The DHHS Office for Human Research Protections has just issued a ridiculous ruling. According to them the consent forms for SUPPORT were not sufficiently clear about risks of blindness in the higher oxygen group, and the risks of death in the lower oxygen group.
To give a little background the SUPPORT trial was a ground-breaking trial, the arm of the study which the OHRP are concerned about was a randomized comparison of 2 different target ranges of oxygen. The higher oxygen target was between 91 and 95% and the lower was between 85 and 89%. The study found unexpectedly that there was a higher mortality in the lower saturation group, and confirmed what was suspected, but not known, that having very low saturations gave less retinopathy than having modestly low saturations. Healthy babies at sea level have saturations over 95% so even the ‘high’ saturation level was already lower than ‘normal’. There was no good evidence how much lower than normal we should keep the babies saturations.
We must remember that the previous trials of oxygen therapy that showed the harm to the eyes of too much oxygen were in no way comparable to SUPPORT. There were 3 performed in the 50s, without any way to continuously monitor the babies oxygen concentration. As one example the study of Patz, 1954 compared the Experimental group (restricted oxygen) in which infants received oxygen only for clinical indications, and to a maximum FiO2 of 0.4. The range of duration of oxygen in this group was 1 day – 2 weeks. The comparison was the Control group (liberal oxygen): infants were placed in supplemental oxygen of 60-70% for 4-7 weeks, then weaned over one week. (Quoted from Lisa Askie’s Cochrane review).
So in one group the maximum FiO2 was 40% even if the baby was blue and bradycardic, in the other group the babies got over 60% oxygen whether they needed it or not! Despite these features, there was no difference in mortality.
The only other RCT data we had before SUPPORT were 2 small trials (from 1968 and 1972) that did not measure RoP, were mostly concerned with mortality and with resolution of lung disease. These two trials used intermittent blood oxygen monitoring, (not used in the 3 trials from the 50’s) and found no difference in mortality.
The other factor to remember is that prior to the results of SUPPORT there was a very wide variability of saturation targets in use in different NICUs across the country. Some were allowing saturations as low as 82-85%, others did not let the saturations go below 94%. So a baby in an NICU in the USA could be exposed to a saturation that was similar to the 2 ranges tested, or below or above the ranges tested in this trial.
So what did the NICHD network do? They did the most ethically appropriate thing, and launched a randomized trial. The trial protocol was developed and approved by the network centers, it was funded by the network, and was sent to ethics review committees at 18 institutions who approved the trial. Ethics review committees, IRBs usually have little to say about the scientific basis for a trial that has already been peer-reviewed and received funding. They mostly concentrate on the consent form to ensure that it is clear, understandable and describes any specific risks to participants.
The results of the trial as I mentioned were a little surprising, there was more mortality in the low oxygen group. The high oxygen group had more retinopathy, and more treatment for retinopathy with laser, but no difference in blindness.
So what did the OHRP say? First of all that the babies in the study were exposed to increased risk compared to babies treated according to ‘standard care’. They state the following
‘According to the study design, on average, infants assigned to the upper range received more oxygen than average infants receiving standard care, and infants assigned to the lower range received less.’
This is totally ridiculous, and clearly shows that the assessors were incompetent. You can’t average all the oxygen exposure of all the babies in the 2 groups, and then compare to some non-existent standard care. There was no standard of care, which the OHRP do not seem to be aware of. A child outside of the trial could well have had either of these target ranges, or ranges even more variable.
They also state the following
‘It would have been appropriate for the consent form to explain (i) that the study involves substantial risks, and that there is significant evidence from past research indicating that the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies; (ii) that by participating in this study, the level of oxygen an infant receives would in many instances be changed from what they would have otherwise received, though it is not possible to predict what that change will be; (iii) that some infants would receive more oxygen than they otherwise would have, in which case, if the researchers are correct in how they suppose oxygen affects eye development, those infants have a greater risk of going blind; and (iv) that the level of oxygen being provided to some infants, compared to the level they would have received had they not participated, could increase the risk of brain injury or death.’
This again shows the lack of insight of the OHRP into these issues. Yes, being a very preterm baby in an NICU carries significant risks. We now know and did not know before the study, that having a saturation just below 90% increases mortality, compared to just above 90%. We now know that having a saturation in the low 90’s increases RoP compared to the high 80’s but that doesn’t increase blindness.
The OHRP thinks we should have know that before doing the study and included it in the consent forms. If we had known it we would not have done the study. (I say we, as I was involved in the Canadian version of this trial).
The OHRP is using an impossible standard. It is of note that they say nothing about the other arm of this trial which compared 2 other interventions, early CPAP to immediate intubation for surfactant. As that trial did not have a significant difference in the outcomes, they say nothing about the consent for that arm, but the potential differences were at least as great as for the O2 comparison. The only reason they have focused on the O2 is that there was a difference in the outcomes. So presumably someone complained and the OHRP don’t like the idea that the network funded a trial which had more deaths in one group. They have to realize that that is going to be a risk in funding research in critical populations, and if they don’t like it we will just have to stop doing research.
This is already a longer post than my usual, so I will take a break, but there is even more stupidity to come in this ruling. Which is now being repeated, including in an editorial in the New York Times.
Neonatal Research 