Overview of Postmarketing Safety Surveillance in FDA
(For Drugs and Biologics)

Min Chen, M.S., R.Ph.

Associate Director

Division of Drug Risk Evaluation

Office of Drug Safety

CDER

Outline

Office of Drug Safety Organization

Postmarketing Reporting Regulations

Adverse Event Reporting System (AERS)

Evaluation of Reports and Assessment of Safety Issues

Regulatory Actions and Risk Management for Safety Issues

Office of Drug Safety in CDER

Office of Drug Safety

Overall ODS Organization

Supports 15 OND Review Divisions

Currently 95 Staff members

Safety Evaluators

Clinical Pharmacists, Physicians

Epidemiologists

Clinical Epidemiologists (MD, MPHs), PhDs

Functional pool with specialty expertise

Social scientists

Project Managers

IT support

Why Postmarketing?
Limitations of Premarketing Clinical Trials

Size of the patient population studied

Narrow population - often not providing for special groups

Elderly, children, women

Narrow indications studied

Exclusion of certain disease states

Short duration

Not reflective of a drug’s potential chronic use

Beyond Approval-
Postmarketing Monitoring

Low frequency reactions (not identified in clinical trials)

High risk groups

Long-term effects

Drug-drug/food interactions

Increased severity and / or frequency of known reactions

1962 Harris-Kefauver Amendments to FD&C Act

Adverse Event Reporting

Proof of Efficacy

Current Regulations on Safety Reporting

21 CFR 312.32 - IND safety reports

310.305 - “Grandfathered” drugs (pre-1938)

314.80 - Postmarketing Rx drugs - NDA

314.98 - Generic drugs - ANDA

600.80 - Biologics

OTC drugs - No reporting requirement unless drug was approved under NDA

Dietary supplement and food - voluntary reporting

Source of Reports

Voluntary/spontaneous reporting

Health care professionals, consumers/ patients, or others

Manufacturers: Required for postmarketing reporting (>90%)

All adverse drug experience information obtained or otherwise received from any source, foreign or domestic

What Manufacturers Must Report (21CFR 314.80)

Commercial marketing experience

Postmarketing studies

Scientific literature

All domestic spontaneous reports

Foreign and literature reports - Serious, Unlabeled

Study reports - Serious, Unlabeled, "Reasonable Possibility" that event is related to drug

Regulatory Definition of Serious
(21 CFR 314.80)

Death

Life-threatening

Hospitalization (initial or prolonged)

Persistent or significant disability

Congenital anomaly

Important medical events that may jeopardize the patient and may require medical or surgical intervention to prevent one of the above outcomes

AERS Report Counts by Type:
1990 through 2001

Factors Affecting Reporting

Nature of the Adverse event

Type of drug product and indication

Rx or OTC drug status

Length of time on market

Public or media attention

Extent and quality of manufacturer’s surveillance system

Limitations of Spontaneous Reports

Passive surveillance

Underreporting occurs and is variable from drug to drug and over time

Reporting bias exists

Quality of the reports is variable and often incomplete

Cannot reliably estimate rates of events

Numerator uncertain

Denominator can only be projected

Adverse Event Reporting System (AERS)

Database of spontaneous reports established in 1969 and restructured in 1997 with greater capacity to:

Accommodate internationally accepted E2B data format

Adopt internationally accepted MedDRA coding terminology for adverse events and indications

Allow electronic transmission using international standard

AERS Process Flow

Contractors:

All MedWatch reports scanned into images

Full text data entered (E2B format)

AEs and indications coded in MedDRA at Preferred Term level

Safety Evaluators:

Receive and review reports in “Inbox” for 15-day & direct reports

Screen and monitor potential signals

Review division: Access thru AERS Datamart

Electronic submission: MFR reports directly via gateway

ODS Safety Evaluators

Main mission: To identify and assess previously unrecognized (unlabeled) and serious adverse drug events

Hands-on daily review of all 15-day and direct reports, monitor any safety issues including known adverse events

Most intensive monitoring over first several years but continued over the drug's lifetime

Elements of a "Good" Report:

Contains complete data

Suspect drug therapy dates

Concomitant drug(s) therapy dates

Patient medical history

Patient's baseline status documented

Confirmed diagnosis of the event/disease

Temporal relationship to drug may be established

Including dechallenge / rechallenge

Signal Generation

One or more good case reports from AERS, literature publication or other sources can trigger further evaluation of a potential safety signal

Monitoring of AERS crude data from the frequency of PT and other higher level grouping case counts may indicate emerging signals

Evaluation of Reports

One very good case or case series reviewed collectively - follow up if needed

Establish temporal relationship at case level

Establish case definition whenever feasible

Look for trends and patterns of events - age, sex, time to onset, dose, severity, outcome

Identify risk factors

Evaluate strength of evidence for causal relationship between drug and event

Assess clinical significance of the issue

Epidemiologic Assessment of Selected Safety Issues

Reporting rates vs. background incidence rates-

Drug utilization data and literature

Query large databases

Cooperative agreements

Medicaid, large health plans, etc.

Active surveillance methods under evaluation- looking for drug-related adverse events in a prospective fashion

Drug Safety Assessment

In addition to signal generation, the office responds to consult requests from OND review divisions, CDER, FDA, there are interests from :

Congress, HHS, FBI, CPSC, DEA, foreign regulatory authorities

Develop risk management programs

Advisory Committee Meetings:

e.g., PPA, COX-2, non-sedating antihistamines

Communicating Safety Information Within the FDA

Maintain informal communication and collaborative efforts with Review Divisions and Office of Pediatric Therapeutics

Pre-approval Safety Conferences

Regular Safety Conferences

Advisory Committee Meetings

Written communication

Summary analysis and assessment of specific safety issue or overall safety review of a drug

Regulatory Actions/Risk Management Recommendation to Review Division

Labeling changes- Adverse Reactions, Precautions, and Warnings sections

Restricted use, registry, special monitoring

Evaluate the effectiveness of the risk management program

Withdrawal from market

Risk Communication

Physician and patient labeling, MedGuide

"Dear Doctor" letter (for specific warnings), FDA Talk Papers and Public Health Advisories, publications

FDA MedWatch website posting of all safety related information (http://www.fda.gov/medwatch)

The Mission of Office of Drug Safety is to provide pharmaacovigilance and epidemiologic resources to CDER to ensure the safety of marketed drug products.

Division of Drug Risk Evaluation evaluates the safety of marketed drugs,w e review and monitor the adverse event reports, bring up safety concerns, perform epidemiology assessment, and recommend appropriate actions including risk management programs.

DMETS evaluates and provides recommendations on proprietary names, identifies error-prone aspects of labels, labeling & packaging of drug products from a safety perspective to minimize medication errors, and reviews postmarketing medication error reports to prevent further errors.

DSRCS reviews Medication Guides & patient labeling, consults on drug utilization databases, oversees the MedWatch program, and handles data resources, risk communication, outcome/effectiveness research components of drug safety related risk management programs.

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Risk communication activities involve patient labeling,patient package inserts, and MedGuide development to inform the consumers and health care professionals for specific safety concerns. For those products posing a serious and significant public health concern, patient labeling could help prevent serious adverse effects.

MedWatch outreach program will notify safety alerts and updates to health care professional organizations and subscribers

FDA

New Reviewer Course 6/17/96

Overview of Functions of Division of Pharmacovigilence and Epid

Added slides to existing presentation from TPH Regulatory Science Course

Carol Pamer

1996-11-21T09:02:32