Guidelines for Emergency Trials outside of the CTR and the MDR

Read about the requirements and concepts related to health science research in emergency trials.

1.1 Generally about Research on Persons without Legal Capacity

Generally, research may only be conducted with trial subjects who have lost their legal capacity if the trial cannot be carried out with the same benefit using competent trial subjects. This also applies to research in emergency treatment situations. If the new knowledge sought from the trial can instead be obtained by involving trial subjects who have not lost their legal capacity, the trial should be conducted as a regular trial, where prior consent is obtained.

1.2 What is Considered an Emergency Situation in the Context of the Committee Law?

Primarily, this refers to research involving the treatment of trial subjects who suddenly lose their legal capacity due to causes such as unconsciousness, cardiac arrest, brain hemorrhage, thrombosis, or other spontaneous injuries.

For research in an emergency treatment situation to be allowed without having obtained consent, as per committee law, it is a prerequisite that the nature of the research project means it can only be conducted in emergency situations. The nature of the research project means that consent cannot be awaited without forfeiting the purpose of the research. In other words, the intervention (initiation of treatment/method) must be urgent.

The trial subject's sudden condition and the urgency of the trial are decisive in determining whether it is an emergency situation. Difficulties in contacting the nearest relative, holder of parental rights, or the guardian alone do not justify the use of rules about emergency trials.

Generally, the following conditions can be established for a research project to be considered an emergency in the sense of committee law:

• The research project can, by its nature, only be conducted in situations where the trial subject suddenly loses their legal capacity, e.g., due to a thrombosis, brain hemorrhage, unconsciousness, cardiac arrest, severe injuries, or trauma, etc., and
• Consent (informed or representative) cannot be awaited without forfeiting the purpose of the research. In other words, the intervention (initiation of treatment/method) is urgent.

1.3 What Applies to Emergency Trials without Medicinal Products (Including Trials with Clinical Evaluation of Medical Equipment)?

In emergency trials without medicinal products, the trial can be conducted without prior consent from the trial subject (or representative) if the trial could, in the long term,

- Improve the specific trial subject's health, or
- Improve the condition of other patients with the same disease, and participation in the trial only entails minimal burden and risk.

Furthermore, the trial responsible must, as soon as possible afterward, try to obtain consent from the trial subject themselves or a representative, e.g., holder of parental rights, guardian, or nearest relative plus trial guardian (committee law § 11, para. 2 and §§ 3-5). (see about the trial guardian below).

1.4 What Applies in Trials with Medicinal Products under the Directive?

An emergency trial with medicinal products can only be conducted if prior consent is obtained from a trial guardian (see about the trial guardian below) before the trial subject's inclusion in the trial.

Additionally, it is required that the trial is presumed to improve the specific trial subject's health in the long term.

Furthermore, the trial responsible must, as soon as possible afterward, try to obtain consent from the trial subject themselves or a representative.

In an emergency medicinal trial, several forms of consent must therefore be obtained: prior consent from a trial guardian, subsequent representative consent (normally from relatives and a trial guardian), and/or consent from the trial subject themselves if, for example, they regain consciousness during the trial (committee law § 12, para. 2 and §§ 3- 5).

1.5 What is a Trial Guardian?

The trial guardian is a doctor who must represent the trial subject's interests by giving prior consent in emergency medicinal trials (committee law § 12, para. 1)

In addition, a trial guardian, along with the nearest relative, must give a representative consent as soon as possible after inclusion in an emergency trial, if trial subjects do not regain their legal capacity during the trial (§ 4, para. 3, cf. §§ 11, para. 2 and 12, para. 2).

A trial guardian must be independent of the trial responsible's interests and of interests in the trial project in general and have professional knowledge in the research area. The trial guardian should be an external doctor who is not in a hierarchical relationship with the trial responsible.

It must be described in the protocol how the trial guardian is appointed. The appointment will depend on the nature and extent of the trial. A trial guardian could, for example, be an on-call doctor in a hospital department with knowledge in the relevant professional area.

Be aware that in emergency medicinal trials, there are two different consent situations where written consent must be obtained from a trial guardian - the prior consent for the emergency trial (§ 12) and the subsequent representative consent (§ 4, para. 3). Both situations should be described in the protocol, and it is not necessarily the same trial guardian who should give consent in the two situations.

1.6 Trial Guardian's Consent in Practice

The trial guardian must, based on their knowledge in the trial's professional area and based on the information material for the specific trial and the trial subject's condition, have a basis for giving consent for the trial. The trial guardian must thus assess whether it is justifiable for the trial subject in their given condition to participate in the specific trial.

