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, 2013Sofitel Hotel Washington, D.C. Lafayette Square

The EveryLife Foundation For Rare Diseases• 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+

Workshop Series Topics• Workshop #1 Statistical analyses of

rare disease studies• Workshop #2Clinical evaluation of

rare disease treatments• Workshop #3Surrogate 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

Morning Session8:30 - 9:00 AM REGISTRATION AND BREAKFAST Introduction9:00 AM Welcome, Brief Review of FDASIA, Draft White Paper & Overall Workshop Goals

Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases

Session A: Challenges in Utilizing the Accelerated Approval Pathway9:30 AM Factors that Should Enhance Rare Disease Treatment Access to Accelerated

ApprovalMark Thornton, MD, PhD, President, Sarcoma Foundation of America (SFA)

9:50 AM Assessing Benefit/Risk of Potential Treatments by Patients and Patient Groups

Pat Furlong, President & CEO, Parent Project Muscular Dystrophy

10:10 AM Challenges in Qualifying Surrogates: FDA Perspective

Marc Walton, MD, PhD Office of Translational Sciences, CDER, FDA

10:40 AM DISCUSSION: Maximizing Reasonable Access to Accelerated Approval 11:00 AM BREAK

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

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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 clearKey question: How do we practically qualify biomarkers for

use with little prior clinical experience?

In FDASIA (PDUFA V)US Congress Legislation: H.R. 4132: FASTIntroduced By Rep. Stearns and TownesBetter access to Accelerated Approval Pathway

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“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.”

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 FDASIAWork Shop #5 Key Goal• Review a proposed White Paper on

recommendations for access and qualification considertions for AA

Workshop #5: Accel Approval in Rare DiseasesReview of a White Paper Proposal

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RARE DISEASE WORKSHOP SERIES Improving the Clinical Development Process

EVERYLIFE PROPOSED CRITERIA

FOR QUALIFICATION OF A DISEASE/DRUG/BIOMARKER SET FOR ACCELERATED APPROVAL IN RARE DISEASES

A) Disease Considerations

Cause of disease clearly understood based on a measurable entity or single gene disorder Pathophysiology mechanisms relating to clinical disease/outcome reasonably understood Rare diseases with critical need for AA as plausible pathway: extremely high unmet medical need

(lacking any current effective treatments with high morbidity and mortality), extreme rarity of the disorder or lack of any prior clinical studies, long time horizons for progression, disconnects between time of pathophysiologic damage and clinical expression, late diagnosis relative to the irreversible progression of disease, substantial clinical heterogeneity in a small population

B) Drug Considerations

Drug mechanism of action is direct and known Drug pharmacokinetics, pharmacodynamics and metabolism are relevant to the disease process

being treated and can be accurately and readily measured Drug can be made reproducibly with appropriate quality to provide consistent effect

C) Biomarker Considerations

Biomarker has direct relationship to important disease cause and process Sampling compartment for biomarker predicts the important disease compartment/tissue Biomarker assay is a valid and reproducible: Sensitive, accurate, precise and specific with a

sufficient dynamic range to calibrate change in biomarker with change in pathology Biomarker is a clinical physiologic assessment used in regular clinical practice for diagnosis and

management

D) Preclinical Considerations Magnitude/type of treatment effect is relevant and substantial relative to the human disease state Preclinical treatment studies show an appropriate dynamic dose-response relationship of the

biomarker on pathophysiology and or clinical effect Preclinical studies show a meaningful clinical or physiologic effect on the disease if the models

reflect human disease reasonably accurately Evaluation of alternative adverse effect pathways that are independent of efficacy that may

mitigate or eliminate a determination of positive risk-benefit

E) Clinical Considerations A cross sectional clinical study or retrospective medical chart survey of affected patients shows a

relationship between severity/progression/disease level to a biomarker measure Comparable disease states based on similar biology or pathophysiology, if they exist, have

supportive associations between a similar biomarker and relevant clinical benefit Absence of reliable or consistent clinical endpoints or extreme heterogeneity of important clinical

evaluations provide few or no alternatives to AA

White Paper on AA in Rare DiseasesWorking Group Industry and Foundations

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Marc Boutin National Health CouncilSusan Boynton Shire HGTMladenBozic Shire HGTGerald Cox Genzyme, A Sanofi CompanyPat Furlong Parent Project MDMark Hayes SynagevaEmil Kakkis EveryLife Foundation for Rare DiseasesCori Leonard Ultragenyx PharmaceuticalRachel Mack Vertex Pharmaceuticals Inc.Mary O'Donovan BioMarinMay Orfali PfizerMark Thornton Sarcoma Foundation of AmericaJack Weet Seaside Therapeutics

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 definedNeed a practical implementation of concepts

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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

12“Reasonably likely to predict clinical benefit”

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

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I. IntroductionII. BackgroundII. Considerations regarding the benefit-risk

assessmentIV. Scientific considerations for the qualification of

biomarkers V. Summary considerations for qualification of a

disease/drug/biomarker VI. Clinical trial design considerations VII. Conclusions VIII. References

White Paper Table of Contents

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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

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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

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2) Scientific Basis Considerations for a Disease/Drug/Biomarker GroupData in hand before extensive preclinical/clinical research

• Disease considerations• Drug considerations• Biomarkers considerations

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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

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19

MPS Disease/Endpoint/Drug ConsiderationsD

ISE

AS

EB

IOM

AR

KE

RD

RU

G

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

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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

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4) Post-marketing Confirmation

• Requirements and challenges• Confirmatory study designs

–Complexities–Alternative designs

• Placebo and natural history controls• Withdrawal

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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

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

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Morning Session8:30 - 9:00 AM REGISTRATION AND BREAKFAST Introduction9:00 AM Welcome, Brief Review of FDASIA, Draft White Paper & Overall Workshop Goals

Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases

Session A: Challenges in Utilizing the Accelerated Approval Pathway9:30 AM Factors that Should Enhance Rare Disease Treatment Access to Accelerated

ApprovalMark Thornton, MD, PhD, President, Sarcoma Foundation of America (SFA)

9:50 AM Assessing Benefit/Risk of Potential Treatments by Patients and Patient Groups

Pat Furlong, President & CEO, Parent Project Muscular Dystrophy

10:10 AM Challenges in Qualifying Surrogates: FDA Perspective Marc Walton, MD, PhD Office of Translational Sciences, CDER, FDA

10:40 AM DISCUSSION: Maximizing Reasonable Access to Accelerated Approval 11:00 AM BREAK