The CRASH 2 Trial involves patients who have suffered serious injuries and are at risk of life threatening haemorrhage. In this situation, most patients will have some impairment in their level of consciousness caused either by blood loss or coexisting head-injury. In this emergency situation, patients may not be able to provide written informed consent. In addition, the trial treatment has to be administered as soon as possible after injury.

From 1 May 2004 it is necessary that trials be compliant with Directive 2001/20/EC in the UK. To implement this directive, the UK regulation titled "The Medicines for Human Use (Clinical Trials) Regulations (2004)" was published which requires that certain conditions and principles are applied to enable an incapacitated adult to be part of a clinical trial. See CONDITIONS below. For the full regulation please visit the following website:
http://medicines.mhra.gov.uk/ourwork/licensingmeds/types/ctregsdraft.pdf

The EU Directive (2001/20/EC) requires that, prior to participation in a trial, written consent from a legal representative of any person unable to consent for him or herself be obtained.

In the first instance, the legal representative of a person unable to give consent should be close to that person, aware of his/her wishes and independent of the research. This person would be termed the Personal Legal Representative (PeLR).

If this is not possible and there is no one sufficiently close to the potential subject who is willing or able to take on the role, or if a person close enough to the potential subject cannot be contacted before it is medically necessary to give the intervention then someone nominated by the NHS Trust as a Professional Legal Representative (PrLR) will fulfil this role.

The CRASH 2 Trial is conducted in an emergency situation and the protocol requires that treatment is administered as soon as possible after injury. In the majority of cases, patients are unaccompanied. In addition, it can take time for the police to identify and contact someone who can potentially be a PeLR.

In most cases, it is expected that consent for participation will have to be obtained from a PrLR for patients to be enrolled.

OBTAINING LEGAL REPRESENTATIVE CONSENT FOR THE CRASH 2 TRIAL

• It is the responsibility of each NHS Trust collaborating in the CRASH Trial to nominate suitable personnel to act as PrLR.

• It is the responsibility of each NHS Trust collaborating in the CRASH Trial to provide general training about the role of a PrLR.

• It is the responsibility of each NHS Trust collaborating in the CRASH Trial to provide Indemnity for PrLRs.

• It is the responsibility of each Principal Investigator and the Trial Co-ordinating Centre to provide written trial specific information about the trial to PrLRs to allow them to make an informed decision.

PROCESS FOR OBTAINING CONSENT

PATIENT FULFILS ELIGIBILITY CRITERIA

Is a person who has a close personal relationship with the patient available and knowledgeable about their wishes?

Is this person willing and able to take on the responsibilities of PeLR in this emergency situation?

NO »»»»»»»»»»

• If YES, explanation to be given in person by a member of the trial team.
• Written consent to be signed by PeLR
• If PeLR not present in person, verbal consent to be obtained by telephone (to be witnessed and recorded in medical records). Written consent to be obtained as soon as possible.
• If / when patient regains competence, inform of participation, provide patient information sheet and obtain consent for use of information.

Is there any reason to presume that this patient would NOT be willing to participate?

If no, Trial Team to contact identified PrLR and obtain written consent.

If no PrLR is available in the emergency situation (e.g during night time hours), patient can be randomised into the trial, if there is local agreed pre-arrangement, and written consent obtained from PrLR as soon as possible thereafter.

If / when patient regains competence, or should a PeLR be identified, inform of participation, provide patient information sheet and obtain consent for use of information.

STATUTORY INSTRUMENTS - MEDICINES
The Medicines for Human Use (Clinical Trials) Regulations (2004)

PART 5: CONDITIONS AND PRINCIPLES WHICH APPLY IN RELATION TO AN INCAPACITATED ADULT

Conditions
1. The subject's legal representative has had an interview with the investigator, or another member of the investigating team, in which he has been given the opportunity to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.
2. The legal representative has been provided with a contact point where he may obtain further information about the trial.
3. The legal representative has been informed of the right to withdraw the subject from the trial at any time.
4. The legal representative has given his informed consent to the subject taking part in the trial.
5. The legal representative may, without the subject being subject to any resulting detriment, withdraw the subject from the trial at any time by revoking his informed consent.
6. The subject has received information according to his capacity of understanding regarding the trial, its risks and its benefits.
7. The explicit wish of a subject who is capable of forming an opinion and assessing the information referred to in the previous paragraph to refuse participation in, or to be withdrawn from, the clinical trial at any time is considered by the investigator.
8. No incentives or financial inducements are given to the subject or their legal representative, except provision for compensation in the event of injury or loss.
9. There are grounds for expecting that administering the medicinal product to be tested in the trial will produce a benefit to the subject outweighing the risks or produce no risk at all.
10. The clinical trial is essential to validate data obtained

a) in other clinical trials involving persons able to give informed consent, or
b) by other research methods

11. The clinical trial relates directly to a life-threatening or debilitating clinical condition from which the subject suffers.

Principles
12. Informed consent given by a legal representative to an incapacitated adult in a clinical trial shall represent that adult's presumed will.
13. The clinical trial has been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the cognitive abilities of the patient.
14. The risk threshold and the degree of distress have to be specially defined and constantly monitored.
The interests of the patient always prevail over those of science and society.
15. The interests of the patient always prevail over those of science and society.