Public consultation on Delegated Act on Post-Authorisation efficacy studies PGEU RESPONSE
INTRODUCTION The Pharmaceutical Group of the European Union (PGEU) is the association representing community pharmacists in 32 European countries. In Europe over 400.000 community pharmacists provide services throughout a network of more than 160.000 pharmacies, to an estimated 46 million European citizens daily. PGEU s objective is to promote the role of pharmacists as key players in healthcare systems throughout Europe and to ensure that the views of the pharmacy profession are taken into account in the EU decision-making process. PGEU welcomes this consultation paper to support the Commission in further exploring the application of a delegated act to post-authorisation efficacy studies (PAES), which complement efficacy data available at the initial authorisation stage, for the purpose of ensuring public health protection in the EU. In this context, PGEU recalls the important role the European network of pharmacies may play in collaborating with Authorities and Marketing Authorisation Holders (MAH) to collect post-authorisation real-world data, both for safety, and for effectiveness studies. Community pharmacies are the most accessible health care facility to the general public where highly qualified healthcare professionals provide a wide range of professional services to EU citizens. The public health mission of community pharmacists goes far beyond the use of medicines. It is part of a broader public health strategy focusing on the population, and aims to improve the health status and quality of life. Additionally, 99.99% of the European pharmacies are computerized and equipped with information systems that support dispensing, but often include other features as well, such as tracking medication history in an electronic patient record. The unique position of community pharmacies, at the heart of communities and very often the first and last point of the patient s interaction with health system, represent a unique research opportunities. Pharmacies can collect medicines use as well as patient experience data and assist National Authorities and MAH, for the purpose of a truly pro-active and systematic pharmacovigilance throughout the entire life cycle of the medicines, in the public health interest. Consultation Item No 1: Do you think that a delegated act on the situations in which a post authorisation efficacy study may be required will be of added value and that the Commission should consider bringing forward a draft delegated act? Please provide reasons for your opinion. Yes. The possibility for the Commission to adopt this delegated act and establish clear reference points for situations in which these studies may be required is in the interest of public health and will bring further regulatory clarity. However it is important to implement this provision with caution so it is not abused, when for example bringing products that do not have well established safety profile on the market, before answering all the necessary concerns. We hope that transparency would be the key issue in all post-authorisation studies conducted in the EU. Unequivocally, society demands a transparent and
an integrated assessment of benefits and risks, under real life conditions, as the next logical step after clinical trials. Consultation Item No 2: Do you have any comments on the above? Do you agree that generally speaking post-authorisation efficacy studies should focus on generating efficacy data? It is well recognized the existing gap between efficacy and effectiveness. Addressing efficacy studies alone poses a problem of how well the real world patient population of a particular medicine is represented in efficacy studies, especially in situations that might have a negative impact on effectiveness and that may only be captured in large and real world samples (e.g. wide prescribing variations, off-label prescribing, prescribing far outside guidelines, co-morbidities, polypharmacy, adherence and persistence severe issues, etc). The discussion around making use of a delegated act in the public health interest should not be a discussion between two methodologies. Both efficacy and effectiveness post-authorisation studies are important and complement one another. Therefore, PGEU supports the need not to exclude both strategies from the delegated act set out for reference standards for PAES studies. Instead, the emphasis should be made at sound and robust epidemiological and statistical methods for both designs and for the important role of both efficacy and effectiveness studies. On the other hand, risk should not be neglected. When considering how to maximize or indeed assess the risk-benefit balance the paramount of medicines evaluation risks need to be understood in the context of benefit. Consultation Item No 3: Please comment on the seven different situations described above. Do you agree that in these situations, a competent authority may ask for a post-authorisation efficacy study? Are there any other situations not covered by points 5.1 to 5.7 in which it would also be justified to oblige a marketing authorisation holder to conduct an efficacy study? If this is the case, could you please elaborate on these situations, if possible, give pscific examples to underpin the need? Yes, all of the outlined seven situations may be considered possible PAES scenarios requested by a competent authority. In the context of the different situations described in the concept paper, PGEU would like to point out two situations where European community pharmacies may play key role in collaboration with Authorities and Marketing Authorisation Holders (MAH) to collect post-authorisation real-world data. Studies in sub-populations Several sub-populations are not included in RCTs that lead to the marketing authorisation. Paediatric and geriatric populations are two most evident examples. In addition, aging European population and increasing proportion of the elderly together with co-morbidities, polipharmacy, adherence / persistence Page 3 of 5
