The Office for Human Research Protections Caught 23 Universities and Medical Institutions in Producing Unethical Research Consent Protocols — Regarding Variably Oxygenating Preterm Infants — an Example of What Can Go Wrong, when Medical Professionals Don’t Think Critically — and Continuing Proof that the Institutional Review Board System that Is Supposed to Prevent these Abuses Doesn’t Work

11 April 2013

The point

The moral of this essay is that patients (and their guardians) should be aware that medical institutions often get so caught up in their self-interested enthusiasms, that they forget the range of nuances involved in “patient first” principles.

What follows stands as a relatively typical example of one of the more subtle failures of our medical system and the institutional review boards that purportedly oversee medical research ethics.

What happened — parents were not told about the risks that their preterm infants were taking on, while participating in an experiment revolving around providing different levels of supplemental oxygen

Sabrina Tavernise, writing for the New York Times, summed the situation admirably:

A federal agency has found that a number of prestigious universities failed to tell more than a thousand families in a government-financed study of oxygen levels for extremely premature babies that the risks could include increased chances of blindness or death.

But it isn’t just black and white — and that’s the corollary point

Critical, holistic thinking is not one of the medical establishment’s obvious strengths. This preterm infant case involves the kind of analytical and ethical subtleties that medical professionals and patients often miss.

It was not bad faith that led these 23 institutions to screw up their informed consent forms. It was their apparent inability to:

(a) appropriately sift through what they already knew in regard to oxygenating preterm infants

and

(b) extract out those data pieces that reasonable, conscientious parents would also want to have known, before subjecting their infants to the proposed research process.

What is informed consent?

Informed consent means that you have to be granted:

(a) an opportunity to make up your mind about whether to undergo some process or agreement,

(b) based on all the situation’s pertinent facts and reasonable projections.

Writer Kendra Cherry (accurately) explains that:

Informed consent is a legal procedure to ensure that a patient, client, and research participants are aware of all the potential risks and costs involved in a treatment or procedure.

The elements of informed consent include informing the client of the nature of the treatment, possible alternative treatments, and the potential risks and benefits of the treatment.

In order for informed consent to be considered valid, the client must be competent and the consent should be given voluntarily.

Why is informed consent important?

We do not want medical providers doing things to us (or our children) that we don’t understand and may want to avoid.

For example — from legal, medical, and ethical points of view — the parents of the babies, who were recruited into the preterm infant research process, had the right to know what risks they were taking by participating.

Administrative procedure — how the feds got involved

The Department of Health and Human Services runs ethics checks on medical experiments conducted with federal money. These reviews are conducted by its Office for Human Research Protections.

The Office decided to take a look at the informed consent paperwork that had been used in an experiment that was initially published in the New England Journal of Medicine in 2010:

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Target Ranges of Oxygen Saturation in Extremely Preterm Infants, New England Journal of Medicine [NEJM] 362:1959-1969, DOI: 10.1056/NEJMoa0911781 (27 May 2010)

In a letter to the University of Alabama at Birmingham, a member of the institutional research team, the Office concluded that the informed consent forms used to recruit infants into the SUPPORT research design were ethically inadequate.

About the experiment itself

The details of this experiment are important because they underlie the analytical complexity of the consent process.

Keep in mind that the medical institutions involved evidently:

(i) got so fixated on finding analytically sound scientific answers to their research questions,

(ii) that they overlooked equally obvious ethical problems with their consent forms.

On the medical side, the research team wanted to find out whether they were right in thinking that avoiding giving high levels of oxygen supplementation to preterm infants would reduce retinal damage, as well as mortality.

In somewhat obtuse language, they wrote afterward that:

We conducted the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT), a controlled, multicenter trial with a 2-by-2 factorial design, to compare two target levels of oxygen saturation and two ventilation approaches [:]

continuous positive airway pressure [CPAP] initiated in the delivery room with a protocol-driven strategy of limited ventilation

vs.

intratracheal administration of surfactant with a protocol-driven strategy of conventional ventilation.

The oxygen-saturation component of the trial tested the hypothesis that [:]

a lower target range of oxygen saturation (85 to 89%),

as compared with

a higher target range (91 to 95%),

would reduce the incidence of the composite outcome of severe retinopathy of prematurity or death among infants who were born between 24 weeks 0 days of gestation and 27 weeks 6 days of gestation.

