When Is Waiver of Consent Appropriate in a Neonatal Clinical Trial?

Comments by Dr Susan Wootton, Dr Cody Arnold, and Dr Jon Tyson

This trial is needed for 3 reasons. First, the rationale for immediate tracheal suctioning is the assumption that severe MAS results from meconium aspiration at or shortly before birth.^1,2 In fact, severe pulmonary artery hypertension in fatal MAS is associated with anatomic changes in pulmonary vessels likely to have developed well before birth.

Second, even in expert hands, immediate tracheal suctioning may increase the likelihood of severe lung disease, brain damage, and death by intensifying the hypoxia, hypercapnia, acidosis, and pulmonary artery hypertension in these infants at birth. Physicians can optimize the risk/benefit ratio of tracheal suctioning by reserving it for infants intubated for resuscitation or mechanical ventilation and performing it only after they are well stabilized.

Finally, no randomized trial has demonstrated that suctioning any part of the airway before or after an infant’s chest is delivered prevents or ameliorates MAS in vigorous or nonvigorous infants.^3–5 The presumed benefits of immediate tracheal suctioning are inferred from observational studies using historical controls reported in the 1970s.⁶

The trial would be augmented if neurologic and pulmonary outcomes at 2 years could be assessed. However, the trial would contribute valuable information even it is not feasible to perform this assessment or conduct a large trial. To obtain unbiased estimates of treatment effect, it is better to perform the largest feasible randomized trial than no trial at all.^7,8

When consent cannot be reasonably obtained after birth, as in this case, IRBs may require antenatal consent. However, such a requirement would be misguided for this trial. First, it would result in underrepresentation of infants whose mothers have the least education, least prenatal care, most advanced labor at admission, worst pregnancy complications, or greatest problems with intrapartum care. Such selection bias can greatly increase the likelihood of missing important treatment benefits or hazards and reaching erroneous conclusions harmful to large numbers of future infants.

Second, antenatal consent would not be practicable. Because MSAF is often first identified shortly before delivery, a trial of reasonable length would require seeking consent from all women in labor at ≥35 weeks’ gestation. Yet very few of them, ≤3% in a recent study,⁹ deliver nonvigorous infants with MSAF. This approach to consent would impose unreasonable personnel time and cost per infant enrolled and intrude on many laboring women who would not need and may not want the information provided.

Third, seeking antenatal consent from all these women might be harmful, a legitimate concern^10,11 that IRBs would not ordinarily consider. Experimental studies in humans^12–14 and in nonhuman primates¹⁵ indicate that greater anxiety during labor can increase maternal or neonatal complications. There is no reason to assume that adverse outcomes would not be increased by detailed risk disclosure about intubation, tracheal suctioning, and severe MAS to most or all laboring women at ≥35 weeks’ gestation.

For all these reasons, requiring antenatal consent for this trial may be considered contrary to the ethical principles of respect for persons, beneficence, and nonmaleficence.

Waiver of consent (not “deferred consent”) for this trial may be justified under federal regulations allowing waivers for minimal risk research in restricted circumstances. Some IRB members may assume that any trial in seriously ill patients involves more than minimal risk. However, the federal IRB guidebook defines risk as “the probability of harm or injury . . . occurring as a result of participation in a research study” (italics ours).¹⁶ The Office for Human Research Protections recently emphasized that “the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).”¹⁷ IRBs should assess risks from the best available evidence. As indicated earlier, the best evidence provides no basis to conclude that patient risk would be greater in this trial than with the immediate tracheal intubation and suctioning that is routinely provided.

Federal regulations specifically for emergency research consent waiver provide a strong and less contestable basis for approval. These regulations require that “the human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, [and] the collection of valid scientific evidence . . . is necessary to determine the safety and effectiveness of particular interventions.”¹⁸ The proposed study meets these criteria: The subjects have an increased risk of death, the invasive emergency intervention under investigation is unproven, and valid scientific evidence to determine its safety and effectiveness is most likely to be collected in a proper randomized trial.

The parents should be asked to consent to the collection of outcome data, there should be oversight from a data and safety monitoring board, and there should be prior community disclosure and consultation. To meet these requirements the investigators might post information in prenatal clinic waiting areas and seek input from women attending these clinics, parents of high-risk infants attending neonatal follow-up clinics, or members of a parental advisory board for perinatal research in the study centers.

Antenatal consent is not practicable or appropriate for this important trial. As indicated earlier, waiver of consent is allowable under the federal regulations for emergency research consent if not also the regulations for minimal risk research.

This study highlights a very common situation. Many therapies, particularly emergency therapies, have never been rigorously studied. They may have little value or even be harmful.

Studies such as this ought to be encouraged. Current regulations are based on outdated and simplistic distinctions between research and practice^19,20 and inadvertently discourage proper testing and encourage routine use of unproven therapies.^19–21 An approach to regulation and to informed consent based on whether there is foreseeable incremental risk over that in clinical practice will help foster a learning health care system to accelerate advances in patient care and outcomes.²²

Comments by Dr Dalia Feltman and Dr Thomas Wiswell

We would analyze the issues in this case by focusing on 2 questions. First, is there clinical equipoise between the 2 treatments so that randomization is ethically defensible? Second, is waiver of consent the best approach to conducting this study?

Randomly assigning a subject to 1 of 2 treatments is considered morally acceptable if the treatments are believed equally effective or if there is not enough scientific evidence to prefer one to the other. Randomization is ethical if there is “honest, professional disagreement among expert clinicians about the preferred treatment.”²³ That is the case here. As noted earlier, this study addresses an important scientific question. There is good reason to believe that at least some infants born with MSAF would be better off without immediate intubation and suctioning in the delivery room.

