ASGCT Submits Comment on FDA Gene Therapy Guidance Documents
ASGCT Staff - December 11, 2018
ASGCT submitted comments to the FDA regarding six draft guidance documents on gene therapy development on Dec. 10. ASGCT welcomes the provisional guidance in the development of gene therapies and submitted 71 individual recommendations and requests for clarification for FDA consideration.
ASGCT submitted comments to the FDA regarding six draft guidance documents on gene therapy development on Dec. 10. The FDA drafts include the first disease-specific guidance documents on gene therapy. ASGCT welcomes the provisional guidance in the development of gene therapies and submitted 71 individual recommendations and requests for clarification for FDA consideration.
Among the notes regarding draft guidance on gene therapy for retinal diseases, ASGCT finds treating with vehicle control, the use of empty vectors to compare treatment and control groups, to compare to a treatment group, to be unethical, specifically when administration poses unacceptable risks. The Society proposes adding a well-controlled prospective natural history study to the list of alternatives to vehicle control. Similarly, ASGCT does not believe a patient’s other eye should be sham-treated as an experimental control when the patient's eyes are at different stages of the disease; instead, the Society recommends designing a relative difference scale.
ASGCT recommends requiring post-infusion testing for replication competent lentivirus (RCL) and replication competent retrovirus (RCR) only in the case of an adverse event given the overwhelming evidence that modern split-packaging gammaretroviral and lentiviral packaging systems never generate RCR/RCL. Additionally, the Society believes researchers should not need to test vectors that have been free of RCL/RCR based on data from either a study sponsor or generally-available data.
ASGCT supports vector- and disease-specific requirements for long-term follow-up reporting as proposed in the guidance, and agrees that the 15-year reporting requirement for many gene therapy applications is no longer relevant to many in vivo DNA vector applications. Within the section on post-marketing monitoring plans, ASGCT recommends that FDA clarify that use of patient registries is an allowable choice for complying with long-term monitoring requirements.
While clotting factor activity assay discrepancies may hinder reliable interpretation of the results, that doesn’t mean clotting factor activity cannot be used as an endpoint or outcome being measured by a clinical trial. ASGCT recommends that the FDA clarify that sponsors may explain discrepancies in clotting factor activity tests based on differing methodologies rather than ruling out use of clotting factor activity as an endpoint. The Society also recommends monitoring for adverse events for 2-5 years after exposure to non-integrating gene therapy products, as stated in the draft guidance on long term follow-up, rather than the guidance from the documents on hemophilia, which recommend at least 5 years.
Rather than complying with an arbitrary FDA limit (10 ng HC DNA/dose), ASGCT recommends IND applications document the levels of contaminating host-cell DNA and strongly transforming oncogene DNA in products. Also, if plasmids do not directly become part of the drug substance or drug product, they may be defined as starting materials or reagents and their quality ensured by appropriate controls for critical starting materials. Because the document lacks clarity on whether several types of information discussed should be submitted at the IND submission stage, ASGCT requests clarification on this timing.
For all relevant guidance documents, including the guidance on Human Gene Therapy for Rare Diseases (final comment letter), ASGCT contends that biodistribution studies should not need to be repeated to assess the pharmacokinetic profile of a gene therapy product when the biodistribution of the vector being used has been well defined and well characterized, and the product differs only in the transgene encoded.
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