Since the first gene therapy trial in 1990, the regulatory landscape has shifted from broad, loosely defined guidance with little variation between different cell and gene therapies to a more robust collection of guidelines and directives focused on testing and manufacturing considerations for these products in specific disease states and therapeutic settings. This article will explore the importance of new factors in gene therapy clinical study start-up, including environmental risk assessment and biosafety, as well as how guidances from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) continue to evolve in a rapidly changing regulatory landscape.
 
U.S. and EU regulatory guidelines: catching up with the research
In the U.S., the FDA appears intent on bringing regulatory guidance up to speed with recent advances in cell and gene therapy research. Indeed, the FDA has issued nine separate guidances since January 2020, specifically focusing on cell and gene therapy.¹ The National Institutes of Health (NIH) likewise recently released guidelines specifying biosafety practices and containment strategies for constructing and handling gene therapy products.² 
 
In addition, the Recombinant DNA Advisory Committee (RAC), originally established in 1975, refocused its role to follow and provide advice on safety and ethical issues associated with emerging biotechnologies and renamed itself the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC), reflecting its broader outlook.
 
The landscape is more complex in the United Kingdom (UK) and European Union (EU), where there are two distinct decision pathways to approval and the added complication of different directives across individual member states, each of which delineates implementation of guidelines by the relevant health authority, ethics committees (ECs), and/or genetically modified organism (GMO) authority. Additionally, the EMA’s Committee of Advanced Therapies (CAT) bestows product classification upon advanced therapy medicinal products (ATMPs), which can either be gene therapy medicinal products (GTMPs), somatic cell-therapy medicinal products (sCTMPs), tissue-engineered medicinal products (TEMPs), or combinations thereof.
 
In the spotlight: environmental risk assessment and biosafety
What the U.S., UK, and EU have in common is that the regulatory authorities appear to be increasingly focused on providing drug developers with meaningful insight in answering critical regulatory and study start-up questions, particularly those pertaining to environmental risk assessment and biosafety. Drug developers, in turn, must be vigilant about providing the authorities with actionable information to facilitate regulatory decision-making.
 
A key feature of the FDA’s recent guidances on cell and gene therapy is a renewed emphasis on weighing potential risks identified in nonclinical data as considerations for clinical trial design. Such risks include the integration activity of the gene therapy product into the genome, genome editing, prolonged expression of the transgene, latency, and persistent infections. As a result, formal pharmacokinetic studies have become less relevant in gene therapy trials and have taken a back seat to toxicology and biodistribution studies.
 
While biodistribution studies in animal models can be relatively straightforward, in that one can perform necropsy to assess where vector sequences are found across the entire organism, this clearly cannot be done in a patient. Consequently, sponsors should incorporate biodistribution data into a very strong preclinical package that shows where the vector travels, information that very much depends on the route of administration.
 
However, it can be challenging to collect numerous additional nonclinical data points prior to entering the clinic, especially when the literature offers limited information on similar products. For example, when there are little or no preclinical data on vector persistence, the sponsor must assume persistence and therefore conduct additional long-term follow-up assessments. That underscores the importance of up-front collection of nonclinical data to reduce the long-term follow-up period.  
 
Safety considerations: keeping the patient in mind
Other critical regulatory considerations reflect the industry’s increasing focus on patient centricity. These manifest as a heightened focus on reviewing patient populations, targeted tissue, characteristics of expressed transgenes, vector type, in vivo versus ex vivo transduction, and related safety deliberations.
 
With regard to safety, regulators are increasingly insisting that clinical trial protocols incorporate strategies to minimize inadvertent horizontal and vertical transmission of genetic material and/or vectors. Such strategies may require up to 15 years of long-term follow-up, with regular blood draws and collection of other samples from trial participants. As burdensome as those requirements may be for participants, they are essential for ensuring their safety. Changes to guidance are now allowing for questionnaires and phone calls to be utilized later in the follow-up period instead of in-clinic assessment to help alleviate the patient burden.
 
Mode of action helps to determine product classification
In considering the many potential avenues to approval, regulators increasingly look at the mode of action when classifying products, in addition to reviewing the manufacturing process from drug substance to drug product. This approach to classification can sow confusion among trial sponsors, particularly for studies conducted in the UK and EU. For example, for a trial involving a genetically modified cell therapy product, the EMA may make a case for classifying it as a GTMP. Even if the genetic manipulation was ex vivo, it would still count as a GTMP and therefore must comply with applicable gene therapy guidelines and regulations.
 
A GTMP incorporating a medical device would raise a whole other set of questions, including “Is it really a combination product?” and “Is the mode of action really related to the medical device, or is the device merely meant to supplement for the administration of the investigational medical product (IMP)?”
 
The uncertainty makes it especially important to discuss these questions up-front with the regulators, especially the EMA, as the competent authorities (CAs) in different EU member states each seem to view these issues differently.
 
