The Case
Your patient is deciding whether to enroll in a clinical trial at your institution and wants your advice about whether to participate. The study compares two drugs for acute pain following minor outpatient surgery. One drug is a newly developed analgesic that may soon be approved by the U.S. Food and Drug Administration. The other is an older, generic drug that has been around for decades. The protocol randomly assigns study subjects to one of several doses of the novel medication or a fixed dose of the older analgesic.
You are aware of review articles by pain experts describing how physicians commonly underdose the older drug. In fact, prior studies suggest that the “usual” or “standard” dose of the older drug—the one used in the study protocol—provides inadequate pain relief in nearly half of patients. That is why pain specialists carefully up-titrate the dose of this medication to achieve pain relief and routinely recommend that other clinicians do the same. The older drug’s package insert allows a wide range of doses; the study protocol’s fixed dose is at the lower end of this range.
You recognize that your patient may have her pain undertreated if she’s assigned to receive the older drug.
Do you advise your patient to enroll? Do you see any ethical concerns about the design of this study?
Discussion
This scenario raises an issue often faced by researchers designing a study to explore the effectiveness of a new therapy: What is the appropriate comparator? Although a placebo-controlled design represents the gold standard for clinical trials, assigning one group to receive a treatment expected to be ineffective is ethically problematic. Ideally, the control group should (at the very least) receive treatment considered to be the standard of care.
However, in the case described, the trial proposes a comparison group that receives a dose of pain medication known to undertreat pain in many patients. Even though the protocol employs a commonly used dose, the protocol does not allow optimal dosing. Thus, this protocol may be unethical because it assigns some patients to a suboptimal treatment regimen. In addition, the design may be biased toward the new drug because a range of doses of the new drug are being compared to a fixed, commonly ineffective dose of the older drug.
The counter-argument is that this study has a limited goal: to compare a new drug to a commonly prescribed dose of an old drug that would be considered by many clinicians to represent the standard of care. However, this justification raises ethical concerns as well.
What Constitutes an Ethical Clinical Trial?
The policies and recommendations contained in the Nuremberg Code, the Belmont Report, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects and related consensus guidelines represent significant progress in the evolution of ethical clinical trials.1-3 As institutional review boards are expected to take these well-established guidelines to heart, the question of ensuring an ethical trial may seem academic. However, when common or usual care is also suboptimal, deciding whether a study protocol is ethical may not be straightforward.