Postmarketing Pharmacovigilance

Practice at FDA

Lanh Green, Pharm.D., M.P.H.Office of Surveillance and Epidemiology

June 21, 2006

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ObjectivesParticipants 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

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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)

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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)

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Serious Adverse Event (21 CFR 314.80)

• Death

• Life-threatening

• Hospitalization (initial or prolonged)• Disability• Congenital anomaly• Important medical events

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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

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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)

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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

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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

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AERS Report Counts by Type: 1990 through 2005

050000100000150000200000250000300000350000400000450000500000

1990 1992 1994 1996 1998 2000 2002 2004

Direct15-dayPeriodic

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Questions?

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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