ASGCT Members Provide Recommendations During FDA Liaison Meeting

ASGCT held its fifth annual liaison meeting with FDA CBER’s Office of Tissues and Advanced Therapies (OTAT) on Nov. 14, 2022. A group of Society leaders and members gave two presentations to FDA on significant topics in the field, followed by a presentation from FDA. Dr. Keith Wonnacott, ASGCT’s Regulatory Affairs Committee Chair, chaired the meeting and moderated discussion. 

Selected Updates and Assessment of FDA’s Adoption of ASGCT’s 2018-2021 Recommendations 

Presenters: Hans-Peter Kiem, MD, PhD, Fred Hutchinson Cancer Center; Ravishankar Vadali, PhD, Ocugen Inc.; Jack Brownrigg, MD, PhD, BioMarin Pharmaceutical Inc.; and S. Kaye Spratt, PhD, independent Advanced CGT Regulatory Consultant 

Presentation slides

To mark the fifth year of ASGCT’s Liaison Meetings, the Society’s first presentation looked back to review previous recommendations. ASGCT President Dr. Hans-Peter Kiem explained that the goal was to express thanks and give constructive feedback in cases where FDA has moved in a positive direction and reiterate key points and suggest a path forward in other instances. The presentation focused on Chemistry, Manufacturing and Controls (CMC); clinical issues; and logistics and procedural topics. 

Dr. Ravi Vadali began with CMC issues. ASGCT’s recommendations focused on several key points, including treatment of certain plasmids and viral vectors as raw materials or reagents; process validation (PV); and product specification challenges related to identity, sterility, acceptance criteria/range, and impurities including HCP and DNA levels. Dr. Vadali also noted that ASGCT had made previous recommendations related to comparability, and that the Society is looking forward to the expected draft guidance on Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Draft Guidance for Industry as included in the 2022 CBER Guidance Agenda. 

Dr. Jack Brownrigg next took up clinical considerations. He reiterated previous ASGCT recommendations on innovative trial design, surrogate endpoints and accelerated approval,; and immunogenicity and immunosuppression. On endpoints and benefit-risk assessment, he highlighted several past suggestions and added a new recommendation on the criticality of leveraging opportunities for dialogue, including additional options available to sponsors under PDUFA VII. On long-term follow-up (LTFU), Dr. Brownrigg highlighted additional recommendations on the use of data collected pre-approval to fulfil post-approval requirements, and on the use of risk evaluation and mitigation strategies (REMS) for long-term safety data collection and surveillance. 

Dr. Kaye Spratt rounded out the presentation with a discussion on procedural and logistical issues. She thanked CBER, and OTAT in particular, for their significant efforts in recent months to promote interactive communications between regulators, sponsors, and patient groups. Dr. Spratt shared a number of recommendations to help further that productive engagement, including a suggestion that OTAT repeat their 2021 listening session to capture impacts of the OTAT Growth Program and that FDA post an FAQ or host a town hall on RMAT designations to help lower the denial rate. The key message of Dr. Spratt’s presentation was to ask FDA to consider avenues to publicly share certain aggregated/generalized information that would benefit or impact a significant subset of sponsors or development programs. Dr. Spratt closed with the pledge that ASGCT wants to play a positive, proactive role to work with OTAT to advance the entire gene and cell therapy field.  

In a brief discussion period, Dr. Wilson Bryan, Director of OTAT, expressed appreciation for the way the presentation was formatted, making it simple for different offices to take the recommendations back. He next discussed guidance documents generally, noting that FDA frequently gets requests for guidance before they have sufficient experience in a given area, but that sponsors’ highlighting of issues is helpful for FDA even if they are not prepared to issue a guidance. Finally, Dr. Bryan said that written response only (WRO) levels will continue to be dependent on workload, with additional PDUFA VII resources balanced against ever-increasing IND submissions. He noted that the quality of WRO responses is critical, and that OTAT is reviewing their internal processes to ensure sponsors have opportunities for clarification when needed. 

Opportunities for Gene Therapy Development With Novel Engineered AAV Capsids 

Presenters: Eric Kelsic, PhD, Dyno Therapeutics; Beverly Davidson, PhD, Children’s Hospital of Philadelphia; and Sharif Tabebordbar, PhD, Kate Therapeutics 

Presentation slides

ASGCT’s second presentation addressed novel engineered AAV capsids, which hold the promise to improve the safety and efficacy of gene therapies. Dr. Eric Kelsic explained that engineered AAV capsids could be created in a variety of ways, as opposed to “natural AAV capsids” which are isolated from a natural sample. Surrogate capsids, meanwhile, are capsids substituted for clinical capsids in certain preclinical studies, such as to enable sufficient delivery to target cells of a surrogate animal disease model. Novel engineered AAV capsids hold promise to reduce biodistribution and transduction to off-target cells/organs and improve the efficiency of payload delivery to target cells/organs, but come with unknowns. Importantly, some engineered capsids have different biodistribution and transduction profiles for on-target and off-target tissues across species.  

Advancements in technologies across the gene therapy field are helping improved gene therapies to reach more patients; in the case of novel engineered AAV capsids, Dr. Kelsic noted that there are open questions from sponsors that would benefit from additional regulatory clarity. In that vein, Dr. Bev Davidson, ASGCT’s immediate past President, shared the Society’s recommendations for FDA, including that the Agency: 

• Provide guidance to sponsors regarding how to separately demonstrate the translatability of capsid efficacy and payload efficacy to humans. 

