ASGCT Members Share Regulatory Recommendations During FDA Liaison Meeting

Last month, ASGCT held its sixth annual liaison meeting with FDA CBER’s Office of Therapeutic Products (OTP). 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. Kristin Van Goor, ASGCT’s Regulatory Affairs Committee Chair, opened the meeting and Dr. Keith Wonnacott moderated discussion.  

FDA leaders in attendance included FDA’s Dr. Peter Marks and Dr. Nicole Verdun. Both thanked ASGCT for engaging with the Agency throughout the year. Olivia Ziolkowski, the CBER Ombudsman, also introduced herself and highlighted her office’s role in facilitating formal or informal dispute resolution between CBER and sponsors.  

ASGCT Presentation 1: Class Considerations for Determining Safety and Efficacy Outcomes for AAV Gene Therapies  

Presenters: Nimi Chhina, PhD, JD, BioMarin Pharmaceutical; James Nickas, PharmD, BioMarin Pharmaceutical; Terence Flotte, MD, ASGCT Board of Directors, University of Massachusetts Chan Medical School; Snehal Naik, PhD, Spark Therapeutics  

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ASGCT’s first presentation focused on safety and efficacy for AAV gene therapies. Dr. Nimi Chhina opened by noting that ASGCT’s goal is foster regulatory clarity and predictability by streamlining product development and reducing duplicative efforts. She explained that FDA has information across this class of products that is more comprehensive than any one individual sponsor or trial PI, and that the purpose of the presentation is to encourage FDA to share their learnings where possible on issues that are relevant across the AAV class. While ASGCT’s liaison meeting presentation focused on two topics - integration and theoretical oncogenicity risk plus immunogenicity – there are a number of other issues that warrant further discussion including shedding, biodistribution, immunosuppression, contraception, and alcohol abstinence. Dr. Chhina proposed that ASGCT co-host a public workshop with FDA to work toward consensus on these topics and share information that would benefit the entire field.   

Dr. Jim Nickas gave an overview of the current state of knowledge on AAV integration, noting that the risk of AAV-mediated oncogenesis in humans is currently theoretical. He discussed considerations for risk-proportionate labelling versus class-wide labeling on the risks of integration and tumorgenicity, and suggested to FDA that specific AAV-vector based guidance could facilitate consistent labeling that better educates physicians and patients to inform benefit-risk treatment decisions. Finally he highlighted some of the topics that would be appropriate to pursue in a workshop such as Dr. Chhina had proposed, and in subsequent guidance documents. Those include translatability concerns from rodents to human subjects; that prolonged observation periods for gene therapies are likely to increase the reporting rate of malignancies; questions about the appropriate regulatory response if clinical malignancies do occur; and how to approach evidence-based updates to labeling statements.  

Dr. Terence Flotte next took up the topic of AAV immunogenicity. He focused on whether there are attributes of immunologic assays/tests that sponsors should consider across serotypes. Dr. Flotte explained that there are no standard assays for pre-existing neutralizing antibodies (NAB) or total antibodies (TAB), which has led to variation in assays and cut off criteria. He shared ASGCT’s recommendation that FDA should participate in efforts to harmonize tests of serologic status used in indications and contraindications. Further, Dr. Flotte discussed the timing of safety assessments and the need for a standardized approach for AAV therapies on early (3-14 days post-administration) and late monitoring. Finally, Dr. Flotte pointed to T-cell response assays as a future opportunity to converge standard approaches.  

The presentation wrapped up with Dr. Snehal Naik, who thanked the Agency for the opportunity to share ASGCT’s recommendations on the topic. She pointed to the November announcement of FDA’s investigation into malignancies in BCMA- or CD-19 directed CAR T-cell therapies, noting that it illustrated both the opportunity and need for early information sharing in the field in a way that would collectively help sponsors, patients, and the wider development community. She reiterated that ASGCT’s proposed collaborative workshop on AAV class considerations would be a positive step toward that goal.  

