Cancer Research Versus Care: Just How Different Are the Goals?

OncologyLive, Vol. 20/No. 22, Volume 20, Issue 22

The often intense and frequently highly focused effort to seek scientific purity in answering questions within cancer clinical trials raises serious concerns regarding the ethical foundation of certain studies.

Maurie Markman, MD

An unavoidable tension exists between the roles of a treating oncologist and an investigator when a patient is asked to participate in a clinical research study. This state of affairs is certainly not a recent development. In his 1982 autobiography, Morris Abram, a civil rights lawyer who had leukemia, described this conflict during his care by a prominent clinical cancer investigator.1 During an intense discussion with Mr Abram and his daughter regarding his potential participation in an experimental trial, the physician commented, “My duty is to advise. You must bear in mind that I am not your father’s physician; I am an investigator.”

The difficulty in accommodating the dual roles of a “physician” versus that of a “clinical investigator” has likely been intensified, particularly in the oncology arena, through the efforts of some in the biomedical ethics community who have vigorously stressed a concept associated with participation in a clinical trial labeled as the therapeutic misconception.2 Those who support this view argue that a substantial percentage of patients with cancer who agree to be research subjects in a clinical trial “mistakenly believe” that a primary—or the primary—reason for such participation is for them to benefit personally. In fact, this argument states, the primary purpose of such trials is to generate objectively valid and scientifically valuable knowledge, with any direct benefit (eg, improvement in symptoms, prolongation of time to disease progression, or improved survival) achieved by an individual participant being secondary to attaining such data.

This quite problematic perspective on the nature of cancer clinical trials has permitted some to justify the use of placebo controls in randomized studies when there is the unequivocal potential that an active therapy may result in a highly meaningful outcome for an individual participant. After all, the therapeutic misconception argument goes, investigators do not focus on the “best interests of a patient” in the design and conduct of a randomized trial but rather on the optimal scientific manner in which to answer a particular question, such as whether drug A improves survival compared with drug B, involving a required number of research subjects.

The mantra of such scientific purity in cancer medicine has even been highlighted by scientists who have no direct experience in the arena but appear to simply support the hypothesis that patients should agree to participate in such studies for the theoretical benefit that might accrue to future generations of patients. An example of this rather profound support for the absolute priority of the randomized clinical trial is a remarkable statement by the late eminent scientific leader Carl Sagan in his otherwise insightful book The Demon-Haunted World.3 In a chapter entitled “The Fine Art of Baloney Detection,” Dr Sagan declares, “Control experiments are essential. If, for example, a new medicine is alleged to cure a disease 20 percent of the time, we must make sure that a control population, taking a dummy sugar pill which as far as the subjects know might be the new drug, does not also experience spontaneous remission of the disease 20 percent of the time.”

So, this argument goes, if a phase II study of drug A in metastatic cancer B with a recognized cure rate of 0% is revealed to produce a “cure rate” or, perhaps alternatively, a 10- to 15-year disease-free survival rate of 20%, investigators must conduct a phase III randomized trial comparing drug A with the recognized ineffective standard of care to confirm this finding.

Unethical Trial Designs

Is this really what ethically valid science demands of clinical investigators and research subjects? This often intense and frequently highly focused effort to seek scientific purity in answering questions within cancer clinical trials raises serious concerns regarding the ethical foundation of certain studies.

How else does one explain the regulatory decision several years ago to conduct the landmark phase III randomized trial in malignant melanoma comparing the BRAF inhibitor vemurafenib with a control arm of dacarbazine, a standard-of-care drug known for less than marginal efficacy in this clinical setting, without permitting crossover from the control arm to the experimental agent at the time of disease progression? The study allowed crossover only later, after 675 patients had been randomized, not at its initiation.4 At the time this randomized study was initiated, investigators knew that the biological and clinical activity of vemurafenib was vastly superior to that of dacarbazine,5 but, apparently to preserve the scientific purity of the trial’s survival end point, they decided not to permit patients randomized to the essentially inactive control arm to switch to the more effective therapeutic. The term guinea pig may come to mind but likely only if one argues that the best interests of participants in clinical trials should always be considered at least equivalent to those of the objective goals to achieve the optimal scientific end point.

Fortunately, emerging evidence shows that the ethical foundation of therapeutic cancer trials is shifting to include a greater recognition that a research subject is also always a patient whose specific interest in being a participant is to attain a meaningful degree of direct clinical benefit. Such thinking is likely strongly influenced by increasingly powerful data indicating the substantial clinical utility observed even in early-phase, molecularly based cancer investigative efforts.

It is encouraging to note, for example, that the American Society of Clinical Oncology recently issued guidelines related to trial-associated biopsies that emphasize the critical relevance of ensuring that the potential scientific value of such testing of a research subject is closely aligned with possible risk to the individual patient.6


  1. Abram MB. The Day Is Short: An Autobiography. New York, NY: Harcourt Brace Javanovich; 1982.
  2. Henderson GE, Chruchill LR, Davis AM, et al. Clinical trials and medical care: defining the therapeutic misconception. PLoS Med. 2007;4(11):e324. doi: 10.1371/journal.pmed.0040324.
  3. Sagan C. The Demon-Haunted World: Science as a Candle in the Dark. New York, NY: Ballantine Books; 1996.
  4. Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRCA V600E mutation. N Eng J Med. 2011;364(26):2507-2516. doi: 10.1056/NEJMoa1103782.
  5. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819. doi: 10.1056/NEJMoa1002011.
  6. Levit LA, Peppercorn JM, Tam AL, et al. Ethical framework for including research biopsies in oncology clinical trials: American Society of Clinical Oncology research statement. J Clin Oncol. 2019;37(26):2368-2377. doi: 10.1200/JCO.19.01479.