Bridging the Ethical Divide Between Cancer Care and Clinical Research

The topic of the ethical conduct of clinical cancer care and research never gets old, only more complex. Considering the rather substantial scholarship and attention given to what has been loosely labeled “ethical concerns” in the clinical domain since the end of World War II, it is not unreasonable to have hoped the majority of such issues would be both anticipated and relatively clearly understood, with universal (or near universal) agreement within the medical, regulatory, and professional ethics communities regarding appropriate responses and resolutions.^1,2 However, from the perspective of this multidecade observer who has had a front-row seat to the evolution of cancer medicine, I would suggest nothing could be further from reality.

Consider, for example, the truly fundamental question in interventional cancer research as to whether it is ethically mandated or alternatively simply unethical to consider crossover from the control arm of a regulatory-approval quality phase 3 randomized study to receive the investigative agent at the time of disease progression. Of course, crossover assumes the individual’s current medical condition permits the reasonably safe delivery of the agent and that the patient continues to desire to receive the therapy.

In one corner of this debate are often statisticians, drug regulatory agencies, academic purists, and third-party payers who may argue it is unethical to routinely consider the inclusion of such crossover because of a realistic potential that such an approach will negatively affect the ability to objectively measure a crucial overall survival (OS) study end point. In the opposite corner are clinicians and others within the cancer community who would argue it is unethical to fail to consider crossover if the individual patient desires this option and remains an appropriate candidate to potentially benefit from the agent’s therapeutic effects after experiencing progression on the study control arm.

So, to summarize, the principal question being debated here is whether the highest-level (primary) ethical goal in a randomized interventional cancer trial is to provide a definitive answer as to the effect of an investigative regimen on OS compared with the standard-of-care (SOC) program or whether the highest-level (primary) ethical goal is to maximize the opportunity for a favorable clinical outcome for individual study participants, which includes all medically appropriate efforts to ensure their safety as research participants. One might argue that this rather straightforward question has yet to be adequately addressed by the cancer research community and by those responsible for oversight of this large and often quite complex domain. The dilemma has recently been highlighted in a JAMA editorial entitled “Protecting Participants Is Not the Top Priority in Clinical Research,” written by Jerry Menikoff, MD, JD, a well-known academic ethicist.³ Menikoff opines:

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 participants.

As thought-provoking as these words are for the potential ethical conflict between clinical care and what may change when the individual agrees to become a research participant, it is perhaps the specifics that Menikoff provides that mandate the greatest discussion:

Among the things that might take place in research that could conflict with the goal of only doing what is in that person’s best interests are randomizing participants to different treatment groups, failing to individualize treatments, requiring possibly risky tests whose results will not alter the participant’s treatment, and failing to disclose interim results.

Although the most rational response to this dilemma would be to suggest the critical relevance of both goals, individual patient welfare and attaining critical knowledge that will inform future clinical therapeutics and related decisions (regulatory approval, payments), in the opinion of this commentator who has spent his career as both a cancer physician and investigator, it is important to appreciate that conflict is inevitable. When a patient’s oncologist offers participation in a therapeutic clinical trial and the patient agrees to become a research participant, does that change the nature of the obligations that the physician has to the patient? If an oncologist would not otherwise elect to treat a patient with a commercially available agent (as part of the SOC or investigative study arm) or at a dose being employed in a trial due to concerns for potential adverse effects in this individual, is it ethical for the physician to suggest study entry?⁴

If a clinician, based on their experience and/or knowledge of the literature, believes a novel agent/strategy is likely to be more effective than an SOC option in a randomized trial, is it ethical for the clinician to suggest the patient enter the trial?⁵ Asking the question slightly differently, outside the research setting, would an oncologist ever offer their patients a regimen they believed, based on their medical knowledge and experience, to be inferior to an alternative superior approach? Of course, the answer to this question is no. So how could that oncologist recommend participation in a trial where their patient may be randomly assigned to a regimen they believe to be inferior?

Although the sometimes palpable conflict highlighted in this all-too-brief commentary has been smoldering for decades and will almost certainly continue to challenge ethical thinking within the cancer community, there is one additional point that requires mention, and this was the final item in Menikoff’s list: “failing to disclose interim results.” In fact, this concern might be extended to ask how often research participants are provided with information related to the final outcomes of a completed study.⁶

What if the initial 4, 6, or 8 patients treated in a single-arm phase 2 cancer study do not achieve an objective response to an experimental agent? Should oncologists considering future patients for study entry be informed of these facts and provide these data to prospective research subjects? If not, what is the ethical justification for this decision? Finally, is it possible that the potential lack of transparency highlighted in this commentary within the clinical research domain is one of many reasons for the strikingly limited participation of patients with cancer in clinical trials?⁷

References

1. Beecher HK. Ethics and clinical research. N Engl J Med. 1966;274(24):1354-1360. doi:10.1056/NEJM196606162742405
2. Jones DS, Grady C, Lederer SE. “Ethics and clinical research”--the 50th anniversary of Beecher’s bombshell. N Engl J Med. 2016;374(24):2393-2398. doi:10.1056/NEJMms1603756
3. Menikoff J. Protecting participants is not the top priority in clinical research. JAMA. 2024;332(3):195-196. doi:10.1001/jama.2024.7677
4. 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-e320. doi:10.1200/JCO.2010.28.9934
5. Hellman S, Hellman DS. Of mice but not men: problems of the randomized clinical trial. N Engl J Med. 1991;324(22):1585-1589. doi:10.1056/NEJM199105303242208
6. Markman M. What must research subjects be told regarding the results of completed randomized trials? IRB. 2004;26(3):8-10. doi:10.2307/3563750
7. Unger JM, Vaidya R, Hershman DL, Minasian LM, Fleury ME. Systematic review and meta-analysis of the magnitude of structural, clinical, and physician and patient barriers to cancer clinical trial participation. J Natl Cancer Inst. 2019;111(3):245-255. doi:10.1093/jnci/djy221