New regulatory ‘playbook’ from FDA-supported Bespoke Gene Therapy Consortium aims to accelerate development

Yesterday, the Bespoke Gene Therapy Consortium, a public-private partnership focused on creating resources to streamline the process for moving AAV-based gene therapies from the lab to the clinic, published a comprehensive summary of the lessons the group has learned so far. The regulatory playbook acts as a comprehensive resource – especially for those not well-versed in how the FDA’s regulatory processes function.

The Bespoke Gene Therapy Consortium

• A collaborative effort, the Bespoke Gene Therapy Consortium (BGTC) was launched in October 2021 to “accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease.” The overarching goal of the project was to develop a suite of gene therapy resources that could be used by the research community to streamline gene therapy development for rare disorders, making the process more efficient and less costly.
• The consortium is funded by a public-private partnership called the Accelerating Medicines Partnership (AMP), through which the Foundation for the NIH (FNIH) administers funds provided by industry, government, and nonprofits to scientists working on applicable basic or clinical research to advance gene therapy development for rare diseases. Prior to the creation of the Consortium, one of the BGTC’s key government partners, NIH’s National Center for Advancing Translational Sciences (NCATS), had invested significant resources into a pilot program to determine whether the efficiency of gene therapy trials to treat different rare diseases could be improved by using a standardized process, with the same capsid and manufacturing methods. The pilot focused on identifying commonalities across products using Adeno-Associated Virus (AAV) vectors to reduce duplication of efforts across individual therapeutic programs and to encourage the field to move away from the current “one-disease-at-a-time approach.” BGTC was intended to expand further on these efforts by bringing this platform approach to life.
• To reach the BGTC’s ambitious goal of streamlining gene therapy development, there were several objectives outlined the Consortium’s initial plan. One of the challenges members set out to address was the need for a more robust understanding of the adeno-associated virus vector. As Agency IQ discussed when the BGTC was first announced, the Consortium would thus facilitate research on the basic biology, biological and mechanistic steps of vector production, human vector delivery and how genes are activated once they reach the target cells. Furthermore, the Consortium would also work to develop standardized approaches to nonclinical testing as well as a set of standardized analytical methods, which could be used to assess product quality and manufacturing processes and controls. Finally, the Consortium would support between four and six trials for products to treat rare diseases that lack existing treatment options.
• In May 2023, it was announced by FNIH that the Consortium had selected eight rare diseases to make up its clinical trial portfolio. According to the press release (and further detailed by a fact sheet on FNIH’s website), the selection of these diseases followed a rigorous scientific and technical review by a panel of gene therapy experts, based on factors such as “adequacy of the gene for insertion into an adeno-associated virus (AAV) vector, sufficient proof of concept and natural history data, the existence of an established disease model, a lack of available treatment, and an overall readiness for entering into a clinical trial.”
• Also in May 2023, CBER Director PETER MARKS offered his perspective on the factors that led to the BGTC’s creation and the evolution of the challenges faced by gene therapy developers. According to Marks, the BGTC was originally created to de-risk and incentivize the timely development of gene therapies to treat noncommercially viable rare diseases (i.e., diseases in which the cost to develop a treatment is anticipated to outweigh its estimated revenue generation). At the time of its inception, the organizers hoped the BGTC would help to stimulate the flow of venture capital to companies working on gene therapies to treat rare diseases. Ironically, due to the pandemic and other economic developments since then, venture capital has continued to dry up and is today even harder for companies in this space to come by. Marks stated that this reason alone points to the continued importance of the BGTC’s work, explaining “Right now I think that when people look at this area, they see challenges in getting things through clinical trials, challenges in endpoints, challenges in manufacturing, and challenges in reimbursement.” Marks expressed optimism that the program will continue to pick up steam as it is utilized more, despite these current challenges “I think the idea is if you can get together a playbook and show that it works for a couple of these, then we can start cranking things through.”

