21. februar 2019

What to notify?

Health research projects must be notified to a research ethics committee. Below are listed research projects subject to notification and those not subject to notification.

Health research projects must be notified to a research ethics committee. When in doubt, the committee assesses the specific duty to notify for the case at hand under the provisions of the Act on Research Ethics Review of Health Research Projects (the Committee Act).

The duty to notify comprises:

  • Trials involving live-born human individuals, human gametes intended for fertilisation, fertilised human eggs, embryos and foetuses, tissue, cells and genetic material from humans, foetuses etc. or deceased persons (section 2(1) of the Committee Act).
  • Clinical trials on medicinal products for human use (in Danish), viz. trials on a human being intended to identify the clinical, pharmacological or pharmacodynamic effects of one or more investigational medicinal products or the adverse reactions of one or more investigational medicinal products or study the absorption, distribution, metabolism or excretion of one or more investigational medicinal products in order to evaluate the safety or efficacy of the medicinal product (section 2(2) of the Committee Act).
  • Clinical testing of CE marked and non-CE marked medical devices, viz. trials involving human beings intended to identify or verify the safety or the performance of medical devices (section 2(iii) of the Committee Act). Please also see the Danish Medicines Agency’s website on clinical investigations of medical devices.
  • Medical devices are devices used to examine, monitor, treat or otherwise relieve the diseases in human beings, such as syringes, surgical devices, hospital beds, pacemakers, iliac grafts, crutches or condoms.

The following should not be notified:

  • Surveys using questionnaires and interviews that do not involve human biological material (section 14(2) of the Committee Act)
  • Register-based research projects that do not involve human biological material but are based on pure data, viz. letters, numbers, characters and so on (section 14(2) of the Committee Act). See here for notification to other public authorities
  • Research projects that involve only anonymous human biological material (in Danish) which has been collected in compliance with applicable local legislation, viz. material that cannot neither directly nor indirectly be irreversibly associated with specific individuals (although an exception applies to research projects listed in section 25 of the act on assisted reproduction in connection with medical treatment, diagnostics and research etc. which must be notified).
  • Trials involving cell lines etc. which originate from an authorised trial involving collection of cells or tissue and which have been duly authorised (with the exception of trials involving the use of fertilised eggs, stem cells and stem cell lines from these, cf. sections 25 and 27(2) of the act on assisted reproduction in connection with medical treatment, diagnostics and research etc., which must be notified).
  • Non-interventional studies defined in the Executive Order on Good Clinical Practice (in Danish) in connection with clinical trials of medicines in humans, section 2(5).
  • Patient treatment or trial treatments, see below.
  • Quality assurance or quality control, see below.

What is health scientific research?

Since the field of health science comprises treatment, examination and prevention as well as rehabilitation, this definition can capture that trials which may involve relevant ethical aspects are conducted within all fields of health scientific research.

Health scientific research concerns primarily the science of medicine, pharmaceuticals, nursing, orthodontics etc. A range of research methods are applied related to various fields such as biology, clinical epidemiology, social medicine and psychology.

In its 2010 report no. 1515, the committee set up to revise the ethical committee system (Udvalget om Revision af det Videnskabsetiske Komitésystem, Sundhedsministeriet) proposed that “research projects subject to notification are restricted to health scientific intervention research. This displays that research projects subject to notification must involve a research participant (or material from a research participant) who is exposed to an intervention, and in most cases by far this will mean treatment, examination or preventive intervention.”

As can be understood, the purpose of health scientific research is to acquire new knowledge or verify existing knowledge about such matters as

  • the appearance of a disease or the treatment, diagnostic procedures, prevention, rehabilitation of people; and
  • human biological, physiological or psychological processes and genetic material (genes).

To classify a health scientific project as subject to notification the project must have a health scientific purpose and involve intervention.

Patient treatment

Prevention, diagnostic procedures and therapy etc. involving a specific individual need not be notified. Nor need treatment trials be notified where the doctor based on strict informed consent assumes the responsibility of a trial treatment of a specific, critically ill patient as a “last resort”.

According to the wording of guidelines no. 11052 of 2 July 1999 concerning the introduction of new forms of treatment in the healthcare system (in Danish) issued by the Danish Health Authority: “Where the choice of the method of treatment is to some degree associated with an – implicit or explicit – intention to test one or more hypotheses and generate knowledge, the patient not only becomes an “objective” but also a “means”, viz. a means to acquire new knowledge, as regards the treatment. This means that – especially from the point of view of the patient – the patient’s specific interest in a good treatment outcome and the doctor's interest in applying the treatment do not correlate clearly and unambiguously. These are the sort of situations that require an ethical evaluation of the procedure and hence that the procedure must comply with formal requirements and be notified.”

If there is doubt as to whether new treatment methods should be notified as a research project, the purpose of the project is the determining factor. Is the purpose to generate new knowledge, besides treating the patient, the project must be notified.

Provided extensive clinical experience exists that demonstrates the efficacy, adverse reactions and inherent risks of the treatment, a project need not be notified to a research ethics committee or produce a protocol. For this reason, the doctor responsible needs to consider whether there is sufficient evidence to introduce the treatment. If in doubt, the trial must be notified to the research ethics committee system. This also applies if there is any doubt as to the medical results that form the background for introducing a new treatment.

Quality control and quality development

Quality control and quality development need not be notified to a research ethics committee.

The guidelines no. 11052 of 2 July 1999 concerning the introduction of new forms of treatment in the healthcare system (in Danish) states the following about quality control: “A quality control does not aim to procure new knowledge about the value of a treatment but tests the function of the clinical unit.”

Quality development aims to develop new methods or new indicators within the scope of already established areas. This adds new knowledge locally in the organisation but cannot be applied in general outside of this sphere.

