# Presentation: 210714

## GCP  COMPLIANCE:Emerging Issues in Worldwide Clinical Trials

- David A. Lepay, M.D., Ph.D.
- Director, Division of Scientific Investigations, CDER
- June 29, 1999

## FDA Does Accept non-U.S. Clinical Trial Data for Purposes of Review

- Studies conducted under U.S. IND
- Non-IND Studies pursuant to provisions of 21 CFR Parts 312.120 and 314.106

## DSI’s Traditional Approach for Ensuring Quality in Multinational Trials

- Regulations  (21 CFR Parts 50, 56 and 312, including 312.120)
- Inspections
- Compliance/Enforcement
- Ability to reject data:  Single site or entire study/application
- Ability to disqualify clinical investigators (when under U.S. IND)

## Bioresearch Monitoring Program:Concerns

- Changes in the clinical trial “landscape”
- More studies; more CI’s and sites per study
- Expansion and fluidity of CI pool
- Delegation of functions/authority
- “New” players in new roles (CRO’s, SMO’s)
- New technologies (electronic record-keeping)
- Trials in geographic areas new to FDA expectations and requirements

## First-Time Clinical Inspection(By Country)

**First-Time Clinical Inspection****(By Country)**

**1992**
**Italy**
**Spain**
**1993**
**Belgium**
**Israel**
**New Zealand**
**1994**
**Poland**
**South Africa**

**1995**
**Argentina**
** ****1996**
**Brazil**
**Costa Rica**
**Peru**
**Russia**

**  ****1997**
** ****Austria**
** ****Nigeria**
** ****Panama**
** ****Philippines **
**  ****1998**
** ****Czechoslovakia**
** ****Slovenia**
** ****Hungary**
** ****Romania **

## Related Issue

- The number of applications containing pivotal data from non-U.S. studies is increasing and this has necessitated an increase in FDA’s international inspectional activity.
- Percentage of clinical investigator inspections at non-U.S. sites has increased from 5% in FY 92 and 7% in FY 95 to 17% in FY 98.

## Clinical Inspections - International

**Clinical Inspections - International**

** ****5**

** ****13**

**23**

**23**

**22**

**47**

**36**

**61**

## Emerging Approaches to Ensure Data Quality and Subject Protection

- International Standard Setting
- ICH Consolidated Guideline  (Published in FR on May 9, 1997 as FDA guidance)
- Access to Information
- Internet  (FDA Home Page);  Outreach
- Attention to Systems Approaches
- Study monitoring
- Upfront dialogue on QC/QA

## Systems Approaches have been Facilitated by International Standard Setting

- ICH-GCP Consolidated Guideline:
- Section 5.18:  Monitoring
- Selection and Qualifications of Monitors;  Extent and Nature of Monitoring; Monitor’s Responsibilities; Monitoring Procedures; Monitoring Report
- Section 5.19:  Audit
- Purpose; Selection and Qualifications of Auditors; Auditing Procedures

## Systems Approaches have been Facilitated by International Standard Setting

- The Contents of a Trial Protocol should generally include the following topics:
- 6.11  Quality Control and Quality Assurance
- The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.   (Section 5.18.3)

## How Is DSI Moving Toward Systems Approaches

- Educating ourselves on implementation of monitoring programs and standards
- “Survey” of Monitoring Practices during Routine Clinical Investigator Inspections

## What is Covered in this “Survey” ?

- Information already part of FDA’s Clinical Investigator Compliance Program  (7348.811)
- Log of on-site monitoring visits (method and frequency of monitoring)
- Source data verification
- Information to CI’s
- Notification of problems; prompt correction

## Status of “Survey”

- January 1998 - April 1999:  340 assignments issued with specific request for monitoring “survey” information
- January 1998 - April 1999:  262 EIRs received
- To date:  164 surveys logged in

## Who is Monitoring?January 1998 - April 1999

- 54%

- 31%

- 11%

- N = 164

## The Good News(Preliminary Findings)

- 38% = NAI; 58% = VAI
- Surveys showed in majority of cases that
- CIs felt generally that studies were adequately explained to them by the monitors
- Monitoring logs show who visited sites, dates of visits, and general purpose of visit
- Monitors compared CRFs to source documents, reviewed AE reports, sought clarification and correction of data, examined drug accountability records.

