# Presentation: 706520

## Good Clinical Practices andFDA Inspections  

- Patricia Holobaugh
- Chief, Bioresearch Monitoring Branch
- Division of Inspections and Surveillance
- Office of Compliance and Biologics Quality

## Agenda

- Define Good Clinical Practices
- Describe FDA’s Bioresearch Monitoring Program for on-site inspections of clinical and animal studies
- Explain when and how inspections are performed
- Describe common deficiencies and what happens after the inspection

**Notes:**

.....common deficiencies and what happens after an inspection

## Good Clinical Practices

- GCP is a standard for the design, conduct, performance monitoring auditing, recording, analysis, and reporting of clinical trials.
- www.fda.gov/oc/gcp/

## Regulations

*Investigational Application*
- 21 CFR Part 312	IND  *drugs and biologics*
- 21 CFR Part 812	IDE
- 21 CFR Part 809	IVD
*Marketing Application*
- 21 CFR Part 601	BLA biologics
- 21 CFR Part 314	NDA drugs
- 21 CFR Part 814	PMA devices

## Regulations

- 21 CFR 50	Protection of Human Subjects
- 				Informed Consent
- 				Safeguards for Children
- 21 CFR Part 56	Institutional Review Boards
- 21 CFR Part 11	Electronic Records; Electronic
- 				    Signatures

## Examples of GCP Guidance Documents

- Guideline for Monitoring Clinical Investigations (1998)
- Information Sheets for IRBs and Clinical Investigators (1998)
- ICH GCP Consolidated Guideline E6 (1997)

## Regulations                   Guidance  

## FDA’s Bioresearch Monitoring Program (BIMO)

- Clinical Investigators
- Sponsor/Monitor/Contract Research
-          Organizations
- Institutional Review Boards
- Nonclinical Laboratories

## When are BIMO Inspections conducted?	

- Submission of BLA	 / PMA
- Referrals from CBER staff
- Referrals from other Centers/ORA
- Complaints from sponsor, IRBs, and consumers
- Routine surveillance of ongoing studies
- 		target 50 pediatric sites this FY

**Notes:**
CBER started its surveillance program in 2000 following the death of a subject in a gene therapy study.

We have issued approximately 200 surveillance inspections.

Have expanded surveillance to all product areas:
	blood products under IND
	vaccines
	cell therapies
	gene therapies
	“other” OCTGT products

## Profile of CBER BIMO InspectionsFY04-05  (thru 3/9/05)

- 189   Assignments issued
- 			BLA	45     	PMA	15
- CI surveillance  102
- IRB    		   22
- GLP			   12
- Complaints	   12

## True or False???

- Clinical investigator:  “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”

## True or False???

- Clinical investigator:  “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”
*FALSE*
- Clinical investigators of studies in all phases may (_*and are*_) inspected by FDA....
- 		And _ALL_ GCP regulations apply.

## CBER continues its program toinspect ongoing studies under IND/IDE“Real-time” surveillance of phases 1/2/3

- Cell therapies
- Gene transfer
- Vaccines
- Blood products
- Devices

- For FY 2005, we issued assignments to inspect 50 sites enrolling _pediatric _subjects

**Notes:**
We perform about 50 of these per year, and now cover all areas of active INDs and IDEs.   

## History of CBER Surveillance Program

- Started in 2000 following Gelsinger’s death in gene therapy study
- Expanded to cell therapies, and then to all CBER IND/IDEs

## Surveillance – Cross-Section of Sponsors (FY00-05)

- 		Individuals 		64
- 		NIH + DOD		29**
- 		Hospitals +
- 			universities	11
- 		“Big” companies	48
- 		“Small” companies	84

## Inspections for BLA / PMAHow Many Sites per BLA/PMA?	

- Usually 3 to 5 study sites
- ...but sometimes more
- Will inspect foreign sites when needed:
- 		No US study or sites
- 		Foreign data are critical

## Inspections for BLA / PMAFactors in Site Selection

- Distribution of subjects
- Distribution of subjects whose data are excluded
-         from S&E analyses
- Inspection history of investigators
- Inconsistent data for one site
**        *****increased efficacy***
***        ******decreased incidence of adverse events***

## Inspections for BLA / PMA Factors in Site Selection

- GCP problems reported by sponsor
- Randomization cannot be reconstructed
- Number of sub-investigators / sub-sites*
- Pending workloads in FDA Districts

## FDA Inspection “101”

- Inspections are performed by ORA by specially-trained investigators
- 		Center reviewers may participate
_**Most**_ inspections are pre-announced
- Interview: who did what, and how
- Review of records
- Closing discussion & issue Form FDA 483

**Notes:**
CBER scientists can participate in the inspection, and can bring their knowledge of the application to look at specific aspects of the study.  