It is assumed that the trial guardian has access to the trial protocol and/or the written participant information. Trial material could, for example, be available in the hospital department where the trial guardian is appointed. An evaluation must be made for each individual patient. Therefore, the trial guardian's consent cannot be given generally in advance, for example, to persons with certain traumas, etc.

The trial guardian must sign a consent declaration.

This also applies to the prior consent that the trial guardian gives in emergency medicinal trials. In this situation, the written consent does not need to be signed while the healthcare professional conducting the trial is present. The consent can be confirmed in advance, for example, by phone. Such telephonic consent must always be followed up with written consent (committee law § 12, para. 1).

This guideline is aimed at researchers who are to report acute scientific research projects and describes the overarching conditions of the committee law for conducting acute research. Reference is made to the committee system's Researcher Guide (about content requirements) - special requirements for acute trials.

The guidelines also address the regional scientific ethics committees as they describe the practice in the treatment of specific research projects and will be updated in line with developments in the field.

3.1 Trials with subsequent consent acquisition

According to the predominant rule, informed or proxy consent as per the committee law's §§ 3-5 should be acquired prior to a participant's inclusion in a medical research project. However, in acute situations, research can proceed without prior consent under specific conditions:

• The nature of the research project means it can only be conducted in acute situations where the test person suddenly loses their ability to act, e.g., due to a blood clot, brain hemorrhage, unconsciousness, cardiac arrest, severe injuries, or traumas.
• Consent (informed or substitute) cannot be awaited without the research's objective being missed. In other words, the intervention (initiation of treatment/method) is imperative.
• The ethical science committee has assessed that the above conditions are met.
• The researcher, as soon as possible afterward, obtains a standard informed consent or a substitute consent according to §§ 3-5 of the committee law. For drug trials, however, consent from a test guardian must also be obtained before the trial starts. See below for drug trials.

Furthermore, there are qualitative conditions regarding benefits for the test person or the patient group in acute trials, see below under point 3. Rules about acute research are provided in the committee law's2 § 11 and § 12.

3.2 What is an acute situation?

An acute situation means research intervention can't be postponed until consent is achieved. The NVK, in a specific case3, determined that if a research intervention is initiated within 12-24 hours, it cannot be classified as acute. The intervention should occur shortly after the onset of a disease or trauma to qualify as an acute situation.

3.3 The concept of "lack of ability to act" in acute trials

A person lacks the ability to act if they're incapable of looking after their own affairs. In the context of the committee law, a test person is considered lacking the ability to act if they are physically or mentally in a state where they can't decide to participate in the trial.

A person lacks the ability to act if they're incapable of looking after their own affairs. In the context of the committee law, a test person is considered lacking the ability to act if they are physically or mentally in a state where they can't decide to participate in the trial.

Such cases can be challenging to evaluate. Therefore, for the committee's approval of the project, the inclusion criterion must be precisely formulated, so there's no doubt that the project involves people unquestionably in an acute treatment situation and have lost their ability to act. The likelihood that capable people will meet the inclusion criteria must be minimized as much as possible for the trial to meet the criteria for approval as an acute trial.

3.4 It must concern a patient group that lacks the ability to act

In general, research can only be conducted with test people who have lost their ability to act if the trial can't be conducted on capable individuals with the same benefit4. This also applies to acute trials that can only be conducted where the test person can't provide informed consent. If the new knowledge can be obtained by including capable individuals in the trial, the trial must be conducted as a regular trial with informed consent and not by using the special acute provisions.

The inclusion criteria in an acute trial should ensure that only test people lacking the ability to act are included. However, see below about control groups. The formulation of inclusion criteria is crucial. If the criteria suggest both capable and those without the ability to act are included, doubts may arise about whether the trial could instead be conducted on capable individuals as a regular trial. If the trial can be conducted with the same effect on capable individuals, it must be conducted as a regular trial with capable individuals.

If a specific test person, who meets the criteria for an approved acute trial, is still able to give consent themselves, the person cannot be included in the acute trial.

In a specific case5, the NVK found that populations in part 1 of the project were heterogeneous and overall mentally in a state where they could be considered lacking the ability to act, as they were either unconscious, sedated, or significantly affected in consciousness. Some participants were delirious with reduced consciousness intensity and clarity. However, some patients in sub-project 2 were capable and thus able to give informed consent. A condition was added to the decision that such patients couldn't be included in the project.

