Consensus Study Report

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International Standard Book Number-13: 978-0-309-72655-9
International Standard Book Number-10: 0-309-72655-7
Digital Object Identifier: https://doi.org/10.17226/27968

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Regulatory processes for rare disease drugs in the United States and European Union: Flexibilities and collaborative opportunities. Washington, DC: The National Academies Press. https://doi.org/10.17226/27968.

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COMMITTEE ON PROCESSES TO EVALUATE THE SAFETY AND EFFICACY OF DRUGS FOR RARE DISEASES OR CONDITIONS IN THE UNITED STATES AND THE EUROPEAN UNION¹

JEFFREY P. KAHN (Chair), Andreas C. Dracopoulos Director and Levi Professor of Bioethics and Public Policy, Johns Hopkins Berman Institute of Bioethics

RONALD J. BARTEK, President, Director, and Co-Founder, Friedreich’s Ataxia Research Alliance

TERRY JO BICHELL, Founder and Director, COMBINEDBrain

EDWARD A. BOTCHWEY, Professor, Georgia Tech and Emory University

SHEIN-CHUNG CHOW, Professor of Biostatistics and Bioinformatics, Duke University School of Medicine

HANS-GEORG EICHLER, Consulting Physician, Austrian Association of Social Insurance Bodies

PAT FURLONG, Founding President and Chief Executive Officer, Parent Project Muscular Dystrophy

STEVEN K. GALSON, Senior Advisor, Boston Consulting Group

GAVIN HUNTLEY-FENNER, Principal Consultant, Huntley-Fenner Advisors

ANAEZE C. OFFODILE II, Chief Strategy Officer, Memorial Sloan Kettering Cancer Center

ANNE R. PARISER, Physician, Indian Health Service, Crow/Northern Cheyenne Hospital

JONATHAN H. WATANABE, Professor of Clinical Pharmacy, Associate Dean of Assessment and Quality, University of California, Irvine, School of Pharmacy and Pharmaceutical Sciences

National Academies of Medicine Fellow

SANKET DHRUVA, University of California, San Francisco

Study Staff

CAROLYN K. SHORE, Study Co-Director and Senior Program Officer

TEQUAM L. WORKU, Study Co-Director and Program Officer (as of March 2024)

EESHAN KHANDEKAR, Study Co-Director and Program Officer (until March 2024)

___________________

¹ See Appendix A: Disclosure of Unavoidable Conflicts of Interest

CARSON SMITH, Research Associate

MELVIN JOPPY, Senior Program Assistant

NOAH ONTJES, Associate Program Officer

KYLE CAVAGNINI, Associate Program Officer (from April to June 2024)

CLARE STROUD, Senior Board Director, Board on Health Sciences Policy

Consultants

ERIN HAMMERS FORSTAG, Science Writer

MAGDA BUJAR, Centre for Innovation in Regulatory Science

ADEM KERMAD, Centre for Innovation in Regulatory Science

JUAN LARA, Centre for Innovation in Regulatory Science

NEIL MCAUSLANE, Centre for Innovation in Regulatory Science

ANNA SOMUYIWA, Centre for Innovation in Regulatory Science

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by ELI Y. ADASHI, Brown University, and DAN G. BLAZER, Duke University. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

Acknowledgments

To begin, the committee would like to thank the sponsor of this study. This report would not be possible without the U.S. Food and Drug Administration (FDA), whose affiliates were instrumental in conceptualizing the study’s statement of task. Numerous individuals and organizations made important contributions to the study process and this report. In particular, the committee wishes to thank the staff teams at FDA, particularly Rachael Anatol, Jacqueline Corrigan-Curay, Martha Donoghue, Lewis Fermaglich, Emily Freilich, Kerry Jo Lee, Akua Mfum-Gyau, James Myers, Miranda Raggio, Sandra Retzky, Quyen B. Tran, Katherine Tyner, Julienne Vaillancourt, Celia Witten, Sarah Zaidi, Samantha Zenlea, and Hao Zhu; and the European Medicines Agency, particularly Steffen Thirstrup, for lending their time and expertise, sharing information and data with the committee, and providing technical review of draft manuscript sections.

