Abstract
This case raises issues in relation to clinical equipoise and non-therapeutic research. Clinical equipoise is the ethical requirement that at the time a trial is carried out there be genuine uncertainty within the scientific community as to the efficacy or safety of the drug or treatment being tested.
It is commonly applied in relation to randomized controlled trials. So if there is good reason to believe, prior to a trial, that the treatment is effective and superior to existing treatments then it would be unethical to deny it to subjects in a control group as part of a clinical trial. The Declaration of Helsinki requires that a physician should act in the best interests of the patient. Therefore, they should not enrol patients in a trial where they will be denied what medical evidence already suggests is superior treatment. Most medical research involves risks and burdens and, according to the Declaration of Helsinki, article 21 (2008), ‘Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.’ If the efficacy or safety of a new treatment is known – if there is not scientific uncertainty – then clinical trials are unnecessary and would expose participants to burdens (and possibly risks) without justification. However, as the Declaration of Helsinki (article 7) recognizes, treatments need to be continually evaluated and so research for that purpose will be ethically justifiable, but only if and when doubts arise about efficacy or safety.
Of course, the contrary argument is that early evidence of efficacy can be misleading and needs supplementing with evidence of safety that can only be attained through clinical trials. So doctors are ethically required to conduct clinical trials. And it may be that the current best treatment is unsuitable for some patients (possibly due to side-effects or other contra-indications) and so an alternative needs to be found, necessitating trials in which the current best available treatment is not provided.
How does this apply to the migraine case which is not a randomized trial? Clinical equipoise can be more generally understood as the requirement that patients not be enrolled in any clinical trial to develop treatment that is inferior to the current best available treatment. Patients in this study are being asked to temporarily forgo effective treatment in order to help develop a different treatment for migraine. But is the treatment being tested inferior to their current treatment?
It might be thought that it is, because the aim is to develop a test to warn of the onset of migraine which will maximize the efficacy of conventional drug treatment. But conventional drug treatment is unnecessary if the patient is already using the dental device. However, the device is not effective in 20% of cases. Therefore, developing a test for the onset of migraine for this group of sufferers will provide them with a more effective treatment than is currently available to them. While it is hoped that mapping peptides from before the onset of a migraine will help develop an early warning test, there is no guarantee that it will – there is uncertainty. The trial, therefore, complies with the requirement for clinical equipoise.
But there is a further issue. The participants are being asked to take part in non-therapeutic research. They are being asked to forgo the best treatment for them in order to help develop an effective treatment for others. All ethical guidelines for clinical research require that the risks and burdens of non-therapeutic research be minimal.
The risk is the 90% chance of suffering a migraine. This is a harm to health and may affect the participant’s ability to work. Further burdens are associated with the need to wear a dental device which very accurately monitors the level and types of peptides present in the mouth. We are not told how intrusive and burdensome this will be. It would be fair to say, even without this information, that the risks and burdens are not minimal. However, they are not serious. The participants will recover from a migraine (if they have one) and there are no anticipated further effects once the participant goes back to wearing the dental device that protects against migraine. However, it is still possible that there will be unknown and so unanticipated effects.
We are told that the information sheet is clear and explains all relevant information well. So if a patient consents to take part in the trial we can assume their consent is adequately informed. However, depending on how ‘minimal risks and burdens’ is interpreted, their informed consent may not be sufficient to make the trial ethical. But, given the hoped for benefits for migraine sufferers for whom the dental device is not effective, the research does have an important objective and to that extent goes some way to a justification under article 21 of the Declaration of Helsinki. Furthermore, there may be people for whom the dental device is effective but who would prefer the alternative of a rapid test of onset of migraine and conventional drug therapy. So it is possible that for some prospective participants the research could be regarded as therapeutic – they may benefit from it.
I would suggest that the information sheet make clear the precise nature of the burdens of the experimental dental device and that there be some compensation for any absence from work necessitated by any subsequent migraine, to mitigate some of the burden of participation. Given the unpleasant nature of a migraine, there is a low risk of people being induced by the compensation to take part in the research.