Using additional patient information, the system can guide the dosing of drugs that are eliminated by the kidneys using information about laboratory values such as renal function. 119 The software can be developed in such a way that it is in alignment with the treatment guidelines. 120 The system could also be used to select high-risk patients, who would benefit from a full medication review. The implementation of an adverse drug event alerting system (ADEAS), consisting of about 121 clinical rules, in a hospital pharmacy in the Netherlands resulted in both the selection of different patients by the ADEAS and in more interventions performed by the pharmacist when compared to the conventional medication surveillance method. The added value of the ADEAS were warnings for declined renal function and for the omission of essential concurrent medications. 119 The hospital setting, with more data being shared between health care professionals, could serve as an example for primary care. The need for more information in order to offer high quality and tailored care, is described in more detail later in this background paper. Opportunities for improving medication reviewing More research is needed to clarify if medication reviewing in the elderly is cost-effective and indeed improves clinical outcomes such as hospitalization, mortality, and quality of life. There is still ongoing research in the field of medication reviewing that might give us an answer in the future. 121 It seems that a multi-disciplinary approach in which at least the GP and community pharmacist participate, is beneficial for the outcome; focusing on patients more likely to benefit from the intervention increases the effectiveness of reviewing as well. 1076,1143 In addition, research should be directed towards the intersection of hospital and primary care, and more developed computerised systems, using shared data on clinical values, such as renal function, might offer benefits. 42 Finally, educational programmes in geriatric pharmacology are limited and have not been thoroughly evaluated. 122 Education in geriatric pharmacology should receive more attention in the curricula of health professionals and include topics such as polypharmacy and dose adjustment in organ dysfunction. 5.2 Adverse drug reactions The risk of adverse drug reactions (ADRs) increases with the number of individual medicines a patient is using. Because the elderly are using more medicines in comparison to the younger population, it is expected that more adverse drug reactions occur in people aged 65 and over. 123 The incidence of ADRs in the elderly was found to be about 5%, approximately half that of the non-elderly populations. 124 A meta-analysis suggested that adverse drug reactions rank between the fourth and sixth cause of death in hospitalized patients. 125 A study by Wester (2008) suggested that fatal ADRs were the seventh most common cause of death in the Swedish population, accounting for 3% of all deaths; anti-thrombotic medicines and NSAIDs were most commonly involved. 126 An eight-year survey (1999 to 2006) studied ADR related deaths in populations in the United States. This survey observed an overall increase in ADR related deaths. The age groups of and over75 years were associated

175 Update on 2004 Background Paper, BP 7.3 Elderly with a significant increase in ADR related deaths, with the greatest risk being seen in patients 75 years and over; OR 6.96 (95% CI 6.30 to 7.69). 127 Hospital admissions due to ADRs ADRs are responsible for unnecessary hospital admissions, which result in a loss of health and a waste of money. In several studies prior to 2004, the percentage of hospital admissions due to adverse drugs reactions already ranged from 4.1% in young people, up to 16.6% in the elderly. 128 It is important to realise that many adverse drug reactions are preventable, with the percentage of preventable ADRs in the elderly ranging between 27.6% and 51%. 1243,129,130 In line with the results of these studies, new data from the HARM (preventable Hospital Admissions Related to Medication) study showed that 5.6% of unplanned hospital admissions were medication related, of which 46.5% were potentially preventable. 131 More than a third of the elderly (above 65 years of age) who presented at an emergency department with an ADR needed to be hospitalised. 132 Table shows the reasons for potentially preventable medication related hospital admissions and the associated medicines found by the HARM study. Of the preventable ADR related hospital admissions, almost 15% were due to gastrointestinal bleeding, and 6% were due to problems of the endocrine system. 131 This study found that anti-platelet agents and insulin were most often associated with possible preventable hospital admissions. Recent research confirms these results; a study from 2011 found that, among patients 65 years or older, warfarin, insulin, and oral anti-platelet agents together account for more than 60% of hospitalisations. 132 Both warfarin and insulin require ongoing monitoring, due to their narrow therapeutic index, demonstrating that they are of higher risk with regards to causing adverse drug reactions. Table 7.3.9: Reasons for potentially preventable medication related hospital admissions and the associated drugs. Reason for Admission Digestive system GI tract bleeding Preventable Admissions, No. (%) (n= (14.5) GI tract symptoms (e.g., diarrhoea, constipation) 22 (6.6) Circulatory system: cardiovascular symptoms (e.g., dysrhythmias, heart failure) Respiratory symptoms (e.g., dyspnoea) Endocrine system: hypoglycaemia of hyperglycaemia 35 (10.5) 26 (7.8) 20 (6.0) Associated Drug (No. of Admission*) Antiplatelets (34), NSAIDs (14), anticoagulants (12), oral corticosteroids (4) Oral antidiabetics (4), laxatives (4), diuretics (4), opiates (3), loperamide (3), statins (3), antibacterial drugs (3) β-blockers (15), drugs affecting the RAAS (9), calcium antagonist (9), anticoagulants (7) Diuretics (12), respiratory drugs (6), β-blockers (6), NSAIDs (5) Insulin (18), oral antidiabetics (12), corticosteroids (3), diuretics (3) Abbreviations: GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; RAAS, renin angiotensin aldosterone system. * Ad admissions can be associated with more than 1 drug and is then mentioned more than once in the list. Source: Leendertse AJ, Egberts AC, Stoker LJ, van den Bemt PM. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med 2008 Sep 22;168(17):

176 Update on 2004 Background Paper, BP 7.3 Elderly In addition to specific medication use, the HARM study revealed patient-related risk factors all common attributes of older populations that are significantly associated with preventable hospital admission due to ADRs, as shown in Table Table : Patient-related risk factors significantly associated with preventable hospital admission due to ADRs. Risk factors Odds ratio (95% confidence interval) Impaired cognition OR = 11.9 ( ) Four or more diseases in the patient s medical history OR = 8.1 ( ) Dependent living situation OR = 3.0 ( ) Impaired renal function before hospital admission OR = 2.6 ( ) Non-adherence to the medication regimen OR = 2.3 ( ) Source: Leendertse AJ, Egberts AC, Stoker LJ, van den Bemt PM. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med 2008 Sep 22;168(17): A recent study by Merten et al. showed the incidence of adverse events (AE) in older (65 years or over) as compared to younger (below 65 years of age) hospitalised patients. They showed that the occurrence of AEs was significantly higher among the elderly than among younger people, with an incidence of 6.9% for the older and 4.8% for the younger patients. A fifth of all AEs were medication related in the elderly, and one third of these were preventable. In the younger population, the prevalence of this type of AEs was half of this, which further confirms that we need to focus on the appropriateness of medication in the elderly population. 133 Burden of ADRs ADRs are not only associated with undue harm to the patient, but can also be costly. These costs can be direct medical costs or indirect costs due to the loss of productivity by the patients (when younger than 65 years). Different groups calculated costs due to hospital admissions associated with ADRs, as was described in the first version of this report: In several studies the costs of hospital admissions due to adverse drug reactions have been calculated. The amounts ranged between per year (29-bed ward of general medicine) 134 to per year (23-bed ward of general medicine). 135 These costs are considerable, certainly at a (inter)national level, and may have increased in more recent years because this segment of the population has grown. A recent cost analysis study using data from the HARM study calculated the burden of potentially preventable ADRs and analysed which factors or subgroups contribute most to this burden. The average medical costs of one preventable hospital admission due to an ADR was 5 461, or US$ For individuals younger than 65 years old, the total costs were higher than those for the elderly due to production losses. Looking only at medical costs, the elderly accounted for a higher burden ( 5 637) than the younger patient ( 5 088). 136 More research is needed in order to assess whether interventions to prevent ADRs, such as medication reviewing, lead to a reduction in these ADR related costs

177 Update on 2004 Background Paper, BP 7.3 Elderly 5.3 Adherence Medication adherence is defined as the extent to which patients follow the instructions they are given for prescribed treatments. The adherence rate is said to typically be 50% for prescribed medications, but rates vary widely ranging from 0% to 100% depending on for example population and type of medication. 137 Good health outcomes and the benefit of therapies are hindered when a patient is poorly adherent or non-adherent. Poor adherence leads to higher healthcare costs, preventable hospitalisations, and higher mortality. 42,138 A recent report by the IMS Institute for Healthcare Informatics estimated that they improvement of adherence could lead to a global cost saving of US$ 269 billion of the total of US$ 475 billion avoidable costs in the year There are many different causes for non-adherence, which can be both intentional and unintentional. 140 Non-intentional causes are due to barriers that are beyond the control of the patients, such as lack of understanding, or an inability to pay for the treatment. Intentional non-adherence occurs when the patient decides not to follow the treatment recommendations. 141 A Cochrane Review (2008) investigated the results of RCTs of interventions to increase medication adherence, also measuring treatment outcomes. They divided the interventions into short-term and long-term interventions; an example of a simple short-term intervention was the instruction that all of the medications needed to be consumed. For short-term interventions, only four of the 10 studies showed improvement in adherence and at least one clinical treatment outcome. An example of an intervention on long-term treatment was the simplification of the dosage regimen. This was found to increase adherence significantly, as shown by Claxton et al. They demonstrated that adherence was 79% with one daily dose, 69% with two daily doses, and 51% with three times a day. 142 Complex interventions, such as the combination of thorough patient instructions, close follow-up, rewards for success, reminders or family therapy, were more often seen in chronic therapy. A total of 36 of the 83 interventions reported in the RCTs led to increased adherence, but only 25 improved treatment outcomes. These complex interventions are not very effective, despite the amount of effort and resources they consume. There is an important need for basic and applied research on interventions to assist patients in following the instructions on prescriptions for chronic medical disorders. 137 Although this also applies to the population as a whole, the elderly deserve special attention in this respect. A meta-analysis by Conn et al. investigated the existing evidence on the effects of interventions designed to improve adherence, especially in the elderly. 138 The authors estimated the overall mean effect sizes (ES) of interventions by means of random effect models. Outcomes of interest, besides medication adherence, were increased knowledge of a patient having high blood pressure. Table shows the mean ES of the interventions on these outcomes. Larger ESs correspond with a larger intervention effect, meaning that interventions certainly had a positive effect on adherence, and they improved knowledge to a larger extent. In addition, this study showed larger adherence from interventions employing special medication packaging, dose modification, participant monitoring of medication effects and side effects, and brief written instructions. The meta-analysis also emphasised the need for more primary research in this area, especially on the effects of behavioural rather than cognitive strategies for improving medication adherence. Individuals taking three to five medicines seemed to benefit most from the interventions

178 Update on 2004 Background Paper, BP 7.3 Elderly Fewer medications were easier to handle for the patients, leading to the intervention having less additional value, while more medication taking might require more intense and complex interventions to improve medication adherence. 138 Shared decision making plays an important role in medication adherence. A literature review states that when a patient participates in the decision making process, their perspectives can be evaluated concerning the therapy, and in this way short- and long-term goals can be negotiated. 143 Medication reviewing might be a strategy to improve adherence, but only if the patient fully participates in the process. 107 It should be acknowledged that this may not always be possible in patients with cognitive impairments, which are prevalent among older patients. The NICE guideline on Medicines Adherence adopts this strategy and states that decisions should be made together and that it is a patient s own right to reject a treatment, provided that he or she is completely informed about its risks and benefits. 141 Patient and caregiver empowerment related to adherence is one of the key objectives of the action plan on prescription and adherence to treatment of the European Innovation Partnership on Active and Healthy Ageing. 144 Further general objectives of this plan are to improve patient adherence to medication care plans, deliver improvements in the health care system in order to promote adherence, contribute to the research and methodology on ageing and adherence, and foster communication between different partners/actors in the healing and caring process to improve adherence. Table : Effect sizes of interventions to improve adherence on different outcome variables. Outcome Effect size Adherence 0.33*** Knowledge 0.48*** Health care service utilisation 0.16 Systolic blood pressure 0.21 Diastolic blood pressure 0.19* Levels of significance compared to control group:***p=0.001, *p=0.05 Source: Conn VS, Hafdahl AR, Cooper PS, Ruppar TM, Mehr DR, Russell CL. Interventions to improve medication adherence among older adults: meta-analysis of adherence outcomes among randomized controlled trials. Gerontologist 2009 Aug;49(4): In their 2012 report, IMS Health suggested four strategies to improve adherence: (i) adoption of cross-disease leanings, i.e. the way adherence in HIV therapy was improved in Africa could provide lessons for improving adherence in therapies such as type II diabetes in Western countries, (ii) applying a patient centred approach, comparable to the NICE guideline on shared decision making, (iii) supporting data collection efforts to enable targeted interventions, similar to the marketing and product strategies that target consumer behaviours, (iv) strengthening the role of the pharmacists, who are in a unique position to assess all prescribed medications and who can substantially improve adherence In conclusion, the best strategy to improve adherence in general, but particularly in the elderly, has not been found; effective interventions may be too complex and unsuitable in

