Trends in accessibility to medicines for children in New Zealand:

Transcription

1 et al British Journal of Clinical Pharmacology DOI: /j x Trends in accessibility to medicines for children in New Zealand: Jocelyn Chui,1 June Tordoff,1 Julia Kennedy, 2 & David Reith 3 1 School of Pharmacy, University of Otago, New Zealand; 2 School of Pharmacy, University College Cork, Ireland and 3 Dunedin School of Medicine, University of Otago, New Zealand. Correspondence Dr David Reith, Section of Paediatrics and Child Health, Dunedin School of Medicine, 3rd Floor, Children s Pavilion, Dunedin Hospital, Great King St, Dunedin, New Zealand david.reith@stonebow.otago.ac.nz Fax: Tel: Ext 8226 Background Reported rates of unlicensed and off-label use of medicines in children raise concerns regarding overall access of children to medicines Objective To assess changes in availability of proprietary formulations suitable for infants and young children; licensing of medicines; and subsidization of medicines for children in New Zealand. Methods Review of the New Ethicals Catalogue, New Ethicals Compendium, product data sheets and the New Zealand Pharmaceutical Schedule covering the years inclusive. Received 10 July 2003 Accepted 9 September 2003 Results There was a decrease in the total number of medicines licensed in New Zealand from 2014 to 1840; but there was an increase in the number and percentage of suitable formulations that were licensed for paediatric use from 616[31%] to 642[35%]. The number of suitable paediatric formulations that were subsidized decreased from 281[13.9%] to 260[14.1%]. The number of orally available chemical entities with suitable formulations, licensed and subsidized for paediatric use declined from 101[5.0%] to 94[5.1%], but all of these chemical entities that were withdrawn had therapeutic alternatives that were licensed and subsidized. Only 36% of new medicines that had licensing for children were licensed for the 0 23 month age group. Conclusion There have been modest improvements in licensing of medicines for children in New Zealand from 1998 to Introduction The current extent of unlicensed and off-label drug use is of major concern to clinicians caring for children [1, 2]. Unlicensed drug use refers to the use of a drug that does not have a product license, whilst off-label drug use refers to use of a drug outside the terms of its product license. Several studies have estimated the extent of unlicensed and off-label prescribing in paediatric populations, in different clinical settings [3 14]. In studies carried out in primary care, 0.3 4% of prescriptions were unlicensed and % were off-label [3, 4, 8, 11, 13]. In paediatric wards in hospitals, 7% and 20 39% of prescriptions were unlicensed or off-label, respectively [6, 12]. Furthermore, 36 67% of children admitted to paediatric wards received at least one drug prescribed in an unlicensed or off-label manner. Consid- Br J Clin Pharmacol 57: Blackwell Publishing Ltd

2 Accessibility of medicines for children erably more drugs were prescribed unlicensed or offlabel in neonatal intensive care units than the other clinical settings: % were unlicensed and 47 55% were off-label [5, 9]. Up to 90% of patients in neonatal intensive care units were given drugs that were either unlicensed or off-label, whereas in a paediatric intensive care setting, the proportion was 70% [10]. These studies indicate deficiencies in the provision of safe and efficacious medicines for children. Other factors that determine access to a medicine include the availability of a suitable formulation and the cost of the medicine to the patient. In New Zealand, a number of medicines are licensed for use in children, but not available in a formulation suitable for all children. Conversely, some medicines are available in suitable formulations (e.g. liquids or soluble tablets) but are not licensed for paediatric use. The extent to which these situations occur has not been previously established. New Zealand has a system of approving medicines deemed suitable for subsidy by the health service and listing them on a Pharmaceutical Schedule [15]. Patients (or parents/guardians) pay a standard charge for a subsidized medicine and a lower standard charge for a medicine if the patient is a child. However, only licensed medicines can be subsidized, so parents/guardians of children prescribed an unlicensed and therefore an unsubsidized medicine will need to pay the full cost of that medicine. This could cause financial hardship or may result in the child not receiving the medicine that was prescribed. Hence, it is important for children in New Zealand to have a wide range of licensed and subsidized medicines available so that they have equity of access to these medicines. Aims The aim of this study was to examine the availability of medicines for children in New Zealand by firstly: