The philosopher and mathematician Alfred North Whitehead is credited with the statement that all Western philosophy is a footnote to Plato. Although clearly hyperbole, the point regarding the effect of Plato is clear, as would be a similar statement related to the relevance of the landmark Nuremberg Code to the future establishment of the entire field of biomedical ethics.1
Just as our increasingly complex world challenges societies with difficult philosophical questions, the evolution of biomedical research continues to pose perhaps less lofty but still quite thorny ethical dilemmas. Note the recently completed update to the 60-year-old Declaration of Helsinki, deemed necessary due to ongoing developments in the spheres of medicine, clinical investigation, and international public policy.2,3
The importance of human participants’ research in establishing evidence-based medicine and the absolute need for appropriate protections for individuals participating in such endeavors cannot be overstated. Unfortunately, over the past century, our world (including the United States) has seen multiple painful examples of a profound failure to achieve an acceptably meaningful focus on the rights of individuals within the research enterprise.4,5
A concern arises when clinicians, who are also well-intentioned investigators, fail to appropriately appreciate how their desire to achieve a legitimate scientific objective may collide with the provision of optimal or “best possible” care for their own patients. The uncommonly discussed but potentially serious ethical tension within the clinical research domain when a patient’s physician considers including them in a clinical research study was recently emphasized in a provocative commentary in which the author challenged the medical community regarding these different roles. The title gives away the punch line—“Protecting Participants Is Not the Top Priority in Clinical Research.”6 The author writes:
“Almost always (with rare exceptions) doing what is in the best interests of the patient—and the complementary provision, _primum non nocere_ (“first, do no harm”)—has been at the core of clinical ethics. The problem arises when researchers turn from the ethics of clinical care to the ethics of research. When a physician is conducting research, the goal becomes that of trying to answer a research question. In doing that, the physician’s activities may no longer always be in the best interests of the research participant.”
There is so much to say regarding this topic, but in the interest of space, a published letter in response to this viewpoint provides a meaningful counterpoint.7 The respondents state, “Although the title of the recent viewpoint article, ‘Protecting Participants Is Not the Top Priority in Clinical Research’ is correct, we disagree with this viewpoint because it failed to recognize that at least since the Nuremberg Code protecting participants is the top priority of research ethics.”
Finally, it is relevant to acknowledge that this potential conflict between the ethical responsibilities of a patient’s physician vs the clinician serving as a researcher has existed at least since the dawn of the modern research era, reasonably dated sometime after the end of the Second World War. In his autobiography, The Day is Short, the nationally recognized civil rights lawyer Morris B. Abram recounts a discussion by his daughter with the late eminent cancer researcher James F. Holland, related to the management of the lawyer’s cancer.8 When pressed as to why a particular treatment protocol was being proposed, Holland replied, “My duty is to advise. You must bear in mind that I am not your father’s physician. I am an investigator.”
The tension between the requirements for the ethical practice of clinical medicine and the conduct of optimally scientifically rigorous clinical research is evident in discussions of the use of placebos in cancer and noncancer randomized phase 3 trials. It is also evident in the decision to permit or not permit “crossover” following disease progression from a “standard-of-care” study arm to the investigational agent in such studies.9,10
Although it is not difficult to provide objective examples in multiple areas of oncology where decisions related to clinical research protocols appear to raise serious ethical questions about a physician’s obligations to optimize patient welfare, one rather striking event emphasizes the specific point being made in this commentary.
Pegylated liposomal doxorubicin has long been established as a modestly clinically active antineoplastic agent in the management of platinum-resistant ovarian cancer.11 Although the agent is generally reasonably well tolerated, a potentially serious dose-related adverse effect (AE) is the development of palmar-plantar erythrodysesthesia (PPE), often referred to as hand-foot syndrome. As many as one-fourth of patients were noted to experience this AE at the FDA-approved initial dose (50 mg/m2 every 4 weeks) of the agent. Not surprisingly, following regulatory approval, clinicians investigated the clinical utility (efficacy and toxicity) associated with the delivery of a lower-dose infusion, and extensive peer-reviewed published data revealed similar survival outcomes and reduced PPE associated with initially giving the drug at 40 mg/m2 every 4 weeks (a 20% dose reduction).11 Further, published data revealed the widespread noninvestigative real-world use of this lower dose compared with the higher, more toxic FDA-approved (50 mg/m2 every 4 weeks) regimen.
Yet several phase 3 trials conducted during this era that examined new agents for potential regulatory approval in the setting of platinum-resistant ovarian cancer employed pegylated liposomal doxorubicin as the “control arm” delivered at the regulatory-approved dose of 50 mg/m2 every 4 weeks. This decision presumably was related to FDA requirements, with the higher-dose regimen being the agency’s “approved” standard dosing at the time.
So, in conclusion, there are 3 questions to be asked:
* What was the physician’s/investigator’s _ethical justification_ for administering the higher, more toxic dose level of pegylated liposomal doxorubicin to patients/research participants when they would have been highly likely to have delivered a lower, equally effective, and less toxic drug dose to women who were not participants in this study?
* Were patients/research participants specifically informed of the decision to employ this higher, potentially more toxic dose and the physician’s justification for doing so?
* And if they were not informed, why not?
_Maurie Markman, MD, is president of Medicine & Science at City of Hope Atlanta, Chicago, and Phoenix._
**References**
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1. Shuster E. Fifty years later: the significance of the Nuremberg Code. _N Engl J Med_. 1997;337(20):1436-1440. doi:10.1056/NEJM199711133372006
2. Resneck JS Jr. Revisions to the Declaration of Helsinki on its 60th anniversary: a modernized set of ethical principles to promote and ensure respect for participants in a rapidly innovating medical research ecosystem. _JAMA_. 2025;333(1):15-17. doi:10.1001/jama.2024.21902
3. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human participants. _JAMA_. 2025;333(1):71-74. doi:10.1001/jama.2024.21972
4. Fairchild AL, Bayer R. Uses and abuses of Tuskegee. Science. 1999;284(5416):919-921. doi:10.1126/science.284.5416.919
5. Beecher HK. Ethics and clinical research. _N Engl J Med_. 1966;274(24): 1354-1360. doi:10.1056/NEJM196606162742405
6. Menikoff J. Protecting participants is not the top priority in clinical research. _JAMA_. 2024;332(3):195-196. doi:10.1001/jama.2024.7677
7. Rothstein MA, Siegal G. Protecting participants in clinical research. _JAMA_.
2024;332(20):1760. doi:10.1001/jama.2024.19372
8. Abram MB. The Day Is Short: An Autobiography. Harcourt Brace Javanovich; 1982.
9. Brower V. Science versus ethics: new ethical guidelines regarding the use of placebos in clinical trials have sharpened the conflict between public health and patients’ rights. _EMBO Rep_. 2001;2(5):365-367. doi:10.1093/embo-reports/kve103
10. Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E muta_tion. N Engl J Med_. 2011;364(26):2507-2516. doi:10.1056/NEJMoa1103782
11. Markman M. Serious ethical dilemma of single-agent pegylated liposomal doxorubicin employed as a control arm in ovarian cancer chemotherapy trials. _J Clin Oncol_. 2010;28(19):e319-320. doi:10.1200/JCO.2010.28.9934