This hugely important trial- PARAMEDIC2- has come in for hostile criticism from some bioethicists.

The only ethical problem I have with this trial is that it wasn’t done years ago.

I’ve written about it for the Telegraph, and as a column in the BMJ.

There wasn’t room to go through each point by point the criticisms made by Ruth and Lindsay Stirton, so I am going to do so here.

“Consent, then.  There are two aspects of a consent process: information provision and decision-making.  It’s worth saying that it’s absolutely standard in emergency research not to seek consent from potential participants if doing so will delay the start of treatment.  It would be abhorrent to delay treatment where time was of the essence in order for a participant to read a 30 page information sheet and sign a consent form.  It’s equally problematic to try to seek consent from a relative, or legal representative, as required by Schedule 1, part 5 of the Medicines for Human Use (Clinical Trials) Regulations 2004, since they would have to read the same form.  Delaying the onset of treatment for any reason and reducing the chances of survival is unethical.  So, explicit opt-in consent is not possible in this sort of emergency research; and this leaves us with opt-out consent.  Now, opt-out consent is ethically controversial: it should be a last resort, and if it is resorted to then the details have to be absolutely nailed down.  In addition, it has to be areal opt out system.

According to Jerry Nolan (Newsnight, 13/8/14) the process is still being worked out.  Butthe details we have are that this will be done by

including information about the trial on Ambulance Trust and University Websites, Ambulance Service Public Newsletters, Posters / information leaflets, discussion at public meetings, Annual reports etc.

and people will opt out in some way.  Now, we don’t know about you, but neither of us sit there every evening and think, “Ooh, I might have a cardiac arrest this week, I’ll just check the ambulance service website to see if there’s some research happening that I might need to opt out of.”  If people are not going to think proactively enough to seek the information then it is a fiction to say that this is an opt out consent process.  In order for opt out consent to be real, potential participants must be properly informed and there must be a real opportunity to opt out.  At the very least this requires active information provision.  This trial needs to be in the public consciousness in the area in which it is happening.  Every household needs to be leafleted or mailshot; there needs to be posters in all GP surgeries, pharmacies, community centres, churches, local shopping centres… in fact, anywhere where people congregate; there should be advertisements on the local radio, and discussions in local TV news and in the local print media.  What we are saying is that there needs to be an information storm, and depending on the ethnic make-up of the area, this information needs to be available in a variety of languages.  People in this part of the country should not be able to go anywhere without seeing some information about the trial.  Part of that information should be about how to make a decision.  If the information provision is right and is exhaustive in this way then it is legitimate to say that anyone who has not opted out has consented to participate.  Anything less than this, and it’s a complete fiction to say that there has been consent.”

This is a serious charge.  Stirton and Stirton are essentially saying that unless “People in this part of the country should not be able to go anywhere without seeing some information about the trial” there can be no truly informed consent.

This is never going to be possible in the real world . The standard is impossibly high. This means that trials like PARAMEDIC2 would never get done. It would mean that the CRASH trial wouldn’t have been done (see link to Independent article for links to full details), and we would still be killing people by giving steroids in head injury because we thought they were helpful rather than what they are – harmful.

There are two paradoxes. First, Stirton and Stirton make no stipulation on people in the rest of the country, outwith the trial. For equity, and because the trial is testing adrenaline whose benefits are uncertain, surely they should also be insisting on publicity everywhere else in the UK to tell people they are not part of the trial, and that they may receive adrenaline in a cardiac arrest – which may harm them. Everyone else should be given the chance to fill in a form and say they would rather not have adrenaline. This would be the ideal and it would also make sense. (Overlooking of course,  the practical impossibility.) But it’s not what Stirton and Stirton are calling for. They are creating a double standard – people in one part of the country get information that makes it seem that they are more at’ risk’ from a trial –  when in fact they may be at less risk. The second paradox is that it becomes so difficult (by their criteria) to do hugely important trials that it’s easier to continue to use treatments which may in fact be harmful. This is not in patients best interests. It is ethically bad.

”  There is an increasing public awareness of just how much can be done to us without our knowledge and consequently where the public could have been told there is outcry when they are not.  There is no doubt at all that the cardiac arrest of a relative is a very difficult thing to experience.  But trust in the health service is essential, and there is nothing that breaks trust more than learning after the fact that someone could have informed you about something, but they chose not to.  Why not give ambulances a stack of short (one page) summary information sheets with contacts for further details to hand out to the relatives of any participant in the trial?  The sheet should include a very brief explanation of the purpose of the study, what was done to the participants, who reviewed the study and contact details, which could include a website with a fuller information sheet, for further information.  Yes, it will be painful and difficult, and it will cause distress.  But it would be nothing like as much distress as discovering weeks after that a relative was experimented on without anyone’s knowledge.”

I find the use of  Stirton and Stirton’s language pejorative – ‘experimented on’. Again, following their logic, and in order to provide equity, every single person who has a cardiac arrest outwith this trial should also be told that they received a treatment that might actually be harmful. I’m all for transparency, and I wouldn’t be unhappy with relatives having information that their relative was in a trial, but I think there is more than one right answer. The ethics committee (which included lay people) thought that not routinely informing people whose relative died after a cardiac arrest was the right answer. Language is important. I suspect  that some  people who read the Stirton and Stirton blog will be distressed to find their relative has been ‘experimented’ on, as Stirton and Stirton chose to describe it. I suspect that other people who are given a fair explanation of why the trial was necessary and important will be glad their relative had a chance of receiving the most effective therapy. And we should of course, by Stirton and Stirtons’ logic, tell all other relatives of people who died after cardiac arrest that their treatment might have harmed.