179 Update on 2004 Background Paper, BP 7.3 Elderly daily practice. More research into establishing the most cost-effective interventions is needed. Future emphasis should also be placed on the necessity to actively involve the patient and/or caregivers in treatment decisions when possible. 5.4 Access to medicines Not all patients have equal access to healthcare, including medicines. 145 Access to healthcare might be compromised by multiple factors like discrimination (on the basis of age, gender, race, socio-economic status), lack of reimbursement, or perceived biases in outcomes leading to unintentional underuse. There is variation in access to healthcare within and between countries; for example, lower-income countries show more shortfalls in the use of drugs for the secondary prevention of a cardiovascular disease than middle-income or high-income countries. 146 In this section we focus on the equity of care and the unconscious underuse of medicines in the elderly. Access to medicines Access to healthcare highly depends on the socio-economic situation in a country or a population. For example, in low- and middle-income countries, healthcare is mostly financed by out-of-pocket payments, 147 while the governments of OECD (Organization for Economic Cooperation and Development) countries are more committed to ensuring equitable access to high-quality medical care. 148 Very limited data on inequity in access to medicines in Europe due to age discrimination could be found in the literature. A Spanish study on access to a GP showed the presence of a pro-poor inequity; seniors with a lower income had more access to GP services and used their service more frequently. 145 A Belgian study on the influence of social-economic status on healthcare utilisation showed that it exerted no influence in the elderly population when corrected for healthcare status; this is in contrast to the situation observed in the younger population. However, the elderly with less education did have more frequent contact with a GP. 149 Although the current data do not suggest poor access as a result of age discrimination, the paucity of data hampers drawing firm conclusions. In addition, it is unknown to what extent the ongoing economic recession, and the subsequently undertaken policy measures, might impact healthcare consumption and medicine utilisation in the elderly. Underuse of medicines in the elderly Underuse of medicines is an underestimated problem in the older population; misuse and overuse gain much more attention. A study using a full CGA to estimate the prevalence of prescribing omissions in older people who presented at a geriatric acute care ward, showed that 73.5% of the population under study (n=200) had at least one omission in his or her medication. Those most commonly omitted were treatments for osteoporosis, depression, and dementia, as shown in Table These results should be interpreted with caution however, particularly because treatment for dementia is only effective for short-term benefit. Another study evaluating the treatment of older persons presenting in an internal medicine ward (n=123), whose treatment was compared with the recommended pharmacological treatment guidelines, showed that under-prescribing occurred in 39% of the participants. 151 In this study, the conditions associated with under-prescribing were myocardial infarction, osteoporosis, diabetes mellitus, and heart failure. After evaluating the medication, the GP was asked to explain his or her prescribing choices. In 65% of the cases, the GP had a clear

180 Update on 2004 Background Paper, BP 7.3 Elderly reason for not prescribing; the most reported explanations were limited life expectancy, adverse events, and the indication for a treatment no longer present. These results therefore show that it is important to distinguish between appropriate and inappropriate underprescribing. Another reason for under-prescribing is the relative absence of guidance for prescribing in the elderly in clinical guidelines (see Section 3.2). 151 In Section 5.1, several tools to assess underuse are described, such as the START tool (explicit method) or the CGA. The START tool helps the physician to detect underuse, but is not intended to guide careful clinical decision making. In that case, the Complete Geriatric Assessment, which is time consuming but allows for the assessment of more parameters, such as clinical, cognitive, functional, nutritional and social determinants, could be of use. 150 Table : Therapeutic classes most frequently underused. Therapeutic Class Individuals with Indication, n Individuals in Underuse, n (%) Antiosteoporotic medication (65.0) Vitamin D (64.7) Dementia treatment (49.2) Antidepressant (22.2) Angiotensin-converting enzyme inhibitor or angiotensin (18.8) 2 receptor antagonist Statin (14.4) Antivitamin K 49 7 (14.3) Antiplatlet agent 87 9 (10.3) Beta-blocker 46 2 (4.3) Source: Andro M, Coutard A, Gentric A. Underuse in elderly adults: an underestimated suboptimal prescribing. J Am Geriatr Soc 2012 Aug;60(8): The recent IMS Health report Advancing the Responsible Use of Medicines calls for awareness about the timely use of medicine, which can only occur when there is access to healthcare. This report used type II diabetes mellitus and hepatitis B/C as examples. They defined three strategies for more timely use of medicines in these conditions and estimated cost savings in health care, despite costs for medication use increasing once all patients were treated appropriately. First, support for a national focus on early diagnosis, so that complications can be prevented. Second, leverage economic evaluations, evaluate factors such as the number of cases needed to treat for prevention of communicable conditions. Third, ensure the use of targeted disease management programmes, such as those for diabetes. This way, significant costs can be avoided by preventing macrovascular events. 139 Further research is warranted to assess the extent of inappropriate under-prescribing in the elderly, to evaluate the effectiveness of tools to identify and correct this under-prescribing, and to assess other proposed strategies for more timely use of medicines. 5.5 Palliative care There has been increased amount of attention paid to palliative, or end of life, care over the past few years. End of life care is not easy to handle, given that the prevailing medical philosophy is focused on curing illnesses and prolonging life. Now that people tend to

181 Update on 2004 Background Paper, BP 7.3 Elderly survive acute diseases, they often suffer from chronic diseases, which end in a period in which the patient needs additional support. According to a USA study, about 25% of Medicare expenditures arise in a patient s last year of life, indicating an intense and health consuming phase. 152 Palliative care is therefore becoming more important, 153 as it aims to relieve suffering and to improve the quality of life of patients with advanced illnesses, as well as providing support to their families. 154,155 In 2002, the WHO defined palliative care as an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness. 156 In the development of palliative care, the focus was initially on terminal cancer care, usually in hospices, but this has been expanded to include patients with other diseases and is starting earlier in the disease course. 155,157 In a 2004 WHO report Better Palliative Care for Older People, the second in a series of three reports, made recommendations for future research; such as the investment in research into the geographical variations between and within countries in palliative care that the elderly receive. They promoted collaboration in research between palliative and geriatric medicine, and supported the inclusion of older people in all kinds of innovative research on physical interventions, including drug treatments. They also promoted the development of standardised assessment tools for palliative care in older people; 157 but the needs are far from being met. Because this report lacked specific details about how practices could be changed, a third report was written; Better Palliative Care for Older People: better practices. In this report, more practical suggestions are presented to improve palliative care in various settings such as hospitals, nursing homes, and at home. 158 Polypharmacy is prevalent at the end of life, but optimal prescribing at this stage of life remains largely unexplored. There is, however, increasing acknowledgement that treatment goals may need to be redefined, and guiding principles for appropriate prescribing in endof-life patients have been suggested. 159 These include, for example, revision of therapeutic targets, discontinuation of medications for primary and secondary prevention, avoidance of taking more than five daily medicines, and the graduated withdrawal of medicines, unless the patient or caregivers are unable to cope with the reduced lifespan. Medication review and the simplification of drug regimes in this cohort have been called for. The most important research question related to this topic is whether the presented principles indeed lead to better end-of-life quality. Palliative care generally consists of various aspects, with the most important ones being symptom management; particularly pain, dyspnoea, and depression. Care planning and continuity of care and relieving the burden on caregivers are also key components of palliative care. A systematic review assessed the evidence for several interventions to improve palliative care. Table gives an overview of the findings. 160 The strongest evidence was found in the symptom domains of palliative care such as pain, dyspnoea and depression. Less evidence was found on the more complex domains, such as advance care planning, continuity of care, or caregiver burdens

182 Update on 2004 Background Paper, BP 7.3 Elderly Table : Summary of systematic reviews and additional intervention studies of palliative and end-of-life care. Domain Literature identity* Summary of Evidence and GRADE Ratings ** Symptoms Pain Dyspnoea Depression Advance care planning Continuity Caregiver burdens Nine systematic reviews (25-33) and 24 reports of interventions (34-57) Seven systematic reviews (27, 28, 61-65) and 12 reports of interventions (37, 41, 42, 45, 46, 48, 57, 66-70) Four systematic reviews (26, 27, 30, 71) and 9 reports of interventions (35, 37, 39-42, 72-74) 9 systematic reviews (25, 29, 75-81) and 32 reports of interventions (35, ) Nine systematic reviews (25, 27, 29, ) and 12 reports of intervention (103, 104, 112, ) Eight systematic reviews (25, 27, 29, ) and 19 reports of interventions ( , ) Strong evidence supports approaches to treating cancer pain with nonsteroidals, opioids, radionuclides and radiotherapy. Less consistent evidence supports use of bisphosphonates for pain of painful complications (for example, fracture). Weak evidence supports multidisciplinary teams. No evidence addressed pain management in advanced heart failure of dementia. Strong evidence supports treating dyspnoea with β-agonists and opioid use in COPD, although these trials are small and short in duration. Weak evidence supports opioid use for relieving dyspnoea in cancer. Strong evidence supports pulmonary rehabilitation and oxygen for improving symptoms during shortterm exercise in COPD. Evidence for oxygen use in cancer is weak, and few studies address it. Weak evidence supports care delivery interventions for dyspnoea. No evidence addressed symptomatic dyspnoea management in advanced heart failure. Strong evidence supports psychotherapy, as well as tricyclic antidepressants and SSRIs, for depression treatment in cancer. Moderate evidence supports multicomponent interventions to increase advance directives; however, such studies seldom measure clinically important outcomes. Recent research supports care planning through engaging values, involving skilled facilitators, and focusing on key decision makers (for example, patients, caregivers, and providers) Moderate evidence supports multidisciplinary interventions that target continuity to affect utilization outcomes. Evidence is strong for reducing readmissions in hearts failure, but insufficient evidence was available for other conditions. Successful interventions involved multidisciplinary teaming, addressed patient needs across settings and over time, and facilitated communication by personal and technological means. Weak to moderate evidence suggests that caregiver interventions especially when comprehensive and individually targeted, can improve various measures of caregiver burden, although effect sizes are small. Moderate evidence suggests that palliative care interventions improve caregiver satisfaction. Existing research has focused on dementia and, to a lesser extent, cancer. Source: Lorenz KA, Lynn J, Dy SM, Shugarman LR, Wilkinson A, Mularski RA, et al. Evidence for improving palliative care at the end of life: a systematic review. Ann Intern Med 2008 Jan 15;148(2): Another systematic review evaluated the effectiveness of specialised palliative care in terms of improving quality of life, satisfaction with care, and economic cost. This study found scant evidence for specialised palliative care in these domains. The only statistically significant effect was seen for caregiver satisfaction. The studies included were hindered by methodological challenges and often lacked power or sample size calculations, decreasing the quality of this evidence. Moreover, the tools used to assess quality of life were not validated for the terminally ill patient. Cost calculations indicated a shift from hospital costs

183 Update on 2004 Background Paper, BP 7.3 Elderly towards the costs from hospices and home care that are associated with specialised palliative care. There was a trend in cost-reduction but no cost-effectiveness studies have been performed. These researchers concluded that carefully planned trials using standardised palliative care interventions and measures constructed specifically for this population are needed. 155 Although strong evidence was found for interventions focusing on pain treatment, one of the most difficult aspects of end of life care is pain management. It starts with under-assessment, as stated in the 2004 WHO report on palliative care. 157 A large 1998 survey among patients with cancer reporting daily pain showed that 25% did not receive any kind of pain therapy, and an inverse relation with age was observed; the older the patient, the less pain relief was given. 161 Figure shows the outcome of pharmacological treatment divided by the patient groups of this survey. Figure 7.3.8: Pharmacological treatment of cancer patients with pain according to the World Health Organization's (WHO's) 3-level ladder. The WHO's level 1 is non-opioid analgesics; level 2 is weak opiates; and level 3 includes morphine or similar substances. Source: Bernabei R, Gambassi G, Lapane K, Landi F, Gatsonis C, Dunlop R, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998 Jun 17;279(23): Unfortunately, more recent research does not indicate an improvement in pain treatment in the last phase of life. A study by Yao et al. on the pain management of 1425 end-of-life patients showed that only 42.7% of the patients with pain showed the predicted pain outcome (goal) at discharge or death. This study showed an under-diagnosis and underdocumentation of pain, with only 70% of the pain episodes of the patients on surgical wards were documented. 162 Different barriers exist that hinder adequate pain management: patient barriers such as misconceptions about pain and treatments, and fears and concerns about pain medications and side effects; reluctance to report pain and symptoms; and the complexity of the symptom experience. Barriers related to providers are, for example, lack of knowledge of, skills in, and time for adequate pain and symptom assessment; lack of knowledge about

