CDER Critical Path Opportunities

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CDER Critical PathOpportunities

• Douglas C. Throckmorton, M.D.
• November 5, 2004

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Outline

• Critical Path in CDER
• Identified Critical Path opportunities in CDER
• Examples of proposed opportunities

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CDER Goals for 2005
Achieve Excellence in Management Practices
Increase Science Enterprise Research
Improve Quality of Health Care Services
Enhance health care system to respond to
bioterrorism and other public health challenges
HHS Strategic Goals
Strong FDA
Risk Management/ Innovation
PatientSafety
BetterInformed Consumers
ProtectingAgainstTerrorism
FDAStrategic Goals
QualitySystemStrategicObjectives
CGMPs
Critical Path
StructuredProduct Labeling
CounterTerrorismEfforts
Follow -onBiologics
CDERInitiatives
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• Identified Critical Path Opportunities in CDER

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CDER Critical Path Opportunities

• CDER received around 60 written proposals with
  variable levels of detail. Two types of
  proposals
• (1) Issues Addressable with FDA Data Resources
  
• Goals Data review and analysis to facilitate
  guidance and standards-setting
• (2) Longer-Term Projects
• Related to new, complex issues in drug
  development
• Rely more on external sources of expertise and
  data
• Goals Identify sources of expertise, work
  towards guidance and standards-setting

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Proposals from All 3 Key Dimensions on 'Critical
Path' of Development
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CDER Critical Path Opportunities

• Data Review and Analysis to Facilitate Guidance
  and Standards-Setting

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Assessing Safety

• Development of Safety Biomarkers/Surrogates
• Database on pre-clinical and clinical evaluation
  of arrhythmic risk Search for pre-clinical
  markers to reduce/eliminate need for clinical
  studies
• Data warehouse of electronic electro-cardiograms
  (ECGs) accessible by Industry and FDA
• Databases to facilitate rodent models of
  carcinogenicity, genotoxicity, and reproductive/
  developmental toxicology

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Assessing Safety (continued)

• Develop database of existing Controlled
  Substances Staff recommendations on product abuse
  liability
• Develop a centralized approach to monitor
  outcomes of exposure to drug products during
  pregnancy

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Demonstrating Medical Utility(Proof of Efficacy)

• Development of Efficacy Biomarkers/Surrogates
• Development and evaluation of new rapid
  diagnostic tests for infectious disease
• Development of vascular imaging techniques in
  development of drugs for neuro-cognitive
  disorders, cardiovascular disease, and depression
  
• Assessment of imaging techniques (e.g., MRI) in
  development of drugs for rheumatoid arthritis and
  osteoarthritis
• Assessment of novel biomarkers and clinical
  surrogates for Systemic Lupus Erythematosus,
  Inflammatory Bowel Disease, and Sepsis.
• Evaluate degree of correlation of Hepatitis C
  viral load in blood with histologic findings of
  the liver in Hepatitis C disease to assess
  potential utility of Hepatitis C as a surrogate
  marker in clinical trials.

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Demonstrating Medical Utility (cont) (Proof of
Efficacy)

• Develop data driven model for prediction of
  bioavailability/ bioequivalence from data on drug
  dissolution
• Facilitate or conduct investigations to better
  define the benefit and risk components and to
  improve trial designs of clinical investigations
  for menopausal symptom therapy
• Develop library of pharmacogenomic variation to
  enrich clinical studies of antidepressant drugs
  in the pediatric population

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Industrialization

• Develop methods to assess comparability of
  biologic products, including following
  manufacturing changes (e.g., changes in cell
  culture conditions)
• Use of Gene arrays to assess impact of changes
• Follow-on Biologics

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CDER Critical Path Opportunities

• Guidance and Standards-Setting in New Areas of
  Drug Development

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New Areas of Drug Development

