Naomi Kautz

Gene therapy development is gaining momentum. In 2020 alone, gene therapy attracted $12 billion in global financing through just the first three quarters with more than 370 gene therapy clinical trials underway worldwide.

 The U.S. Food and Drug Administration (FDA) itself predicted it may be approving 10 to 20 gene therapies per year by the year 2025.

 As gene therapy research expands across modalities and therapeutic areas, sponsors are tasked with designing and executing safe, ethical trials in a fast-changing regulatory environment.

In this article, we explore key regulatory, site, and enrollment considerations for gene therapy trials, offering tips on successfully navigating the development process based on evolving best practices and our own experience in this area.

Given the expected increase in gene therapy investigational new drug applications (INDs) and the complexities of successful gene therapy manufacturing, the FDA has issued a number of relevant guidance documents since January 2020 for gene therapy programs being developed under an IND (see Table 1).

Table 1. Recent FDA gene therapy guidance documents

When developing a regulatory strategy, it is important to consider the possibility of expedited pathways. There are gene therapy development programs for serious or life-threatening conditions with significant unmet needs which may be eligible for a quicker path to market through regenerative medicine advanced therapy (RMAT) designation. These programs may also be eligible for accelerated approval, which supports the use of a surrogate endpoint in pivotal studies. Should RMAT designation and the accelerated approval pathway both be granted for a gene therapy program, the sponsor can work with the FDA to develop strategies to efficiently capture the required confirmatory data following initial approval.

The remaining expedited programs for which a gene therapy may be considered include breakthrough therapy designation, fast track designation, and priority review.

 Gene therapy products intended for symptomatic treatment and that do not address a serious condition, however, are subject to the traditional regulatory pathway.

Current regulatory guidance also recommends that, for certain gene therapy programs, sponsors develop companion diagnostic (CDx) assays to assist in the identification of patients who are likely to benefit from the investigational gene therapy or likely to experience treatment-related adverse events. These CDx may be used to:

 If there are no reliable methods for obtaining the necessary genetic diagnosis, a CDx may be needed to confirm the genetic defect and should be considered early in the development process.

 To ensure the therapeutic potential of a gene therapy product, sponsors may consider developing a CDx to detect both total and neutralizing antibodies in patient serum.

If a CDx is required for patient selection in clinical practice, submission of the biologics license application for the gene therapy and the 510(k) for the CDx should be coordinated to support contemporaneous marketing authorizations.

Clinical design depends on the nature of the indication being investigated by the gene therapy. but in general, the initial cohorts in first-in-human gene therapy studies require staggering of patient enrollment and dosing to accurately monitor safety. For rare diseases treated with gene therapies, the FDA recommends conducting first-in-human studies as randomized controlled trials to generate the safety and efficacy data needed to support registration but recognizes there may be feasibility limitations. If historical controls are used, they must be accompanied by knowledge of the natural history of the disease.

Study design can affect enrollment. If the study includes a sham procedure, it is imperative to demonstrate that this procedure does not cause undue burden to the patient and that the participant understands they may not receive the investigational gene therapy product. The regulations and requirements for such a procedure may vary by country. For instance, one partner with which we worked included a sham procedure at the request of the FDA only to have it disapproved by the Ethics Committee in one European Union country. In this case it was necessary to work with the in-country investigators to submit letters of support attesting that the sham procedure would not create undue burden given the limited treatment options available. 

An important regulatory consideration that is often overlooked is the need to obtain approvals, including local approvals such as CE marking in the EU, for any devices used in the administration of the vector or cells. Any customizations made to a device could render any previous approvals null and void and require new approvals, which could result in delays if not proactively addressed.

The need for long-term follow-up presents a special challenge in gene therapy trials. Follow-up observation periods can vary from five to 15 years, depending on geography and characteristics of the gene therapy per its vector and genome editing potential, with implications for patient—and site—engagement. To assist in the collection of patient-reported outcomes and prevent loss to follow-up during the observation period, sponsors may want to consider establishing patient registries and creating mobile health applications or other remote tools to facilitate data collection.

