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.