If you are a critical reader — you will have noticed that there is already a consent problem with this thinking

If the team was correct in anticipating that one group of randomly chosen babies might do better under one therapeutic protocol than another, why wouldn’t the consent form say so?

What the deficient consent forms said

Parents did not receive the medical background information that the research team had used to formulate its hypothesis regarding who would benefit from the high and low oxygen therapies.

The template from which all 23 institutions’ consent forms were generated said only:

Participation in this study may involve some added risks or discomforts. Because all of the treatments proposed in this study are standard of care, there is no predictable increase in risk for your baby.

Infants randomized to the CPAP [continuous positive airway pressure] group may, at some point in their care, require intubation and assisted ventilation (methods to help them breathe).

If the attending physician deems this necessary, participation in the study will not affect this decision.

Some unknown risks may be learned during the study. If these occur, you will be informed by the study personnel.

The only other risk of this study is the risk to confidentiality.

Every effort will be made to keep your child’s medical record confidential. There will be no name or other patient identification in any study report that may be published after the study is completed. Measures taken to protect you and your baby’s identity are described in the confidentiality section of this document.

Letter from Lisa R. Buchanan, Compliance Oversight Coordinator, Office for Human Research Protections, to Richard B. Marchase, V.P. for Research & Economic Development, University of Alabama at Birmingham, Human Research Protections under Federalwide Assurance (FWA) 5960, Office of Human Research Protections – Department of Health & Human Services (07 March 2013) (at page 6) (paragraphs split)

Keep that “standard of care” passage in mind. It is one of the foundations for the Government’s objection to the research institutions’ informed consent forms.

Why the Office of Human Research Protections objected to the consent forms

The Office pointed out that the consent forms did not refer to the results of previous research on oxygen levels’ connection to retinopathy or mortality. Nor did it address the potential differences between being randomized into the high or low oxygen experimental groups.

The research team had not given the parents any hints that outcomes might be different, depending on which experimental group the infant was in, or whether the baby participated at all.

In other words, there was good preliminary reason to think that the babies who had been left completely alone — meaning that they were not recruited into the experiment — would have fared better than some of the babies in either experimental group.

This is an example of why numbers, meaning statistics, are important in both science and ethics.

What was a key problem with the consent forms?

The researchers neglected to consider the implications of their experimental design, as it compared to the medical “standard of care”.

A competent medical attorney would not have missed what the Office of Human Research Protections also picked up — both the high and low oxygen groups noticeably departed from what the University of Alabama (Birmingham) had described as the prevailing standard of care.

This deviation was apparently done so that the research team would be able to detect statistically valid differences in retinopathy, mortality, and neurological outcomes between the 85-89 percent and 91-95 percent oxygen saturation levels.

But, in picking the high and low fringes of prevailing oxygen supplementation practice:

[O]n 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.

© 2013 Letter from Lisa R. Buchanan, Compliance Oversight Coordinator, Office for Human Research Protections, to Richard B. Marchase, V.P. for Research & Economic Development, University of Alabama at Birmingham, Human Research Protections under Federalwide Assurance (FWA) 5960, Office of Human Research Protections – Department of Health & Human Services (07 March 2013) (at page 9) (paragraph split and underlines added)

The standard of care was automatically violated by the structure of the experimental protocol

If we plot the distribution of oxygen delivery for “standard of care” preterm babies — as the University of Alabama at Birmingham had allegedly described it — it would distribute in a Gaussian (bell-shaped) curve.

The majority of babies in the plot would be receiving a middle/median/average amount of oxygen — just as the Office of Human Protections maintains in its letter.

If we visualize the curve in our minds, we see it would be mathematically impossible for the research team to emulate the standard of care by picking only the oxygen saturation levels represented by the extreme ends of the distribution:

Fringe “oxygen sats” — in the real world — go to the fewest babies.

Treatments that go to the fewest patients — in a population of quasi-identical peers —are the antithesis of the standard of care.

In contrast, the “standard” represents (a) the most populated middle of the bell-shaped curve, (b) as treated by a practitioner of average competence.

Consequently, at the outset, the research team’s deviation from the standard of care would have been legally and morally fatal, unless parents were told about it beforehand. Their sick kids were being subjected to one of two treatments, neither of which fell under the protective umbrella of being performed the way medicine has come to think of as effective.

