Overview of Postmarketing Safety Surveillance in FDA For Drugs and Biologics

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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

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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

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Office of Drug Safety in CDER
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Office of Drug Safety
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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

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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 drugs potential chronic use

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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

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1962 Harris-Kefauver Amendments to FDC 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 (gt90)
• 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
• 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 manufacturers 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
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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

• 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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