Cell & Gene Therapy FAQ

Overview

On December 12, 2024, FDA released a draft guidance entitled “Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products”.The FAQ is divided into four sections, outlined below. Much of the information is available elsewhere but having it compiled into one place is helpful for stakeholders.

Interacting with FDA

This section includes information on what INDs should contain, what types of meetings are available and how products are assessed. The guidance discusses which forms should be submitted and the timeline for FDA review.

Product Development

This technical section reviews donor eligibility, product characterization, analytical methods and more. More information about FDA’s CMC (Chemistry, Manufacturing and Controls) requirements can be found in specific CMC guidances.

Conducting Nonclinical Studies

This section includes information on non-human trials, both animal models and in vitro/in silico models. FDA’s underlying assumption is that animal trials will be conducted, however, FDA notes that it encourages “the judicious use of animals in nonclinical development programs” and recommends sponsors consider valid alternatives to animal testing. FDA recommends that sponsors justify the use of data from sources other than animal models if there is no good animal model available.

In animal studies, an analogous product may be used, if the intended clinical product cannot be tested in the animal for scientific reasons (eg differences in homology or xenogenic responses).

If a sponsor is not using animal models, FDA recommends that this be justified and discussed in pre IND/BLA meetings. “FDA is open to alternative methods that are backed by science and produce scientifically valid data and will consider whether such an alternative could be used in place of an animal test method within a particular context of use.”

Conducting Human Trials

Generally, FDA requires two “adequate and well-controlled studies” to establish effectiveness of a drug or biologic.The gold standard for this is a placebo-controlled trial, but other designs are possible, particularly in rare diseases.

Endpoints

Endpoints in traditional approvals directly reflect a meaningful clinical benefit. “A clinical endpoint directly measures a therapeutic effect of a medical product and assesses how a patient feels, functions or how long they survive.”

Endpoints in an accelerated approval are surrogate endpoints that are reasonably likely to predict a clinical benefit or on an intermediate clinical endpoint. Surrogate endpoints can be markers such as biomarkers or imaging tools. Some endpoints are validated, which means the surrogate endpoint is “known to predict clinical benefit”.

Products approved under the accelerated approval pathway require confirmatory studies as part of post-marketing requirements.

Safety

Short and long term follow up are required to monitor safety of CGT products. Staggered enrollment is recommended as a method to “limit the number of subjects exposed to unknown but potentially significant risks.” Trials should also include stopping rules to trigger the suspension of the trial. Long term follow up may include monitoring adverse events for as long as 15 years.

The guidance is not very long as is easy to read, so definitely worth your time if these are topics of interest.