FDA’s Center for Biologics Evaluation and Research Initiatives and Current Priorities Robert A. Yetter, Ph.D. Associate

1. FDA’s Center for Biologics Evaluation and ResearchInitiatives and Current PrioritiesRobert A. Yetter, Ph.D.Associate Director for Review Management

2. CBER’s Vision INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH • Protect and improve public and individual health in the US and, where feasible, globally • Facilitate development, approval and access to safe and effective products and promising new technologies • Strengthen CBER as a preeminent regulatory organization for biologics

3. CBER Strategic Priority 1:Enhance Our Nation’s Preparedness • Vision: Assure the nation is prepared for pandemic influenza, other emerging infectious disease threats, and terrorism • Ensure adequate surveillance of threats • Early post market detection of safety signals • Facilitate critical product development • Enhance regulatory responsiveness

4. A Pandemic Threat • Historically: • 1918 emergence of H1N1 • 1957 emergence of H2N2 • 1968 emergence of H3N2 • 1977 re-emergence of H1N1 • Three criteria for pandemic outbreak: • A novel influenza hemagglutinin (HA) subtype, to which the general population has little or no immunity against, emerges or re-emerges • Causes significant morbidity and mortality • Efficiently transmits from human to human • Since April 21, 2009 when the U.S. Centers for Disease Control and Prevention (CDC) released the first MMWR dispatch on two U.S. cases of the newly emergent 2009 H1N1, the numbers of cases have steadily increased, prompting WHO to declare a pandemic Phase 6 on June 11, 2009.

5. Newly emergent 2009 H1N1 • Index cases: • Ten year old boy from San Diego County, California • Nine year old girl from Imperial County, California • No epidemiological link between the two • No known exposure to zoonotic risk factors • Virus isolates were genetically related (triple reassortant of human, swine, and avian genes) and antigenically similar • Current Landscape (as of Aug 30, 2009)*: • 254,206 confirmed cases reported from 70 different countries • 2,837 deaths • Case fatality rate of approximately 0.01% • Predominant circulating strain in the Southern Hemisphere, and anticipated circulation in the upcoming influenza 2009-2010 season for the Northern Hemisphere

6. FDA Response to the 2009 H1N1 Pandemic Threat • H1N1 Task Force was established April 24, 2009 and comprises several Teams and encompass Center-specific and cross-cutting disciplines • FDA Emergency Operations Center activated, incident management coordination implemented • Frequent conference calls and situational reports • FDA liaison was deployed to CDC Headquarters in Atlanta, GA to facilitate coordination between FDA and CDC

7. FDA H1N1 Task ForceCenter Teams • Antiviral Team (CDER) • Drug Shortage Team (CDER) • Expired Drug Team (CDER) • In-Vitro Diagnostics Team (CDRH) • Personal Protective Equipment Team (CDRH) • Vaccine Team (CBER) • Blood Team (CBER) • Consumer Protection Team (ORA) • Food Safety Team (CFSAN) • Animal Feed Safety (CVM)

8. Ongoing CBER Activities for Vaccine Development • Facilitating the efforts of influenza vaccine manufacturers • to develop H1N1 vaccines using the same process as for the licensed seasonal influenza vaccines • to develop H1N1 vaccines that contain novel adjuvants or utilize other novel approaches • Facilitated efforts of industry and NIAID to develop and initiate clinical trials that are generating data to determine the optimal dosage and number of doses • Collaborating with WHO and other regulatory authorities (e.g., EMEA, Health Canada) regarding development of new H1N1 vaccines, post-marketing safety surveillance, information sharing, etc. • Participating with other WHO Essential Regulatory Laboratories and industry in the production, cross-calibration, and provision of potency reagents to the world as rapidly as possible. • Working with CDC, HHS, and others to develop expanded post-marketing safety surveillance

9. Regulatory Options for pandemic vaccines • Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines http://www.fda.gov/Cber/gdlns/panfluvac.pdf • Vaccines and Related Biological Products Advisory Committee (VRPAC) meeting July 23, 2009: • Agree with FDA approach for manufacturers to submit H1N1 vaccine made with licensed process as a supplement to existing seasonal influenza vaccine license (same approval process for yearly strain changes to seasonal vaccine)

10. CBER Strategic Priority 2: Protect and Enhance Public Health Globally • Vision: Achieve a world where advances in public health and science are applied to critical global health problems; manufacturing capacity and innovative products meet high standards and contribute to the health of all peoples. • Global vaccine assistance program • Harmonization of regulatory standards • Support regulatory capacity building

11. CBER’s Global Assistance, Cooperation & Leadership •WHO -Collaborating Center for Biological Standardization -Blood Regulators Network -Global Collaboration for Blood Safety -FDA/HC Pandemic Regulators • Bilateral MOU with European Medicines Agency (EMEA); Parallel Scientific Advice • International Conference on Harmonisation (ICH) • Pharmaceutical Inspection Cooperation Scheme (PIC/S)

12. Development of International Reference Materials and Standards for Blood Products and Related IVDs • Used by CBER for potency control of biologic products derived from blood and plasma, recombinant DNA technology and related IVDs • Developed in cooperation with WHO collaborating centers (CBER, NIBSC, PEI), other international partners (e.g. CoE/EDQM, ISTH), and regulated industry

