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FDA Role in Post-licensure Vaccine Safety Evaluation

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FDA Role in Post-licensure Vaccine Safety Evaluation

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    1. FDA Role in Post-licensure Vaccine Safety Evaluation M. Miles Braun, MD, MPH Director, Division of Epidemiology OBE, CBER, FDA April 10, 2007 Bethesda, MD

    3. Division of Epidemiology, Vaccine Safety Branch Bob Ball, Chief Dale Burwen Soju Chang Hector Izurieta Ann McMahon Manette Niu Sukhminder Sandhu Jane Woo Azra Dobardzic Wei Hua

    4. Frequent Collaborators Office of Vaccines Division of Biostatistics (OBE) Office of Compliance Office of Communications Office of the Director, CBER CDC

    5. Pharmacoepidemiologic Activities Focus on, and co-manage VAERS Signal detection & public communication VAERS case series & controlled studies Claims databases: CMS, VSD, other Review sponsors’ Periodic [Safety] Reports Review of BLA’s Pharmacovigilance Plans and Phase IV Study planning

    6. Weekly FDA VAERS meetings Serious report clinical review Assessment of vaccine lots Quality control Data Mining

    7. VAERS New Vaccine Review: Scientific Publication Examples Live attenuated influenza Pneumococcal conjugate Varicella Influenza in young children Infant DTAP Vaccines licensed in 2005-6, underway

    8. Published Adverse Event Studies Routine VAERS Review Case Series Alopecia Syncope and falls VAERS Research Arthritis after Lyme vaccine* Anaphylaxis, gelatin and MMR* Autism (risk perception)

    9. “Phase IV” Studies Studies that the FDA and sponsor agree will be performed subsequent to licensure A condition of licensure Observational, epidemiologic studies Clinical trials Other

    10. 2005 ICH Guideline on Pharmacovigilance Planning “E2E” ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Two Main Components of Guideline Safety Specification Pharmacovigilance Plan

    11. Safety Specification: Clinical Limitations of the human safety database Size of study population Exclusions/inclusions Implication of such limitations Worldwide… Exposure Safety issues? Regulatory actions?

    12. Safety Specification: Clinical Populations not studied pre-approval Immunosuppressed Racial/Ethnic Genetic polymorphisms Age groups Pregnant/lactating

    13. Pharmacovigilance Plan: Safety Action Plan-Protocol Issue Objective Action Rationale Oversight Milestones for evaluation & reporting International Society for Pharmacoepidemiology (ISPE) Guidelines

    14. Phase IV Planning: Current FDA Process Early meetings, sometimes before the biologics license application (BLA), with sponsors to discuss possible safety issues Pharmacovigilance plan (ICH “E2E”) generally submitted as part of BLA FDA reviews plan and proposed studies Agreement on (sometimes modified) plan Post-approval communication with sponsors

    15. Phase IV Study Types Observational General Safety: Screening Focused Safety: Adverse Event of Interest Rapid Cycle Analysis (government) Clinical Trials Other Specific examples to follow

    16. Rotashield Experience Clinical trial signal… VAERS signal… … then VSD-wide study initiated Major VSD site was also sponsor’s phase IV site Clear overlap Can we improve process?

    17. Coordination of Sponsors’ Phase IV studies & VSD studies Principles Reduce redundancy that does not add value Complementarity Coordination Standardization Specific Examples Common AE definitions (eg, Brighton Collaboration) Comparable analytic strategies (eg, time windows) Good side effect Functionally expand U.S. safety infrastructure

    18. Rotateq Approval Letter (2006) “…commitment to…evaluate the incidence of intussusception and other safety parameters…in approximately 44,000 subjects (adjustments… to be made based on the background rate of intussusception)…designed to detect an increased risk of intussusception due to vaccine of 2.5 or greater with 80% probability.” May 2006 – final study protocol December 2008 – study completion

    19. Zoster Vaccine Approval Letter (2006) Randomized, placebo-controlled, general safety study with 6K vaccinees & 6K placebo Serious adverse events Main follow-up 42 days, but also 6 months 15% subjects age 80 years or older 20K observational study Emergency room visits Hospitalizations High dose observational study Randomized, placebo-controlled study of subjects on low-moderate maintenance doses of corticosteroids

    20. Human Papillomavirus Vaccine Approval Letter (2006) 44,000 subject observational study Nordic countries cancer registries study 5,500 subjects, 14 year follow-up Effectiveness Non-vaccine type % Norway study: Long-term effectiveness, strain surveillance, pregnancy outcomes US pregnancy registry, at least 5 years

    21. Stockpiled Vaccines: Special Issues Examples: Pandemic influenza, anthrax, smallpox Limited pre-licensure safety data Potential rapid massive use in population Need rapid safety assessment infrastructure Eg, VAERS & VSD May need CMS, DoD, HMOs, VA, insurers, states, etc AE background rates determined in advance Expand routine rapid cycle analyses?

    22. Ideal Post-licensure Vaccine Safety Database Worldwide 100’s of millions of vaccinations tracked Rapid = Electronic Valid and reliable data Captures vaccination, disease, confounders Transparent and accessible Inexpensive (after major investment)

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