On September 29, 2022, FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Tissues and Advanced Therapies (OTAT)held a town hallto answer questions related to gene therapy chemistry, manufacturing, and controls. Wilson Bryan opened this new forum for direct agency feedback by describing the transformation of OTAT into the Office of Therapeutic Products (OTP). The restructuring ofOTAT into a “super-office”will increase its review capabilities, and enhance expertise on new cell and gene therapies.
When on the bleeding edge of new product development, it can be hard to know ahead of time what the agency is looking for in terms of CMC information. The standard practice is for FDA to engage with companies on an individual basis through formal meetings and deliver directed feedback to specific sponsor questions. With the explosion of new gene therapy investigations in recent years, these meetings with industry have become a proverbial black-hole of OTP’s time, energy, and reviewer resources. OTP has spent years communicating industry-wide problems on an individual basis.
The solution that OTP has reached is to address what are very likely to be common industry problems in a public setting. This move is likely to ease the pressure on their overburdened review staff by creating an organic reference Q&A for industry without having to create and iterate a new series of guidance documents. Town Hall forums have been used to great success since the start of the pandemic in CDRH to accelerate the development of new IVD products. Sponsors can interact with FDA in the town hall by submitting questions in advance or by asking a question live during the meeting. It is important to keep in mind that this meeting is for general CMC feedback and sponsors are informed that“FDA is not able to comment on or answer questions regarding specific investigational products or drug applications during the town hall.”
The major theme underpinning their commentary for this first meeting was the need for cell and gene therapy product developers to think ahead to the long term and plan accordingly. While the transcript of the town hall will be posted for a healthy dose of science-filled pleasure reading, we highlight a few key points that hopefully set the tone for what to expect from future meetings:
Comparability
OTP acknowledged the elephant in the room that their expectations for comparability assessment is a “hot topic”, and that to address this complex question, they are developing a specificguidance document(i.e., “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”) that should be released “sometime in the near future.” At this time, they recommend developers followICH Q5ewhen assessing comparability. The Agency’s recommendation is that developers implement changes in product manufacturing as early as possible to reduce the risk in the development program. Depending on the change (e.g., change from an adherent to a suspension cell product system), the Agency might expect both comparability assessments and developmental studies to support that the change does not adversely affect product quality. The Agency emphasized that release testing alone is not sufficient to assess comparability and that additional characterization testing or in process testing be conducted based on risk assessment and developmental studies. In some cases, the effect on the final drug product should also be assessed (e.g., vector manufacturing for a transgene vector).
Process Control and Potency
The Agency recommends determining the process requirements early in the development process because late changes in the development program will introduce uncertainty later that may result in a clinical hold. Product developers should have a robust understanding of their process and process controls. In addition, they should know how to control for analytical method variability prior to starting the clinical trial. The Agency recognized that sponsors may have difficulties establishing a single suitable test for products with complex mechanisms of action, which is why they recommend developers think about characterizing the product and potency assay development during pre-clinical development. The Agency expects that the quantitative test to measure biological function of the product is expected prior to initiating clinical studies. As the product advances in clinical development, expectations are that the potency test be refined to measure biological activity of the product. If developers want to use a surrogate test(s) for function they must comply with product specific considerations, such as whether the test(s) is specific to the product, provides meaningful measure of activity, and contributes to the overall potency assessment. The Agency considers early qualification of assays to characterize the product as critical to the success of the program. The Agency stressed to “think in advance and work hard to getting the data you need to support whatever potency test you submit” as many comments in pre-INDs are regarding inadequate potency tests.
Release Criteria
To determine lot release criteria and to ensure product consistency and quality, OTP recommended that gene therapy product developers use multiple lots during the clinical study, even if one lot is enough to treat everyone in the pivotal study. Use of multiple lots will help developers set commercial specifications and understand the variability in the product and how it affects the clinical trial results. One way to facilitate this strategy would be to conduct PPQ runs and use those few runs during the pivotal study. OTP recognized that this strategy may not be possible for all products (e.g., rare diseases) and recommended developers either leverage data they have from similar products they’ve manufactured from pre-clinical lots, engineering lots, and small-scale development studies, or to design the manufacturing process to allow for more drug product to be used during the clinical study. They recommended product developers to meet the OTP review team if there are still concerns that there will not be enough data to set the commercial lot release criteria.
We look forward to the next town hall and will be sitting in the virtual front-row.
There is also a video recording available via the FDA website, including a (limited) Audio Transcript:
(20min delay)