184 Update on 2004 Background Paper, BP 7.3 Elderly analgesics; symptom interventions; and side effects of therapies. There is also insufficient knowledge on mechanisms underlying pain at the end of life. 163 In December 2009, the EU--funded Access to Opioid Medication in Europe (ATOME) project was started. The project strives to improve access to opioids in 12 Eastern European countries. The commonality between these countries is statistical evidence of very low morphine consumption per capita. 164 To improve access to controlled medicines used for the relief of pain, in harm reduction, and in palliative care, the ATOME project collaborates with national country teams including government officials and healthcare professionals to review national policies and legislation and make recommendations for improvement. One of the first achievements of the ATOME project was the publication of new WHO Policy Guidelines Ensuring Balance in National Policies on Controlled Substances; Guidance for availability and accessibility of controlled medicines, which provides a basis for all subsequent activities. 165 Country workshops confirmed the diversity of aspects that play an important role in limited access, including the lack of education and training, overly restrictive regulations, lack of financial resources and fear of opioids. 166,167 The effectiveness of the approach taken, in terms of access to and use of controlled substances, is unknown and needs to be evaluated. All of the above mentioned results strongly indicate the need for additional focus on pain diagnosis, interventions, and outcomes for end of life patients. In addition, access to controlled substances needs further attention with a focus on understanding and diminishing existing barriers. There is also a need to translate pain science into practice. Practice based datasets may provide insights in practices associated with better outcomes. In conclusion, the focus should lie on pain management and on the evaluation of effective interventions in palliative care. 5.6 Integrated care The integration and continuity of care is extremely important, especially when a patient is multi-morbid, which is the case for many of the elderly. The transitions an older patient makes between sites of care may introduce risks as well as risk opportunities in their medication management; risks in the sense of the loss of information and/or medication discontinuation, and opportunities in the way that these transitions provide a chance to review the patient s medication profile. It has been shown that the highest risks are among patients admitted to an intensive care unit. Now, efforts to reduce medication discontinuation are based on hospital-based medication reconciliation (as described in Section 5.1), medication reviewing, or a complete geriatric assessment (CGA). In contrast, little effort seems to have been done to ensure good communication between physicians (and other health professionals) across different sites of care, including the transfer to a private home or a care residence. 168 It is also important to know what happens with medications when the patients return to their homes. Can the patient manage his/her complex medication regimen, and if not, what can go wrong? To illustrate the challenges of achieving integration of care, we use, as an example, the case of an 82-year-old woman, living alone, who falls and breaks her hip and then moves from her home to the hospital, then to a nursing home, and eventually back to her own home. This example demonstrates the importance of integrated care, and the many points at which things can go wrong

185 Update on 2004 Background Paper, BP 7.3 Elderly Table : The Structure History Taking on Medication use questionnaire (SHIM). Questions asked per drug on the medication list, provided by the community pharmacist 1. Are you using this drug as prescribed (dosage, dose frequency, dosage form)? 2. Are you experiencing any side effects? 3. What is the reason for deviating (from the dosage, dose frequency, or dosage form) or not taking the drug at all? 4. Are you using any other prescription drugs that are not mentioned on this list? (view medication containers) 5. Are you using non-prescription drugs? 6. Are you using homeopathic drugs or herbal medicines (especially St. Johns wort)? 7. Are you using drugs that belong tot family members or friends? 8. Are you using any as needed drugs? 9. Are you using drugs that are no longer prescriped? Questions concerning the use of medicines? 10. Are you taking your medication independently? 11. Are you using a dosage system? 12. Are you experiencing problems taking your medication? 13. In case of inhalation therapy: What kind on inhalation system are you using? Are you experiencing any problems using this system? 14. In case of eye drops: Are you experiencing any difficulties using the eye drops? 15. Do you ever forget to take you medication? If so, which medication, why and what do you do? Other Would you like to comment on or ask a question about your medication? Source: Drenth-van Maanen AC, Spee J, van HL, Jansen PA, Egberts TC, van Marum RJ. Structured history taking of medication use reveals iatrogenic harm due to discrepancies in medication histories in hospital and pharmacy records. J Am Geriatr Soc 2011 Oct;59(10): When a patient is admitted to the hospital, the first step is medical history taking. This is a crucial step in the management of the older patient, especially when they are taking multiple medications. Still, much can go wrong in the taking of a medication history, which leads to discrepancies between medication lists in primary and secondary care. A study on the newly designed method for Structural History taking of Medication use (SHIM, shown in Table ) showed that there was a discrepancy between the usual care provided and SHIM in 92% of older participants. A mean of three discrepancies per patient was found, with omissions being most prevalent. A total of 5% of the discrepancies had a clinical consequence, occurring in 21% of the patients. 169 When a patient is admitted, the medication is adjusted to the formulary of the hospital. Hospitals frequently have their own formulary and the Pharmaceutical and Therapeutic Committee, usually consisting of physicians, hospital pharmacists, the hospital management and others, decides which drugs are included. Hospital formularies may differ substantially from formularies in the community. They are restricted, in comparison to the reimbursement lists of the outpatient-sector. The PHIS (Pharmaceutical Health Information System) Project, commissioned by the Executive Agency for Health and Consumers (EAHC) and co-funded by the Austrian Federal Ministry of Health (BMG), investigated the policies on procurement, distribution, pricing, financing, and use of medicines in the inpatient sector. They used five case study countries to the collect prices of medicines in hospitals. It was shown that considerable discounts and rebates are common and in some cases, medicines are provided cost-free to the hospital. 170 Such inpatient policies may affect the hospital formulary and account for the need of patients to change medication when hospitalised and when discharged

186 Update on 2004 Background Paper, BP 7.3 Elderly Because of the formulary, a transition step from the home medication list to the hospital medication list needs to be included, introducing risks of omission of drugs, or errors in dosing. It is conceivable that some new drugs have been started during admission, such as bisphosphonates and vitamin D for osteoporosis in a hypothetical patient, for example. It is also possible that the hospital has discontinued a drug, due to an adverse event or when an indication is no longer present. When the latter occurs, it is of importance to document the discontinuation. A study has shown that in almost 40% of the cases, reasons for the discontinuation of drugs in the hospital were not documented. 171 Another study showed that ADRs requiring discontinuation were poorly mentioned in discharge letters to the GP and were not communicated at all to the pharmacies. Only 22% of the letters that mentioned ADRs were incorporated into the patient`s GP file. 172 In this case, poor documentation and communication can lead to renewed prescription in primary care, which occurred in 27% of the reported cases within six months after discharge. 171 With electronic prescribing systems, CDSS can be used to support the documentation of discontinuation and generate warnings when drugs are prescribed again after discontinuation. In a pilot study, the implementation of such a system was user friendly and fulfilled the aims of documenting discontinuation and alerting physicians when they prescribed the discontinued medicine again. 173 This type of system works within the same hospital, but when the information does not reach the primary care, there is a chance that drugs are prescribed again in this setting. This illustrates the need for more communication between primary and secondary care. As such, ICT must play a bigger role, making it easier to exchange information. 168 A few decades ago, placing the frail elderly in an innovative geriatric unit with the intention of providing improved diagnostic assessments, therapy, rehabilitation, and placement, resulted in reduced mortality (23.8 versus 48.3%, p<0.005) and time spent in nursing homes (26.9 versuss 46.7%, p<0.05). 174 Similar results were found in a study from 2002, where, after a triage, the frail elderly were placed on a special ward. Here, all relevant disorders were assessed, resulting in significantly increased diagnoses of psychiatric disorders. 175 A 2011 a Cochrane meta-analysis evaluated the effects of CGA in elderly people presenting at an emergency ward on outcomes such as being alive and at home (primary outcome) and various secondary outcomes such as death, residential care, or dependence. They included 22 RCTs with more than elderly and showed that CGA increased the chance of a patient living at home after follow up (mean 12 months; odds ratio 1.16 (95% CI 1.05 to 1.28); p=0.003). Patients receiving CGA were less likely to live in residential care, experience deterioration, or die. However, CGA was only effective when performed in special wards, not when performed by mobile geriatric teams. A possible explanation for this is that the mobile teams find it difficult to modify the behaviour of other healthcare professionals. 34 Evidence suggests that it is important to treat elderly in a geriatric environment. The next step for our hypothetical elderly patient with a hip fracture is discharge from the hospital and a move to a nursing home for further rehabilitation. Some hospitals make use of discharge planning, bridging the gap between the hospital and nursing home environments or the hospital and home. A Cochrane Review from 2010 investigated the effectiveness of discharge planning in terms of appropriate use of care, patient outcome, and costs. They found a small reduction in the hospital length of stay; mean difference of days (95% confidence interval to days), and more patient satisfaction, but no effects on patient outcomes such as mortality. The decreased length of the hospital stay was not

187 Update on 2004 Background Paper, BP 7.3 Elderly necessarily associated with fewer costs, as it could have led to a shift in costs from secondary to primary care. Future research should continue to collect data about hospital lengths of stay and readmission, and attention should be paid to the communication between primary and secondary care, which was often the reason for implementing discharge planning. 176 After discharge, our imaginary patient is transferred to a nursing home. Again, a translation of the medication needs to be effected, introducing new risks of errors. A study published in the JAMA evaluated the risk of potentially unintentional discontinuation of chronic medication following ICU or hospital admission. It was shown that discontinuation of anticoagulant therapy, for example, was more prevalent in patients after hospital admission than in controls, adjusted odd ratio (AOR) 1.86 (95% CI 1.77 to 1.97). This was more pronounced after ICU admission; AOR of 2.31 (95% CI 2.07 to 2.57). More detailed results for other medications are shown in Table These findings illustrate the need for a systematic approach to the transition of healthcare to ensure continuity of care. 177 Table : Outcome of Unintentional Discontinuation by Medication Group. No (%) of Patients ICU Stay a Control Group Hospitalized AOR (95% CI) b No *%) of Patients AOR (95% CI) b Medication discontinued Statins (10.7) (13.6) 1.33 ( ) 1484 (14.6) 1.48 ( ) Antiplatelet or anticoagulants 2535 (11.8) 5564 (19.4) 1.86 ( ) 522 (22.8) 2.31 ( ) Levothyroxine 7114 (11.0) 6831 (12.3) 1.18 ( ) 614 (15) 1.51 ( ) Respiratory inhalers 79 (3.0) 231 (4.5) 1.50 ( ) 20 (5.4) 1.84 ( ) Gastric acid suppressors 4330 (9.4) 7394 (12.9) 1.50 ( ) 670 (15.4) 1.87 ( ) Abbreviations AOR: adjusted odds ratio; CI, confidence interval; ICU, intensive care unit. a Patients with an ICU stay compared with the control group. b Adjusted for age, sex, low-income (defines as individual income <$16,018 or combined household income <$24,175), number of different prescriptions, and number of primary care physician or specialist visits. c There is detailed information for each medication group in etable 3 at hhtp://ww.jama.com. Source: Bell CM, Brener SS, Gunraj N, Huo C, Bierman AS, Scales DC, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA 2011 Aug 24;306(8): The elderly dwell in different environments, depending on their health state, their financial situation and the culture in their country amongst other factors. They may move between the community, nursing homes, residential care, and hospital environments. Nowadays, a greater proportion of the elderly remain living in their own homes, especially in high-income countries such as Europe, the United States, and Japan. 178,179 A strong preference to remain at home is behind this trend. 180 At the same time, hospital stays are kept as short as possible to reduce costs. Thus, home based care has become more important over the years, and new

