CDER Critical Path Opportunities

1. CDER Critical PathOpportunities Douglas C. Throckmorton, M.D. November 5, 2004 CDER Critical Path Opportunities

2. Outline • Critical Path in CDER • Identified Critical Path opportunities in CDER • Examples of proposed opportunities CDER Critical Path Opportunities

3. 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 Critical Path CGMPs Follow -onBiologics StructuredProduct Labeling CounterTerrorismEfforts CDERInitiatives CDER Critical Path Opportunities

4. Identified Critical Path Opportunities in CDER CDER Critical Path Opportunities

5. 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 CDER Critical Path Opportunities

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

7. CDER Critical Path Opportunities Data Review and Analysis to Facilitate Guidance and Standards-Setting CDER Critical Path Opportunities

8. 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 CDER Critical Path Opportunities

9. 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 CDER Critical Path Opportunities

10. 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. CDER Critical Path Opportunities

11. 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 CDER Critical Path Opportunities

12. 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’ CDER Critical Path Opportunities

13. CDER Critical Path Opportunities Guidance and Standards-Setting in New Areas of Drug Development CDER Critical Path Opportunities

14. 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 CDER Critical Path Opportunities

15. 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 CDER Critical Path Opportunities

16. CDER Critical Path Near-Term Opportunities Examples… CDER Critical Path Opportunities

17. ECG Research Database and Toolkit (Assessing Safety) • Needs: • To improve FDA’s 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 CDER Critical Path Opportunities

18. 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 CDER Critical Path Opportunities

19. ECG Research Database and Toolkit (continued) • Target timeline: • Completion of database tool and database: <12 months CDER Critical Path Opportunities

20. 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 CDER Critical Path Opportunities

21. 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) CDER Critical Path Opportunities

22. 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 CDER Critical Path Opportunities

23. 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 CDER Critical Path Opportunities

24. 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 CDER Critical Path Opportunities

25. 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) CDER Critical Path Opportunities

26. 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? CDER Critical Path Opportunities

27. 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 CDER Critical Path Opportunities