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Regulatory Focus™ > News Articles > 11 > BIO Seeks Clarity on FDA’s Gene Therapy Draft Guidances

BIO Seeks Clarity on FDA’s Gene Therapy Draft Guidances

Posted 21 November 2018 | By Zachary Brennan 

BIO Seeks Clarity on FDA’s Gene Therapy Draft Guidances

Industry group BIO recently submitted comments on a series of new draft guidance documents on gene therapy released by the US Food and Drug Administration (FDA) in July.

The six guidance documents focus on developing hemophilia, rare disease and retinal disorder gene therapies, and also include one on chemistry, manufacturing and control (CMC) information, one on long term follow-up observational studies collecting data on adverse events and one on the testing of retroviral vector-based therapies.

On the draft guidance for developing gene therapies for rare diseases, BIO calls for regulatory flexibility in designing clinical trials.

BIO says that FDA should not “use otherwise limiting language such as those recommending specific number of treatment arms, utilizing different doses but the same product administration procedures, or the inclusion of a sham control group. Use of innovative clinical trial design can decrease unnecessary and unethical patient exposure to clinical procedures and experimental products while still advancing clinical development.”

With respect to the inclusion of patient experience data, BIO also seeks additional guidance on what types of data may be the most useful to inform regulatory decision-making.

On the draft guidance on CMC information, BIO notes that several sections directly or indirectly suggest that CMC information provided in the IND represents a “commitment” and “is subject to FDA review prior to releasing a new lot of clinical trial material.”

“The terms ‘commitment’ and ‘lot release’ are generally used in the context of licensed products and in this regard could be interpreted that CMC changes made during clinical development are subject to review and prior approval before implementation. Such a requirement could potentially restrict and delay development including continuous improvement of products under clinical development, which critically depends on regulatory flexibility while process and product knowledge are accumulated. BIO would appreciate if FDA could clarify the meaning of the terms ‘commitment’ and ‘lot release’ in this context or consider removing this language from the Guidance to avoid possible misinterpretation.”

BIO also raises questions on the clarity of the scope of draft CMC guidance. For instance, the draft states that the scope covers gene therapy applications generally but some recommendations, such as those regarding shipping and handling, are specific to ex vivo gene therapies and are not appropriate for in vivo gene therapies.

“In addition, we would appreciate clarification regarding the quality expectations on gene modifying agents, such as viral vectors.  When used in the ex vivo manufacture of gene therapy products, the vector should be considered a critical starting material, which should be well characterized and appropriately controlled but not necessarily to the same extent as a drug substance. We ask FDA to provide specific recommendations for the product type and differentiate recommendations for ex vivo gene therapy products from in vivo gene therapy products,” BIO says.

Other draft recommendations are unclear for which stage of development they would apply to, BIO adds.

On the draft guidances related to hemophilia and retinal disorders, BIO offered several general comments and sought clarity on how the data from biodistribution studies can be used to design preclinical toxicology studies. 

On the draft related to long term follow-up observational studies, BIO said it believes the draft should recognize some of the challenges associated with viral vector persistence and safety risk. But BIO also said it welcomed the updated change in the draft of five to 15 year follow up, “which affords flexibility upon clinical experience and are based on product type.”

And for the draft guidance regarding product testing for replication competent retrovirus (RCR), BIO commends the agency as it’s “well-reasoned and we concur with most recommendations.”


Tags: BIO, gene therapy

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