# Presentation: 450410

## GCP Compliance: FDA Expectations and Recent Findings

**David A. Lepay, MD, PhD**
**Director,**
**Division of Scientific Investigations**
**June 9, 1998**

## Bimo Inspections Completed

- *Data unavailable for In Vivo Bioequivalence prior to FY 93

- 559

- 535

- 461

- 632

- 667

- 618

## Clinical Investigator Inspections

- 324

- 402

- 334

- FY	          92     93     94    95     96    97

- 261

- 229

- 182

## Clinical Inspections - DomesticFY’97

- Clinical Inspections - DomesticFY’97

- n=298

- 40%

- 56%

- 2%

- 2%

## 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

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

## 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

## Clinical Trial MonitoringCurrent Problems

- Limited knowledge of the nature and scope of industry monitoring practices
- Minimal surveillance inspection of monitoring practices
- Monitors generally inspected on for cause basis
- Lack of full problem reporting by sponsors
- QA reports inaccessible
- Monitoring plans and reports not submitted
- Problem investigators not reported

## What is FDA doing?

- Increased focus on monitoring practices at clinical site inspections under existing program
- Nature and frequency of monitoring visits
- Identity of monitors (CRO/Sponsor etc..)
- Specific records examined during monitoring
- Education and feedback from monitors to study site

## What is FDA Doing?

- Increased directed inspections of sponsors/CROs
- based on problem sites and/or investigators
- What’s failed
- FY 98 assignments are currently running at twice the rate for all of FY97

## What is FDA Doing?

- Develop Strategies for improvement
- Examine compliance strategies
- Monitoring Regulations (Revise)
- Compliance programs (Refocus)
- Enforcement Process (Streamline)
- Encourage prospective review of sponsor monitoring plans (EOP2) to promote up front improvement

## What is FDA doing?

- Outreach programs to promote better understanding and dialogue
- IOM-FDA Data Integrity Conference
- 	(April 1998)
- Association of Clinical Research Professionals annual meeting:  San Diego and Anaheim (April 1998)

## Clinical Inspections - Foreign

**Clinical Inspections - Foreign**

**5**

**13**

**23**

**23**

**22**

**47**

**36**

## Current Status of GCP in the United States

- FDA has regulations governing the approval, conduct, review and reporting of clinical research intended for submission
- 21 CFR 312:  IND regulations (rev.1987)
- 21 CFR 50:  Informed consent  (rev.1981)
- 21 CFR 56:  IRB (rev.1981)
- 21 CFR 314:  NDA regulations (rev. 1985)
- These are legally enforceable requirements

## Current Status of GCP in the United States

- FDA has guidance documents which are not legal requirements but state acceptable standards
- Guideline for Monitoring Clinical Investigations  (Jan 1988)
- Information Sheets for IRBs and Clinical Investigators  (Rev. Oct 1995)
- ICH GCP Consolidated Guideline  (May 9, 1997)

## Current Status of GCP in the United States

- FDA has a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of clinical and nonclinical research intended for submission
- To ensure quality and integrity of data
- To ensure protection of research subjects
- To enforce compliance with regulations

## Current Status of GCP in the United States

- Regulations, guidance and inspection programs are continually evaluated and updated to take into account current scientific developments, ethical concerns, industry practices and international standards

## How has/will FDA implement ICH GCP 

- FDA’s existing infrastructure of regulations, guidance and inspection programs fully supports the implementation of  ICH GCPs
- Existing regulations/guidance already implemented are generally consistent with ICH GCP requirements

## ICH GCP GuidelineImplications for U.S. Sponsors of Multinational Applications

- Record Access  (4.8.10(n))
- IC discussion and written IC should explain that by signing the consent form, the subject authorizes access to medical records by:
- Regulatory authorities  (not just US FDA)
- Study monitor(s) and auditor(s)
- IRB/IEC
- Sponsor is responsible for securing agreement from all parties for access to records