188 Update on 2004 Background Paper, BP 7.3 Elderly initiatives have arisen to promote and guide home care. Despite many good initiatives, such as those mentioned in the previous section on polypharmacy, much can go wrong when the elderly patient actually takes medication at home. This can, for example, be due to vision and hearing loss, memory impairment, or osteoarthritis which may hamper their ability to open the packages. 181 It is important to establish how the elderly take their medication at home, what can go wrong, and what is needed in order to improve medication management in the home setting. The concept of patient empowerment, where the patient has the right to decide whether or not to take a drug or to follow the instructions of the healthcare professionals, plays an important role in his or her own home environment. A qualitative study by Tordoff et al. investigated what goes wrong with medication taking in the community-dwelling elderly. A total of 23 elderly were interviewed and the researchers concluded that these elderly could access, afford, and manage their medication well. Three quarters had experienced side effects at least once in the past. It is likely that some bias was present, e.g. elderly giving the socially desirable response. 182 A study by Beckman among 492 community-dwelling elderly (a random selection of elderly aged above 77 years) assessed their cognitive, physical, and visual abilities related to medication taking. Results showed that almost 10% of them could not read the leaflet instruction, and almost 15% of them could not open the plastic flip-top medicine bottle. More than three quarters of the study population did not pass all the tests included in this study. This demonstrates that mediation taking is a difficult task and the elderly have difficulties (cognitive, physical, and visual) that may hinder accurate medication taking. 181 Little is known on the potential role of caregivers in medication management in the home environment, and this topic warrants further research, including an assessment of (cost)effectiveness of caregiver support. Different tools have been developed to assess the ability of patients in managing their medication, and the majority were developed for or validated in the elderly. About 50 specific tools exist in the international literature to assess the functional ability of the elderly in managing their medication that can be applied at home or in a standard setting (e.g. healthcare centre). The Medication Management Ability Assessment (MMAA) and the Drug Regimen Unassisted Grading Scale (DRUGS) were the most frequently applied tools. It has been shown that cognitive impairment and increasing age are determinant factors in the ability to manage one`s own medication. 183 These factors need to be evaluated in order to judge if the tools can predict who is at the greatest risk for drug related problems due to nonadherence. 184 It is of utmost importance to be able to detect inability early, in order to preserve a patient s independence and health. The more medication patients use or the worse their cognitive function is, the more often problems arise. In the Netherlands, a Red Flag Project was designed in which home care nurses document risk situations associated with medication use, e.g. falls, difficulties with opening packages, dizziness when standing up, or the absence of a medication overview. With the use of a checklist, they signal problems and actively react in order to improve the situation. The checklist seems to be valid, but more research is needed to show the effects of using it

189 Update on 2004 Background Paper, BP 7.3 Elderly To provide integrated care to the elderly patient, a multi-disciplinary approach is needed and CGA may be an appropriate tool. When the elderly move between different healthcare settings, information may get lost, leading to the unintentional discontinuation of medication, as well as the represcribing of ADR-causing compounds and other medicines that were intentionally discontinued. This translational care can be improved with organisational changes. First, healthcare information must be collected systematically and exchanged to a greater extent between healthcare professionals, both between and within care settings. 99,168 Now that patients take more medications than ever, a hospitalisation requires more management than before. ICT can present opportunities to achieve this, e.g. with development of software such as the clinical rules mentioned in Section 5.1. Nationally available electronic patient dossiers with relevant information filtered for the healthcare professional could be of high value. This way, laboratory values such as renal functions can be used when pharmacists perform medication reviews, or an up-to-date medication list is available when elderly present at an emergency department in a hospital. Now, a lot of time is lost collecting the correct information before an intervention can be made. This can be of considerable benefit, especially in the frail elderly who are taking many medicines. It should be acknowledged however that ehealth cannot be the solution to everything. Until now, the evidence that ehealth solutions lead to higher quality and safety in healthcare remains absent. Recently, both Great Britain and the United States invested in national ehealth programs and the extent to which this will lead to better care should be studied. In addition, the best way to implement ehealth remains unclear. 186 Second, a multi-disciplinary approach and the development of special geriatric wards in hospitals seem to be beneficial for the elderly. Whether this specific care is cost-effective and/or leads to better health remains uncertain. In conclusion, integrated care is of the utmost importance in order to guarantee the continuation of care when patients move between different (health care) settings. Although various initiatives in this area are ongoing, many of them need further evaluation in order to establish their contribution to better health for elderly. The mapping of existing tools, instruments, methodologies, and best practices, as well as the development of new and better toolkits in this area are the key components of the action plan on replicating and tutoring integrated care for chronic diseases, including remote monitoring at regional levels of the European Innovation Partnership on Active and Healthy Ageing. 187 Communication between primary and secondary care should be facilitated and improved because, current, information is often lost, leading to the inappropriate discontinuation of medications. Medication reviews have become routine practice, but it should be evaluated as to its cost-effectiveness and its capacity to improve clinical outcomes such as hospitalisation, mortality, and quality of life. ICT may provide opportunities to facilitate many of these aspects of integrated care. The role of ehealth in medication reviewing, however, warrants further assessment; issues that need attention are design, implementation, and the (cost- )effectiveness of ehealth. Furthermore, the effectiveness of specialised geriatric care, such as geriatric wards, should be investigated to determine if and how this leads to better care. As the importance of home based care has increased and more elderly remain living in their homes, medication management in this environment needs careful consideration. Initiatives to improve this management should be supported and appraised, and best practices need to be identified and shared

190 Update on 2004 Background Paper, BP 7.3 Elderly 6. Conclusion This cross-cutting background paper addresses special needs in the treatment of elderly patients and describes developments since the previous edition of this report in It highlights existing knowledge gaps and describes implications for future research. First, the treatment of osteoporosis with current medicines is relatively effective, but falls should always be prevented. Various fall prevention programs exist with differing effectiveness, so research should focus on methods to deliver evidence-based fall prevention programs in different care environments, as well as methods for increasing the uptake of and adherence to these interventions by the elderly. As the population grows older, the incidence of cancer increases. The elderly are a heterogeneous group, therefore it is not easy to predict how they will respond to chemotherapy. Which geriatric conditions are predictive of specific clinical outcome in cancer patients, such as quality of life, treatment tolerance, or survival has not yet been clarified. A robust screening tool is therefore needed in order to facilitate treatment decisions and offer tailored care. During the past decade, research has focused on Alzheimer disease, but most cases of dementia are mixed cases in which a vascular component plays an important role. More research on vascular dementia is needed including epidemiology, diagnosis, and treatment. Second, it is clear that the elderly have difficulties with taking their medication, especially with tasks like opening packages, reading leaflet information, and/or swallowing oral medication. Many of these special needs have strong similarities with the needs of children. There is a call for the development of special geriatric formulations, and the steps taken in the development of formulations for paediatrics might serve as an example, taking into account the differences between these groups, of course. Third, it is clear that the elderly are still under-represented in clinical trials. This results in a lack of information about the safety and effectiveness of medicines in the elderly. Therefore, new approaches are needed to assess effectiveness in the elderly. Because the elderly are part of a heterogeneous group, a consensus definition of frailty is needed, as well as better tools to evaluate frailty. This might be of help for the selection and inclusion of elderly in clinical trials. In addition, ways to translate information about treatment of elderly obtained in clinical trials into practical recommendations, in the SPC and/or age specific recommendations in guidelines, need to be further explored. Fourth, various improvements can be made in the medicine usage environment of elderly. Polypharmacy is very common in the elderly and medication reviewing has become daily practice in some countries. However, the benefits of medication reviewing have not been fully proven yet; benefits on harder clinical outcomes such as hospital admissions or death need to be confirmed. The role of computerised systems could be further explored to help achieve this. It could make the reviewing less time consuming and it could help the reviewer to more systematically select those patients that might benefit most from reviewing. Adherence to medication regimes should be improved in the elderly. It is not clear which intervention programs improve adherence in this patient population, so more research in this field is needed. The active participation of the patient in treatment decisions should be further strengthened to achieve better outcomes

191 Update on 2004 Background Paper, BP 7.3 Elderly It is unknown if inequity in the access to medicines exists for elderly. Research to establish this is necessary, especially in light of the ongoing economic recession and the subsequent policy measures that have been undertaken. Under-use and under-prescribing are present in this population. One of the reasons might be the relative absence of guidance on prescribing in the elderly in clinical guidelines. This situation could be improved, similarly to the knowledge gaps on safety and effectiveness of medicines in elderly through fast and extensive data sharing with the aid of computerised systems. Palliative care has become more important over the last few years and is acknowledged as a serious part of healthcare. There is a need for further evaluation of the cost-effectiveness of interventions in the last phase of life. Still, many elderly suffer from pain at the end of life, which calls for improvements in pain treatments. Identifying and resolving the barriers to treatment with opioid medications is also an important step forward, but their effects on optimal treatment need to be further established. Finally, the integration of care in elderly patients is essential to prevent, for example, medication errors due to a loss of information. The elderly dwell in multiple care sites, and each transfer between settings can introduce the potential risk of the unintentional discontinuation of medicines or the re-prescribing of medication that was initially stopped. Effort is put into accurate medication taking in second-line care (hospitals); making use of the medication reviewing of complete geriatric assessments, for example, but little effort is put into communication between first-and second line care. It seems to be beneficial for the older patient to be treated in a geriatric environment; in order to provide them with specialised care in a multi-disciplinary environment, however, how such care should be organised needs to be further investigated. There is also a trend toward the elderly living longer independently, but medication management is complex and many elderly have difficulties that may hinder accurate medication self-management. Tools to assess their ability to manage their medication at home have been developed, but are in need of further evaluation. ehealth might enable faster and easier information exchange between healthcare professionals, making it easier to communicate and thus provide integrated care. Until now, ehealth solutions have not been proven to lead to better health in the general population, consequently, the role of ehealth in this population warrants further investigation. References 1 United Nations, Department of Economic and Social Affairs. Population Database UNDoEaSA Accessed May 13, Economic and Social Affairs. World Population Prospects: The 2010 Revision, Volume 1: Comprehensive Tables. New York: united Nations Population Division UN population division. World Population Prospects, The 2002 revision database Geneva: World Health Organisation. Active Ageing: A policy Framework, report No.: WHO/NMH/NPH/

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203 Update on 2004 Background Paper, BP 7.3 Elderly 172 van der Linden CM, Kerskes MC, Bijl AM, Maas HA, Egberts AC, Jansen PA. Represcription after adverse drug reaction in the elderly: a descriptive study. Arch Intern Med 2006 Aug 14;166(15): van der Linden CM, Jansen PA, van Marum RJ, Grouls RJ, Egberts TC, Korsten EH. An electronic system to document reasons for medication discontinuation and to flag unwanted represcriptions in geriatric patients. Drugs Aging 2012 Dec;29(12): Rubenstein LZ, Josephson KR, Wieland GD, English PA, Sayre JA, Kane RL. Effectiveness of a geriatric evaluation unit. A randomized clinical trial. N Engl J Med 1984 Dec 27;311(26): Saltvedt I, Mo ES, Fayers P, Kaasa S, Sletvold O. Reduced mortality in treating acutely sick, frail older patients in a geriatric evaluation and management unit. A prospective randomized trial. J Am Geriatr Soc 2002 May;50(5): Shepperd S, McClaran J, Phillips CO, Lannin NA, Clemson LM, McCluskey A, et al. Discharge planning from hospital to home. Cochrane Database Syst Rev 2010;(1):CD Bell CM, Brener SS, Gunraj N, Huo C, Bierman AS, Scales DC, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA 2011 Aug 24;306(8): Arai H, Ouchi Y, Yokode M, Ito H, Uematsu H, Eto F, et al. Toward the realization of a better aged society: messages from gerontology and geriatrics. Geriatr Gerontol Int 2012 Jan;12(1): Iwarsson S, Wahl HW, Nygren C, Oswald F, Sixsmith A, Sixsmith J, et al. Importance of the home environment for healthy aging: conceptual and methodological background of the European ENABLE-AGE Project. Gerontologist 2007 Feb;47(1): Nikmat AW, Hawthorne G, Al-Mashoor SH. Quality of life in dementia patients: nursing home versus home care. Int Psychogeriatr 2011 Dec;23(10): Beckman AG, Parker MG, Thorslund M. Can elderly people take their medicine? Patient Educ Couns 2005 Nov;59(2): Tordoff J, Simonsen K, Thomson WM, Norris PT. "It's just routine." A qualitative study of medicinetaking amongst older people in New Zealand. Pharm World Sci 2010 Apr;32(2): Hearing: Need of elderly functional ability assessment to manage their own medication: Advinha AM, Lopes MJ, Oliveira-Martins S, (Jan 10, 2013). 184 Hutchison LC, Jones SK, West DS, Wei JY. Assessment of medication management by communityliving elderly persons with two standardized assessment tools: a cross-sectional study. Am J Geriatr Pharmacother 2006 Jun;4(2): Sino C. Wapperen van vlag legt medicatieprobleem bloot. Tijdschrift LVW 12[1] Black AD, Car J, Pagliari C, Anandan C, Cresswell K, Bokun T, et al. The impact of ehealth on the quality and safety of health care: a systematic overview. PLoS Med 2011;8(1):e European Innovation Partnership on Active and Healthy Ageing. Action Plan on Replicating and tutoring integrated care for chronic diseases, including remote monitoring at regional levels

