Notification procedures: Clinical Trials with GMOs for human or veterinary use

Introduction

Any clinical trial can only be conducted in Belgium if it satisfies several regulatory/ advisory requirements. More details about the Belgian law and its implementing decisions as well as about procedures and application content are available on the website of the Federal Agency for Medicines and Health Products (FAMHP):

When the Investigational Medicinal Product (IMP) used in a clinical trial contain or consists of a genetically modified organism (GMO) the clinical trial can only be conducted if it additionally complies with the legislative provisions on biosafety. With regard to the legislative provisions in Belgium two of the following procedures may be applicable : the "deliberate release" (DR) procedure, which is covered by federal legislation implementing Directive 2001/18/EC, and/or the "contained use" (CU) procedure, which is covered by regional legislation implementing Directive 2009/41/EC. Depending on the characteristics of the GMO and the clinical trial, one of three procedural scenarios may apply of which, based on regulatory submissions since 1998, scenario 1 "contained use-only" is the most common, followed by scenario 2 (contained use and deliberate release) and in very rare cases scenario 3 (deliberate release-only).

In order to help the notifier with the submission of their application for IMP containing or consisting of a GMO, the SBB and the FAMHP co-jointly developed a practical guidance (PDF, last version: April 2019). Also, to facilitate the conduct of clinical trials containing or consisting of GMO in different countries in the EU, a number of application forms for certain types of IMP for human use have been developped. For countries that have endorsed the forms, those can be a part of the biosafety dossier.

Specific case of COVID-19 clinical trials

The EU has adopted the Regulation (EU) 2020/1043 of the European Parliament and of the Council of 15 July 2020 on the conduct of clinical trials with and supply of medicinal products for human use containing or consisting of genetically modified organisms intended to treat or prevent coronavirus disease (COVID-19).

This Regulation provides a temporary derogation from Union legislation on GMOs with a twofold objective: 

  1. To support the development of safe and efficacious products for treatment or prevention of COVID‑19 by facilitating that clinical trials with medicinal products containing or consisting of GMOs can start as soon as possible.
  2. To ensure prompt availability of vaccines and treatments for COVID‑19 in case of emergency.

In concrete terms, this Regulation translates into the following provisions (into force since 18 July 2020):

With regards to clinical trials with investigational medicinal products for COVID-19 containing or consisting of GMOs:

  • These clinical trials can start in the EU in the absence of an environmental risk assessment or approval under the GMO legislation [Directive 2001/18/EC (“deliberate release”) and Directive 2009/41/EC (“contained use”)], when these operations relate to the conduct of a clinical trial authorized in accordance with Directive 2001/20/EC.
  • Sponsors shall implement appropriate measures to minimize foreseeable negative environmental impacts resulting from the intended or unintended release of the investigational medicinal product into the environment.
  • Sites where the genetic modification of wild-type viruses and related activities take place (“manufacturing activities”) continue to be required to comply with Directive 2009/41/EC.

With regards to the use of medicines containing or consisting of GMOs that are intended to treat or prevent COVID-19, without a marketing authorization (to address the needs of individual patients (compassionate use) or in cases where the spread of pathogens, toxins, chemical agents or nuclear radiation could cause harm):

  • The GMO legislation (Directive 2001/18/EC and Directive 2009/41/EC) is not applicable in these exceptional cases.
  • An environmental risk assessment will still be required when these medicinal products will be assessed by the EMA in the frame of an application for marketing authorisation according to Regulation (EC) No 726/2004.

This Regulation is limited in time. It shall apply as long as WHO has declared COVID-19 to be a pandemic or as long as an implementing act by which the Commission recognizes a situation of public health emergency due to COVID-19 applies.

For more information, contact the Federal Agency for Medicines and Health Products, Research and development division (ct.rd@fagg-afmps.be) or the Service Biosafety and Biotechnology (SBB) of Sciensano (contained.use@sciensano.be). 

Possible procedural scenarios

Scenario 1: "contained use-only" :

Activities related to the trial (like preparation and administration of the study medication, conservation of study drug…) are performed in a "contained use" facility (e.g. laboratories, hospital rooms or veterinary facilities).

Physical barriers, or a combination of physical barriers together with chemical and/or biological barriers, are used to limit the exposure of the general population and the environment with the IMP. In a "contained use-only" scenario, the "contained use" procedure is the only biosafety procedure to follow because throughout the duration of the study there is no possible release of the GMO into the environment (this is outside the contained use facility) either because there is no possible shedding or spreading of the GMO into the environment by the subject (the human or animal body acts as a biological containment of the GMO) or because proper management procedures and/or working practices are implemented to prevent the release of the GMO into the environment.

