Rare disease registries: A must for regulatory decision making Carla Jonker

ISBN: 978-94-6419-419-7 Cover and lay-out: Eveline Korving, Schreef Studio Cover illustration and chapter illustrations: Eveline Korving, Schreef Studio Printing: Gildeprint B.V, Enschede, The Netherlands The studies presented in this thesis have been conducted under the umbrella of the Regulatory Science collaboration between the Dutch Medicines Evaluation Board (CBG-MEB), PedNet Haemophilia research Foundation and the Julius Center for Health Sciences and Primary Care of UMC Utrecht. The CBG-MEB is dedicated to ensure that licensed medicinal products during their whole life-cycle have a positive benefit-risk. This role requires intensive collaboration with academic and clinical partners in order to develop new assessment and decision-making methods, to engage with the clinic and to strengthen regulatory science. This PhD thesis aims to go beyond its scientific merits as such by delivering science, learnings and insights to promote public health. Printing of this thesis was kindly supported by the CBG-MEB and the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht. ©2022 Carla Jonker, Warmond, the Netherlands No part of this thesis may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or by any means without prior written permission of the author, or when appropriate, the holder of the copyright.

RARE DISEASE REGISTRIES: A must for regulatory decision making Registers van zeldzame ziekten: een must voor regulatoire besluitvorming (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 15 februari 2022 des middags te 2.15 uur door Clara Johanna Jonker geboren op 14 april 1968 te Terneuzen

Promotoren Prof. dr. A.W. Hoes Prof. dr. P.G.M. Mol Copromotor Dr. H.M. van den Berg

Table of contents General introduction Registries supporting new drug applications Drug registries and approval of drugs: Promises, placebo or a real success? Clinical trials and registries in haemophilia: Opponents or collaborators? Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry-based study Capturing data in rare disease registries to support regulatory decision-making: A survey study among industry and other stakeholders Discussion Summary & Samenvatting List of publications Curriculum Vitae Dankwoord Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 9 21 43 55 75 91 137 151 160 161 162

Chapter 1 General introduction

10 Rare disease registries: a must for regulatory decision-making 1 General introduction Before a new medicine can enter the market, regulatory authorities assess if the balance between efficacy and safety is positive. Randomized controlled trials are the gold standard for the assessment of drug effects, because of its potential to prevent bias. A disadvantage of randomized trials is the limited applicability of the, unbiased, results to daily practice, notably because they often include selected (usually younger, with limited co-morbidity). Thus, such studies focus mainly on assessment of efficacy and shorter-term safety rather than real-life effectiveness and long-term safety.1 For rare diseases with a chronic nature, it can be a challenge to perform randomized controlled trials with an adequate sample size and sufficient duration of follow-up to robustly determine treatment outcomes. As a result the knowledge about a medicinal product for the treatment of a rare disease is often incomplete and data on relevant longerterm outcomes are often lacking at the time of marketing authorisation. Different stakeholders (patient groups, regulatory, clinicians, scientists, industry and payers) have recognized the value of disease registries to learn about the natural course of (especially rare) diseases following standard of care and to monitor long-term collection of safety data to complement data collected in randomized controlled trials.2 First registry The start of registries in the clinical setting seems to be the establishment of a leprosy registry in Norway in 1856, both for health care and research purposes. In Norway physicians collected detailed case histories on all leprosy patients. The knowledge obtained through the leprosy registry played a significant role in the control of the disease, the evaluation of trends in prevalence and had a great impact on the developments in disease control.3 Rheumatology More recent examples of registries that played a major role to learn more about the disease and treatment thereof are rheumatology and haemophilia registries. Since the 1960s rheumatology registries have been set-up because the randomized controlled trials for biologic disease-modifying anti-rheumatic drugs insufficiently addressed the long-term safety of this new class of medicinal products.4 Little was known about the background rates of serious outcomes such as infections and malignancies, what made it difficult to decide what the safety of the biological agents would be.5 Especially in the case of children with juvenile idiopathic arthritis, a rare condition, more outcome data was needed to understand the effects of long-term treatment with immunosuppressive agents as well as the development of comorbidities.5 Registries were able to provide data on longer drug exposure, greater number of patients, pregnancies during biologic therapies and patients with various risk profiles.4 Haemophilia In the case of haemophilia, registries date back to the era of the human immunodeficiency virus (HIV) epidemic in the 1980s as a result of the infusion of

