The Medical Devices Act (Wet op de medische hulpmiddelen, in Dutch) (section 1) offers the following definition of a medical device:
‘Any instrument, apparatus or appliance, any software or material or any other article that is used alone or in combination, including any accessory and the software required for its proper operation, that is intended by the manufacturer to be used specifically for diagnostic or therapeutic purposes, and is intended by the manufacturer to be used for human beings for the purpose of:
- diagnosis, prevention, monitoring, treatment or alleviation of disease;
- diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
- investigation, replacement or modification of the anatomy or of a physiological process;
- control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.'
The Medical Devices Decree (Besluit medische hulpmiddelen, in Dutch) defines the term ‘manufacturer’ as the person, legal entitiy, or the authorised representative of that person, who:
- is responsible for the design, manufacturing, packaging and labeling of a medical device with the aim of marketing said device under one’s own name, regardless of whether these actions are carried out by one and the same person or under the responsibility of a third party; or
- assembles, packages, processes, updates or labels one or more prefabricated products, or who assigns these products as a medical device with the aim of marketing said device under one’s own name.
If a specific medical device that is not (yet) on the market is developed at a health care institution in collaboration between doctors and technicians and within the framework of clinical research, then the institution or technical department in question is not a manufacturer in the sense of the Medical Device Decree. Therefore, no reporting procedure obligation exists towards the Health And Youth Care Inspectorate in accordance with the Decree. However, as soon as the clinical research with the developed medical device in question also extends to other institutions (doctor/researcher and development technicians are no longer within the same [institutional] structure of responsibility), the obligation to notify the Health And Youth Care Inspectorate does apply.
The legal framework and guidelines for clinical research with a medical device are set forth in the Medical Device Decree (section 13) and the Active Implants Decree (section 7). The foundation for the above directives resides in European legislation, namely: the Medical Device Directive 93/42/EEC (Annex VII-2.2. and X) the Directive on Active Implantable Devices 90/385/EC (Annex 6 and 7).
The named decrees hold the manufacturer of the medical device in question to a number of obligations before the clinical trial may begin. One of the explicit conditions is the submission of a positive advice by an accredited MREC to the Health And Youth Care Inspectorate. This review therefore not only takes place on the basis of the Medical Research Involving Human Subjects Act but is also specifically prompted by the legislation regarding medical devices.
For the MRECs this means that the review of clinical research with a medical device is a task in th context of a legal obligation based on the Medical Device Decree. This only applies to clinical research with a medical device which must be reported to the Health And Youth Care Inspectorate.
Medical devices: review by an accredited MREC
Other clinical research with medical devices that falls within the scope of the WMO must be reviewed by an accredited MREC based on the Medical Research Involving Human Subjects Act. An example of such research (i.e. research with medical devices that is subject to the Medical Research Involving Human Subjects Act that does not need to be reported to the Health Care And Youth Inspectorate) is a randomised study where two medical devices with a CE mark are compared to each other.
The accredited MREC that reviews the research file must have at its disposal adequate product information to be able to review the safety and quality of the medical device. The model Investigational Medical Device Dossier (IMDD, plus explanatory notes) can be used for this.
Existing product information is sufficient for medical devices with a CE marking. If a medical device with a CE marking is used for other purposes than those for which the CE marking was issued, then you must make clear how you propose to guarantee the safety and quality of the medical device. You can use the model Investigational Medical Device Dossier (IMDD, plus explanatory notes) for this. The accredited MREC will check if the information is sufficient for an adequate review and if not they will request additional information. The MREC can also decide to ask an external expert for advice.
A full overview of the documents which must be submitted to the MREC are given in the standard research file. The procedure for the submission of a research file can be found under Primary submission.
Reporting to the Health and Youth Care Inspectorate
The Dutch Health And Youth Care Inspectorate is the competent authority for notifying clinical research with a medical device that involves a manufacturer who is responsible for the development of the medical device. Such research must be notified to the Health Inspectorate by the concerned manufacturer. This applies to both medical devices without a CE marking as to those with a CE marking* which use differs from the intended use as defined in the respective conformity review procedure (new indication). The notification procedure is given on the website of the Health And Youth Care Inspectorate (in Dutch).
*A CE marking is often incorrectly seen as a (quality) hallmark. However, a CE certification implies a declaration of conformity of the medical device in question with the essential requirements such as those set forth in the Medical Device Dossier (MDD). Depending on the risk class, the CE marking is issued by the manufacturer himself or by a Notified Body. The CE marking applies to the ‘intended use’ of the medical device as defined by the manufacturer
During and after the study:
reporting to the accredited MREC
The sponsor is required to report the following to the accredited MREC which has issued a positive decision:
- start and end date of the study
- substantial amendments
- progress reports
- SAEs en SADEs
- suspension or (premature) termination of the study
- clinial trial report
Based on article 10, paragraph 1 of the Medical Research Involving Human Subjects Act (WMO) the sponsor is responsible for the reporting of Serious Adverse Events (SAEs) to the reviewing committee (MREC or CCMO), with the exception of SAEs that require no reporting according to the clinical protocol.
SAEs that were fatal or life-threatening for the patient must be reported within 7 days after the sponsor has taken notice of this event. Other SAEs must be reported within 15 days.
SAEs that require no immediate reporting according to the protocol can be reported in periodic line listings and the development safety update report. In some cases SAE reporting can be waived. The procedure of SAE reporting needs to be recorded in the clinical protocol (or in an addendum of the protocol). The Central Committee on Research Involving Human Subjects (CCMO) composed in collaboration with the NVMETC (Dutch Society of MRECs) a guidance document (in Dutch) about the reporting procedure of SAEs. More information about the reporting of SAEs can be found here.
During and after the study:
reporting to the Health And Youth Care Inspectorate
The sponsor of clinical research with a medical device, insofar as it is a non CE marked medical device or a CE marked medical device for which a new indication is being researched, must report SAEs and the termination of the clinical study to the Health And Youth Care Inspectorate. More information is available on the website of the Inspectorate.
Medical device with a medicinal product
The question of whether a clinical investigation with a medical device or active implant falls under the scope of the regulations for research with a medicinal product as laid down in the WMO, is important when the medical device (or active implant) also contains a medicinal product. A medical device that also contains a medicinal product is a medical device if the action of the medicinal product is ancillary to the action of the medical device. Examples are a drug-eluting stent, a bone cement with an antibiotic and a urinary catheter with a local anesthetic. To these products the legislation for clinical investigations with medical devices applies.