With respect to the "contained use" procedure, the regional regulations on contained use of GMOs and/or pathogenic organisms and the relevant notification procedures apply. The biosafety risk assessment is submitted for advice to the Service Biosafety and Biotechnology (SBB), which acts as technical expert for the regional authorities. It is recommended to complete the biosafety dossier with the clinical trial protocol to provide extra information for proper risk assessment.
A notification of the clinical trial by each participating "contained use" facility is requested. A "contained use" authorisation is given for a defined "contained use" activity on a specific site (or facility) for several years. An activity can cover a particular protocol or a whole program of clinical trials (e.g. phase II and III protocols using one type of vector with one transgene of interest in a determined therapeutic area, etc.) which can be considered equal with regard to biosafety aspects.

Scenario 2 : "contained use and deliberate release"

Like scenario 1, activities related to the clinical trial such as the preparation, administration or storage of the IMP are conducted in a "contained use facility" (e.g. laboratories, hospital rooms or veterinary facilities), thereby triggering the contained use procedure. In addition, there is a probability of release of the GMO into the environment as a result of the shedding and spreading of the GMO into the environment for which no sufficient management procedures or working practices are in place to avoid exposure of close contacts outside the contained facility and of the environment. The latter triggers the deliberate release procedure in addition to the contained use procedure. With regards to the deliberate release procedure, the Royal Decree of 21 February 2005 governing the deliberate release of GMOs into the environment and the relevant notification procedures apply. The biosafety dossier is sent to the FAMHP, which will forward a copy of the dossier to the Belgian Biosafety Advisory Council for advice. For more information about the roles and interventions of the Council in the procedure, please consult the Council’s website.
A "deliberate release" authorisation can cover a particular clinical trial conducted in different sites but also a whole program of clinical trials.

Scenario 3 : "deliberate release-only"

In this scenario none of the activities related to the clinical trial are conducted in "contained use" facilities. So far, the "deliberate release-only" procedure has been applied in a very limited number of clinical trials that aimed at testing veterinary vaccines in animals outside containment.

Conducting a clinical trial in humans across different countries in Europe

The biosafety aspects of clinical trials are covered by national regulatory requirements and not all the Member States have the same legislative approach (deliberate release and/or contained use of GMOs) when it comes to the use of GMO as an investigational medicinal product in a clinical trial. The position adopted by different European countries has previously been set out in detail in a report commissioned by the European Commission in 2007). More recently, recognizing the developments in advanced therapy medicinal products (ATMP) and the need of clinical sponsors and investigators of IMP involved in multicentric trials to have an overview of the GMO national regulatory requirements, the European Commission created a FAQ and a repository of national regulatory requirements, which can be retrieved from the webpages dedicated to ATMP. Moreover, building on the experience gained with certain IMP containing or consisting of GMOs, a number of documents and application forms have been created. These documents are endorsed by a large number of countries and aim at streamlining the information that needs to be provided in the context of clinical trials across the EU for both procedures contained use and deliberate release where appropriate. Such documents, which can be retrieved from the same webpages dedicated to ATMP, have been developed for :

  • Adeno-associated viral vectors (AAV) : common application form and good practice
  • Viral vectors: common application form
  • Human cells genetically modified by means of retroviral/lentiviral vectors (*): common application form and good practice

 (*) For clinical trials involving the use of this type of IMP under the conditions described in the corresponding good practice document, scenario 1 "contained use-only" will apply in regards the legislative biosafety provisions in Belgium.

Before submitting an application

In order to help the clinical sponsors and investigators of IMP to determine which procedural requirements should be followed for their clinical trial with GMO-medicinal products, the SBB and the FAMHP developed a practical guidance (PDF, last version: April 2019). It provides information on the legislative procedures on biosafety.

Furthermore, it is also possible to gain preliminary advice on which legislative procedures on biosafety should be followed for a defined trial prior to any mandatory procedure. Such request can be addressed to the FAMHP as part of a scientific-technical advice and is supported by a briefing document provided by the investigator.

 Please consult the FAMHP website for practical information and guidance on how to submit a request for (joint) STA

Content of the biosafety dossier

Information requested for a "contained use" dossier

The information to be provided is listed in an annex of the regional "contained use" decrees. The dossier should provide a detailed description of the GMO, the trial, the infrastructure, the containment measures, the laboratory practices and any other information relevant to assess whether the installations and containment measures comply with the intended contained use.
In order to facilitate the submission of information the SBB has developed notification forms and a user guide, on the basis of the requirements of the regional decrees. Please consult the relevant pages on this website for more information.