Chapter 1 General introduction 11 1 contaminated blood products with HIV and hepatitis C.6 After the introduction of recombinant products in 1992 inhibitor development is the most important outcome measured in registries for patients with haemophilia.7 The role of registries is acknowledged by the World Federation of Haemophilia (WFH), and the European Association for Haemophilia and Allied Disorders (EAHAD). EAHAD recommends the establishment of national haemophilia registries as one of the European principles of haemophilia care.8 One of the oldest registries is the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO), they established a national data-base (NHD) in 1978. The aims of the UKPHDO are to improve haemophilia care, to advance the education of professionals in the knowledge of haemophilia and other inherited bleeding disorders and their treatment and to promote research.9 Mycophenolate mofetil Already in the first year of existence of the Committee for Human Medicinal Products for human use (CHMP), the CHMP described the use of registry data in the regulatory decision-making process. In 1996 mycophenolate mofetil in combination with ciclosporin and corticosteroids was approved for the indication “prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants”.10 For the assessment of mycophenolate mofetil, data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS registry) were used as a historical control.11 Gaucher disease The first product registry used in regulatory decision-making process is the Gaucher registry. This registry is initiated by the company Genzyme and entry of patients is predominately determined by the prescription of a specific drug, imiglucerase.12-13 In the Gaucher registry, data is collected from patients with Gaucher disease, independent of disease severity or treatment status.12 Data from the Gaucher registry provided sufficient evidence for the indication “treatment of long-term enzyme replacement therapy in patients with chronic neuronopathic (Type 3) Gaucher disease”.14 Despite the impressive amount of data collected, shortcomings of the Gaucher’s registry were that no information was collected related to the safety or treatment-associated adverse events and the question remained whether all Gaucher disease phenotypes were represented in this registry.13 Although the Gaucher Registry was not restricted to patients treated with imiglucerase, due to the mandated creation of product registries for alternative treatment options, patients switching from one treatment to another were often lost for follow-up.15 Review of factor VIII products In 2013 data collected by the PedNet and Rodin study group were published.16 These data were later confirmed by the UKHCDO and FranceCoag studies.17-18 For the Pharmacovigilance Risk Assessment Committee (PRAC) these results were the reason to start a referral procedure, which is a request on behalf of the European Union to conduct a scientific assessment of a particular medicine or class of

12 Rare disease registries: a must for regulatory decision-making 1 medicines and is one of the strongest tools the PRAC has to review whether the benefit/risk balance of a medicine is still positive. In the Rodin study about a third of all the children developed factor VIII inhibitors against their medicine, which reduces its benefit and makes bleeding more likely. This is a known risk for all factor VIII products but the authors of the study concluded that children given so-called second generation full-length recombinant factor VIII products were more likely to develop antibodies than those given a third generation recombinant product.16 An increase in inhibitor formation was not seen with other recombinant or plasmaderived factor VIII products. The outcome of the PRAC referral, which took ten months to complete, was that the benefits of treatment with second generation full-length recombinant factor VIII products continue to outweigh their risks in previously untreated patients. The product information was updated to reflect the study results.19 While some uncertainties on the observational nature of the study were expressed, a combined analyses of these three large cohort studies confirmed the trend of an increased risk of inhibitor development in PUPs for one recombinant product.20 Regulatory context The publication of the Rodin study initiated this thesis. At the time any medicinal product is approved, the knowledge about the effectiveness in daily practice and safety is limited.1 Especially in the field of rare diseases the sample size to perform meaningful randomized controlled trials is small. Pre-licensure clinical studies on often selected patients are not powered to identify uncommon or rare adverse reactions.21 Therefore post-authorization studies are needed to assess the effectiveness and safety of medicines. Registries are one of the options described in the Guideline on good pharmacovigilance practices (Figure 1).22 Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 3) Registries A registry is an organised system that uses observational methods to FROOHFW XQLIRUP GDWD RQ VSHFLÀHG RXWFRPHV LQ D SRSXODWLRQ GHÀQHG by a particular disease, condition or exposure. A registry can be used as a data source within which studies can be performed. (QWU\ LQ D UHJLVWU\ LV JHQHUDOO\ GHÀQHG HLWKHU E\ GLDJQRVLV RI D GLVHDVH SUHVFULSWLRQ of a medicinal product, or both (patients with a certain disease treated with D GHÀQHG PHGLFLQDO SURGXFW GHÀQHG DFWLYH VXEVWDQFH RU DQ\ PHGLFLQH RI D GHÀQHG FODVV RI PHGLFLQDO SURGXFWV 7KH FKRLFH RI WKH UHJLVWU\ SRSXODWLRQ DQG WKH GHVLJQ RI WKH UHJLVWU\ VKRXOG EH GULYHQ E\ LWV REMHFWLYH V LQ WHUPV RI outcomes to be measured and analyses and comparisons to be performed.