For example, an OCTGT reviewer went on an inspection of NGVL vector labs. 

## Comparison of Data in BLA / PMA to Source Data

- Comparison of Data in BLA / PMA to Source Data

- Data in
- BLA/PMA
-                Sponsor

- Source Data

- CRF

## Where is “Source Data” Defined?

- NOT defined in 312 or 812
- See GLP regs
- 21 CFR 58.3(k) – “raw data”
- 21 CFR 58.130(e) – describes how data are to be recorded, corrected, and describes automated systems.

## Elements of Data Quality = ALCOA

**	****	****	****A**ttributable
**	****	****	****L**egible/readable
**	****	****	****C**ontemporaneous
**	****	****	****O**riginal
**	****	****	****A**ccurate

## After the Inspection

- Inspected party may respond in a letter - send to address on the Form FDA-483.
- May also ask the FDA investigator for the HQ Center address
- The inspection report is written by the FDA investigator and sent to the Center.

**Notes:**
The items listed on this form will likely have been discussed during the inspection.  By the closing of the inspection, these items should not be a suprise.

This is an opportunity for the inspected party to provide documents not located during the inspection.  

## After the Inspection (2)

- The Center evaluates the report, and determines the corrective action.
- Classifications
- NAI – No Action Indicated
- VAI – Voluntary Action Indicated
- OAI – Official Action Indicated
- We write a letter following most inspections

## Most Common CI Violations

- Failure to follow the protocol
-     *	**example: R**equired testing is incomplete*
- Recordkeeping errors
- Informed consent problems

## Most Significant Violations

- Enrollment of ineligible subjects
- Violation of protocol affecting safety
- Extensive data corrections and questionable changes* *
- Inadequate oversight of study personnel
-     *Inappropriate delegation of authority*
*     **Poor oversight of satellite sites*
- No Informed consent
- Failure to communicate with IRB

## Significance of Violations

***Do the violations***
- ...affect rights, safety, or welfare of subjects?
- ...directly impact integrity of data set?
- ...indicate systemic problems within the     study? *sponsor problems?*
*   **Did the sponsor report the problems to FDA?*
- ...indicate that other studies at that site might be impacted?  *investigator problems*

## Inappropriate delegation to subinvestigators

- Investigator – individual who actually conducts an investigation (i.e., under whose immediate direction the drug is administered or dispensed to subjects.
-  How many miles (or states!) away ????
- Sponsor should assure that the CI controls the study

**Notes:**
For example, we inspected a California investigator who had sub-investigators in Arizona and Nevada.  The investigator NEVER visited the subinvestigators to see that the study was being properly performed.

EACH site should have had a clinical investigator sign a 1572 to be responsible for the study.

## Possible Administrative Actions	

- Warning Letter
- Determine if the data are reliable
- Complete and accurate?
- Delay approval of BLA/PMA
- Clinical hold
- Disapproval of IDE
- Initiate termination of IND
- Initiate disqualification of investigator
- Initiate Application Integrity Policy
- Refer to Office of Criminal Investigations

**Notes:**
We summarize the findings of our inspection in a BIMO Summary Review Memo to the BLA review committee

## Your Questions for CBER

- Can case report forms be source documents?
- 		Yes – protocol should specify how data are to be captured and records are to be maintained.
- Are diaries, questionnaires, photos subject to inspection?
- 		Yes –these need to be maintained by CI per 21 CFR 312.62(c)

## Your Questions for CBER

- What data points should be captured on case report forms?
- What data should be entered into a database for analysis?
- 	Data critical to determining safety and efficacy endpoints.  Protocol is roadmap for required tests.  Consult FDA review team.

## Your Questions for CBER

- Does FDA audit systems & databases to ensure they are validated?
- FDA does not audit computerized systems for clinical trials.
- Sponsor is responsible for QA of computerized systems used by the sponsor, and for determining whether systems used by investigator sites are suitable for their study.
- See FDA Guidance “Computerized Systems Used in Clinical Trials”
- http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

## Your Questions for CBER

- For clinics without medical records system in place, how
- should study records and source documents be
- maintained when subjects participate in one or more
- studies?
- Do you recommend that subject source records and
- health information be maintained in a central file, with
- study-specific CRFs maintained separately?
- No regulation for this.  Records should be retrievable
- and meet 312.62(c) retention requirements.  Records
- must be maintained at site if clinical investigator
- departs.  Recommend SOPS explaining how an alternate
- record system is utilized.

## If You have GCP Questions......

- Contact CBER’s Bioresearch Monitoring Branch  --
- 		Pat Holobaugh   301-827-6347
-      	_[holobaugh@cber.fda.gov](mailto:holobaugh@cber.fda.gov)_
- 					OR
- Contact your IND/IDE reviewer