3.5 Especially about control groups

In a specific case6, the NVK was presented with the question of whether a control group of capable individuals could be established in the trial. The trial consisted of an intervention group, where an acute surgical procedure was to be performed on patients with acute aortic dissection upon hospital arrival. These patients were either in hemodynamic shock or unconscious and intubated on arrival. This part of the trial met the criteria for an acute trial. The NVK also approved that a control group of capable individuals was included, who had to give informed consent according to the committee law's § 3, as these patients had a different underlying disease and treatment need than the intervention group.

4.1 Experiments that do not involve drugs, as well as clinical trials of medical equipment

In experiments that are not drug trials, as well as in clinical trials of medical equipment, according to the committee act § 11, there should be an expectation that the experiment in the long run will either be able to:

• Improve the specific test person's health, or
• Improve the condition of other patients with the same disease.

Otherwise, the experiment cannot be conducted urgently.

Furthermore, the person responsible for the trial must, as soon as possible afterward, attempt to obtain consent from the test person themselves or their proxy (usually relatives and trial guardian), cf. committee act § 11, para. 2 and §§ 3-5.

Trials should generally be conducted, taking into account the test person's rights, safety, and well-being, and these considerations weigh heavier than the interests of science and health, cf. committee act § 1. A somewhat higher risk can be accepted if the nature and severity of the disease mean that the benefits of a trial are greater. For example, a higher risk in trials treating critically ill patients where there are no other alternatives is acceptable. This follows the principle of proportionality.

However, § 11 of the committee act states that the risk in urgent trials that do not involve drugs should entail minimal strain and risk for the test person. Therefore, an absolute limit has been set for how high the risk may be.

4.2 Clinical drug trials

According to the comments on the committee act7, for drug trials, it is a requirement that the trial, in the long run, will be able to:

• Improve the specific test person's health.

Thus, it is not enough that the trial can improve the condition of other patients with the same disease, as mentioned above for experiments that are not drug trials.

Conducting urgent trials presupposes in all types of trials that the trial relates to the clinical condition in which the test person finds themselves.

Furthermore, the person responsible for the trial must, as soon as possible afterward, attempt to obtain consent from the test person themselves or their proxy (usually relatives and trial guardian), cf. committee act § 12, para. 2 and §§ 3-5.

4.3 Especially regarding clinical drug trials – Prior consent from the trial guardian

As mentioned above, regular informed consent or proxy consent is obtained subsequently in urgent trials. However, the GCP directive does not allow for the conducting of urgent trials with subsequent consent, which is why it is necessary to obtain special consent from the trial guardian before the test person is included in the project, cf. committee act § 12.8.

The trial guardian is a doctor who must look after the interests of the test person and is independent of the interests of the person responsible for the trial and the interests of the trial project in general. The trial guardian should be an external doctor, not in a superior/subordinate relationship with the person responsible for the trial.

The trial guardian must, based on their knowledge of the professional area of the trial and based on the information material for the specific trial and the condition of the test person, have a basis for consenting to the trial. The trial guardian must thus assess whether it is justifiable for the test person in the given condition to participate in the specific trial.

An assessment must be made of each individual patient. Consent cannot be given generally in advance, e.g., to people with certain traumas, etc. However, the written consent does not need to be signed in the presence of the person responsible for the trial but can be confirmed – e.g., by phone – verbally before the start of the trial. It should be noted that verbal consent by phone should always be followed by written prior consent from the trial guardian.

The protocol should describe how the trial guardian is selected. The appointment will depend on the nature and extent of the trial. A trial guardian can, for example, be an on-duty doctor at a hospital department with knowledge in the relevant professional area.

It is assumed that the trial guardian has access to the trial protocol and/or the written participant information. Trial material can, for example, be available at the hospital department where the trial guardian is employed.

Please note that in urgent drug trials, there are two different consent situations where written consent must be obtained from a trial guardian – the prior consent for the urgent trial (§ 12) and the subsequent proxy consent (§ 4, para. 3). Both situations should be described in the protocol, and it is not necessarily the same trial guardian who must give consent in the two situations.

Regarding the risk in urgent drug trials with persons without the ability to act, the comments on the law refer to the act's § 19, para. 1. Thus, it applies that:

• The trial is crucial to verify data in trials with capable persons or other trial methods, and
• The trial concerns the patient's clinical condition.

The GCP directive also states that persons without the ability to act should generally only be included when it is believed that the drug will provide such a direct benefit to the test persons that it outweighs the risks. The directive also states that both the risk limit and the level of strain must be set specifically and continuously monitored.

• Ordinance on information and consent to participate in health science research projects and on notification and supervision of health science research projects. BEK no. 1464 of 02/12/2016.
• Law no. 620 of 08/06/2016.
• Law no. 593 of 14 June 2011.