# Presentation: 042284

## DSI Update:  Clinical Investigations

**David A. Lepay, MD, PhD**
**Director,**
** ****Division of Scientific Investigations**
**Office of Compliance,  CDER**
**June 8, 1998**

## Update on Clinical Investigations

- Inspection Metrics
- Domestic
- (Foreign)
- Enforcement Update
- What is FDA Doing?

## NDAs Filed Per Fiscal Year

**73**

**86**

**96**

**111**

**109**

**104**

## Clinical Investigator Inspections

- 324

- 402

- 334

- FY	          92     93     94    95     96    97

- 261

- 229

- 182

## Clinical Inspections - Foreign

**Clinical Inspections - Foreign**

** ****5**

** ****13**

**23**

**23**

**22**

** ****47**

**36**

## Clinical Inspections - DomesticFY’97

- Clinical Inspections - DomesticFY’97

- n=298

- 40%

- 56%

- 2%

- 2%

## Clinical Inspections - ForeignFY’97

- n=36

**58%**

**25%**

**14%**

**3%**

## Current Compliance Concerns

- 	Failure to _*follow the protocol*_ and failure to _*maintain adequate and accurate case histories*_ continue to be the most frequently encountered findings.

## Current Compliance Concerns

- Most commonly observed deficiencies  in these areas include
- Failure to follow the protocol
- Violation of inclusion/exclusion criteria
- Failure to perform required tests
- Failure to maintain adequate and accurate records
- absence of supporting source documents
- inaccurate or incomplete source documents

## Clinical Investigator Deficiency Categories - FY 97

**Clinical Investigator Deficiency Categories - FY 97**

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**25**

**21**

**20**

**13**

**5**

## Clinical Investigator Deficiency Categories - FY 96

**Clinical Investigator Deficiency Categories - FY 96**

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**34**

**29**

**21**

**11**

**11**

## Clinical Inspections - DomesticFY’97

- Clinical Inspections - DomesticFY’97

- n=298

- 40%

- 56%

- 2%

- 2%

## --Wall Street Journal

**--Wall Street Journal**
**   ****August 15, 1997**

**--Los Angeles Times**
**  ****September 27, 1997**

## Current Compliance Concerns

- Failure analysis of monitoring in recent notorious cases
- Six cases were selected based on serious problems
- Source documents completely absent
- Study subjects completely fabricated
- Study staff performing tasks for which they were unqualified
- Other significant deviations from regulations

## Current Compliance Concerns

- Failure analysis of monitoring in recent notorious cases
- Approach
- Identify all sponsors/monitors and applications involved with each investigator to establish scope and impact
- Categorize objectionable findings at each site as detectable or not easily detectable by adequate monitoring

## Current Compliance Concerns

- Failure analysis of monitoring in recent notorious cases
- Examples of Detectable vs. Not Easily Detectable observations during adequate monitoring
- Detectable Observations - missing source data, discrepancies between source data and CRF, failure to follow the protocol
- Not Easily Detectable Observations - manufactured source data, forged documents, fabricated patients

## Current Compliance Concerns

- _CI__	__	__Applications  __	__Sponsors__	_
-  A	  	  	91	      	      47
-  B	  	  	49	      	      25
-  C	  	  	43	               21
-  D	  	  	21	               17
-  E	  	  	12		        6
-  F	    	    	  6                      6

## Current Compliance Concerns

- _#of Sponsors__	_	_# of CIs__	_
- 		 1	 		All 6
-         1		  	  5/6			 7		      	  4/6
-         7	      	         3/6
-        13	      	         2/6

## Current Compliance Concerns

- Multiple problem investigators working on the same application magnify adverse impact
- 	3 sponsors used 3 CIs who contributed data to the 		same application
- 12 sponsors used 2 CIs who contributed data to the same application

## Conclusions

- Failure analysis of monitoring in recent notorious cases
- Serious misconduct not reported by sponsors
- Seriously noncompliant investigators used by multiple sponsors on multiple trials
- Majority of objectionable observations should have been detectable by adequate monitoring
- Small number of investigators have broad impact on many applications by many sponsors

## Quality Solutions 

- Objective
- 	To improve data quality on a larger scale through process improvement than can be accomplished alone through inspection of individual investigators

## What is FDA Doing ?

- Educating ourselves on current industry practices and problems in clinical trial monitoring.
- Reviewing and articulating our expectations and findings.
- Identifying channels for dialogue on process improvement.

## What is FDA Doing ?

- Institute of Medicine Workshop:
- 	*“**Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision-Making”*
*	*
*	**	*April 14-15, 1998
- 		National Academy of Sciences, Washington

## What is DSI doing?

- Educating ourselves on current industry practices and problems in clinical trial monitoring
- Increased focus on monitoring practices during routine inspection of investigator sites
- what’s out there and what’s working
- Increased directed inspections of sponsors/CROs
- based on problem sites and/or investigators

## What is FDA Doing ?

- Officially published ICH GCP Consolidated Guideline as guidance  (Federal Register, May 9, 1997)
- Articulates standards on designing, conducting, recording, and reporting clinical studies  (includes monitoring and auditing of studies)

## What is FDA Doing ?

- Articulating standards for electronic record-keeping; developing guidance on the use of computer systems in clinical trials
- Electronic Records; Electronic Signature Final Rule (21 CFR Part 11:  August 20, 1997)
- Regulation; Legally enforceable
- Draft Guidance:  Computerized Systems Used in Clinical Trials  (FR  June 18, 1997)
- Guidance

## FDA/CDER Home Pagehttp://www.fda.gov/cder

- Disqualified/Restricted/Assurance List for Clinical Investigators
- Debarment list
- Guidance documents
- Compliance Policy Guides
- Regulatory Procedures Manual
- Application Integrity Policy List

## What is FDA Doing ?

- Identifying Channels for Process Improvement
- Inspections
- Outreach
- Building in quality upfront