# Presentation: 778178

## The FDA’s Postmarketing Adverse Drug Experience Inspectional Program

*The FDA’s Postmarketing Adverse Drug Experience Inspectional Program*

*Surveillance Programs Team*
*Office of Compliance*
*Center for Drug Evaluation and Research*
*U.S. Food and Drug Administration*

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## AGENDA

*Postmarketing adverse drug experience reporting regulations*
*Role of headquarters and field*
*Inspectional strategies*

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## 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*

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## Brief Overview of Reporting Regulations

*21 CFR Sections: *
*310.305 - RX drugs not subject to approved applications*
* **314.80 - RX drugs subject to NDAs/ANDAs and OTCs associated with approved applications*
*314.98- RX drugs subject to AADAs*

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## What is an Adverse Drug Experience?

*Any adverse event associated with the use of drug in humans whether or not it is considered drug related.*

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## Serious Adverse Drug Experience

*Death*
*Life threatening (per initial reporter)*
*Permanently or significantly disabling*
*Hospitalization *
*Congenital anomaly/birth defect*
*Important medical events*

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## Unexpected Adverse Drug Experience

*Not listed in current labeling*
*Listed in labeling but greater specificity or severity*
*e.g. renal impairment listed, patient experiences renal failure*

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## Reporting Requirements

*Within 15 calendar days if Serious and Unexpected (domestic and foreign)*
*Follow-up information *
*Non-applicant notifies applicant within five calendar days*

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## Periodic Report

*Quarterly and Annual Reports*
***Serious & Expected ADEs******	***
***All Non-serious***

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## When does the Regulatory Clock Start? 

*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***

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## Forms

*3500A (Medwatch Form)*
*Council for International Organization of Medical Science (CIOMS I Foreign) or other form if approved in advance*

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##  The Headquarter/Field Adverse Event Team

*The headquarters scientists use adverse event reports to evaluate the safety of marketed drugs*
*OC/ADE Team coordinates between regulatory and scientific staff.*
*The field investigators assure industry compliance with reporting regulations *

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## Role of the Field 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.*

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## Role of the Field Investigator

*When reports of adverse events are not*
*submitted, or are  incomplete, inaccurate *
*or late, then document to support *
*appropriate regulatory action.*

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##  Role of the Field Investigator

*Look for adverse events not cited on the product labeling.*
*Do not make medical evaluation of  adverse events.*
*Do not evaluate labeling or make labeling change recommendations*

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## Selection of the Firms Risk Management Approach

*Firms with ADE reporting problems*
*Firms with prior violative history*
*Recalls*
*AIP list*
*NDA field alerts*
*High-risk drugs*

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## References Used Prior, During and After Inspection

*CP 7353.001, Enforcement of the Postmarketing Adverse Drug Experience Reporting Regulations.*
*Regulations*
*Guidance documents*
*Inspectional package*

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## SOPs

*Procedure to specify the minimum qualifications of persons involved in investigating and evaluating ADEs*
*Make sure that current reporting requirements are cited in SOPs*
*SOPs should specify control activities to ensure that ADEs are investigated, followed-up, evaluated and sent to FDA.*

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## Source Documents

*Complaint logs - numerical for completeness*
*Medical Department Logs*
*Distribution records*
*Annual product reviews*

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## 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.*

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## Look for Discrepancies such as...

*Omissions*
*Minimizing results*
*Lack of follow-up*
*Inadequate follow-up*

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## Significance of Deviations

*Most serious - not submitting 15-day reports*
*Serious - report accuracy*
*Moderately  serious - timeliness*

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## If reports are found that have not been filed...

*Determine the nature of the event and  the cause for failure to report.*
*Determine what changes have been made to prevent reoccurrence.*

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## When Discrepancies are Found

*Review raw data*
*Ask questions and understand how the event and investigation was handled*
*Look for patterns or trends *
*Document*

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## Type of Violations Uncovered

*Serious and unlabeled events not submitted in a timely manner (range 30 days up to ten years*
*Lack of assurance that all ADEs were submitted*
*Foreign serious and unlabeled events not submitted from foreign affiliates*

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## Cont. Violations Uncovered

*Failure to conduct prompt and adequate follow-up investigations of ADEs*
*Serious and unlabeled events not assessed properly *
*No periodic reports submitted*

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## Cont. Violations Uncovered

*Computer system used to process and generate ADR reports is not validated*
*Coding errors in Medwatch forms*
*No approved SOPs*

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## Remember

*	**Scientific evaluation of adverse events depends upon the field investigator assuring that industry submits reports that are complete, accurate, and timely.*

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## For Additional Information...Contact the Surveillance Program Team 

*Jay Schmid – 301-827-8929*
*Schmid@cder.fda.gov*
*Carol Krueger – 301-827-8989*
_*[Kruegerc@cder.fda.gov](mailto:Kruegerc@cder.fda.gov)*_
*Juliaette Johnson – 301-827-8928*
_*[Johnsonju@cder.fda.gov](mailto:Johnsonju@cder.fda.gov)*_
*Denis Mackey – 301-827-8926*
_*[Mackey@cder.fda.gov](mailto:Mackey@cder.fda.gov)*_

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## Internet Sites for ADR Information

* **http://www.fda.gov/cder/aers/index.htm*
*http://www.fda.gov/cder/regguide.htm*
*http://www.fda.gov/medwatch*

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