CMQ - February 2005
Correspondence between Prof, Douglas Chamberlain, CBE KSG MD HonDSc FRCP FRCA FESC FACC and Dr. Ian Jessiman KSG MA MBBChir FRCP DCH
As you know, I have serious reservations about proposals that 'invasive medical research should not be permitted in people who cannot consent' in the Mental Capacity Bill. In fact serious difficulties for research have already arisen from the legal interpretation of the UK Statutory Instrument (2004 No 1031) (Medicines for Human Use (Clinical Trials) Regulations 2004).
I offer some examples from my own field. First one can cite the recent CRASH study that examined the use of steroid drugs in acute head injury. Steroids had commonly been used in this situation based on inconclusive evidence that nevertheless seemed compelling to many. People were very surprised when the research showed that steroids in acute head injury were actually increasing mortality! It is as well that this trial was done before new regulations made it impossible! If 'invasive research' had been illegal when the trial was conceived, this treatment would still be used routinely in many centres.
Secondly, and on the other side of the coin: the use of hypothermia for patients who remain unconscious after resuscitation has recently been proved - it is already saving many lives and limiting neurological damage. It could not have become accepted without randomised trials. Two trials were reported in 2002 and changed international practice.
A third relatds to treatment of out-of-hospital sudden and unexpected cardiac arrest - a tragedy that is familiar to all. At present. the survival rate in the United Kingdom is believed, on the basis of a large audit, to be not better than 2%. Major advances are being made in this area, likely to improve markedly the dire results achieved at present. One option - supported by a very positive pilot observational study - is to use clot dissolving drugs as part of the emergency treatment to counter the activation of the clotting cascade that is activated in cardiac arrest. A major trial is under way in 11 European countries. The United Kingdom is alone in being unable to participate, despite having ethics approval, because of the way that Parliament interpreted the EU Directive through its Statutory Instrument that lacked the exclusion clauses included in the enabling legislation of most other countries.
A fourth relates to another trial for victims of cardiac arrest. Studies in Seattle and Oslo have shown that simply reversing the order of two essential components of treatment (ie routine chest compressions before any attempted defibrillation) appreciably and significantly improved survival - a finding that was surprising to many but is now becoming better understood. To change national and international guidelines, however, requires a final definitive study that we had hoped to undertake in the United Kingdom where the opportunity had seemed best. All preparation for this trial - that would have involved many ambulance services - has now been stopped because it can no longer be undertaken legally. We have missed the opportunity to influence the 2005 international guideline committee that now may or may not be persuaded by two small studies that were not designed to be definitive.
The Mental Capacity Bill could offer a solution to the unintended effects of the Satutory Instrument based on the EU Directive though it requires one very minor amendment (the word 'attributable' ). My concern, however, was for the apparent blanket opposition to ALL research on subjects with mental incapacity, which would have the effect of limiting the help we can give in many cases. The conditions and safeguards are another issue, although such safeguards have already been widely discussed and sound suggestions have been made for how they may be achieved. A blanket ban on research on this group of patients can, however, only harm those we are trying to protect.
The original European Parliament Directive 2001/20/EC does seem to require written consent in all cases. I wonder how other countries got around that? They also say that `Medicinal products for trial may be administered to all such individuals (those incapable of giving their consent) only when there are grounds for assuming that the direct benefit to the patient outweighs the risks.' (Preamble 4) In addition they refer to the use of 'legal respresentatives' (Preamble 5) whereas it has been a long standing lacuna in our law that there is no provision for anyone to act on behalf of an incapable adult. Are other countries less afraid of litigation? I think it is well recognised that of all the EU countries we are the ones who interpret their rules most strictly!
You hint at one of the major flaws in the current proposals in that there is no distinction in any of the government documents between the permanently incapacitated and those who are merely transiently incapable because of an acute remediable illness.
It looks to me as if the sort of research you are concerned with would require to be able to proceed without any formal consent. In the clot buster case, if you are merely trying a new form of treatment which could be of benefit to the patient themselves, then under emergency conditions their use could be justified by `necessity' (eg 'clot busters')? However, in the other two, there seems already to be some evidence that one of the two arms is better than the other. If they were equal there should be no problem and they would only be 'trials' at all because there would have been randomisation? To involve the (temporarily) incapable in such a trial would be to 'presume' on their generosity? Are we entitled to do that? As patients, do we have an obligation to allow such presumption?
Now, of course, the reason for the strict rules about consent for the incapable is so that the truly 'disabled' are not used as guinea pigs. Unfortunately the idea that another doctor (MCB 32 (10)(a)) or a person nominated by the researcher (MCB 32 (3)) - even though the government claim these will be strictly controlled by the guidelines of the Secretary of State - looks awfully like 'big brother' and certainly alarmed me if nobody else!
So what options are there? At one time, some years ago, I attempted to get around this problem by suggesting that, in the case of adults who had at one time had capacity, their next of kin should be able to say 'they would have consented' (ie even if it was not necessarily in their own direct best interest) - but this could not apply to those who had never been capable of giving consent. This did not meet with much approval! Even that, however, leaves a problem of how to investigate treatment for 'never capable' medical conditions where it is not necessarily in their own immediate best interests.
I was interested in the idea you mentioned earlier, of special 'authorisation' committees. I suspect they would meet with the same general suspicion as all govenment appointees. However, I understand you had had a public consultation on the thrombolysis trial in two cities and that the result was favourable, because I would think that would have been essential. Given, then, that both your consultation and the MREC had agreed, who stopped the trial?
