Introducing and establishing an infrastructure for ethics review in medical fields

Ethics review in medical field has a relatively longer tradition if compared to ethics review in non-medical fields. Its origins can be traced back to one of the first editions of the Helsinki Declaration (DoH) (1975) which established the requirement that “The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment and guidance.” General term “specially appointed independent committee” used in the first version of DoH has been replaced with more specific ones such as “Research Ethics Committee” or “Institutional Review Board” (more commonly used in North America) nowadays.

Heterogeneity of RECs in Europe

There is, however, a variety of models how different countries have implemented the requirement of ethical review into their legal and organizational systems. Research ethics committees (REC) vary depending on the scope of review (i.e. what kind of research they assess), and on their affiliation (i.e. national, regional or institutional).

Also their legal status, composition, functions, areas of responsibility, working principles and length of time to grant research permission vary across countries. For example, in some countries RECs perform follow-up of the studies approved, in some – not (e.g. Finland[1]). In some countries there are no appeal mechanisms after a negative decision by a REC, in others– such mechanisms exist. Not all EU member states have established RECs’ responsibility to report to some organization.[2] In some countries (e.g. England, Lithuania, Norway) RECs are regulated and supported by a REC control body. In some others (e.g. Finland) one of the central REC’s tasks is to provide local RECs with guidance and education and to give second opinions in the case of complaints, however, it has no formal power over local RECs and has not taken a leadership role1. Data from 2009 show that the number of RECs in a single country can vary from one to 264, from 0,05 (Romania) to 13,55 (Bulgaria) research ethics committees per million inhabitants[3]. Although the actual number of research projects per country was not taken into consideration by this study on RECs in european countries, it may be important to note that in order to maintain its professional competency RECs must review a certain minimal number of proposals per year. For example, the Central Committee on Research Involving Human Subjects (CCMO) of the Netherlands has stated that to get accredited an REC has to assess at least 10 protocols per year[4].10

Find more information on organization, composition and challenges of RECs in the Module “Research ethics committees: main tasks and challenges”. For the conceptual and procedural issues related to the work of RECs please also see section 2 of the E-manual available at http://eneri.eu/reri-manual/.

International regulatory framework

At the European level, the role of RECs is regulated by the following legally binding instruments:

• Directive 2001/20/EC on clinical trials on medicinal products for human use[5]. This is a European Union text, which will soon be replaced by the
• Regulation No 536/2014 on clinical trials on medicinal products for human use, to come into force in the beginning of 2020
• Regulation (EU) 2017/745 on medical devices[6] and Regulation (EU) 2017/746 on in vitro diagnostic medical devices[7]
• The Convention on Human Rights and Biomedicine (Oviedo Convention)[8] and
• its Additional Protocol concerning Biomedical Research[9]

The latter two are legally binding only in the States where they have been ratified.

• At world level, the sole legally binding provision is Article 7 of the International Covenant on Civil and Political Rights, and reiterated in the UN Convention on the Rights of Persons with Disabilities, but it addresses only one aspect of research[10].

The EU Regulations require that clinical investigations be subjected to scientific and ethical review performed by an ethics committee. They  define ‘Ethics committee’ as “an  independent body established in  a  Member State  in  accordance with the  law  of  that Member State and empowered to give opinions for  the purposes of  this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations”, which shall include at least one lay person.

Additional Protocol frames the requirement in the following way: “Every research project shall be submitted for independent examination of its ethical acceptability to an ethics committee” (Art. 9). According to the Protocol, the primary purpose of this examination shall be to protect “the dignity, rights, safety and well-being of research participants”.

CIOMS guidelines also explicitly state that RECs should conduct further reviews of approved research projects[11].

It is important also to note that majority of recognized scientific journals require an evidence of ethics review for human research studies to be published. For example, ICMJE requests that a statement indicating that the research was approved by a relevant ethics review body be included in the Methods section[12].

Institutional, regional or national review?

