Commentary: safety of participants in non-therapeutic research must be ensured

British Medical Journal, March 21, 1998 by Julian Savulescu

When retrospectively evaluating research what matters is not the harm that actually resulted from the research, but the risk to which researchers exposed participants when all the knowledge available at the time is taken into account. At least five questions are relevant to this discussion.

Was there known to have been a risk to participants before the study began, and what was the magnitude of that risk as evaluated by the evidence available at the time?

There was evidence that a reduction in the pressure of inspired oxygen might be causally related to sudden infant death[1] at the time Parkins and colleagues began their study. Is it reasonable to impose a risk of death on healthy infants to gain more knowledge about physiological responses to hypaxia? It could be argued that monitoring procedures removed this risk. Even if the study design were perfect, the chance of human and mechanical error[2] could not be entirely removed.

This study is an example of non-voluntary, non-therapeutic research. It is generally accepted that the risk posed to participants by such research must be minimal.[3 4] The Royal College of Physicians suggests that participants in this type of research should be exposed to no more risk than that taken by a passenger flying on an aeroplane.[3] Indeed, the justification presented by the researchers for exposing normal infants to hypoxia is that "[m]any infants travelling on aeroplanes or to holidays at high altitude are exposed to similar or even more markedly reduced partial pressures of inspired oxygen. Yet this exposure is considered safe."

There are several problems with this argument. In the first place, researchers may have access to information which is not available to the public. Flying in an aeroplane may be more dangerous for some people--for example, those with emphysematous bullae. If an airline or responsible authority was unaware of the risks to travellers with emphysema they might allow them to travel on aeroplanes without restrictions. However, this would not provide justification for an interventional study which exposed these travellers to lower air pressures.

In the second place, even when information on risk is available some people behave recklessly; it would be opportunistic for researchers to take advantage of such behaviour. A prospective interventional study of behaviour during actual drink driving would be unethical even if resuscitation were available and there were no shortage of willing participants.

There is a related problem that occurs when judgments about the reasonableness of risk are based on assumptions drawn from behaviour. People judge that some risks are worth taking, but it is up to them to make that evaluation. Though driving a car or flying in an aeroplane does entail risk, it is wrong to assume that a person would take on this risk to participate in research. This is illustrated by the public's reaction to the scandal surrounding bovine spongiform encephalopathy. People may choose not to engage in an activity with a very small risk of death if they perceive that the benefits are outweighed by the risks. Were the parents in this study explicitly told that participation entailed a small risk to their infant's life? Participants must be scrupulously informed of such risks.

Standards of practice cannot be used to define the appropriate level of safety that should be provided to participants in research. We should look to the inherent risk. There are some concerns raised by this study by Parkins et al. Firstly, why was a saturation of [much less than] 80% for [much greater than] 1 minute chosen as the criterion for ending exposure to hypoxia, and what evidence is there that it is safe to expose infants to hypoxia? Hypoxia was clearly clinically significant in some infants who were described as becoming "severely hypoxaemic." Indeed, one required supplemental oxygen for 1 hour.

Secondly, the methods section states: "Infants and monitors were observed continuously by an experienced paediatrician. According to our protocol, exposure to hypoxia would end if oxygen saturation fell to [much less than] 80% for [much greater than] 1 minute." The results section states: "Oxygen saturation had been [much less than] 80% for [much greater than] 1 minute in three infants." It is not clear from the protocol whether there was a definite upper limit to the time an infant might spend at an oxygen saturation below 80%. How long had oxygen saturation been [much less than] 80% in these infants?

Thirdly, part of the reason for performing this study was because the researchers became aware of two infants who had died after travelling on an intercontinental flight. Why then did the follow up of infants exposed to hypoxia last only about 10 hours, given that one infant died 40 hours after travelling by aeroplane?

Should any non-human or epidemiological research, systematic overview, or computer modelling have been done before the study to better estimate the risk to participants or to eliminate the need to use human participants?