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POSTMARKETINGADVERSE DRUG EXPERIENCE
INSPECTIONAL PROGRAM
CDR Thomas R. Berry, RPhFDA, 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 DrugsOffice of
Medical Policy
Ten Additional Offices with
Functions Related to Regulation of
Investigational and Marketed
Drugs/Biologics
Office of Drug Evaluation IV
Office of Drug Evaluation I
Office of Drug Evaluation VI
Office of Drug Evaluation II
Office of Drug Evaluation III
Office of Drug Evaluation V
Office of the Center DirectorCenter for Drug Evaluation and Research
(CDER)
Office of New Drugs
~100 colleagues focus on pharmacovigilance activities for marketed drug products
Office of Biostatistics
Office of Drug Safety
Division of Drug Risk
Evaluation
Division of Medication Errors
and Technical Support
Division of Surveillance, Research and
Communication
Office of Pharmacoepidemiologyand Statistical Science (OPaSS)
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
Reports to FDA directly from individuals
<10% of all reports (“direct”)
FDA database “AERS”
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
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 severityrenal 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:
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
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 ???