The Office of Human Research Protections concluded that the parents should have been told that:

the risks and benefits of being in the two experimental oxygen groups deviated from the standard of care,

retinopathy was more likely to occur in the high oxygen group,

and less likely in the lower oxygen group.

The consent forms should have explained that:

(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.

Accordingly, we determine that the informed consent document for this trial failed to adequately inform parents of the reasonably foreseeable risks and discomforts of research participation.

The results of the experiment supported the Office’s concerns

The Office’s letter to the University of Alabama at Birmingham pointed to what the SUPPORT study eventually discovered:

The results of the SUPPORT study were published in the New England Journal of Medicine in 2010. [here]

The rate of severe ROP [retinopathy of prematurity] among the infants who survived was significantly different between the low and high oxygen groups.

Among the infants who were treated with low oxygen, only 41 out of 475 developed severe ROP, or 8.6%.

In the high oxygen arm, more than double that percentage of infants developed severe eye disease: 91 out of 509, for a rate of 17.9%.

The difference between these two groups was highly significant, with a P value less than 0.001.

On the other hand, the low oxygen group had a higher percentage of deaths before discharge. 130 out of the 654 infants in that group died (19.9%), in comparison to the 107 out of 662 infants who died in the high oxygen group (16.2%).

This difference was not as large as that seen with regard to developing eye disease, but it was nonetheless statistically significant (P=0.04).

Thus, it appeared that while low oxygen produced fewer cases of severe ROP in the infants who survived, this was being accomplished at the cost of fewer infants surviving.

The research team had reason to suspect this outcome before the experiment began

The Office of Human Research Protections’ letter points out that the study’s authors were aware that previous studies had shown increased mortality at lower oxygen levels, as well as decreased retinopathy.

And their study confirmed the earlier findings:

“[O]ur data suggest that there is one additional death for approximately every two cases of severe retinopathy that are prevented.”

“[C]aution should be exercised regarding a strategy of targeting levels of oxygen saturation in the low range for preterm infants, since it may lead to increased mortality.”

The ethically saddening part

According to the Office of Human Research Protections letter (at page 7), all of the 23 prestigious facilities had similarly deficient consent forms.

Who were the culprit institutions?

People who should have known better:

Brown University

Case Western Reserve University

Children's Healthcare of Atlanta

Duke University

Emory University

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH)

Indiana University

RTI International

Stanford University

Tufts Medical Center

Universities of:

Alabama – Birmingham

California – San Diego

Cincinnati

Iowa

Miami

New Mexico

Rochester

Texas

Texans Southwestern

Utah

Wake Forest University

Wayne State University

Yale University

Why this is disturbing — even in the absence of the alleged deviations from the standard of care

Even we dismiss the Office of Human Research Protections’ allegations about deviation from the standard of care — we are still left with evidence that:

(a) anticipated the reduction in retinopathy in the low oxygen group

and

(b) forecast the increased death rate in that same low oxygen group.

Inarguably, parents of the preterm patients should have been informed.

Most parents would likely have decided that having a live, but sight-impaired child was preferable to losing one. They almost certainly would not have permitted randomization into the low oxygen group.

Similarly, given a choice between mid-level oxygen saturation and a higher one — which was more likely to lead to retinopathy — they probably would have adopted the middle (standard of care) ground. Unless, of course, their physician came to them and said their infant’s life was in danger and more oxygen might help.

In both cases, the Office of Human Research Protections is almost certainly correct. The standard of care was violated, and the parents had an ethical (and legal) right to know that.

The moral? — Medicine suffers from a combination of paternalistic arrogance and often surprisingly poor critical thinking

The SUPPORT experimental consent process exposed some of the dangers that the medical establishment unwittingly subjects its patients to.

On the positive side, the SUPPORT consent fiasco was almost certainly not a case of bad faith.

On the negative hand, it is one of intellectual and moral ineptitude — both arguably compounded by the blindness that professional arrogance and a failure of situational empathy bestows.

The legal and ethical criticisms of institutional review boards, which I made in 2001, and again in 2010, still apply:

Research participants are still at the mercy of a system designed, in practical application, to look out for everyone’s interests but theirs.

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