The committee thanks representatives from the following companies for taking the time to participate in a series of semi-structured qualitative interviews that helped inform the committee’s deliberations: AMO Pharma; AbbVie; Affinia Therapeutics; Agios; Bayer; BioMarin Pharmaceuticals; Biogen; BridgeBio; Dyne Therapeutics; GlaxoSmithKline; Glycomine; Janssen Pharmaceutical Companies of Johnson & Johnson; Mahzi Therapeutics; Prilenia Therapeutics; Reata; Recordati; Roche; Sanofi; Stealth BioTherapeutics; Takeda; Ultragenyx Pharmaceutical Inc. The committee would also like to acknowledge the many individuals who took the time to share information, perspectives, and insights during open sessions of committee meetings. Their names and affiliations can be found in the committee meeting agendas in Appendix B.

The committee wish to express special thanks to the Centre for Innovation in Regulatory Science (CIRS) for its commissioned and pro bono contribution to this report. At CIRS, the committee thanks Magda Bujar, Adem Kermad, Juan Lara, Neil McAuslane, and Anna Somuyiwa, and for their collaboration and for carrying out the data analyses that helped inform this report (Appendix D).

The committee would also like to thank National Academy of Medicine fellow, Sanket Dhruva, for his thoughtful contributions throughout the study process; Erin Hammers Forstag for her writing contributions; and additional National Academies’ staff, without whom this report would not have been possible: Christie Bell, Lori Brenig, Samantha Chao, Robert Day, Amber McLaughlin, Marguerite Romatelli, Leslie Sim, Clare Stroud, Taryn Young, Megan Lowry, Will Andersen, Christopher Lao-Scott, and Rebecca Morgan.

Above all, the committee would like to express its gratitude to the many patient groups, and people living with rare diseases—including caregivers and their families—for taking time to share their invaluable insights, experiences, and perspectives, which helped shape this report and inform the committee’s recommendations.

Contents

ACRONYMS AND ABBREVIATIONS

PREFACE

SUMMARY

Regulatory Flexibilities, Authorities, and Mechanisms

Use of Alternative and Confirmatory Data

FDA and EMA Collaboration

1 INTRODUCTION

Clinical Trials for Rare Diseases and Conditions

Context for this Study

Study Approach

References

2 FDA FLEXIBILITIES, AUTHORITIES, AND MECHANISMS

Drug Review and Approval

Designation for Rare Disease Products

Expedited Regulatory Programs

Inclusion of Pediatric Populations

Stakeholder Engagement

Select Rare Disease Programs

Transparency

Summary of Conclusions and Recommendations

References

3 EMA FLEXIBILITIES, AUTHORITIES, AND MECHANISMS

Drug Review and Approval

Orphan Medicine Designation

Expedited Regulatory Programs

Stakeholder Engagement

Rare Disease Initiatives

Transparency

References

4 ALTERNATIVE AND CONFIRMATORY DATA

Guidance on Alternative and Confirmatory Data

Sources of Alternative and Confirmatory Data

Trends in Regulatory Use

Novel Approaches for Data Analysis

Biomarkers

Opportunities to Enhance Innovation

Summary of Conclusions and Recommendations

References

5 FDA AND EMA COLLABORATION

Similarities and Differences Between FDA and EMA

Collaboration Between Regulatory Agencies

Opportunities for Enhanced Collaboration

Summary of Conclusions and Recommendations

References

APPENDIXES

A Biographical Sketches of Committee Members And Staff

B Disclosures of Unavoidable Conflicts of Interest

C Public Meeting Agendas

D Centre for Innovation in Regulatory Science Data Analysis Methodology

E Qualitative Interview Summary and Methodology

F Non-Exhaustive List of Patient Focused Drug Development Meetings and Patient Listening Sessions for Rare Diseases Between 2013 and 2023

G List of Orphan Approvals by FDA or EMA Between 2018 and 2022

H Select Examples of Rare Disease Drug Products

I FDA and EMA Resources, Policies, and Programs Relevant for Drug Development for Rare Diseases and Conditions

