A Deep Dive into Cell and Gene Therapy Regulatory Considerations: Part Four

What are some of the product and regulatory challenges companies developing cell and gene therapy (CGT) products may face during late-stage development?

At the ISPE Annual Meeting held in Orlando, Florida, in early November, Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) Division of Cellular and Gene Therapies Branch Chief Melanie Eacho discussed common issues her office sees CGT product development.

Part Four of the four-part story focuses on Eacho’s discussion of CMC expectations and challenges in late-phase development. Part One focused on insights into FDA’s New Office of Therapeutic Products.  Part Two explored common CMC issues in early development. Part Three examined product CQAs, lot release, and device considerations.

CMC Expectations and Challenges in Late-Phase Development

Eacho provided advice for CGT product developers about to commence Phase 2 studies.

“To begin with, there is an expectation to have a qualified potency assay or a matrix in place. In addition, that you lock down your manufacturing process as much as possible before the start of your phase three study,” she explained. “Major changes may require a formal comparability study, so locking it down early is always the best, as much as possible.”

“We recommend that commercial manufacturing facilities be introduced as early as possible, preferably before the start of phase three. For those introduced during late-phase we typically request you established comparability under the IND before you submit a BLA so there aren’t any surprises.”

Potency Assay Attributes

Potency is a measure of a relevant biological activity as it relates to the clinical outcome and mechanism of action. FDA recommends a matrix approach – the examination of multiple assays or methods to explain the product potency.

CGT products are complex, and there are many different mechanisms at play. While many assays are qualitative, it is recommended to have at least one that is quantitative.

The validation of potency assays for CGT products is difficult, as they are highly variable. The potency assay should be developed early on and qualified before the start of the phase three study.

“If the potency assay is not qualified prior to the start of the phase three study, that can be a reason to place an IND on hold,” Eacho cautioned. “And in the BLA, the potency assay should be validated, and the validation report should be included.” Having a robust potency assay will be important when inevitable manufacturing changes occur.

Regarding manufacturing changes, when they are made, “sponsors should be evaluating how the change may impact the product and if comparability can be established by analytical means. ICH Q5E is a great resource to guide you through this whole process.”

If a comparability study is needed for the manufacturing process change, it is recommended to:

• Perform a risk assessment to evaluate the impact of the change
• Assess the CQAs
• Determine acceptance criteria for comparability evaluation
• Determine a statistical method for comparison, and
• Conduct the study itself.

“We recommend making manufacturing changes prior to initiating clinical trials that are intended to support efficacy for the BLA, in other words, prior to the start of the pivotal or phase three study,” Eacho stressed.

“Changes introduced during later stage development will have significantly higher expectations for demonstrating comparability. We also highly recommend that you submit a comparability protocol for our review prior to executing your study.”

Keyword Search in the Redica Systems Platform

As stated above, the validation of potency assays for CGT products is difficult, as they are highly variable. Redica Systems gives additional insights into documents pertaining to potency assay using our Platform.

Since we want to look at documents containing the phrase “potency assay” we will first head over to the documents tab and type out our desired phrase in the search bar at the top of the page.

The results from the search totaled 205 documents. 170 being FDA non-conformance documents (483s, Warning Letters, and  EIR) and 35 from Regulatory Surveillance signals.

To take a peek at the contents of these documents and other search capabilities of the Redica Systems Platform, schedule a working session with us today.