Clinical Trial Ethics: One Standard Does Not Fit All
Authors: Sudeep Gupta, Seema Gulia, Nishita Shetty
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: In their recent commentary on the ethics of clinical trials in low-resource settings, Joffe and Miller have raised several pertinent points and questioned some established norms. Their core argument—that choice of control arm treatment in lowresource settings should be considered in the context of local standards—has considerable merit. Imposition of uniform, some would say artificial, control arm standards on clinical trials conducted in various economic settings can impede this invaluable component of health care activity. However, two further considerations deserve attention before this viewpoint can be unequivocally endorsed. First, in many lowto middle-income countries, the host community is not a homogeneous monolith; rather, it is a complex collection of individuals and groups with widely varying privileges. In India, for example, potential patients for a trial of systemic therapy in human epidermal growth factor receptor 2 (HER2) –positive early breast cancer will range from the majority in whom the nontrial standard would be only anthracycline-taxane based chemotherapy to a minority in whom the full recommended course of trastuzumab would be eminently feasible. What would be an ethical control arm for a systemic therapy trial in this subtype of breast cancer that will preserve the balance of risks and benefits for all patients? Would a trial with a no-trastuzumab control arm, justified on consideration of local standards, be open only to underprivileged patients? Joffe and Miller seem to have oversimplified the situation when they assert that “every participant has an ex ante chance of receiving an intervention that is potentially beneficial as compared with the local standard of care.” Second, in an era rife with new standards in oncology practice, it is time to establish some sort of hierarchy within these standards. For example, imatinib in chronic myeloid leukemia, rituximab in CD20 aggressive lymphomas, and trastuzumab in HER2-positive early breast cancer have conferred unprecedented benefits on patients, including lives saved from cancer-related death. It could be argued that to conduct systemic therapy clinical trials in these diseases without the corresponding agents in the control arm would be ethically unjustified regardless of local standard considerations. The same cannot be said for many other targeted therapies in metastatic cancers that have, at best, been shown to result in only modest gains, often in the form of improvement in progression-free survival unaccompanied by overall survival or quality-of-life benefits. We believe that a careful appraisal of each clinical trial setting, including the efficacy and feasibility of standard therapeutic choices, will lead to appropriate design of the control arm in most instances. It is about time that the medical ethics community acknowledged that a one-standard-fits-all approach approach to conducting trials has outlived its usefulness, and a more nuanced personalized approach will be in the best interests of all stakeholders.