Research In Emergency Situations
Emergency Research And Alternative Ways Of Protecting Participants
One way to justify emergency research without initial consent is to say that the values that are secured by informed consent (respect for autonomy and protection of well-being) can be secured by other means[1]. These safeguards are required in most of the recent guidelines and legal acts, both globally and at the European level. A prevalent algorithm to justify research in emergency situations without prior consent includes the following:
- the research is directly related to the patient’s medical condition that prevents giving informed consent (WMA Declaration of Helsinki[2], EU Clinical Trials Regulation[3]);
- it cannot be delayed due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition (WMA Declaration of Helsinki, EU Clinical Trials Regulation) and
- research of comparable effectiveness cannot be carried out on persons in nonemergency situations (Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research[4]; EU Clinical Trials Regulation).
In addition to what was mentioned, the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research also requires a careful balancing of risks and benefits and specifies two types of permissible research in emergency situations:
1) it has the potential to produce results of direct benefit to the health of the person concerned; or
2) it has the aim of contributing, through significant improvement in the scientific understanding of the individual's condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same category or afflicted with the same disease or disorder or having the same condition and entails only minimal risk and minimal burden. (Art. 15, para 2)
Limitations Of Emergency Research In The EU Clinical Trials Regulation
It is worth mentioning that under the new EU Clinical Trials Regulation and the EU Regulation on Medical Devices[5], only the first type of research studies specified above would be justified. The EU Clinical Trials Regulation only allows “therapeutic” research with minimal risk and minimal burden as its relevant provision reads as follows “there should be scientific grounds to expect that participation of the subject in the clinical trial will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition and the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition”. Currently applied EU Directive 2001/20/EC[6] provides with the requirement to obtain the informed consent of the legal representative of an incapacitated person and does not provide with any exemptions for, e.g. emergency research studies.
The discrepancy between the two European documents also reflects the ongoing debate in the ethics of research that involves incapacitated patients. On the one hand, there are those who only justify research when potential direct benefits to the participants exceed the study risks. On the other hand, the others argue that the importance of knowledge that could reasonably be expected to result from the research and that could only benefit future patients, is also justified in some circumstances. The proponents of the second position argue that although a core principle compensating the waiver of informed consent is the principle of beneficence, medical research per se is aimed at collecting knowledge in order to develop new methods of treatment. Therefore, by definition, very often no promises about the superiority of an experimental therapy can be made to an individual participant. The requirement of a direct benefit may be problematic also due to the fact that within one research project some interventions or procedures may help participants (such as the proposed intervention), and others are done solely to generate knowledge (randomization, blinding, additional blood draws, tests and questionnaires that are not normally included in standard care of such patients).
Informed Consent Issues
As already mentioned, prior informed consent may be waived, if due to the nature of the research when a subject is unable to receive prior information on the clinical trial and to provide prior informed consent, and it is not possible within the therapeutic window to supply all prior information and obtain prior informed consent from his or her legally designated representative (WMA Declaration of Helsinki, ICH Guideline E6 for Good Clinical Practice[7], EU Clinical Trials Regulation). There are, however, additional safeguards in respect to the informed consent in emergency research provided by international guidelines:
- there should be no conflicting preferences (i.e., there should be no compelling reason to think that participation in the research conflicts with enrolled patients' will not to take part in the research). Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, EU Clinical Trials Regulation and EU Regulation on Medical Devices requires the researcher to respect patient’s previously expressed objections to participate in the research, but does not specify what measures should be taken to ensure if the patient has registered an objection. As the emergency research must commence rapidly, it may be time consuming to undertake a search of archives, for instance. On the other hand, informed consent should not be compromised merely because there is not enough study staff to contact relatives.
- consent for ongoing emergency research is obtained as soon as possible. It is of the utmost importance to get a proper informed consent for continued participation in the research study either from the participant or from the patient’s representative as soon as possible. In all cases in which research has been approved to begin without prior consent of incapacitated persons because of suddenly occurring conditions, they must be given all relevant information as soon as they regain capacity, and their consent to remain in the study must be obtained as soon as reasonably possible. However, it is not defined what does ‘reasonably possible' mean. The CIOMS guideline[8] suggests the researcher and the research ethics committee to agree to a maximum time of involvement of an individual without obtaining either the individual’s own informed consent or surrogate consent if the person continues to be unable to give consent. If, by that time, there is no individual or surrogate consent, the participant should be withdrawn from the study provided that withdrawal will not make the participant worse off. (CIOMS guideline 16). The participant or the surrogate should be offered an opportunity to object to the use of data derived from participation of the patient without consent or permission.
