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POSTMARKETING
ADVERSE DRUG EXPERIENCE
INSPECTIONAL PROGRAM
CDR Thomas R. Berry, RPh
FDA, Investigator
RAL-RP / ATL-DO
PADE Inspectional Program
 Headquarters scientists use adverse event
reports to evaluate the safety of marketed
drugs
 OC/ADE Team coordinates between
regulatory, investigational, and scientific staff
 Field investigators assure industry
compliance with reporting regulations
Clinical Safety of Drugs
Office of
Medical Policy
Office of New
Drugs
Office of the Center Director
Center for Drug Evaluation and Research
(CDER)
Office of Pharmacoepidemiology
and Statistical Science (OPaSS)
Office of Drug
Evaluation I
Office of
Biostatistics
Office of
Drug Safety
Ten Additional
Offices with
Functions Related
to Regulation of
Investigational and
Marketed
Drugs/Biologics
Office of Drug
Evaluation II
Office of Drug
Evaluation III
Office of Drug
Evaluation V
Office of Drug
Evaluation IV
Office of Drug
Evaluation VI
Division of
Drug Risk
Evaluation
Division of
Medication Errors
and Technical
Support
Division of
Surveillance,
Research and
Communication
~100 colleagues focus on pharmacovigilance
activities for marketed drug products
The Safety Report Flow in CDER
Safety Reports
Voluntary Reports
Manufacturer Reports
MedWatch
Central Triage Unit
Central Document Room
AERS
eSubs
ODS
FDA Adverse Event
Reporting System Database
• Database Origin 1969
• 3 million reports in database
• Contains Drug , Therapeutic Biologic and
Therapeutic Blood Reports
• exception = vaccines
VAERS 1-800-822-7967
Source of Individual Safety Reports for
AERS
Reports from manufacturers to FDA
> 90% of all reports
FDA database
“AERS”
Reports to FDA directly from individuals
<10% of all reports (“direct”)
Purpose of ADE Regulations
 To obtain additional information on adverse
events that may not have been detected prior
to marketing
 To improve the labeling of drug products
Reporting Regulations
 21 CFR Sections
 310.305 – Rx drugs not subject to approved applications
“Grandfathered” drugs that were marketed pre-1938
 314.80 – Rx drugs subject to NDAs/ANDAs and OTCs
associated with approved applications (Marketed Drugs)
 314.98 – Rx drugs subject to ANDAs (Generic Drugs)
 Compliance Program Guideline 7353.001
09/30/99
 Guidance for Industry – Postmarketing Safety Reporting
for Human Drug and Biological Products including
Vaccines
March 2001
Adverse Drug Experience
 Any adverse event associated with the use
of drugs in humans whether or not it is
considered drug related
Serious Adverse Drug Experience
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Death
Life threatening (per initial reporter)
Permanently or significantly disabling
Hospitalization
Congenital anomaly / birth defect
Important medical event
Unexpected Adverse Drug Event
 Not listed in current labeling
 Listed in labeling but greater specificity
or severity
renal impairment listed, patient experiences
renal failure
Reporting Requirements
 Within 15 calendar days if serious and
unexpected (domestic and foreign)
 Follow-up information
 Non-applicant notifies applicant within
five calendar days
Regulatory Start Clock
 First day a firm or any affiliate receives
event data containing all four elements:
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An identifiable patient
An identifiable reporter
A suspect drug
An adverse event or fatal outcome
Reporting Forms
 3500A (MedWatch Form)
 Council for International Organization of
Medical Science (CIOMS I Foreign)
 Other form if approved by FDA in advance
Literature Searches
 The 15-day reporting requirements apply
only to reports found in scientific and
medical journals either as case reports or
as the result of a formal clinical trial.
 Form 3500A (MedWatch)
 Copy of the published article
Periodic Reports
 Quarterly and Annual Reports
 Quarterly for the first 3 years, then annually
 Usually based on the date the NDA/ANDA
was approved
 Serious and Expected ADEs
 All Non-serious ADEs
Recordkeeping
 Maintain for 10 years - Records of all
adverse drug experiences
 Raw Data
 Any correspondence relating to adverse drug
experiences
Role of the Investigator
 To verify through on-site visits that firms are
submitting all required reports of adverse
events to FDA and the reports are complete,
accurate and timely
 Document violations to support appropriate
regulatory action
We are looking for …
 Outcomes to identify problem areas for
inspectional coverage
 What system failure(s) caused the firm not
to comply with the regulations
 Patterns and trends
Source Documents
 SOPs – should specify control for all
functions and duties for the surveillance,
receipt, evaluation and reporting of
ADEs to the FDA.
 Call log
 Complaint logs
 Contracts for PADE services
 Training
Note Discrepancies
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Omissions
Minimizing results
Lack of Drug Effectiveness
Potential Product Complaints
Lack of follow-up
Inadequate follow-up
If reports are found …
 Determine the nature of the event and the
cause for failure to report
 Determine what changes have been made to
prevent reoccurrence
 Late 15 day alert reports
 Explanation in MedWatch narrative (Recommended)
 Explanation in transmittal letter (Recommended)
Types of Violations
 Serious and unlabeled events not submitted
in a timely manner (range 30 days up to 10
years)
 Lack of assurance that all ADEs were
submitted
 Foreign serious and unlabeled events not
submitted from foreign affiliates
Types of Violations
 Failure to conduct prompt and adequate
follow-up investigations of ADEs
 Serious and unlabeled events not assessed
properly
 SOPs are not established for the surveillance,
receipt, evaluation, and reporting to FDA of
postmarketing adverse drug experiences
 No periodic reports submitted
Current Issues
 HEALTH INSURANCE PORTABILITY AND
ACCOUNTABILITY ACT (HIPAA)
 Transfer of responsibility for 21 CFR 314.80
from the applicant to affiliates / contractors
Turbo EIR
 Provides more consistency between
inspections and investigators
 Provides specific citations and examples
of violations
Internet Sites for ADR
Information
 www.fda.gov/cder/aers/default.htm
 www.fda.gov/medwatch
 http://www.fda.gov/cder/learn/ADE/ADE_Pagex.htm
PADE Compliance Team
CDER Office of Compliance
Denis Mackey
[email protected] (301-827-8926)
Carol Krueger
[email protected] (301-827-8989)
PADE Inspectional Program
Questions ???