1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. The Route to Approval Mid-Atlantic Bio Robert A. Yetter, Ph.D. Associate Director for Review Management Center for Biologics Evaluation and Research Food and Drug Administration

3. Avoiding the Rocks and Shoals

4. 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

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

6. 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?

7. 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

8. 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

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

10. Does it matter when you submit? Timing of submissions 2-3x the number of submissions in the 4 th quarter compared to any other quarter in a calendar year 4 th 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 4 th quarter applications are of lower quality

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

12. 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

13. 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

14. 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

15. 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/GuidanceComplianceRegul atoryInformation/Guidances/UCM153222.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegul atoryInformation/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

16. 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

17. 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

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

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

20. Resources CBER’s webpage: http://www.fda.gov/BiologicsBloodVaccines/ default.htm http://www.fda.gov/BiologicsBloodVaccines/ default.htm Contacting CBER: http://www.fda.gov/AboutFDA/CentersOffic es/CBER/ucm106001.htm http://www.fda.gov/AboutFDA/CentersOffic es/CBER/ucm106001.htm