Importantly, if the clinical trial involves the use of IMP for which common application forms have been developed (see section above "conducting a clinical trial across different countries in Europe"), these forms can be used instead of the form “TECHNISCHE INFO ACTIVITEIT” , the form “TECHNICAL Dossier- INFO Operation” or the form INFO OPERATION DOSSIER Technique” in case the CT is conducted in the Flemish Region, the Brussels-Capital Region or Wallonia respectively.

Before any administrative step, the applicant is invited to consult the SBB (not mandatory).

Information requested for a "deliberate release" dossier

The information to be provided is listed in article 13 of the Royal Decree of 21 February 2005 on the deliberate release of GMOs. It comprises amongst others:

  • A technical dossier containing the information mentioned in Annex IIIA of the Royal Decree (art 13§2 c) and a copy of the bibliographic references.
  • An environmental risk assessment containing the information mentioned in Annex II of the Royal Decree (art 13§2 e) and a copy of the bibliographic references. Note that the information provided according Annex IIIA and II will be made available in the context of a public consultation (art 17 §3) unless part of it is considered as confidential and submitted as such (art 13 §2 c intend 8). According to art 43 of the Royal decree it is not acceptable to consider all information mentioned in Annex IIIA (technical dossier) and Annex II (environmental risk assessment) as confidential. Therefore the notifier may consider to submit two versions of both the technical dossier and the environmental risk assessment with one of the versions only containing non-confidential information (that can be made publicly available) and the other containing information that will remain confidential.
    • Important !! For IMP containing or consisting of adeno-associated viral vectors (AAV) or viral vectors, all necessary information for the technical dossier and the environmental risk assessment can be provided by means of the common application form developed for AAV or viral vectors respectively (see above, Conducting a clinical trial in humans across different countries in Europe). If reference is made to bibliographic literature, please be sure to accompany the form with a copy of the corresponding scientific papers.
  • The Summary Notification Information Format (SNIF) (art 13 §2 d)
    The SNIF is a document in a specific format that is aimed at enabling the exchange of information between competent authorities and the Commission and the competent authority of the Member State within whose territory the deliberate release will take place. The SNIF needs to be completed in English. This form is forwarded to the European Commission and to the other Member States for potential comments and is published on the website of the Joint Research Center. For example the SNIF should refer to all applications/authorizations for deliberate release in Europe.
  • Information for the public according to Annex VIII.A of the Royal Decree. In Belgium, the Royal Decrees for the deliberate release of GMOs have always foreseen that each notification should contain information intended specifically for the public. The main objectives of the public dossier is to inform citizens about the activities of companies or research institutes in the biotechnology field, and to stimulate public awareness and education. The information for the public should correspond with the information of the SNIF and must at least contain the following elements :
    • A didactic description of the GMO;
    • The nature and goal of the foreseen deliberate release;
    • The framework of research and/or development;
    • The potential advantages of the deliberate release;
    • The assessment of the potential risks for human health and the environment linked to the deliberate release;
    • The proposed measures to limit the potential risks, to control and to ensure follow-up of the deliberate release.
    The information for the public should be readable and understandable. It is therefore important to use a comprehensible language, which is accessible to everyone. It should be provided in the language of the region where the clinical trial will be conducted (French and/or Dutch).
  • Declaration of civil liability: according to art 13 §2 f, the declaration should include a signed statement that assures the accountability for any damage to humans and/or animal health, to goods or to the environment resulting from the trial.
  • A declaration of the notifier with respect to the delivery of control sample of the GMO (art 13§2 h): statement of the notifier that they agree to deliver to the SBB a control sample of the GMO and the related scientific documentation at the latest 15 days after the start of the trial. This sample is asked to enable the detection and identification of the genetically modified virus or micro-organism and to be able to differentiate it from its parental organisms. This sample will be used upon request of inspection services or following an unintended or accidental release. The nature and quantity of the GMO will depend of the detection method proposed by the notifier in the application. In respect to the scientific information that should accompany the delivery of the GMO, the applicant is requested to provide Sciensano with a detailed protocol including a method of conservation of the GMO and the proposed method of detection and identification. A quality test is sufficient, there is no need for a quantification test. In meeting this request, the applicant may consider a guideline describing the data to be presented by the notifier. This guideline also provides further information on contact points to whom the reference material should be addressed.

Documents that would greatly facilitate the evaluation of an application under the "deliberate release" procedure:
It is recommended to accompany the technical dossier with the clinical protocol(s), the investigator's brochure, relevant GMP/quality data, the information for the patient (patient information sheet and informed consent form) and study staff instructions (a 2-4 page technical sheet comprising all handling instructions for health care workers and staff, including detailed instructions in case of spill and on waste management).