Transcript Document 7126117

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
FDA
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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

FDA
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Office of Drug Safety in CDER
CDER Director
Janet Woodcock, M.D.
Office of New Drugs
John Jenkins, M.D.
Office of Pharmaceutical Sciences
Helen Winkle
Office of Training & Communication
Nancy Smith, Ph.D.
Office of Information Technology
Office of Management
Russ Abbott
Office of Medical Policy
Robert Temple, MD
Office of Compliance
David Horowitz
Office of Pharmacoepidemiology& Statistical Science
Paul Seligman, MD
Office of Drug Safety
Victor Raczkowski, MD
Robert O'Neill, PhD
Office of Biostatistics
Office of Regulatory Policy
Jane Axelrad
FDA
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Office of Drug Safety
Office of Drug Safety (ODS)
Director: Victor Raczkowski, MD
Division of Drug Risk Evaluation (DDRE)
Director: Julie Beitz, MD
Division of Medication Errors &
Technical Support (DMETS)
Acting Director: Jerry Phillips
Division of Surveillance, Research, &
Communication Support (DSRCS)
Director: Anne Trontell, MD
FDA
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Overall ODS Organization
Supports 15 OND Review Divisions
 Currently 95 Staff members
 Safety Evaluators

 Clinical

Epidemiologists
 Clinical

Pharmacists, Physicians
Epidemiologists (MD, MPHs), PhDs
Functional pool with specialty expertise
 Social
scientists
 Project Managers
 IT support
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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
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Beyond ApprovalPostmarketing 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
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1962 Harris-Kefauver
Amendments to FD&C Act
Adverse Event Reporting
 Proof of Efficacy
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Current Regulations on Safety Reporting
21 CFR 312.32 - IND safety reports
 310.304 - “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
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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
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What Manufacturers Must Report
(21CFR 314.80)
Commercial marketing experience
 Postmarketing studies
 Scientific literature
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All domestic spontaneous reports
Foreign and literature reports - Serious,
Unlabeled
Study reports - Serious, Unlabeled, "Reasonable
Possibility" that event is related to drug
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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
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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
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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
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AERS Report Counts by Type:
1990 through 2001
300000
250000
200000
Direct
15-day
Periodic
150000
100000
50000
0
90 991 992 993 994 995 996 997 998 999 000 001
9
1
1
1
1
1
1
1
1
1
1
2
2
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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
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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
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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
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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
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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
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Evaluation of Reports

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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
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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
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Drug Safety Assessment

In addition to signal generation, the office
responds to consult requests from OND
review divisions, CDER, FDA, outside:
 Congress,
GAO, DHHS, FBI, CPSC, foreign
regulatory authorities
Develop risk management programs
 Advisory committee involvement:

 e.g.,
PPA, COX-2, non-sedating antihistamines
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Communicating Safety
Information Within the FDA
Maintain informal communication and
collaborative efforts with Review Divisions
 Pre-approval Safety Conferences (PSC)
 Regular Safety Conferences
 Written communication

 Summary
analysis and assessment of specific
safety issue or overall safety review of a drug

Advisory Committee Meetings
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Regulatory Actions/Risk Management
Labeling changes- ADR, Precautions,
Warnings sections
 Restricted use, registry, special monitoring
 Evaluate the effectiveness of the risk
management program
 Withdrawal from market
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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
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