1. Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, Switzerland September 15, 2008

2. Topics for today
Approaches, needs, and opportunities to further enhance safety of vaccines and other biological products, with focus on post-marketing surveillance systems
Importance of international collaborations
Articulating a vision of an enhanced safety system

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

4. Biological Products Regulated by CBER
Vaccines (preventive and therapeutic)
Blood, blood components and derivatives
Allergenics
Cell and Gene Therapies
Tissues
Xenotransplantation Products
Related Devices (including certain IVDs)

5. Major CBER Initiatives
Pandemic influenza and emerging threat preparedness
Enhancing product safety
Integrated safety teams and use of informatics
Manufacturing and product quality activities
Critical path
Global collaboration

6. Enhancing Product Safety
Multi-disciplinary safety teams for vaccines, blood, and tissues (epidemiologists, clinical/product reviewers, compliance/manufacturing experts, communications) to improve acquisition, analysis, and communication of safety information
Encompasses entire product life cycle and all data relevant to safety, manufacturing, and compliance
Uses data to evaluate emerging safety issues
Coordinates FDA response to emerging safety issues with other HHS agencies (CDC, NVPO, NIH), industry
Enhances collaboration with other govt. agencies, WHO, and other entities on safety initiatives
Proactive: develop research, policy, outreach agenda

7. Assuring Product Safety
Pre-licensure
Evaluate clinical, nonclinical, product, and manufacturing data, including facility inspection
Pharmacovigilance plan evaluated as part of biologics license application and informs post-marketing surveillance and studies
Post-licensure
Lot release
Biennial inspections
Evaluation of post-marketing adverse event reports (VAERS for vaccines and AERS for other products) and studies

8. Pharmacovigilance Plan (ICH E2E)
Basis for design of Phase 4 studies, passive surveillance and other components of pharmacovigilance plan is through analysis of Safety Specifications:
Important identified risks
Important potential risks
Important missing information
Manufacturer should consider actions to address any such concerns

9. Pharmacovigilance Plan (cont)
Staff member from the Division of Epidemiology is assigned to the Biologics License Application (BLA) review team
Primary responsibility for review of pharmacovigilance plan and agreement with manufacturer regarding post-marketing safety studies is with Division of Epidemiology, working together with rest of multi-disciplinary review team
As appropriate, pharmacovigilance plan is presented to FDA Advisory Committee, together with efficacy and safety data from BLA prior to licensure

10. Why do we need post-marketing surveillance?
Rare adverse events may not be detected in pre-licensure studies
Why? Because even very large clinical trials have limitations. For example, to detect a doubling in an adverse event that occurs at a rate of 1/1000 would require a sample size of 50,000 (two-arm, power=80%, alpha=5%)
The post-marketing surveillance activities described in the slides that follow focus on vaccines, but the same principles are applicable to other medical products

11. Post-Marketing Surveillance for Vaccines: Passive Approach
Vaccine Adverse Event Reporting System (VAERS)
National system for passive surveillance of adverse events after vaccination established in 1990 in response to the National Childhood Vaccine Injury Act of 1986
Jointly managed by FDA and CDC
VAERS contractor receives reports, manages report database, and conducts routine report follow-up
Reports received from health professionals, vaccine manufacturers, and the public

12. Adverse Event Report Review
Manufacturer “15 day reports” of serious unexpected events and direct reports of death and serious adverse events are forwarded by VAERS contractor to assigned CBER staff within 1 business day
Reviewed daily for unexpected events
Follow-up with reporters as necessary
Periodic reports/periodic safety update reports reviewed when submitted
Weekly vaccine safety surveillance meeting

13. VAERS: Advantages National in scope, covers diverse populations
Able to detect rare adverse events
Rapid detection of possible signals (hypothesis generating)
Can assess adverse events by lot

14. VAERS: Limitations Reported diagnoses not verified
Lack of consistent diagnostic criteria
Wide range of data quality
Underreporting
Inadequate denominator data (i.e., number of persons vaccinated)
No unvaccinated control group
No information on background rates of conditions in general population
Usually not possible to assess whether vaccine caused the reported adverse event

15. Post-Marketing Surveillance for Vaccines: Active Approaches
Manufacturers’ phase 4 studies
FDA sentinel initiative
Activities ongoing or under development with Centers for Medicare and Medicaid Services, Department of Veterans Affairs, Department of Defense large medical encounter and claims databases for controlled observational studies of specific safety issues
Other public-private partnerships being sought
FDA Amendments Act of 2007 prescribes an active post-market risk identification and analysis system intended to link and analyze safety data from multiple sources, with goal of including 25M patients by 2010 and 100M patients by 2012

16. Post-Marketing Surveillance for Vaccines: Active Approaches
CDC’s Vaccine Safety Datalink (VSD)
8 geographically diverse health maintenance organizations that participate in large linked database that tracks
Vaccination (exposure)
Outpatient, emergency department, hospital and laboratory data (health outcomes)
Demographic variables (confounders)
Includes approximately 3% of U.S. population
“Hypothesis testing” studies can be conducted

17. VSD Analyses: Advantages
All medical encounters are available at most sites
Allows calculation of background rates of various conditions of interest
Medical chart review is accessible
Available for urgent studies

18. VSD Analyses: Limitations
Sample size may be inadequate for very rare adverse events (e.g., Guillain-Barre syndrome with incidence rate of 1-2/100,000 per year)
Lack of demographic and socioeconomic diversity in HMO practices
Variable accuracy of coded data used for studies
Unvaccinated population may be small

19. FDA and CDC Interactions on Vaccine Safety
FDA and CDC, in conjunction with HHS and other agencies, work closely together on vaccine safety surveillance activities (e.g., VAERS, VSD and other active surveillance activities) and the analysis and communication of safety concerns