determining the licensing, labelling and suitability of formulations of medicines for children in New Zealand using published product information over a five-year period ( ); and secondly by: determining the availability of subsidized medicines for children using the New Zealand Pharmaceutical Schedule over the same time period. Methods Using the May to November editions of the New Ethicals Catalogue, all licensed medicines available in New Zealand between 1998 and 2002 were examined [16]. Because some products may not have been listed in the New Ethicals Catalogue, or their data may have been abbreviated, New Ethicals Compendium 6th and 7th editions were used as secondary references [17]. Where the statement detailed information: refer manufacturer s product literature was noted in the New Ethicals Catalogue, information was obtained from either the data sheet in the New Ethicals Compendium or the product s data sheet, when existent, on the Medsafe website, operated by the New Zealand Medicine and Medical Device Safety Authority [18]. Information was obtained from data sheets concurrent with the catalogues. There were some items where no information was available and these products were assumed to have no paediatric indications. Products such as condoms and diagnostic strips were excluded from the analysis. The following data on each product licensed between 1998 and 2002 were identified: brand names, generic names, indications, types of formulation, paediatric licensing information and whether there was a dosage recommendation for children. All the data were entered onto a Microsoft Excel spreadsheet. All of the licensed items were then classified according to their formulation as: suitable oral, i.e. oral formulations able to be taken by an infant or young child, included liquid, powder, oral spray and soluble tablets; unsuitable oral, included tablets, capsules and other solid formulations; ear/eye, i.e. topical otic or ocular medications; inhaler, i.e. aerosolized medicines for inhalation; injectable; nasal, i.e. topical or aerosolized nasal medication; rectal; dermal, i.e. medicines applied topically to the skin; and other preparations. The medications/formulations were then further categorized as: suitable formulations, including injectable, dermal, ear/ eye, liquid, soluble and powdered oral preparations; suitable formulations licensed for paediatric use; and suitable formulations that were both licensed for paediatric use and also subsidized. Licensing was attributed to an age category where the age range for the licensing spanned the age category. Products withdrawn or introduced into the licensing system for paediatric administration were identified and classified according to their formulation types and therapeutic indications. The changes in total number of each formulation and product (withdrawn or introduced) between the years 1998 and 2002 were determined for each therapeutic indication by comparing the data from the year 1998 with that from A search for therapeutic equivalents (generics) and therapeutic alternatives (medicines indicated for the same purpose) was made using the spreadsheet and New Ethicals Catalogues. Only formulations licensed for paediatric use were considered acceptable alternatives. The subsidy status of those formulations with paediatric licensing indications was identified from the Br J Clin Pharmacol 57:3 323

3 J. Chui et al August editions of the New Zealand Pharmaceutical Schedule [15]. If a paediatric formulation was subsidized in that particular year, the conditions and restrictions on prescribing the subsidized product were recorded. Items that were subsidized for paediatric use in the calendar years 1998 and 2002 were compared. Those formulations that were withdrawn from the subsidy system in the interim period were identified. A search was made from the 2002 database for suitable licensed and subsidized paediatric therapeutic equivalents and alternatives. In order to determine the status of each chemical entity, all the oral formulations licensed in New Zealand were identified from the information on the Microsoft Excel Spreadsheet and were listed in alphabetical order of their chemical entities. The availability of suitable oral formulations, the paediatric licensing status and the subsidized conditions and restrictions of each chemical entity was determined. Results Between the years 1998 and 2002 there was a decrease in the total number of medicines licensed in New Zealand from 2014 to 1840 [Table 1]. There was an increase in the number and percentage of suitable formulations that were licensed for paediatric use from 1998 to In particular, there was an increase in the proportion of inhalers, nasal preparations and ear/eye preparations that were licensed for children [Figure 1]. In contrast, there was a decline in the number, but not the percentage, of