Chapter 1 General introduction 13 1 Registries are particularly useful when dealing with a rare disease, rare exposure or special population. In many cases, registries can be enriched with data on outcomes, FRQIRXQGLQJ YDULDEOHV DQG HIIHFW PRGLÀHUV REWDLQHG IURP D OLQNDJH WR DQ H[LVWLQJ database such as national cancer registries, prescription databases or mortality records. Depending on their objective, registries may provide data on patient, disease and treatment outcomes, and of their determinants. Data on outcomes may include data on patient-reported outcomes, clinical conditions, medicines utilisation patterns DQG VDIHW\ DQG HIIHFWLYHQHVV ,W LV DFNQRZOHGJHG WKDW RQ RFFDVLRQ UHJLVWULHV PD\ EH WKH RQO\ RSSRUWXQLW\ WR SURYLGH LQVLJKW LQWR HIÀFDF\ DVSHFWV RI D PHGLFLQDO product. However, observational registries should not normally be used to GHPRQVWUDWH HIÀFDF\ 5DWKHU RQFH HIÀFDF\ KDV EHHQ GHPRQVWUDWHG LQ UDQGRPLVHG FOLQLFDO WULDOV 5&7V SDWLHQW UHJLVWULHV PD\ EH XVHIXO WR VWXG\ HIIHFWLYHQHVV LQ KHWHURJHQHRXV SRSXODWLRQV HIIHFW PRGLÀHUV VXFK DV GRVHV WKDW KDYH EHHQ SUHVFULEHG E\ SK\VLFLDQV DQG WKDW PD\ GLIIHU IURP WKRVH XVHG LQ 5&7V SDWLHQW VXE JURXSV GHÀQHG E\ YDULDEOHV VXFK DV DJH FR PRUELGLWLHV XVH RI FRQFRPLWDQW PHGLFDWLRQ RU JHQHWLF IDFWRUV RU IDFWRUV UHODWHG WR D GHÀQHG FRXQWU\ RU KHDOWKFDUH V\VWHP Where adequate data are already available or can be collected, patient registries PD\ EH XVHG WR FRPSDUH ULVNV RI RXWFRPHV EHWZHHQ GLIIHUHQW JURXSV )RU example, a case-control study may be performed to compare the exposure WR WKH PHGLFLQDO SURGXFW RI FDVHV RI VHYHUH DGYHUVH UHDFWLRQV LGHQWLÀHG IURP the registry and of controls selected from either patients within the registry RU IURP RXWVLGH WKH UHJLVWU\ /LNHZLVH D FRKRUW VWXG\ PD\ EH HPEHGGHG LQ D UHJLVWU\ &DVH RQO\ GHVLJQV PD\ DOVR EH DSSOLHG VHH 9,,, $SS 3DWLHQW UHJLVWULHV PD\ DGGUHVV H[SRVXUH WR PHGLFLQDO SURGXFWV LQ VSHFLÀF populations, such as pregnant women. Patients may be followed over time and included in a cohort study to collect data on adverse events using standardised questionnaires. Simple cohort studies may measure incidence, but, without a comparison group, cannot evaluate any association between exposures and RXWFRPHV 1RQHWKHOHVV WKH\ PD\ EH XVHIXO IRU VLJQDO DPSOLÀFDWLRQ SDUWLFXODUO\ IRU UDUH RXWFRPHV 7KLV W\SH RI UHJLVWU\ PD\ EH YHU\ YDOXDEOH ZKHQ H[DPLQLQJ WKH VDIHW\ RI DQ RUSKDQ PHGLFLQDO SURGXFW DXWKRULVHG IRU D VSHFLÀF FRQGLWLRQ Guideline on good pharmacovigilance practices (GVP) – Module VIII (Rev 3) Figure 1. Description of a registry in the guideline on good pharmacovigilance practices (GPV) Registry data can be collected either in disease or product registries.23 Disease registries are often created by public organisations such as academia or medical research associations of health care professionals or patients. They may have different objectives, such as to describe the natural history of a disorder, to monitor the efficacy or safety of treatments. For example in subpopulations (e.g. geriatric patients) for which pre-authorisation data are limited, registries can be used to describe the impact of a

14 Rare disease registries: a must for regulatory decision-making 1 disease on patients’ health and quality of life or to identify patients suitable for (studies on) new treatments. Irrespective of the original aim pursued by the registry, the data collected may also be useful to support the regulatory evaluation of benefits and risks of medicines. For disease registries the entry is determined by the diagnosis of a disease, in product registries by the prescription of a specific drug. In general, disease registries gather insights on clinical outcomes of conditions in patients receiving different treatments, rather than on the outcomes of a specific treatment, and they may support a wider range of study designs, e.g., controlled designs without an external data source. They are also generally better integrated into health care systems and are therefore more likely to be sustainable and provide long-term follow-up data on patients.2 For example, in the field of lysosomal storage disorders two companies independently set-up a product registry to collect data to enable an annual reassessment of the benefit/risk profile of their product.15 The added values of both registries are increased knowledge about the effect of enzyme replacement therapy on clinical outcomes in females and paediatric patients, but can also lead to a better understanding of the natural course of the disease.24-25 However, because of the lack of collaboration between the two product registries, after more than ten years of experience important questions are still not answered. This is due to fragmentation of data, lack of quality and completeness of data and the impossibility to compare different treatments.15 Patient registry initiative In 2015 the European Medicines Agency (EMA) set up the initiative for patient registries. 26 The goal of the initiative is to make better use of existing registries to support their contribution to the benefit-risk evaluation of medicinal products.27 At time of the start of the patient registry initiative there were a number of challenges such as coordination between ongoing initiatives at the national and international level; harmonised protocols, scientific methods and data structures; data sharing and transparency and sustainability of a registry. To address these problems the patient registry initiative promotes dialogue between regulators, companies and registry holders to understand barriers and opportunities of using disease registries (Figure 2). They organised a number of disease-specific workshops with stakeholders, including registry owners, patients, regulators, reimbursement bodies, employees of pharmaceutical companies and health technology assessment bodies. The participants of these workshops gave recommendations on the use of registries in the disease areas cystic fibrosis, multiple sclerosis, chimeric antigen receptor T-cell therapy, haemophilia and cancer therapies based on genetic and molecular features. The main recommendations included the topics core data elements, informed consents, governance, data sharing and interoperability. For each workshop the EMA published a report on their website.26

