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3. Respect for human subjects involved in medical research

3. Respect for human subjects involved in medical research

In any type of scientific research, an absolute prerequisite is to respect the participants and their rights. In medical research, this prerequisite is fundamental. It is also enshrined in the law in various ways; in particular the rights that research subjects have to protect their physical and mental integrity and their privacy. Lastly, respect for subjects involved in research is essential if the trust and cooperation of potential participants is to be secured for the future.

Respect for the persons or participants cannot be fully captured in rules or procedures. This means that respect for participants is not only obeying rules and following verification procedures, it is a setting of your mind. Researchers need to be open to and feel responsible for those interests of participants that could be affected by the research, and to ensure that the participants are aware of this.  

   
Figure 1 Medical research in human subjects

Medical research can be broadly divided into three types according to the degree of subjects' involvement (Figure 1):

  1.  Research on human subjects, i.e. research in which patients are subjected to certain interventions or investigations, e.g. administration of a trial drug (medicinal product) in order to compare it with a well known registered drug, or taking samples of body material for analysis.
  2. Research on body material (blood, tissue, urine, spinal fluid, DNA, et cetera) that is already available for one reason or another (e.g. material that was taken in the course of diagnosis or treatment).
  3. Research on (other) data that is already available from patients' medical records or elsewhere, or that is collected directly from the subjects.

3.1 Research on human subjects

'Medical research that includes subjecting persons to interventions or imposing a particular course of conduct upon them' is subject to the Medical Research involving Human Subjects Act ( Wet Medisch-wetenschappelijk Onderzoek met mensen; WMO ).
For research applying to WMO the research in question can be carried out only if a detailed research protocol has been approved by a certified Medical Ethics Committee (MEC). In some cases approval has to be given by the Central Committee on Research Involving Human Subjects (Centrale Commissie Mensgebonden Onderzoek; CCMO ) in The Hague. A step-by-step approach with respect to the choice of an accredited MEC is provided at the CCMO website .

Both AMC and VUmc have their own MEC, as do all other university hospitals and several other hospitals and institutes in the Netherlands. Most of the criteria used by the committee are laid down in international documents, e.g. the Declaration of Helsinki (revised in Seoul in October 2013) and the Good Clinical Practice guidelines (applicable to interventional clinical research with medicinal products in the EU, the US and Japan).
In essence the legal requirements are as follows:

  • The research must be worthwhile and should lead to medical progress as regards the question it sets out to answer, be sound as regards design and execution, and be reasonable, i.e. its value must be in proportion to the burden on and the risks to the subjects.
  • The subjects (or their legally acceptable representatives) must have been properly informed in writing and have given their written consent. The information provided must include the purpose, nature and duration of the research and the risks and problems it could entail for subjects.
  • The subjects must be adequately insured (specific WMO insurance).
  • More stringent requirements apply in the case of minors, incompetent adults and subjects who are dependent in some other way.

Since 1 March 2006, the WMO-law was changed, implementing the international Good Clinical Practice guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ( ICH ); see also Chapter 5. This implies that clinical research with either registered or nonregistered medicinal products must be conducted in compliance with these guidelines. Other research not applying to WMO should preferably also be conducted in the spirit of the ICH Good Clinical Practice guideline. This is not a regulatory requirement, but a common sense approach.

For research that is not subject to the WMO, less stringent requirements apply: in principle oral informed consent written down in the file of the patients is adequate and there is no need for specific insurance.

For research with healthy volunteers there are additional requirements in both AMC and VUmc. Employees of AMC and VUmc are not allowed to participate in research of their own department, see the  Informatie over proefpersonen METc of VUmc.

3.2 Research on body material

The statutory rules concerning research on body material are still under development. In recent decades, hospitals and the research community have put a lot of effort into establishing de novo biobanks (prospective collections of patient material) for broad research goals, especially to enable future studies. All Dutch university medical centres participate in the collaboration on these biobanks, for example in the String of Pearls initiative . The statements below apply both to these biobanks and to other kinds of research on stored patient specimens.

