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Current procedural aspects for the authorisation of gene therapy clinical trials in Belgium
(Authors: M. Sneyers and M. Goossens - Last revised:
February 11, 2010
)
1. Review process
As far as biosafety regulation is concerned, whatever the legal basis and the competent authority could be, proposals of gene therapy clinical protocols or clinical protocols with a medicinal product involving a genetically modified organism are reviewed by the ad hoc Expert group "Recombinant viral vectors, virosomes, recombinant vaccines, gene therapy" of the Belgian Biosafety Advisory Council or directly by the experts of the Division of Biosafety and Biotechnology (SBB) as a function of the the regulatory framework and of the degree of familiarity of the Biosafety Council with the proposed project.
The review process involves two steps: (1) assessment of the risks to human health and the environment by the use of the vector, in a particular clinical gene therapy protocol; (2) evaluation of the safety measures, including manufacturing practices, appropriate inclusion and exclusion criteria of the patient, monitoring of the vector, waste disposal and local laboratory and clinical practices proposed to manage those risks.
2. Application under the scope of the Belgian regional regulations on contained use of GMO's and/or pathogen organisms
During the procedure,
the biosafety dossier is submitted for advice to the Division of Biosafety
and Biotechnology (SBB), who acts as technical expert for the Regional
competent authorities.
These procedural aspects are described on this Web site in the general chapter: "Contained
use of GMO's and/or pathogens"
Application content
The forms to be used
can be found in the general chapter: "Contained
use of GMO's and/or pathogens"
In addition to the environmental risk assessment the applicant is requested to provide:
• the clinical protocol(s) and EUDRACT nr,
• the investigator's brochure,
• the GMP/quality data.
All parts of the dossier can be written in Dutch, in French or in
English except the forms of the public dossier which must be written in the official language
of the region where the trial will take place.
3. Application under the scope of the Belgian regulation on deliberate release of GMO's
The text of this regulation is available from this Web site,
in Dutch and
in French.
The application
is submitted to the Competent authority which forward a copy to the SBB; the
dossier is reviewed by the Belgian Biosafety Council which transmits its advice
to the competent
authority for final decision. This decision is delivered after
maximum 90 days.
Application content
Conform Art.13 the Royal Decree of 21 February 2005 the biosafety dossier is mainly constituted by:
• A technical dossier conform to Annex III of the Royal
Decree of 21 February 2005 including: the clinical protocol(s), the EUDRACT nr., the investigator's brochure and the GMP/quality
data ;
• the Summary Notification Information Format (SNIF).
The SNIF needs to be completed in english (a template for organisms other than
plants is available on the web site of Joint Research Center (JRC) of the European
Commission (link)).
This form is forwarded to the European Commission and to
the other Member States for potential comments and is published on the web site
of Joint Research Center (JRC) of the European Commission (link) ;
• an environmental risk assessment conform to Annex II of the Royal Decree of 21 February 2005 ;
• a proposal for public information in dutch and in french (guidelines for public information are available in English as PDF file)
• an electronic version of the complete dossier is requested (PDF files + word version of the English version of the SNIF).
An application under the scope of the Belgian regulation on deliberate release of GMO's do not exempt to apply a dossier under the scope of the Belgian regional regulations on contained use of GMO's and/or pathogen organisms. It will cover all the related contained use activities (storage and handling of medication, biological samples, hospital rooms, waste disposal...)
Control sample
The Royal Decree of 21 February 2005 requires that the notification contains a declaration of the notifier where he agrees to deliver to the SBB a control sample and the related scientific documentation the latest 15 days after the start of the trial.
This sample is asked to make the detection and identification of the recombinant virus or micro-organism possible 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. But the notifier should comply to the following requirements :
• the reference material has to be nucleic acid (i.e. the intact vector and the restriction map of the full vector including the inserted fragment) ;
• with the reference material the notifier will transmit instructions about the conditions for conservation, the maximum length of conservation, the detection method/protocol with details about its sensitivity and specificity for identifying the recombinant vector ;
• the detection protocol has to be in a format that can be used as a standard procedure for a routine laboratory : scope, material and methodl.
This material and related information is for the sole purpose of the execution of the SBB mandate as provided by the Royal Decree. Material and info are handled as strictly confidential. The intellectual property rights remains with the notifier.
4. Operations vs clinical protocols
As far as contained
use is concerned, the authorisation is given for a defined operation in a given
installation for several years (e.g. 5 years). An operation can not
only cover a particular protocol but also a whole program of clinical trials.
This program may integrate several protocols of the same kind (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. Also, after
clinical research has been approved in a given installation with
reference to the first submitted protocol, changes (e.g. a new
protocol, new formulation of or new specifications for the gene
therapy product) can therafter be allowed if there is no modification
in the biosafety frame of the program. As far as deliberate release
is concerned, the authorisation can cover a particular gene therapy
clinical trial conducted in different sites but also a whole program of clinical trials.
The two procedures can be managed together.
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