1. DEVELOPING EVIDENCE ON VACCINE SAFETY Susan S. Ellenberg, Ph.D. Center for Clinical Epidemiology and Biostatistics U Penn School of Medicine Global Vaccines 202X: Access, Equity, Ethics Philadelphia, PA May 2, 2011 CCEB

2. 2 THE NEED FOR EVIDENCE  Primary need Virtually everyone will be exposed to vaccines Essential to ensure that they are safe!  Secondary need Vaccination is a critical component of public health protection Public concern about vaccine safety may lead to reduced coverage and ensuing re- emergence of vaccine-preventable diseases 2

3. 3 3 THE PROBLEM  Given the universal exposure to vaccines, particularly in high-risk populations such as infants, some serious medical events will occur coincidentally after vaccination  Usually impossible to ascertain likelihood of causal connection with vaccine

4. 4 HOW DO WE “DETECT” A RISK?  In some cases where biological plausibility is extremely strong, observing even a single case can establish a causal relationship Vaccine-strain polio Anaphylaxis occurring shortly after vaccination  For common adverse events that also occur in background, controlled trials of moderate size can show whether event is more likely to occur after vaccination Fever Extended crying 4

5. 5 MORE DIFFICULT  Less common events that also occur in background Autism SIDS Asthma  Observing a case post-vaccination cannot establish causality  Connecting increases in events over time to introduction of new vaccines is problematic Ignores changes in diagnostic patterns Ignores other environmental changes 5

6. 6 APPROACHES TO STUDYING SAFETY OF MEDICAL TREATMENTS  Formal studies Randomized controlled trial Observational study of those using treatment Case-control study (rare events)  Studying vaccine-outcome associations in existing cohorts Claims data bases Large research cohorts with ongoing follow-up  Monitoring spontaneous reports to FDA and/or product manufacturer

7. 7 PRE-MARKETING VACCINE STUDIES  Strong focus on safety outcomes in pre-market trials  Size of studies generally determined by efficacy outcome  Common acute adverse events (occurring at rates of up to 1/100) well understood by end of pre-marketing program Fever Swelling at injection site Fussiness

8. 8 EVIDENCE FROM PRE-MARKET CONTROLLED STUDIES  Size of pre-market studies typically based on establishing protection against disease  Sample sizes of pre-market controlled studies vary widely Varicella vaccine: 956 Pneumococcal conjugate: 38,000 HPV: 20,000 (4 trials) Meningococcal conjugate: 6700 (3 trials) 8

9. 9 WHAT WE DON’T KNOW AT THE TIME OF VACCINE APPROVAL  Whether less common serious events might be associated with vaccine  Whether serious adverse outcomes with delayed onset might be associated with vaccine 9

10. 10 WHAT NEXT?  Rarely is there reason to suspect that vaccine might cause such outcomes  Still important to get more information about safety after licensure  Primary post-marketing approaches Passive surveillance: spontaneous reporting Active surveillance: post-market studies or registries In between: use of records in claims databases 10

11. 11 SPONTANEOUS REPORTING  Possible side effect may be observed by patient and/or physician  Effect may be known (ie, already mentioned in label) or unknown  Physician or patient may report event to FDA (or to vaccine manufacturer, which is then required to convey report to FDA)

12. 12 VACCINE ADVERSE EVENT REPORTING SYSTEM (VAERS)  Historically the primary focus of vaccine safety surveillance efforts  The worst type of data base imaginable No numerator—reporting is voluntary, and no evidence except (perceived) temporal association that drug caused event No denominator—don’t know how many were exposed No quality control—all reports submitted get put in data base “as is” Subject to influence by publicity  Utility: relatively inexpensive to run, national coverage, can generate useful signals

13. 13 ACTIVE SURVEILLANCE  Post-marketing observational studies conducted by manufacturer  Each person vaccinated followed for occurrence of adverse events  Can establish incidence rates of vaccine- related events more reliably  Can in principle generate signals of possible concern but causality still difficult to establish without controls 13

14. 14 HEALTH CARE DATABASES  Advantages Data already collected for financial purposes Definable numerators and denominators Data available over time  Limitations Medical information restricted; chart review often required Little information on outpatient events (including deaths) Difficult to control for “confounding by indication” – those who get a treatment may be different from those who don’t

15. 15 VACCINE SAFETY DATALINK  Consortium of MCO databases funded by CDC to perform investigations into vaccine safety issues  Total population of nearly 9 million  Continuing enhancement of capabilities Studies of events arising from VAERS signals or public concerns Real-time monitoring of events of possible concern based on pre-market data or emerging VAERS signals 15

16. 16 RESEARCH COHORT  National Children’s Study will identify and follow 100,000 children from gestation through age 21  Detailed information on genetic characteristics, exposures and health outcomes will be collected  Possible that this cohort may ultimately provide useful data on vaccine effects, depending on available resources 16

17. 17 LOOKING TO THE FUTURE  Critical to have reliable data on vaccine safety Exposure of large and healthy populations Need to ensure acceptability of immunization  Most reliable data will come from randomized controlled trials; these should be large but can never be large enough to detect all rare events  Public concerns about safety are unlikely to diminish  More attention and resources are needed to improve our understanding of vaccine effects, and to communicate the data effectively 17

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