In many countries, RECs must be established in every institution or organisations conducting respective medical research.  The United States are the best well known example of the country where ethical review is performed by the Institutional Review Boards (IRBs) from the very beginning of the establishment of the system in early 60s. A number of European countries have introduced similar model as well.

The core criticism towards institutionally affiliated RECs deals with the issue of their independence (i.e. financial and decisional independence from research site).  For example, in Finland RECs were initially based in central hospitals, where most clinical research occurred. Thus, RECs were only semi-independent from the research sites. Later the number of RECs was reduced and more projects were evaluated outside the responsible institution.1

Some countries have a centralized system of ethical review. For example, in smaller countries clinical trials can be reviewed and approval must be obtained from the central (national) REC. Central (national) RECs are usually established by some ministry or national research agency.

Some countries combine central and regional, or regional and institutional ethics assessment by allocating specific roles for different RECs[13]. For example, Finnish National Committee on Medical Research Ethics is responsible for issuing opinions on the ethics of clinical drug trials that are to be run in Finland (unless this task is delegated to a regional ethics committee). In Lithuania, national REC approves clinical drug trials and bi-regional research studies only upon the recommendation of the regional RECs. Contrary to Denmark where National committee does not review research proposals, but acts as coordinating, policy making and appeal body for 11 regional committees.

Some countries do not have central REC, e.g. Estonia, where there are two ethics committees hosted by two biggest universities in the country, that review all kind of human studies (including psychological and behavioral studies), biomedical research and clinical trials.[14]

In a number of countries RECs are also attached to Medical Associations (e.g. Germany, Poland).

Some countries have established systems of accreditation of RECs (Netherlands, Spain), which is managed by the central REC. One can claim that accreditation system enables coexistence of RECs at different levels (institutional, local or regional) “without implying a hierarchy between them”[15].

Private or public REC?

In some cases, RECs may be set up by private organisations. The biggest advantage of private RECs is their independence of research sites. On the other hand, they may be dependent on the fees paid by the applicants. It has been thus strongly argued that private RECs must be publicly accountable (e.g. through accreditation). There is little evidence to suggest that the quality of ethics review conducted by private RECs varies from those established by a public institution or organisation. Private RECs are not common in Europe if compared with North America. England’s few private RECs were amalgamated with the NHS system by 20131.

Scope and proportionality of ethics review

It must be noted that the scope of research which required ethical review following the DoH has considerably changed during the last decades. Initially the DoH covered only clinical experiments with the direct involvement of a person at the beginning, while the recent editions of the DoH[16] require that also research on human biological materials and personal data to be subjected to ethical review.  RECs’ members have to deal with very wide range of medical research nowadays: from those involving patients to those using stored biological samples and personal data.

However, the scope of medical research where ethical review is required by the law differs in different EU member states. For example, in some countries only “medical research studies” are required to be scrutinized by the REC, in some – only clinical drug trials. Those countries that have ratified the CoE Oviedo Convention and its Additional protocol on Biomedical Research are also legally obliged to guarantee ethical review of biomedical research which is defined as “research activities in the health field involving interventions on human beings”.

All European Union member states now have legislation on clinical drug trials due to the implementation of the Directive 2001/20/EC and, consequently, have implemented systems for ethical review for drug studies. (It is expected that the new Regulation on Clinical Devices, which will to come in force in 2020, will harmonise the legislative framework for research on medical devices in Europe in a similar way.)

“Proportionality of ethics review”. The primary purpose of the requirement that the proposed research be reviewed by some independent body is to protect safety and wellbeing of research participants. Therefore, the system of ethical review of human research is based on the premise that research projects imposing equal or similar amount of risks and inconveniences on research participants should be subjected to equally or similarly stringent review procedures[17].  According to D. Hunter, “the level of ethical review and scrutiny given to a research project ought to reflect the level of ethical risk represented by that project”[18].

However, in a number of EU countries, regulatory legislation applies only to clinical trials on drugs and medical devices. This leaves large areas of biomedical research, including behavioral research, research on stored biological materials, associated personal data, or epidemiological studies less regulated by legal instruments.