And then there is trust. Trust in the health services are essential, which is why the most trustworthy thing to do is to say: we don’t know whether adrenaline in cardiac arrest is useful or harmful, and we need to do a fair test. That’s trustworthy. Continuing to do something that may be harmful just because it’s easier not to test it – that’s untrustworthy behaviour.

“Given the obvious difficulties, the case for a RCT needs to be justified in terms of the incremental benefits of double-blind randomisation over the next-best research design.  When Ruth appeared on Newsnight to discuss this trial, she  suggested doing a mass observation study in the UK to get some reliable evidence that adrenaline is harmful to cardiac arrest patients.  Such a study might proceed by informing those present with cardiac arrest patients of the known risks of adrenaline and asking whether they wanted adrenaline to be given.  Or alternatively, given that there is concern about the harm that might arise from adrenaline, there must be a body of paramedics who are not supportive of giving adrenaline, as well as a body of paramedics who are.  It would be possible to create the comparator groups on this basis, rather than rather than using randomisation.”

This is absurd. As the documentation in the trial website already makes clear (and I’ve referred to this and other work in the BMJ column) observational studies have already been done and make it clear. The use of adrenaline might be harmful, or it might not –  it is of uncertain benefit. The patient is in cardiac arrest. They are technically dead. Stirton and Stirton claim that this is a good time to ask for informed consent from a relative present. First, it can take  10 minutes to try and establish whether the adult present with a patient is next of kin and that the patient has nominated them as proxy; truly informed consent is not reached while their relative has no heartbeat and is in the middle of having CPR administered / being defibrillated. (Is it even ethical to ask for consent for a trial in these circumstances? Would the circumstances allow people to make informed choices? What is the opportunity cost of a paramedic seeking consent rather than treating the patient? ) Their second idea rests of the idea that paramedics are currently doing different things  in cardiac arrests/or should be able to do different things in cardiac arrest. It implies that it’s okay for professionals to make clinical decisions, which their patients are not privy to knowing about, on the basis that they are personally ‘not supportive’ of adrenaline. But cardiac arrests run to tightly governed protocols. Everyone is doing the same. Giving adrenaline is part of that protocol.  Stirton and Stirton seem to think that it’s okay for paramedics to give adrenaline or not based on their personal bias and as part of an observational trial. I think this is bizarre.

“How much would be lost by an approach such as this, or by whatever other non-randomised research design the researchers thought would best capture the potential neurological effects of adrenaline?  Certainly something is lost: the research might be biased because (for example) adrenaline was opted for in the most serious cases, or because medical personnel (again, perhaps subconsciously) acted differently towards patients in other ways, or because patients who received adrenaline believed they had better (or worse) treatment and this affected their recovery.”

Again, this fails to understand the tight guidelines and audit that goes on with cardiac arrest treatment as it stands. An RCT is needed because at the moment everyone is doing the same thing with adrenaline in cardiac arrest. We need a control group of people who don’t get adrenaline to compare them to people who do.

“Then again, this is the sort of problem that social scientists (who rarely have the luxury of the level of control over the research context to conduct RCTs) face all the time. And as a result they have developed techniques to deal with just these sort of problems.  James Heckman won a Nobel Prize in Economics for “his development of theory and methods for analyzing selective samples”.  So-called “Heckman models” have become an accepted way of handling the problem of selection bias in economics and throughout the social sciences.  Propensity score matching is another common technique that social scientists use to control for the effect of factors which might confound an estimate of a treatment effect.”

Are these methods as effective as a properly conducted RCT?  Probably not, but perhaps they come close.  Properly used, we could think of them as a “silver standard”, providing pretty reliable means for the analysis of non-randomised data.  Ultimately, there is a balancing act to be done.  The reliability of the research must be balanced against the ethical concerns associated with collecting the data in a particular way.  In the case of adrenaline for the treatment of cardiac arrest, the silver standard – a mass observation study, properly analysed – seems to be more than adequate.  Unless it can be shown that the incremental (and not the total) benefits of using the gold standard – the RCT – are substantial, then the significant ethical issues highlighted above point towards the silver standard as being the more appropriate methodology.

Again, observational studies have already been done and have suggested that adrenaline may not help and may be harmful. These studies are not powerful enough to say whether adrenaline is useful or harmful. That’s why an RCT is needed. Currently use of adrenaline is consistent in the same situations across the country. I’ve looked on Pubmed for any trials using Heckman models in clinical trials and can’t find any. Suggesting a poorer or unproven way to work out whether adrenaline is useful or harmful seems to me to be in itself harmful – capable of delaying further this important trial. I don’t see evidence that social science methodology will be robust in sorting out whether adrenaline is useful or harmful in cardiac arrest.

Furthermore, Ruth Stirton went onto Newsnight to raise her concerns about the trial.  She said

” I think that because these patients are so vulnerable I think we ‘Might’ ‘Not’ ‘Know’ or equipoise is not strong enough I think we need to be sure or know or have a very very significant hunch that it’s actually harmful because so many of them die why not just give them everything even if it MIGHT benefit ”

This is the point and where I think there is such a massive, ethical misunderstanding. There is not a ‘hunch’ , there are serial animal and observational trials that show adrenaline might be harmful, not helpful. Ruth Stirton seems to think it is more ethical to give a patient in cardiac arrest a drug (adrenaline) which might be harmful because it might also be helpful.

This is the whole point of a trial. The CRASH trial was very similar. We could easily still be giving steroids in head injury, and killing people because of them, had we followed the same philosophy that they ‘might’ work.

I’d like Ruth and Lindsay Stirton to explain whether they would like to receive adrenaline or not in cardiac arrest, and to make the basis for their preferences explicit.

For further information about why fair tests of treatments are needed, see www.testingtreatments.org