204 Update on 2004 Background Paper, BP 7.3 Elderly Available at: Accessed May 14,

205 Update on 2004 Background Paper, BP 7.3 Elderly Annexes Annex 7.3.1: Cancer prevalence by age at prevalence (US data )

206 Update on 2004 Background Paper, BP 7.3 Elderly

207 Update on 2004 Background Paper, BP 7.3 Elderly Annex 7.3.2: Charter for the rights of older people in clinical trials Charter for the Rights of Older People in Clinical Trials 1. OLDER PEOPLE HAVE THE RIGHT TO ACCESS EVIDENCE-BASED TREATMENTS 1.1 Older people have the right to be offered evidence-based treatments. 1.2 Older people should expect to be offered drugs and other treatments that have been properly evaluated in clinical trials and demonstrated to be effective in people their age. 2. PROMOTING THE INCLUSION OF OLDER PEOPLE IN CLINICAL TRIALS AND PREVENTING DISCRIMINATION 2.1 Older people should not be discriminated against in the recruitment for clinical trials Older people should be informed about and invited to participate in clinical trials of treatments that are intended for use in older people National and international regulators should ensure that older people are included in clinical trials without discrimination on grounds of age, gender, ethnicity or social class Research ethics committees, sponsors, medical journal editors and regulators should review all studies critically for unjustified exclusions based on age, other illnesses, disability and existing drug treatment. All such exclusions must be justified. 2.2 The participation in clinical trials of people with multiple morbidities should be encouraged National and international regulators should require that trials with drugs or other treatments intended for use in older people include those with multiple morbidities that are common in later life National and international regulators should require that trials with drugs or other treatments intended for use in later life include older people who are taking commonly prescribed medications. 3. CLINICAL TRIALS SHOULD BE MADE AS PRACTICABLE AS POSSIBLE FOR OLDER PEOPLE 3.1 Clinical trials should be designed so that older people can participate easily Older people should receive information about clinical trials that helps them make an informed decision about participation. Informed consent procedure should be adapted to the specific needs of older people, taking into account their level of literacy, any sensory deficits, and involving their family or caregiver if needed Specific training is needed in order to perform clinical trials in older people. Researchers should be trained to conduct clinical trials in people with communication, sensory, mobility or cognitive problems Researchers should be prepared to spend additional time with older people participating in a clinical trial in order to support their participation and adherence

208 Update on 2004 Background Paper, BP 7.3 Elderly Trial sponsors should recognise that older people may need extra support to take part in trials. Trial sponsors should provide support to enhance the inclusion and adherence of older people, especially those with mobility and communication problems and those who also have responsibilities caring for others National and international regulators should encourage clinical trials that are designed to make the participation of older people easier. 4. THE SAFETY OF CLINICAL TRIALS IN OLDER PEOPLE 4.1 Clinical trials in older people should be as safe as possible Researchers should assess the benefits and risks of older people s participation in clinical trials. 5. OUTCOME MEASURES SHOULD BE RELEVANT FOR OLDER PEOPLE 5.1 Clinical trials for common conditions in older people should employ outcome measures that are relevant for older people Researchers, trial sponsors and regulators should ensure that clinical trials for common conditions in older people use outcome measures that are relevant for older people, including quality of life measurements Clinical trial sponsors should involve older people and carers in the design of clinical trials and in the choice of outcome measures for clinical trials of diseases of later life. 6. THE VALUES OF OLDER PEOPLE PARTICIPATING IN CLINICAL TRIALS SHOULD BE RESPECTED 6.1 The individual values of each older person participating in clinical trials should be respected Researchers should respect the values of each older person as an individual Older people should be able to withdraw from clinical trials without detriment to other treatments and their overall care

209 Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Background Paper 7.4 Pharmacogenetics and Stratified Medicine By Susanne J.H. Vijverberg, Anke-Hilse Maitland-van der Zee March 30, 2013 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands This Background Paper was commissioned by the WHO Collaborating Centre for Pharmaceutical Policy and Regulation ( This work was financially supported by the Dutch Ministry of Health, Welfare and Sport.

210 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Table of Contents Acknowledgements... 3 Glossary of Terms... 4 Executive Summary Introduction From personalised medicine to stratified medicine From monogenic to polygenic approaches Biomarkers and disease profiling Research Study design Defining Outcomes From candidate-gene approach to GWAS and whole-genome sequencing Other -omics technologies Replication and validation of findings Future diagnostics: from genotype to diagnosis What European collaborations and EU-funded initiatives exist? Genomics initiatives in low resource settings Challenges for implementation Pricing and reimbursement Assessing clinical value Regulation of products Legal and ethical issues The emergence of orphan populations Technology infrastructure Education and training Identified gaps and recommendations for research and policy References

211 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Acknowledgements We would like to acknowledge Christine Leopold (Austrian Health Institute) for her assistance on the pricing and reimbursement section, as well as Naho Yamazaki and Richard Malham (The Academy of Medical Sciences, United Kingdom) for their valuable comments and suggestions on this chapter

212 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Glossary of Terms Adverse drug reaction: an unintended, harmful reaction to medicines. Biobank: collection of biological samples and associated information stored for research purposes. DNA: molecule that carries the genetic information in a cell. DNA composed of nucleotides. DNA methylation: biochemical process in which a methyl group is added to cytosine or adenine nucleotides. Disease profiling: genetic or molecular profiling of disease. Enzyme: protein involved in a specific chemical conversion. Exome: part of the genome formed by DNA sequences that encode genes (exons). Gene: segment of DNA coding for an inheritable characteristic. Genetic variation: naturally occurring genetic differences between individuals. Genome: total content of genetic information in a cell. Genotype: genetic constitution of an individual. Genome-Wide Association Study (GWAS): study to assess common genetic variations across the entire genome of a large population of individuals in order to study whether any of the investigated variations is associated with a phenotype of interest. Linkage studies: Genetic linkage is the tendency of DNA segments to be inherited together. A genetic linkage studies aims to identify a genetic marker that inherits with the (unidentified) gene associated with the phenotype of interest. Metabonomics (or metabolomics): study of the effect of a systematic change in a biological system caused by an intervention (such as drug administration or specialized nutrition). Monogenetic trait: phenotype caused by one single gene. Non-coding RNA: RNA molecule that is not translated into a protein. Pharmacoepigenomics: assessing the relationship between variation in physical DNA structure and treatment outcome. Pharmacogenetics: assessing the relationship between variation in a gene and treatment outcome. Pharmacogenomics: assessing the relationship of variation in various genes (or genomewide) and treatment outcome. Phenotype: observable characteristics of an individual, e.g. disease or poor treatment response. Polygenetic trait: phenotype caused by multiple genes. Proteomics: study of the proteome; the regulation and production of the proteins in a cell. Quality adjusted life year (QALY): measure of the quality of remaining life-years. Often used in cost-effectiveness analysis. SNP: Single Nucleotide Polymorphism is the most common type of genetic variation, in which a single nucleotide is altered at a certain position in the genome. Transcriptomics: study of the transcriptome; the RNA transcripts produced by the genome and the regulation of that process

213 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Executive Summary Stratified or personalised medicine is a rapidly developing field that will have major impact on healthcare in the coming decades. Without applying the concept of stratified medicine, a particular treatment is targeted to the whole patient group, without being able to predict the treatment response in patients. Stratified medicine allows medicines to be targeted to those patients who (best) respond to therapy and/or to be avoided in patients who are most likely to experience side effects. Thus, stratified medicine shows great promise in the improved and safer usage of existing medicines in high, as well as low, resource settings- In addition, it demonstrates potential for the identification of new drug targets and the development of new diagnostic tools. The term stratified medicine, however, might be more accurate than the term personalised medicine in encompassing the potential and hopes of the new -omics era for medicine and public health, in which the main focus will be in the stratification of patient populations on the basis of biomarkers (e.g. genetic variations and protein expression). Scientific technologies in the field of genomics and biomarker discovery are advancing at a rapid pace, shifting from single to complex multifactorial diseases and from monogenic (assessing one single gene) to polygenic (assessing multiple genes at the same time) approaches. Despite the rapid scientific advances, the implementation of stratified medicine in health care systems remains low. This is due in part to (current) scientific limitations, and the lack of standardization for response outcomes (i.e. adverse drug reactions which complicate the comparability of studies), which complicates the comparability of studies. Furthermore, successful replication is generally low, and a global or European pharmacogenomic database with a thorough inventory of available knowledge and biological specimens is lacking. Moreover, societal and regulatory limitations hinder implementation; there is a need for a well-organised technology infrastructure, professional training in the use and interpretation of testing, as well as internationally aligned ethical, legal and regulatory frameworks. A summary of research and policy priorities for stratified medicine is given in Box The clinical implementation of stratified medicine also requires basic, translational, as well as regulatory studies. Box 7.4.1: Key Summary of Research and Policy Priorities for Stratified Medicine Establishing a funded European research network Safer use of existing medicines is underused The effect of non-genomic factors influencing treatment response should not be underestimated Need for a European catalogue of pharmacogenomic datasets and harmonization program Current regulatory guidelines and reimbursement procedures hamper implementation Stratified medicine in low resource settings is rare Stratified medicine in vulnerable groups should be stimulated Clinical added value should be assessed Barriers to implementation should be diminished Ethical, legal and social implications of stratified medicine should be further investigated 7.4-5

214 Update on 2004 Background Paper, BP 7.4 Stratified Medicines 1. Introduction Stratified medicine is a rapidly developing field that is likely to have important clinical consequences in the coming decades. It holds strong promise for the improvement of both the drug efficiency and the drug safety of existing drugs due to the identification of drug responders and non-responders based on biological markers (see Box 7.4.2: the abacavir case). Furthermore, as a result of increasing knowledge about complex multifactorial diseases, the identification of new drug targets and the development of new diagnostic tools will also be possible. Genomics and other omic technologies are rapidly evolving and are key elements in the future of stratified medicine. Historically, human diseases have been treated on a one-sizefits-all basis where one drug suits all patients. The choice of a drug has been guided by evidence-based information, professional guidelines and a trial-and-error approach. When a patient does not respond adequately with a prescribed drug or showed substantial adverse drug reactions, the dosage can be adjusted or the medicine itself might be replaced by another. However, with the unravelling of the molecular pathways underlying disease processes and the rapid emergence of new -omic technologies (including epigenomics, proteomics and metabonomics), research is rapidly producing new insights that will open the door to more tailored forms of drug selection, drug dosing, drug development and diagnostics. In this chapter we will focus mainly on the role of pharmacogenomics in stratified medicine, as this particular field has been most successfully translated into clinical practice in comparison to the other -omics fields. Pharmacogenomics study the influence of genomic variation on treatment response. Two successful pharmacogenomics examples include HLA-B*5701 genotyping and the risk of hypersensitivity to the antiretroviral treatment abacavir and HER2 testing in breast tumour biopsies and clinical response to the antineoplastic agent trastuzumab. Based on individual or disease-specific biomarkers, the drug choice can be tailored in order to improve efficacy and to minimize the occurrence of adverse drug reactions. In addition to tailored treatment, -omics advances also hold promise for new approaches to drug development and a better use of existing drugs, as well as the prevention of disease by the identification of individuals at risk. Nevertheless, despite the predictions that the era of stratified medicine has arrived, clinical implementation has been limited. 1 In this paper we will address the evolution of the field, its current level of development, as well as the challenges and opportunities for future research and for implementation in clinical practice

215 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Box 7.4.2: The abacavir case; uptake of genetic HLA-B*5701 testing In 1998, abacavir, an anti-retroviral treatment for HIV was approved by the FDA and in 1999 by the EMEA (now EMA). The drug was generally well tolerated; however, it caused a drug hypersensitivity reaction in a small group of patients (5 to 8%) that could be life-threatening. From 2001 onwards there was increasing evidence of a relationship between a genetic variation in the HLA-B*5701 gene (a gene that codes for a protein involved in immunity) and the risk of abacavir hypersensitivity. Sales of abacavir containing drugs subsequently declined. A genetic test to assess the HLA-B*5701 was introduced in 2005, but test utilization remained low due to concerns about differences in HLA-B*5701 prevalence between individuals of different populations and residual risks upon negative genetic results (See Figure for test uptake in the United States). A shift took place in 2007 upon the completion of two industry-sponsored studies that showed the generalizability of the genetic test across diverse geographical patient populations and patients with different genetic ancestry and a very high negative predictive value. This together with the development of a skin patch test to immunologically confirm the genetic test led to the rapid adoption of HLA- B*5701 testing by HIV practitioners and the incorporation of the test in clinical guidelines. It was only in July 2008 that the FDA included HLA-B*5701 testing recommendations on the drug label of abacavir. 2, 3 Genetic testing of HLA-B*5701 kept abacavir on the market because it is now possible to target the drug to a patient population with almost no risk in developing the severe hypersensitivity reaction. Figure 7.4.1: uptake of genetic testing of HLA-B*5701 in the US Source: Lai-Goldman M, Faruki H. Abacavir hypersensitivity: a model system for pharmacogenetic test adoption. Genet Med 2008; 10(12):

