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Department of Health and Human Services
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
September 20, 1993
Dear Sponsor of an IND Using a Retroviral Vector:
Because of the recently-described severe toxicity of replication competent retroviruses (RCR) in immunosuppressed primates (Donahue, et al, J. Exp. Med., 176:1125, 1992) we have the following requests regarding patient monitoring in your ongoing and future clinical trials:
- Please include periodic monitoring for evidence of RCR infection. We recommend that this monitoring include serological assays for evidence of antibody to retroviral envelope proteins, assays for reverse transcriptase, and direct assays for viral nucleic acid in peripheral blood leukocytes (PBL) using a polymerase chain reaction (PCR) technique. The PCR should utilize a radioactive (or equally sensitive) detection system. In certain cases not all these tests will be appropriate or feasible; in those cases, please provide a rationale for not including a specific type of test in your monitoring program. We recommend that you monitor patients at least monthly during treatment, monthly for the first three months following completion of treatment, every three months for the remainder of the year following completion of treatment, and then at least yearly thereafter. In addition, please obtain and hold frozen sera and PBL from each patient at each time point in the monitoring program. These samples should be held indefinitely. Please obtain sufficient sample prior to beginning treatment to ensure that control materials will be available for subsequent patient monitoring.
- For patients with positive results in any of the above assays, please attempt to identify infectious retrovirus by direct culture of patient PBL. For this assay, we recommend that you perform a co-culture of the patient PBL with a cell line susceptible to retroviral infection.
- Please include the results of this RCR monitoring in your annual progress reports. This should include all primary data, even when interpreted as negative. In addition, please include the identity of the retroviral vector, the number of patients treated with the vector, the titer and quantity of retroviral vector each patient's cells received in ex-vivo transductions, and the duration of such treatment, as well as any other relevant data. As a reminder progress reports are required at intervals not exceeding one year and are due within 60 days of the anniversary of the date that the IND went into effect.
- For any confirmed positive RCR test, please file a written IND safety report as described under 21 CFR 312.32(c)(1).
- If you have previously observed evidence of RCR infection in patients, please file an IND amendment including all relevant data, including the total number of patients you have treated, duration of treatment, and the identity of the vector.
- If you have not provided the information requested in paragraph 3 above in your previous annual progress reports, please file an IND amendment supplementing your previous annual progress reports with all the information requested in paragraph 3. If some of these data are unavailable, please provide an explanation.
Your prompt attention to these matters is appreciated. In particular, we request that you expedite the request under paragraph 6 above. All information concerning this matter should be forwarded in triplicate, identified with the BB-IND number assigned, and addressed as follows:
Center for Biologics Evaluation and Research
Attn: Office of Therapeutics Research and Review
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
If you have any questions, please call the Cytokine and Gene Therapies Branch Chief at 301-827-5101.
Sincerely yours,
--- signature ---
Janet Woodcock, M.D.
Director
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
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