issues, etc, that are typical to this sub-population, substantially increases the probability of important deviations to the benefit/risk profile, when comparing RCT populations vs real-world populations. The threshold for investigating both safety and efficacy concerns in specific populations further will depend upon the indication, the target population, and the likely impact on public health. Requests from EMA or from the National Agency in the initial MA or later on shall be a reality. The accessibility, wide distribution, the expertise on medicines and the relationship based on trust between patients and pharmacists make community pharmacies a key player for collecting data for studies in sub-populations. For these reasons, community pharmacists come in contact with a broad range of the population, without selection criteria such as those used in RCT, and thus, the community pharmacies are better positioned to identify patients and collect real data for post-authorisation studies in all the types of sub-populations. Studies in everyday medical practice This is particularly important for patients affected by chronic diseases where there is a perceived strong gap between efficacy demonstrated in RCTs and effectiveness under real life conditions. It is often due to different real patient population, wrong patient selection, prescribing patterns, off-label prescribing, prevailing prescribing patterns outside guidelines, comorbidities/polypharmacy, patient adherence/persistence and utilisation severe issues, etc. People with chronic diseases managed by medication visit their community pharmacists more frequently than any other healthcare professional. Thus, European community pharmacists are well aware of the problems, experiences and outcomes of these patients. As stated, vaccines are also another example where the need for assessing the effectiveness is crucial. Here, medicine utilisation data represents a vehicle to enhance regulatory dialogue. Medicine utilisation research is an eclectic discipline, integrating descriptive and analytical methods for the quantification, the understanding and the evaluation of the processes of prescribing, dispensing and consumption of medicines; and for the testing of interventions to enhance the quality of these processes. In this field, pharmacoepidemiology as a discipline has a key role on understanding the evidence base and interpreting data on drug utilization. Evaluation of external validity of published clinical trials data by comparing its data to observational data obtained from clinical daily practice in EU should not be neglected. Consultation Item No 4: Do you have any comments on the above? As previously stated, the delegated act should not elaborate, in our point of view, on methodological issues for PAES design, as these are progressing over time. It should not adopt a preference stand for interventional studies, as outlined. Instead, it should recommend that both efficacy and effectiveness are addressed in future PAES, calling for robust methods. We suggest that methodological standards defined by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) should be recommended for these studies. Page 4 of 5
Furthermore, considering the importance of the patient as a key player in pharmacovigilance systems, already recognized in the directive, PGEU believes that patients role should also be considered under the delegated act on PAES. It is expected that patient preferences and patient reported outcomes will become more important for marketing authorization purposes. As the validity and reliability of such metrics tend to improve, it is important to allow PAES that include a Patient Reported Outcomes (PRO). Finally, although out of the scope of the Pharmacovigilance Directive, PGEU believes that the EC may take this opportunity to address economic and financial issues related to medicine utilisation. Several factors put national health systems under pressure, such as demographic, economic and changing risk factors to health. Thus, the situations in which pharmacoeconomics studies and medicine utilisation studies in compliance with existent clinical and prescribing guidelines adopted at National level may be needed, can also be assessed and discussed at European level. These studies are an essential tool to promote public health, cost-effectiveness of the treatments and sustainability of the national health systems. For example, certain medicines are second and third line therapies (when patients do not respond to the first line therapy) and, hence, were authorised for a particular patient subgroup or condition. However, prescribing influence by marketing authorization holders (marketing bias) may have an impact in widening the use of the medicine in the real world setting to a broader population and scope of conditions. Often, the first sign is the increasing consumption pattern of the new medicine vs expected patterns based on approved indication. Studies linked to increasing consumption of medicines which are not first line therapies and/or indications limited to a patient subgroup or in a restricted condition, are one example of a situation that can contribute to a better use of medicines and to reduce costs both for patients and for States. In conclusion, community pharmacies in Europe are ready to collaborate with the National Authorities, in implementing an effective pharmacovigilance system throughout the entire life cycle of the medicines, in the public health interest. Community pharmacists are prepared to assume more responsibility and intervene in post-authorisation studies for pharmacoviligance, pharmacoeconomics and pharmacoepidemiological purposes. Page 5 of 5