216 Update on 2004 Background Paper, BP 7.4 Stratified Medicines 2. From personalised medicine to stratified medicine The term personalised medicine is increasingly being replaced by the term stratified medicine. 4 According to the European Commission workshop report Stratification biomarkers in personalised medicine from 2010, personalised medicine may be defined as a medical model using molecular profiling technologies for tailoring the right therapeutic strategy for the right person at the right time, and determine the predisposition to disease at the population level and to deliver timely and stratified prevention. 5 Genomic and non-genomic biomarkers will enable us to increasingly target treatment specifically to subpopulations of patients who are more likely to respond to a particular treatment and are less likely to develop adverse drug reactions, and will lead to subpopulation-unique instead of to individual-unique drug targeting and development (Figure 7.4.2). In this way, the benefit-risk profile of the medicine can be assessed per population stratum, and unnecessary (in case of non-response) or harmful (in case of toxic effects) use of medicines may be prevented. In this sense the other cross-cutting themes in this background paper (children, women and the elderly) are also examples of stratified medicine. A recent report of the United States National Academy of Sciences on the development of a new framework for the taxonomy of human disease, however, advocates the term precision medicine for the use of genomic, epigenomic, exposure, and other data to define individual patterns of disease, potentially leading to better individual treatment. 6 While the term stratified medicine reflects the realistic effect on patient/population-level, precision medicine reflects the clinical consequences a better treatment. Both terms seem to reflect more precisely the promises and hopes of the new genomic era than personalised medicine, which might have been an overambitious definition promising individualised unique drug targeting and development. In this report we will use the term stratified medicine. Figure 7.4.2: Concept of stratified medicine. Biomarkers will enable us to target treatment specifically to subpopulations of patients who are more likely to benefit from a particular treatment. Source:

217 Update on 2004 Background Paper, BP 7.4 Stratified Medicines 3. From monogenic to polygenic approaches In April 2003, the human genome project was declared complete with the sequencing of 99% of the human genome. 8 From 2003 onwards, data production in the field of genomics has continued to grow exponentially, and instead of focusing on the human genome as an end in itself, genomic researchers have turned their attention towards the role of DNA, RNA, proteins, and metabolites in disease aetiology. As part of this trend toward more complexity, interest shifted from the relatively rare monogenic diseases, which result from modifications in a single gene, such as Huntington s disease, cystic fibrosis and thalassaemia, to the more common complex diseases, including cardiovascular disorders, type 2 diabetes, cancer, depression, and Alzheimer disease. 9 Simultaneously with the genomic revolution, the evolution of pharmacogenetics into pharmacogenomics took place. 10 Pharmacogenetics is the study of variations in a single gene as related to drug response, whereas pharmacogenomics is often described as the wholegenome application of pharmacogenetics where variations in multiple genes are assessed at the same time. Although both terms are still used interchangeably, the term pharmacogenomics is broader and also includes new genome-wide DNA technologies and RNA. 11 Successful early examples of pharmacogenetics involve identifying variations in genes coding for drug metabolism enzymes which influence drug concentration and have major effects on therapy response or the occurrence of side effects: thiopurine methyltransferase (TPMT) 10 and CYP2D6, for example. The enzyme thiopurine methyltransferase is involved in the methylation of thiopurine drugs. Thiopurines are widely used to treat acute lymphoblastic childhood leukaemia (ALL), inflammatory bowel disease, autoimmune diseases and organ transplant recipients. Genetic variation in the gene coding for this enzyme influences the enzyme activity. Approximately 10% of individuals have lower activity for this enzyme (carriers of one gene variant: heterozygotes) and 0.3% lack enzyme activity (carriers of two gene variants: homozygotes) 12, and are very susceptible to severe haematological toxicity when treated with thiopurine drugs (i.e. azathioprine and 6- mercaptopurine) due to a slower metabolizing of the drugs. In 2004, the U.S. Food and Drug Administration (FDA) recommended TMPT testing prior to the start of treatment with azathioprine with a message on the product label of the drug, in order to enable the adjustment of individual treatment dosages. Cytochrome P450 2D6 (CYP2D6) codes for debrisoquine-sparteine hydroxylase, an enzyme involved in the metabolism of xenobiotics, and is implicated in the oxidation of 20-25% of all clinical drugs (including various antidepressants, antipsychotics and antiarrhythmic). 13 Variations in the gene can lead to altered enzyme activity, based on the presence of these variations individuals can be classified as: poor, intermediate, extensive and ultrarapid metabolizers. Approximately 7% of Caucasians are poor metabolizers, due to two variant CYP2D6 alleles. These individuals may suffer from adverse drug reactions when treated with standard xenobiotic drug dosages, or may not respond to drugs that require activation by the enzyme. Conversely, ultrarapid metabolizers (estimated to be ~1% of the Caucasian population 14 ) may also suffer from adverse drug reaction due to the toxicity of prodrugs that need to be activated by the enzyme, or a lack of therapeutic effect when treated with standard drugs with a narrow therapeutic window. In 2004, a microarray based 7.4-9

218 Update on 2004 Background Paper, BP 7.4 Stratified Medicines pharmacogenetic test, the Roch AmpliChip 450 test was approved for clinical use in the EU, and in 2005 in the United States. 15, 16 It has been used mostly in psychiatry, but is thought to be valuable in the oncology field as well. 13 CYP2D6 and TMPT both act according to a monogenic model where variation in one single gene has a substantial influence on drug concentration and thereby drug effect. However, with the rapid advances in genomics, it became increasingly clear that multiple proteins participate in the metabolism of most drugs. Therefore, in order to evaluate the full contribution of genetic variation in drug response, multiple genes in a drug signalling pathway should be studied concurrently. 10 This approach requires large numbers of cases in order to have enough statistical power to identify the small effects of common gene variants. 4. Biomarkers and disease profiling The summary report of the workshop Stratification biomarkers in personalised medicine organized by the Directorate General for Research and Innovation of the European Commission 5 defined biomarkers as follows: A biological characteristic, which can be molecular, anatomic, physiologic or biochemical. They act as indicators of a normal or a pathogenic biological process. They allow assessing the pharmacological response to a therapeutic intervention. A biomarker shows a specific physical trait or a measurable biologically produced change in the body that is linked to a disease or a particular health condition. The report describes four distinct types of biomarkers based on the purpose for which they are used: 1) diagnosis (in patients), 2) risk assessment (in healthy individuals), 3) prognosis of disease (in patients) and 4) treatment prediction (in patients) (Table 7.4.1). Scientific literature shows an explosion in the discovery of biomarkers, however, only a few have been validated for routine clinical practice. 17 So far, most advances have been made in the oncology field, in which molecular and genetic tumour profiling is increasingly used to predict therapy response and/or prognosis. An important factor in the success of tumour profiling is the development of targeted therapies in which drugs block the tumour by binding to tumour-specific molecules. A classic case of a targeted therapy and associated biomarkers is trastuzumab (trade-name: Herceptin ) and HER2 testing. Trastuzumab is a chemotherapy agent that can block human epidermal growth factor receptor 2 (HER2). This protein is encoded by the ERBB2 gene and the gene is overexpressed in approximately 15-30% of the patients with breast cancer. 18 Only patients with high levels of HER2 are likely to respond to trastuzumab. 19 In 2006, the FDA and European Medicines Agency (EMA) approved trastuzumab for the treatment of HER2 overexpressing breast cancer and in 2010 for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, 20, 21 and HER2 testing has been imbedded in clinical guidelines. 22 Another successful example of a targeted anti-cancer therapy is imatinib (trade-name: Gleevec (USA) or Glivec (EU)). The treatment blocks the working of a tumour-specific enzyme, which is often produced in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Blockage of this enzyme inhibits tumour development and the activity of the enzyme is frequently monitored in patients using imatinib in order to monitor the efficiency of the treatment

219 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Tumour profiling can also be used for prognostic purposes such as in the case of MammaPrint (or 70-gene strategy). The test assesses the expression of 70 genes from breast cancer biopsies in order to predict the risk of reoccurrence of the breast cancer and to guide treatment with adjuvant chemotherapy. 24 It classifies patients into low or high risk for the reoccurrence of breast cancer. MammaPrint became available in Europe in 2004, and the FDA cleared the MammaPrint as a diagnostic tool for the United States market in A large prospective multi-centre trial (MINDACT) with breast cancer patients is being performed to validate the guidance of treatment based on the combination of the MammaPrint and the establishment of standard clinical criteria is currently ongoing. 26 Costeffectiveness models suggest a high likelihood of cost-effectiveness for the MammaPrint compared to standard clinical guidelines. 27, 28 In a cost-effectiveness analysis based on three MammaPrint validation studies where MammaPrint was compared to the clinically used guidelines of St. Gallen and Adjuvant Online software, it was shown that MammaPrint had lower total health care costs per patients compared to St. Gallen ( , respectively, ), but higher total costs than Adjuvant Online Software ( ). Nevertheless, MammaPrint yielded more quality adjusted life years (QALY) (12.44) compared to Adjuvant Online Software (12.20) or St. Gallen (11.24) 27. It should be noted that the gain is limited and leads to the question of how much society is willing to pay for gained QALY s. Compared to the Adjuvant Online strategy the 70-gene strategy was estimated to costs per QALY gained. Table 7.4.1: Classifying biomarkers according to test outcome Type of biomarker Diagnostic Example Genetic testing of the Huntington s disease gene in an individual with suggestive symptoms in order to confirm diagnosis. Susceptibility/risk Genetic testing of the Huntington s disease gene in an individual with a family history of the disease but without symptoms in order to assess the risk of Huntington s disease later in life. Prognostic Assessment of the expression of a set of genes with the MammaPrint in a tumour biopsy of a breast cancer patient to assess the risk of reoccurrence of the disease and the need for additional chemotherapy. Predictive (for treatment response) Measurement of HER2 protein levels in the tumour biopsy of a breast cancer patient to predict response to trastuzumab treatment Source: European Commission, DG Research. Workshop report: Stratification biomarkers in personalised medicine Available at: Accessed April 24. Disease profiling and targeted therapies are not restricted to the oncology field. Disease profiling and guiding of treatment also occur in other fields, including the treatment of infectious diseases such as HIV 29 and inflammatory diseases such as asthma, where promising results are being seen for anti-interleukin-13 treatment lebrikuzimab. The drug was successful in Phase 2 studies with asthmatic patients unresponsive to standard

220 Update on 2004 Background Paper, BP 7.4 Stratified Medicines glucocorticoid therapy, especially in patients with a disease characterized with high levels of the serum protein periostin. Periostin is thought to be a surrogate biomarker for the level of interleukin In the case of lebrikuzimab, periostin can be measured in the blood serum of individuals; nevertheless, a general limitation of disease profiling is the need of local disease tissue, which often requires an invasive procedure to measure locally produced proteins or molecules. Pharmacogenomics, however, focuses on the genetic variations that influence therapy response; these genetic variations are present in all tissue and can generally be measured in DNA obtained non-invasively through mouth swabs or saliva. 5. Research 5.1 Study design Generally, there are three types of epidemiological study design for pharmacogenomic studies: 31 1) randomized clinical trials (RCT), 2) observational case-control studies and, 3) studies based on biobanks (potentially linked to electronic health records) (Figure 7.4.3). Currently, Randomized Clinical Trials (RCT s) are the gold standard in drug research (See Background Paper 8.4). In a RCT, an individual is randomized to a specific treatment/placebo or alternative medication, often using a double-blind method: neither the study participant nor the researcher knows to which treatment the individual is assigned. Due to the randomization and regular monitoring, bias and confounding are minimal. The European Pharmacogenetics of AntiCoagulant Therapy-study (EU-PACT) is an example of a pharmacogenomics RCT. This study, financed by the Seventh Framework Program (FP7) of the EU, focuses on genetic variation and oral coagulation drugs (coumarin derivatives) in the prevention of thrombotic disorders. These drugs have a narrow therapeutic window; the dosage needs to be high enough to prevent blood clotting, yet not high enough to cause severe bleeding. The correct dosage differs from person to person. Various factors, including age, sex, diet and co-medication, as well as genetic variation (especially in the CYP2C9 and VKOR genes) are thought to play a role. The EU-PACT study is an ongoing multi-centre trial in 7 European countries and compares two coumarin dosages strategies: 1) dosing based on clinical information and genotype, and 2) dosing based on clinical information alone (standard care). 32 In addition to the added clinical value, EU-PACT will also assess the costeffectiveness of this pharmacogenomics approach. Another example is the recently published RCT based on prospective testing of genetic variation in the ADRB2 gene in 62 children with chronic asthma. Asthmatic children homozygous for the variant genotype seemed to benefit more from a leukotriene antagonist than from a long-acting beta(2)-agonist. Children (homozygous for the variant genotype) were randomized to a long-acting beta(2)-agonist combined with an inhaled corticosteroid (LABA and ICS) or to a leukotriene antagonist combined with an inhaled corticosteroid (LTRA and ICS). The ICS and LTRA group scored better on asthma symptoms and quality of life, used less rescue medication and were absent fewer days from school when compared to