[1] Largent EA, Wendler D, Emanuel E, Miller FG. Is Emergency Research Without Initial Consent Justified? The Consent Substitute Model. Arch Intern Med. 2010;170(8):668–674. doi:10.1001/archinternmed.2010.80.
[2] WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects.
[3] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials in medicinal products for human use and repealing Directive 2001/20/EC. Off. J. 2014;L 158(27.05.2014):1.
[4] Council of Europe. Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, 2005. https://www.coe.int/en/web/conventions/full-list/-/conventions/treaty/195.
[5] 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. OJ L 117, 5.5.2017, p. 1–175. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745.
[6] 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 application of good clinical practice in the conduct of clinical trials with medicinal products for human use. Off. J. 2001;(34) EC No L 121.
[7] ICH Guideline for Good Clinical Practice (E 6), CPMP/ICH/135/95, CPMP. https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice.
[8] CIOMS. International Ethical Guidelines for Health-related Research Involving Humans. 2016. https://cioms.ch/shop/product/international-ethical-guidelines-for-health-related-research-involving-humans/.
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- Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Health-related Research Involving Humans. Guideline 17. Geneva, 2016. Fourth Edition. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
- Council of Europe Additional Protocol to the Convention on Human Rights and Biomedicine on Biomedical Research.
- Explanatory Report to Additional Protocol to the Convention on Human Rights and Biomedicine on Biomedical research: https://rm.coe.int/16800d3810.
- WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
- International Conference of Harmonization (ICH). ICH Tripartite Guideline for Good Clinical Practices E6 (R1) (1996, last update in 2016). https://www.ich.org/products/guidelines/efficacy/efficacy-single/article/integrated-addendum-good-clinical-practice.html
- Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf
- 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
- 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
- FDA Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors. Exception from Informed Consent Requirements for Emergency Research (2013)
- The Norwegian National Research Ethics Committees. https://www.etikkom.no/en/library/topics/research-on-particular-groups/barn/
- European Commission. European Textbook on Ethics in Research. European Luxembourg: Publications Office of the European Union, 2010. https://ec.europa.eu/research/science-society/document_library/pdf_06/textbook-on-ethics-report_en.pdf
Learning Objectives
- to understand ethical issues raised by research in emergency situations
- to analyze additional safeguards aimed to protect the interests and welfare of the patients involved in emergency research
- to evaluate these safeguards when analyzing suggested emergency research cases
Introduction
Emergency research should only be undertaken in emergency situations and is intended to improve emergency response or care[1]. Emergency situations are acute, unforeseen clinical situations requiring a prompt action (e.g., severe trauma, cardiac arrest, acute congestive heart failure, sepsis or hemorrhage, stroke, a drug overdose, etc.). Patients in the emergency situation are at high risk of morbidity or death, may be in great need of novel therapies and even might be willing to assume some risk for a potential benefit, but because of the urgency of the situation (the intervention must be delivered within limited time of an acute and entirely unexpected life-threatening medical condition) an investigator generally cannot obtain informed consent for such a research from the patient or the patient’s representative. Thus, emergency research raises a fundamental ethical dilemma: abstain from a valuable research because informed consent is not possible or to carry on such a research and enroll patients without informed consent[2].
Since the Nuremberg trials and the Nuremberg code (1947), the requirement of free and informed consent has been accepted as the cornerstone of any medical research involving human beings. Therefore, medical research on incapacitated persons has sometimes been questioned as a violation not only of personal autonomy but also of human rights[3]. However, is a prior consent an absolute requirement for the conduct of research?
[1] Ezekiel J. Emanuel, Christine C. Grady, Robert A. Crouch, Reidar K. Lie, Franklin G. Miller, David D. Wendler. The Oxford Textbook of Clinical Research Ethics. Oxford University Press, 2008.
[2] Ezekiel J. Emanuel, Christine C. Grady, Robert A. Crouch, Reidar K. Lie, Franklin G. Miller, David D. Wendler. The Oxford Textbook of Clinical Research Ethics. Oxford University Press, 2008.
[3] S Lötjönen. Medical research in clinical emergency settings in Europe. J Med Ethics 2002, 28: 183–187.