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 1

AGENDA Postmarketing adverse drug experience reporting regulations Role of headquarters and field Inspectional strategies 2

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 3

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 4

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. 5

Serious Adverse Drug Experience Death Life threatening (per initial reporter) Permanently or significantly disabling Hospitalization Congenital anomaly/birth defect Important medical events 6

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 7

Reporting Requirements Within 15 calendar days if Serious and Unexpected (domestic and foreign) Follow-up information Non-applicant notifies applicant within five calendar days 8

Periodic Report Quarterly and Annual Reports Serious & Expected ADEs All Non-serious 9

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 10

Forms 3500A (Medwatch Form) Council for International Organization of Medical Science (CIOMS I Foreign) or other form if approved in advance 11

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 12

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. 13

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. 14

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 15

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 16

References Used Prior, During and After Inspection CP 7353.001, Enforcement of the Postmarketing Adverse Drug Experience Reporting Regulations. Regulations Guidance documents Inspectional package 17

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. 18

Source Documents Complaint logs - numerical for completeness Medical Department Logs Distribution records Annual product reviews 19

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. 20

Look for Discrepancies such as... Omissions Minimizing results Lack of follow-up Inadequate follow-up 21

Significance of Deviations Most serious - not submitting 15-day reports Serious - report accuracy Moderately serious - timeliness 22

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. 23

When Discrepancies are Found Review raw data Ask questions and understand how the event and investigation was handled Look for patterns or trends Document 24

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 25

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 26

Cont. Violations Uncovered Computer system used to process and generate ADR reports is not validated Coding errors in Medwatch forms No approved SOPs 27

Remember Scientific evaluation of adverse events depends upon the field investigator assuring that industry submits reports that are complete, accurate, and timely. 28

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 Juliaette Johnson – 301-827-8928 Johnsonju@cder.fda.gov Denis Mackey – 301-827-8926 Mackey@cder.fda.gov 29

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 30