Optimizing site selection to smooth the regulatory pathway
Once the regulators determine the product classification, sponsors can then look at the regulatory pathway. In the U.S., 68 percent of novel drug approvals in 2020 used at least one of the FDA’s expedited development and review pathways to speed approval.³ These include the well-known Fast Track designation, and the Regenerative Medicine Approved Therapy designation, which covers a growing number of gene therapy products.
 
The determinants of product classification make site selection critically important. For human gene transfer studies, each site must receive Institutional Biosafety Committee approval, a process that entails additional scientific review. Similarly, studies of T-cell therapies can only be conducted at a limited number of FDA-approved sites. Sponsors must therefore be mindful of the factors that determine product classification and ensure that each site has the requisite capabilities and processes in place to handle that particular class of product.
 
Navigating the complex UK and European regulatory environment
As noted above, there are two distinct routes to approval in the UK and EU. One route considers contained use, which is 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.”⁴ The other pathway focuses on deliberate release, or “any intentional introduction into the environment… for which no specific containment measures are used.”⁵ 

Some EU member states, such as Germany, favor the deliberate release route and have specialized CAs for biologics and gene therapy, with specific gene therapy documents required for submission and an ethics committee review and approval process that is the same as that for a standard IMP. The advantage of this approach is that there is one CA that reviews the product not only from the clinical trial directive but also from the deliberate release directive.
 
Others, such as the UK, often assume the contained use route. The Health and Safety Executive (HSE) is the GMO authority in the UK and does not require additional approval for a Class 1 (no or negligible risk⁶) contained-use product, though trial sites need an HSE permit to certify that they have the right procedures in place for handling and managing such products. Additionally, rather than having a single standard ethics committee review process, the UK currently has four specialized ECs known as the Gene Therapy Advisory Committee (GTAC), which grants ethical approval for gene therapy clinical trials.
 
Individual sites must also secure approval from the Gene Therapy Modification Safety Committee (GMSC), which reviews gene therapy trial protocols and assesses the risks associated with the IMP. Adding to the UK regulatory mix is the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBVEAG), a division of the Medicines and Healthcare products Regulatory Agency (MHRA) that oversees biologics and gene therapy products, and which may require additional meetings to discuss challenging or complex trials, such as first-in-human trials for CAR-T cell products or other novel therapies.
 
But to further appreciate the complexity of the EU regulatory landscape for gene therapy clinical trials, look no further than Poland, which requires prior GMO authority approval before a sponsor can submit the clinical trial application for standard competent authority and ethics committee review, which are done in parallel. Moreover, GMO authority approval in Poland is a two-step process. The first step is a site permit that allows sites to work with a certain class of products (i.e., those with no/negligible or low risk⁴). The second step is a study-specific GMO authority approval, which can only take place once all the sites have appropriate permits. That places a premium on-site selection; if a sponsor chooses sites that already have permits in hand, it can accelerate the study start-up process.
 
Harmonization on the EU horizon
The forthcoming EU Regulation 536/2014, which is expected to be implemented by early 2022, will institute a harmonized electronic submission process for both competent authority and ethics committee review and approval in all EU member states. That should obviate the need for prior GMO approval in countries like Poland. However, GMO authorities will not be subject to the new regulation, meaning that the thicket of additional approvals and processes will likely remain in place for gene therapy clinical trial applications. Sponsors will need to submit critical documents, including Environmental Risk Assessment reports, the Summary Notification Information Format Form for environmental release, and the Common Application Form for viral vector-based therapies.
 
Information within these documents often will go straight into an EU public registry for clinical trial applications involving environmental release. There may also be a need for additional import and export licenses for biological samples. Suffice it to say that the new regulation will heighten the need for transparency, awareness, and data-sharing between sponsors, regulators, and trial sites.
 
The way gene therapy clinical trials are regulated has come a long way in just a few short years. Nevertheless, even as U.S. and UK/EU guidances continue to evolve to meet the needs of industry and society, the regulatory framework remains slightly behind the gene therapy research community in terms of advancing innovation. It remains to be seen whether the recent FDA guidances and the coming EU harmonization regulations will enable the regulators to catch up with the researchers, but one thing is certain: the rapidly changing regulatory matrix will continue to present hurdles to gene therapy trial approval and start-up. Those trial sponsors that are vigilant and transparent about tracking and complying with the evolving regulatory strictures will be the ones that successfully negotiate those hurdles.
 
References
1. U.S. Food and Drug Administration. Cellular & Gene Therapy Guidances. Available at: https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances. [Accessed 2021 April 12]
2. National Institutes of Health. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), April 2019. Available at: https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf. [Accessed 2021 April 12]
3. U.S. Food and Drug Administration. New Drug Therapy Approvals 2020. Available at: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020. [Accessed 2021 April 12]
4. Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms (recast); 2009. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32009L0041&from=EN. [Accessed 2021 April 12]
5. Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC – Commission Declaration; 2001. Available at: https://eur-lex.europa.eu/eli/dir/2001/18/oj. [Accessed 2021 April 12]
6. Health and Safety Executive. The Genetically Modified Organisms (Contained Use) Regulations 2014. Available at: hse.gov.uk/pubns/priced/l29.pdf. [Accessed 2021 April 13]