221 Update on 2004 Background Paper, BP 7.4 Stratified Medicines the group of children treated with LABA and ICS. 33 These results are particularly interesting since they demonstrate a genetic effect on the efficacy of existing medicines. Figure 7.4.3: A visual display of the three primary epidemiologic study designs used in pharmacogenomics: randomized clinical trials, case control and biobanks. Source: Ritchie MD. The success of pharmacogenomics in moving genetic association studies from bench to bedside: study design and implementation of precision medicine in the post-gwas era. Hum Genet 2012; 131(10):

222 Update on 2004 Background Paper, BP 7.4 Stratified Medicines A RCT can only be performed when relevant genetic variations have already been identified, and they are time consuming and costly. A more common and less expensive design that can be used to explore relevant genetic variations is the observational case-control study. Patients are enrolled based on their phenotype or drug response (i.e. efficacy, adverse events, toxicity). Since information based on the drugs they have used is often collected retrospectively, the majority of pharmacogenomic studies are appended to existing projects, for example to a clinical trial for a new drug or new treatment regime in which DNA has also been sampled. The cases are the patients that have had an adverse drug reaction, experienced drug toxicity or those that did not improve significantly. The controls are the patients that did not experience an adverse drug reaction, did not experience drug toxicity or did improve on the drug regime. A pharmacogenomic case-control study can also be designed based on an observational cohort study, such as the Pharmacogenomics of Asthma medication in Children with Antiinflammatory effects (PACMAN)-cohort study. 34 This Dutch cohort study recruited children that used asthma medication through community pharmacies. During a study visit, saliva for DNA analysis and phenotypic information (including health care visits in the past year and asthma symptoms in the past year) was collected. Cases and controls were subsequently assigned within the cohort based on the collected information. In the PACMAN cohort study, the cases were the children that had not responded well to asthma treatment (based on symptoms scores or exacerbations despite treatment in the past year), while controls were the children that had responded well to asthma treatment. 35 A limitation of this type of design is recall bias. Since the patient has to report symptoms, exposure, and toxicity retrospectively, they might not always recall these events correctly. Furthermore, in comparison to a clinical trial, there is less monitoring and control, and issues such as nonadherence to treatment and dosage changes might lead to bias. However, this likely reflects standard clinical practice. A third and upcoming study design is based on a DNA-biobank (See Background Paper 8.5) using data that is collected in a prospective or retrospective observational manner. An increasing number of medical centres collect biological specimens (including DNA samples) for research purposes and have these samples coupled to electronic health records. When this information also includes drug exposure and phenotype outcomes (i.e. adverse drug reactions), pharmacogenomics studies can be set up. An alternative strategy is to first identify cases and controls in the electronic health database and subsequently go back to the patients to obtain a DNA sample. An advantage of a biobank design is the large study populations available. Nevertheless, studies based on this design are limited by the information available in the electronic health records and in comparison to the other two designs, there is little control over the phenotype information that is collected. In addition, there are also large scale prospective longitudinal observational population cohort-studies which involve extensive phenotyping of individuals, but do not originate from medical centres with electronic health records (e.g. United Kingdom Biobank, Qatar Biobank). In these studies, phenotype information is tightly controlled and standardized. Observational studies and biobank studies are generally used to assess (currently unknown) genetic/genomic variations, whereas RCTs are the current standard used to determine the clinical value of newly discovered gene-drug interactions before implementation in clinical practice. However, a RCT might not always be feasible, due to ethical or cost/resource limitations. In the case of cost or resource limitations, an adaptive trial design could be a

223 Update on 2004 Background Paper, BP 7.4 Stratified Medicines desirable alternative. An adaptive trial enables the researcher to implement prior knowledge (from observational studies or knowledge obtained during the early phase of the clinical trial itself) to optimize the remainder of the trial, which, for example, could lead to adjusted sample sizes Defining Outcomes A crucial step in pharmacogenomics research is defining the phenotype of interest or the outcome of the study. Many aspects of therapy response may be of interest as the outcome. Often pharmacogenomics studies focus on drug efficacy or toxicity; however, when addressing these issues, there is a wide variation in the phenotypes being studied, which makes comparability between studies difficult. It is also complicated to determine what defines a successful drug response outcome (differences in drug dosage, length of time that a patient is symptom-free, and different clinical measures of improvement), and study results may differ based on the definition of outcome. 37 Hence, there is a need for the standardization of phenotypes of efficacy and adverse drug reactions From candidate-gene approach to GWAS and whole-genome sequencing Within the field of genomics, there are two approaches to DNA analysis: a hypothesis-driven approach (e.g. candidate-gene studies) and a data-driven approach (e.g. linkage studies, genome-wide association studies, whole-genome/exome-sequencing). In a candidate gene approach, the association between variations in selected genes and an outcome (i.e. disease susceptibility, therapy response) is studied. Genes are selected based on biological knowledge. For example, when studying drug-response, genes coding for proteins in the drug-metabolizing pathway might be selected as interesting candidates. This type of study is not designed to identify novel genomic areas that might be associated with the outcome, but rather to confirm a hypothesized association between a gene and the studied outcome. In contrast, data-driven approaches including genome-wide association studies (GWAS), linkage studies and whole genome/exome sequencing are used to identify novel genomic variants. Genes are not selected based on a priori knowledge in this approach, but variation in the genome is studied in an unbiased context. Linkage studies have been used a great deal in the genetics field in order to genetically map diseases. In a linkage study, genetic markers are studied in families where a certain trait (e.g. disease) is inherited by several generations. The key is to identify a genomic region that is always inherited by the affected family members, but not inherited by the unaffected family members, and then narrow the genomic region down as much as possible. These studies are appropriate for the study of monogenetic traits. However, linkage studies are less suitable for drug response studies as it is rare to find a family with a well-characterized drug response. Compared to traditional genetic linkage studies, GWAS have higher statistical power to detect small to modest genetic effects. In a GWAS many common genetic variations across the entire genome are assessed in a large population of individuals to study whether any of the investigated variations are associated with a phenotype of interest (e.g. disease susceptibility, therapy response). 39 The first GWAS was performed in 2005 on genetic variations associated with age-related macular degeneration, 40 and the first pharmacogenomics GWAS was performed in 2008 on statin-induced myopathy. At present, over GWAS have been performed (Figure 7.4.4), and a list of all the published GWAS performed can be found at the website of

224 Update on 2004 Background Paper, BP 7.4 Stratified Medicines the National Human Genome Research Institute. 41 The majority of GWAS have focused mainly on the identification of disease susceptibility genes and far less on pharmacogenomics, yet GWAS are increasingly being used in that area. 42 GWAS on treatment outcomes have mainly focused on drugs for which the dose needs to be individualized or on drugs to which a poor response has severe clinical consequences. 42 One of the drawbacks of GWAS for pharmacogenomics is the large sample size requirements. Expected genetic effect sizes are often small, especially when studying outcomes such as rare adverse drug reactions, therefore it might be difficult to recruit large sets of patients. However, it seems that the genetic effect size for drug response is often higher than those reported for the genetic susceptibility for common complex diseases, and GWAS studies studying drug response with small sample sizes and highly significant findings do exist. 43, 44 Nevertheless, large international research consortia are required to increase samples sizes and facilitate biomarker discovery and replication. Figure 7.7.4: Number of GWAS published between 2005 and 2012 Source: A Catalog of Published Genome-Wide Association Studies. Available at: Accessed January 9, Furthermore, GWAS is less suitable in capturing rare variants, as the GWAS arrays are often designed to include mainly common genetic variants. Moreover, GWAS are very susceptible to finding false positives due to multiple testing. 45 Correction for multiple testing is common practice in genomic research, however, it is complicated due to the existence of various methods that all have their own limitations. 46 Traditional solutions (such as the Bonferonni correction) work well in settings were few genetic variants are studied, but may be too conservative for GWAS settings. Balancing the risk associated with finding false positives versus the risk that important genetic variants are missed (false negatives) remains an important challenge

225 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Whole genome sequencing would be more accurate in assessing rare variants, though it is still rather costly. The 1000 dollar genome is expected to be realized in the near future 47, as sequencing costs are decreasing rapidly (Figure 7.4.5), yet currently it still costs over US dollars to sequence the complete DNA sequence of an individual. A cheaper and promising alternative is whole-exome sequencing, whereby only the exonic regions of the genome are sequenced. Exonic regions code for functional proteins and comprise approximately 1% of the human genome. An important advantage of this strategy is that rare variants with larger effects can be detected. However, current exome strategies do not cover all the exomes present in the human genome, nor can they detect structural variants or chromosomal rearrangements. 48 An innovative approach, which combines the hypothesis-driven and data-driven DNA analyses is the sequencing of cancer-related genes of biopsies of cancer patients. In the Netherlands, three cancer centres are collaborating in the Center for Personalized Cancer Treatment (CPCT), and all patients with metastasized disease are asked to participate. Mutations in cancer-related genes are being assessed in order to identify predictive and prognostic biomarkers. 49 Figure 7.4.5: Decrease in costs per genome sequencing over time Source: National Human Genome Research Institute. Available at: Accessed April 23, Other -omics technologies Pharmacogenomics is only one of the many -omics technologies that have emerged. All of these technologies, to a greater or lesser extent, hold the promise of improving the prediction of disease, the prediction of drug response and the phenotyping of disease. 44 Advances in these fields might provide valuable information about the biological pathways of disease and health and drug response variability. We will now address some of the more promising - omics technologies

226 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Pharmacoepigenomics is a relatively new field that focuses on environmentally-driven, inheritable variations in the DNA structure and its effect on drug response. 51 As it seems, not only do variations in the sequence of DNA play a role in explaining heterogeneity to treatment response, but variations in the physical DNA structure also play a role. The structure of DNA is highly dynamic and regulates gene expression. Especially in cases where there is a strong observed inter-individual heterogeneity in treatment response, but no clear genomic association, epigenomic variations might be the missing link. Important epigenetic mechanisms include DNA methylation, posttranslational modifications of histone proteins and modulation of gene expression by noncoding RNAs. 52 An example of pharmacoepigenomics is the observation that hypermethylation of the WRN promoter in colorectal tumours is associated with a clinical response to the drug irinotecan. 53 Increased methylation of the gene promoter leads to the silencing of the gene and hypersensitivity to topoisomerase inhibitors and DNA-damaging agents such as irinotecan. Transcriptomics investigates the transcriptome, the RNA transcripts produced by the genome, and the regulation of that process. In order to translate genetic information into proteins, DNA needs to be transcribed into RNA. Subsequently these RNA molecules can be used to produce proteins. However, a cell also produces RNA molecules that do not code for a protein (non-coding RNA), but still have regulatory functions within the cell. An important project which also involves transcriptomics is the Encyclopedia of DNA Elements (ENCODE) consortium. It focuses on the control of transcription by assessing regulatory pathways and regulatory DNA elements, and it aims to characterize the genome from a functional point of view. Current analyses include the study of genome-wide datasets from 147 different cell types, 54 in order to gain more knowledge on the regulation of gene expression in health and disease. Proteomics assesses the proteome of the cells, and the regulation and production of all the proteins in a cell. An alteration in the genome or transcriptome does not necessarily correlate with an alteration in a functional protein; therefore, proteomic profiling may sometimes be more accurate in predicting treatment response. Proteomics studies have, for example, assessed the influence of chemotherapeutics on the dynamics of protein response in cancer cells. 55 Nevertheless, progress in proteomics has been limited thus far by labour-intensive procedures and lack of high-throughput arrays. Metabonomics (or metabolomics) assesses the effect of a systematic change in a biological system caused by an intervention (such as drug administration or specialized nutrition). 56 The assessment of the gut microbiome appears especially promising, since there is increasing knowledge about the metabolic interactions between individuals and gut bacteria and the effect on disease development, drug efficacy and adverse drug reactions Replication and validation of findings To validate pharmacogenomic findings, replication studies in different cohorts are essential. Functional studies to assess the effect of the genetic variant on gene expression and protein function are crucial as well. However, this might be complicated by the variances in outcome definitions or phenotype descriptions. Furthermore, in order to profit optimally from identified risk SNPs (single nucleotide polymorphisms), we have to understand causative

