Review by CCMO
As of the 1st of February 2006 the 'new' Central Review Decree (Besluit Centrale Beoordeling medisch-wetenschappelijk onderzoek met mensen, BCB, in Dutch) came into force.
This states that the CCMO is the assigned reviewing committee for for ‘scientific research aimed at the development of cell therapy, whereby living cells are used’.' The explanatory notes of the BCB mentions the following on cell therapy:
'Treatments are often given in the clinic whereby use is made of human body and stem cells which are administered to the research subject after processing in the laboratory. Many forms of cell therapy are still experimental and are researched within the framework of the Medical Research Involving Human Subjects Act on the safety and effectiveness. Examples are injecting the heart muscle with autologous stem cells which are extracted from bone marrow, administering the research subject with dendric cells which are ‘loaded’ outside of the body with tumour proteins with the aim of studying the manifestation of a defence reaction against the patient’s tumour, and the generation of bone tissue whereby the generated material is transplanted into the patient. The indication concerns primarily cell therapeutic research whereby living human cells are used, and not research with dead cells.’ (non official translation)
Since the 1st of November 2009 this description is given for research with one or more non-authorised vaccines. An authorised vaccine has an RVG (national authorised medicinal product) or EU (European authorised medicinal product) number.
As a serice to the field, the CCMO has drafted a working definition for cell therapy research, which goes further than the definitions of cellular medicinal products for advanced therapies. The definition is as follows:
‘Cell therapy research is understood to mean the administration of human (autologous or allogenic) or xenogenic living, nucleated cells to humans, in situations in which the isolation, processing and/or administration involves individual living cells and where (processing and/or administration of) the cells are the subject of the research question.’ (non official translation)
According to this working definition, studies in which somatic and/or germ line cells are administered to research subjects are both considered to be cell therapy. The transplantation of tissues (with the exception of tissues consisting of loose cells, such as bone marrow) or organs is not considered to be cell therapy, unless the individual cells are processed individually without direct interaction (cell-cell contact or cell-matrix contact) prior to administration. This means that clinical research with stem cells harvested from bone marrow for haematological conditions is also covered by the definition for cell therapy, and must be reviewed by the CCMO.
European legislation: ATMP
The majority of cellular products fall under the European classification of medicinal products for advanced therapies (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 somatic cell therapy medicinal products (sCTMPs) is: Medicinal product for somatic cell therapy: existing of cells or tissues which are essentially manipulated or of cells or tissues not intended to perform the same task in the recipient as in the donor. The definition of TEPs (tissue engineerd products) is: tissue manipulation products made up of manipulated cells or tissues for regeneration, repair or replacement of human tissue. The official definitions are given in the Directive 2009/120 and the European Regulation 1394/2007.
The Legal framework for medicinal products for advances therapy (ATMP) is laid down in the European Regulation (EG) nr. 1394/2007. An overview of the European legislation on various relevant subjects with regards to advanced therapies can be found at advanced therapies, a theme page on the website of the EMA.
An institution license used to be required for clinical research in the field of cell therapy which falls under the scope of the Medical Research Involving Human Subjects Act (WMO). However, this no longer applies as of the 1st of July 2012. The scrapping of the license obligation was made possible by an update of the Particular Medical Activites Act (Wet op de bijzondere medische verrichtingen, Wbmv, in Dutch). In practice this means that approval of the research file by the CCMO (as central reviewing committee) and a No grounds for non-acceptance by the Ministry of Health, Welfare and Sport (as competent authority) are sufficient to carry out a cell therapy research. An institution license may however be required for other kinds of cell transplantation which do not fall under the scope of the WMO.
Of course, licenses are needed for the preparation of the product, such as the Manufacturer’s license (Fabrikantenvergunning, in Dutch) for medicinal products for advanced therapies.
Foundations of cellular therapies
In reviewing cellular therapies, the CCMO regularly encounters the lack of a clear foundation of the proposed use of the therapy. Sometimes this causes the rejection of a research proposal. To address this issue, a discussion in more general terms was conducted with the research field. In this consultation it has been concluded that in research with cellular therapies, a clear hypothesis about a presumed mechanism must be provided for each study. The study should aim to test this hypothesis. All choices made, such as cells of autologous or allogenic origin and dosage, must be substantiated in the research file. For more information, see the Note Foundations of cellular therapies (in Dutch).