## The Good News - But...(Preliminary Findings)

- Monitoring logs alone are not specific enough to determine what monitors do at site.
- Problems:
- Changes were made by monitors to CRFs without having the changes approved by the CI.
- Monitor used out of date SOPs at site.

## The Bad News

- 2% = OAI
- Some comments from CI’s:
- Was told to “try to do these things” [listed in the protocol], but that it was more of a “general guide,” and that following the protocol was “not necessary”
- Concerned about “running out” of the study drug because CI was told it “was expensive”.  “Juggled” the doses so as “not to waste it”.  “...Wanted to get mileage out of the product”.

## The Bad News

- Some comments from CI’s:
- “Was not aware of responsibility to obtain IRB approval PRIOR to initiation of the clinical investigation”
- “Was not told that might receive an FDA audit inspection.”
- And from monitors:
- Can’t challenge,  Dr. [X] is a “god of urology” !

## The Bad News - Continued  

- DSI has also started to look at study monitoring in cases of highly violative CI’s.
- Worst Case Scenario:  Single violative CI working on as many as 91 applications for up to 47 sponsors.
- Warning Letters to Sponsors/Monitors/CRO’s
- Other Sanctions ?

## Are Approaches Paying Off ?  Clinical Inspections, Non-U.S. sites:  FY 97-98

**17%**

**25%**

**58%**

**NAI**

**VAI**

**OAI**

**FY 97**
**n = 36**

**Pending**

**49%**

**43%**

**5%**

**3%**

**FY 98**
**n = 61**

## ... But Still a Ways to GoClinical Investigator Deficiency Categories - FY 98

- ... But Still a Ways to GoClinical Investigator Deficiency Categories - FY 98

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**29**

**23**

**15**

**14**

**12**

## So Where is DSI Headed ?

- Continue “monitoring” survey during CI inspections.
- More Sponsor/Monitor/CRO inspections as appropriate
- Follow-Up to Violative CI inspections
- High Risk Studies
- ? New Molecular Entities

## So Where is DSI Headed ?

- Upfront Dialogue to Better Focus Sponsor QC/QA and FDA Inspectional Follow-Up
- Key safety and efficacy data most critical to human subject protection and FDA decision-making
- Pilot as part of End-Of-Phase 2 meetings  (Stay Tuned)

## Center for Drug Evaluation & Research

- Office of the Center
- Director
- Janet Woodcock, M.D.

- Office of Medical Policy
- Robert Temple, M.D., Director
- Rachel Behrman, M.D., Acting Deputy Director

- Division of Drug Marketing,
- Advertising & Communication
- Norman A. Drezin, R.Ph, J.D.
- Acting Director

- Division of Scientific
- Investigations
- David A. Lepay, M.D., Ph.D.
- Director

## Division of Scientific InvestigationsPhone #301-594-0020      FAX #301-594-1204 

- Director
- David A. Lepay, MD, PhD

- Deputy Director
- Stan W. Woollen

- Secretary

- Program Management Staff

- Case Management Staff

- GLP/BEQ Branch
- C. Viswanathan, PhD

- GCP I Branch
- ODE I (part), II, III
- Bette Barton, PhD, MD

- GCP II Branch
- ODE I (part), IV, V
- Antoine El-Hage, PhD

## Closing Perspectives

- Traditional approaches (Regulation; Inspection; Enforcement)  have worked.
- Clinical trials continue to evolve.
- DSI will increasingly focus on upfront dialogue and systems-oriented approaches as adjuncts to traditional methods.