Chapter 1 General introduction 15 1 Present…’the broken triangle’ Future… more cooperation! Figure 2. ‘Broken Triangle’ barrier to better use of patient (disease) registries. Source: Nicola Ruperto, PRINTO Research aim and outline of the thesis The aim for this thesis is to investigate the value of registries for regulatory decisionmaking. The field of haemophilia has been used as a case study, because of the longterm follow-up of patients included in haemophilia registries. The studies reported in this thesis highlight how registries are used in the regulatory decision-making process and discuss what the direction will be for the use of registries in this context. We started to investigate what the experiences were with registries for medical products approved by the CHMP. Chapter 2 provides an overview of all registries that have been proposed for all new medicinal products, which were approved in the European Union between 2007 and 2010. We reviewed the frequency, the type, and the reason for requiring a registry. Chapter 3 shows the results of a review on whether registry studies for new medicinal products indeed were performed as agreed at time of approval. We continue the thesis with data available from the PedNet registry. In the PedNet registry data are collected from children with haemophilia, who are followed from birth onwards. The aim of the registry it to enable studies on side effects and outcome of treatment. All newly diagnosed patients with haemophilia A or B with a factor VIII or IX activity below 25%, born from 1 January 2000 and treated in one of the participating centres are eligible for inclusion.28 In Chapter 4 outcome data of the PedNet registry are compared with a number of clinical trials. The clinical guideline that describes the requirements for the performance of clinical trials in the field of haemophilia A was the starting point for this investigation.29 InChapter 5 we studied whether a disease registry, the PedNet haemophilia registry, could serve as a suitable alternative to clinical studies to investigate the safety of a recombinant factor VIII product in previously untreated patients with severe haemophilia A. The problems described inChapter 2 and 3, the opportunities identified in Chapter 4 and 5 and the experience gained over time with the patient registry initiative hopefully lead to a better understanding of the key elements of registries. Little is known, about whether stakeholders find the key elements: collection of comment data elements, data quality and governance aspects important and feasible Regulatory authorities Registry holders/academia Pharmaceutical companies Regulatory authorities Registry holders/academia Pharmaceutical companies

16 Rare disease registries: a must for regulatory decision-making 1 in the context of registries. In collaboration with the patient registry initiative a survey was set up among industry and other stakeholders on what matters for the capturing of data in registries in the field of rare diseases for regulatory decision-making. The results of this survey are presented in Chapter 6. In Chapter 7 the main findings of these studies and results are discussed in the light of the benefits and the challenges to use registry data for regulatory decision-making. And finally inChapter 8 the main findings of these studies are summarized.

Chapter 1 General introduction 17 1 References 1. Eichler HG, Pignatti F, Flamion B, et al. Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nat Rev Drug Discov. 2008;7(10):818-826. 2. Registries for Evaluating Patient Outcomes: A User's Guide [Internet]. 3rd edition. Rare Disease Registries books/NBK208609/#ch20.s1(last accessed 17 July 2020). 3. Irgens LM, Bjerkedal T., Epidemiology of leprosy in Norway: the history of The National Leprosy Registry of Norway from 1856 until today. Int J Epidemiol. 1973;2(1):81-89. 4. Elkayam O, Pavelka K. Biologic registries in rheumatology: lessons learned and expectations for the future. Autoimmun Rev. 2012;12(2):329-336. 5. Beukelman T, et al. A survey of national and multi-national registries and cohort studies in juvenile idiopathic arthritis: challenges and opportunities. Pediatr Rheumatol Online J. 2017;15(1):31-40. 6. Darby SC, Rizza CR, Doll R, et al. Incidence of AIDS and excess of mortality associated with HIV in haemophiliacs in the United Kingdom: report on behalf of the directors of haemophilia centres in the United Kingdom. BMJ. 1989;298:1064–1068. 7. Osooli M, Berntorp E. Registry-based outcome assessment in haemophilia: a scoping study to explore the available evidence. J Intern Med. 2016; 279(6):502-514. 8. Colvin BT, Astermark J, Fischer K et al. European principles of haemophilia care. Haemophilia. 2008;14:361–374. 9. About UKHCDO (last accessed 4 September 2020). 10. EPAR mycophenolate mofetil (last assessed 8 July 2020). 11. Dharnidharka VR, Ho PL, Stablein DM, et al. Mycophenolate, tacrolimus and posttransplant lymphoproliferative disorder: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 2002;6(5):396-399. 12. Charrow J, Andersson HC, Kaplan P, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch. Intern. Med. 2000;160(18):2835-2843 13. Weinreb N. J. and Kaplan P. The history and accomplishments of the ICGG Gaucher-registry. Am J Hematol. 2015;90(Suppl 1):S2-S5. 14. EPAR imiglucerase cerezyme-epar-scientific-discussion_en.pdf (last accessed 7 July 2020). 15. Hollak CEAJ, Ayme S, Manuel J. Limitations of drug registries to evaluate orphan medicinal products for the treatment of lysosomal storage disorders. Orphanet J Rare Dis. 2011;6:16-22. 16. Gouw SC, van der Bom JG, Ljung R, et al.; PedNet and RODIN Study Group. Factor VIII Products and Inhibitor Development in Severe Hemophilia A. N Engl J Med. 2013;368(3):231-239. 17. Collins PW, Palmer BP, Chalmers EA, et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood. 2014;124(23):3389-3397. 18. Calvez T, Chambost H, Claeyssens-Donadel S, et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood. 2014;124(23):3398-3408.

