Learn How ASGCT Impacted FDA Guidance for CGT

ASGCT recently impacted how FDA addresses gene therapies for neurodegenerative diseases and CGTs that utilize multiple versions of a product throughout one clinical trial. In 2021, we commented on two draft guidances that were finalized last fall. We are happy to see FDA acknowledgment of our comments in the final versions of those two guidances: FDA Human Gene Therapy for Neurodegenerative Diseases and Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial.  

The final guidance on the first document, which focuses on gene therapy for neurodegenerative diseases, was released in October 2022. In comments submitted to the agency, ASGCT began by acknowledging the importance of early and frequent communication between FDA and sponsors. We also noted the Society’s support for additional FDA resources under the PDUFA VII agreement.  

FDA accepted several recommendations and made changes to the draft guidance to align with ASGCT’s suggestions:  

• In the section on CMC, the Agency accepted the Society’s recommendation to clarify that comparability (as a post-change analysis) is not considered a type of risk analysis (which is conducted pre-change).  

• In a later section related to comparability of products delivered by a device, FDA initially stated that “the delivery device, product concentration (tested over the planned dose range), drug product formulation, final infusion volume, duration and rate of infusion, and temperature should be the same for the device compatibility studies as they will be in the clinic.” In the final version, FDA took ASGCT’s advice that sameness is not a realistic standard and changed the final guidance to ask that samples be “representative.”    

• A section of the guidance covers considerations for clinical trial design and when sponsors might appropriately propose an innovative trial design as opposed to the randomized, placebo-controlled standard. ASGCT noted in our comments that randomized trials are often challenging if not entirely infeasible for rare diseases. In the final guidance FDA specified that randomized trials may be most appropriate in poorly characterized/understood and highly variable disorders (such as sporadic amyotrophic lateral sclerosis [ALS] or Alzheimer’s), and in doing so drew a clearer distinction between the disorders that might be amenable to innovative trial designs.   

• In our draft guidance comments and at our 2022 FDA Liaison Meeting, ASGCT shared concerns about FDA recommendations that products should have residual host cell-DNA levels of less than 10 ng/dose. While the specific 10 ng/dose reference was removed from this guidance, it does still exist in the cross-referenced final guidance CMC Information for Human Gene Therapy INDs. 

The final version of the second guidance document, which focuses on studying multiple versions of a CGT product in an early-phase clinical trial, was released in November 2022. Within our comments,  ASGCT noted that the Agency focused specifically on early-phase studies and suggested FDA should consider broadening the scope of the guidance to apply to any situation where multiple versions of a cellular or gene therapy product may be evaluated in the same trial. FDA did not choose to implement that suggestion, but ASGCT is hopeful that future guidance may do so. 

However, the Agency did acknowledge other recommendations and provided several technical adjustments to the draft guidance in line with ASGCT’s comments. Those successes include:  

• FDA amended the guidance to allow for discussion of multiple version-based development plans at either pre-Investigational New Drug (IND) or Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) meetings, rather than only at pre-IND meetings as the draft guidance allowed. 

• In our comments ASGCT expressed concern that the outlined system for submitting primary and secondary IND filings for the different versions would be repetitive and potentially confusing. In the final version, FDA adjusted the system to address that concern differently than ASGCT suggested.  

ASGCT appreciates any opportunity to fulfill our mission to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease. We appreciate FDA for thoughtfully considering ASGCT's comments and recommendations.  

ChiChi is ASGCT's regulatory affairs manager.

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