FDA Guidance on Gene Therapy Products: RCR Testing and Monitoring – Focus on Documenting Test Results & Post-Licensure Considerations

July 19, 2021

In January 2020, FDA issued a final guidance document on the topic of “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up.” The document supersedes the Agency’s previous guidance published in 2006, entitled “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 from the 2006 guidance document include:

  • No longer recommending Replication Competent Retrovirus (RCR) testing on working cell banks for retroviral producer cells
  • Revised recommendation for amount of vector tested
  • All retroviral vector transduced cell products should be tested for RCR
  • Alternative methods for lot release testing of ex-vivo transduced cells may be used in lieu of culture based methods
  • Revised recommendation for active monitoring of patients following drug administration
  • Post-licensure consideration for RCR testing and risk assessment added

The guidance was initially released as a draft in 2018, and last year’s final version remains largely unchanged, serving mainly as a supplement to the chemistry, manufacturing, and controls (CMC) and long-term follow-up guidance documents also published in January 2020.

In three of our recent cell and gene therapy 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.  We also outlined specifics of the patient monitoring section of the guidance. Now, to wrap up the series, we are going to take a look at FDA’s recommendations related to documentation of RCR results as well as the Agency’s post-licensure considerations.

Documentation of RCR Testing Results

FDA recommends documenting RCR testing results from production lots and patient monitoring in amendments to the Investigational New Drug (IND) application. Positive RCR testing results should be reported immediately as an adverse experience in the form of an IND safety report, while negative results can be reported annually in the appropriate report format.

Post-Licensure Considerations

FDA’s post-licensure considerations include the recommendation that “labeling for retroviral vector-based gene therapy products incorporate relevant data and information to clearly present the immediate and long-term risks associated with RCR.” In addition, FDA also recommends continuation of RCR testing during vector manufacture and release after licensure.

In the guidance document, the Agency notes that at the time of Biologics License Application (BLA) submission, “you should have accumulated sufficient manufacturing and clinical safety data to determine whether there is a significant risk of RCR developing with your product.” Sponsor’s may use the risk assessment to demonstrate that periodic post-licensure patient monitoring for RCR is not necessary for the cell and gene therapy product in question. Furthermore, FDA also states that the BLA should include a statement related to the collection of relevant clinical samples for RCR testing upon development of an adverse event suggestive of a retrovirus-associated disease.

Finally, FDA’s guidance document also provides recommendations related to continued long-term patient follow-up in accordance with the Long-Term Follow-up guidance. In the case of patient death, RCR testing should also be performed on biopsy samples.

ProPharma Group Cell and Gene Therapy Center of Excellence: Your Partner Throughout the Entire Lifecycle

RCR contamination of retroviral vector-based human gene therapy products is a serious concern. FDA’s guidance makes clear that it is incumbent on Sponsors of retroviral vector-based gene therapies to monitor critical manufacturing stages and clinical outcomes prior to licensure to assess the potential for RCR contamination. For increased safety, the expectation is that RCR testing during vector manufacture and release will continue after licensure. RCR monitoring also extends to include long-term patient follow-up, for as long as 15 years after dosing.

Are you in the process of developing a CBER-regulated product subject to the recommendations outlined in this guidance document? Our Cell and Gene Therapy Center of Excellence has extensive experience in all facets of cell and gene therapy product development, and we can help ensure your product is set up for successful interactions with FDA. Contact us today to learn more about our services and how we can help you.




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