Navigating the maze of environmental risk assessments for genetically modified products including ATMPs/CGTs

Jörg Schneider

by Jörg Schneider

The market for medicines containing genetically modified organisms is expected to grow at a fast pace in the coming years due to the availability of the first approved products, new technology developments, increased availability of funding from various public and private institutions and big pharma entering the field.

One underappreciated aspect of gene therapy development is the different attitudes of the major regulatory jurisdictions towards the potential environmental risks posed (see Table 1). In the EU, clinical trials with medicinal products that contain or consist of Genetically Modified Organisms (GMOs) are subject to both clinical trials and environmental legislations under national competences, where an ERA needs to be submitted at each step of clinical development. In the US, an ERA is necessary for clinical trials only in specific cases, and when the product nears commercialisation.

Compared to the European situation, developers in the US do not need to produce as much information to conduct the ERA at an early stage of development or deal with the administrative burden that it entails.


Table 1: Environmental risk assessment step procedure in the EU and the US


Table 1: Environmental risk assessment step procedure in the EU and the US

US approach

According to the FDA´s Guidance for Industry “Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and related recombinant viral or microbial products (GTVVs)”: those products that consist of GTVVs should be evaluated for the need of an ERA. FDA regulations specify that an ERA must be submitted as part of investigations for new drug (IND) applications, and for the BLA of a biologic product, unless it qualifies for an ERA exemption, also called categorical exclusion. IND applications for the development of a GTVV are ordinarily categorically excluded from the requirement to submit an ERA, unless extraordinary circumstances indicate that the specific action may significantly affect the quality of the environment. Possible exceptions may usually occur for use of virulent organisms or organisms that are ecologically more fit than their wild-type counterparts. The reason to consider a categorical exclusion for clinical development is that a clinical study involves small quantities of a medicinal product and a limited number of patients, not having a significant cumulative effect into the environment. Therefore, the regulatory process is very short, since the trials are usually exempt from an ERA. The ERA exemption may also be applicable for the BLA in cases where the GTVVs “occur naturally in the environment”, meaning that the product includes functional protein-coding sequences from one or more species within a single genus. This definition also includes products that differ from a wild-type substance only in attenuating point mutations or deletions, or that have been killed or inactivated by undergoing a specific manufacturing step designed to eliminate their ability to replicate. Thus, most BLAs for GTVVs will require an ERA, since they usually include functional protein-coding sequences from a different genus. However, unlike in the EU, genetically modified human cells are considered substances that “occur naturally in the environment”, since these cells are not viable in the environment and are degraded into naturally occurring substances. In fact, the two approved CAR-T therapies in the US were granted with a categorical exclusion. In those cases where the ERA is required, the necessary information is usually collected while conducting trials and not at an earlier stage of development.

EU approach

In Europe, an ERA is a mandatory procedure required by the regulatory authorities in order to further develop the products containing a GMO. This procedure is submitted prior to first-in-human clinical trial, during the subsequent clinical development and for the marketing authorisation application (MAA). The documents to be submitted at these stages, and the regulatory authorities that will assess the procedure are different in every member state. During clinical development, the ERA is conducted according to the requirements of the EU Member State in which the trial will be performed, whereas for the MAA it is centralised and reviewed by the Committee for Advanced Therapies (CAT), along with the Committee for Medicinal Products for Human Use (CHMP), at the European Medicines Agency (EMA).

According to the EU definitions, there are two possible ways in which a GMO can come into contact with the environment: a “contained use” and a “deliberate release”. Contained use refers to any activity in which microorganisms are genetically modified or in which such genetically modified microorganisms are cultured, stored, transported, destroyed, disposed of or used in any other way, and 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, for instance the use of GMOs in confined laboratories (Directive 2009/41/ EC 2009). By contrast, deliberate release refers to any intentional introduction into the environment of a GMO 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. In some EU member states however, following the deliberate release framework is mandatory for any product.

In terms of clinical development in the EU, two types of authorisations should be obtained in order to conduct a clinical trial with a GMO-containing medicinal product: one for the clinical trial application (CTA) reviewed by the ethics committees and competent national health authorities, and another one for the GMO application in order to “release” or to administer the GMO-containing medicinal product in that trial. The competent authorities (CAs) of each Member State in charge of GMO evaluations are the Ministries or agencies responsible for the environment in each country, along with a scientific advisory committee. The GMO application is usually submitted in parallel with the CTA, yet in some Member States such as Bulgaria, Poland, Romania, Slovenia and Slovakia, sponsors are required to obtain the GMO authorisation before the CTA can be submitted. The information to be submitted comprises the comparison of the characteristics of the parental and the modified organisms, details on the genetic modifications, effects of inserted or deleted sequences, details on the release and the receiving environment, possible interactions between the GMO and the environment, and information on the monitoring, control, waste treatment and emergency response plans.

