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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.

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welcome to workshop 5 accelerated approval aa in rare diseases review of a white paper proposal

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+

The EveryLife Foundation For Rare Diseases
workshop series topics
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


Can we do better developing treatments?Sly Disease has been successfully treated in animals but no children have ever been treated
the challenges for aa in rare diseases
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: 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.”

workshop 5 accel approval in rare diseases review of a white paper proposal
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
white paper on aa in rare diseases working group industry and foundations
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

surrogate endpoint considerations
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


developing a scientific framework for for qualification of a biomarker for aa
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”

white paper improving scientifically sound access to the aa pathway
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


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


accelerated approval standard finding the balance in benefit risk
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


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


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


scientific context of use for a disease drug biomarker set
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


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


3 clinical study data for approval and for post marketing confirmation
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


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


making aa practically assessable when it is the best choice for development
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
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


session a benefit risk discussion
Session A : Benefit-Risk Discussion
  • What are the key issues to be considered that impact access to AA?
    • Degree of Rarity
    • Severity, unmet medical need
    • Difficult biology like brain, bone?
    • Difficulty conducting a traditional trial?
scientific considerations regarding the disease the drug and the biomarker

Scientific Considerations Regarding the Disease, the Drug and the Biomarker

Emil D. Kakkis, M.D., Ph.D.

President, EveryLife Foundation for Rare Diseases

CEO, Ultragenyx Pharmaceutical Inc.

scientific framework for aa considerations for qualifying a biomarker for use
Scientific Framework for AAConsiderations for Qualifying a Biomarker for Use
  • A set of considerations consisting of specific scientific data that support the interpretation of predictive value
    • Disease, Drug and BioMarker
  • Data support the relationship between the disease mechanism, drug action and biomarker biology
  • Not a checklist, but an outline of data that collectively improve predictive value
the value of providing a scientific framework for qualification
The value of providing a scientific framework for qualification
  • Guides early research toward collecting the informative data
  • Provides sponsors a common framework for evaluating opportunities that may depend on AA for investment
  • Standardizes considerations during regulatory review and development
  • Does not substitute for good judgment
    • Supports good decisions
summary considerations for qualification of a disease drug biomarker set for accelerated approval
Summary Considerations for Qualification of a Disease/Drug/BioMarker Set for Accelerated Approval






disease c onsiderations
Disease Considerations
  • Cause is clear
    • E.g., single gene, specific biology
    • Single known pathophysiologic cause
  • Pathophysiologic pathway is understood
  • No known adverse pathways that cannot be measured

The more known is about the disease and how it causes clinical problems, the more confidence exists in the direct link to the drug and the biomarker measuring the disease

the disease is clear phe in pku
The Disease is Clear: Phe in PKU

PAH Enz.


In Liver

Brain injury

High Phe level



[ Blood Phe]

59 uM 360-2500 uM

10x to 50x

Compartment Question

Degree of long-term

Brain Injury

Measure Blood Phe Level

BH4 Increases

PAH in Liver

Brain injury reduced

due to lower Phe level

[ Blood Phe]


drug c onsiderations
Drug Considerations
  • The drug’s structure and identity are clear
  • The mechanism of action of the drug is direct and understood.
  • The pharmacologic action and specific function of the drug can be demonstrated
  • Studies of the drug in models demonstrate relevant absorption, distribution, metabolism and excretion (ADME).
  • There appear to be no significant off-target alternative adverse activities of the drug
replacing a missing protein with a recombinant version of the protein
Replacing a missing protein with a recombinant version of the protein
  • Factor VIII deficiency
  • Lysosomal enzyme replacement therapy
  • a1-antitrypsin deficiency
Enzyme replacement therapy (ERT) for MPS 1

Enzyme reaches target and delivered to site of action

  • rhIDU is targeted for uptake
  • Reaches intracellular compartment


The enzyme


Filled with MPS



biomarker c onsiderations
BioMarker Considerations
  • Directly in line within the pathophysiological map
  • Sampling compartment predicts the disease compartment
  • Assay is sensitive and specific with a sufficient range.
  • Reasonable biologic stability.
  • Assay methodology should be validated
  • Accepted clinical physiologic measures may be considered predictive if they measure major clinical problems in the rare disease.

Measuring a disease process, reliably and accurately with a biomarker directly line of the disease process.

Biomarkers for Brain DiseaseCerebrospinal fluid and the Brain in LSD’sDoes it reflect brain biochemistry/biology?

Will CSF Samples

Reflect the brain?

pathophysiologic map mps i brain gag
Pathophysiologic Map: MPS I & Brain GAG

Meningeal storage




Cord Compression


Neuronal loss

Myelination abnl

Storage in neurons, glia

Microglia and meninges

Multiple cell type storage

IDUA Deficient

In Cells & LSD



Cell Leakage

Rupture release

Heparan sulfate

Diffusion via

Tissue fluid to CSF



Clinical Outcome

Compartment: Does Urinary GAG reflect tissue storage and outcome?


