Advancing Gene Therapy Development: Key Regulatory and Clinical Trial Considerations

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Jessica Merryfield

Naomi Kautz









Advancing Gene Therapy Development: Key Regulatory and Clinical Trial Considerations

By Naomi Kautz, Vice President, Regulatory Affairs, Premier Consulting

By Jessica Merryfield, Senior Director, Program Delivery, Rare Disease, Premier Research


Insights into the human genome have created myriad therapeutic opportunities for previously untreatable diseases. Gene therapy offers promise for addressing unmet medical needs across therapeutic areas and even the potential for curing certain genetically based conditions. As research tools and technology become more sophisticated, gene therapy development is accelerating at an unprecedented pace. According to the American Society of Gene & Cell Therapy, there are currently 19 gene therapies, including genetically modified cell therapies, approved for clinical use globally.[1] Nearly 1,900 gene therapies are in development, of which 34 are in Phase 3 or pre-registration trials.[1]

Gene therapy development is a complex endeavor, with evolving regulations and complicated study logistics. In this article, we explore the regulatory and clinical trial landscape for gene therapy trials and offer strategies for successfully negotiating the challenges of executing these studies.

Regulatory Landscape

U.S. Framework

Due to their unique mechanism of action and the associated novel risks, gene therapy products are subject to some regulations that are not applied to small molecule therapeutics. In recent years, coinciding with research advances and marketing approvals, the gene therapy regulatory landscape has shifted from high-level guidance to more detailed guidelines focused on testing, manufacturing, or specific disease states. Since January 2020, the U.S. Food and Drug Administration (FDA) has issued ten guidance documents for gene therapy program sponsors to align with the advances in research.[2]

A key feature of the FDA’s recent guidance documents on gene therapy is an emphasis on weighing potential risks identified in nonclinical data when designing clinical trials. Such risks include genomic integration of the gene therapy product, genome editing, prolonged transgene expression, latency, and persistent infections. Additionally, biodistribution studies have become increasingly relevant in preclinical gene therapy studies. In addition, the National Institutes of Health recently released guidelines on biosafety practices and containment strategies for constructing and handling gene therapy products.[3]

EU Framework

In the European Union (EU), the overarching gene therapy guideline is the European Medicines Agency (EMA) Guideline on the quality, non-clinical, and clinical aspects of gene therapy medicinal products. Each member state, however, has its own directives that may require additional reviews by a relevant health authority, ethics committee (EC), or genetically modified organism (GMO) authority. To ease the complexity, the EMA created the Committee for Advanced Therapies, which provides scientific recommendations on the classification of all advanced therapy medicinal products (ATMPs), including gene therapies, during their development, provides scientific advice on ATMP programs, and reviews ATMP dossiers.

The EU guidelines on Environmental Risk Assessment of gene therapy investigational products also need to be considered in the context of:[3]

  • Contained use: Defined as “any activity for which specific containment measures are used to limit their contact with, and to provide a high level of safety for, the general population and the environment.” Most clinical trials are categorized within this classification.
  • Deliberate release: Defined as “any intentional introduction into the environment…for which no specific containment measures are used.” There are Member States (Germany) that place clinical trial administered gene therapies into this more conservative category.

Expedited Approval Pathways

Gene therapy products intended to treat serious or life-threatening diseases or conditions with significant unmet medical needs may be eligible for expedited approval. The FDA offers the following designations or pathways:

  • Fast Track designation offers more frequent communication with the FDA and rolling review of the biologic license application (BLA). Fast track products may also be eligible for Priority Review and Accelerated Approval.[4]
  • Breakthrough Therapy designation provides the same benefits as Fast Track, plus intensive product development guidance.[5]
  • Priority Review designation comes with regulatory review within six months, rather than the standard 10 months.[6]
  • Accelerated Approval allows for approval based on either a surrogate endpoint or an intermediate clinical endpoint.[7]
  • Regenerative Medicine Advanced Therapy (RMAT) designation may apply if preliminary clinical evidence supports the product’s potential to address unmet medical needs.[8] If a gene therapy program is granted both RMAT designation and accelerated approval, the sponsor can work with the FDA to agree on approaches for capturing the necessary confirmatory data following initial market approval.

The FDA also offers the Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) program for products that “introduce unique challenges due to unknown safety profiles resulting from the use of complex manufacturing technologies, development of innovative devices, or cutting-edge testing methodologies.”[9] This program enables sponsors to obtain advice on a wide range of development-related topics through an informal, non-binding consultation with CBER (Center for Biologics Evaluation and Research) staff.

In the EU, the primary path to expedited approval is the Priority Medicines (PRIME) designation. Other pathways include accelerated assessment and conditional approval.

Companion diagnostics

For certain gene therapy programs, the FDA recommends the development of companion diagnostic (CDx) assays to assist in the identification of those patients who are most likely to benefit from — or experience adverse events related to — the investigational gene therapy. CDx may also be useful for confirming the genetic defect targeted by the gene therapy product or for assessing the therapeutic potential of the gene therapy product.[10] If it is expected that a CDx will ultimately be used for patient selection in clinical practice, sponsors should coordinate submission of the gene therapy BLA and the CDx 510(k) so that marketing authorizations for both would be obtained at the same time.[11]

Study Considerations

Study design

Requirements for gene therapy clinical trial design will vary by study phase and indication. Natural history studies may be important for understanding the genotype-phenotype relationship. Generally, first-in-human (FIH) studies for gene therapy programs require staggering of enrollment and dosing to monitor safety. For rare diseases treated with gene therapies, the FDA recommends that the sponsor explores whether the FIH studies could be randomized controlled trials to generate the safety and efficacy data necessary to support registration. Historical controls can only be used if they are accompanied by knowledge of the natural history of the disease, which may be lacking in rare diseases.[11] 

If the study includes a sham procedure, it is essential to not only demonstrate that this procedure does not cause undue risk or burden, but also ensure that the participant understands they may not receive the investigational gene therapy product. Country-specific regulations and requirements for sham procedures may differ and may require extra steps for EC approval. Moreover, if devices or specialized equipment are used in vector or cell administration, additional approvals — including such local approvals as CE marking — are needed. Overlooking these requirements can result in study delays, so planning is key.

