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 disordersNeurologic 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

Current RecommendationsAssays

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

Current RecommendationsTesting Schedule

Current RecommendationsTesting 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 RecommendationsClinical Follow-up Yearly clinical history

CancerNeurologic disorders Hematologic disorders

Suspect clinical outcomes may trigger additional analysis of archived samples

Current RecommendationsClinical Follow-up (continued)If a study participant Develops de novo neoplasm

Neoplastic tissue should be tested for RCR

DiesAn autopsy should be obtained and

sampled tissue tested for RCR.

Current RecommendationsDocumentation

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 TherapyFDA Survey

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

#/n %

Sponsors 33/50 66

INDs 51/71 72

Clinical trials 81/110 74

Retroviral Vector Gene TherapyLong-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

Sponsor’s Comments to FDACosts

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

Sponsor)

Sponsor’s Comments to FDAClinical 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)

Sponsor’s Comments to FDACommitment

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

Long-Term Monitoring SurveyAutopsies

Lack of standardization (core facility?)

Sensitivity

Validation

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

Long-Term Monitoring SurveyAssays/Testing methods

IND Inactivation or withdrawal 15% of INDs Sponsor committed to annual follow-

up of patients FDA will accept expedited and annual

reports

Administrative ActionsAssurance 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.