Perspectives on Improving International Vaccine Safety

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Ralf Horton
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Biostatistics and Epidemiology Center for Biologics

1 Perspectives on Improving International Vaccine Safety Robert Ball, MD, MPH, ScM Director, Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research U.S. Food and Drug Administration 1

2 The Cow Pox-or-the Wonderful Effects of the New Inoculation (From the publications of the Anti-Vaccine Society/J. Gilray, 1802) 2

3 Some Important Events in Vaccine Safety History 1901 Horse Named Jim beginning of regulation in US 3

4 Historical Approaches to Regulation for Risk Management in US Biologics Control Act of 1902 and Food and Drug Act of 1906 Safety required inspection and approval before marketing Products must not be adulterated or impure Labels must not be false or misleading Protecting America s Health: The FDA, Business, and One Hundred Years of Regulation, Philip J. Hilts 4

5 Historical Approaches to Regulation for Risk Management in US Biologics Control Act of 1902 and Food and Drug Act of 1906 Safety required inspection and approval before marketing Products must not be adulterated or impure Labels must not be false or misleading Food, Drug and Cosmetic Act of 1938 Drugs must be safe before being given broadly to patients Protecting America s Health: The FDA, Business, and One Hundred Years of Regulation, Philip J. Hilts 5

6 Some Important Events in Vaccine Safety History 1955 Cutter Incident with incompletely inactivated polio vaccine Pre-licensure safety testing, vaccine manufacturing process control, and clinical trials are critical foundations, but postlicensure monitoring is essential to ensure safety when vaccines are used in large numbers of people Government agencies, both regulatory and scientific, play important and beneficial roles in ensuring vaccine safety 6

7 Historical Approaches to Regulation for Risk Management in US Biologics Control Act of 1902 and Food and Drug Act of 1906 Safety required inspection and approval before marketing Products must not be adulterated or impure Labels must not be false or misleading Food, Drug and Cosmetic Act of 1938 Drugs must be safe before being given broadly to patients Kefauver-Harris amendments of 1962 Adequate and well-controlled investigations required for licensure Protecting America s Health: The FDA, Business, and One Hundred Years of Regulation, Philip J. Hilts 7

8 Some Important Events in Vaccine Safety History Swine flu vaccine and Guillain Barré Syndrome (GBS) 1980 s Concern about DTP vaccine and encephalopathy leads to decline in vaccine coverage in some countries 8

9 National Childhood Vaccine Injury Act of 1986 Address vaccine liability concerns for pediatric vaccines Mandated U.S. vaccine safety infrastructure National Vaccine Program Office (NVPO) National Vaccine Injury Compensation Program (NVICP): Vaccine Excise Tax + Vaccine Injury Table Vaccine Information Statements (VIS) Institute of Medicine (IOM) review committee Vaccine Adverse Event Reporting System (VAERS) 9

10 Some Important Events in Vaccine Safety History Post-NCVIA 1990 s ACIP recommendation to use IPV instead of OPV in US to prevent cases of vaccine associated paralytic polio in absence of natural disease 1998 Concern about MMR and autism 1999 Concern about thimerosal, neurodevelopmental conditions and autism Rotashield vaccine and intussusception 2005 Concern about Menactra and GBS 10

11 Child Develops Eczema Vaccinatum After Father Has Smallpox Vaccination Reuters Health Information Reuters Ltd. By Maggie Fox WASHINGTON (Reuters) Mar 19 - The 2-year-old son of a soldier deployed to Iraq is in critical condition after developing a reaction to his father's smallpox vaccination, the U.S. Centers for Disease Control and Prevention said on Saturday. The child, being treated in a Chicago hospital, has eczema vaccinatum, the CDC said. It is the first such case since vaccination against smallpox resumed in 2002, said CDC pox virus expert Dr. Inger Damon. The toddler's father is a soldier vaccinated while on deployment to Iraq. The father was unexpectedly furloughed and evidently his wife and son touched the vaccine site and became infected, the CDC said. "They can get a particularly noxious and sometimes fatal rash," Dr. Damon said in a telephone interview. Because smallpox vaccine uses live vaccinia virus, it can sometimes cause severe and sometimes fatal side effects. "The child is a dependent of a U.S. Army Service member deploying to Iraq," the CDC said in a statement. "We don't know what the soldier's reaction was like at his vaccination but he is doing well now and hasn't described any illness that we are aware of," Dr. Damon said.the child has been treated with immune globulin, the antiviral drug cidofovir, and an experimental antiviral made by Siga Technologies called SIGA-246, Dr. Damon said. "We are cautiously optimistic that the child is improving," Dr. Damon said. Between 1959 and 1968, when smallpox vaccination was common, 12 cases of eczema vaccinatum were reported in the United States, with an 18% fatality rate. The United States resumed vaccinating some people in 2002, including 40,000 civilian health workers and hundreds of thousands of military personnel. Many civilians resisted getting inoculated because of the vaccine's notorious side effects, but the CDC has reported only two very severe cases, both involving heart conditions that potentially could have been caused by the vaccine. Dr. Damon said a stringent screening program had made vaccination safer than in years past. Anyone predisposed to side effects, such as people known to have eczema, are not supposed to get the vaccine. So I think this is one of those unfortunate events where a family member who was at risk from vaccinia ends up coming in contact with a vaccinated individual," she said. 11

