Managing complex GMO requirements for gene therapy clinical trials

Liron Sarid-Krebs | Senior Consultant and Team Lead, Biopharma Excellence

Regulators and industry organizations have raised concerns that Europe may be falling behind the United States and Asia when it comes to bringing cell and gene therapies to market. Decentralized regulatory processes have been highlighted as one of the biggest barriers.

Major efforts are being made towards harmonization of key processes in the EU, and some of the issues might have been resolved with the introduction of the Clinical Trials Regulation, which centralizes clinical trial authorizations (CTAs) between member states. Nevertheless, one regulatory issue of concern for advanced therapy is the requirement to undergo genetically modified organism (GMO) assessments at all development stages.

Medicinal products that contain or consist of GMOs must undergo an environmental risk assessment (ERA) that considers potential adverse effects for humans (e.g., non-patients directly exposed to the therapy, such as clinic staff), for animals, for plants and micro-organisms, as well as for general impact on the environment[i].

While medicinal therapy companies are accustomed to meeting regulatory requirements to carry out clinical trials, GMO requirements pose several significant hurdles. First, the regulations were created with plants in mind, specifically the potential for those plants to spread their seeds and impact other plants and the environment. Clinical trials, on the other hand, are conducted under controlled settings with transient expression of the genetically modified vector. The second big hurdle is, again, the lack of harmonization between European member states.

Adapting a regulation

GMO regulations are based on the framework of contained use and deliberate release directives. According to the EPA guidelines, contained use refers to “the use of physical barriers, or the combined use of physical barriers, to limit contact between the GMO and the environment and to provide protection for the general public”[ii]. Deliberate release is defined as “any intentional introduction into the environment of a GMO or a combination of GMOs for which no 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”[iii].

To complicate matters, each country implemented the regulations differently, with some saying most of these products fall under the directive of contained use, and some always using the deliberate release directive.

Furthermore, while there are commonalities with regards to implementing the environmental risk assessment requirements, each country has specific requirements, including around language, and the biggest hurdle for developers is to understand the requirements in each country. Until the introduction of the CTR, this was the same hurdle companies faced with their clinical trial applications, and meant companies needed to work with CROs with hands-on experience for each country. Today, with the Clinical Trials Information System (CTIS) portal, the clinical trial application process will become more streamlined, but the same is not true (thus far) for GMO requirements.

Harmonization and centralization needed

Another big hurdle for companies is that the GMO information is not centralized on the European Medicines Agency website, and companies often struggle to find the specific GMO requirements for each country. In addition, the timelines for the clinical trial application and GMO assessments are different, meaning that companies must manage two separate processes in parallel.

Compounding the challenge is the requirement for the clinical site to have the proper GMO risk mitigation  in place, which again is a different process. Sites must ensure clinical procedures, such as control measures to prevent dissemination into the environment and emergency response plans, are properly followed and have been authorized by the agencies before the trial starts.

Although steps are being taken to harmonize GMO documentation across the EU/EEA (with regard to the common application forms and good practice guides of the more commonly used viral vectors), the need to centralize the process is still pressing. As the clinical trial application process is harmonized by the new CTR, the GMO assessment procedure, which is part of this process, should also be harmonized. At the very least, steps should be taken to ensure information about what is required by the different competent authorities is centrally available and current.

The European pharmaceutical body, EFPIA has called for greater harmonization of GMO procedures for medicinal products, noting that the existing process does pose challenges to companies trying to coordinate with their clinical trial applications[iv].

The European Commission Directorate-General for Health and Food Safety (DG SANTE) and the EMA are looking at steps to foster and streamline ATMP development, including speaking with national competent authorities to try to reduce discrepancies across the EU regarding the application of GMO rules[v].

As previously discussed, Europe does risk falling behind some other parts of the world when it comes to ATMP innovation and approvals. For example, the U.S. has a categorical exclusion that applies to most clinical trials, making the process for managing GMOs far less onerous. To address these issues, regulatory authorities in Europe need to take steps to simplify, harmonize and centralize all processes, including GMO requirements.

Liron will present at a European Medical Writers Association webinar on 15 September, titled “Assessing and Reporting Environmental Risk for Human Medicinal Products throughout Development”.

About the author:

Liron Sarid-Krebs is Senior Consultant and Team Lead at Biopharma Excellence, where she brings her extensive experience with ATMPs and other biopharmaceuticals to provide integrated drug development strategies, regulatory preparation and support with the regulatory agencies.

[i] Guideline on Scientific Requirements for the Environmental Risk Assessment of Gene Therapy Medicinal Products, CHMP, 2008,

[ii] Contained use of GMOs, EPA,

[iii] Deliberate release of GMOs into the environment, EPA,

[iv] EFPIA calls for a Greater Harmonisation of Genetically Modified Organism (GMO) Procedures for Investigative Medicinal Products, October 2021,

[v] Advanced therapy medicinal products (ATMPs): DG SANTE and EMA launch new action plan, European Commission,




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