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 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

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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. 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

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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MPS Disease/Endpoint/Drug Considerations

DIS

EA

SE

BIO

MA

RK

ER

DR

UG

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

Session A: Presentations

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?

Mid-Morning Break

Session B: Qualification of Biomarkers for a Specific Disease and Drug11:15 AM Scientific Considerations Regarding the Disease, the Drug and its

Action, and the BiomarkerEmil Kakkis, MD, PhDPresident, EveryLife Foundation for Rare Diseases

11:35 AM Preclinical Data to Support Biomarker QualificationGerald Cox, MD, PhDSenior Director, Genzyme Corporation

11:55 AM Cross-Sectional Surveys and Natural History Studies to Support Clinical InterpretationP.K. Tandon, PhDSr. VP Global Biomedical Data Sciences & Informatics, Genzyme Corporation

12:15 PM DISCUSSION: Qualification Criteria12:45 - 1:15 PM LUNCH

Scientific Considerations Regarding the Disease, the Drug and the Biomarker

Emil D. Kakkis, M.D., Ph.D.President, EveryLife Foundation for

Rare DiseasesCEO, Ultragenyx Pharmaceutical Inc.

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• 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

A. DISEASE CONSIDERATIONS

B. DRUG CONSIDERATIONS

C. BIOMARKER CONSIDERATIONS

D. PRECLINICAL DATA CONSIDERATIONS

E. CLINICAL DATA CONSIDERATIONS FOR BIOMARKER QUALIFICATION

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

PAH Enz.DefectiveIn Liver

[ Blood Phe] Blood-BrainBarrier

Brain injuryHigh Phe level59 uM 360-2500 uM

10x to 50x

Measure Blood Phe LevelDegree of long-term

Brain Injury

Compartment Question

BH4 IncreasesPAH in Liver

[ Blood Phe]Brain injury reduced

due to lower Phe levelBBB

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

• Factor VIII deficiency• Lysosomal enzyme replacement therapy• a1-antitrypsin deficiency

• rhIDU is targeted for uptake• Reaches intracellular compartment

untreated

treated

Enzyme replacement therapy (ERT) for MPS 1 Enzyme reaches target and delivered to site of action

nucleus

LysosomeFilled with MPS

The enzyme

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 SamplesReflect the brain?

Pathophysiologic Map: MPS I & Brain GAG

IDUA DeficientIn Cells & LSD

Cell LeakageRupture releaseHeparan sulfate

Diffusion viaTissue fluid to

CSF

ERT Diffuses,Replaces Def

[ Cell Rupture] Clinical Outcome Improved

Meningeal storageMicroglialNeuronalGlial

Storage in neurons, gliaMicroglia and meninges Multiple cell type storage

Cord CompressionInflammation Neuronal lossMyelination abnl

Biomarker

Clinical Outcome

Compartment: Does Urinary GAG reflect tissue storage and outcome?

[ Cell storage]

?Heparan Accumulation

Treatment

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

Total GAGTotal GAG

pGAG

pGAG

Data: Dickson Laboratory work using Zacharon Pharmaceuticals SensiPro Assay

Total GAG

pGAG

RANGE

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?

www.ultragenyx.com 45

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

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• Clinical data to support the qualification of the biomarker

Presentations

Summary of Preclinical and Clinical Data

Preclinical• 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 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 QualificationQualification 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.

Lunch Break

Afternoon SessionSession C: Clinical Studies to Support Accelerated Approval1:15 PM Phase 3 Clinical Studies for Accelerated Approval

Emil Kakkis, MD, PhDPresident, EveryLife Foundation for Rare Diseases

1:35 AM Challenges in Utilizing Accelerated ApprovalRobert Temple, MDDeputy Director for Clinical Science, FDA

1:55 PM DISCUSSION: Clinical Data for Surrogate Qualification and Clinical Studies for Accelerated Approval

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

• 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• 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 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

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www.ultragenyx.com 56

• 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

UX003-CL201: Blinded Start Design

Wk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70dose 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

A 48 wk 1 mg/kg 4 mg/kg 2 mg/kg

B placebo 40 wk 1 mg/kg 4 mg/kg 2 mg/kg

C placebo 32 wk 1 mg/kg 4 mg/kg 2 mg/kg

D placebo 24 wk 1 mg/kg 4 mg/kg 2 mg/kg

Blinded period Dose titration period

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

• 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

Session D: Post-Marketing Confirmatory Studies of Clinical Benefit2:20 PM Post-Marketing Confirmatory Studies

Susan BoyntonVice President, Global Regulatory Affairs, ShireMary O'DonovanSenior Director, Regulatory Affairs and Policy, BioMarin

2:50 PM DISCUSSION: How Do We Accurately Confirm Clinical Benefit Post-Marketing?

3:20 PM Summary and Final Discussion, Steps Going Forward and Closing Remarks Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases

3:45 PM END OF WORKSHOP

The End

Thanks to all the Sponsors

EveryLife Foundation

For Rare Diseases