1. Postmarketing Pharmacovigilance Practice at FDA Lanh Green, Pharm.D., M.P.H. Office of Surveillance and Epidemiology June 21, 2006

2. 2 Objectives Participants will gain knowledge on: Postmarketing Safety Reporting Regulation and Guidance Suspected Adverse Drug Reaction (SADR) Proposed Rule Adverse Event Reporting System (AERS) Pharmacovigilance Practice at FDA

3. 3 Office of Surveillance and Epidemiology (OSE) Mission: To evaluate product risks and promote the safe use of products by the American people Three Divisions Within OSE: Division of Drug Risk Evaluation (DDRE) Division of Medication Errors and Technical Support (DMETS) Division of Surveillance, Research and Communication Support (DSRCS)

4. 4 Regulations 310.305 - “Grandfathered” drugs (pre-1938) 314.80 - Postmarketing drugs 314.98- Generic drugs 600.80- Biologics No reporting requirements for OTC drugs except for: NDA-switched OTC products Timed release dosage forms 21 CFR §310.502(a)(14)

5. 5 Serious Adverse Event (21 CFR 314.80) Death Life-threatening Hospitalization (initial or prolonged) Disability Congenital anomaly Important medical events

6. 6 SADR Proposed Rule Codify ICH-developed guidelines toward global harmonization Increase quality of reports Include medication errors Timely acquisition, evaluation and submission of safety information to promote public health

7. 7 Adverse Event Reporting System (AERS) Database originated in 1969 (SRS) AERS implemented in Nov 1997 Reports from Spontaneous Reporting System (SRS) migrated with mapping of COSTART to MedDRA More structured data, more detailed coding terminology, and greater capacity Electronic submissions (E2BM)

8. 8 Type of Reports Manufacturer Reports (mandatory): ~94% of reports –Health care professional, consumer, and literature 15-day reports - Foreign and domestic, serious and unexpected (unlabeled) Periodic reports - Quarterly for 3 years from approval, then annually Direct Reports (voluntary): ~6% of reports –Health care professionals and consumers

9. 9 Limitations of Spontaneous Reports Passive surveillance system Under-reporting exists Quality of the reports is variable/incomplete Duplicate reporting occurs Incidence rate cannot be determined Numerator is uncertain Denominator can only be projected

10. 10 AERS Report Counts by Type: 1990 through 2005

11. 11 Pharmacovigilance Practice Applies to postmarketing activities Involves all activities relating to monitoring of product safety Collection Detection Assessment of adverse effects or risks of products

12. 12 Elements of AE Report Details of adverse event (AE) Baseline patient status (age, co-morbid conditions, concomitant medications, risk factors) Therapy details (dose, dates/duration of use) Temporal relationship to drug Dechallenge and rechallenge information Method of diagnosis of AE Clinical course of AE including outcomes Lab results at baseline and during event

13. 13 Safety Evaluator Report Review Main mission: To identify and assess previously unrecognized (unlabeled) serious adverse events Hands-on daily review of all 15-day and direct reports, monitors any safety issues including known adverse events Most intensive monitoring over first several years New Molecular Entities (NMEs) but continued over the drug's lifetime

14. 14 Principles of Case Evaluation Disease occurrence in expected time Absence of symptoms prior to exposure Positive dechallenge or rechallenge Consistent with pharmacological effects Consistent with known effects in the class Event identified in clinical trials Absence of alternative explanations

15. 15 Safety Signals New unlabeled adverse events An observed increase in a labeled event in its severity or specificity New drug or food interactions Newly identified at-risk population

16. 16 Identifying Safety Signals Depends on Good Reporting Practice to acquire quality case information to perform case-level review or case-series Acquire complete information during initial contacts and subsequent follow up Entail a focused line of questioning

17. 17 Evaluating Potential Signals Safety issue of interest identified AERS search for related cases Use of MedDRA-cases coded at PT level Customize search (broad or narrow) as appropriate; can combine various MedDRA terms/levels into one search Case definition established; cases reviewed Additional cases: Literature, WHO, foreign regulators

18. 18 Data Mining Compares observed frequency of reports for specific drug/event combination to expected frequency of reports for that AE in entire AERS database (Empirical Baysian scores ≥ 2 worthy of investigation) Provides additional support to the case report evaluation and other safety information

19. 19 Epidemiologic Analysis Reporting Rates = cases/estimated usage (e.g., dispensed prescriptions) Comparison with background rates Comparison to drugs within the same class Comparison to drugs for similar indication Interpretation difficult to make Additional study in longitudinal databases Cooperative Agreements Review and analysis of Phase IV studies

20. 20 Communication Within CDER Open communication and collaboration with Office of New Drug (OND) and Office of Compliance Pre-approval Safety Conferences Safety Conferences with OND Safety question response– formal consult, e-mail, or in person Written communication – summary and analysis Assistance in decision-making process for safety- related regulatory action

21. 21 Potential Regulatory Action Labeling change "Dear Health Care Professional" letter Risk management plan/program –Targeted Education and Outreach –Reminder Systems –Fail-Safe Systems Product withdrawal

22. 22 Guidance for Industry Risk Assessment (premarketing) http://www.fda.gov/cder/guidance/6357fnl.htm Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (postmarketing) http://www.fda.gov/cder/guidance/6359.OCC.htm

23. 23 Websites Office of Surveillance and Epidemiology http://www.fda.gov/cder/offices/ods/default.htm Adverse Event Reporting System http://www.fda.gov/cder/aers/default.htm –Reporting Regulations –Guidances –Updates

24. 24 Questions?

25. 25 Objectives Participants are knowledgeable with: Postmarketing Safety Reporting Regulation and Guidance Suspected Adverse Drug Reaction (SADR) Proposed Rule Adverse Event Reporting System (AERS) Pharmacovigilance Practice at FDA