1 / 64

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

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.

ferrol
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

  4. 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?

  6. 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.”

  7. 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

  8. 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

  9. 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

  10. 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”

  11. 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

  12. 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

  13. 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

  14. 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

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

  16. 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

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

  18. 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

  19. 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

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

  21. 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

  22. 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

  23. Session A: Presentations

  24. 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?

  25. Mid-Morning Break

  26. 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.

  27. 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

  28. 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

  29. Summary Considerations for Qualification of a Disease/Drug/BioMarker Set for Accelerated Approval A. DISEASE CONSIDERATIONS B. DRUG CONSIDERATIONS C. BIOMARKER CONSIDERATIONS D. PRECLINICALData CONSIDERATIONS E. CLINICAL DATA CONSIDERATIONS FOR BIOMARKER QUALIFICATION

  30. 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

  31. The Disease is Clear: Phe in PKU PAH Enz. Defective In Liver Brain injury High Phe level Blood-Brain Barrier [ 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] BBB

  32. 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

  33. Replacing a missing protein with a recombinant version of the protein • Factor VIII deficiency • Lysosomal enzyme replacement therapy • a1-antitrypsin deficiency

  34. Enzyme replacement therapy (ERT) for MPS 1 Enzyme reaches target and delivered to site of action • rhIDU is targeted for uptake • Reaches intracellular compartment untreated The enzyme Lysosome Filled with MPS treated nucleus

  35. 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.

  36. Biomarkers for Brain DiseaseCerebrospinal fluid and the Brain in LSD’sDoes it reflect brain biochemistry/biology? Will CSF Samples Reflect the brain?

  37. Pathophysiologic Map: MPS I & Brain GAG Meningeal storage Microglial Neuronal Glial Cord Compression Inflammation Neuronal loss Myelination abnl Storage in neurons, glia Microglia and meninges Multiple cell type storage IDUA Deficient In Cells & LSD Biomarker ? Cell Leakage Rupture release Heparan sulfate Diffusion via Tissue fluid to CSF Heparan Accumulation Clinical Outcome Compartment: Does Urinary GAG reflect tissue storage and outcome? Treatment Clinical Outcome Improved ERT Diffuses, Replaces Def [ Cell Rupture] [ Cell storage]

  38. Dynamic Range of a BiomarkerpGAG specific to abnormal GAG has larger dynamic range and is more sensitive to treatment change RANGE Total GAG Total GAG Total GAG pGAG pGAG pGAG Data: Dickson Laboratory work using Zacharon Pharmaceuticals SensiPro Assay

  39. Compartment is importantIT ERT Normalizes Brain pGAG levelsReflected by CSF pGAG levels

  40. 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?

  41. 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

  42. Presentations • Clinical data to support the qualification of the biomarker Preclinical data on the disease/drug action

  43. 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

  44. 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

  45. 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.

  46. Lunch Break

More Related