Ethics Forum: The Ethical Pitfalls of Clinical Trials

In fact, past trials of rheumatoid arthritis could be criticized for underdosing methotrexate in the comparator group.^4,5 More recently, trials comparing febuxostat with allopurinol required those in the allopurinol group to remain on a maximal dose of allopurinol known to inadequately suppress uric acid in a substantial proportion of patients with gout.^6-10

Of course, there may be situations when a treatment considered to be the standard of care is suboptimal but still an ethical choice for a clinical protocol. Concerns regarding cost, tolerability, and accessibility of a highly effective drug may make it a less useful comparator in a clinical trial. So, researchers may reasonably choose a more commonly used (but less effective) regimen. However, none of these considerations apply to the clinical scenario or trials mentioned above.

In thinking about the ethics of treatment trial design, an important paper by Emanuel and colleagues is worth consideration.¹¹ In it, the authors propose a number of principles by which the ethics of clinical trials should be judged. Among them, two are potentially violated by the study of pain medication described above:

• Value: The question this study can answer (How does a common dose of an old drug compare to a new drug?) is not the one clinicians need answered (How does an optimal dose of an old drug compare to a new drug?); and
• Favorable risk–benefit ratio: This study design does not maximize potential benefit to the study subjects as it could have by allowing up-titration of the older pain medication.

Another principle, informed consent, is also at risk if the study protocol did not clearly explain the known failure rate of the old drug at the designated, fixed dose. In fact, it is not clear that the consent could be written in a way that accurately discloses the discrepancy between optimal (rather than common) practice while also encouraging enrollment. Study recruits might decline enrollment if they know they might be assigned to a group with a good chance of having their pain undertreated.

The Importance of Equipoise

Ideally, a study should address treatment groups from the starting point of equipoise—that is, the investigators should be unsure which therapeutic arm will be better treated.¹² While the results of clinical trials are rarely certain before completion, those assigned to an undertreated comparator group are at a distinct disadvantage. This raises the potential criticism that the study design was “rigged” to favor the new drug at the expense of the study subjects in the comparator group.

Would You Enroll?

When faced with a clinical decision, many patients ask their physicians, “What would you do?” A similar question could be asked here: Would you want to enroll as a subject knowing that you might be assigned to the older drug at a dose that is commonly ineffective when dose adjustment could provide relief? If the answer is no (or even I’m not sure), should you encourage your patients to participate in such a trial?