suitable paediatric formulations that were subsidized. A comparison of the calendar years 1998 and 2002 showed there were more paediatric licensed formulations introduced than withdrawn (192 introduced vs 163 withdrawn), a net gain of 29. However there was a net loss of formulations in some categories, e.g. the numbers of antibacterial/antifungal, antipyretic/analgesic agents and bronchodilators introduced were only half of those withdrawn. In contrast a much larger number of antiviral agents and vaccines were licensed for paediatric uses over the period of the study. For 72 of the paediatric formulations that were withdrawn from the licensing system, identical formulations were available. For the remainder, different therapeutic equivalent (generic) formulations were identified for 27 items but 11 of these were for a different route of administration. All of the 64 withdrawn items that had no therapeutic equivalent (generic) formulations had a therapeutic alternative, i.e an alternative licensed medication with the same therapeutic indication. Thus, no loss of access to a licensed paediatric formulation for any individual indication was identified over the time period of the study. Proportion of formulations Figure Year Proportions of formulations licensed for children by type of formulation. Suitable oral ( ), unsuitable oral ( ), inhalers ( ), nasal ( ), dermal ( ), ear/eye ( ), injectable ( ), rectal ( ) Table 1 Formulations that were licensed and subsidized for paediatric uses in New Zealand between 1998 and 2002 Year Total items Items licensed for paediatric use, n (%) 616 (30.6) 660 (32.2) 675 (33.5) 653 (33.9) 642 (34.9) Items subsidized for paediatric use, n (%) 473 (23.5) 502 (24.5) 471 (23.4) 443 (23.0) 427 (23.2) Suitable formulations, n (%) 1195 (59.3) 1215 (59.4) 1211 (60.1) 1183 (61.5) 1142 (62.1) Suitable formulations licensed for paediatric use, n (%) 399 (19.8) 422 (20.6) 441 (21.9) 431 (22.4) 442 (24.0) Suitable formulations licensed for paediatric use and subsidized, n (%) 281 (13.9) 291 (14.2) 274 (13.6) 261 (13.6) 260 (14.1) :3 Br J Clin Pharmacol

4 Accessibility of medicines for children Of those medicines introduced between 1998 and 2002 that had paediatric indications, 100 were new chemical entities, or were chemical entities not previously licensed for children. Thirty-six percent were licensed for the 0 23 month age group, 69% for the 2 6 years age group, 83% for the 7 12 years age group, and 85% were licensed for the years age group. By therapeutic group, respiratory agents were more likely to be licensed for the younger age groups [Table 2]. When formulations that were subsidized for paediatric use in the calendar years 1998 and 2002 were compared, 152 items were found to be withdrawn from the subsidy status. One hundred and twenty-nine were removed because they were no longer licensed in New Zealand. Fifty-eight out of 152 had identical formulations that were subsidized for children. Of the remainder, 25 had therapeutic equivalent (generic) formulations, 3 of which were for a different route of administration. Other therapeutic alternatives were available for the remaining 69 withdrawn formulations. Thus there was no overall change in access to licenced, subsidized paediatric formulations. The number of chemical entities with suitable oral formulations, the number of chemical entities with paediatric indications, and the number of chemical entities that had both a suitable formulation and were licensed for paediatric indications did not show a definite trend over the five-year period [Table 3]. In contrast, the num- Table 2 Percentage of new paediatric medicines licensed for each age group Therapeutic group 0 23 Months 2 6 Years 7 12 Years Years No information** Anti-infectives (n = 20) Special foods (n = 14) Nervous system (n = 13) Vaccines (n = 11) Anaesthetics (n = 8) Respiratory (n = 8) Contrast media (n = 7) Hormones (n = 5) Haematological (n = 4) Oncology/immunology (n = 4) Alimentary(n = 2) Intravenous nutrition (n = 2) Cardiovascular (n = 1) Musculoskeletal (n = 1) All categories **no information in New Ethicals catalogue, compendium, or data sheet. Table 3 Availability of chemical entities for paediatric use in New Zealand between May 1998 and May 2002 Year Orally available chemical entities Orally available chemical entities with suitable paediatric 210 (33.6) 221 (35.6) 225 (36.3) 225 (36.0) 218 (35.8) formulations, n (%) Orally available chemical entities with paediatric license, n (%) 234 (37.4) 230 (37.0) 235 (37.9) 228 (36.5) 228 (37.4) Orally available chemical entities with paediatric license and 118 (18.9) 121 (19.5) 124 (20.0) 120 (19.2) 125 (20.5) suitable formulations, n (%) Orally available chemical entities with suitable formulation, licensed and subsidized for paediatric use, n (%) 101 (16.2) 107 (17.2) 100 (16.1) 99 (15.8) 94 (15.4) Br J Clin Pharmacol 57:3 325

