The US Department of Health and Human Services held a public meeting about consent issues for research on August the 28th, largely as a result of the controversy surrounding SUPPORT. It was called ‘Matters Related to Protection of Human Subjects and Research Considering Standard of Care Interventions’.
It was streamed live on the internet, but I only got to watch an hour or so, I suppose that much of it will be available in various forms in the future, hopefully all in one place on the HHS website.
Some of the presentations are already available elsewhere, for example the presentation by 2 people who call themselves ‘historians of medicine and human subjects’ research’. They are Alice Dreger, PhD, Professor of Medial Humanities and Bioethics, Northwestern University, Chicago, IL and Susan M. Reverby, PhD Professor in the History of Ideas and Professor of Women’s and Gender Studies at Wellesley College, MA.
The document is apparently a written version of their testimony to the panel set up by the HHS. It is a great example of the false dichotomy between clinical care and research; a lack of understanding of standard of care; a series of pontifications about acute care neonatology which only show they haven’t got a clue; and a misunderstanding of risk.
Drs Dreger and Reverby commence by claiming that doctors are being pushed into performing unethical research because of the pressure to publish, by the emphasis placed on academic productivity, and, even though they pay lip service to the idea that we may be motivated by a beneficent desire to do good, apparently that is being perverted by today’s academic climate. They of course give no data to support these offensive claims. There is of course also no acknowledgement that professional ethicists wholly supported by university salaries have academic pressure effectively coercing them into making scurrilous accusations about medical ethical lapses, nor that their livelihoods are threatened by physicians who have re-appropriated clinical ethics, so it is really good for their career prospects if they can claim that doctors are unethical and can’t be allowed to police themselves. (And in fact we don’t, IRBs all have non-medical and lay members, and more and more granting agencies require participation from families).
I will quote several illuminating passages:
As the OHRP found, parents should have been told that randomization into restricted trial arms in this study could potentially increase (or decrease) the odds that their babies would suffer death and particular impairments. The protocol and publications show that the study was designed to determine just those risks. Consent was so poorly handled in this trial, OHRP should have required—and should still require—that the involved institutions now inform parents what they should have been told before enrollment—that being in the SUPPORT study was likely to have changed how their baby was treated in the neonatal intensive care unit (NICU) and might have increased the risk of death and disability.
Of course, most of that is not true, parents were informed that this was study to examine different oxygen saturation targets, and being in the study did not increase risks of death or disability. There was, I re-iterate, no difference in disability between the groups, although a potential difference was one of the reasons the study was done, there was no reason to believe that the 1300 babies enrolled in the trial would have more deaths or disability than 1300 similar babies treated outside of the trial. There still is no reason to believe that mortality was higher for the group as a whole, it is likely that as a group they benefited.
Parents were of course told that being in the trial might change how their baby was treated, that is what the consent process is all about, that is what clinical trials such as this one are all about; not continuing to do something when we are unsure what to do, but randomly comparing alternatives, which might not have been what the doctor would otherwise have done, but would have been acceptable alternatives.
Dreger and Reverby are very agitated about the use of the term Standard of Care. They believe that the use of this term is ‘most egregious’, seemingly being ‘designed to reassure parents who might enroll their very premature babies that it would have made no real difference whether or not they enrolled’. It was of course a statement of fact. Oxygen saturation targets differed greatly according to different hospital protocols, none of which were based on good evidence regarding clinical outcomes, and therefore were within usual acceptable standards of care. The ranges tested in SUPPORT were less extreme than some in active use at the time.
Standard of Care is sometimes used as a legalistic term (the Standard of Care for a ruptured appendix is immediate surgery, so you are negligent if you didn’t follow the Standard) but often in medicine there is no such Standard, and a wide range of approaches are within current acceptable limits, and can be considered to be standard of care. That is how the term was used here, and it is accurate, both oxygen saturation ranges were within the limits of acceptable contemporary practice, they were all within ‘standard of care’.
If the best clinical judgment in NICUs was not evidence-based because we lacked the data the SUPPORT study was designed to generate, then the parents needed to be told that.
But they were told that! They were told: we don’t know which saturation range is best, that is why we are doing this study. In fact parents going into the trial were better informed than those who were not asked for consent. How many parents outside of the trial were told that the use of oxygen was extremely variable around the world, that the limits chosen in the unit where their baby would be treated were entirely arbitrary, and the saturation target limits chosen by their hospital might increase the risk of retinopathy or of disability?
Even if the same range of risks existed in ordinary NICU care, parents needed to understand their baby might be subject to a different subset of risk odds, and ultimately a different set of harms, via enrollment into this randomized clinical trial (RCT). The consent forms for the SUPPORT trial should have explained what care outside the trial would look like, and what risks were associated with that care.
I think you might expect that I don’t agree with this. at all.
The purpose of consent is to ensure that reasonably foreseeable risks of the research are explained. If the same range of risks exists in ordinary NICU care then to exaggerate the risks of being in the study by pretending that those risks are due to the research is untruthful. To try to guess what ‘subset of risk odds’ and what ‘different set of harms’ that parents need to understand is usually impossible until after the research is done.
We are also alarmed that pregnant women and their partners were asked to consider enrollment of their babies in this study just at the moment when those women were facing the very premature birth of their child. It is not clear to us that any mother, or her partner, in such a situation could have the mental wherewithal to seriously consider enrollment of their extremely premature baby in a major trial, particularly one that might change risks of death or disability. We hasten to remind those here that, much as we would dearly love data on certain interventions, there are sometimes trials that simply cannot be done ethically.