18 Rare disease registries: a must for regulatory decision-making 1 19. Factor VIII article 31 referral. Available at human/refels/factor-viii#overview-section (last accessed 1 May 2020). 20. Volkers P, Hanschmann KM, Calvez T, et al. Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies. Haemophilia. 2019;25:398–407. 21. Kempf L, Goldsmith JC, Temple R. Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet. 2018;176:773–783. 22. Guideline on good pharmacovigilance practices (GVP)- Module VIII – Postauthorisation safety studies (Rev 3) scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-moduleviii-post-authorisation-safety-studies-rev-3_en.pdf (last assessed 8 July 2020). 23. Maier WC, Christensen RA, Anderson P. Post-approval Studies for Rare Disease Treatments and Orphan Drugs. Adv Exp Med Biol. 2017;1031:197-205. 24. Spada M, Baron R, Elliott PM, Falissard B, Hilz MJ, Monserrat L, Tøndel C, TylkiSzymańska A, Wanner C, Germain DP. The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts. Mol Genet Metab. 2019;126(3):212-223. 25. Germain DP, Elliott PM, Falissard B, et al. The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease – A systematic literature review by a European panel of experts. Molecular Genetics and Metab. 2019;126(3):224-235. 26. Patient registries post-authorisation/patient-registries (last accessed 17 July 2020). 27. McGettigan P, Alonso Olmo C, Plueschke K, et al. Patient registries: an underused resource for medicines evaluation. Drug Saf. 2019;42(11):1343-1351. 28. Haemophilia registry (last assessed 8 July 2020). 29. Guideline on the clinical investigation of recombinant and human plasmaderived factor VIII products. scientific-guideline/guideline-clinical-investigation-recombinant-human-plasmaderived-factor-viii-products-revision-2_en.pdf. (last accessed June 15, 2020).


Chapter 2 Registries supporting new drug applications Carla J. Jonker H. Marijke van den Berg Marcel S.G. Kwa Arno W. Hoes Peter G.M. Mol Pharmacoepidemiol Drug Saf. 2017;26:1451–1457

22 Rare disease registries: a must for regulatory decision-making 2 Abstract Purpose Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post-approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010 we reviewed the frequency, the type, and the reason for requiring a registry. Methods The European Public Assessment Reports (EPARs), published on the website of the European Medicine Agency were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry). Results Out of 116 new drugs approved in the predefined period, for 43 (37%), one to six registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For nine drugs the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post-approval registries (OR 10.3 (95% CI 1.0-103.9) and OR 2.8 (95% CI 1.0-7.5); respectively). Conclusions The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for postapproval data collection for orphan and innovative drugs.

Chapter 2Registries supporting new drug applications 23 2 Introduction Evidence regarding benefit and especially risks of drugs is still limited by the time they are approved by regulatory agencies. Therefore, regulators require additional evidence regarding safety and real-world effectiveness throughout the remainder of the drug’s life-cycle.1 In some situations, companies are required to provide data from randomized controlled trials in order to establish remaining uncertainties about the benefits and risks of new drugs. Once approved, the number of patients exposed to the drug will be much larger, long-term data will become available and safety concerns that could not be detected during clinical trials may be identified. Hence, data collected post-authorization are critical for learning more about the benefit-risk balance of new drugs. The Food and Drug Administration (FDA) in the USA and the European Medicine Agency (EMA) in Europe have developed extensive guidance for industry indicating how to address identified and potential safety concerns and how to deal with missing data.2, 3 These pharmacovigilance activities focus on monitoring real-life clinical use, including the systematic collection of observational data in registries. Data collected post-approval through these registries can be used to complement pre-registration study data to address existing knowledge gaps, e.g. missing data regarding children, use during pregnancy, and effects of long-term treatment. A registry can be used as a data source for other studies, such as studies to measure the effectiveness of risk minimization measures and drug utilization studies.3 In Europe, the Committee for Medicinal Products for Human Use (CHMP) is responsible for the scientific evaluation and approval of drugs for use within the European Union. Increasingly more drugs have been approved based on limited data sets during the last decade, e.g. 30 drugs were conditionally approved between 2006 and June 2016.4 Earlier we have shown that this trend has not necessarily lead to more safety issues.5 For many of these drugs, registries have been proposed to fill the knowledge gap. Although registries are suggested and approved as a tool for post-approval collection of additional data for new drugs, it is currently unknown how often this tool is being used, for how many and what type of drugs, and what the rationale is to for requesting a registry. Therefore, the goal of this study was to assess the frequency and the reasons for requesting post-approval registries in Europe and to examine the type of registries (drug or disease). Further we investigated, whether registries had been imposed by the regulatory authority as a specific obligation or had been ‘spontaneously’ promised by a company in order to address remaining uncertainties on drug benefits and risks. We examined the rationale (e.g. safety concerns or long term efficacy) underlying the decision to set up a registry. Additionally, we explored what drug characteristics (e.g. ATC-code, level of innovation and size of pre-approval safety population) and procedure-related determinants (e.g. type of procedure or the existence of an orphan status) predicted a post-marketing registry to be included in a drug dossier.

