The underpinning Kantian principle (36) is that people should not be used as the means to someone else’s ends. Medical research is, as we said, a means to better future care, but usually of people other than the research subjects. This use of one set of people for the potential benefit of another, future set of people creates ethical tension.
Many tensions in research are the expression of conflict between competing human needs, wants, values, ambitions, and objectives, which give rise to what are termed people’s agendas (35). The several parties to clinical trials—for example, patient, physician-investigator, sponsor—all have different agendas. If the patient’s agenda is guided by his or her need to be well, the physician may share this objective through a good doctor’s desire to help the patient; but both patient and physician have other agenda items. The physician-investigator’s wish to help the patient is tempered by a competing desire also to be a good investigator, and the first objective of the trial is not the good of the individual patient. The tension is resolved if the patient expressly adds to his or her agenda a wish to help the physician or future patients. This, in an informed, competent, and autonomous patient, is what is meant by consent.

The consent of human subjects is required for whatever is done to them, in treatment and other interventions or in research. This principle, stated explicitly or implicitly in virtually all codes of ethics and documents of guidance on ethical practice since the Nuremberg trials (41), pervades medical ethics and should underpin the practice of modern medicine. It upholds autonomy, or the right to self-determination and the notion of respect for persons (36), against paternalism, the view that doctors know far more than patients and therefore know best, without need to consult them (5,21,27). It stands against utilitarian arguments, flawed but seductive, that the benefits that medical research brings to many sufficiently justify harm done to a few on the way.

Nevertheless, circumstances may erode autonomy (15,22,24), particularly that of dependent patients. Autonomy is affected, for example, by limited availability of treatment in a given society. Offers of free or improved care (25) are an inducement to consent (“consent or be discharged” [18]), and inducement casts doubt on how voluntary it is. That this occurs in headache trials is not in doubt; it happens because access to health care for headache disorders is limited and new treatments are haphazardly or systematically restricted. Where there is no state-supported health care for headache, the only means of obtaining treatment for some people is to enter a clinical trial. This “trade” is rarely discussed openly between investigator and patient.

Support for the principle of medical confidentiality, set out in the Hippocratic Oath, is common to virtually all ethical guidance to doctors throughout history and across the civilized world (e.g., General Medical Council [19]). It is deeply rooted in pragmatism. Mutual trust and respect are essential ingredients in the doctor-patient relationship because patients who are not assured of confidentiality—and therefore fail to disclose relevant details—may not receive optimal treatment.

In research, confidentiality is commonly breached. Personal information initially collected for the purposes of clinical management is scrutinized by and shared among researchers who may have no involvement in the patient’s care. This is especially true of trials monitored as part of the quality assurance of Good Clinical Practice (GCP) (see below); the recent and rather sudden expansion of pharmaceutical interest in headache has brought many such trials to parts of the world where medical confidentiality is not well protected by law. The increasing use of third-party monitors, some with lesser professional qualifications, widens the range of people having direct access to patients’ medical records.

Breach of confidentiality itself requires consent. It is made acceptable by consent, but only if the scale and scope of the breach are clear to potential subjects when they consider participating in research. In particular, they “should be told of the limits to the investigator’s ability to safeguard confidentiality and the possible consequences of breaches of confidentiality” (7).

One of the most important current ethical concerns in headache research relates to what research is actually done. It is not obvious who makes choices, according to what agenda(s), with respect to what research is needed and what is undertaken. What the public needs (and to a lesser extent what the public wants) should be decisive. Unfortunately, except in those few countries with legally based systems of research ethics control that have strong lay representation, public opinion in these matters has no clear means for coherent expression. Least likely to be involved in choice making are people with headache.