During a brief discussion period, FDA staff noted that the Agency has been thinking about the issues included in ASGCT’s presentation and what would be helpful to include in future guidances. 

ASGCT Presentation 2: Comprehensive On- and Off-target Analysis for Genome Editing Presenters: Daniel Bauer, MD, PhD, ASGCT Board of Directors, Harvard Medical School, Dana-Farber Children’s Hospital, Boston Children's Hospital; Jessica Seitzer, Intellia Therapeutics; Nate Manley, PhD, Dark Horse Consulting 

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ASGCT’s second presentation assessed on- and off-target analysis for genome editing. Dr. Daniel Bauer began by noting ASGCT’s hope that the presentation would be helpful to inform FDA’s higher-level thinking about expectations of sponsors, acceptable methodologies for off-target assessment, and how regulations in this space can be balanced to protect patient safety while also supporting efficient product development. 

Dr. Bauer then gave an overview of considerations for on-target analysis, highlighting several of the challenges sponsors face across the gene editing field. Those include that on-target gene edit distribution may be heterogeneous with respect to alleles, productivity, and potency; that a combination of assays is often needed to fully characterize on-target effects; and that on-target structural variants may have uncertain biological significance. Dr. Bauer also pointed to approaches sponsors might use to address these challenges and considerations for regulators. 

Jessica Seitzer presented a case study of a comprehensive genotoxicity evaluation as a way to illustrate how a sponsor might choose to biologically derisk their development program. She first outlined the initial steps taken to select the guideRNA and characterize potential off-target editing loci. She then shared a proposed testing strategy to characterize off-target editing risk potential for in-vivo applications. She explained that such an approach, incorporating off-target genome-wide discovery and validation workflow in conjunction with a tiered approach to biological impact assessment, can be applied to assess biological risk of confirmed off-targets in the primary cell type. She also emphasized that a tiered approach for additional relevant cell types (as determined by in vivo biodistribution) leveraging UMI count from the genome-wide discovery assay and chromatin accessibility can be implemented to assess risk of off-target editing potential in additional relevant cell types. 

Dr. Nate Manley concluded the presentation with a discussion of CMC considerations. He focused on the challenges of implementing editing reagent sourcing and off-target analysis in a phase-appropriate manner, given their potential to gate other key CMC activities and overall product development. Dr. Manley stressed that changes in editing reagent quality or production process are common both in preclinical and clinical stages of development, and that there should be opportunities to reduce comparability burden providing sufficient understanding of pre- and post-change editing reagents. Further, off-target analysis methods and data interpretation can vary widely among programs, and the potential relationship between off-target findings and product safety remains largely unknown. He shared several recommendations to address those challenges, including that FDA should issue further guidance and consider other ways to share information to facilitate standardization of off-target analysis and data interpretation. Finally, he encouraged FDA to accept risk-based approaches from sponsors to address off-target findings and to inform routine product testing. 

During discussion, FDA reviewers thanked Dr. Bauer for his focus on on-target characterization and genomic integrity, noting that can get overlooked by developers. They also thanked ASGCT for the specific recommendations on areas that the Society believes FDA should issue further guidance. Related to comparability studies, FDA staff indicated that the Agency could be open to ASGCT’s recommended approach, provided appropriate data is provided by sponsors.  

FDA Presentation: OTP Overview and Key Initiatives  
Presenter: Nicole Verdun, MD, Office of Therapeutic Products, Center for Biologics Evaluation and Research  

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For the final presentation of the day, Dr. Nicole Verdun discussed the Office of Therapeutic Products’ (OTP) organization and key initiatives. She noted that the 2022 reorganization was focused on enabling the super office to expedite development and ensure patients can access safe and effective therapies. She shared information about a number of new CBER/OTP initiatives. Those include:  

• Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot  

  • FDA is selecting up to 3 eligible products in the first round, whose selected sponsors would be able to access enhanced communications with FDA.  