According to the Code for Proper Secondary Use of Human Tissue ( FMVV , 2011), research on anonymous (i.e. untraceable) body material is permitted unless the person in question has at any time indicated that he/she objects to this further use. For storing and using human tissue for research that is not anonymous (such as encoded tissue), the informed written consent of patients is required, unless this is impossible (e.g. the patient is deceased) or reasonably impracticable (e.g. very large cohorts of patients). Explicit informed consent should always be obtained before material is taken specifically for the purpose of research. In most cases, consent can be of a broad nature.

If there is a substantial likelihood of findings being produced that are of clinical value to the health or wellbeing of the person concerned and are actionable ('individual research findings'), this issue should be specifically mentioned to potential research participants. They should be informed about the 'reporting back policy' of the researcher/biobank, the possibility to indicate that they prefer not to be informed about new findings, and that this preference can be overruled if serious harm to themselves or their family members can be prevented. If patients find this policy difficult to accept, they should not participate.

The MEC of the AMC or the VUmc is always involved at an early stage in the procurement and use of body material for research purposes. At the AMC, a dedicated committee evaluates the legal and ethical aspects of existing and new biobanks according to a standard procedure, including rules with respect to the supervision of the biobank. The MEC of the VUmc intends to install a similar committee.

It is important to realize that even research that only entails analysing blood, tissue or other material can interfere with people's interests and rights, as it produces information about them that could be of value to themselves and/or others. The key points described in the Code for Proper Secondary Use of Human Tissue are:

  • Safety
    Biological material obtained in the course of diagnostic tests on or treatment of patients should be processed and kept in accordance with the guidelines for specific diagnostic requirements (microbiology, clinical chemistry, pathology, etc.), taking current health and safety standards into consideration. This includes paying attention to deterioration, the risk of infection, encoding and the risk of mix-ups.
  • Carefulness
    The fact that patient material is involved means that carefulness is required in the sense of accurate identification and storage, as well as confidentiality.
  • Responsibility
    The hospital (and specifically the head of the department where the specimens are stored) where the patient is being treated is responsible for storing patient material and laying down rules on the matter. The patient should sign an informed consent document during the first consultation.
  • Traceability
    Records of patient material should be encoded, that is, they should be traceable to the patient only through an encrypted code. The head of department oversees access. Material obtained for research purposes can also be filed in other database systems; here, the head of the research team oversees traceability.
  • Informed consent
    Informed consent from the patient is required if the results of analyses of body material carried out for research purposes can be traced to the patient. Completely anonymous archival material can be used for research purposes provided this does not conflict with the permissible storage period and the purpose for which it was originally taken, and provided the patient has no objection.
  • Storage periods
    Patient material obtained for diagnostic purposes must be kept as long as is deemed necessary for proper care. Proper care may indicate that this is extended to the family of the participant, and even to his/her offspring, which may extend the period during which samples will be stored. Material that is obtained specifically for future research can be kept as long as agreed upon in the informed consent document. Guidelines on storage periods are generally drawn up by the professional association of the medical specialty.

3.3 Research on other data


Of the three types of research identified, research on data other than those indicated in 3.1 and 3.2 is, in principle, the least intrusive. Two comments need to be made, however. Firstly, some types of data research are potentially more burdensome than others, for example research in which the data has to be collected from the subjects by means of, for instance, interviews or questionnaires, as compared to research that is based on patient information that the doctor/researcher already has at his/her disposal in his/her capacity as practitioner. Second, a particular study of data could be more intrusive in terms of burden and risks than a relatively 'harmless' study using body material or humans.

The protection of the rights of participants in data research is a subject of continuous debate in the Netherlands and other countries. This reflects not only the fact that the casuistry is sometimes complex, but also the potential tension between the importance of protecting privacy on the one hand and the interests of scientific research on the other. Quality control and the proper documentation of the data management are important for safeguarding scientific integrity as well. More information can be found in Chapter 7.

