Science and Technology CommitteeWritten evidence submitted by the London School of Hygiene & Tropical Medicine

Thank you for the opportunity to submit written evidence to the Select Committee on Clinical Trials.

This submission responds to the question: “Do the European Commission’s proposed revisions to the Clinical Trials Directive address the main barriers to conducting clinical trials in the UK and EU?”

My concern relates to the conduct of clinical trials in emergency situations. Such clinical trials are essential in improving the safety and effectiveness of emergency care. For example, few of the treatments currently used in the emergency management of patients with head injuries have ever been shown to be safe and effective. Indeed, corticosteroids were widely used to treat head injury until a large clinical trial (the CRASH-1 trial) showed that they increased, rather than decreased, the risk of death.1

There are many treatments in daily use for which there is uncertainty about their effectiveness and safety.

When evidence is uncertain and the decision to give treatment A or treatment B does not have a sound scientific basis: some patients will get treatment A and some will get treatment B as part of their normal medical care. For example, before the CRASH-1 trial, just over half of doctors used corticosteroids and the rest did not. In the CRASH-1 trial, patients were randomly allocated to corticosteroids or placebo, so that we could find out whether or not corticosteroids were helpful. Because the allocation was made in a truly random way, we had two comparable groups of patients, half of whom received corticosteroids and half of whom did not. By comparing the outcomes in the two groups, we discovered that the doctors who used corticosteroids were wrong. The treatment did not work—it was harmful—thanks to the trial the doctors who used corticosteroids could stop doing so. This important information could not have obtained without a proper trial. However, there are many more uncertainties that need to be resolved.

Patients in emergency care trials are often in life threatening situations where urgent treatment is necessary. Because of the urgency of the situation and the patients’ clinical condition they are usually unable to give written informed consent to trial participation. These situations are a wholly appropriate exception to the general rule of written informed consent.

In this respect, Article 32 of the proposed Regulation, on clinical trials in emergency situations states the conditions for waiving “consent at the time”.

Informed consent may be obtained after the start of the clinical trial to continue the clinical trial and information on the clinical trial may be given after the start of the clinical trial provided that all of the following conditions are fulfilled:

(a)due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, it is impossible to obtain prior informed consent from the subject and it is impossible to supply prior information to the subject;

(b)no legal representative is available;

(c)the subject has not previously expressed objections known to the investigator;

(d)the research relates directly to a medical condition which causes the impossibility to obtain prior informed consent and to supply prior information; and

(e)the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject.

It is my view that the wording of the new Clinical Trial Regulation could undermine the progress we’ve made in the UK to date on this important issue. There are particular difficulties with (b) and (e).

(b) It is likely that in many situations a relative or other legal representative may indeed be “available”. However, no consideration is given to the ability of a relative to give consent in such an emergency situation. In cardiac arrest, severe trauma or major bleeding, it is unlikely that a relative or other legal representative would have the time or mental capacity to make an informed decision. The distress experienced by a relative when their loved one is at high risk of death must not be underestimated. Secondly, in some situations obtaining consent from a legal representative whether a relative or other, delays the administration of potentially life-saving interventions. For example, we have shown that in the CRASH-2 clinical trial of tranexamic acid in life threatening bleeding, the delay incurred by seeking consent from a relative, prevented many patients from receiving the early treatment benefits and that some patients died as a result of this needless “consent ritual”.2 , 3

(e) Many emergency conditions require the testing of new treatments. For example, in the case of traumatic brain injury, a condition with a high case-fatality rate, few proven treatments have ever been proved to be effective. New treatments are urgently needed. The risk associated with new treatments might not be known in the early stages of development. If only trials with minimal risk are permitted, new treatments for many emergency conditions with high death rates will never be developed. Treatments which are specific for patients with a particular condition need to be tested in the relevant population. If only minimal risk trials are allowed, this will undermine development of new treatments.

The Clinical Trials Directive 2001/20/EC presented a major threat to emergency care research and it required a statutory instrument (Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006), five years later to correct this and allow clinical trials in emergency care to be conducted.

We must be careful not to cause more problems with the new proposals.

February 2013

1 The CRASH Trial Collaborators: Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH Trial): a randomised placebo-controlled trial. Lancet 2004;364:1321-28.

2 The CRASH-2 collaborators.The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. The Lancet 2011;377:1096-101.

3 Roberts, I, Prieto-Merino, D, Shakur, H, Chalmers, I, Nicholl, J. Effect of consent rituals on mortality in emergency care research (2011) The Lancet, 377 (9771), pp. 1071-1072

Prepared 16th September 2013