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May 19, 2021 Life Science Consulting

FDA Guidance on Gene Therapy Products: RCR Testing and Monitoring

Fred Wiles Senior Consultant, Product Lifecycle Management

Gene therapy holds the promise of curing severe genetic diseases at the genetic level rather than merely treating the symptoms as is accomplished using conventional small-molecule drug therapies. In a genetic disease, one or more genes are defective as a result of a mutation either passed down from generation to generation or incurred due to an environmental condition. Gene therapy attempts to remedy the disease by inserting a corrected version of the mutated gene into the chromatin of a target cell using direct physical or chemical methods (e.g., microinjection or lipofection, respectively) or by using a specifically designed gene vector such as a retrovirus.

A critical concern for the manufacture of retroviral vector-based gene therapy products is the potential for contamination by replication competent retrovirus (RCR). Ideally, retroviral vector-based gene therapy products consist only of a replicative deficient retrovirus; that is, retrovirus having inhibited replication abilities. However, any retroviral vector-based gene therapy manufacturing process has the potential to introduce a high titer of replicative competent retrovirus which can lead to undesirable or even fatal side effects due to insertional mutagenesis. Insertional mutagenesis due to excessive RCR in gene therapy products has been linked in several animal and human studies to the subsequent development of adverse diseases such as lymphoma. As a result of these concerns, the FDA published an updated guidance document in January of 2020, providing recommendations for Sponsors of retroviral vector-based human gene therapy products. Specifically, the recommendations address the types and frequency of testing that is expected to be conducted to detect potential RCR contamination during manufacturing and post-administration patient monitoring. According to the guidance, all retroviral vector transduced cell products, including those cultured four days or less, should be tested for RCR.

The January 2020 guidance, entitled “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up,” supersedes the Agency’s guidance document published in 2006 titled, “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 include:

  • No longer recommending 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 January 2020 guidance is largely unchanged from the July 2018 draft guidance and serves as a supplement to the chemistry, manufacturing, and controls (CMC) and long-term follow-up guidance documents also published in January 2020. The guidance covers four main subject areas:

  • Recommendations for Product Testing
  • Recommendations for Patient Monitoring
  • Documentation of RCR Testing Results
  • Post licensure Considerations

Interested in learning more? In this four-part blog series, we will dive into each of these subject areas in more detail. Stay tuned for our next blog in the series, where we will discuss FDA’s recommendations for product testing.

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

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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