Regarding marketing authorisation, the MAA submitted to the EMA has to include an ERA, which corresponds to Section 1.6.2 of the MAA dossier included in Module 1, in accordance with the principles of deliberate release and assessed as part of the centralised procedure. This ERA, in accordance with Annex II of the Directive 2001/18/EC (2001), should follow the following general principles: the GMO should be compared to the non-modified organism from which it is derived, the ERA should rely on data derived from specific testing of the GMO during the development and performed on a case-by-case basis, and the ERA needs to be reevaluated if new information on the GMO or its effects on human health or the environment becomes available. The information to be submitted is outlined in the Annex IIIA, which applies to releases of all types of GMOs other than higher plants, and Annex IV of Directive 2001/18/EC (2001).

The EMA has developed two guidelines to provide guidance on the preparation of the ERA for MAA (EMEA/ CHMP/BWP/473191/2006 – Corr 2006; EMEA/CHMP/GTWP/ 125491/2006 2008). At the EMA, committee members from various states meet to make decisions about marketing approval, and the designated GMO. Competent Authorities of all Member States are also consulted for review of the ERA. Due to the procedural and scientific complexities associated with the ERA evaluation, the EMA recommends to request pre-submission meetings one year in advance of submission of the MAA (EMEA/CHMP/BWP/135148/2004 2005). Finally, after marketing authorisation the GMO-containing medicinal product is subject to traceability and a monitoring plan has to be performed. This monitoring plan should include systemic distribution and shedding and in some cases, surveillance of long-term side effects, information about adverse or unexpected effects, monitoring effects in individuals other than the patient, if applicable, and information about off-label use (EMEA/CHMP/BWP/473191/2006 – Corr 2006).

Although the mentioned European Directives define the legal framework and objectives to be met by the Member States regarding ERAs, these Directives have been implemented differently across European countries leading to different GMOs procedures and requirements. This lack of harmonisation has an impact on the logistics of product development that might affect times, costs and managerial burden.

This burden has been recognized by the EU, particularly in the light of the urgency required for development of vaccines against SARS-CoV-2. In July 2020, the European Parliament and the Council of the EU adopted a Regulation on the conduct of clinical trials with treatments and vaccines against COVID-19 containing genetically modified organisms (GMOs). The regulation aims to speed up the conduct of clinical trials by providing a temporary derogation from the mandatory environmental risk assessment for these substances during the COVID-19 pandemic. And to grant a temporary derogation from the requirements concerning a prior environmental risk assessment and consent under Directives 2001/18/EC and 2009/41/EC for the duration of the COVID-19 pandemic or as long as COVID-19 is a public health emergency. The derogation should be limited to clinical trials with investigational medicinal products containing or consisting of GMOs intended to treat or prevent COVID-19.

Different legal framework across EU countries

Another hurdle for applicants in the authorisation of multinational clinical trials are the differences in the implementation of legislation among the Member States. The release of a GMO within the context of a clinical trial can be included within “contained use” or “deliberate release” regulations depending on the country. This results in a wide variability on how the risk is assessed, the requirements and the documents to be submitted, as well as the procedure to be followed. Some Member States decide, on the basis of several factors of a clinical trial, whether a notification for deliberate or contained use is needed. Some of the factors are related with the features of the GMO (e.g. replication deficient), probability of shedding (i.e. when the GMO is released into the environment via the patients’ excreta), if proper management procedures and/or working practices are taken to prevent any possible release of the GMO, or if patients are hospitalised in a room that fulfils the contained use criteria or treated on an out-patient basis. For the other Member States, a clinical trial where GMO-containing medicinal products will be administered falls under the deliberate release legislation, regardless of the specific circumstances of the clinical trial.

For some countries, the sponsor must decide into which category the GMO falls based on a preliminary risk assessment and considering the interpretation of national legislation for each procedure. In these cases, it is highly recommended to determine with the competent body which are the GMO classification and/or the procedure to follow before proceeding with the GMO evaluation. Since the CTA and the GMO procedures are reviewed by separate national agencies, some countries offer the possibility of coordinating a scientific advisory panel between both competent bodies, such as the case of Belgium. Other countries like the Netherlands offer an informal preliminary consultation of the draft GMO application in order to discuss whether sufficient information for a full risk assessment has been included, avoiding time delays after its submission.

In summary, ERAs are required to conduct clinical trials and obtain Marketing Authorisations. In particular for Europe, due to the complex set-up of the EU regulations, timely implementation of GMO applications and ERAs is required. Biopharma Excellence has supported multiple applications in the EU, US, Canada and Australia and possesses a wealth of experience, knowledge and experts to help navigate your ATMP to a success. Contact us now and find the shortest way through the GMO/ERA maze.

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