Boxes, Figures, and Tables

BOXES

1-1 Orphan Designation

1-2 Types of Clinical Trials

1-3 Select Publications on Regulatory Processes for Evaluating the Safety and Efficacy of Drugs to Treat Rare Diseases and Conditions

1-4 Statement of Task

1-5 Key Terms and Definitions

2-1 Benefit–Risk Assessment

2-2 Reforms and Future Direction of Accelerated Approval

2-3 Pilot Program: Collaboration on Gene Therapies Global Pilot

2-4 Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA)

2-5 What is Patient-Focused Drug Development?

2-6 Select Eastern Research Group Report Findings and Recommendations

4-1 Use Case: SkyClarys (Friedreich’s Ataxia)

4-2 Diseases Studied by Ongoing and Past FDA Office of Orphan Products Development Natural History Grants from 2016 to 2023

4-3 Diseases Covered by Critical Path Institute’s Rare Disease Cures Accelerator–Data and Analytics Platform

4-4 Use Case: Relyvrio (Amyotrophic Lateral Sclerosis)

4-5 Application of Bayesian Method: Hypoxic Ischaemic Encephalopathy

4-6 Use Case: Nexviazyme^® (Pompe Disease)

4-7 Regulatory Guidance and Guidelines on Biomarkers

5-1 FDA Demonstration of Discretion about Disclosure: COVID-19 Pandemic

5-2 Gaucher Disease: A Strategic Collaborative Approach from EMA and FDA

5-3 Select Examples of Drug Products to Treat Rare Diseases and Conditions that Received Parallel Scientific Advice

FIGURES

S-1 Number of orphan drugs approved by FDA and EMA from 2018 to 2022

2-1 FDA drug review process

2-2 Proportion of CDER novel drug approvals that were orphan from 2010 to 2022

2-3 Proportion of CBER novel biologic approvals that were orphan from 2010 to 2022

2-4 Novel approval rates for non-orphan and orphan new drug applications submitted to CDER from 2015 to 2020 by office

2-5 FDA approval of orphan and non-orphan drugs by therapeutic area from 2013 to 2022

2-6 Entry points of expedited approval programs by clinical development stage

2-7 FDA approval rates for orphan and non-orphan drugs using expedited approval pathways from 2013 to 2022

2-8 Number of orphan and non-orphan drug products that received accelerated approval designation by FDA between 2013 and 2022

2-9 Number of orphan and non-orphan drug products that received fast track designation approved by FDA between 2013 and 2022

2-10 Number of orphan and non-orphan drug products that received breakthrough therapy designation approved by FDA between 2013 and 2022

2-11 Number of orphan and non-orphan drug products that received priority review designation approved by FDA between 2013 and 2022

2-12 Number of orphan and non-orphan drug products using the real-time oncology review program approved by FDA between 2013 and 2022

2-13 Approval time of orphan and non-orphan drug products approved by FDA from 2018 to 2022 by regulatory pathway

2-14 Use of expedited development programs in CDER and CBER from 2013 to 2022

2-15 Expedited program approvals for new molecular entities and novel biologics in CDER and CBER from 2013 to 2022

3-1 EMA committees in human medicines regulatory process

3-2 Orphan product designation and maintenance along drug life cycle

3-3 Designation and authorization of orphan medicines in the EU from 2001 to 2022

3-4 EMA approval rates for orphan and non-orphan drugs using expedited approval pathways from 2015 to 2020

3-5 Approval rates for non-orphan and orphan NAS applications submitted to EMA from 2015 to 2020 per therapeutic area

3-6 Evolution of the number of orphan medicinal products that have received a non-standard marketing authorization, are non-small molecules, and have benefited from accelerated assessment

3-7 Patient involvement along the medicines lifecycle at EMA

4-1 Distribution of types of alternative and confirmatory data referenced by EMA and FDA for orphan drug products between 2013 and 2022

