The European GMO legislation for gene therapy products in clinical trials and its pitfalls

by Theodor Tiko and Dr. Annegret Vaggelas

Advanced Therapy Medicinal Products (ATMPs) such as Gene and Cell Therapy medicinal products are innovative biopharmaceuticals with the potential to bring high therapeutic value. Especially the new gene editing tools such as CRISPR-Cas9 are expected to shift the focus of medicine from treating symptoms to curing diseases. However, especially their clinical development faces specific challenges. For products containing genetically modified organisms (GMOs), an additional risk assessment step in the clinical trial authorisation (CTA) procedure is required. Although a European regulatory framework for this matter exists, it has been implemented differently into the Member State (MS) national legislation, leading to different documentation requirements and review and approval frameworks between the Member States.

In this article, Theodor Tiko and Dr. Annegret Vaggelas review the current status of the European GMO legislation for gene therapy products in clinical trials, including its pitfalls for clinical trial applicants.

Advanced Therapy Medicinal Products (ATMPs) such as Gene and Cell Therapy medicinal products are innovative biopharmaceuticals with the potential to bring high therapeutic value to a broad range of medical conditions where conventional approaches have been inadequate. Especially the new gene editing tools such as CRISPR-Cas9 are expected to shift the focus of medicine from treating symptoms to curing diseases.  Despite ATMP's game-changing potential, especially their clinical development faces specific challenges. For gene therapies (GTMPs), these challenges are compounded by an additional risk assessment step in the clinical trial authorisation (CTA) procedure when they consist of or contain genetically modified organisms (GMOs). 

The European Union has established a legal framework since 1990 to ensure that the development of GMOs is performed safely. This consists of the current Directives:
 

  • Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms;
  • Directive 2009/41/EC on the contained use of genetically modified micro-organisms; 


Therein GMOs are defined as “cellular microbiological entities capable of transferring genetic material, which is altered in a way that does not occur naturally by mating and/or natural recombination” and their regulation requires a safety risk assessment with respect to their possible impact on human/animal health and the environment.

Contained use is defined as any activity with GMOs for which specific containment measures are used to limit their contact with the environment. The focus of Directive 2009/41/EC is on the assessment of the biosafety level classification of the GMO and the implementation of physical, chemical and biological barriers.

All contained use procedures are classified based on the performed risk assessment into one of the following four categories: 
 

  • Class 1: No or negligible risk, level 1 containment
  • Class 2: Low risk, level 2 containment
  • Class 3: Moderate risk, level 3 containment
  • Class 4: High risk, level 4 containment


Class 3 / 4 GMOs always require prior consent from the competent authority but most ATMPs fall into Class 1 / 2. Of note is, that contained use often requires clinical site-specific notifications and submissions to authorities, which requires specific discussions with the clinical sites.

Deliberate release is defined as any activity with GMOs that is not contained use. Directive 2001/18/EC is based on an environmental risk assessment (ERA) covering effects on human health or the environment. The ERA should be carried out in accordance with the principles set out in Annex II of this Directive and includes five steps:
 

  1. identification of potential adverse effects,
  2. evaluation of consequences,
  3. estimation of the likelihood,
  4. risk estimation,
  5. risk management
  6. assessment of the overall environmental impact


All submissions for deliberate release must contain the following
 

a.     information relating to the GMOs
b.     information relating to the conditions of release and the potential receiving environment
c.     information on the interactions between the GMO(s) and the environment
d.     Information on monitoring, control, waste treatment and emergency response plans


It is also required that a dossier in the summary notification information format (SNIF) is submitted, which is added to a publicly available EU register.

Unfortunately, the two Directives have been implemented differently into the Member State (MS) national legislation, leading to different documentation requirements and review and approval frameworks between the Member States. Especially in the case of multi-state trials, there can be dissimilarities between MSs in classification as “contained use” or “deliberate release” as well as in the definition of GMO. Moreover, if there is a choice of contained use / deliberate release procedures in the MS, the sponsor must decide which category the GMO falls under and make the justification for that decision based on the ERA. These discrepancies create additional difficulties for applicants in the authorization of multinational clinical trials.

As the legislation concerned with GMO was drafted primarily with plant GMOs in mind with a goal to protect food consumers and crops from contamination, the information requested is not always relevant and application forms are generally not designed for medicinal products. In addition, the authority responsible for review of GMOs is often not the competent health authority and varies between Member States. Certain MS agencies responsible for GMO evaluations can also be responsible for transgenic plants, genetically-modified foods and environmental biosafety. Thus, they are not specialized in reviewing the application with a focus on clinical studies in a hospital environment. Furthermore, in some EU Member States, the GMO application must be approved before the CTA is submitted, in some after approval of the CTA and in others in parallel. The involvement of different stakeholders at different time points adds complexity to the application and can create additional delay because of different timetables for assessment and need for extra communication.

In some countries, the GMO requirements will involve interactions with many different entities including the national and/or regional responsible GMO authority, the investigators and biological safety officers of the clinical sites, and the laboratories that will manipulate samples from the patients. In Germany, the federal states are e.g. responsible for the monitoring of genetic engineering installations and operations in frame of the German Genetic Engineering Act and have to be consulted on top of the Paul-Ehrlich Institute for example in case of longtime storage (>3 days) of GMOs at the clinical sites. But here it is important to clarify at first if the GMO even falls under the Genetic Engineering Act as for example gene editing tools like CRISPR-Cas9 transferring just RNA without a vector or plasmid do currently not fulfill the definition of genetic engineering in Germany and thus at the moment do not require permission. That proves that is of outmost importance to identify the different stakeholders per country involved in the approval of GMO containing investigational ATMPs (ATIMP) early during planning. 

In conclusion, the application process for conducting clinical trials with an ATIMP consisting of or containing a GMO in the EU involves the need for differentiation between contained use and deliberate release review by different responsible authorities, with specific documents and procedures in addition to the standard CTA review by a competent health authority and the Ethics Committee. Such reviews require expertise and understanding of the information related to ATIMPs in the application. Recently there has been intense discussion, e.g. during a multi-stakeholder meeting at EMA regarding the lack of harmonisation of the GMO requirements and the challenge to integrate the GMO assessment in the clinical trial process. Moreover, a just recently published position paper from European Biopharmaceutical Enterprises (EBE), the Alliance for Regenerative Medicine (ARM), the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the European Association for Bioindustries (EuropaBio) brings this topic into focus and aims at supporting European competitiveness in the biomedical sector and avoiding delays for patient access. These efforts are welcomed and hopefully urge the authorities in the different Member States to consider a harmonization and streamlining of the GMO and CTA processes for GTIMPs.

We at Biopharma Excellence have the specialized knowledge, information, and resources needed to guide GTIMPs carefully on their way to GMO approval. Do not hesitate to contact us for more information.