3.4 Research in developing countries


The ethical principles that apply to research in Europe naturally also apply to research in developing countries. Research with partners in developing countries, just like research with partners in the Netherlands or elsewhere in Europe, is based on trust, collaboration, taking pleasure in the work, complimentarily and a shared goa, see also the Montreal statement of the 3rd World Conference on Research Integrity . Both partners have something to offer and can learn from each other: together they can achieve more and move further ahead. Basic research and research that does not have an immediately apparent application are important in developing countries too, but in many cases applied research will be more appropriate because of the limited availability of resources and the scarcity of staff and funds.
Neither the AMC nor the VUmc wishes to support research in developing countries that benefits only the Western researcher: medical tourism and exploitation need to be avoided. The following are a few points that merit special attention.

Review
The research question and research plan are subject to scientific scrutiny. Proposals for research involving humans or materials taken from humans should also be submitted to a Medical Ethics Committee (MEC). Such committees do not exist in all institutions and in all countries, but where they do exist the proposals should be submitted to them. If there is no such committee, the project may provide a good opportunity to initiate a debate within the local institution by, for instance, trying to set up an ad hoc committee and discussing the research within the institution. The research protocol should be approved by the MEC of the AMC or the VUmc and by that of the local institution.

Research done by AMC or VUmc researchers in developing countries remains the responsibility of the institution. If it cannot be reviewed locally, the MEC of the AMC or the VUmc can be asked to issue a certificate of no objection. It is not possible for these MECs to verify compliance of the research in developing countries with the Dutch legislation ( the Medical Research involving Human Subjects Act; WMO ), as the act applies only to the Dutch situation and the MECs cannot be expected to be aware of local rules and regulations. They can, however, carry out an unofficial check based on general principles and issue a certificate of no objection, if appropriate. In addition, local institutions or partners often want the proposal to be reviewed in the Netherlands. The name of the institution that is sponsoring (and is therefore legally responsible for) the project must be clearly stated.

Patient consent
Patients need to give their informed consent to participation in the project. The information must be provided in the patient's own language, which usually makes it impossible for the researcher to check it. On top of this, oral consent is often accepted, which is not ideal because in such cases there is no documented evidence of the consent. The information should preferably be provided in the presence of a witness who speaks the language in question (as well as a language in which the researcher can communicate); the name of this witness should be documented on the written informed consent form that is signed by the patient, the researcher and the witness. The use of a fingerprint or another mark to indicate consent is considered acceptable.

Informing the authorities
The local partner should ensure that the regulatory and other competent authorities concerned are informed about the project. These authorities include the board and management team of the district hospital where the work is to take place, the district medical officer, the provincial medical officer, representatives of the local population, etc. Whether the Ministry of Health or one of its departments needs to be informed will depend on various factors, for example the country and its rules, the nature of the research and the local institution. As this is best decided by the partner, it is wise to discuss it with the latter.

Personal and cultural factors
Each organization in the Netherlands and Europe has its own culture when it comes to dealing with one another and with research, and this applies equally in developing countries. The researcher should be prepared for this. Patience is often called for, and talent for improvisation and a contemplative disposition can help; one can ask oneself, for instance, why something is done in a particular way, and it will often turn out that there are good local reasons. Anyone who cannot handle uncertainty may be better off not doing research in or in collaboration with developing countries. But for someone who is keen to gain new impressions and experiences, and is willing and able to improvise, research in developing countries is both a challenge and rewarding. It is often more demanding but it has more to offer - ideally to both parties.

  Law   Remark
 WMO  The Medical Research involving Human Subjects Act (Wet Medisch- wetenschappelijk Onderzoek met mensen ) is the research law governing all interventional trials.
 WGBO  The Medical Contract Bill (Wet Geneeskundige Behandelingsovereenkomst ).
 WBP

 Data Protection Law ( Wet Bescherming Persoonsgegevens ).

 GW  Medicine Law (Geneesmiddelenwet ).
 WBIG  Law for the Qualifications and Accreditation of Medical Professions
(Wet Beroepen in de Gezondheidszorg ).
 KWZ  Quality Law for Health Institutions
(Kwaliteitswet Zorginstellingen ).

Table 1 Laws and regulations. All these laws can be found at www.wetten.nl

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