13. CBER Strategic Priority 3:Keep Products and Patients Safe • Vision: Harness the power of bioinformatics at the population, patient and molecular levels to monitor and enhance safety, improve risk/benefit communication, and pave the way to personalized medicine • Integrate genomics technology into product development • Utilize statistical modeling and data mining tools • Leverage large healthcare databases, including near real time analysis • Improve public communication

14. CBER Strategic Priority 4:Modernize Biologics Manufacturing and Product Quality • Vision: Facilitate innovation and excellence in manufacturing and quality and provide oversight that prevents problems • Life cycle approach utilizing risk management principles • Quality Management System for CMC review • Consolidation and external accreditation of product testing laboratory • Develop rapid microbial detection methods • Direct Recall Classification

15. CBER Strategic Priority 5: Innovative Products to Patients – Critical Path • Vision: Advanced science and technology permit better prediction of product safety and efficacy, facilitating availability of novel products to address unmet needs • Novel therapies initiative • Improve clinical trials through use of new clinical biomarkers and adaptive designs • Mission targeted research

16. CBER Strategic Priority 6: Strengthen Human Organizational Resources and Performance • Vision: CBER continues as a global standard, leader and collaborator in biologics science, evaluation and regulation, with a culture and record of excellence • Continual Process Improvement • Leadership development and succession planning • Recruitment and retention • Move to White Oak campus (2012)

17. Let’s talk smart!

18. Booz Allen Hamilton Booz Allen Hamilton “Independent Evaluation of FDA’s First Cycle Review Performance – Retrospective Analysis Final Report” January 2006 http://www.fda.gov/ope/pdufa/PDUFA1stCycle/pdufa1stcycle.pdf

19. Effect of End of Phase 2 Meetings on Approval Rate

20. Issues may be raised early but…responsiveness is needed • 71% of major deficiencies are identified at a pre-submission meeting but not resolved by first action • Lack of clarity on severity? • Belief that issue can be resolved during review? • Unwillingness of sponsor to comply and/or postpone submission of application? • Desire for a comprehensive review of application and identification of other deficiencies?

21. Responsiveness to issues (cont.) • Alternative pathways are a possibility! • Modification or unbundling of indication • “Can this trial be saved? • Need early and open discussions on acceptable resolution pathways from FDA and sponsors

22. Interestingly enough… • Compliance with FDA recommendations more critical for CMC deficiencies • Alternative pathways, including postmarketing study commitments, appear to be more of an option for non-CMC deficiencies • Note: Additional policies under development for PMC and PMR development and tracking

23. Disposition of Significant First Action Deficiencies in Multi-Cycle Approvals

24. Does it matter when you submit? Timing of submissions • 2-3x the number of submissions in the 4th quarter compared to any other quarter in a calendar year • 4th quarter applications have the lowest rate of first-cycle approval without any apparent differences in application quality • FDA workload? Note: anecdotally, FDA staff believe that 4th quarter applications are of lower quality

25. Submission Timing vs. Number of Submissions or First-Cycle Approval Rates

26. What Reviewers are saying: • Do your homework – use Guidance Documents • Hire consultants if you do not have in-house expertise – do not ask FDA to develop your program • Science, not marketing, should drive your program

27. Avoid “Rookie Mistakes” • Failure to submit a complete application • If you have to ask “Can we submit the [fill in the blank] section of the application [fill in the length of time] after we submit the application?” you are not ready • Don’t submit your application prematurely according to corporate targets – multiple review cycles are NOT faster

28. Avoid “Rookie Mistakes” • Insufficient attention to details related to electronic submissions • Not following advice or addressing a concern • Persisting disagreements over issue resolution  approval delays • Delay or avoid meeting with FDA

29. Use Meetings Wisely • Follow the Guidance for Industry, Formal Meetings with Sponsors and Applicants for PDUFA Products (May 2009) • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM153222.pdf • End-of-Phase 2 meetings are the most important • Pre-submission meetings are too late to fix the big problems • Pay attention to what is being said • Be aware of “regulatory speak” • Understand and consider our perspective

30. For a Successful Meeting - Do • Provide a brief background summary • Assume the meeting package has been read • Show how study fits overall development plan • Focus on questions • Limit your presentation • Summarize agreements/disagreements • Bring hardcopy of slides for RPM

31. Please, Don’t - • Regurgitate the meeting package • Expect FDA to guess your critical issues • Request a pre-BLA before pivotal trial results shown to demonstrate efficacy and safety • Present issues outside proposed agenda • Send new data just before meeting • Expect evaluation of new data presented at meeting

32. After the Meeting - • Review agreements • Request FDA minutes of meeting • Notify FDA of any differences • Follow through

33. We’re Here to Help You! • CBER’s Office of Communication, Outreach and Development at : 301-827-2000 • Consumers, Healthcare providers: ocod@fda.hhs.gov • Industry, Consultants: matt@fda.hhs.gov • Contact me via phone at: 301-827-0373 • Or contact me via e-mail at: Robert.yetter@fda.hhs.gov

34. Resources • CBER’s webpage: http://www.fda.gov/BiologicsBloodVaccines/default.htm • Contacting CBER: http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm • FDA’s H1N1 information: http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm150305.htm • FDA Pandemic Influenza Preparedness Strategic Plan http://www.fda.gov/oc/op/pandemic/strategicplan03_07.html • WHO: http://www.who.int/en/