20. A Case Study: Rotavirus Vaccine and Intussusception (IS)
First rotavirus vaccine (Rotashield) licensed by FDA in August 1998
Pre-licensure: IS noted as possible AE, difference in rate between vaccine and placebo groups not statistically significant
Post-licensure: likely excess of IS noted in VAERS, CDC-conducted epidemiological studies show elevated risk, and in October 1999, ACIP withdraws recommendation for vaccine and manufacturer voluntarily withdraws vaccine from market

21. How did this impact next rotavirus vaccine?
Second rotavirus vaccine (Rotateq) licensed by FDA in February 2006
Pre-licensure: very large safety study (70,000 infants, 1:1 vaccine to placebo), no increased risk of IS
Post-licensure surveillance: VAERS, manufacturer’s phase 4 study (44,000 infants) and CDC’s VSD study (90,000 infants)
To date, no signal of increased risk of IS after Rotateq (Pediatrics 2008;121: )
Updates communicated through changes to labeling and patient information, Public Health Notification, MMWR publication

22. Other Recent Examples of Vaccine Safety Issues
Possible increased risk of Guillain-Barre syndrome after Menactra (quadrivalent meningococcal conjugate vaccine)
Possible increased risk of febrile seizures after Proquad (combined Measles, Mumps, Rubella and Varicella Vaccine)
Update on the safety of Gardasil (human papillomavirus vaccine)

23. Global Collaboration CBER is a WHO Collaborating Center
Expert Committee on Biologic Standards
Strategic Advisory Group of Experts
Global Advisory Committee on Vaccine Safety
Global Collaboration on Blood Safety and Blood Regulators Network
Expert consultation in specific product areas
Participates in WHO prequalified vaccines program
Participates in WHO teams to assess competency of national regulatory authorities (NRA) around the world
Training: Works with WHO Developing Countries Vaccine Regulators Network to help build global regulatory capacity of NRAs with regard to vaccines

24. Global Collaboration
Information sharing arrangements and engagement in priority areas with various regulatory authorities and WHO
Brighton collaboration for standardized case definitions of adverse events following immunization
CIOMS vaccine safety working group
Partnering with WHO and NGOs to explore additional means of providing global regulatory assistance and capacity building
International Conference on Harmonisation
Pharmaceutical Inspection Cooperation/Scheme

25. FDA Amendments Act (2007): Some Highlights
Pediatric Research Equity Act: Pediatric studies required with application or supplement for new active ingredient, indication, dosage form, dosing regimen, or route of administration, unless deferral or waiver granted
Safety: FDA to require post-marketing studies or clinical trials at time of approval, or after approval, based on certain safety concerns (e.g., to assess known serious risk or signal of serious risk, or to identify expected serious risk if data indicate such potential)

26. FDA Amendments Act (cont)
Safety Labeling Changes: FDA to require if new safety information needs to be included, specific timelines noted
Risk Evaluation and Mitigation Strategies: FDA can require at time of or after approval, if deemed necessary to ensure that benefits outweigh risks
Active Post-market Risk Identification and Analysis System: to link and analyze safety data from multiple sources, with goal of including
at least 25M patients by 2010,
at least 100M patients by 2012

27. Vision for Post-Market Surveillance
All patients’ vaccinations and health outcomes are immediately and continuously accessible in automated database(s) allowing optimal detection and analysis of potential problems in vaccine safety
Not there yet – both major limitations and opportunities in current health information systems
Both problems and solutions to enhance vaccine safety information and analysis are applicable to safety initiatives for other medical products

28. Post-Market Surveillance: Needs
Access to more patients and better data
Given diversity of data sources, innovative approaches to retrieval of key data may have great potential vs. single unified system
Better background rates, comparable “control” populations
More consistent event/disease nomenclature, IT architecture, data interchangeability, quality
Increase in “non-medical” data sources – e.g., pharmacy, supermarket, employer vaccination

29. Post-Market Surveillance: Opportunities
Access to additional health systems data: CMS, VA, DoD, managed care organizations
Access to global data: regulatory, inspectional, health systems, international surveillance and pharmacovigilance
Better analytic tools and methods

30. Communications and Transparency
Early and continuing communication of possible safety signals is expected and beneficial to consumers, health care providers, science
Critical to confidence in integrity of vaccine safety system, government and industry
Enhances reporting and informs decision-making of consumers and health care providers
Initial information and medical/scientific opinion and assessments often evolve
Conveying uncertainty of risk difficult, includes potential for decreased use of safe and effective products

31. Summary
Pre-licensure clinical, product, and manufacturing data are critical foundations for evaluating the safety and effectiveness
However, post-licensure surveillance is essential to assure product safety
Vaccines and other medical products have risks that may include rare serious adverse events not detected in pre-licensure studies
Government agencies play an important role in monitoring, analyzing, and communicating re safety of vaccines and other medical products

32. Summary (cont)
Passive and active surveillance, including observational studies, after licensure are needed to detect and evaluate vaccine safety concerns
Need for robust, continuously operating and technologically advanced safety monitoring systems that include epidemiological, clinical, and laboratory assessments of causality
Public communication and engagement regarding vaccine safety concerns is critical to maintaining confidence in the vaccine safety system, optimal vaccine coverage, and the public health

33. Acknowledgments Robert Ball, MD, MPH, ScM Jesse Goodman, MD, MPH
John Iskander, MD, MPH
Douglas Pratt, MD, MPH
Joan Blair, MA

34. CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH
Thank you!
We are actively engaged in assuring the safety, effectiveness, and availability of products that touch so many lives and are critical for public health and preparedness
Emerging threats, technologies, and opportunities demand constant renewal of scientific expertise and capacity
The challenges and opportunities for leadership and public health are truly global – and collaboration is key!
CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

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