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.

 RCR-specific antibodies 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 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 Ü Cancer Ü Neurologic disorders Ü 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 Ü Neoplastic tissue should be tested for RCR  Dies Ù An autopsy should be obtained and sampled tissue tested for RCR.

Current Recommendations Documentation Expedited reports (21 CFR )  Positive results (laboratory or clinical) Annual Reports (21 CFR )  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 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) 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) 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 Long-Term Monitoring Survey Autopsies

 Lack of standardization (core facility?)  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 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 Ü Logistically difficult, Ü Costly, and Ü Requires an unusual level of commitment.  FDA’s enforcement options are limited.