Clinical Outcome Improved

ERT Diffuses,

Replaces Def

[ Cell Rupture]

[ Cell storage]

Dynamic Range of a BiomarkerpGAG specific to abnormal GAG has larger dynamic range and is more sensitive to treatment change


Total GAG

Total GAG

Total GAG




Data: Dickson Laboratory work using Zacharon Pharmaceuticals SensiPro Assay

compartment is important it ert normalizes brain pgag levels reflected by csf pgag levels
Compartment is importantIT ERT Normalizes Brain pGAG levelsReflected by CSF pGAG levels
CSF samples do reflect the brain compartment metabolicallyPreclinical Intrathecal enzyme replacement provides the therapeutic predictive insight
  • MPS I canines
  • Sanfilippo A dogs and mice
  • Neuronal ceroid lipofuscinosis 2 mouse and dogs
  • MLD studies
  • Adrenoleukodystrophy

How will be successfully develop treatments for neuronal storage diseases?

early versus late markers in the pathway map
Early versus Late Markers in the Pathway Map
  • “Early” disease markers closest to source of disease, least prone to variation or unknown influences
  • “Late” pathophysiology markers closes to clinical disease and outcome but potentially more unknown influences
preclinical data on the disease drug action
  • Clinical data to support the qualification of the biomarker
Preclinical data on the disease/drug action
summary of preclinical and clinical data
Summary of Preclinical and Clinical Data


  • Dose-response curve well defined
    • Subtherapeutic and therapeutic doses
  • Dynamic response: start and remove Rx
    • Sensitivity to mitigating effects (Ab response)
  • Strong correlation to pathophysiologic effect
  • No substantial evidence of an alternative adverse pathway activated by Rx
clinical data considerations in absence of clinical outcome information
Clinical data considerationsin absence of clinical outcome information
  • Natural history studies are best but hard to complete: Time and patient numbers
  • Cross-sectional survey in untreated patients at different stages of disease severity
    • Develop correlation of marker with severity
    • Can cover decades of disease progression
  • Comparable disease states with homologous markers do show association with clinical benefit in similar context of use
section b scientific framework for qualification
Section B : Scientific Framework for Qualification

Qualification criteria

  • Are there other factors in the science of a disease/drug/biomarker set that should be considered?
    • Diseases are complex: can we readily define clarity of cause?
    • Drug mechanism relative to disease is important: is defining action critical to qualifying a drug or just supporrtive?
    • How direct is direct in biomarkers?
    • How hard is it to define alternative adverse pathways
  • Supporting qualification with clinical data
    • What are the risks or issues with using cross-sectional human data can be used to support biomarker qualification?
    • Natural history data use in support of surrogate meaning.
pivotal study trial design concepts for studies using a primary surrogate marker endpoint
Pivotal Study Trial Design: Concepts for studies using a primary surrogate marker endpoint
  • Randomized, controlled studies are preferred when feasible and appropriate
    • Should be conducted in most situations
  • An adequate assessment of safety is required
    • Smaller size studies still requires sufficient “n”
  • Accelerated approval should not require internal validation of the biomarker
    • Clinical endpoint was not feasible in first place
randomized placebo controlled studies more plausible using a biomarker primary
Randomized, placebo-controlled studies: More plausible using a biomarker primary
  • Power often increased, allow small randomized controlled studies
  • Need to assess safety optimally with placebo control when possible
  • Can still conduct valid clinical assessments if underpowered
  • Risk of conflict between biomarker and clinical results
alternative clinical study designs
Alternative Clinical Study Designs
  • When reasonable and feasible, should do randomized controlled studies
  • What about when not possible?
    • Too small, variable population
    • Ethical issues
  • Randomized controlled, without placebo
  • Cross over designs, single, double, N=1
  • Blinded observations but open label design
blinded observations in open label studies ethical or challenging clinical situations
Blinded Observations in Open Label StudiesEthical or challenging clinical situations
  • Example: late infantile Batten’s Disease Severe neurologic disease, onset 2-5 yrs
  • Cannot ethically conduct intraventricular ERT therapy using placebo
  • Study of a neurologic biomarker and imaging, neurologic scoring
    • Use blinded specimens for the biomarker
    • Blind and randomize sequence of MRI
    • Scoring behaviors by video if possible
ux003 cl201 blinded start design
UX003-CL201: Blinded Start Design
  • 12 subjects randomized to one of four (A-D) groups to either start on 2 mg/kg UX003 (A) or start on placebo (B-D) and cross over to 2 mg/kg UX003 in blinded manner at different pre-defined timepoints
  • Subjects and observers do not know when subjects cross onto drug Rx
  • Dosed every other week for 48 weeks. All groups receive a minimum of 24 weeks of 2 mg/kg UX003 therapy
natural history control strategies
Natural history control strategies
  • Extremely challenging to provide comparable non-parallel control
    • Variations in patients, ancillary treatment, differences in observation
  • Need to control patient comparability
  • Difficult to use in pre-marketing setting and requires consultation and preparation
clinical study section in the white paper
Clinical study section in the White Paper
  • Focused on high-level recommendations
  • Not intended to provide specific study design recommendations
  • Supporting the need for quality study designs to maximize information
  • Safety evaluation still needed
  • Consideration for how confirmation of clinical benefit will occur is important
the end thanks to all the sponsors

The EndThanks to all the Sponsors

EveryLife Foundation

For Rare Diseases