  • During Q&A FDA noted that they are not being overwhelmed by applications for the pilot, and encouraged sponsors not to assume they won’t be accepted for START or any other program. He noted that the goal is to step up the communication available to participants compared to RMAT or Breakthrough Designation. Dr. Peter Marks also addressed the differing eligibility criteria between CBER and CDER, saying that the initial pilot is limited with the hope that additional resources will be available to expand in the future.  

• Rare Disease Endpoint Advancement (RDEA) Pilot Program  

  • This pilot focuses on the efficacy endpoint development process. Admitted sponsors can request meetings with FDA to discuss proposed novel endpoints.  

  • During Q&A FDA noted not many companies had applied for this pilot, and encouraged sponsors to consider doing so. 

• Platform technologies   

  • Platform technologies, under certain conditions, allow sponsors to leverage non-clinical data and manufacturing information from one product to accelerate development of a related technology.  

  • Dr. Verdun encouraged sponsors to communicate with FDA even if they don’t think they fit the scope of a formal Platform Technology Designation. 

  • During Q&A Dr. Verdun clarified that a platform technology may be applicable in the pre-clinical space as well as later in development.   

  • The Q&A period also encouraged discussion of the potential for multiple academic sponsors or investigators to share a platform designation, looking especially to the ultra-rare disease space. Dr. Verdun said that while a formal Platform Technology Designation would not be applicable in that case, given that’s meant for a single sponsor, she agreed that it was important to be able to leverage shared data and avoid needless repetition in cases where academic investigators pick up a development program that has been discontinued by industry. 

• Collaboration on Gene Therapies (CoGenT) Pilot   

  • This pilot is at the proposal stage. Global regulatory authorities would be able to participate with the goal of increasing dialogue between agencies and with sponsors to avoid unnecessary duplication of effort. Dr. Verdun said more information on this pilot will be available in the coming months.  

  • During Q&A there was a discussion of the major barriers to simultaneous submissions across regulatory agencies. Dr. Keith Wonnacott noted that in his experience, workload and the wide variety of regional requirements were the primary reasons a company might choose not to pursue that route. If there was a single submission process that multiple health authorities could use, therefore, Dr. Wonnacott said that would be extremely attractive to sponsors. 

  • Dr. Marks also addressed the question of whether the CoGenT pilot would be applicable before approval submission (meaning pre-BLA in the United States). He said that under existing parallel scientific advice programs, sponsors can approve FDA to invite other global regulators into the room. He agreed though that further formalization of that process is one of the items to consider as the GoGenT pilot is finalized and expanded. 

Dr. Marks explained that FDA recognized not all pilots might succeed, and that the breadth of new programs was intended to ensure that the Agency had multiple opportunities to get things right. He also noted that FDA has increasingly leaned into horizon scanning to identify proactive opportunities to engage with the field and stay current on rapid scientific developments.  

To round out the discussion, Dr. Wonnacott presented a slide with feedback on FDA’s CMC Development and Readiness Pilot (CDRP). At FDA’s request, the Society conducted a limited, voluntary, and anonymous survey of certain ASGCT committee members.  

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Three key themes emerged about perceptions of the program: that participation is difficult due to very narrow eligibility criteria; that uncertainty exists around the potential for public data sharing; and that benefits of the program are unclear. For each concern, Dr. Wonnacott shared a way that FDA might address it. He also stressed the Society’s appreciation that FDA is trying to lean into new opportunities to advance the field and learn from sponsors on what is and isn’t most useful to them. FDA staff noted that participation in the program has been lower than expected, and expressed their thanks for the feedback. They also recommended that sponsors who are concerned about data sharing can look to other FDA programs for examples of the types of information that’s likely to be requested and how it might be shared in a generalized way. 

Christina is ASGCT's Senior Manager of Government Affairs.

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