1. FDA’s “Critical Path” Initiative Presentation to FDA Science Board Janet Woodcock, M.D. Acting Deputy Commissioner for Operations

2. The Challenge  Multiple serious diseases afflict our population and require better treatments: autism, addictive disorders, Alzheimer’s disease, AIDS, bipolar disorders, cancer, cystic fibrosis, heart diseases, diabetes, morbid obesity, multiple sclerosis, muscular dystrophy, rheumatoid arthritis, osteoarthritis, systemic lupus, schizophrenia, stroke, and many more

3. Prevention  Prevention of diseases is an equally important goal  Primary prevention: certain cancers, AIDS, heart disease  Early detection and intervention: diabetes, cancers, obesity, Alzheimer’s disease

4. The Societal Challenge  Urgency of need – timely development  Aging of population  Mounting burden of illness  Benefits of prevention vs. secondary intervention  High degree of certainty related to performance  Providing access & affordability

5. Optimism Based on New Biomedical Discoveries  Sequencing of the human genome  Genomic and proteomic technologies  Systems biology  Advances in medical imaging  Nanotechnology advances  Tissue engineering  Drug discovery: combinatorial chemistry and automated microscale screening

6. Ten Year Investment Trends  Doubling over 5 years of NIH funding  Pharmaceutical R&D investment increasing at the same rate  Major investments in biotechnology

8. A Matching Acceleration of Product Development Has Been Expected

10. 10-Year Trends in Device Premarket Applications

11. In Addition, Medical Product Development Costs are Escalating Rapidly  Costs of bringing a successful drug to market estimated between $0.8 – 1.7B  Higher failure rate of candidates in clinical development

12. What’s the Diagnosis?  Investment & progress in basic biomedical science has for 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 century’s advances

13. Rx  Utilize new scientific knowledge to improve the medical product development process  Develop robust applied research program into critical path scientific areas, to lead to generalized knowledge  Strengthen academic bases for critical path disciplines  Intensify FDA involvement in critical path research and standards development

14. The Critical Path for Medical Product Development

15. Three Dimensions of the Critical Path  Assessment of Safety – how to predict if a potential product will be harmful?  Proof of Efficacy -- how to determine if a potential product will have medical benefit?  Industrialization – how to manufacture a product at commercial scale with consistently high quality?

16. Working in Three Dimensions on the Critical Path

17. Critical Path Science Base  The science necessary to evaluate and predict safety and efficacy, and to enable manufacture is different from the science that generates the new idea for a drug, biologic, or device.  In general, NIH and academia do not perform research in this area  CP research is complementary to basic and translational research, but results in the creation of new tools for the product development process.

18. Research Support for Product Development

19. Evaluative Tools  In early stages, developers use scientific tools to select candidates that are predicted to have a high probability of safety and effectiveness  Laboratory tests, computer models and animal studies are used to make these predictions

20. Evaluative tools  In the later stages of development, human testing is used to confirm earlier predictions  Early human safety and efficacy testing is not extensive enough for confirmation, but preliminary estimates are made using biomarkers

21. What is a Predictive Safety Tool?  Genomic expression system evaluating compound impact on liver cell function

22. Predictive Safety Tool?  Reference standards and Test System for Gene Therapy Vector Potency

23. Predictive Efficacy Tool?  Computer model for outcomes of incremental device modifications

24. Predictive Efficacy Tool?  Quantitative biomarker that can be used both in Animal & early Human Trials to indicate effect and guide Dose & Regimen Decisions

25. Confirmatory Safety Tool  Standardized Acceptable Trial Design to Definitively Assess a Safety risk (hepatotoxicity, QTc prolongation, etc.)

26. Confirmatory Safety Tool  Available clinical trial network to rapidly and efficiently answer specific safety queries using a large simple trial format

27. Confirmatory Efficacy Tool  FDA guidance document on use of a specific technology as an accepted surrogate marker within a specific clinical trial framework

28. Confirmatory Efficacy Tool  Consortium – based trial frameworks to allow manufacturers to pool resources to answer specific efficacy question pertaining to a class of devices or drugs

29. Confirmatory Efficacy Tool  Standardized case report forms  Data collection and data format standards for clinical trials

30. FDA’s Critical Path Initiative A serious attempt to bring attention and focus to the need for targeted scientific efforts to modernize the techniques and methods used to evaluate the safety, efficacy and quality of medical products as they move from product selection and design to mass manufacture.

31. FDA Initiative Goals  Get more innovative products to patients.  Achieve robust product development pathways that are efficient and predictable.  Develop new toolkits that bring scientific advances into the product development process.  Perform research on tools that remove specific identified obstacles in product development.

32. Why FDA? Unique Role of the Agency vis-à-vis the Critical Path  FDA scientists are involved in review during product development--they see the successes, failures, and missed opportunities  FDA guidance documents are known to foster innovation and improve chances of success.  Convening and coordinating role for new biomarker and clinical method development

34. Biomarker Questions or Surrogate Marker  How to accumulate existing “data” into “Knowledge”, (or, even better) into generalizable “principles”?  Who is responsible for doing this?  Cross-series and study analysis  Evaluation of the primary data  Identification of gaps  Conduct of research to close gaps  How would the “Knowledge” be then incorporated into an evaluation protocol or tool?

35. Example: Biomarker or Surrogate Marker Development  Marker developed by academic or industrial scientists as part of research project  After publication of method, used in more laboratories  Begins to be adopted by academic clinicians (home brew)

36. Example: Biomarker or Surrogate Marker  Widespread clinical use: series describing correlations with outcomes (not in trials) reported  Use in trials – summary data reported  Calls for use as biomarker or surrogate markers for evaluation of new technologies

37. Access to New Medical Technology: Part of FDA Mission “....The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science- based information they need to use medicines and foods to improve their health.”

38. Initial Steps  “Innovation/Stagnation” Report, announced by Commissioner McClellan and Deputy Commissioner Dr. Crawford on March 16  Today’s Presentation to FDA Science Board  Extensive discussions with stakeholders: patient groups, industry, academia, government scientists

39. The Path Forward  Identify/prioritize the most severe development problems and areas that provide the greatest opportunity -- solicit input from wide variety of sources.  Construct a national Critical Path Opportunities List and publicize it.  Re-focus internal activities and research.  Seek community concurs on additional steps

40. Conclusions  FDA’s Critical Path Report raises serious concerns about the ability of the current development process to get innovations to patients rapidly and efficiently  Preliminary discussions with key experts in industry and academia are validating this analysis of the development problem

41. Conclusions  FDA is continuing this dialog with a wide range of stakeholders—to reach agreement on the problem scope and definition  We are also working on defining specific opportunities for overcoming these hurdles—the opportunities list should provide examples of concrete, deliverable steps that could be accomplished