It should also be noted that human research studies that do not fall within the field of biomedical research are the least legally regulated examples of human research on the European and international level. There are no binding European regulations covering, for example, sociological or psychological human studies, even though these studies rather often raise sensitive ethical issues. Usually, these types of human research are left to the self-regulatory mechanisms of universities, professional organisations and scientific journals17.

Therefore, while establishing ethics review system for human research it is of vital importance to take into account potential risks posed not only by medical research, but also those arising in the context of social and behavioral research studies, such as anthropology, cognitive sciences, political science, psychology, social work, and health services research.

(Ethical review systems of non-medical research is discussed in the Module “Setting up an infrastructure for ethics review in non-medical fields” in more detail).

Expedited procedures for studies involving minimal risk

Considering different levels and nature of risks posed by different research projects, also keeping the principle of proportionality of review, some countries / RECs offer possibility for researchers to undergo an expedited review procedure.

RECs can adopt a proportionate approach to ethics evaluation: the greater the burden of research, the greater the scrutiny. An evaluation can be completed by the REC’s full committee or by a sub-committee (expedited review). Expedited review is allowed by certain RECs for research that poses only minimal burden to participants (when the amount of harm expected in the research is less than that ordinarily encountered in daily life, or in routine medical, dental, or psychological exams) [19].

For example, at WHO ethics review committee a proposal can be circulated for expedited review when the research procedures present no more than minimal harm to the research participants or communities[20].

In the USA the following criteria must be met before a protocol may be considered for an expedited review process:

1.   The activity must present no more than minimal risk to subjects; and

2.  The protocol procedures must be listed as one of the categories in the regulations' list of procedures that qualify for an expedited review process. The research categories that may qualify for an expedited review process are listed below[21].

The concept of “minimal risk” have been dealt with in more detail in the Module “Core principles of research ethics”.

It should be noted, that ethical review is not required in Finland if the research is based on public or published documents, registries or archived data. For further information on Recommendations, References to VHPs for Researchers, RECs and Research Institutions please refer to the Handbook of Recommendations for Research Ethics and Research Integrity. A guide for Researchers, Members of Research Ethics Committees and of Research Integrity Offices (D2.3) (Part A).

Introducing and establishing national or institutional training on research ethics for RECs

Although it seems that in most of the countries there is no formal requirement for ongoing training and education for RECs’ members[22], there is at the time much evidence that systematic training of members is one of the basic components of building RECs’ capacity, credibility and know-how[23].

Although there is no obligatory requirement for training, in many countries central RECs, institutions of higher education or governmental bodies offer training for their RECs in the form of introductory courses, continuing training covering new topics and refreshing knowledge, periodic meetings, etc1.

Continuous training is especially important taking into consideration the rapidly changing nature of methods used in medical research and ethical issues they involve. Ethical issues raised by social media research can serve an an example. The results of a recent study revealed that while more experienced REC members’ approach to ethical decision making was more nuanced, they still fell short in terms of moving beyond traditional perceptions of de-identifications and consent as representing adequate safeguards to mitigate risk[24].

A short overview of training opportunities in the UK could serve as an example of good practice in this field. In the UK training for REC members is organized by NHS Health Research Authority or universities (for example, Universities of Bristol Centre for Ethics in Medicines organizes training for NHS REC members)[25]. The NHS Health Research Authority has a special training team which provides an extensive programme of training for REC members. It offers different modalities of training, for example, induction training for new REC members and refresher courses for existing REC members.  To achieve maximum flexibility for new and existing REC members, the NHS Health Research Authority also offers a number of online courses and self-directed learning [26].

[1] Elina Hemminki. Research Ethics Committees in the Regulation of Clinical Research: Comparison of Finland to England, Canada, and the United States. Health Research Policy and Systems. 2016; 14:5. Link: https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-016-0078-3.

[2] Veerus P. Legislative regulation and ethical governance of medical research in different European Union countries. J Med Ethics. 2014 Jun;40(6):409-13. Link: https://www.ncbi.nlm.nih.gov/pubmed/23665856?dopt=Abstract.

