1. FDA’s Critical Path Research Initiative & Intro to the CBER Research Program Kathryn M. Carbone, M.D. Associate Director for Research CBER/FDA

3. Sponsor Perspective “…success isn’t measured by how much [drug industry employees] have contributed to a drug…on the market…it means ‘hitting your numbers’… Trouble is, that approach is hugely inefficient.” Drug discovery and development can run as high as $1.9 billion. “Lowering that number is the current Holy Grail of the industry.” How can the FDA help make biological product development more efficient and support more safe and effective products reaching the public? J. Mervis, Science, Vol 309, July 29, 2005 I

4. Sponsor Perspective “…’it’s not the number of targets validated, or the number of chemicals selected. It’s proof of concept in patients [Yamada, GSK]…[a drug] is not a success until we’ve treated a patient with it.’ [Fishman, Novartis]” “…’it’s still a crapshoot…after 30 years in this business, I haven’t met anybody who could [pick winners]’ [Ruffolo, Wyeth] But they aren’t true winners until documentation of safety, efficacy and manufacturing sufficient for FDA approval…too many drugs fail too late in the development process…. J. Mervis, Science, Vol 309, July 29, 2005 I

5. Sponsor Perspective “…’you can’t manage [product development] science. But it needs to be. [Ruffolo, Wyeth]” “…Knowing how to maintain a healthy [product development] pipeline…’is more or less a matter of intuition.’ [Scheller, Genentech]” Consider the value, then, of science carefully managed to target the development of tools and knowledge for demonstration of product safety, efficacy and manufacturing = Critical Path Science…

6. “Intuition” ? “ Intuition” is often cited when there really is a valid process, but the process may be implicit and non- transparent. Implicit processes give the impression of capricious decision making—even when good decisions are made for good reasons

7. FDA Critical Path Research Initiative www.fda.gov/oc/initiatives/criticalpath.htm –Identify, focus upon and manage to regulatory & scientific opportunities to improve product development process and availability –Potency/effectiveness/standards –Safety –Consistency/manufacturing/quality Needed policy and guidance Preserve a science based FDA

8. IND BLA Attending to the Critical Path of Medical Product Development

9. Why FDA? Unique perspective of the Agency vis-a-vis leads to a valuable role in convening and coordinating Critical Path Research Combination of FDA intramural, FDA intramural/extramural collaborations, and extramural research efforts

10. Integral Role of Research to Inform Policy of Product Evaluation

11. Subcommittee for the External Review of CBER Research, 2/98 “The Researcher/Reviewer Model is essential to providing CBER with top-level expertise in a regulatory culture.”“The Researcher/Reviewer Model is essential to providing CBER with top-level expertise in a regulatory culture.” Working closely with CBER Regulatory Scientists and Clinical Review Scientists to perform high quality evaluation of novel biological productsWorking closely with CBER Regulatory Scientists and Clinical Review Scientists to perform high quality evaluation of novel biological products

12. Multitasking at the FDA: Research Supports Regulatory Mission Research Programs organized by Product Offices CBER researchers are fully integrated into the regulatory process (~50% average time) = “Researcher-Regulator” model –Review INDs and BLAs –Development of Policy and Guidance Documents –Meeting with Sponsors and Advisory Committees –Participation in Pre-license and Biennial Inspections –Evaluation of Adverse Drug Reactions and Risk Assessment –Performing research relevant to product evaluation of safety, efficacy, manufacturing: Developing/evaluating scientific tools & knowledge

13. Mission Relevance of Research Programs Hundreds of Biologics Licensing Applications and Investigational New Drug Applications directly supported by research programs More than 50% of the Research Programs have applicability to evaluation of Counterterrorism- relevant biological products CBER research in the public domain supports development of safe and effective biologics across entire product classes

14. Center Director/ADR Office Director/ADR Division Director/ Branch Chief Staff Proposals Priorities/Agenda Managing Research Programs at CBER

15. Internal & External input into research priorities and agenda decision making –Advisory Committees, e.g., Office Research Site Visits to be conducted in FY05 & ’06 Cross-Office Coordinated Research Expertise Teams to identify Center research strengths and gaps Priority decisions include public health impact, current and anticipated submissions, unique FDA expertise, scientific information needed that is not likely to be provided elsewhere, Critical Path Challenges

16. Turning Challenges Into Solutions Evaluation of past achievements and future proposals: Quality, regulatory impact, relevance –Internal Management reviews: Yearly cycle using Annual Research Program reporting: E.g., Publications, Regulatory Policy/Guidances, Invited talks, Research QA/QC –External Laboratory/Res-Reg Site Visits: Four year cycle Used to determine intramural support for research programs –Fact of life: must also compete for select sources of extramural funding to support research programs

17. CBER Research: Supporting Innovation WNV blood donor screening advances: enhanced IND NAT testing = 1000+ units detected New tests and standards for biologic products: HIV, hepatitis, blood typing, blood cross-matching,, IGIV immune globulin,  -1 proteinase, thrombin, WNV New safety evaluations: HBOC oxidative toxicity; prion detection and removal

18. OCTGT Products & Toxicology Far from traditional pharm tox Requires expertise in DNA vectors and cell/tissue biology OCTGT staffs led a novel collaboration with NTP/NIEHS to establish methods for evaluating DNA-based product toxicities and evaluating safety test designs Will serve as a model for future NTP-CBER collaborations—more later from Dr. Epstein

19. Examples of CBER Critical Path Investment Opportunities –Develop/make available well characterized cell banks (and methods to assay for safety/adventitious agents) for vaccine and biologics production – & update guidance – Characterization of cell therapies & links to standardized clinical/lab outcomes (e.g. HPSCs) –New assays, standards, biomarkers, surrogates for complex biologics safety, efficacy and quality –Methods & validation of pathogen inactivation for blood, plasma, tissues and other products –Multipathogen and rapid detection methodologies –Improving longevity/storage of blood and tissues –Flu vaccine assays, standards and reagents –Enhanced clinical trial design/analysis

20. We are proud of our research contributions in public health, biodefense, product safety and availability. New technologies need innovative and interactive regulation, new models, standards and assays. Expertise and partnerships essential. We welcome your input. CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH Contact me: carbonek@cber.fda.gov or 301-827-0372@cber.fda.gov