# Presentation: 757083

## DSI:  Presentations at 1998 DIA

- Office of Compliance Update  (6/8)
- AM:  DSI Update 1  (BEQ, GLP, HSP)
- PM:  Computer Systems in Clinical Trials
-   DSI Update 2  (CI Program:  Study monitoring)
- Inspection and Audit of Clinical Studies (6/9)
- GCP Compliance:  International inspection program

## DSI Update:  GLP, Bioequivalence, and Human Subject Protection Programs

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

## Division of Scientific Investigations

- David A. Lepay
- MD, PhD
- Director

- Stan Woollen
- Deputy
- Director

- Clinical
- Investigations
- Dr. B. Barton
- Chief

- Human
- Subject
- Protection

- Project
- Management
- Staff

- GLP &
- Bioequivalence
- Dr. C. Viswanathan
- Associate Director

**Notes:**
2
3

## Bimo Inspections Completed

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

- 559

- 535

- 461

- 632

- 667

- 618

## Bioequivalence Inspections

- FY   93     94     95     96     97     98*

- *Inspections completed from October 1997 - April 1998

- 30

- 36

- 52

- 82

- 87

- 47

- 84 inspections
- projected
- through
- end of FY 98

## InVivo Bioequivalence Program

- 1979-1992: Inspection of bioequivalence studies of generic drugs on an ad hoc basis
- Late 1980’s: Generic Drug Scandal
- 1992: Dr. Viswanathan joins DSI as dedicated expert on bioequivalence
- 1993: Separate bioequivalence unit formed within DSI

## Bioequivalence Inspections  ANDAs

- First Generics
- For Cause Inspections
- NDAs
- Bridging studies
- New formulations or new routes of administration of a marketed drug

## Bioequivalence InspectionsANDAs vs. NDAs

- 34%

- 66%

- 49%

- 51%

- NDAs

- ANDAs

- FY 94-95
- n = 88

- FY 96-97
- n = 169

## Bioequivalence Inspections

- Clinical Component
- Inspection and data audit similar to CI program
- Particular attention to subject selection, dosing, test article identity/accountability, biological specimen collection, handling, and analysis.
- Analytical Component
- Laboratory facilities, practices, and personnel
- Laboratory analytical techniques; audit of analytical raw data.

## Bioequivalence InspectionsProblems Encountered

- Clinical component
- Dosing errors
- Violation of inclusion/exclusion criteria
- Failure to retain samples
- Analytical component
- Inadequate methods validation
- Inadequate quality control
- Selective data reporting

## In Vivo Bioequivalence Program Initiatives

- Initial inspection of domestic bioequivalence facilities contributing data to ANDAs & NDAs
- Inspection of foreign bioequivalence facilities contributing pivotal data to U.S. applications
- Investigation of citizens’ petitions and therapeutic failure complaints

## Good Laboratory Practice (GLP) Program

- Distinct compliance program (CP 7348.808)
- Provides for inspections and data audits of nonclinical labs (toxicology labs) conducting animal safety testing of FDA regulated commodities
- Comprehensive physical inspection of laboratory facilities and operations
- Data audit of selected studies

## GLP Inspections(FY)

- 88

- 82

- 69

- 72

- 31

- 47

- FY   92    93    94     95    96    97    98*

- 28

- *Inspections completed from October 1997 - April 1998

- 48 inspections
- projected
- through
- end of FY 98

## GLP InspectionsMost Common Deficiencies

- Failure to adequately and accurately record experimental data
- Standard Operating Procedures
- Failure to maintain/calibrate equipment
- Inadequate analytical testing/accountability of test/control articles
- Inadequate animal/testing facilities; animal      care

## GLP Program Initiatives

- Review-Oriented Targeting of GLP assignments
- Application-related data audits
- Unaudited integrated safety data summaries submitted to the Agency
- IND hold issues
- Broadening DSI’s base of PhD pharmacologists contributing scientifically to GLP inspections
- Advanced field training in GLPs (ORA’s National GLP Course)
- International GLP harmonization efforts

