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
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
• Workshop #2
• Workshop #3
• Workshop #4
• Workshop #5
Statistical analyses of
rare disease studies
Clinical evaluation of
rare disease treatments
Surrogate endpoints &
accelerated approval
Developing Policy Recommendations
for Accelerated Approval
Accelerated Approval in Rare Disease:
Review of a White Paper Proposal
Find slides from prior workshops at
www.everylifefoundation.org
Morning Session
8:30 - 9:00 AM
REGISTRATION AND BREAKFAST
Introduction
9:00 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 Pathway
9:30 AM
Factors that Should Enhance Rare Disease Treatment Access to Accelerated
Approval
Mark 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
11:00 AM
DISCUSSION: Maximizing Reasonable Access to Accelerated Approval
BREAK
Can we do better developing treatments?
Sly Disease has been successfully treated in
animals but no children have ever been treated
5
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?
In FDASIA (PDUFA V)
US Congress Legislation: H.R. 4132: FAST
Introduced By Rep. Stearns and Townes
Better 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.”
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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
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
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White Paper on AA in Rare Diseases
Working 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
10
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
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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
“Reasonably likely to predict clinical benefit”
12
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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White Paper Table of Contents
I.
Introduction
II.
Background
II.
Considerations regarding the benefit-risk
assessment
IV.
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
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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 Group
Data 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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DRUG
BIOMARKER
DISEASE
MPS Disease/Endpoint/Drug Considerations
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Scientific Data Considerations for a
Disease/Drug/Biomarker Group
Data 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 Session
8:30 - 9:00 AM
REGISTRATION AND BREAKFAST
Introduction
9:00 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 Pathway
9:30 AM
Factors that Should Enhance Rare Disease Treatment Access to Accelerated
Approval
Mark 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
11:00 AM
DISCUSSION: Maximizing Reasonable Access to Accelerated Approval
BREAK