• Primarily require a sponsor to provide evidence of effective delivery to target cell types in the most scientifically relevant available model, noting that most recently the greatest confidence has come from data using non-human primates (NHPs). 

• Guide sponsors to demonstrate payload efficacy in the most relevant cellular context. 

• Make no distinction between natural or engineered AAV capsids with regard to required criteria for supporting the safety of AAV gene therapies. 

To demonstrate how these recommendations might be applied in real-world situations, Dr. Sharif Tabebordbar presented a series of scenarios featuring capsids with varying transduction characteristics. The scenarios began with the most straightforward situation, in which the capsid variant transduces the target tissue across species, enabling demonstration of capsid efficacy in NHPs and payload efficacy in a mouse disease model. Dr. Tabedbordbar also explained how to calculate a minimally efficacious dose from data generated by the two studies.  

Dr. Tabebordbar next considered a situation in which the capsid variant transduces the target tissue in NHPs but not in mice, supporting the use of a surrogate capsid to demonstrate payload efficacy. Finally, he presented a scenario in which the capsid variant is known to show efficacy in NHPs, but there is not an established/available disease model in which to define the minimum efficacious transgene protein, supporting the use of a separate in vitro cellular transduction assay to evaluate payload efficacy and information from human genetics to guide dose finding. 

FDA/CBER Office of Tissues and Advanced Therapies (OTAT) Update 

Presenter: Wilson Bryan, MD, Office of Tissues and Advanced Therapies 

Presentation slides

Finishing out the day, Dr. Wilson Bryan shared updates on several aspects of OTAT operations. He started by highlighting the recent approvals of Zynteglo (betibeglogene auotemcel) and Skysona (elivaldogene autotemcel). He pointed out that successful programs rely on good science to make it across the finish line. That includes knowing the disease, its natural history, and its pathophysiology deeply, and understanding the characteristics of the product that are going to have an impact on the target disease. He expressed hope that, as the field matures, the field will get better at speeding up development.  

Dr. Bryan explained that IND submissions and meeting requests have skyrocketed since 2016 and outpaced OTAT’s workload capacity. He expressed thanks to ASGCT and other organizations that advocated for OTAT to receive additional resources in coming years. As a way to prioritize the workload, Dr. Bryan explained that Breakthrough Therapy (BTD) and Regenerative Medicine Advanced Therapy (RMAT) designations help focus FDA attention on the products most likely to succeed and have a substantial improvement over available therapies. BTD requests have had an overall 30% success rate, while RMAT requests have had an overall 37% success rate.  

Dr. Bryan broke down the common reasons for denial of RMAT designations, with the majority relating to clinical concerns: clinical study design, insufficient data submission, provision of data that’s difficult for FDA to interpret, or inconsistent results. He highlighted that single-arm, open label studies in particular can be very difficult for FDA to interpret. CMC and administrative issues rounded out the top reasons for denial. After denial, Dr. Bryan said that FDA had received 40 re-submissions to date for 33 different INDs, which had an approximately 33% success rate. In nearly all successful re-submissions, Dr. Bryan said sponsors have included new data to support that the product has activity showing the potential to address unmet needs. In a few uncommon cases, successful re-submissions have included a new analysis or way of looking at the same data. And in a single successful case, the re-submission was simply an appeal that FDA had decided wrongly and needed to reassess.  

Finally, complimenting efforts to prioritize products with higher chances of success, Dr. Bryan summarized efforts to actively increase CBER’s overall capacity. He noted the upcoming CBER reorganization (tentatively beginning in February) that will turn OTAT into the Office of Therapeutic Products (OTP), a super-office with six sub-offices. He explained that the new structure should provide additional opportunities to ensure new review staff can get up to speed faster and provide more consistent review outcomes across all reviewers. He also highlighted the additional 228 FTEs allowed under PDUFA VII, plus efforts to enhance communications including projects highlighted in ASGCT’s first presentation of the day.  

During discussion, Dr. Bryan clarified that there have been rare disease products approved based on single-arm studies, including most if not all of the currently approved CAR T products and Zolgensma, and that there are times when single-arm studies are appropriate. He stressed that single-arm studies are most credible when outcome measures are reliably different from the disease’s natural history – for example, remission in the case of CAR T products for blood cancers. He also pointed out, however, that in rare diseases, natural history data can be insufficient to determine whether a given outcome measure is typical. In other cases, good natural history data does exist but shows a highly heterogenous disease course. Dr. Bryan therefore stressed that any company going into rare disease should ensure that they’re actively collecting natural history data.  

Dr. Wonnacott brought up the Q&A guidance CBER agreed to under PDUFA VII, noting that it would allow FDA to address more limited or emerging issues that may not have enough content for a comprehensive guidance. Dr. Bryan said that many of the PDUFA VII commitments are rooted in the spirit of communication, and that in addition to the specific agreements FDA made, the Agency is thinking about other ways to communicate better. He noted Q&A guidance(s) may be a good option to achieve that. 

Dr. Wonnacott finally asked about the pending retirement of many experienced reviewers and the expected influx of new reviewers, looking to both challenges and opportunities. Dr. Bryan said that FDA would feel the loss of cumulative centuries of experience as senior review staff left, but also pointed out that new, enthusiastic, and diverse perspectives are a necessary component to any growing organization. He said that, with attention to guidances and management structure, and with appropriate training for staff who may not have direct development experience, there are many opportunities ahead—in short, it’s an exciting time to be at FDA.   

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