5 J. Chui et al ber of suitable oral chemical entities that were licensed and subsidized for children declined slightly. Overall, the proportion of chemical entities licensed for paediatric use was similar to the proportion of formulations licensed for paediatric use. Discussion The present study indicates a general decrease in the number of medicines licensed in New Zealand, an increase in the proportion of medicines licensed for children, an improvement in the suitability of formulations for licensed medicines for children, but a decrease in the number of formulations subsidized for use by children. When corrected for the availability of therapeutic equivalents and therapeutic alternatives there was no overall change in the access of children to medicines because all of the paediatric licensed medicines withdrawn from New Zealand had licensed therapeutic alternatives. However, the absence of improvement in licensing of medicines for children indicates that any increase in the number of studies performed on children by pharmaceutical companies, as a result of policy changes in their major markets, have yet to make an impact in minor markets such as New Zealand. There appears to be continuing discrimination against children regarding access to licensed and subsidised medicines. Almost all medicines are licensed for adults but only one-third are licensed for paediatric use. This situation primarily results from lack of data because there are fewer clinical trials undertaken in children [19]. Moreover, data from studies in adults cannot be extrapolated to predict the pharmacokinetics, toxicity and therapeutic effects of a medicine in children. Drug metabolism, clearance and distribution alter throughout childhood because of maturing hepatic and renal functions, particularly in neonates and infants [20]. Hence, separate clinical trials in children are necessary to assess appropriate dosage regimens in order to achieve the desired therapeutic effect whilst avoiding toxicity. There are several reasons why the pharmaceutical companies are reluctant to study medicines in children [21]. The market for the sale of medicines to children is much smaller than that for adults. It is unrealistic for the pharmaceutical industry to carry out large randomized clinical trials in children to meet the registration requirement since the investment is not financially attractive. In addition there are ethical and technical difficulties to performing clinical trials in children. In the major pharmaceutical markets, such as the USA and Europe, changes in the regulatory environment have either been enacted or are proposed, in order to facilitate the licensing of medicines for children. In the USA incentives have been provided to the pharmaceutical industry to apply for licensing of medicines to children. The Food and Drug Administration has provided financial incentives for the development and marketing of medicines for children. In the Food and Drug Administration Modernization Act 1997, the FDA waived fees for supplemental application for paediatric approval for new drugs that had already been approved for adult use [22, 23]. Furthermore, six additional months of exclusivity or patent protection is given to manufacturers conducting paediatric studies on drugs. In 1998, the FDA published a priority list of drugs where further paediatric studies would be beneficial [22]. The FDA may target certain drugs on the list and seek an explanation from the manufacturers as to why these drugs have not been tested in children. Proposed changes in licensing requirements by the European Medicines Evaluation Agency would press the manufacturers to provide detailed data for prescribing for children whenever the drug is likely to be used for them [24]. The manufacturers are also urged to develop formulations that are suitable for children. In addition, a European Network for Drug Investigation in Children has been established to facilitate the development of pharmaceutical research in children [21]. The impact of these approaches has yet to be evaluated. Unlicensed and off-label use of drugs appears to be associated with a higher risk of adverse events, although the data is limited [7, 14, 25, 26]. This risk may be higher in those children with more severe clinical conditions [14], and in addition the more severe adverse drug reactions may be associated with unlicensed and off-label use of medicines [25]. In an intensive care setting around one-third of the adverse reactions may be linked with the use of an off-label drug [26]. In a recent study carried out in paediatric outpatients in France, the incidence of adverse drug reactions was 1.41% in the whole population studied and 2.00% in patients exposed to at least one off-label prescription [7]. Off-label drug use was significantly associated with adverse drug reactions with a relative risk of Hence, concerns about unlicensed and off-label use of medicines in children may be well founded. However, the prescribing of medicine to children in an unlicensed manner and/or off-label may often be appropriate. Paediatricians, and other prescribers caring for children, are faced with difficult choices and the medicine with the best risk benefit profile may just happen to be unlicensed for paediatric use. Furthermore, the labelling may not reflect currently accepted practice. Hence, many health professionals are forced into a situation of prescribing unlicensed or off-label drugs in :3 Br J Clin Pharmacol