227 Update on 2004 Background Paper, BP 7.4 Stratified Medicines relationships and underlying biological pathways 58, 59 and to understand whether the identified SNP is a functional SNP or a surrogate marker. Replication has become a standard practice in genomic research, stimulated by guidelines produced by journals on how to report genetic association studies. 60 Nevertheless, translation of pharmacogenetic markers to clinical practice has been severely limited due to the low rate of successful replication. Failure to replicate could be due to the overestimation of the effect estimate and the use of an underpowered sample size, but it may also be due to the underestimation of the influence of environmental factors. 5.6 Future diagnostics: from genotype to diagnosis With the rapid advances in -omics technologies and the emergence of new biological knowledge, it is becoming evident that the current way we classify diseases has become outdated. 6 Diseases with distinct molecular causes are still classified as one disease (e.g. depression, lung cancer), while diseases that share a common molecular pathology are classified into a multitude of different diseases. With emerging biological knowledge, increased understanding of disease biology and the discovery of disease biomarkers, future clinical practice will increasingly diagnose and treat patients based on molecular disease mechanisms instead of, or in addition to, clinical symptoms. For research purposes there is a need to understand phenotypic extremes and endophenotypes (surrogate endpoints that reflect biological pathway activity). Furthermore, biomarker discoveries will most likely be more successful in patient groups with a homogenous molecular disease background. Patient selection before randomization in a clinical trial ( enrichment ) to increase study power, to identify patients with a greater likelihood of having the event of interest, or patients that are more likely to benefit from the drug 61, will increasingly be based on omics markers What European collaborations and EU-funded initiatives exist? There are two main European networks in the field of pharmacogenomics: the European Society of Pharmacogenomics and Theranostics, which mainly focuses on the implementation of pharmacogenomics, and the European Research Network Pharmacogenetics/genomics, which mainly focuses on research. Additionally, The European Personalised Medicine Association (EPEMED) is a not-for-profit organisation that aims to bring global forces in stratified medicine together in order to harmonize stratified medicine development and implementation across Europe, with a focus on diagnostics. It aims to represent members from academia and industry, as well as patient groups and professional service firms. 63 Furthermore, various large international Europe-wide pharmacogenomics studies are emerging (See Table 7.4.2)

228 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Table 7.4.2: EU-funded Initiatives and European consortia on stratified medicine Study acronym Topic of investigation Funding EU-PACT Pharmacogenomics of anti-coagulant therapy EU-FP7* FLIP Progression of non-alcoholic fatty liver disease and the validation EU-FP7 of diagnostic and prognostic markers TINN Efficacy and safety of anti-infectious drugs in neonates EU-FP7 EuroTARGET Targeted therapy in renal cell cancer EU-FP7 BIOSTAT-CHF Pharmacogenomics and biomarker project on chronic heart failure EU-FP7 MoMoTx Diagnostics in kidney transplant patients EU INTEREG IVa U-BIOPRED Biomarkers of severe asthma IMI** IMI-DIRECT Patient stratification in type 2 diabetes IMI IMI-SUMMIT Micro- and macro-vascular hard endpoints for innovative diabetes IMI tools PADRE Pharmacogenomics of antidepressant response prediction EU-funded but through national funding authorities ITCH International Consortium on Drug-induced skin and Not EU funded hypersensitivity idilic International Consortium on Pharmacogenomics of Drug-induced liver injury Not EU funded * EU-FP7: European Union s 7 th Framework program ** IMI: public-private Innovative Medicines Initiative 7. Genomics initiatives in low resource settings Genomics initiatives have started to emerge in some low- and middle-income countries such as Mexico 64, India 65 and Gambia 66 ; nevertheless, for the majority of low- and middle-income countries, stratified medicine seems to be far out of reach. 67 At present, there is a lack of technical and financial resources and infrastructure. In 2005, a report from the Royal Society on stratified medicine 68 advocated the development and use of simple phenotypic tests in order to screen common genetic defects in order to address medical needs in those countries. This idea is demonstrated in the case of glucose-6- phopshate dehydrogenase (G6PD) deficiency, this disorder is common in malaria endemic regions and causes severe anaemia after the use of (among other drugs) the anti-malarial agent, primaquine. The gold standard in assessing the G6PD status of an individual is a spectrophotometric assay of red cell G6PD content, but this requires a laboratory setting. 69 Simple enzyme-based UV tests ( fluorescent spot test ), which can be performed in the field, are available, but they are not widely being used. According to a recent meeting report of the WHO Malaria Policy Advisory Committee, implementation of such tests requires quality control of the field laboratory results, as well as a cold chain to transport and store reagents. 70 New point-of-care tests are currently under development. In addition to G6PD, various other genetic factors are thought to influence the effectiveness of anti-malarial agents, but there is a lack of pharmacogenetic data in low- and middleincome countries, where they bear a disproportionate disease burden. 71 In order to gain knowledge, collaborations between parasitologists, national public health programmes and genetic researchers should be promoted. 71 Dried blood spots collected for efficacy studies

229 Update on 2004 Background Paper, BP 7.4 Stratified Medicines could be used for pharmacogenetic studies as well, as long as consent is obtained for retrospective DNA testing. We have to bear in mind, however, that the use of genetic testing might not be cost-effective in low- and middle-income countries where basic health care is limited and appropriate drugs are not always available. An alternative and novel approach to disease profiling is the recently developed Xpert MTB/RIF to diagnose tuberculosis (TB) and drug-resistant TB on a molecular basis. It is a rapid test, taking less than two hours, that assesses the tuberculosis genome in patient sputum samples with high sensitivity and specificity. However, a recent cost and affordability analysis showed that the test is currently not financially viable in lowincome countries as long as funding for tuberculosis and cost reductions are not increased. 72 Nevertheless, after a successful South-African pilot-study, the technology is currently being rolled out nationwide by the South African National Department of Health. Xpert platforms will be placed in all laboratories in nine designated high case-load districts and in all other existing TB laboratories. It is estimated that the technology will substantially increase the number of TB diagnoses, yet will also increase annual costs for TB diagnostics and treatment. 73 (See Background Paper Chapter 6.8 on Tuberculosis) So far, most pharmacogenomics research has focused on Caucasians. However, clinically relevant SNPs might be present in non-caucasian populations, but be virtually absent in Caucasians; a good example of this being the HLA-B*1502 allele. Individuals with this allele have a higher risk for severe cutaneous allergic reactions caused by anti-epileptic drugs. The allele is more prevalent in populations with Asian ancestry (10-15%) compared to Caucasians (1-2%). 74 The Pharmacogenetics for Every Nation Initiative (PGENI) was developed to support pharmacogenomic research in low resource settings by developing and integrating local risk data. This USA-based non-profit organization aims to sample 500 individuals from every ethnic group that represents 1% or more of the population in 104 low- and middleincome countries. 71, 75 Another important initiative is the China Kadoori Biobank which has collected data from over half a million individuals from ten geographically defined Chinese regions. 76 The researchers goal is to follow the individual s health for at least two decades, with a wide range of measurements have been performed, including the collection of blood and DNA. Particularly in low resource settings, (pharmaco)genomic approaches may hold promise in addressing their limited health resources as efficiently as possible. The focus here should lie on a better use of existing medicines. 8. Challenges for implementation In order to successfully bring stratified medicine to the clinic setting, there are several challenges to overcome, including the following: pricing and reimbursement, assessing its clinical value, regulation of products, legal and ethical issues, dealing with orphan drugs and patients, addressing the need for a well-organised technology infrastructure and public and professional training

230 Update on 2004 Background Paper, BP 7.4 Stratified Medicines 8.1 Pricing and reimbursement In recent years, stratified medicine (drugs and associated biomarkers), also known as codependent technologies or joint products or therapeutics with companion diagnostics, has gained more and more relevance, which poses certain challenges to the pricing and reimbursement authorities. Three main points should be highlighted: 1. In Europe, most stratified medicine belongs to a group of high-cost medicines for which public funding either through hospital budgets or through the outpatient reimbursement sector can be a challenge for public authorities (See Background Paper 8.2 on Pricing and Reimbursement). One well-known example is trastuzumab, for which European countries pay, on average, 600 per 150 mg powder vial (See Figure 7.4.6). 78 Prices for medical tests, such as the HER2-positive breast cancer tests (FISH test), are not publicly available and can be freely set by the manufactures. According to a study by the Institute for Prospective Technological Studies, costs for the FISH-test (including material and personnel costs) varied between 220 in the United Kingdom to 495 in the Netherlands in , Stratified medicine combines the use of medical devices, such as tests, with medicines and new reimbursement assessment procedures often in the course of health technology assessments that take into account the whole treatment package that needs to be developed. In a benchmarking report examining factors that support or hinder market access to stratified medicine in reimbursement systems in European countries, countries were ranked as supportive (e.g. Germany, the United Kingdom and France) when reimbursement systems for the diagnostic and therapeutic were combined. However, for other countries (e.g. Netherlands, Finland and Norway), no clear pathways for evaluation and funding of stratified medicine were identified Stratified medicine is at the juncture of the inpatient and the outpatient sectors, which is especially relevant with regard to funding. A study undertaken in the framework of the EMINet (European Medicines Information Network; to support policy makers of the network of Competent Authorities of Pricing and Reimbursement (CAPR)) surveyed funding models and pricing practices for the treatment package of trastuzumab and its accompanying diagnostics in 27 European countries, as an example of personalised medicine. 82 The results showed split funding in several countries; medicine expenses were funded by third-party payers and the tests were paid for by the hospitals, which further increased the pressure on hospital budgets. Furthermore, pharmacogenomic tests were only reimbursed when clinical utility of the test was established. However, there is little consensus on what evidence is needed for tests to have sufficient clinical value. 1 Some countries are countering this gap by establishing prescribing guidelines which consider both the medical device and the medicine or interdisciplinary committees with representatives from hospitals and third party payers

231 Update on 2004 Background Paper, BP 7.4 Stratified Medicines Figure 7.4.6: List prices of one 150 mg vial of trastuzumab at unit ex-factory price level in EURO in thirteen European countries, 2005 and AT = Austria, BE = Belgium, DE Germany, DK = Denmark, EL = Greece, ES = Spain, FI = Finland, FR = France, IS = Iceland, IT = Italy, NL = Netherlands, NO = Norway, SE = Sweden, UK = United Kingdom. (Source for abbreviations: UK: price paid by the National Health Service Prices as of December 2005 and June 2011 Prices in Non-Euro-countries were converted with the corresponding monthly exchange rate as published by the European Central Bank. Source: Pharma Price Information (PPI) service. Gesundheit Österreich GmbH (Austrian Health Institute) Assessing clinical value The assessment of the clinical value of a test or a marker demands the development of a strategy for translational research in which evidence is gathered over time in order to allow the incorporation of various tests into health care practice within a certain time frame, while also assessing clinical utility and cost-effectiveness. Gathering evidence needs to take place in several phases, similar to the phases of pharmacological research. A four phase framework for translational research of genomic medicine was proposed by Khoury and colleagues. 84 Phase 1 seeks to move a basic genome-based discovery into a health application: an example is the construction of a genomic profile that predicts individual reactions to drugs. Phase 2 would lead to the development of evidence-based guidelines. A clinical trial that shows that the adapting treatment to the genomic profile in a large group of study participants is effective in avoiding side effects would fit into this phase. Phase 3 attempts to move evidence-based guidelines into health practice. An implementation project to ensure that all people in an entire country to whom a certain drug is being prescribed are first tested using the genomic profile to determine their risk of side effects would fit in phase 3. Phase 4 seeks to evaluate the real world health outcomes of a genomic application in practice. The evaluation of the occurrence of side effects to show that fewer people are affected after the implementation of the genomic profile would be the phase 4 study of our example. It is estimated that no more than 3% of published genomics research focuses on phase 2 and