After the OHRP meetings and their evaluation of the SUPPORT controversy, the OHRP have now released what they call “Draft Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care”

The conclusion of the draft guidance starts with the following sentence, which is supposed to clarify their position.

In summary, if a research study examining standards of care includes as a purpose evaluating identified risks associated with those standards of care, the identified risks associated with the standards of care being evaluated that are different from the risks of standards of care at least some of the subjects would be exposed to outside of the research study are generally considered by OHRP to be reasonably foreseeable risks of research.

As we say, “clear as mud”.

Immediately before the conclusion they give an example which has the advantage of being somewhat clearer :

Consider this hypothetical example: It is known that treatment using surgery and radiation has a high likelihood of curing a particular form of childhood cancer, but that the radiation produces a significant risk of other cancers developing later in the child’s life. Consequently, some doctors treating children with this cancer use a smaller amount of radiation.  Both amounts of radiation are consistent with clinical care guidelines and considered to be within the standard of care. There is little evidence available comparing the outcomes of the two treatments in terms of their cure rates or the development of later cancers.  A randomized clinical trial is proposed with subjects to be assigned to treatment with the higher or lower amount of radiation to compare the effectiveness of the two treatments in curing the current cancer and how often later cancers occur.  Parents should receive and evaluate appropriate information before deciding whether to permit their child to participate in this greater-than-minimal-risk study. This decision is important and consequential. They should be told about the reasonably foreseeable risks of the study, that the treatment with the larger amount of radiation poses a possibly increased risk of cancer in later life, and that the treatment with the smaller amount of radiation poses a possibly increased risk of the original cancer not being cured.

Of course what that implies, but is not specifically stated in this draft guidance or in this example, is that you should then go on to say, the treatment with a larger amount of radiation poses a possibly increased risk of death, and treatment with a smaller amount of radiation poses a possibly increased risk of death.

In this example there is good reason to guess what the different risks might be, and to perform a study to try and find the balance between those risks might be justifiable, I might suggest though, that if those risks are already known, and can be quantified, based on prior data or experience, then the study might be questionable. Don’t you already have enough data to engage the child and family in a shared decision?

All standards of care do not pose identical risks, either in terms of the nature or the degree of the risks, and individuals often may have reasons to prefer the risks of one standard of care over the risks of another. Disclosing the reasonably foreseeable risks of research to prospective subjects recognizes the ethical obligation to give prospective subjects sufficient information to make a knowledgeable decision about whether or not to participate.

Its hard to disagree with those sentiments, but putting them into practice when you really have little idea what the balance of risks and benefits are is more of a problem. What is a reasonably foreseeable risk of the research into (to pick an example entirely at random) whether we should treat hypotension numbers with dopamine, in very preterm babies, or whether we can wait to see if a baby develops signs of end-organ hypoperfusion? Dopamine might increase the risk of IVH, or, under-perfusion of the brain might predispose to IVH, and may not be detectable clinically, and the same comment could be made about any of the common complications of prematurity. Do parents want 2 lists of all the common complications of prematurity, and a statement that they may be either increased or decreased by the therapy?

I do agree that parents must know that the whole idea of the research project is that there might be a difference in one or other of those outcomes, and, at the end of the trial, it may be that there is an advantage to being in one group or the other.

In one sense that is what we want; we don’t want to always do research with a null result. We want to have a real difference so we can advance care, and participants also, I think, want the same thing; they want to participate in research that improves future care, as long as we don’t expose them to additional risks over what they may be exposed to in any case.

If we try to apply the reasoning in the guidance to the SUPPORT trial, then I guess you would have to say, if today you were asking for consent for the trial, with the same understanding that we had when it was performed, that randomization to the low saturation group poses a possibly increased risk of adverse outcomes, including death, cerebral palsy, and developmental delay, and randomization to the high saturation group poses a possibly increased risk of adverse outcomes, including death, cerebral palsy, developmental delay and retinopathy.

(Before the trial was performed, the extra oxygen exposure in the high group was thought to maybe increase the risk of bronchopulmonary dysplasia, which is associated with more death and adverse long term outcomes. Indeed, there is more oxygen dependence at 36 weeks, by a little less than 10% in the high saturation target groups. For most of the trials it is not significant (and therefore could just be due to chance), but in the combined BOOST-2 data it is statistically significant. )

I think it must also be stated, and this is not clear I don’t think from this guidance, that when there is no known advantage of any of either arm of the study, then that should also be in the consent process, as an explanation of why the heck you would want to do the trial.

I think we should focus on the fact that the consent forms are only a small part (not necessarily the most important) of the consent process. They constitute the basic minimum, and the part which is documented.

Shouldn’t we be looking for other, adaptive, more complete ways of informing participants in trials? I think we should be developing websites for informed consent, sites where participants (or parents) can go and get whatever detail of information interests them, where the parents can find the complete protocol, all the references, or a selected group of key references, and all the justification for the trial; if they want it. If they don’t want to wade through all the detail (and they should and could decide themselves) they could give consent after a ‘bare-bones’ description of the trial. Also a parent/participant could then go back to the consent website and get more information later, whenever they wanted. If there were a web platform designed to do this, it could be relatively simple to fill the various parts with the information.