FDAs Critical Path Initiative

1
FDAs Critical Path Initiative

• Janet Woodcock, M.D.
• Deputy Commissioner
• for Operations, FDA
• May 11, 2006

2
Biomedical Discoveries are Not Effectively
Translated

• Huge Investment in U.S. Biomedical Research
• Lack of corresponding new products available to
  patients
• Major increases in medical product development
  costs
• Major rise in healthcare costs

3
Predictability Problem

• Product development success rate has declined
• New compounds entering Phase I development today
  have 8 chance of reaching market, vs. 14 chance
  15 years ago.
• Phase III failure rate now reported to be 50,
  vs. 20 in Phase III, 10 years ago.

4
Speculation on Causes of Translational Problems

• Genomics other new science not at full
  potential (10-15 yrs)
• Easy targets taken chronic disease harder to
  study
• Rapidly escalating costs complexity decrease
  willingness and ability to bring many candidates
  forward into the clinic
• Mergers and other business arrangements
• Some people blame FDA

5
Whats the Diagnosis?

• Investment and progress in basic biomedical
  science has far surpassed investment and progress
  in the medical product development process
• The development process the critical path to
  patients becoming a serious bottleneck to
  delivery of new products
• We are using the evaluation tools and
  infrastructure of the last century to develop
  this centurys advances

6
What is the Critical Path?

• There is a critical path stretching from
  candidate identification to commercial product
• Involves serial evaluation of product performance
  through preclinical testing and clinical
  evaluation
• FDAs Critical Path Initiative focuses on the
  science used for these evaluations

7
Evaluative Science Underlying The Critical Path
Science to predict and evaluate safety efficacy
performance of new products, and enable
manufacture, is different from basic discovery
science
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"Critical PathDimensions

• Evaluative science to address 3 key product
  performance dimensions
• Assessment of Safety how to predict and asses
  the risks of a potential product?
• Proof of Efficacy -- how to predict and
  demonstrate that a potential product will have
  medical benefit?
• Industrialization how to manufacture a product
  at commercial scale with consistently high
  quality?

9
Guiding Principles of FDA Initiative

• Collaborative efforts among government, academia,
  industry and patient groups
• Infrastructure and toolkit development, not
  product development
• Build support for academic science bases in
  relevant disciplines
• Build opportunities to share existing knowledge
  database
• Develop enabling standards

10
Steps to Date

• Published Initial Report 5/04
• Opened Docket for public comment and discussed
  with FDA Science Board and other Advisory
  Committees
• Initiating multiple public-private partnership
  consortia with non-profit conveners
• Publication of Critical Path Opportunities
  Report and List in March 06 project report
  soon
• Organizational structures being established at
  FDA CDER Office of Translational Science
  Office of Commissioner

11
Major Opportunities for Modernization per March
Report

• Biomarker Qualification
• In-vitro diagnostics
• Imaging
• Preclinical toxicogenomics
• Clinical Trial Modernization
• Bioinformatics
• Modernizing Manufacturing
• Pediatric Treatments
• Public Health Emergencies

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Biomarker Qualification

• Qualification of a biomarker means developing
  the correlative information that lets us
  understand its clinical meaning in a given
  situation
• Examples
• Drug metabolizing enzyme genotypes
• Metabolic imaging of tumors
• Acute risk of cardiac event serum assays

13
Biomarker Qualification

• Amount of correlative information needed depends
  on use of biomarker
• In drug development (examples)
• Candidate activity
• Dose-response information
• Selection for trial enrollment
• Surrogate endpoint

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Biomarker Qualification Two Major Opportunities

• Develop conceptual framework
• Reach general consensus on amount/type of data
  needed for various uses
• Publish FDA guidance
• Develop consortia for qualification of specific
  biomarkers

15
Biomarker Qualification Framework Progress

• Multiple FDA and Advisory Committee Discussions
• Deliberations by academia and industry
• Center for Drugs Endpoint Survey
• Research collaborations with private sector to
  study process in specific biomarker qualification
  efforts

16
Development of Consortia for Biomarker
Qualification

• OBQI (Oncology Biomarker Qualification
  Initiative) Announced in January
• FDA-NCI-CMS consortium to qualify new cancer
  biomarkers
• First project involves FDG-PET in non-Hodgkins
  Lymphoma
• Other major consortia in development