12 Post-NCVIA Approaches to Risk Management in US 1990 s - Development of CDC Vaccine Safety Data Link 2000 s - Development of CDC Clinical Immunization Safety Assessment Centers 2000 s - Brighton Collaboration for adverse event case definitions 2005 FDA and ICH guidance on pharmacovigilance planning applied to post-marketing commitments for vaccine safety 2000 s FDA expands collaborations to evaluate vaccine safety in government and private health systems 12

13 Do we need to do more? Patients are risk averse Patients want more transparency and communication High unmet medical needs, but disease prevention depends on public acceptance of vaccines Failure of medical practice to deal effectively with managing risk of pharmaceutical products via traditional approaches (e.g. product labeling) Need a systems approach to managing risks Globalization of health and disease 13

14 Do we need to do more? Limitations of Clinical Trials Limited sample sizes and observation periods typically limit reliable detection of side effects to the most common ones with relatively short latency intervals Enrollment exclusions more stringent than post-licensure utilization limit generalizability of results Multiple comparisons and post hoc analyses often limit inferences from observed safety issues to hypothesis generation (signals of possible risks) Knowledge of risks evolves with product use 14

15 New Era of Regulatory Risk Management in US Biologics Control Act of 1902 and Food and Drug Act of 1906 Food, Drug and Cosmetic Act of 1938 Kefauver-Harris amendments of 1962 FDA Amendments Act of 2007 Require postmarketing studies and clinical trials Require sponsors to make safety related labeling changes Require sponsors to develop and comply with risk evaluation and mitigation strategies (REMS) Establish active surveillance system for 25 million people by 2010 and 100 million by FDA Sentinel Network 15

16 Vision for Post-Market Safety Monitoring All patients biologic product exposures 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 16

17 Post-Market Safety Monitoring: 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 17

18 Post-Market Safety Monitoring: Opportunities Access to additional health systems data Access to global data: regulatory, inspectional, health systems, international safety monitoring, including epidemiological investigation Better analytic tools and methods 18

19 Communications and Transparency Respect and autonomy of patients should be a guiding principle 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 19

20 Case Study: 2009 Pandemic H1N1 Influenza Vaccine New strain, monovalent vaccine Large numbers of vaccinees expected Heightened public attention Expected increase in adverse event reporting, regardless of causal association to vaccination Expectation for robust safety monitoring Need for adaptable toolbox 20

21 2009 Pandemic H1N1 Influenza Vaccine Safety Monitoring Strategy Federal government coordination provided by National Vaccine Program Office Independent safety oversight provided by working group of National Vaccine Advisory Committee ( 21

22 2009 Pandemic H1N1 Influenza Vaccine Safety Monitoring Strategy (cont.) Enhanced/more timely pharmacovigilance tools Signal detection (passive surveillance systems) Signal strengthening and confirmation Rapid cycle analysis (RCA) statistical methods accounting for multiple sequential analyses of cumulative data in near real-time Increased communication/collaboration among U.S. agencies and internationally Methods Sharing of preliminary safety surveillance results Signal validation and confirmation of potential associations 22

23 Summary Although rare, vaccines have real risks that may include serious adverse effects A strong post-marketing safety evaluation system is needed: Founded on pre-marketing safety evaluation and manufacturing process control Rooted in surveillance and controlled epidemiological studies Extended to include clinical and laboratory (including genomic) study of etiology, prevention, and management Government agencies, both regulatory and scientific, play an important role in monitoring, analyzing, and communicating the safety of vaccines 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 Need for collaboration Too big for any single agency, company or country 23

Responding to Vaccine Safety Events

Responding to Vaccine Safety Events Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Conference Berne, Switzerland September 19, 2008 1 Vision for CBER INNOVATIVE