Typically, quality control or quality development are activities that form part of the operation of the health service, as an example this could be in relation to the treatment results achieved by a hospital department for a given patient group. It could be comparing a specific treatment with the adopted treatment instructions, evaluation of the effect or the costs of different treatment principles. Often the studies will be retrospective or observatory prospective not involving intervention in the treatment etc.

The same applies to commercial product development, for example calibration of an apparatus using blood. In this case the purpose is not to acquire new knowledge but to test the clinical function of a hospital department or the effect of a product.

Research into alternative forms of therapy

Research into alternative forms of therapy may be subject to notification provided the research project fulfils the above objectives. As an example, trials involving mindfulness have been found to be subject to notification to the committee system. Although the intervention as such can be characterised as being alternative, the requirements to carefully defined inclusion and exclusion criteria and end points remain the same, and the interventions must be reproducible.

The public or the private sector

The project can be carried out in the public sector, at regional, municipal or university level, or in the private sector. Projects concerning preventive measures at municipal level, with evaluation as part of the project, could for example be health scientific research – for example identifying likely effective disease prevention measures – and the health improving initiatives can be supplemented with a scientific approach/measurement in order to obtain knowledge about the health-related effect. Click here to learn more about this (in Danish).

Research activities in Denmark

Only research activities in Denmark by a principal investigator working in Denmark must be notified to a research ethics committee.

A project may be transnational, either because research participants travel into or out of the country or by import or export of biological material. If for example research participants travel out of Denmark for additional examination or to be diagnosed as part of a trial, the project must also be notified to the relevant ethics committee in that country since the Danish committee does not have the authority to lay down the conditions for activities in other countries. The Danish committee may, however, decline acceptance of the research activity in Denmark if the project has been unable to verify satisfactory protection of the safety, rights and well-being of the research participants for the part of the project taking place outside of Denmark. Similar conditions apply when research participants enter Denmark as part of an international trial. A research project involving for example imported personally identifiable biological material must also be notified. The critical point is that the research activity is conducted in Denmark.

Should a principal investigator wish to conduct research in Denmark using biological material from abroad (for example from a clinical biobank in another country) with the purpose of acquiring new knowledge about a disease area or the like, this must be notified to the regional research ethics committee in Denmark.

Conversely, if a Danish researcher or a laboratory department analyses biological material from another country on behalf of a researcher or a company operating abroad, this need not be notified. In such cases, when only laboratory services and similar procedures are conducted and results of these are returned to the researcher or the company abroad, the research project is not conducted in Denmark.

The competent research ethics committee

In-depth information about which committee to submit notification to can be found here (in Danish).

Specific examples

Below are some examples of the practices of the committee system as regards the duty to notify.

When in doubt whether to notify a project to a research ethics committee, the project ought to be notified to the committee.

A trial involving a method to differentiate flavours in food ingredients

The purpose of one trial was to identify a method to differentiate flavours in food ingredients by registration of electric brain response (EEG) to sucrose, among other things, in healthy subjects who were given intermittent stimuli with the ingredients in the right and the left side of their tongues.

The determining factor why the committee determined that the trial was subject to notification was:

  • that the trial involved live-born human individuals, and that
  • the project would intervene through examination of the biological processes in the brain in connection with consumption of sweeteners with the purpose of generating new, general knowledge about certain processes.

The committee emphasised:

  • Legislation lay down threshold values determining to which foods these ingredients may be added and which quantities may be consumed in order not to pose a health hazard.
  • In connection with EEG measurement of the brain, incidental findings of relevance to the research participants might be generated.
  • Examining whether the brain can differentiate between the characteristic flavours of food ingredients that may benefit your health, such as obesity prevention or diabetes.

A trial involving mindfulness – duty to notify

The purpose of one trial was to examine whether the cognitive mechanisms of action used in mindfulness training would impact on working memory capacity, attention, determination training and stress. The project involved physical testing and behavioural testing in healthy research participants (young athletes).

The critical factors determining the duty to notify were as follows:

  • The trial involved live-born human individuals.
  • The trial concerned therapeutic intervention with end points reflecting that a clinical effect of the intervention was expected for various psychological and somatic parameters.

The committee emphasised:

  • Some clinical departments use mindfulness as a method of treatment.
  • That the pulse of the research participants would be measured and blood sampled.

A trial involving genome sequencing of archaeological material in a demographic study

In one study, the researcher believed to have found, based on SNP chip analyses, that the population of Central Asia exhibited considerable traits consistent with European, Caucasian, South Siberian and East Asian origin. They wanted to conduct a complete genome sequencing process in order to carry out an in-depth demographic study. In addition to this they also wanted to record areas of the genome which are subject to natural selection and, if possible, determine regional genomes that have lent the population of Central Asia adaptive advantages in relation to their environments. Sputum had been sampled from living individuals of Central Asian origin. Furthermore, they wanted to “produce genome-covering data from 140 prehistoric human beings.”

NCHRE was of the opinion that the project did not have a duty to notify on the following grounds:

  • The main purpose of the project was to conduct demographic studies and examine which genomes had provided the Central Asian population with adaptive advantages relative to their environments.
  • They would use health scientific research results to support other research findings that were unrelated to medical research.
  • Although knowledge about the biological evolution of the Central Asian population could potentially be generated through the study, this was not the purpose of the project.
  • Thereby the main purpose of the project was not to acquire new knowledge about the appearance of diseases or the prevention, diagnoses or treatment of diseases.
  • Merely mapping the human genetic material (thereby making it possible to generate knowledge about biological processes) did not in itself mean that it was a health research project with a duty to notify.
  • The project also mapped genetic material from archaeological samples where the level of protection (of individuals and their next of kin) is not the same.