Doctors who are aware of deficiencies in health care and interested in undertaking research to repair them are frequently unable to secure financial support for it. Government-supported research into the better management of headache has low priority. Public finance for research is available to a limited extent from charitable and patient-led organizations that have been set up with support for research into headache as one of their objectives. Although these sources of support are of significant potential benefit to headache sufferers, they are sporadic and there is no oversight to ensure justice in the sense of bringing about a distribution of fair shares to all in need (12). The pharmaceutical industry has the means to support research across most therapeutic areas but is market driven in its choices, and it is not at all evident that market forces are just. A good example is the massive pharmaceutical investment in drug development in the last 15 years, which has brought undoubted benefits to those with migraine, who are barely one fifth of all sufferers from headache.
The majority, namely those with tension-type headache, and the most disabled, namely those with chronic daily headache, have little current expectation from research in the pharmaceutical industry.

Ethically, the number of people exposed to an unproven drug—or to placebo—should be not excessive but sufficient to demonstrate efficacy and safety. Proof of efficacy in headache disorders requires relatively large numbers because endpoints are subjective and placebo-response rates are commonly high. Efficacy is proved only if endpoints, as well as being statistically sensitive, are clinically relevant and respect patients’ values (58). Although thoughtful recommendations exist (32, 33, 34), there is no universal agreement on what are the best measures of efficacy in headache trials.

Efficacy and safety of new drugs for headache may need to be evaluated for multiple dosages in children, adults, the elderly, in specialist clinics, and in primary care. The clinical characteristics of headache (including need for and response to drug treatment) as well as the safety of treatments may differ between these groups. It is necessary to establish the minimum effective dose and, sometimes, the maximum tolerated dose. Full evaluation of headache therapy may require testing within several permutations of these circumstances. This calls on the participation of many patients, which has to be so.

Where pharmaceutical companies compete for clinical trials resources, as they recently have been doing in migraine, every trial undertaken has an opportunity cost that affects other trials that are being or might have been performed. Studies that aim solely to support marketing, if they direct resources away from trials properly investigating safety or efficacy, are unethical and in stringent national control systems are treated accordingly.

The use of placebos in clinical trials is still debated generally (26,28,50,56). In headache, unlike some other therapeutic areas, ethical use of placebo does not depend on whether or not there are better standard treatments. The Declaration of Helsinki (67) states that “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods.” Because standard treatments do exist for both acute and prophylactic treatment of headache, this appears to rule placebo unethical (50).

But central to acceptable deliberate use of treatments less efficacious than standard treatments is autonomous patients’ consent voluntarily to forego the latter. Details of those treatment options that will be foregone are part of the information that must be given to potential subjects when they consider whether or not they wish to participate. Most headaches occur transiently; where this is so, the consensual withholding of best therapy will not lead to any significant or long-term harm, especially with professional surveillance and rescue medications available (58). The International Headache Society (IHS) Ethics Subcommittee found that the use of placebo always requires justification (35), but they expressly rejected the argument, for headache trials, that “even informed patients may not be disinterested enough to decide rationally whether it is tolerable to be deprived of an accepted treatment” (50). Use of placebo is more problematic in long-term studies because consent must be continuing, not merely given at the start. Nonetheless, the issues are similar.

As for justification, placebo controls may be demanded by regulatory authorities as proof of drug efficacy, but this is not an ethical argument. On the other hand, patients may be fruitlessly exposed to risk if a trial produces equivocal results because of inappropriate experimental control. Comparison with placebo reduces the exposure to an unknown drug needed to establish its efficacy. In a particular group of patients in a trial, if a new drug and an active comparator evoke similar responses without placebo control, it is not known in that group if either has improved outcome over natural history (56) (previous evaluations of the comparator against placebo are historical). Comparison with active agents can come later if prescribers wish to know what advantage a new treatment offers over alternatives (21,28). This may help to determine what should be offered as first-line treatment but, in reality, patients can establish the advantage(s) to themselves of each by trying each one—a reasonable proposal for acute therapy. With prophylactic drugs, the situation is different in that many currently available (that might be used as comparators) are not themselves reliably superior to placebo.