4-2 The Rare Disease Cures Accelerator–Data and Analytics Platform process

4-3 Use of alternative and confirmatory data by FDA and EMA in marketing authorization approvals for orphan drug products from 2013 to 2022

4-4 Accepted alternative and confirmatory data for orphan drug products approved by FDA and EMA from 2013 to 2022 by therapeutic area

4-5 Comparison between Bayesian and frequentist approaches

4-6 The number of annual QSP publications deposited to PubMed vs. QSP-based regulatory submissions reported by FDA from 2008 to 2022

5-1 Number of orphan drugs approved by FDA and EMA from 2018 to 2022

5-2 Discordance on the approval of orphan new active substances approved by FDA and EMA from 2018 to 2022

5-3 Approval rates for new active substance applications submitted to FDA and EMA between 2015 and 2020

5-4 Novel approval rates for non-orphan and orphan new drug applications submitted to the Center for Drug Evaluation and Research from 2015 to 2020 by office

5-5 Approval rates for non-orphan and orphan new active substance applications submitted to the European Medicines Agency from 2015 to 2020 per therapeutic area

5-6 FDA and EMA expedited programs

5-7 20 years of EU/U.S. collaboration on medicines regulation

5-8 Top topic areas discussed in clusters

5-9 Accepted Parallel Scientific Advice requests (N=26) by product category from 2017 to 2021

5-10 Parallel Scientific Advice submissions by year from 2017 to 2021

D-1 Project timelines and steps

D-2 Overall methods and data sources used based on the contract agreement with the National Academies

TABLES

1-1 Clinical Trial Options for Rare Disease Drug Development

2-1 Components of an Action Package for an NDA or BLA

2-2 CDER Decisions to Grant or Deny Breakthrough Therapy Designation Requests for Non-Oncology Drugs and Biological Products from 2017 to 2019

2-3 FDA Guidance on Pediatric Drug Development

3-1 Components of European Public Assessment Reports

3-2 EMA Guidelines on Collection of Data

4-1 Examples of Types of Confirmatory Evidence from FDA Guidance

4-2 EMA Resources on Trial Design, Statistical Methods, and Alternative and Confirmatory Data

5-1 Examples of Clusters Relevant for Rare Diseases

5-2 Timeline for Parallel Scientific Advice

D-1 Variables and Data Points Collected for Each New Active Substance

Preface

The challenges for people living with rare diseases and conditions are numerous and often daunting. The Orphan Drug Act, passed some 40 years ago, was an attempt to remove policy roadblocks and create market incentives to increase research and development and bring new therapies for rare diseases to market. The impact was real, with nearly 900 new drugs for rare diseases since the Act was passed, but it was insufficient as that number barely scratches the surface in terms of the need. Of the rare diseases so far identified, fewer than 5 percent have available therapies.

This committee was tasked with examining regulatory processes in both the United States and the European Union for evaluating the safety and efficacy of drugs for rare diseases, and with identifying flexibilities and mechanisms available to regulators, all in service of increasing the number of available therapies.

Our conclusions and recommendations were informed by data available to us from both FDA and EMA, from information about policies and practices shared by colleagues from both agencies, by oral and written feedback from rare disease advocates, and by the experiences and expertise of our diverse committee members. This report represents the work of true consensus—a committee that was focused on its charge, careful in its analyses, informed by each other’s expertise, and committed to going wherever the facts would take us, free of personal or self-interested agenda. The result is a clear-eyed assessment of the status quo, conclusions that point to needed change, and actionable recommendations for doing so.

We were aided by an incredibly committed, hardworking, and expert National Academies staff: Carolyn Shore, Eeshan Khandekar, Carson Smith, Tequam Worku, Melvin Joppy, Noah Ontjes, Kyle Cavagnini, and Clare Stroud. This report truly would not have been possible without them. Lastly, my personal thanks to my committee colleagues, for their careful attention and parsing of often complex data, for their patience and willingness to learn from each other, and mostly for their incredible commitment to improving the lives of those with rare diseases. It was truly a privilege to work with you all.

Jeffrey P. Kahn, Chair
Committee on Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union

Acronyms and Abbreviations