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 is based on a genetically modified organism (GMO) the clinical trial can only be conducted if it additionally complies with the legislative provisions on biosafety regarding contained use of GMOs and/or deliberate release of GMOs in the environment.

Procedure: 3 options

The procedural requirements related to the biosafety aspects of a clinical trial using GMOs or involving medicinal products containing GMOs depend on the characteristics of the trial. Three procedural options can be envisaged:

Option 1. The full trial or some 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)
=> The regional regulations on contained use of GMOs and/or pathogenic organisms and the relevant notification procedures apply. In the frame of the procedure, the biosafety risk assessment is submitted for advice to the Biosafety and Biotechnology Unit (SBB), who 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 not only cover a particular protocol but also 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.

Option 2. The clinical trial cannot be conducted in authorised ‘contained use’ facilities
=> The Royal Decree of 21 February 2005 governing the deliberate release of GMOs into the environment and the relevant notification procedures apply.
The FAMHP 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, check 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.

Option 3. The clinical trial is performed in a 'contained use' facility (option 1) and there is a possibility of release of the GMO in the environment (GM medication taken at home or risk of shedding, spreading…) that cannot be avoided by proper management procedures or working practices
=> Both the 'contained use' (option 1) and 'deliberate release' (option 2) procedural requirements apply.

Note:

In Belgium the two specific regulations in the field of biosafety (contained use and deliberate release into the environment) can therefore potentially be applied in the case of clinical trials involving GMOs. This option has been chosen (since 1998) to guarantee optimum assessment of the risks to human health and the environment.
It should be pointed out that this modus operandi is not applied uniformly at European level. Not all the Member States have the same approach to distinguish between aspects relating to deliberate release and contained use in the specific case of clinical trials. The approaches adopted by our Dutch and British neighbours illustrate two extremes: For the first, only the "Deliberate Release" regulation is appropriate to adequately assess and manage the risks; for the second, the biological confinement of gene therapy vectors and their use in controlled hospital environments mean that they should first be assessed under the "Contained Use" regulatory framework. The position adopted by these countries and other European countries is set out in detail in a report commissioned by the European Commission in 2007 (
Perseus_2006_Clinical_Trials.pdf). Recognizing the developments in advanced therapy medicinal products (ATMP) and the need of applicants of investigational products to have an overview of the GMO national regulatory requirements, the European Commission created a number of documents to this effect which can be retrieved from the webpages dedicated to ATMP.

Before submitting an application

In order to help the applicants 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).
Moreover, formal advice on which option should be followed for a defined trial will be given by the competent authority at the federal level (FAMHP) as part of a scientific-technical advice (STA) based on preliminary information provided by the applicant. This advice will be given together with the SBB (e.g. on demand of the applicant or upon recommendation of the FAMHP and SBB) depending on the specific nature of the questions for which formal advice is requested prior to Clinical trial application (CTA) submission (i.e. through a joint scientific-technical advice request).

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.
Before any administrative step, the applicant is also invited to consult the SBB.

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).
  • An environmental risk assessment containing the information mentioned in Annex II of the Royal Decree (art 13§2 e).
    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. 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). 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 publically available) and the other containing information that will remain confidential.
  • The Summary Notification Information Format (SNIF) (art 13 §2 d)
    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.
    The information for the public should correspond with the information of the SNIF. It should be provided in the language where the clinical trial will be conducted (French or Dutch).
  • Declaration of civil responsibility: according to art 13 §2 f, the declaration should refer to any damage to humans, animals and the environment resulting from the trial.
  • A declaration of the notifier- control sample (art 13§2 h): statement of the notifier that he agrees 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 recombinant virus or micro-organism in case of inspection or accidental release. The nature and quantity of the sample 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 control sample, the applicant is requested to provide Sciensano with a detailed protocol for the method of conservation and analysis of the control sample. 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 relative to reference material disposition.

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, the 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). It is also recommended to provide a copy of the bibliographic references (mentioned in Annex II and Annex IIIA).