Running With Scissors: The FDA Moves to Tame Gene Therapy Drug Development


With several newly approved therapies hitting the market and an overflowing pipeline, the FDA has stepped in to help keep the burgeoning world of biotech on track.

It’s no question that it has been a challenging year for biotech. Early-phase failures, unexpected adverse events, and an increasingly crowded landscape have sent some once-promising firms packing with their pipelines in hand.

Still, there’s no shortage of exciting things to come from the field of cell and gene therapy. With 26 current therapies FDA-approved,1 3 new gene therapies approved this year alone, and a 5-year pipeline filled with nearly 40 contenders,2 it’s clear that everyone should be paying very close attention to this burgeoning space.

With such an expansive pipeline comes a flood of clinical trials, and that’s where the FDA took particular action in 2022. Looking to homogenize expectations around clinical trial design and execution,the FDA released 3 separate guidance documents in 2022 focused on the following topics: gene editing, gene therapy for neurodegenerative diseases, and gene therapy umbrella trials.3-5 

Human Genome Editing

Early in the year, the FDA’s Center for Biologics Evaluation and Research issued draft guidance for industry players developing gene therapy products that involve gene editing. The document reflects the concerns surrounding safety of gene-editing strategies—namely off-target effects—for the treatment of a range of disorders.3

Touching on product design, manufacturing, testing, as well as preclinical safety and clinical trial design, the guidance outlines information that should be included in a sponsor’s investigational new drug application in order for the agency to effectively evaluate the investigational therapy.

The guidance primarily focused on reducing and assessing risk at every stage, including in preclinical studies, where the agency suggested that studies be designed to assess toxicity associated with delivery of the therapy, modification of the genomic structure, and expression of the gene product, as well as any off-target activity and chromosomal rearrangements, and the consequences of such.

At the clinical stage, the guidance emphasized the importance of selecting first-in-human study populations based on risk-benefit and with staggered patient enrollment to best evaluate administration of a gene editing product.

Lastly, the guidance addresses the unknown, with the FDA recommending that industry sponsors follow clinical trial participants who undergo gene editing for a minimum of 15 years to better capture both immediate and long-term safety developments that can be a direct result of gene editing, including “off-target editing, unintended consequences of on- and off-target editing, and the unknown long-term effects of on- and off-target editing,” the agency wrote.

FDA guidance for gene therapies

FDA guidance

Gene Therapy for Neurodegenerative Diseases

In October 2022, the FDA followed up by releasing afinalized guidance document for industry focused on gene therapies for neurodegenerative diseases,4 which touched on considerations for chemistry, manufacturing, and controls, as well as preclinical studiesand clinical trials. Although most considerations for gene therapies in this space are similar to others, the administration of the gene therapy product requires special consideration in this population.

The FDA acknowledged that the range of “neurodegenerative diseases” is variable and wide, advising that innovative trial designs may be more fitting in monogenic disorders with a well-characterized and consistent natural history instead of randomized, placebo-controlled trials to expedite clinical development when there is an expected, clinically meaningful treatment benefit. On the other hand, disorders with poorly understood etiology and variable natural history may benefit best from randomized, placebo-controlled trials. In all cases, the FDA encouraged sponsors to consider innovative clinical trial designs as gene therapies are fundamentally different from other drugs and should not limited for evaluation by traditional clinical trial designs.

Dealing with such a vulnerable population, the agency stressed that all participants in gene therapy trials for neurodegenerative diseases receive the best standard of care, and to this end some gene therapy products should be evaluated in conjunction with approved treatments. Participants should also be allowed to crossover to other treatment cohorts when appropriate and follow-up should continue after crossover.Concerningplacebo/sham-controlled trials, the FDA said that sham procedures should be as minimally invasive as possible, and in fact, external controls may be appropriate when there is an unmet medical need, controls are not practical or ethical, populations are comparable, there is a large, expected treatment effect, and the disease course is well understood.

