1. FDA1 Overview of Postmarketing Safety Surveillance in FDA (For Drugs and Biologics) Min Chen, M.S., R.Ph. Min Chen, M.S., R.Ph. Associate Director Division of Drug Risk Evaluation Office of Drug Safety CDER

2. FDA2 Outline n Office of Drug Safety Organization n Postmarketing Reporting Regulations n Adverse Event Reporting System (AERS) n Evaluation of Reports and Assessment of Safety Issues n Regulatory Actions and Risk Management for Safety Issues

3. FDA3 Office of Drug Safety in CDER

4. FDA4 Office of Drug Safety

5. FDA5 Overall ODS Organization n Supports 15 OND Review Divisions n Currently 95 Staff members n Safety Evaluators u Clinical Pharmacists, Physicians n Epidemiologists u Clinical Epidemiologists (MD, MPHs), PhDs n Functional pool with specialty expertise u Social scientists u Project Managers u IT support

6. FDA6 Why Postmarketing? Limitations of Premarketing Clinical Trials n Size of the patient population studied n Narrow population - often not providing for special groups u Elderly, children, women n Narrow indications studied u Exclusion of certain disease states n Short duration u Not reflective of a drug’s potential chronic use

7. FDA7 Beyond Approval- Postmarketing Monitoring n Low frequency reactions (not identified in clinical trials) n High risk groups n Long-term effects n Drug-drug/food interactions n Increased severity and / or frequency of known reactions

8. FDA8 1962 Harris-Kefauver Amendments to FD&C Act n Adverse Event Reporting n Proof of Efficacy

9. FDA9 Current Regulations on Safety Reporting n 21 CFR 312.32 - IND safety reports n 310.304 - “Grandfathered” drugs (pre-1938) n 314.80 - Postmarketing Rx drugs - NDA n 314.98 - Generic drugs - ANDA n 600.80 - Biologics n OTC drugs - No reporting requirement unless drug was approved under NDA n Dietary supplement and food - voluntary reporting

10. FDA10 Source of Reports n Voluntary/spontaneous reporting n Health care professionals, consumers/ patients, or others n Manufacturers: Required for postmarketing reporting (>90%) u All adverse drug experience information obtained or otherwise received from any source, foreign or domestic

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12. FDA12 What Manufacturers Must Report (21CFR 314.80) n Commercial marketing experience n Postmarketing studies n Scientific literature n All domestic spontaneous reports n Foreign and literature reports - Serious, Unlabeled n Study reports - Serious, Unlabeled, "Reasonable Possibility" that event is related to drug

13. FDA13 Regulatory Definition of Serious (21 CFR 314.80) n Death n Life-threatening n Hospitalization (initial or prolonged) n Persistent or significant disability n Congenital anomaly n Important medical events that may jeopardize the patient and may require medical or surgical intervention to prevent one of the above outcomes

14. FDA14 Factors Affecting Reporting n Nature of the Adverse event n Type of drug product and indication n Rx or OTC drug status n Length of time on market n Public or media attention n Extent and quality of manufacturer’s surveillance system

15. FDA15 Limitations of Spontaneous Reports n Passive surveillance u Underreporting occurs and is variable from drug to drug and over time n Reporting bias exists n Quality of the reports is variable and often incomplete n Cannot reliably estimate rates of events u Numerator uncertain u Denominator can only be projected

16. FDA16 AERS Report Counts by Type: 1990 through 2001

17. FDA17 Adverse Event Reporting System (AERS) n Database of spontaneous reports established in 1969 and restructured in 1997 with greater capacity to: u Accommodate internationally accepted E2B data format u Adopt internationally accepted MedDRA coding terminology for adverse events and indications u Allow electronic transmission using international standard

18. FDA18 AERS Process Flow n Contractors: u All MedWatch reports scanned into images u Full text data entered (E2B format) u AEs and indications coded in MedDRA at Preferred Term level n Safety Evaluators: u Receive and review reports in “Inbox” for 15-day & direct reports u Screen and monitor potential signals n Review division: Access thru AERS Datamart n Electronic submission: MFR reports directly via gateway

19. FDA19 ODS Safety Evaluators n Main mission: To identify and assess previously unrecognized (unlabeled) and serious adverse drug events n Hands-on daily review of all 15-day and direct reports, monitor any safety issues including known adverse events n Most intensive monitoring over first several years but continued over the drug's lifetime

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22. FDA22 Elements of a "Good" Report: n Contains complete data u Suspect drug therapy dates u Concomitant drug(s) therapy dates u Patient medical history u Patient's baseline status documented u Confirmed diagnosis of the event/disease n Temporal relationship to drug may be established u Including dechallenge / rechallenge

23. FDA23 Signal Generation n One or more good case reports from AERS, literature publication or other sources can trigger further evaluation of a potential safety signal n Monitoring of AERS crude data from the frequency of PT and other higher level grouping case counts may indicate emerging signals

24. FDA24 Evaluation of Reports n One very good case or case series reviewed collectively - follow up if needed n Establish temporal relationship at case level n Establish case definition whenever feasible n Look for trends and patterns of events - age, sex, time to onset, dose, severity, outcome n Identify risk factors n Evaluate strength of evidence for causal relationship between drug and event n Assess clinical significance of the issue

25. FDA25 Epidemiologic Assessment of Selected Safety Issues n Reporting rates vs. background incidence rates- u Drug utilization data and literature n Query large databases u Cooperative agreements u Medicaid, large health plans, etc. n Active surveillance methods under evaluation- looking for drug-related adverse events in a prospective fashion

26. FDA26 Drug Safety Assessment n In addition to signal generation, the office responds to consult requests from OND review divisions, CDER, FDA, outside: u Congress, GAO, DHHS, FBI, CPSC, foreign regulatory authorities n Develop risk management programs n Advisory committee involvement: u e.g., PPA, COX-2, non-sedating antihistamines

27. FDA27 Communicating Safety Information Within the FDA n Maintain informal communication and collaborative efforts with Review Divisions n Pre-approval Safety Conferences (PSC) n Regular Safety Conferences n Written communication u Summary analysis and assessment of specific safety issue or overall safety review of a drug n Advisory Committee Meetings

28. FDA28 Regulatory Actions/Risk Management n Labeling changes- ADR, Precautions, Warnings sections n Restricted use, registry, special monitoring n Evaluate the effectiveness of the risk management program n Withdrawal from market

29. FDA29 Risk Communication n Physician and patient labeling, MedGuide n "Dear Doctor" letter (for specific warnings), FDA Talk Papers and Public Health Advisories, publications n FDA MedWatch website posting

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