Environmental risk, biosafety and other key regulatory considerations  for cell and gene therapy trials

In recent years, the gene therapy regulatory landscape has evolved from a broad, general guidance to a narrower focus on testing and manufacturing considerations in specific disease states. This article explores how factors such as environmental risk assessment and biosafety can impact gene therapy clinical study start-up as well as the continuing evolution of guidances from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).

Tracking the complexity in the global regulatory landscape

The regulatory landscape in the United Kingdom (UK) and European Union (EU) is increasingly complex, reflecting the advancement of gene therapy research. Aside from the EMA, a gene therapy product will have to undergo review by individual member states’ competent authorities (CAs), ethics committees (ECs), and/or genetically modified organism (GMO) authorities. To ease the complexity, the EMA has created the Committee of Advanced Therapies (CAT), whose responsibilities include providing scientific recommendations on the classification of advanced therapy medicinal products (ATMPs) as gene therapy medicinal products (GTMPs), somatic cell-therapy medicinal products (sCTMPs), tissue-engineered medicines (TEPs), or combinations thereof.

Since January 2020, the FDA has issued nine separate guidances specifically focusing on cell and gene therapy,1 including recommendations regarding the design of long-term follow-up studies.2 Additionally, the Recombinant DNA Advisory Committee (RAC) recently 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.

These developments have led to faster approval timelines, with 68% of novel drug approvals in the US in 2020 using at least one of the FDA’s expedited development and review pathways to speed approval.3 These include the agency’s Fast-Track designation, and the Regenerative Medicine Approved Therapy designation, which covers a growing number of gene therapy products.

Environmental risk assessment and  biosafety take centre stage

Sponsors seeking rapid and efficient study start-up must provide actionable information to facilitate regulatory decision-making. Such information should include assessment of potential risks identified in preclinical studies (eg, integration activities of the gene therapy product into the genome, genome editing, prolonged transgene expression, latency, persistent infections) and how they may affect clinical trial design.

Consequently, toxicology and biodistribution studies have become increasingly relevant in gene therapy trials. The strength of the preclinical package, therefore, often depends on biodistribution data that show where the vector travels, a factor largely determined by the route of administration. That underscores the importance of up-front collection of non-clinical data to shorten long-term follow-up, especially when the literature offers limited information on similar products.

Paralleling the industry’s heightened focus on patient-centricity, regulators increasingly insist that clinical trial protocols incorporate strategies to minimise inadvertent horizontal and vertical transmission of genetic material and/or vectors. Though essential for ensuring trial participants’ safety, such strategies may necessitate up to 15 years of long-term follow-up with regular collection of blood and other samples.2

Mode of action and regulatory pathway selection

Mode of action is a key consideration in product classification and regulatory pathway selection, though it can sow confusion among trial sponsors, particularly for studies conducted in the UK and EU. For example, the EMA may classify a genetically modified cell therapy product as a GTMP, even if the genetic manipulation was ex vivo, necessitating compliance with applicable gene therapy guidelines and regulations.

A GTMP incorporating a medical device would raise additional questions, including, “Is it really a combination product?” and “Is the mode of action really related to the medical device, or does the device merely supplement for administration of the investigational medical product (IMP)?”

The uncertainty underscores the importance of up-front discussion with the regulators, especially the EMA, as CAs in different EU member states seem to view these issues differently.

Managing the competent authorities

The varying perspectives of the different states’ CAs largely reflect the two distinct decision routes to approval:

  • 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’4
  • Deliberate Release, or ‘any intentional introduction into the environment…for which no specific containment measures are used’. 5

Germany, for example, favours the deliberate release route and has specialised CAs for biologics and gene therapy, with specific gene therapy documents required for submission and an EC review and approval process that is the same as that for a standard IMP. The advantage of this approach is that one CA reviews the product not only from the clinical trial directive but also from the deliberate release directive.

By contrast, the UK often assumes the contained use route. The Health and Safety Executive (HSE), the UK GMO authority, 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 such products. Additionally, instead of a single standard EC review, the UK may require specialised reviews from each of the following:

  • Gene Therapy Advisory Committee (GTAC), which grants ethical approval for gene therapy clinical trials
  • Gene Therapy Modification Safety Committee (GMSC), which reviews trial protocols and assesses potential risks and from which individual sites must also secure approval
  • Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBVEAG), a division of the Medicines and Healthcare products Regulatory Agency (MHRA) that oversees certain biologics and gene therapy products, and which may require additional meetings to discuss challenging or complex trials.

Of all the EU member states, Poland presents what may be one of the most complex regulatory landscapes for gene therapy clinical trials. Poland requires prior GMO authority approval before a sponsor can submit the standard clinical trial application, parallel CA and EC review, and mandates a two-step process for GMO authority approval. The first step is a site permit that allows sites to work with specific classes of products.4 The second step is a study-specific approval, which can only occur once all study sites have appropriate permits. If a sponsor chooses sites that already have permits, it can accelerate the study start-up process.

EU harmonisation is coming

EU Regulation 536/2014, expected to be implemented by early 2022 (with a three-year transition period), will institute a harmonised electronic submission process for CA and EC review and approval in all member states. That should eliminate the need for prior GMO approval in countries like Poland. However, GMO authorities will not be subject to the new regulation, meaning that gene therapy clinical trial applications will likely continue to be subject to additional review and approvals.

For clinical trial applications involving environmental release, certain information from documents such as Environmental Risk Assessment reports, the Summary Notification Information Format Form, and the Common Application Form for viral vector-based therapies will often go straight into an EU public registry. Biological samples may also require additional import and export licences. The new regulation will therefore heighten the need for transparency, awareness and data-sharing between sponsors, regulators and trial sites.

Optimising site selection

The determinants of product classification, and their implications for regulatory pathway selection, make site selection critically important. Sponsors must therefore ensure that each site has the requisite capabilities and processes to handle that particular class of product. For example, for US-based human gene transfer studies, each site must receive Institutional Biosafety Committee approval, a process that entails additional scientific review. Moreover, the FDA has approved only a limited number of sites for studies of T-cell therapies, further heightening the importance of meticulous site selection.


The way gene therapy clinical trials are regulated has advanced considerably in just a few short years. However, even as UK/EU and US guidances continue to evolve, the regulatory framework remains slightly behind the gene therapy research community in terms of advancing innovation. It remains to be seen whether the coming EU harmonisation and the recent FDA guidances will enable the regulators to catch up with the research. Nevertheless, we can be sure that the rapidly changing regulatory matrix will continue to present hurdles to gene therapy trial approval and start-up. Trial sponsors that keep pace with the evolving regulatory strictures will be the ones that successfully negotiate those hurdles.  π

1. US FDA. Cellular & Gene Therapy Guidances. Available at: https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances. [Accessed 2021 April 19]

2. US FDA. Long Term Follow-up After Administration of Human Gene Therapy Products: Guidance for Industry, January 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-products. [Accessed 2021 April 19]

3. US FDA. 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]

April Marquick is a cell and gene therapy expert at Premier Research