## GCP’s:  DSI’s Human Subject Protection Program

- Dedicated Human Subject Protection Team
- Advises CDER’s review divisions on IRB and informed consent issues.
- Provides for regularly scheduled inspections of IRB’s (and RDRC’s) to verify compliance with regulations.
- Traditional focus on IRB operations and procedures as a tool to ensuring protection of the rights and welfare of human subjects

## IRB Inspections

**185**

**150**

**149**

## Classification of IRB Inspections

- FY 97
- n = 149

- 84%

- 13%

- 3%

## DeficienciesIRB Inspections: FY95-97

**Continuing Review**

## Common Deficiencies Found in Informed Consent Documents

- Common Deficiencies Found in Informed Consent Documents

- 50.25(a)(7) Identification of person to contact regarding research, rights and injury
- 50.25(a)(4) Incomplete description of alternative procedures
- 50.25(a)(5) Inadequate confidentiality statement
- 50.25(a)(1) Incomplete description of research procedures
- 50.25(a)(6) Incomplete description of compensation and treatment for research-related injury

## Update on Human Subject Protection

- Regulations/Guidance
- 21 CFR 50.24:  Emergency Research Informed Consent Exception
- Foreign studies not conducted under an IND
- ICH GCP Consolidated Guideline
- Declaration of Helsinki
- HSP Program Initiatives

## Informed Consent - Exception for Emergency Research

- 21 CFR 50.24, effective Nov. 1, 1996
- Creates a narrow exception to requirement to obtain and document informed consent
- Applies to a limited class of research activities involving human subjects who are in need of emergency medical intervention but cannot provide legally effective informed consent.

## Informed Consent - Exception for Emergency Research

- Total requests received by FDA:	10
- CDER:		 	6
- CBER:			3
- CDRH:		1
- Allowed to proceed:
- CDER:			1
- CBER:			3
- CDRH:		1

## Informed Consent - Exception for Emergency Research

- Most common deficiencies:
- Study not appropriate for 50.24 exception
- No informed consent document or procedures
- Inadequate community consultation
- Inadequate public disclosure
- No procedures for informing legally authorized representative or family member that subject was enrolled in study (in the event of the subject’s death)

## Update on Human Subject Protection

- Regulations/Guidance
- 21 CFR 50.24:  Emergency Research Informed Consent Exception
- Foreign studies not conducted under an IND
- ICH GCP Consolidated Guideline
- Declaration of Helsinki
- HSP Program Initiatives

## 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

## ICH GCP Consolidated Guideline

- Published in the Federal Register, May 9, 1997
- Provides greater protection than the Declaration of Helsinki as last amended
- Therefore, where ICH-GCP is adopted by foreign authorities, this will serve as FDA’s human subject protection standard for accepting clinical studies for review.

## Declaration of Helsinki

- Adopted June 1964  (18th World Medical Assembly)
- Last Amended 1996  (South Africa)
- AMA is identifying and examining issues toward a proposed amendment.

## Update on Human Subject Protection

- Regulations/Guidance
- 21 CFR 50.24:  Emergency Research Informed Consent Exception
- Foreign studies not conducted under an IND
- ICH GCP Consolidated Guideline
- Declaration of Helsinki
- HSP Program Initiatives

## HSP Program Initiatives

- Coordinating GCP operations
- Linking CI and IRB inspection assignments
- Increase focus on IRB’s overseeing large numbers of studies and/or large numbers of subjects.
- Examination of ongoing studies in addition to examination of the IRB’s general operations
- Focus on performance in protecting human subjects

## HSP Program Initiatives

- Promoting better feedback to IRB’s
- Official actions against CI’s conducting research at IRBs’ institution(s)
- Adverse events: e.g., compilations and assessments of adverse-event reports prepared by sponsors or DSMB’s

## Summary

- Programs are dynamic
- Increasing focus on results (GPRA,
- 	  PDUFA 2) and process improvements
- Underlying objectives remain constant
- Protection of human subjects
- Ensuring data quality and integrity
- Compliance with federal law and regulations

## DeficienciesIRB Inspections: FY95-97

**Informed Consent**