Innovative Clinical Trial Designs Generate New Ethical Dilemmas

Maurie Markman, MD

Fifty years after Henry Beecher’s landmark critique finally helped begin breaking the “code-of-silence” regarding the conduct of unethical clinical research in the United States—sadly including the oncology arena—many serious concerns linger.¹

First of all, there is the low accrual of patients with cancer into clinical trials and the disquieting fact that a large proportion of National Cancer Institute-sponsored studies cannot be completed to the point that an answer to the question ad- dressed by the study can never be provided.²

This particular outcome raises the serious ethical concern that the investigators have failed to fulfill their contractual obligation to study participants to produce information that will hopefully be of value to future patients.

Then there are the questions about the fundamental moral justification for conducting phase III trials when earlier-phase data have revealed objectively defined, well-documented clinical response rates that are simply unheard of in the specific setting.

Although there are multiple examples of questionable clinical trials mandated by a regulatory agency, none is more powerful and painful than the stunning decision to require the conduct of a phase III randomized trial comparing vemurafenib, a first-in-class BRAF inhibitor, against the antineoplastic agent dacarbazine—widely recognized as highly toxic and essentially clinically inactive—in patients with metastatic melanoma.³

This occurred despite the fact that early-phase data of exceptionally high quality had previously revealed an unprecedented >50% to 60% objective response rate with an acceptable toxicity profile with vemurafenib in this clinical setting if a tumor was demonstrated to possess a BRAF mutation (present in approximately 50% of patients with malignant melanoma).⁴

Problems With Novel Concepts

The devastating impact of this regulatory decision on individual patients and their families was magnificently captured in a distressing commentary that raised serious ethical concerns in The New York Times several years ago.⁵ It is appropriate to inquire whether anything of substance has changed in drug regulatory policy since that date.Recently, a new and potentially quite problematic ethical concern has been added to those noted above. In an appropriate effort to improve the efficiency of the antineoplastic drug development process, investigators have begun to explore the utility of adaptive study designs.⁶

Through these novel randomization processes, the probability that a given research subject will be treated with a specific antineoplastic regimen will be based on the prospectively defined degree of activity such as objective responses, a decrease in tumor markers, or time to progression already demonstrated for that agent/strategy within the study in question.

While clearly a more complex concept than a simple 1:1 randomization schema, the idea is to evaluate the potential clinical benefit of a particular strategy more efficiently. The next step would likely be to move on to a more traditional examination of the approach in a phase III randomized trial. Simple enough. Right?

But what happens when such a study reveals, as recently reported in a high-impact peer-reviewed medical journal, that the delivery of a combination of carboplatin plus veliparib to patients with breast cancer “had an 88% predicted probability of success in a [future] phase III trial” compared with the control arm?⁷

That poses this fundamental question: If a phase III randomized clinical trial is planned to test the novel drug against the standard of care, and a patient is informed during the consent process that the experimental arm has an 88% probability of success compared with the control group, why would that patient agree to be randomized to receive what is strongly suggested to be a less effective strategy? In ethical terms, does such an approach satisfy the morally essential concept of equipoise?

Of course, there are concerns with the limited overall experience with this novel type of statistical analysis, the size of the study population in the specific trial, and the potentially understated and possibly still unknown toxicities of the particular investigative approach being evaluated.

But the question remains: Why, under the circumstances just described and the data just presented, would patients with advanced cancers searching for what they believe to be the best approach to manage their own illness be asked to become research subjects in a phase III trial that gave them a flip-of-a-coin chance to receive what certainly appears to be the superior therapy and a similar chance to be treated with what seems to be a far less effective strategy?

Why would they not request—or perhaps even demand—to be treated with the alternative strongly suggested to have the greatest clinical utility?

These questions deserve an answer. No, to be clear, they require an answer.

A response from the academic community and governmental regulators likely would highlight all of the unknowns previously stated in an attempt to provide such a justification. Such analysis and any subsequent debate would likely be published in the medical literature, the recognized standard form of communication between researchers and the regulatory communities.

However, the far more relevant groups who should be providing their input into this discussion and debate are individual patients, their families, and ultimately our society. And who do you think should have the final say in this matter?

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

References

1. 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.
2. Bennette CS, Ramsey SD, McDermott CL, et al. Predicting low accrual in the National Cancer Institute’s Cooperative Group Clinical Trials. J Natl Cancer Inst. 2015;108(2). pii:dvj324.
3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRCA V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
4. 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.
5. Harmon A. New drugs stir debate on rules of clinical trials. The New York Times. http://goo.gl/jjgdJQ. Posted: September 18, 2010. Accessed September 2, 2016.
6. Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med. 2016;375(1):65-74.
7. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23-34.