[3] Druml et al. Research ethics committees in Europe: trials and tribulations. Intensive Care Med (2009) 35:1636–1640. http://ethikkommission.meduniwien.ac.at/fileadmin/ethik/media/dokumente/publikationen/25-research_ethics_committees_europe.pdf.

[4] Halila R.  Evaluation of the work of hospital districts’ research ethics committees in Finland. J Med Ethics 2014;40:866–868. Link: https://jme.bmj.com/content/40/12/866.

[5] Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

[6] Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC.

[7] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. Link: https://ec.europa.eu/growth/sectors/medical-devices/regulatory-framework_en.

[8] Council of Europe. Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. 1997. http://conventions.coe.int/Treaty/en/Treaties/Html/164.htm.

[9] Council of Europe. Additional protocol to the convention on human rights and biomedicine, concerning biomedical research. 2005. http://conventions.coe.int/treaty/en/Treaties/Html/195.htm

[10] Guide for Research Ethics Committees. Council of Europe, 2012. https://www.coe.int/t/dg3/healthbioethic/activities/02_biomedical_research_en/Guide/Guide_EN.pdf.

[11] International Ethical Guidelines for Health-related Research Involving Humans, Fourth Edition. Geneva. Council for International Organizations of Medical Sciences (CIOMS); 2016. Guideline 23. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf.

[12] Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in Medical Journals. Updated December 2017. http://www.icmje.org/recommendations/.

[13] National Committee on Medical Research Ethics TUKIJA official website. http://tukija.fi/en/frontpage

[14] European Network of Research Ethics Committees – EUREC official website. http://www.eurecnet.org/index.html.

[15] Clinical Research Ethics Committees in Spain. European Network of Research Ethics Committees – EUREC official website. http://www.eurecnet.org/information/spain.html.

[16] Declaration of Helsinki (2013). https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/.

[17] Gefenas et al. Non-equivalent Stringency of Ethical Review in the Baltic States: A Sign of a Systematic Problem in Europe? J Med Ethics, 2010; No. 36, p. 435-439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072805/pdf/nihms281058.pdf.

[18] Hunter D. Proportional Ethical Review and the Identification of Ethical Issues. J Med Ethics. 2007; 33:241–5. [PubMed: 17400625]

[19] European Patients‘ Academy – EUPATI offcial website. https://www.eupati.eu/what-is-eupati/

[20] ERC Review Process. World Health Organisation (WHO) offcial website. http://www.who.int/rpc/research_ethics/review_process/en/

[21] Expedited Review Process (2016). Office of Human Subjects Research – Institutional Review Board. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/guidelines/expedited_review.html

[22] Druml Ch. at al. Research Ethics Committees in Europe: Trials and Tribulations. Intensive Care Med (2009) 35:1636–1640. http://ethikkommission.meduniwien.ac.at/fileadmin/ethik/media/dokumente/publikationen/25-research_ethics_committees_europe.pdf

[23] Giovanna Ricci, Nunzia Cannovo. The Importance of the Training of Ethics Committee Members. Medicine and Law, 2009.

[24] Hibbin, G. Samuel, and G. E. Derrick. From “a Fair Game” to “a Form of Covert Research”: Research Ethics Committee Members’ Differing Notions of Consent and Potential Risk to Participants Within Social Media Research. Journal of Empirical Research on Human Research Ethics 2018, Vol. 13(2) 149–159. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873513/.

[25] Training and Professional Development Courses. Centre for Ethics in Medicine. University of Bristol. https://www.bristol.ac.uk/population-health-sciences/centres/ethics/courses-programmes/committee-training.html.

[26] REC Members Learning Resouces (2018). NHS Health Research Authority. https://www.hra.nhs.uk/planning-and-improving-research/learning/rec-member-learning-resources/

Resources:

Horizon 2020 Online Manual. European Commission.

Other ethics issues, page 40. in European Commission (2019) Horizon 2020 Programme. How to complete your ethics self-assessment-material guidance. European Commission. Directorate-General for Research & Innovation.