Topics for today

1. Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy DirectorCenter for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, SwitzerlandSeptember 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. 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;121:1206-1212) • 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) • http://www.fda.gov/cber/safety/gbs102006.htm • Possible increased risk of febrile seizures after Proquad (combined Measles, Mumps, Rubella and Varicella Vaccine) • http://www.fda.gov/cber/label/proquadLBinfo.htm • Update on the safety of Gardasil (human papillomavirus vaccine) • http://www.fda.gov/cber/safety/gardasil071408.htm

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. 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

35. CBER Contact Informationhttp://www.fda.gov/cber Manufacturers: matt@fda.hhs.gov Consumers, health care professionals: octma@fda.hhs.gov Phone: 301-827-1800