17
Why Public-Private Biomarker Consortia?

• Successful biomarker qualification is quite
  uncommon
• New biomarkers are critical to clinical medicine
  and efficient product development
• No single entity charged with accomplishing
  qualification
• All parties (government, industry, insurers,
  academia, patients) have a big stake however

18
New Biomarkers Example

• Pharmacogenomic markers
• Drug metabolism polymorphisms avoiding serious
  side effectsfirst tests have been approved
  (project with C-Path and University of Utah
  proposed)
• Predictors of drug response or nonresponse
  (narrow population)consortia being explored
• Genetic basis of adverse eventsavoid treating
  those at riskprevention is preferable to
  warningsconsortium under construction

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New Biomarkers

• Advanced Imaging Technologies
• Distinguish disease subgroups for therapy
• Rapidly evaluate response to treatment
• Use as response measure in clinical trials
• OBQI exploring additional imaging biomarker
  qualification

20
Modernizing Clinical Trials Opportunities

• Move to automated environment
• Develop new methodological approaches to
  evaluation
• Move towards greater mechanistic understanding,
  incorporating biomarkers

21
Modernizing Clinical Trials Automation

• E-clinical trials initiative trial conduct and
  regulatory submission
• Clinical trial networks (Ca-BIG)
• FDA e-submission standards (ICH)
• NIH roadmap projects on disease area terminology
• Continue development of standards
• CDISC--trial standards organizationto lead on--
• Case Report Form standards
• BiMo Initiative (FDA project)
• Modernize FDA oversight of clinical trials and
  IRBs
• Will require industry cooperation as per Product
  Quality for the 21st Century

22
Modernizing Clinical Trials Move Away from Trial
and Error Evaluation

• Employ rigorous, informative assessments in
  preclinical and early clinical studies build
  generalized knowledge from results
• Will require new processes and pathways
• Will require development and regulatory
  acceptance of new evaluative tools
• Final trials would be confirmatory-however,
  confirmatory trial process also needs to be
  redesigned

23
The Current Clinical Development Model

• The randomized controlled clinical trial
  represented a scientific triumph over anecdotal
  medicine in the 1960s
• Used to control for bias and the impact of
  random (unexplainable) variability
• Basis for many of the advances of modern medicine

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Limitations of Controlled Trials

• Theoretically can answer any and all questions
  via controlled experiments
• Can answer one or a few questions per trial
• There are an unlimited number of questions about
  the appropriate use of medical products and the
  outcomes of such use, and these questions evolve
  over time
• There is a decidedly limited universe of funding,
  patients, investigators, time and resources to
  conduct trials to answer these questions

25
Limitations of Controlled Trials

• Fact at the end of most drug development
  programs, after huge expenditures of time and
  resources, we dont know a great deal about the
  drug
• Were quite confident it has a measurable
  beneficial effect in a described population-but
  the overall treatment effect is often small. Did
  few people respond a lot or did a lot of people
  respond a bit?
• Often many of the people who take the drug do not
  benefit

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Healthcare Consequences of Current Development

• Health care cost controversy Debates about value
  of products we cant quantify
• Health care policy community believes that
  increased technologygreater expense, and usually
  lower productivity
• Safety controversies Products are Safe or
  Unsafe
• Health care quality Confusing results and
  conflicting reports lead to anecdotal approach to
  care

27
More Informative Clinical Trial Designs

• Pair diagnostic(s) with therapeutic in
  development to identify responsive subgroup(s),
  or prevent toxicity
• Adaptive designs to answer series of
  questionsi.e, what dose is correct for which
  group

28
New Trial Designs for Personalized Therapy

• Hope that industry, FDA and NIH can collaborate
  on new types of trials through public-private
  partnership arrangements
• Plans for such trials, using new biomarkers,
  being explored
• Use genetic, genomic, proteomic or imaging
  information to direct or modulate therapy

29
Bioinformatics

• Develop publicly available quantitative disease
  models (natural history and response to
  intervention)
• Perform modeling and simulation of trials of new
  interventions
• Assess in silico the impact of device design
  modifications
• Assemble databases necessary for qualification of
  biomarkers

30
Critical Path Payoff for Patients

• More predictable development process for new
  drugs lower development costs more choices
• More and better information about risks and
  benefits
• Personalized treatments who should use the
  product and how, who should not use it!
• More positive outcomes of therapy, avoidance of
  side effects

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Summary

• Critical Path Initiative moving into
  implementation phase
• Structures being set up within agency and as
  consortia
• Pace is defined by (limited) available resources
• Large payoffs for patients if critical path
  initiative is successful