Depending on its vector and genome editing potential, an investigational gene therapy product may require long-term follow up (LTFU) of up to 15 years. The need for LTFU presents a significant challenge to patient and site engagement and should be considered carefully in the process of study design. Establishing patient registries and creating mobile applications can be invaluable in collecting patient-reported outcomes and minimizing data loss during the prolonged follow-up period.

If the study involves pediatric patients, retention may be an even bigger hurdle as patients may relocate or mature to being followed by an adult physician who is not affiliated with the trial. To address this, sponsors may need to qualify, initiate, and train new sites during the LTFU period.

Site selection

Due to the complexity involved in gene therapy administration, it is paramount for sites to be experienced with gene therapy, familiar with the therapeutic area, and accessible to eligible patients. Sites also need appropriate facilities and procedures for receiving, storing, and preparing the gene therapy product. To the extent possible, aligning protocol requirements with existing site workflow and policies will help to limit site burden and facilitate staff engagement.

When qualifying sites, it may be useful to ask the following questions:

  • Are all stakeholders, including pharmacy staff, available and willing to participate in a gene therapy trial?
  • What is their experience and past performance in gene therapy studies?
  • Do they have access to the target study population?
  • What is their track record in meeting regulatory and protocol requirements?
  • If the study involves a GMO, do they have GMO-specific standard operating procedures?
  • Are they involved in competing trials?
  • How much experience do they have with the mode of administration?

Relevant experience with the mode of administration is especially important in autologous gene therapy studies or trials that require an intracranial procedure.

Every study is unique. Even if a site has previous experience, it is important for sponsors to establish processes for training and supporting all sites to optimize performance. Training for site staff should include guidance on how to address GMO-related questions and concerns that patients and families may have. Performing a dry run of the protocol requirements at the site initiation visit may help reduce errors, identify risk mitigation tactics, and increase the confidence of site staff.

Recruitment and retention

As many investigational gene therapies target rare diseases, these trials face the same challenges with recruitment as other rare disease studies. Seeking and incorporating patient and caregiver feedback into the trial protocol helps ensure feasibility of the study design. That feedback helps validate that the study will be of interest and does not create excess burden to patients or their families. Sponsors may find it useful for patient support and advocacy groups to use in increasing awareness of the study through their networks.

Many patients may be unfamiliar with gene therapy. Consequently, education and informed consent are essential to successful enrollment in gene therapy trials. Setting appropriate expectations, particularly in studies that involve a sham procedure, and providing information on the risks and complicated logistics associated with gene therapy can help to alleviate concerns.

To ensure successful recruitment and retention, sponsors should focus on minimizing study-related burden and enabling participation, even under extraordinary circumstances. This is true for any clinical trial but is particularly important in gene therapy studies that require long-term follow-up. For patients who are traveling long distances, coordinating transportation and lodging can minimize the stress of site visits. If cross-border enrollment is expected, it is critical to implement processes and procedures that ensure seamless transitions.

Implementing a hub and spoke model, in which gene therapy administration occurs at a centralized, specialized location and follow-up is performed locally, may increase the accessibility and diversity of a study and facilitate enrollment. To the extent possible to do so without compromising data quality, opportunities to incorporate mobile research nursing visits and integrate technology for remote data capture should not be overlooked. Leveraging any combination of these strategies to minimize burden may not only boost enrollment and enhance retention, but also improve the overall study experience for patients and their families.

Throughout the duration of the study, it may also be useful to communicate regularly with patients and caregivers. Providing educational materials or routine updates on study progress will foster a sense of belonging and encourage engagement. These communications are a powerful reminder to patients and their families that, by participating in the study, they are part of a larger effort to advance scientific knowledge and bring novel therapies to those who need them most.


In 2020, the FDA received more than 900 new investigational gene or cell therapy drug applications.[11] By the year 2025, the agency anticipates that 10 to 20 gene therapies will be approved per year.[12] Gene therapy sponsors need to consistently meet the challenge of conducting safe, ethical, patient-focused studies in a dynamic regulatory and clinical trial environment. To successfully navigate the journey to marketing authorization, sponsors must understand — and plan for — all of the nuances associated with designing and executing these complex studies.


[1] American Society of Gene + Cell Therapy and Informa Pharma Intelligence. Gene, Cell & RNA Therapy Landscape, Q3 2021 Quarterly Data Report. Published October 2021. Available at

[2] Food and Drug Administration. Cellular & Gene Therapy Guidances, as of December 10, 2021. Available at

[3] Official Journal of the European Union. Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained used of genetically modified micro-organisms. Available at

[4] U.S. Food and Drug Administration. Fast Track. Last updated 4 January 2018.

[5] U.S. Food and Drug Administration. Breakthrough Therapy. Last updated 4 January 2018.

[6] U.S. Food and Drug Administration. Priority Review. Last updated 4 January 2018.

[7] U.S. Food and Drug Administration. Priority Review. Last updated 4 January 2018.

[8] U.S. Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation.

[9] U.S. Food and Drug Administration. INTERACT Meetings.

[10] US Food and Drug Administration. Human Gene Therapy for Rare Diseases: Draft Guidance for Industry.

[11] Cell Culture DISH. A Remarkable Year for Gene Therapies.

[12] U.S. Food and Drug Administration. 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.