# Presentation: 817222

## Long Term Follow Up of Subjects in Gene Transfer Clinical Trials

**Philippe Bishop, MD**
**FDA/CBER**
**Division of Clinical Trial Design and Analysis**
**Oncology Branch**

## September 20, 1993 Letter to Sponsors

**RCR related lymphoma in Rhesus monkeys (Donahue RE et al, **_**J Exp Med**_** 176:1125, 1992)**
**Limited clinical experience with retroviral vectors**

## Life Long Monitoring:A Key Principle

**Clinical exposure to integrating vectors may pose risks to subjects that may not become apparent until years later.**
***De novo***** cancer **
**Autoimmune disease **
**Hematologic disorders**
**Neurologic disorders**

## October 18, 2000 Guidance Document

**Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials using Retroviral Vectors.**
**http://www.fda.gov/cber/guidelines.htm**

## RCR-specific antibodies 
or
PCR for RCR-specific sequences in peripheral blood mononuclear cells

**or**
**PCR for RCR-specific sequences in peripheral blood mononuclear cells**

**Current Recommendations****Assays**

## Pre-treatment 
3 months
6 months
1 year after treatment
Yearly thereafter

**3 months**
**6 months**
**1 year after treatment**
**Yearly thereafter**

**Current Recommendations****Testing Schedule**

## Current RecommendationsTesting Schedule (continued)

**Yearly archival **
**if samples are negative for RCR **
**for 1 year post-treatment**
**Additional testing and patient follow-up **
**if clinically indicated and/or **
**sample is positive for RCR.**

## Current RecommendationsClinical Follow-up

**Yearly clinical history **
**Cancer**
**Neurologic disorders **
**Hematologic disorders**
**Suspect clinical outcomes may trigger additional analysis of archived samples**

## Current RecommendationsClinical Follow-up (continued)

**If a study participant **
**Develops***** de novo***** neoplasm **
**Neoplastic tissue should be tested for RCR **
** ****Dies**
**An autopsy should be obtained and sampled tissue tested for RCR.**

## Current RecommendationsDocumentation

_**Expedited reports**_** (21 CFR 312.32)**
**Positive results (laboratory or clinical)**
_**Annual Reports**_** (21 CFR 312.33)**
**Other laboratory data**
**Clinical summaries**
**Autopsy results**

## Retroviral Vector Gene TherapyFDA Survey

**Sponsors were contacted and asked to comment on their experience implementing life long monitoring protocols **

## Retroviral Vector Gene TherapyLong-Term Monitoring Survey

**89% of INDs have an established long-term follow-up protocol**

## Estimates: $1,500-$5,000/patient/year
Inadequate resources (limited grants)
Sub-optimal 3rd party reimbursement

**Inadequate resources (limited grants)**
**Sub-optimal 3rd party reimbursement**

**Sponsor’s Comments to FDA****Costs**

## Study participants move
Geographic distance
Patient and referring MD lose interest
Inadequate reporting (MD to PI; PI to Sponsor)

**Geographic distance**
**Patient and referring MD lose interest**
**Inadequate reporting (MD to PI; PI to Sponsor)**

**Sponsor’s Comments to FDA****Clinical follow-up**

## PI moves to another institution
PI leaves academia to private sector/industry
Industry mergers/Bankruptcy
Sponsor/Institution reluctant to devote indefinite resources (program closure)

**PI leaves academia to private sector/industry**
**Industry mergers/Bankruptcy**
**Sponsor/Institution reluctant to devote indefinite resources (program closure)**

**Sponsor’s Comments to FDA****Commitment**

## Most patients die at home or away from research centers 
PIs are not notified in time
Families are not asked or decline to consent
Sampling for RCR is not performed or specimen collection is sub-optimal

**PIs are not notified in time**
**Families are not asked or decline to consent**
**Sampling for RCR is not performed or specimen collection is sub-optimal**

**Long-Term Monitoring Survey****Autopsies**

## Lack of standardization (core facility?) 
Sensitivity
Validation
Clinical relevance:  (ex vivo vs in vivo gene transfer studies)

**Sensitivity**
**Validation**
**Clinical relevance:  (*****ex vivo***** vs *****in vivo***** gene transfer studies)**

**Long-Term Monitoring Survey****Assays/Testing methods**

## IND Inactivation or withdrawal
15% of INDs
Sponsor committed to annual follow-up of patients
FDA will accept expedited and annual reports

**15% of INDs**
**Sponsor committed to annual follow-up of patients**
**FDA will accept expedited and annual reports**

**Administrative Actions****Assurance of Continued Monitoring**

## Enforcement Options 

**Clinical Hold**
**Site visit/inspection**
**Warning letter**
**Disqualification**

## Summary

**Updated guidance document **
**Sponsors expressed concerns that life long monitoring is **
**Logistically difficult, **
**Costly, and **
**Requires an unusual level of commitment.  **
**FDA’s enforcement options are limited.**