6 Accessibility of medicines for children order to ensure the most effective treatment regimen for children, because the benefit of using unlicensed or offlabel drugs is more likely to outweigh the risk of using them. The present study is unable to determine whether the changes in New Zealand are a localized phenomenon or part of worldwide trends. There are limited data available on this subject. In a European study reviewing the registration of new medicines for paediatric use, 45 new substances licensed between January 95 and April 98, 29 were of possible use in children but only 10 were actually licensed for paediatric use [27]. For the remaining 19, nine of their manufacturers claimed that their use in children has not been established. Further research is required to determine if the regulatory changes in the United States or Europe have resulted in improvements in the access of children to medicines in those markets. Further research is also indicated to determine if the trends in New Zealand demonstrated in the present study continue into the future. Conclusion There have been modest improvements in licensing, labelling and availability of formulations for children in New Zealand from 1998 to There has been a decrease in the number of paediatric formulations subsidized but, because of the availability of therapeutic alternatives, this does not necessarily represent a decrease in access to effective treatment. References 1 Moore P. Children are not small adults. Lancet, 1998; 352: Turner S. Unlicensed and off-label drug use in Australia. Paediatric Perinatal Drug Ther, 2000; 4: Bücheler R, Schwab M, Mörike K, Kalchthaler B, Mohr H, Schröder H et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ, 2002; 324: Chalumeau M, Tréluyer JM, Salanave B, Assathiany R, Chéron G, Crocheton N et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child, 2000; 83: Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed, 1999; 80: F142 F Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Invest Children BMJ, 2000; 320: Horen B, Montastruc J-L, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol, 2002; 54: McInyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child, 2000; 83: O Donnell CP, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics, 2002; 110: E Turner S, Gill A, Nunn T, Hewitt B, Choonara I. Use of off-label and unlicensed drugs in paediatric intensive care unit. Lancet, 1996; 347: Schirm E, Tobi H, de Jong-van den Berg LTW. Unlicensed and offlabel drug use by children in the community: cross sectional study. BMJ, 2002; 324: Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ, 1998; 316: W t Jong G, Eland IA, Sturkenboom MCJM, van den Anker JN, Stricker BH. Unlicensed and off-label prescription of drugs to children: population based cohort study. BMJ, 2002; 324: Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr, 1999; 88: Pharmaceutical Management Agency. New Zealand Pharmaceutical Schedule, August (Ed. by Wellington) Australasian Drug Information Services. New Ethicals Catalogues, May (Ed. by Auckland). ADIS Press Australasian Drug Information Services. New Ethicals Compendium, 6th and 7th edns. Auckland: ADIS Press. 1997: Medsafe Kauffman RE. Clinical trials in children: problems and pitfalls. Paediatr Drugs, 2000; 2: Anderson GD. Children versus adults: Pharmacokinetic and adverse-effect differences. Epilepsia : 2002; 43: Conroy S, McIntyre J, Choonara I, Stephenson T. Drug trials in children: problems and the way forward. Br J Clin Pharmacol, 2000; 49: Center for Drug Evaluation and Research.. Pediatric Drug Development, Nahata MC. Pediatric drug formulations: challenges and potential solutions. The Ann Pharmacotherapy, 1999; 33: Collier J. Paediatric prescribing: using unlicensed drugs and medicines outside their licensed indications. Br J Clin Pharmacol, 1999; 48: Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf, 2002; 25: Gill AM, Leach HJ, Hughes J, Barker C, Nunn AJ, Choonara I. Adverse drug reactions in a paediatric intensive care unit. Acta Paediatr, 1995; 84: Impicciatore P, Choonara I. Status of new medicines approved by the European Medicines Evaluation Agency regarding paediatric use. Br J Clin Pharmacol, 1999; 48: Br J Clin Pharmacol 57:3 327