In July 2018, FDA issued a draft guidance document entitled “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up.” In January 2020, FDA finalized the draft guidance document, with the final recommendations remaining largely unchanged, covering the following main topics:
The updated guidance document replaces a guidance document from 2006 in which FDA provided recommendations on “Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors.”
Revisions in the new guidance include:
In two of our recent blogs, we introduced the guidance document, providing a general overview of its contents and dove into the FDA’s specific recommendations related to product testing. Now, the spotlight is focused on patient monitoring.
In its guidance document, FDA recommends patient monitoring be performed on a periodic basis to ensure no retroviral infection is evident after administration of retroviral vector-based gene therapy products. The following timelines for RCR testing of patient samples should be included in the long-term follow-up protocol: pre-treatment, three, six, and twelve months after treatment, and yearly for up to 15 years. However, if all patient assays are found negative for the first year, a yearly review of the patient medical history may be substituted for the yearly collection of follow-up samples. The long-term follow-up protocol should also include a requirement to submit a yearly long-term follow-up clinical report to the Investigational New Drug (IND) application.
If any post treatment samples are found positive at any timepoint during long-term follow-up, the product’s Sponsor should consult with CBER to determine if a more extensive patient follow-up is warranted. Additionally, upon development of an adverse event suggestive of a retrovirus-associated disease, the guidance recommends collecting and testing relevant samples for RCR. In the event of a patient death during a gene therapy trial (within 15 years), a biopsy sample of the neoplastic tissue or pertinent autopsy tissue should be assayed for RCR.
Two methods are currently in use for detecting evidence of RCR infection in patients. These methods are:
In the guidance, FDA suggests that PCR may be a better option than serologic monitoring in immunocompromised patients where antibody production may be limited or non-existent. Regardless of the method employed, all confirmed positive results should be followed by direct culture assay to obtain and characterize the infectious viral isolate.
Interested in learning more? There is one more blog post coming your way, as this is only part three in our four-part blog series. Stay tuned, because in the final blog post in the series we will dive into the FDA’s recommendations related to RCR testing results and post-licensure considerations.
Are you in the process of developing a cell and gene therapy product subject to the recommendations outlined in this guidance document? Our Cell and Gene Therapy Center of Excellence has experience with all facets of cell and gene therapy regulation and compliance. We are ready to help you achieve successful interactions with FDA, so contact us today to learn more about our cell and gene therapy-specific services and qualifications.
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