24 Rare disease registries: a must for regulatory decision-making 2 Key points • One third of all drugs approved in Europe, between 2007 and 2010, were coupled with a requirement for a registry, mainly with the purpose of providing additional data due to safety concerns. • The majority of these registries are existing disease registries. • For orphan and innovative drugs registries are an important tool for post-approval data collection. Methods We performed a retrospective review of drugs approved by the CHMP in the European Union. Data source We identified drugs that were approved by the CHMP between 1 January 2007 and 31 December 2010 from the European Commission’s Community Register ( index_en.htm). Only drugs approved on the basis of a full application dossier for a new active substance and biosimilars were included in the dataset. The date of approval is defined as the date of publication of the European decision. Primary outcome The aim of the study was to investigate the frequency and reason for a requirement for a post-approval registry study to complement the marketing authorization dossier of new drugs. Scientific and regulatory information was collected from the European Public Assessment Reports (EPARs), which are accessible through the EMA website ( The requirement to set up a registry was identified from the Risk Management Plan (RMP) summary of the EPAR. In this summary safety specifications, proposed pharmacovigilance and risk minimisation activities are recorded. We included all registries that were mentioned in the EPAR. A registry is defined as an organised system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition, or exposure.3 We excluded studies with a single research question collecting data from one or more electronic health records database. In line with Bouvy et al., we also excluded non-interventional, open-label, prospective short-term observational studies (2 years or less).6 These studies were considered to be designed for a specific research question rather than a long-term study in a registry where routine clinical data are collected systematically. Both registries recorded as a specific or imposed obligation conform annex II of the Marketing Authorization and those required to investigate a safety concern are included. If more details were needed or if the information in the EPAR was not conclusive, data were obtained from the RMPs and study reports, which were retrieved from the

Chapter 2Registries supporting new drug applications 25 2 database available at the Medicine Evaluation Board (MEB). Data were extracted by CJ, all data were systematically checked by PM or MK to ensure accuracy of extracted information. Any discrepancies were resolved in discussion with CJ, MK and PM. Characteristics of registries, drugs and procedures We retrieved a number of relevant characteristics of the identified registries. First, we identified in the dossier the primary goal for requiring the registry; e.g. to address safety, effectiveness or pregnancy outcomes. Second, we ascertained whether the specified outcome was defined by the disease (disease registry) or exposure to a single product or drug (drug registry). Drug registries could also include a class of drugs, but in our data set only single-drug registries were identified. To identify determinants for requiring a post-approval registry, we identified characteristics related to the nature of drug and the nature of the procedure that we hypothesized could influence the decision to require a registry. First, the therapeutic area was classified using the anatomical main group of the Anatomical Therapeutic and Chemical code (ATC-1 level, Second, the type of molecule was categorized as either a small molecule, vaccine or biosimilar, in accordance with the European legal definitions.7 Third, we classified the level of innovation of a new drug using an algorithm developed by Motola et al.8 Drugs were classified based on a sequential assessment of the availability of alternative treatment options for a particular disease and the therapeutic effect they had demonstrated in clinical studies, both as assessed at the time of approval. The algorithm graded drugs based on these considerations as (A) important, (B) moderate or (C) modest innovations, or as ‘mere’ pharmacological/technological innovations.8 Consequently, drugs classified as important innovations target diseases where treatment is not available and have demonstrated major benefits on clinical endpoints or established surrogate parameters.9 Fourth, we determined the size of the safety population; the total number of subjects exposed to the drug for any duration in the clinical development program before approval. Finally two procedural characteristics were identified; orphan drug and registration type (standard, under exceptional circumstances or receiving conditional approval) as defined in the Notes to Applicant.10 Statistical analyses Univariate and multivariate logistic regressions were applied to identify, which key drug and procedural characteristics were independent determinants of the requirement for a post-approval registry. Characteristics that were potentially associated with inclusion of a registry in the dossier (p<0.1) were included in the multivariate model. In the final model, only characteristics reaching a significant level of p<0.05 were considered as statistically significantly associated with the primary outcome.

26 Rare disease registries: a must for regulatory decision-making 2 Table 1. Key characteristics of 73 registries All registries N (%) Total 73 (100%) a y goa Prim r l Safety 39 Safety & Effectiveness 7 Pregnancy 27 Disease 6 (63%) 4 Drug 27 (37%) u be o eg st es pe d ug N m r f r i ri r r None 73 One 29 Two 6 Three 4 More than four 6 eg st y posed R i r im Yes 9 (12%) No 64 (88%) Results Between 1 January 2007 and 31 December 2010, 116 new drugs (new active substances and biosimilars) were approved in Europe by the CHMP. A total of 73 registries were included in the RMPs of 43 (37%) of these newly approved products. For 29 of these new drugs, there was a post-approval requirement for a single registry and for 14 drugs there was a requirement for between two and six registries (Table 1), implying that for 73 new drugs there was no need for a registry. For only nine drugs registries were imposed by the CHMP. For drugs subjected to a registry the size of safety population ranged between 94 and 13,000 patients; 15 drugs had an orphan status and 13 drugs were approved under exceptional circumstances or were conditionally approved (Table 2, and Supplementary Table 1 for individual drugs). The primary goal of 39 of the 73 registries was to collect safety outcomes, in seven cases, it was to collect safety outcome and real-world effectiveness data; and in 27 cases, it was to collect data on potential birth defects when the drug orphan status and 13 drugs were approved under exceptional circumstances or were conditionally approved (Table 2, and Supplementary Table 1 for individual drugs). was taken during pregnancy. The most common aims of these registries were to increase knowledge on identified and potential risks or information that was missing – especially pregnancy outcome – at the time of approval.

