# Presentation: 775730

## Overview of Gene Therapy Surveillance Inspections 

- Joseph P Salewski, Chief
- Bioresearch Monitoring Branch
- CBER

## PURPOSE ofBIMO

- To ensure the quality and integrity of data submitted to FDA in support of a marketing permit (IND, PLA/BLA, IDE, NDA)
- To ensure the protection of the rights and welfare of research subjects

## FDA’s BIMO Program

- Each Center has a BIMO Program staff
- Program is coordinated by the Office of Regulatory Affairs/ Office of Enforcement
- Inspections are conducted by ORA field staff, with Center experts as needed

## Bioresearch MonitoringCompliance Programs

- CP 7348.808	Nonclinical Laboratories
- CP 7348.809	Institutional Review Boards
- CP 7348.810	Sponsors, Monitors/Contract 			Research Organizations
- CP 7348.811	Clinical Investigators

## When does BIMO become involved?

- Submission of PLA/BLA
- Referrals from CBER staff
- Referrals from other Centers

## BIMO Involvement

- Complaints from Sponsors, IRBs, consumers
- Routine Surveillance

## Typical 10 Month

- Review Cycle

- Day
- 0

- Day
- 45

- Day
- 10

- Day 300

- CBER Receives
-  PLA/BLA

- Pre-PLA/BLA Meeting

- 1st Committee
- meeting

- Filing letter
- sent or RTF

- BIMO review of
- PLA -prepare
- assignments

- Internal Review
- Clinical and
- Manufacturing

- BIMO
- Inspections

- EIR’s come in

- BIMO Summary
- to Committee

- ACTION

## Site Selection Factors

- Number of subjects at each site
- Geographical distribution of sites
- Inspectional history of investigators
- Inconsistency of data at site
- Review committee’s concerns

## Site Selection Factors

- Number of subjects at each site
- Geographical distribution of sites
- Inspectional history of investigators
- Inconsistency of data at site
- Review committee’s concerns

## Assignment Content

- Background info on study and product
- Specific concerns/questions of review staff
- adverse events
- protocol followed
- blinding
- dosage and schedule
- endpoint met?

## Classifications

- No Action Indicated (NAI)
- Voluntary Action Indicated (VAI):
- objectionable conditions or practices are found, but the agency is not prepared to take administrative or regulatory action
- Official Action Indicated (OAI):
- regulatory and/or administrative actions will be recommended

## Correspondence

- Non-titled letter
- for NAI and VAI classifications
- Titled letters
- Warning Letters
- Notice of Initiation of Disqualification Proceedings and the Opportunity to Explain

## Administrative Actions

- Determination that data is unreliable
- Refusal to file PLA/BLA
- Clinical hold
- Termination of IND
- Disqualification
- Initiation of Application Integrity Policy

## GT Inspections

- Randomized selection of 30 active INDs out of 211 active INDs
- Resulted in:
- 24 Sponsors
- 70 Clinical Investigators

## GT Inspections

- Sponsors:
- commercial		6   =   25%
- government		1   =   4.1%
- independent		17 =   70.8%

## GT Inspections

- Clinical Investigators:
- commercial		46   =   65.7%
- government		  5   =     7.1%
- independent		19   =   27.1%

## GT Inspections

- Field time expended:
- total hours		4042.5 hours
- range			24 hrs to 208 hrs
- average		74.86 hours/inspection
- FTE equivalent	4.44 operational FTEs

## GT Inspections

- Overall results:
- Wash Outs		11   =   15.7%
- NAI			23   =   32.8%
- VAI			33   =   47.1%
- OAI			  3   =     4.2%

## GT Inspections

- Voluntary Action Indicated:
- objectionable conditions or practices are found but the agency is not prepared to take or recommend administrative or regulatory action
- Official Action Indicated:
- regulatory and/or administrative actions will be recommended

## GT Inspections

- Commercial sponsors	46 CI
- WO	  6  =  13%		8.5% overall
- NAI	14  =  30.4%	20%      "
- VAI	23  =  50%		32.8%    "
- OAI	  3  =    6.5%	  4.2%    "

## GT Inspections

- Government:		5 CIs
- WO	0
- NAI	3  =  60%		4.2% overall
- VAI	2  =  40%		2.8%      "

## GT Inspections

- Independent:		19 CIs
- WO	5  =  26.3%	7.1% overall
- NAI	6  =  31.5%	8.5%      "
- VAI	8  =  42.1%	11.4%     "

## GT Inspectionsa comparison

-        		NAI		VAI		OAI
- GT			38%		55.9%	 5.0%
- 2000 total	30.9%	57.1%	11.9%
- 2000w/o GT	21.4%	60%		18.5%
- 1999		28.5%	54.2%	17.1%
- 1998		34.9%	53%		12%

## GT Inspections

- The random surveillance inspections of Phase 1 and 2 gene therapy clinical trails indicates that the trials were being properly conducted with fewer deviations than found in Phase 3 studies.

## GT Inspectionsmost common deficiencies

- Failure to follow the protocol
- Inadequate Consent Form
- Lack of supporting data for CRF entries
- Discrepancies between source documents and CRFs
- Inadequate drug accountability records
- Failure to notify IRB of AEs and deaths
- Failure to notify IRBs of protocol changes