A medicinal product for gene therapy is a medicinal product which has been produced by means of a series of manufacturing techniques aimed at the in vivo or ex vivo transfer of prophylactic, diagnostic or therapeutic gene (a nuclein acid) to human or animal cells and the following expression in vivo. The expression occurs during the gene transfer with the aid of an administration system, the so-called ‘vector’, which can have a viral or non-viral origin.
Genetically modified organisms (GMO) are all organisms of which the genetic make-up has been altered though not naturally by way of reproduction and/or natural recombination. An organism is described as any biological entity which can replicate or transfer genetic material.
Gene therapy can be divided into somatic cell therapy and germ line gene therapy, depending on the cells in which the genetic material is altered. In the case of somatic gene therapy the genetic material of human cells are altered. Such alterations cannot be genetically transferred. In the case of germ line gene therapy the genetic material of gametes are altered. The alterations are transferred to the offspring and are therefore genetically transferred. This form of gene therapy is prohibited in the Netherlands.
Review by the CCMO
The Central Review Decree (Besluit Centrale Beoordeling, BCB) came into force on the 5th of March 1999. Section 1, paragraph a, states the CCMO is the assigned reviewing committee for ‘scientific research whereby genetic material in human body cells are intentionally altered’. The updated BCB of the 3rd of January 2006 has a broader definition of ‘…or the performance of the genetic material is specifically influenced’, to make possible the central review of research with antisense oligonucleotides or RNA interference. This type of research does not fall under gene therapy research.
Furthermore, the updated BCB was altered at Section 1, paragraph 6, to include review of the CCMO of ‘scientific research with a medicinal product for genetically modified organisms’ as intended in Section 1, first paragraph, sub f, of the Decree genetically modified organisms environmental management (Besluit genetisch gemodificeerde organismen milieubeheer, in Dutch). This applies to research whereby genetically modified organisms are administered which to not purposefully alter the genetic material in the body cells of the research subject.
Through the central review of the research as laid down in the BCB, knowledge can be clustered and new insights can be gained into the further developments of these new techniques and the implications they have for society.
More information on the review by the CCMO can be found at reviewing procedure and Primary submission. The WMO offers the CCMO the possibility to extend the review timeline for certain types of research, such as research into gene therapy, with a maximum of 30 days (on top of the timeline of 60 days). The review timeline then amounts to a maximum of 90 days.
Review by other authorities
Research into gene therapy or with medicinal products which contain GMOs must be reviewed by various authorities in the Netherlands. This type of research falls under the definition of research with a medicinal product and must undergo a marginal review by the competent authority, in this case the Ministry of Health, Welfare and Sport.
Besides this, a license is needed for activities with GMOs on the grounds of the Decree genetically modified organisms environmental management (Besluit genetisch gemodificeerde organismen milieubeheer, in Dutch). The Bureau Genetically Modified Organisms (Bureau GGO, in Dutch) is reponsible or the issuing of licences for activities with GMOs which have to be reviewed on the risks to humans and the environment. This is carried out under the authority of the Ministry of Infrastructure and Environment, which carries final responsibility.
Gene Therapy Office (Loket gentherapie)
A research proposal in the field of gene therapy of with medicinal product which contacin a GMO must be submitted to the Gene Therapy Office. The Gene Therapy Office forwards the file to the involved government authorities (CCMO, the Ministry of Infrastructure and Environment/Bureau GGO and the Ministry of Health, Welfare and Sport) and communicates this to the submitting party. See for more information the information the website of the Gene Therapy Office.
- SAEs, SUSARs and other serious and unexpected events with consequences for the environment
The Gene Therapy Office website gives information on the reporting of serious events, undesired events and unexpected events with consequences for the environmental safety. See Reports (in Dutch).
European legislation: ATMP
Medicinal products for gene therapy fall under the European classification of medicinal products for advanced therapy (advanced therapy medicinal product; ATMP). There are three categories for medicinal products for advanced therapy:
- gene therapy medicinal products; GTMPs;
- somatic cell therapy medicinal products; sCTMPs;
- tissue engineered products; TEPs.
The definition of GTMPs is as follows: medicinal products for gene therapy contain a recombinant nuclein acid as active material; the activity is directly linked with the included recombinant nuclein acid sequence. The official definitions are given in Guideline 2009/120 (GTMPs and sCTMPs) and the European Regulation 1394/2007.
The legal framework for medicinal products for advanced therapy (ATMP) is laid down in the European Regulation (EG) nr. 1394/2007. An overview of the European legislation, legal guidelines and guidances on various relevant subjects with regards to advanced therapies can be found at advanced therapies, a theme page on the EMA website.