Chapter 2Registries supporting new drug applications 27 2 Table 2. Key characteristics of new drugs approved1 with and without registries 2007 – 2010 All drugs N (%) Registry2 N (%) Univariate Multivariate Yes No Total 116 (100) 43 (37) 73 (63) OR (95%CI) OR (95%CI) Drug characteristics Therapeutic area (ATC 1 level) A B J L Other3 12 (100) 12 (100) 26 (100) 29 (100) 37 (100) 5 (42) 3 (25) 12 (46) 13 (45) 10 (27) 7 (58) 9 (75) 14 (54) 16 (55) 27 (73) 1.9 (0.5;7.5) 0.9 (0.2;4.0) 2.3 (0.8;6.7) 2.2 (0.8;6.2) Ref Type of molecule Biological Small molecule Vaccine 30 (100) 71 (100) 15 (100) 15 (50) 22 (31) 6 (40) 15 (50) 49 (69) 9 (60) 1.5 (0.4;5.3) 0.7 (0.2;2.1) Ref Level of innovation4 A: important B: moderate C: modest Pharm/Tech 7 (100) 42 (100) 23 (100) 44 (100) 6 (86) 18 (43) 7 (30) 12 (27) 1 (14) 24 (57) 16 (70) 32 (73) 16.0 (1.7;147.1) 2.0 (0.8;4.9) 1.2 (0.4;3.6) Ref 10.3 (1.0;103.9) 1.2 (0.4;3.5) 0.8 (0.2;2.6) Ref Size of safety population5 Median (range) 1549 (94-13,000) 1002 (9413,000) 1811 (11910,257) 1.0 (1.0;1.0); p=0.11 Procedural characteristics Orphan medicinal drug6 (yes) 26 (100) 15 (58) 11 (42) 3.0 (1.2;7.4) 2.8 (1.0;7.5) CA7 and EC8 registration (yes) 23 (100) 13 (57) 10 (43) 2.7 (1.1;6.9) 1.7 (0.6;5.0) 1Date of approval is date of publication of European Decision 2 A registry was promised in the European Public Assessment Report (EPAR, as part of the RMP) 3 Therapeutic area classified using the anatomical main group of the Anatomical Therapeutic and Chemical Code. All drugs that are not classified as A (alimentary tract and metabolism), B (blood and blood forming organs), J (anti-infectives for systemic use) or L (antineoplastic and immunomodulating agents) are classified as other. 4 The drug is an important, moderate, modest of pharmacological or technological innovation 5 Size of safety population is the number of patients that have been analysed in the safety analysis (initial application, in EPAR) 6 The drug has an orphan status 7 The drug was given a conditional approval (CA) 8 The drug is approved under exceptional circumstances (EC) P<0.05 in bold type face, * all determinants with p<0.1 were included in the multivariate analyses

28 Rare disease registries: a must for regulatory decision-making 2 We identified 27 (37%) drug registries that were set up by companies to monitor use and outcomes of their drug specifically. Only patients using these specific drug are enrolled into these registries. The use and outcomes of treatment with a drug is monitored in 46 (63%) disease registries, in which patients will be enrolled with a specific diagnosis or disease, irrespective of the drug(s) they are using. Examples of disease registries are the Swedish and German rheumatology registries Antirheumatic Therapies In Sweden (ARTIS) and Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT), in which safety data is collected in patients with rheumatoid arthritis for the recently approved drugs abatacept, certolizumab, golimumab and tocilizumab.11 Similarly, for three filgrastim biosimilars, safety and immunogenicity are collected in the Severe Chronic Neutropenia (SCN) European registry. The SCN registry monitors clinical progress and treatment and adverse events for patients with SCN, regardless of their therapy.12 A specific kind of registry is the pregnancy registry. Of the 27 identified pregnancy registries, 11 were set up specifically to monitor the impact on offspring of a specific drug taken during pregnancy. In the remaining 16 cases, data were collected from existing pregnancy registries; e.g. for darunavir, etravirine, maraviroc, raltegravir and telbivudine pregnancy outcome data are collected from the Antiretroviral Pregnancy Registry. This is an existing pregnancy registry, set up in 1989 for pregnant women who are exposed to antiretroviral drugs, intending to generate early signals of teratogenic effects associated with prenatal exposure to antiretroviral products.13 The registry enrolls human immunodeficiency virus infected patients through their health care providers ( We identified registries that were imposed by the CHMP for only nine drugs, suggesting that registries are specific measures taken in the framework of the marketing authorization. Six of these drugs (amifampridine, canakinumab, idursulfase, mecasermin, rilonacept, and tocofersolan) were approved under exceptional circumstances, because at the time of approval no comprehensive data on the safety and efficacy under normal conditions of use could be provided. Two drugs (both pandemic influenza vaccines) had received a conditional approval, this means that the company will be required to provide confirmative data in a short timeframe, and one drug (lenalidomide) had a regular approval. Four of the imposed registries were set up with the aim to collect safety and real-world effectiveness data: amifampridine (symptomatic treatment of adults with LambertEaton myasthenic syndrome); canakinumab, rilonacept (both for the treatment of patients with severely symptomatic cryopyrin-associated periodic syndromes (CAPS)); and idursulfase (for the treatment of patients with Hunter syndrome). Three registry studies set up for, respectively, mecasermin (treatment of growth failure in children and adolescents with severe primary insulin-like growth factor-1 deficiency); lenalidomide (for the treatment of multiple myeloma), and tocofersolan (vitamin E deficiency due to digestive malabsorption in paediatric patients with congenital chronic cholestasis or hereditary chronic cholestasis) focused on the collection of safety data.