With best wishes,
I am involved from time to time in research that is pan-European and so I do come across attitudes and practices from other countries. As you say, most countries DO want written consent at some stage. But for emergency research where informed consent cannot be obtained at the time, it is common to seek written consent afterwards for permission to use the data. In resuscitation, results being what they are, this is more often from a surviving family member than from the patient. The major trial on fibrinolysis as treatment for cardiac arrest (that is running at present in II countries) had this built into the protocol from the outset. In another recent trial with which I was involved (the international trial of vasopressin in cardiac arrest), only one individual of several hundred patients or relatives refused such consent if I recall correctly.
As you understand very well, there is a problem in relation to 'legal representatives' for trials where time is of the essence. In cardiac arrest, the attrition in survival is more than 20% per minute of delay to defibrillation from the time of collapse. It has been suggested that the healthcare professional in attendance might act as the legal representative - but personally I do not think that is appropriate. Anyway in the UK paramedics would not do it. (I have been heavily involved in the Ambulance Service locally and nationally for about 30 years and for interest I have asked quite a number of paramedics: only one has said he would). If we are to do research in cardiac arrest and similar emergencies in future in the UK, there would have to be a system of prior consent. Progress depends on such research and will not be made without it.
I do not think that the difference between countries is anything to do with litigation - though that does seem to be more common here than in many countries (in Chile that I know well, doctors do not even have indemnity insurance, there is no need!). Is it not more to do with all the scandals we have had here: Alder Hay, Bristol etc? Blown up by the tabloid press for their own ends - which is not to deny that bad things happen... And as you rightly cite, there is widespread distrust of scientists and their opinion: BSE is a valid example and the triple vaccine issue another wrong-headed tabloid-enhanced one!
I do think, Ian, that ALL research should have consent from somebody who is properly informed and is willing and able to make a proper decision. In all usual circumstances that would be the subject him or herself but this cannot be the case in the sorts of trials we have been discussing. In some countries at present there is a stipulation that the research should be likely to be of benefit to the individual subject as mentioned in paragraph one of your first letter. But that seems to most of us to oppose the principle of equipoise. Both the fibrinolytic trial and the change in the sequence of resuscitation shall have a sufficient element of equipoise - the suggestive evidence in their favour is not in any way definitive at least in terms of applicability. The change worked impressively in Oslo, but there are many important differences between systems, so that we do not know that the findings can be generalized.
I do not know for sure that a committee to give prior consent would work, but I believe it is the best option. It would be tragic not to be able to do research in the most serious of all conditions - cardiac arrest qualifies well for a place in that group. I am convinced that proper evaluation of several approaches for which there is suggestive evidence could indeed improve survival in terms of mortality and subsequent morbidity, I want to see them tested for the good of many many victims of unexpected cardiac arrest! The idea of prior consent from committees was not originally mine but came from Julian Bion who is President of the European Society of Intensive Care (he is an Intensivist in Birmingham). Membership would not be an enviable position because decisions could attract criticism, but there is strength and comfort in numbers - better a group than one person! And it provides a system of checks and balances if it were different from the ethics committee.
Our trial of fibrinolysis in cardiac arrest was not stopped. The Chairman of the ethics committee (MREC) did wonder - as you do - why it did not go ahead when ethics approval was granted and after public consultation. But it does not comply strictly with the terms of the Statutory Instrument - the DH lawyers agree that it does not. Consent was to be obtained retrospectively - as mentioned above - for permission to include the data. In that situation it would be illegal in the UK, so I was unwilling to go ahead, as was the trial sponsor (Boehringer Ingleheim). All who have considered the matter - including one of the health Ministers - agree that it is a highly desirable trial and would like to find a way to make it legal! As yet they have not found one. But I do not want the MCB to add to our problems!!
I also have a good test that I apply, but it may not commend itself to others. It is a question of whether or not one would be willing to see a family member included in a trial. The answer is by no means always affirmative which does suggest that carefully considered change is appropriate!
all good wishes,
If we seek to define what is needed, would the following do:
"authorisation for an incapable person to take part in a trial to investigate/compare treatment(s) for an acute condition from which they are suffering at the time (one effect of which has been to render them incapable of giving consent) and for which treatment is required without delay"?
(The part between ( ) only applies to those who have at one time had capacity to give consent). We cannot, of course, rely on claiming that it will be in their own best interests. I do not think, ethically speaking, that retrospective consent for the use of data really covers the situation at all.
I agree that retrospective consent does not cover the situation adequately. This, however, has been the practice in parts of Continental Europe for several years. We need something better that will permit ethical and morally acceptable emergency research in temporarily incapacitated individuals.
To turn away from facing our present unsatisfactory results seems to me not an ethical approach when there is good reason to believe we can and should do so much better in caring for those who are helpless.
Draft Proposal for Legislation & Consent by Dr. Jessiman
Therapeutic research shall be where the treatment(s) or procedure(s) proposed are intended to be of clinical benefit to the subject. Non-therapeutic research shall be where the treatment(s) or procedure(s) proposed are not intended to be of clinical benefit to the subject.
Therapeutic research may proceed without formal consent when the nature of the condition is such that it is impossible to obtain such consent and where a delay is considered not to be in the patient's best interests. In such a case retrospective explanation must be given and consent obtained, on the part of the subject if he or she regains competence, to the use of the data.
Invasive non-therapeutic research must not be permitted in any subject without the subject's prior informed consent.
It has been pointed out that this does not address the question of the permissibility of non-invasive non-therapeutic research (questionnaires or use of already collected data) even in incompetent patients.