FDA Role in Postlicensure Vaccine Safety Evaluation

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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

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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

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Frequent Collaborators

• Office of Vaccines
• Division of Biostatistics (OBE)
• Office of Compliance
• Office of Communications
• Office of the Director, CBER
• CDC

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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 BLAs Pharmacovigilance Plans and Phase
  IV Study planning

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Weekly FDA VAERS meetings

• Serious report clinical review
• Assessment of vaccine lots
• Quality control
• Data Mining

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VAERS New Vaccine ReviewScientific Publication
Examples

• Live attenuated influenza
• Pneumococcal conjugate
• Varicella
• Influenza in young children
• Infant DTAP
• Vaccines licensed in 2005-6, underway

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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)

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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

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2005 ICH Guideline onPharmacovigilance 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

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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?

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Safety Specification Clinical

• Populations not studied pre-approval
• Immunosuppressed
• Racial/Ethnic
• Genetic polymorphisms
• Age groups
• Pregnant/lactating

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Pharmacovigilance Plan Safety Action
Plan-Protocol

• Issue
• Objective
• Action
• Rationale
• Oversight
• Milestones for evaluation reporting
• International Society for Pharmacoepidemiology
  (ISPE) Guidelines

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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

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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

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Rotashield Experience

• Clinical trial signal
• VAERS signal
• then VSD-wide study initiated
• Major VSD site was also sponsors phase IV site
• Clear overlap
• Can we improve process?

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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

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Rotateq Approval Letter (2006)

• commitment toevaluate the incidence of
  intussusception and other safety parametersin
  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

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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

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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

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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?

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Ideal Post-licensure Vaccine Safety Database

• Worldwide
• 100s 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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