Emil D. Kakkis, M.D., Ph.D. President and Founder EveryLife Foundation for Rare Diseases

1. Welcome to Workshop #5: Accelerated Approval (AA) in Rare Diseases:Review of a White Paper Proposal Emil D. Kakkis, M.D., Ph.D. President and Founder EveryLife Foundation for Rare Diseases May 15, 2013 Sofitel Hotel Washington, D.C. Lafayette Square

2. Formed to focus on improving the development of treatments of rare diseases in February 2009 Conducting workshops and participating in conferences to help promote scientifically sound change Supporter of ULTRA/FAST legislation in FDASIA Working toward scientifically sound change to improve the accessibility of the Accelerated Approval pathway 181 Partners+ The EveryLife Foundation For Rare Diseases

3. Workshop Series Topics • Workshop #1 Statistical analyses of rare disease studies • Workshop #2 Clinical evaluation of rare disease treatments • Workshop #3 Surrogate endpoints & accelerated approval • Workshop #4Developing Policy Recommendations for Accelerated Approval • Workshop #5 Accelerated Approval in Rare Disease: Review of a White Paper Proposal Find slides from prior workshops at www.everylifefoundation.org

5. Can we do better developing treatments?Sly Disease has been successfully treated in animals but no children have ever been treated

6. The challenges for AA in Rare Diseases • Challenges in qualifying a surrogate to be “reasonably likely to predict clinical benefit” • Lack of prior clinical outcome & treatment data • Limited prior clinical studies or natural history • Difficult clinical biology not easily studied • Yet science and medicine may be solid and clear Key question: How do we practically qualify biomarkers for use with little prior clinical experience?

7. In FDASIA (PDUFA V)US Congress Legislation: H.R. 4132: FASTIntroduced By Rep. Stearns and TownesBetter access to Accelerated Approval Pathway “Considerations. – In developing the guidance . . . . the Secretary shall consider . . . . for drugs designated for a rare disease or condition under section 526 of the Federal, Food, Drug, and Cosmetic Act; and (2) how to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical.”

8. Workshop #5: Accel Approval in Rare Diseases Review of a White Paper Proposal At Workshop #4, created the plan • Draft set of criteria were considered • A working group was formed • White paper to consolidate recommendations for AA under FDASIA Work Shop #5 Key Goal • Review a proposed White Paper on recommendations for access and qualification considertions for AA

10. White Paper on AA in Rare DiseasesWorking Group Industry and Foundations Marc Boutin National Health Council Susan Boynton Shire HGT Mladen Bozic Shire HGT Gerald Cox Genzyme, A Sanofi Company Pat Furlong Parent Project MD Mark Hayes Synageva Emil Kakkis EveryLife Foundation for Rare Diseases Cori Leonard Ultragenyx Pharmaceutical Rachel Mack Vertex Pharmaceuticals Inc. Mary O'Donovan BioMarin May Orfali Pfizer Mark Thornton Sarcoma Foundation of America Jack Weet Seaside Therapeutics

11. Surrogate endpoint considerations • Prentice criteria: A set of mathematical criteria on how one variable represents another: not biological • Fleming (2005) reworked to focus on biological pathway issues • Direct measures versus parallel measures • Alternative unmeasured adverse pathways • Tiers of surrogates proposed Fleming concepts valid but not experimentally defined Need a practical implementation of concepts 11

12. Developing a scientific framework for for qualification of a biomarker for AA • Breakdown the surrogate endpoint analysis into individual specific scientific considerations • Disease, Drug, Biomarker • Better understanding of science at each level provides greater support for predictive value • Support the underlying science • Preclinical data and clinical supportive information • Find the balance of data that meets the standard “Reasonably likely to predict clinical benefit”

13. White Paper: Improving Scientifically Sound Access to the AA Pathway • Reviews the criteria for rare disease access • What factors should be considered in flexibility for AA as a pathway? • Defines Disease, Drug, BioMarker characteristics that enhance predictability • Defines preclinical and clinical data to support the qualification • Discusses Clinical Trial Design and Confirmatory studies 13

14. White Paper Table of Contents • Introduction • Background • Considerations regarding the benefit-risk assessment • IV. Scientific considerations for the qualification of biomarkers • Summary considerations for qualification of a disease/drug/biomarker • Clinical trial design considerations • Conclusions • VIII. References 14

15. Accelerated approval standard:Finding the balance in Benefit/risk • “A surrogate endpoint or clinical endpoint earlier than irreversible morbidity and mortality” that is “reasonably likely to predict clinical benefit” • What should set the standard for benefit-risk in rare diseases? • The disease matters: • Rarity, severity, biology, unmet need • Science behind the disease, endpoint and drug mechanism 15

16. 1) Benefit-Risk Considerations Assessment should be evaluate the specific context of the disease, its rarity and other factors. • Extremely high unmet medical need • Extreme rarity • Absence of any prior clinical study or clinical data • Slow or irreversible disease • Significant delay between the onset of irreversible disease and clinical diagnosis • Lack of readily measurable clinical endpoints due to unusual clinical disease manifestations 16

17. 2) Scientific Basis Considerations for a Disease/Drug/Biomarker GroupData in hand before extensive preclinical/clinical research • Disease considerations • Drug considerations • Biomarkers considerations 17

18. Scientific Context of Use for a Disease/Drug/Biomarker Set • A biomarker must be viewed in its context: • A disease mechanism connected to a certain drug action, leading to a biomarker result • The scientific relationship is critical to value as a surrogate • The group must be considered linked • Changing the drug mechanism or biomarker might not provide the same predictive value 18

19. MPS Disease/Endpoint/Drug Considerations DISEASE BIOMARKER DRUG

20. Scientific Data Considerations for a Disease/Drug/Biomarker GroupData developed from preclinical & clinical research • Preclinical research • Specific research data to support the relationships/validity of insights • Clinical data to support qualification • Cross-sectional survey • Natural history data • Other data 20

21. 3) Clinical Study Data for Approval and for Post-marketing Confirmation • Adequate well-controlled studies • Pivotal study designs • Efficacy/biomarker • Safety • Placebo control • Alternative use of blinded evaluation • Natural history comparison 21

22. 4) Post-marketing Confirmation • Requirements and challenges • Confirmatory study designs • Complexities • Alternative designs • Placebo and natural history controls • Withdrawal 22

23. Making AA practically assessable when it is the best choice for development • Predictable set of issues to collect and present at a pre-IND meeting • Need the opportunity early in development • Patient benefit-risk input via a sophisticated quality survey at the start • Provides the data on right benefit-risk choice • Early AA accessibility means more investment in more treatments

24. Goals of today’s workshop • Discuss the elements of the guidance • Benefit/risk, Scientific qualification, Studies for approval, Confirmatory studies • Identify major omissions or issues that need to be resolved • Collect the major unresolved challenges for qualification • Provide examples for inclusion in the white paper • Build consensus of an improved document 24