Chapter 2Registries supporting new drug applications 29 2 Pregnancy registries were imposed for two (adjuvanted) pandemic influenza vaccines. Safety during pregnancy (e.g., risk of birth defects) was unknown at the time of marketing approval, due to the lack of evidence in pregnant women. The regulatory authorities designated the lack of a pre-registration data as important missing information, considering that pregnant women are an important target population for these vaccines as influenza is likely to cause more severe illness in pregnant women.14 It is noteworthy, though, that the applications for the pandemic influenza vaccines and rilonacept are now withdrawn in the European Union, all three for commercial reasons. Determinants for registries We explored if specific drug or procedural characteristics were associated with whether a registry was imposed by the regulatory authority or the initiative of the applicant. We used logistic regression to examine this issue. In the univariate analysis, level of innovation (important innovation OR 16.0 (95% CI 1.7-147.1)), orphan drug (OR 3.0 (95% CI 1.2-7.4)) and approval under exceptional circumstances or conditional approval (OR 2.7 (95% CI 1.1-6.9)) (for all p<0,05), were associated with initiation of a registry. In the multivariate analysis, drugs considered as having an important level of innovation (OR 10.3 (95% CI 1.0-103.9) and orphan drugs (OR 2.8 (95% CI 1.0-7.5) (both p<0,05) remained significantly associated with registries. Therapeutic area, type of molecule and size of safety population were not associated with a registry included in the marketing dossier. Discussion Our study indicates that for one third of new drugs approved between 2007 and 2010, a commitment was made to perform studies in one or more registries to address remaining uncertainties of the drug’s effects at the time of approval. The goal was primarily to collect further safety data (39 registries, 53%), or impact of drug use during pregnancy (27 registries, 37%) and only seven registries (10%) collected data on both safety and drug effectiveness. Only for nine out of 43 drugs, the registry was explicitly requested (imposed) by the CHMP as a specific obligation in the framework of the marketing authorization; the rest were proposed by the applicants. The majority of the registries involved were from existing disease registries (43 out of 73, 59%), implying that data collection was already ongoing and that a - sometimes only historical - control group may be available. In a large proportion of new drug approvals registries are planned for the post-approval period, suggesting that regulators and/or companies feel a need to collect ‘real world’ data to supplement incomplete knowledge at time of approval. This may not be a surprising development in an era of increasing availability of electronic health data.15-16 The main reason for ‘real world’ data collection is to address remaining safety concerns as well as generate data in low exposure groups notably pregnant women. This reflects the EU Pharmacovigilance legislation introduced in 2012. The legislation and the establishment of the Pharmacovigilance Risk Assessment Committee focus on all aspects of the risk management of drugs for human use17, including the assessment of the risk

30 Rare disease registries: a must for regulatory decision-making 2 of adverse reactions, while taking the therapeutic effect of the medicine into account. With regard to pregnancy data, in 2002 the FDA issued an amendment describing the requirement for the collection of pregnancy data through registries.18 A recent review concluded that these type of registries remain an important tool to collect safety data in the absence of randomized controlled trial data on pregnant women.19 Moreover, the FDA did accept registries for regulatory purposes in the evaluation of medical devices and is exploring further ways to use real-world data in support of drug applications.20 Two-thirds of the registries are existing disease registries, which is the approach promoted by EMA’s Cross-committee Task Force on Registries. This is an initiative of the European regulators to facilitate better use of existing registries for the assessment of product safety and efficacy in daily clinical practice.21 An example of a disease registry set up and exclusively sponsored by one company are the following two orphan drugs. The first registry is for amifampridine which also includes patients who do not use amifampridine.22 The second registry is the Hunter Outcome Survey, in which patients with Hunter syndrome who are treated with enzyme replacement therapy are included.23 The majority of patients however, received the drug marketed by the company. Recently, this approach was criticized by Hollak et al., who expressed a strong preference for disease registries to collect data, analyzed by independent statisticians, supervised by patients, health-care professionals and other relevant stakeholders, and to be launched early in the development of orphan drugs to obtain natural history data.24 We support this recommendation for a disease registry that is owned by an independent party. This guarantees that data of all drugs used can be included, thereby enabling future comparative analyses, which is in the interest of the patients and may be an instrument to control the price of drugs. Still, a third of all registries collect data on a single product, this limits their usability for continued learning. Innovative drugs require more often a registry. These drugs fulfil unmet medical needs of patients eagerly awaiting these drugs. Innovative drugs are often ‘first-inclass’ drugs with a new mechanism of action, where the full benefit-risk profile - and in particular evidence about safety - may not be complete at the time of approval. Four out of seven (57%) of the innovative drugs in this study were authorized through a conditional approval or an approval under exceptional circumstances, emphasizing that the data were limited at the time of marketing authorization. In addition, orphan drugs status by itself was an independent determinant for an approval with a registry in this study. This may be partly due to the large number of existing disease registries available in orphan diseases25 and is in line with our finding that in most cases data will be collected from existing disease registries. Earlier we have shown that higher levels of innovation or approval under exceptional circumstances/ conditional approval are not related to more safety issues post-approval.5, 9 Registry studies are considered valuable to increase our understanding of drug effects, especially for these drugs where the knowledge is incomplete at time of approval.