• Develop Statistical guidance applicable to
  multiple therapeutic areas
• Non-inferiority testing, Bayesian methods,
  Missing data, and Adaptive trial designs
• Create a new framework for understanding product
  manufacturing and assessment within the Context
  of Complexity of Products and Manufacturing
  Processes
• Develop instrument calibration standards
• Evaluate statistical methods to supplement
  pre-clinical safety data bootstrap
  methodologies and re-sampling

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New Areas of Drug Development (continued)

• Develop guidance pertaining to patient-reported
  outcomes (PRO) endpoints in phase III studies
• Develop adequate analytical methods to fully
  characterize novel dosage forms
• e.g., liposomes, patches, topicals, inhalants
• Determine bioequivalence of locally-acting drug
  products

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• CDER Critical Path
• Near-Term Opportunities
• Examples

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ECG Research Database and Toolkit (Assessing
Safety)

• Needs
• To improve FDAs ability to evaluate drugs for
  cardiac safety
• To enhance efficiency of ECG data collection and
  submission
• Goals
• Develop standard for electronic exchange of ECGs
• Develop ECG research database and web-based tool
• Support development of clear standards, guidance,
  and tools to test and guide development of
  product safety

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ECG Research Database and Toolkit (continued)

• Contributes to
• A more efficient assessment of cardiac risk
• Increases ability of sponsors to predict success
  and failure in earlier stages of product
  development
• identification of novel ECG markers to predict
  clinical toxicity
• Lower costs for new product development
• more efficient ECG data collection and submission
• Increases ability of sponsors to produce high
  quality products and applications

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ECG Research Database and Toolkit (continued)

• Target timeline
• Completion of database tool and database lt12
  months

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Pediatrics Trial Database Development and
Analysis (Demonstrating Medical Utility)

• Needs
• To evaluate the assumptions used to design
  pediatric drug studies
• Goals
• Develop analytic database of pediatric trials
  conducted since initiation of pediatric
  exclusivity and Best Pharmaceuticals for Children
  Act (BPCA)
• Assess appropriateness for extrapolation of
  safety and efficacy data from adults to children
• Determine best practices for novel trial designs
• Develop guidance for future pediatric trials
  based on this review

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Pediatrics Trial Database(continued)

• Contributes to
• Increased interest in and feasibility of product
  development for unmet public health needs
• Increased sponsor ability to produce high quality
  products and applications
• Target Timeline
• Develop analytical database (12-24 months)
• Determine best practices (24-36 months)
• Discuss and publish guidance on best practices
  (36-48 months)

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Instrument Calibration Guidance
(Industrialization)

• Needs
• Expand concept of product quality by design
• Facilitate more efficiently produced and
  consistently formulated drug products
• Proactively support the use of new instrumental
  methods for drug manufacture as described in CGMP
  initiative

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Instrument Calibration Guidance (continued)

• Goals
• Develop methods for defining and validating
  calibration standards
• Develop instrument calibration standards
• Publish guidance describing standards
• Provide training to CDER staff on new
  instrumentation and standards

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Instrument Calibration Guidance(continued)

• Contributes to
• Increase FDA Utilization of Quality by Design and
  Risk-Based Assessment in Product Quality Review
  by promoting the use of novel analytic methods to
  assess manufacturing quality and consistency
• Reduce Likelihood of Production of Low Quality
  Products by promoting consistent use of new
  technology in ensuring quality of products
• Maintain Low Risk of Defective and Contaminated
  Products Reaching Market

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Instrument Calibration Guidance(continued)

• Target Timeline
• Research and identify candidate instrument
  reference standards (12 months)
• Conduct studies on instrumentation (12-24 months)
• Discuss and publish guidance (36 months)

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CDER Critical Path Summary

• Present state of health product development is
  not sustainable
• FDA must lead effort to question any assumptions
  that limit or slow new product development
• Are they justified?
• Are there more efficient alternatives?
• If so, why are the alternatives not being
  utilized?

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CDER Critical Path Summary

• Critical Path is integrated into the CDER goals
• CDER has identified a preliminary list of
  Critical Path opportunities that will have
  substantial impact if funded