# Presentation: 518988

## SAFETY REPORTING FDA’s Perspective 

- Nancy Haggard, M.P.H.
- Post-Marketing Adverse Drug Experience Manager
- Office of Compliance
- Center for Drug Evaluation and Research
- U.S. Food and Drug Administration
- June 13, 2000

## Agenda

-  FDA Safety Reporting Regulations
- Root causes for failure to comply
- Inspectional Findings by FDA Investigators

## Agenda

- Critical Areas
- Industry Corrective Actions
- Industry Challenges
- Lessons Learned

## Purpose of the Program

-    To assure that firms submit required
-    adverse drug event reports to FDA and
-    that they are complete, accurate, and timely.
- .

## Geographic Profile of FDA Applicants

*60*

*45*

*12*

*4*

*1*

*1*

*N=123*

*Total=757*

## Brief Overview of Postmarketing Reporting Regulations

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

## Significance of Deviations

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

## Common Causes for Failure to Report ADRs

- Not understanding the regulations
- Contractual agreements between companies
- Not auditing outside vendors
- Validation of computer systems
- Human error

## Training of Staff

- Staff not knowledgeable
- Staff not aware of global differences
- Not aware  of current thinking

## Contractual agreements

- Not covered in written procedure
- Timeframes and notification methods are not being followed

## Patient Assistance Programs

- Inclusion in written procedures and contracts
- Prompt communication of ADEs to drug safety units
- Initial information and follow-up
- Audits of vendors

## Electronic Transmission Issues

- Cases not forwarded to global database
-  Cases sent but not received
- Cases transmitted, but no action taken

## Even with Electronic Advances...

- Some reports are not entered in database
- Human error

## Problems with Process Flow 

- Information not shared among departments
- Collecting Unit to Reporting Unit
- Marketing Office to International Drug Safety Group
-  Clinical data vs. Postmarketing data

## Problems Found inStandard Operating Procedures

- Global procedures are not included at local sites
- Outdated procedures
- Contradictory procedures
- Incomplete
- SOPs based on premarketing requirements

## Elements of GoodStandard Operating Procedures

- State the minimum qualifications for those evaluating ADEs
- State reporting requirements
- Set forth the controls necessary to ensure that ADEs are evaluated, investigated and sent to FDA

## Significance of Deviations

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

## Incomplete or Inaccurate Reporting

- Not informative
- Information does not match initial reporter’s data
- Incorrect receipt dates

## Inspectional Scope

- Compare raw data with reported information in 3500A

## Source Documents

- Complaint/customer logs
- Medical ADE Department Logs and files
- Distribution records and  returned goods
- Computer systems

## Source of Adverse Events

- Company rep
- Consumer
- Health care professionals
- Electronic media
- Anonymous

- Licensees
- Contract research organizations
- Other firms
- Distributors/packers
- Foreign affiliates
- Regulatory authorities
- Registries

## Lateness

- Data that does not come to FDA can not be evaluated
- Four basic elements

## Percent of FDA-483s Containing the Listed ADE Deficiencies1997-2000

- N = 76

**Notes:**
Based on 137 inspections

## Outcomes of Inspections

- Firms refocus attention on requirements of reporting and procedures
- Firms meet with FDA
- Warning Letters
- Injunction
- Prosecution
- Revocation of application

## Industry Corrective Actions

- Reassessment of ADE process flow information technology
- staff needs and organization changes
- multi-functional teams
- relocation of units

## Industry Corrective Actions

- Improvements in QC/QA processes
- retro-review of cases
- periodic reconciliation of cases
- procedure changes

## Industry Corrective Actions

- Communication
- reassessment of contracts
- globalization of training
- increased audits

## Industry Challenges

- Harmonization  between domestic vs. foreign
- Data transfer issues
- Process for handling ADEs may cause  reporting delays

## Cont. Industry Challenges

- Labeling assessment issues:
- Labeling: International vs. Local
- Differences in medical interpretation of seriousness
- Insufficient information provided to determine seriousness

## Cont. Industry Challenges

- CROS and licensing partners may not be complying with agreements
- Initial reporters may not want to provide information regarding adverse event

## Recordkeeping Requirements

- Firms are required to maintain all adverse
- drug experiences, including raw data and any
- correspondence relating to ADEs for a period
- of  10 years.

## ADE Inspections5-Year Summary

*112*

**As of 6/5/00*

## Lessons LearnedIntegrated Systems

- _Integrated Systems_
- Training
- Computer Systems
- Procedures
- Audits

## For More Information...

- Nancy Haggard, M.P.H.
- Phone # (301) 827-7309
- Fax (301) 594-0167
- e-mail address haggardn@cder.fda.gov