Gene therapy administration is a highly specialized process. As such, we have found that experience with gene therapy and familiarity with the disease under investigation are critical screening criteria in site selection. When assessing the quality of sites, sponsors should also consider:

 and relationships with providers who can refer patients with the disease of interest and provide post-treatment care

Experience in meeting country and local requirements

 from both a regulatory and protocol design standpoint

Maturity of site genetically modified organism (GMO) processes

 including availability of GMO standard operating procedures

Experience with similar modes of administration

, which is especially important in autologous gene therapy studies and studies requiring intracranial administration of the vector or cells

It may be useful to examine how the requirements of the study protocol align with existing institutional policies as limiting site burden can enhance study engagement.

Partnering with a contract research organization that has strong gene therapy experience and a well-qualified network of investigative sites can accelerate the site selection process. Given the increase in gene therapy research activity, being aware of the existence and potential impact of competing trials at each site can help mitigate recruitment risk. An approach that we have also seen to be effective is selecting lesser-known sites that have the capability to execute gene therapy studies which can not only reduce competition, but also increase access for patients in underserved geographies. This approach requires strong experience and access to appropriate processes to effectively train and support sites to ensure high quality performance.


Given that gene therapy is a relatively new treatment modality, patients may be unfamiliar with the risks and mechanics of a gene therapy trial, making informed consent and education essential components of successful enrollment. Patients who are weighing the option of participating in a gene therapy trial may have concerns related to the nature of gene therapy, such as:

What is the evidence supporting the potential efficacy of the gene therapy?

How will participation in a gene therapy trial affect eligibility for other investigational studies?

If it works for me, will my affected sibling get access to the treatment?

Setting appropriate expectations and providing detailed education can help address these concerns and facilitate the informed consent process.

Approximately 80% of rare diseases have a genetic basis, making these diseases targets for gene therapy.

As with other rare disease trials, gene therapy trials may face recruitment challenges. Involving patients and their caregivers in the development process and getting their input on the protocol helps ensure that the study design is feasible and does not create excess burden. Engaging with patient support and advocacy groups can also help to increase study awareness and enhance enrollment.

If study participants are expected to come from outside the borders of the country in which the trial is being conducted, sponsors should consider cross-border enrollment and the associated processes and procedures that need to be implemented to ensure smooth transitions for these patients.

For studies that require long-term follow-up, making it as easy as possible for patients and their caregivers to participate is paramount. Using technology for remote data capture or enabling off-site visits may not only enhance retention, but also improve overall satisfaction with the study experience. Education is also a powerful retention tool. Patients and caregivers who appreciate the importance and value of staying in a trial are more likely to remain engaged for the long term. Sending out periodic updates throughout the trial—and even post-approval—is a simple yet effective way to demonstrate how study participation impacts not only the patients and caregivers, but also future patients and scientific knowledge at large.

Designing and conducting a gene therapy trial is a complicated undertaking made more complex by unique regulatory, site, and enrollment considerations. Developing new pathways to overcome study-related challenges is key to realizing the promise of the latest gene therapies.

is the Senior Director, Regulatory Affairs, Regulatory Professionals, A Division of Premier Research; and

is the Executive Director, Gene and Cell Therapy, Premier Research

Alliance for Regenerative Medicine. The Alliance for Regenerative Medicine Announces Record Sector Financing in 2020, November 19, 2020. https://alliancerm.org/press-release/the-alliance-for-regenerative-medicine-announces-record-sector-financing-in-2020/.

Gottlieb, S., M.D. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies, January 15, 2019. Retrieved from https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics.

US Food and Drug Administration. Cellular & Gene Therapy Guidances. Last updated January 5, 2021. https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances.

US Food and Drug Administration; Center for Biologics Evaluation and Research. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions. Guidance for Industry. Published February 2019. https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf.

US Food and Drug Administration; Center for Biologics Evaluation and Research. Human Gene Therapy for Rare Diseases. Draft Guidance for Industry. Published July 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610802.pdf. Published July 2018.

FDA Statement. Statement from FDA Commissioner Scott Gottlieb, MD and Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. US Food and Drug Administration website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629493.htm. Published January 15, 2019.

FDA Law Blog. Novel Clinical Trial Designs for Gene Therapies: An Exploration of Challenges by the National Academies’ Forum on Regenerative Medicine, November 22, 2019.

National Center for Advancing Translational Sciences. Rare diseases are not rare! Challenge offers new tools to raise awareness. Posted January 2019. https://ncats.nih.gov/news/releases/2019/rare-diseases-challenge 

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Developing new pathways to overcome study-related challenges is key to realizing the promise of the latest gene therapies.

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