Eligibility should consider disease severity as part of the risk-benefit profile, andtrials should first enroll adults and then pediatric patients when assessing diseases that affect both populations. Additional considerations and safeguards apply for children in these trials, including minimal risk or an acceptable risk-benefit profile.

The FDA advised that most early-phase gene therapy trials should incorporate a dose-ranging study design with dose exploration and expansion. One-time products should start with a likely therapeutic dose, so participants have a chance to benefit. These doses should be informed by preclinical studies. Some invasive gene therapy procedures should be done unilaterally before being cleared for bilateral administration. 

As in other gene therapy trials, safety and immunogenicity are top concerns. To mitigate immune responses, participants should be closely monitored and cellular and humoral immune responses to the vector and transgene measured by immunoassays. Immunosuppressants may be used to minimize immune response before and after treatment, with adequate justification. Participants should continue to be closely monitored while on immunosuppressants.

While early-phase trials primarily assess safety and tolerability of gene therapy products, the FDA encouraged that trials also assess activity, efficacy, potential clinical benefit, biomarkers, and potential surrogate endpointsof these products to guide further clinical development. For pivotal trials, endpoints should be clinically meaningful and measure or predict a clinical benefit. Surrogate endpoints may be appropriate under the accelerated approval pathway when targeted well-understood underlying monogenic changes; these must be communicated with the FDA before clinical trials.

The FDA continued to recommendlong-term follow-up to assess safety and durability and to collect patient experience data. It also touched on available expedited program designations, including regenerative medicine advanced therapy, breakthrough therapy, and fast track designations; accelerated approval; and priority review. Again, the FDA encouraged communication throughout the development process and highlighted meetings available, such as pre-investigational new drug (IND) meetings and INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings.

Umbrella Clinical Trials

Most recently, in November 2022, the FDA released final guidance for umbrella trials studying multiple versions of a cell or gene therapy product in early-phase clinical trials.5 The agency noted that these kinds of umbrella trials provide beneficial flexibility and efficiency in developing novel therapies butreinforced the need for multiple INDs, primary and secondaries, for each version of the therapy being studied. It provided recommendations for organization and structure of INDs, submission of data, and decisions regarding versions to advance to later-stage trials. Safety reporting, and therefore potential clinical holds, may affect single INDs/arms or the whole trial. Primary/secondary INDs must be updated as priorities in development shift and some product versions are dropped and others advanced. Alternative approaches are available and, if desired, the FDA urged sponsors to contact the agency.

In an interview with CGTLive, Peter Bross, MD, chief, oncology branch, Center for Biologics Evaluation and Research,spoke about how academia and industry can work best with the FDA to ensure clear communication and efficient pathways to approval.

“When working with the FDA, it’s a matter of clear communication and transparency. We are very limited in time. We encourage sponsors, both academic and commercial industry, to request meetings. Unfortunately, sometimes we can't accommodate everyone's requests,” Bross said.“I just hope that people recognize that we have a lot of competing priorities, but we want to help and will help as best we can. In terms of how we can optimize that communication, transparency is very important.”

This article is part of a feature series with our sister site, HCPLive, called "This Year in Medicine." To see the full series, click here.

1. Approved Cellular and Gene Therapy Products. US Food and Drug Administration website. Updated November 22, 2022.
2. Gene Therapy Pipeline 3Q 2022-1Q 2027. CVS Health. Updated July 12, 2022.
3. US Food and Drug Administration. Human Gene Therapy Products Incorporating Human Genome Editing: Draft Guidance for Industry. Updated March 21, 2022. Accessed November 30, 2022.
4. US Food and Drug Administration. Human gene therapy for neurodegenerative diseases: Guidance for industry. Updated October 25, 2022. Accessed December 2, 2022.
5. US Food and Drug Administration. Studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial: Guidance for industry. Updated November 18, 2022. Accessed December 2, 2022.
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