1. Postmarketing Risk Assessment of Drug Products Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research

2. 2 Office of Drug Safety

3. 3 DDRE: Division Mission Detect and assess drug safety signals Conduct epidemiological analyses Provide consultation on drug safety questions Disseminate important drug safety information Formulate risk management programs

4. 4 Postmarketing Risk Assessment: Why? At the time of marketing approval, clinical trial data are available on limited numbers of patients for relatively short periods At-risk patients and use of selected concomitant meds are often not studied Detection of rare adverse events (AEs) is difficult if not impossible

5. 5 Postmarketing Risk Assessment: Why? After marketing, new information on drug safety becomes available –Domestic use of the product –Experience in other countries New safety information may be generated on other drugs in the same class Benefit-risk profile of approved drugs is continually assessed throughout the life of the drug

6. 6 Postmarketing Risk Assessment: Goals Detect drug safety signals or hypotheses about drug-AE associations –Does a risk exist? Assess the magnitude of the risk –Patient Outcomes serious? reversible? –Population Are there specific populations at increased risk? Reduce the risk of drug toxicity to enhance safe use

7. 7 Postmarketing Risk Assessment: Tools Case Reports, Case Series –Useful for detecting rare AEs and potential host risk factors –Spontaneously reported; medical literature Epidemiological Studies –Useful for evaluating signals from case reports and for quantifying RRs associated with specific drug exposures Randomized Clinical Trials –Useful for exploring causal relationships

8. 8 Adverse Event Reports System: AERS Voluntary reporting system Manufacturers submit > 90% of reports –21 CFR 314.80 –All domestic adverse drug experiences whether or not considered drug related –Foreign reports and scientific literature Only serious & unlabeled –Post-marketing studies Only serious & unlabeled and “reasonable possibility that the drug caused the adverse experience”

9. 9 Adverse Event Reports System: AERS Contains nearly 3 million adverse event reports Trends over the last decade –Increasing number of reports –Increasing number of 15-day expedited reports –Direct reports: ~ 5 - 10% per year –Reports related to OTC drugs: ~ 5 - 10% per year

10. 10 AERS Report Counts by Type: 1990 - 2001

11. 11 Assessment of Spontaneous Reports Individual case assessment –Reporter follow-up, as needed –Temporal association –Time of onset –Effect of dechallenge / rechallenge –Presence of alternative explanations (e.g., concomitant meds, coexistent disease) –Clinical features may distinguish AE from underlying disease

12. 12 Assessment of Spontaneous Reports Individual cases are included in a case series and assessed in the context of –Literature case reports –Current product labeling –Drug usage estimates –Background incidence rates, if available There is no “threshold” number of cases needed to signal a safety concern

13. 13 Spontaneous Reporting System: Limitations Number of exposed patients unknown –Spontaneous reports cannot be used to determine incidence rates of adverse events Information often incomplete Under-reporting Reporting biases

14. 14 Factors Affecting Reporting Nature of the event Length of time drug is on the market Market share Publicity Quality of manufacturer’s surveillance systems Reporting regulations

15. Spontaneous Reports are Not Enough!

16. 16 Assessment of Other Evidence Epidemiologic evidence –Studies in claims databases –Prospective observational studies Pharmacologic effects of the drug Results of pre-clinical animal testing Evidence from randomized clinical trials

17. 17 Postmarketing Risk Assessment: What can we learn*? Changes in labeled events –severity, outcomes, susceptible populations Serious and as yet unlabeled events Drug-drug interactions Experience with overdose, drug abuse or misuse *ICH Guideline on Clinical Safety Data Management, May 19, 1997

18. 18 Postmarketing Risk Assessment: What can we learn*? Experience in pregnancy, lactation Experience in special patient populations –children, elderly, organ impaired Effects of long-term exposure *ICH Guideline on Clinical Safety Data Management, May 19, 1997

19. 19 Putting it All Together Signals from spontaneous reports may support signals from studies Signals from spontaneous reports may be missed or be unassessable –Confounding variables, lack of information –Under-reporting results in reporting rates below background rates

20. 20 Putting it All Together Absence or small numbers of spontaneous reports will not refute a signal generated from other sources

21. 21 The Way Forward Safety data in accord with labeling? –Continue to monitor spontaneous reports New safety data identified? –Labeling revisions to highlight new concerns, susceptible populations? –Additional studies to test hypotheses? –What constitutes rational risk management while new data are generated?