Yes of course parents are stressed when their baby is in, or likely to be admitted to, intensive care, but we simply cannot accept the idea that there are some issues that cannot be investigated ethically as a result of their stress. As a group of people who talk to stressed parents every day of our professional lives (except when we are writing blogs) neonatologists are much more aware of this than most academic ethical thinkers. I have spoken to parents at 2 am who have just had a baby admitted to the NICU, and yes you can get a valid research consent in those circumstances. If the alternative is to give up, then I refuse that alternative.
we also must insist that discussing the SUPPORT trial as a case of so-called “standard of care research” is just plain wrong. Several of the experimental interventions in the SUPPORT study did not represent commonly used clinical interventions. For example, we are unaware of any NICU that would carefully seek to maintain a very premature baby at an oxygen saturation level of 85-89% regardless of the baby’s clinical status, as happened to babies in one arm of the oxygen saturation intervention. We are unaware of any NICU that would regularly withhold surfactant from very premature babies. Surfactant is a treatment widely believed to make an enormous difference in survivability of extreme prematurity. We are also unaware of NICUs where practitioners would, outside of research, be blinded as to the real oxygen saturation levels of children they are treating.
Unlike these authors, the SUPPORT investigators actually knew what goes on in an NICU. And yes, before the SUPPORT trial was published there were (and maybe there still are) NICUs that maintained a babies saturation in that range for as long as they needed oxygen, regardless of other issues.
The statement about surfactant is perhaps the most revealing of the authors’ ignorance. In this trial surfactant was either given routinely after intubation in the delivery room or according to a different protocol which tried to avoid intubation until it was clear that the individual baby needed it. ‘Withholding life-saving surfactant’ sounds terrible doesn’t it, especially if you are totally uninformed; the babies in the restricted surfactant group DID BETTER. There was a 9% reduction in the rate of BPD which was almost significant. Infants who had their ‘life-saving surfactant’ withheld less frequently required intubation or postnatal corticosteroids for BPD (P<0.001), and required fewer days of mechanical ventilation (P = 0.03), so they were better off if they were in the ‘surfactant withholding’ arm of the trial. Babies benefit from surfactant if they need it, but exactly when you can be sure they need it still isn’t clear, even after SUPPORT. This landmark study showed that if you don’t intubate for surfactant until the baby reaches 50% oxygen, then they do better than giving them all ‘life-saving surfactant’.
As I said, I think this statement is very revealing, it really shows how little the authors know about neonatal care, but they still feel qualified to malign the doctors who performed this trial. ‘We are unaware of any NICU that would regularly withhold surfactant from very premature babies’. That could only have written by someone who has no conception of what the study was about, and never bothered to ask a neonatologist.
The statement about the masking of the saturation monitors is just bonkers. If the 2 approaches are clinically acceptable then to compare them in a masked fashion just makes the study more reliable. Of course you don’t do that outside of a trial, but it doesn’t make the trial non ‘standard of care’.
The authors object to the idea that health care should become
a so-called “learning health care system,” in which
essentially every patient becomes a subject (as this) requires a system where the line between patient and research subject necessarily becomes blurry. We strongly object to this idea.
Well sorry, the line is already blurry. We must continually learn about what we are doing. There are many ways in which evaluation of patient outcomes are used to try and improve the care that we give. Even the most unreliable reasons for changing how we deliver care (such as what happened to the last patient you treated) are based on data from other patients. The idea of building learning health care systems is to make that process reliable, and to benefit everybody, including current patients. If I analyze anonymized retrospective data to see if one hospital has better outcomes than another, then all of the patients whose data I look at are contributing to that process. A process which, in that situation, is without any risk to the individual, but which is limited, it can only give indications, and potential questions to answer.
Formally comparing current treatment approaches in randomized trials still treats all the patients as patients, who should, and in my experience do, receive compassionate thoughtful care. In fact, I would like to restate what I said above, there is no line, even a blurry one, between being a patient and a research subject, you can be both.
thanks for your engagement in this odd story. I believe it’s crucial that experts in the field of neonatology go public and start sharing their opinion against these ideas of some academic ethical thinkers. Otherwise there is a risk that neonatal research is going down just because of exteme barriers to do reasonable research.
Neonatologist from Switzerland
Dear Keith, I have been very interested in this debate, as I am undertaking a clinical doctorate and am sure such issues will become more prominent. What would have happened to the likes of the TOBY trial and cooling in this instance , where researchers faced similar issues of standard of care/consent immediately after birth, and which has had a huge impact to our patients.
I think some of the consent issues are similar, and others are different, when studying new innovations in care, such as cooling for asphyxia. Preliminary studies and data from other research, with animals for example, did give an idea of what complications might be expected in the cooled babies. We knew very well the kind of complications that asphyxiated babies experience, and did not know which of them would be better or worse in the babies who got randomized to cooling. Because cooling babies was an innovation, and not in general use anywhere then any complications of cooling could indeed by ascribed to the research. So to enumerate the various reasonably foreseeable risks would mean that the forms should have mentioned blood clotting abnormalities, and possible effects on heart function.
I think the overall purpose of getting consent is the same for trials of innovation and for trials comparing treatments within standard of care, but the question is which risks should be considered the risks of the research. That is where the differences of opinion lie.
Good luck with the doctorate
All of the presentations at the public meeting are now online as a youtube playlist!