The first version of the playbook has been published

• Yesterday, the FNIH published “Version 1.0” of the Bespoke Gene Therapy Consortium (BGTC) Regulatory Playbook. Far from just an outline of the work completed by Consortium members to date, the Playbook is a thoughtfully organized “how-to-guide” which walks readers through some of the major milestones of early clinical development in just over one hundred pages. In terms of organization, the playbook starts with an introduction to the BGTC, provides an overview of the playbook’s development, and offers advice on it can be used. Per the document’s prologue, the playbook has been intentionally prepared in plain language to “serve AAV drug developers of all backgrounds, but primarily those who could benefit from simplified language, guidelines, and templates for this complex process (e.g., family groups, non-profits, patient foundations, academic research labs, small biotechs, but not necessarily large pharmaceutical companies).”
• Although the document briefly touches on the technical aspects of drug development, most of the content in the playbook focuses on early touchpoints between sponsors and FDA. Some chapters, such as Chapter 3 (Formal FDA Meeting Types) and Chapter 6 (Program Selection), provide an overview of topics that may be unfamiliar to small biotechs or academic labs but are important to be aware of early-on for planning purposes. In contrast, other sections like Chapter 4 (INTERACT Meetings) provide a detailed overview of a particular process, with advice about what to do, and—in some cases—what not to do when preparing for that particular milestone. Tips are scattered throughout these sections in call-out bubbles, presumably from sponsors who participated in BGTC or from FDA contributors. In any case, these tidbits provide unique context for AAV product developers that are not likely to be found in FDA guidance documents or any other resources published by regulators.
• In addition to providing a thorough discussion of FDA-sponsor meetings, the publication also walks through the IND submission process in detail. Again, instead of walking through the technical aspects of application submissions, this section provides more of a what-to-expect breakdown of each section and explains how it contributes to FDA’s overall evaluation of the application. Even in this abbreviated form, Chapter 7 (IND submission) is the second longest chapter in the publication at about 30 pages total.
• While sponsor-FDA meetings and IND submission are covered in-depth, the playbook doesn’t—at least right now—provide much insight on the conduct of nonclinical studies. While some of the content may be useful for sponsors looking down the road towards later stages in development, the first milestone which the guide offers tangible advice on is preparing for INTERACT meetings. This means that developers in search of information or advice on conducting proof-of-concept in vitro and in vivo nonclinical studies demonstrating preliminary evidence of safety and efficacy are out of luck.
• The playbook is still under development, and future iterations are already being planned for development. For example, as is noted in Chapter 1.4 (Minimum Pre-clinical Testing), BGTC plans to add an overview of the minimum pre-clinical testing requirements in a future iteration of the playbook. The content under development focuses on animal toxicology studies to generate adequate safety data for IND submission, and will include information regarding animal species, dose, and length of study. Later on, the publication states that similar content on critical quality attributes (CQAs) are also being developed. In addition to taking some of the guesswork out of the required testing for product quality, the goal of BGTC is that this set of minimum manufacturing requirements will also provide “uniformity across different qualified manufacturers and different gene therapy products, thereby benefitting the AAV gene therapy field more broadly.”

What’s next?

• A work in progress: The playbook states that BGTC has chosen to take an iterative approach to developing the playbook so that it can be further refined and enhanced as new learnings are gained with each asset. In addition to supplementing the playbook with “lessons learned” as further experience is gained, the playbook states that these experiences will also enhance the minimum sets of requirements on nonclinical and CMC studies, and will allow for more specific information to be added on product-specific topics like AAV serotypes, routes of administration, affected organ/tissue, etc. Future versions will also offer templates for many of the steps it covers.
• Even though the playbook may not be ready to serve as a standalone resource for sponsors with AAV gene therapies in development, it does offer insight on topics that aren’t easy to find in any one resource. Per an article in Nature authored by members of the BGTC and published yesterday, coinciding with the release of the playbook, seven of the eight projects currently supported by BGTC are led and conducted by academic groups. Given the process to develop this document pulled from the actual experiences of these teams working to bring their AAV gene therapy products from bench to bedside, the focus on these touchpoints likely indicates that these are areas where existing resources (e.g., guidance documents) fell short of answering the questions that they had. By focusing first on opportunities where developers can directly engage with regulators, the playbook can guide academic teams or startups without much regulatory experience to the right people to answer their questions—an invaluable resource.

Featuring previous research by Kirsten Messmer.
To contact the author of this item, please email Rachel Coe ( [email protected]).
To contact the editor of this item, please email Alexander Gaffney ( [email protected]).

Key Documents:

• Bespoke Gene Therapy Consortium (BGTC) Regulatory Playbook: Version 1.0