## ICH GCP GuidelineImplications for U.S. Sponsors of Multinational Applications

- Retention of Records (Sponsor and CI)
- Retain at least 2 years after:
- Last marketing approval in ICH regions (not just U.S.)
- No pending/contemplated action in any ICH region
- Retain longer than 2 years if:
- Required by regulatory requirements  (e.g.. EU)

## ICH GCP GuidelineImplications for U.S. Sponsors of Multinational Applications

- Sponsor Responsibilities
- Sponsor should obtain from investigator/ institution  (5.11.1(b)):
- Statement IRB/IEC is in compliance with laws, regulations, and GCP
- Sponsor should verify (5.15.2)
- Each subject consented in writing to direct access to his/her original medical records.

## Reporting Time Frames of ADRs

**ICH***
**7 **
**Calendar**
**Days**
**15**
**Calendar**
**Days**

**FDA**
**(old regs)**
**3**
**Working **
**Days**
**10**
**Working**
**Days**

**FDA***
**(new regs)**
**7**
**Calendar **
**Days**
**15**
**Calendar **
**Days**

**Fatal**
**or Life-**
**Threatening**
**All Serious**

***ICH Consolidated Guideline 5.17.1, 2 and 3; FDA regulations, FR 10/7/97, p. 52237**

## ICH GCP GuidelineImplications for U.S. Sponsors of Multinational Applications

- Inspections of U.S. sites/sponsors by non U.S. regulatory authorities

## How has/will FDA implement ICH GCP

**FDA WILL**:
- Consider clinical studies conducted under ICH GCP as meeting GCP standards acceptable to FDA.
- Take into account ICH GCPs when developing new or revising existing regulations and guidance as part of regular GCP program maintenance

## Criteria for FDA Acceptance of Foreign Non-IND Data(21 CFR 312.120 and 314.106)

- Ethics acceptable to the world community
- Protection equal or greater than the Declaration of Helsinki (e.g., ICH-GCP)
- Trial well-designed and well-conducted
- Investigators qualified
- Trial approved by independent review committee
- Trial may be inspected

## Challenges in Implementing  GCP

- Challenges Experienced by FDA
- Resistance to Government regulation of clinical trials
- Ethical considerations
- Problems inherent to the conduct of clinical trials

## Challenges in Implementing  GCP

- Resistance to government regulation of clinical trials
- Misunderstanding of regulatory expectations
- Lack of familiarity (with GCP requirements) by CI’s
- Authority to inspect
- Credentials of inspectors
- Access to medical records
- Legal
- Ethical

## Challenges in Implementing  GCP

- Ethical Considerations
- Imposing new requirements on an established institutional infrastructure (IRB/IEC)
- Achieving results without being too prescriptive
- Selecting an appropriate enforcement approach
- Perform valuable community service
- Composed of volunteers, limited resources
- Allies to regulators, sponsors and CI’s in protecting human subjects

## Challenges in Implementing GCP

- Problems inherent in clinical trials
- Inadequate and inaccurate records
- Failure to adhere to protocol
- Drug accountability
- Informed consent form
- Reporting of adverse events

## Clinical Investigator Inspections(FY 96-97)

-  U.S.
- n = 654

-   EU
- n = 47

- 55%

- 57%

- 15%

- 28%

- NAI

- VAI

- OAI

- 42%

- 2%

## Issue

- Clinical trials are expanding to geographic areas new to FDA regulations, expectations, and inspections

**Notes:**
51
45
52

## 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

**Notes:**
52
46
53

## Non-US  CI InspectionsEU

- FY 94-95
- n = 30

- FY 96-97
- n = 47

- 80%

- 13%

- 6%

- 57%

- 15%

- 28%

- NAI

- VAI

- OAI

## ICH GCP Contributions

- Declaration of 13 Principles
- Clear Assignment of Responsibilities and Duties to:  IRB/IEC, Investigator, Sponsor
- Standardization of IRB/IEC Membership
- Agreement on “Essential Documents”
- Consent in Emergency Care Research
- 	Slide Courtesy of Ronald Garutti, Schering-Plough Research