This situation is analogous to one that existed with regard to vigorous infants 20 years ago. Before a multicenter study by Wiswell et al⁵ in 2000, the Neonatal Resuscitation Program standard was intubation for endotracheal suctioning of every infant. After studies were done (using waiver of consent), a Cochrane meta-analysis concluded, “Routine endotracheal intubation of vigorous term babies born through meconium-stained amniotic fluid cannot be recommended. For non-vigorous babies endotracheal intubation is probably indicated until more information becomes available.”²⁴

This study is designed to provide more information.

One could argue that endotracheal suctioning of a vigorous infant who has inhaled meconium while crying may not be effective, whereas a depressed infant may still benefit from removal of meconium before it moves to the lower respiratory tract. On the other hand, in utero aspiration of meconium might be what led to the newborn’s depressed state. In that case, postnatal endotracheal suctioning is unlikely to prevent respiratory complications. Furthermore, intubation entails risks such as laryngeal trauma and reflex bradycardia. Delaying resuscitation attempts while suctioning may compound the state that caused depression, possibly worsening hypoxic ischemic injury. Given these balanced risks and benefits, we believe that randomization is justified.

We now turn to the proposed consent waiver. We know that 2 previous randomized studies of interventions for newborns born with MSAF waived parental consent. That decision was based on the federal regulations, noted earlier, that allow waiver of informed consent if 4 criteria are met.

These 2 previous studies emphasized the value of testing common practices in defending consent waiver. According to Vain et al, “Use of unproven policies and practices should not be perpetuated and proper testing of emergency procedures will result in improved medical care.”³ Both studies led to changes in standard practices regarding newborns with MSAF. The proposed protocol carries no more risk to its subjects than did the previous protocols for which consent was waived. According to US Department of Health & Human Services regulations, “Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”¹⁸ Determining minimal risk for the “ordinary daily life” for the nonvigorous infant currently born with MSAF is problematic because by default this life starts with endotracheal intubation, which carries more than minimal risk. However, because random assignment to intubation or no intubation probably carries equal risk to the patient, we believe study enrollment carries no more than minimal risk compared with standard care.

As in the previous studies, the emergency nature of the detection MSAF and infant’s depressed state make traditional parental informed consent impossible. Recent neonatal trials with similar time constraints have sought antenatal consent, which causes problems. Rich et al²⁵ showed that such an approach was inefficient and led to selection bias. Investigators in 1 such study had to obtain consent from 5 times as many pregnant women as needed to enroll enough infants in the study. Those who did enroll were more likely to have had prenatal care and to have received antenatal steroids than those not enrolled, leading to decreased generalizability.

Institutional consent in lieu of parental informed consent with the opportunity for parents to opt out was used by Vohra and Reilly’s Vermont–Oxford Network Heat Loss Prevention Study.²⁶ The results are not yet published.

A third approach is described by Allmark and Mason²⁷ in which participation in a hypothermia study was presented in a stepwise fashion to parents of children who might be eligible. Although their approach included traditional informed consent of a parent before randomization (afforded by the longer therapeutic window intrinsic to the cooling protocol), their process of continued engagement with the parents allowed people to drop out of the study at several points.

Proponents of waiving informed consent argue that a mother in the emergency situation of labor complicated by an urgent newborn condition is unable to give proper informed consent because of her physical and emotional distress.^28–30 Clearly, the issues surrounding emergency consent in the delivery room for a study on an unstable infant may preclude ideal parental informed consent. But we believe that some shared decision making is better than none. Allmark and Spedding³¹ suggest that preserving societal respect for the family unit may be a more important goal of traditional parental consent than protecting the child from risks, because the latter task is shared by most research investigators and IRBs. Care must be taken to ensure that circumventing traditional parental consent does not erode parental trust in the medical team or in future neonatal research.

With these considerations in mind, we would allow waiver of parental consent to randomization. We suggest that, when possible (ie, when time and circumstances allow), parents be given an opportunity to opt out. This could be done by giving all laboring mothers who are admitted at ≥37 weeks some written information about the study. This information should include the study goals and an assessment of the risks and benefits. It should clearly explain that most infants will not be eligible for the study but that determination of eligibility cannot be determined before birth. At that point, parents will be asked only whether they want to opt out of the study. If they do not opt out, and if their infant meets enrollment criteria, then randomization will occur.

For those ultimately enrolled, debriefings must occur in person between parents and the treating physician, and more specific information with investigators’ contact information should reiterate the parents’ option to decline further participation (ie, information collection).

To inform future practices, we recommend a secondary analysis of parents’ perspectives on this opt-out process.

Comments by Dr Mark S. Schreiner

The case study describes a randomized, double-blind clinical trial that compares 2 commonly used treatment approaches. This is an increasingly common scenario. Clinicians often must choose between treatment options based on bias, inadequate data, and anecdote rather than solid evidence. Comparative effectiveness research (CER) strives to compare treatments in common use where there is a lack of consensus about which is best. Considerable controversy exists about which risks should be taken into account when reviewing CER.^32–34

The federal requirements for approval are outlined in 45 Code of Federal Regulations (CFR) 46.111 and for this study Subpart D: Additional Protections for Research Involving Children as Subjects.³⁵ Rather than examining each regulatory requirement, I will focus only on the most controversial issues raised by this study, specifically the requirement for the research to minimize risk, the risk and benefit assessment, the determination of the appropriate Subpart D risk/benefit category, and finally the informed consent requirements.