Ethical Considerations for Phase 1 Clinical Trials

May 14, 2010


Robert G. Mennel, MD
Texas Oncology PA

Patients with metastatic cancer are often faced with an ultimately fatal disease. This often causes patients to consider any therapy that may be construed as providing any chance for improved survival. The stress of their situation may also make patients less able to evaluate data. Patients with metastatic cancer are looking for positive news, and may interpret their physician’s suggestion for palliative care as their physician “giving up on them.” The physician often does not like to give bad news and may be less direct when explaining to patients the expected results of a recommended treatment. If a patient wants treatment and their physician thinks that standard therapy is not likely to be helpful, a phase I trial examining a new therapy is a reasonable option.

On average, however, phase I trials are unlikely to help the patient. Phase I trials are more likely to advance the science of oncology than to improve the survival of an individual. Before targeted therapies, the likelihood that a patient would respond to a phase I trial was approximately 3%. Since the advent of phase I trials based on the biology of the tumor and the pharmacology of the drug being tested, the response rate has increased, but only to approximately 7%.

Phase I trials are testing new drugs and there is almost no data to present to the patient about expected results. Their purpose is centered on the drug—toxicity and starting dose—rather than the patient. This is uncomfortable for the patient and the oncologist. It is difficult to explain to the patient why he or she should be on a trial where the focus of attention is on the drug and not on improving the individual disease.

As oncologists we are trained to represent the best interest of our patients. We are also schooled in the benefit and the necessity of clinical trials. When considering phase I trials for a patient, are these two goals mutually exclusive? This is the basis of the question, “Are phase I trials ethical?”, which is posed to our two discussants. Anthony W. Tolcher, MD, is an internationally respected phase I trialist who is director of the South Texas Accelerated Research Therapeutics (START) Phase I group. Robert L. Fine, MD, is an internist who is nationally and internationally known for his work in medical ethics and palliative care.

Applying Ethical Principles to Phase I Trials

Robert L. Fine, MD, FACP
Director, Office of Clinical Ethics and Palliative Care Baylor Health Care System

Medical practice without ethical reflection reduces the physician to mere technician and robs us of our professionalism. In posing the question, “Are phase I trials ethical?”, Dr. Mennel challenges not only Dr. Tolcher and me, but every reader, for the discipline of medical ethics belongs to every medical professional willing to take responsibility for it, not just those recognized as “experts.”

When confronted with a question of medical ethics, it is prudent to first clarify its meaning and reflect on how we arrive at answers to ethical questions. Only after that should we face the particular question of the moment.

At the most basic level, medical ethics is about what we believe to be good or bad, right or wrong about the goals of medicine and the means used to pursue those goals. Medical ethics is not the same as medical jurisprudence, psychology, spirituality, or religion (though each may be useful in the practice of clinical ethics). Medical ethics is a philosophical discipline that informs us of what we should do, thus complementing the medical science that informs us of what we can do.

So how do we decide if something is good or bad? How do we answer questions like, “Is this ethical?”

Throughout history, ethicists have proposed various theories of ethical reasoning and have offered various justifications for those theories by appeal to intuition, reason, religious faith, social norms, and more. For example, duty-based ethics (Deontology) suggests that an action is right or wrong based upon particular duties, irrespective of the consequences of carrying out a particular duty. If one has a duty to advance the cause of science, then phase I trials are ethical, even though the vast majority of research subjects will not benefit personally. Consequentialist ethics (Utilitarianism) suggests that it is the outcome of an action that determines if the action was ethical. The consequentialist might argue that phase I trials are ethical, noting that the patient will die with or without enrolling in the trial, but with enrollment the good consequence of advancing science will be enhanced.

One common analytic method for determining what is ethically right or wrong within the medical endeavor involves applying a set of ethical principles or virtues to the ethical question at hand. Principles of medical ethics such as beneficence or non-maleficence may guide our actions through the storm of our patient’s terminal illness as a navigation beacon guides a pilot through turbulent skies, while ethical virtues such as patience, honesty, or equanimity (William Osler’s favorite virtue) may refine our character and enhance our bedside behavior when our patients are in the greatest need.

The thoughtful reader will quickly recognize that one may use the discipline of medical ethics to justify all sorts of actions. Interestingly, modern neuroscience suggests that humans, moral mammals that we are, formulate ethical judgments of right and wrong at a subconscious level, before the notions of good or bad reach our conscious awareness. I believe we then apply some ethical reasoning to the determination our subconscious mind has already reached as we consciously decide to either accept or reject our inner judgment of right or wrong.

So what is your ethical judgment about phase I trials? Are they ethical? Yes… no… it depends? I prefer an affirmative answer as long as those involved in the research endeavor of phase I trials strive to honor three important concepts: fidelity, autonomy, and communitarian values.

  • Fidelity (faithfulness). Fidelity to the patient must take priority over faithfulness to the research endeavor. Our faithfulness to the patient must always be more important than the needs of the research institution, company, colleagues, or our own career. Patients give all physicians our professional raison d’etre—our reason for being physicians. Without patients we cannot practice our profession. When we ignore the principle of fidelity, we undermine the very reason for being physicians in the first place: to serve patients.

  • Autonomy (self-governance). Autonomy is the ethical principle at the heart of informed consent. If there is no belief in the principle of autonomy, there is no need for informed consent. True respect for autonomy, however, is more than simply allowing a patient to make a choice. Unfortunately, sometimes we allow patients to make bad decisions out of a shallow respect for autonomy, failing to recognize that the patient’s ability to make a truly informed decision is impaired. The psychological stresses of facing a terminal illness may so impair a patient’s ability to be selfgoverning that the virtuous physician must give extra time and attention to the consent process. Within that process, the researcher’s interest in protecting the patient’s autonomy must take priority over the researcher’s interest in obtaining another trial patient (see “fidelity”). Both fidelity and true respect for patient autonomy may lead the ethical physician away from enrolling a particular patient in a phase I trial.

  • Communitarian values. It is difficult to argue that phase I trials benefit the patients involved, and as such they can be seen as violating traditional notions of beneficence. (“Whatever houses I may visit, I will come for the benefit of the sick,” notes the Hippocratic Oath.) The phase I trial participant is extremely unlikely to achieve the benefit of response, let alone cure. Within the discipline of ethics, we strive to avoid abandoning a prima facie ethical good unless it is counterbalanced by some other essential ethical good. In the case of the phase I trial, the patient is unlikely to have the benefit of response, but they may reap the emotional and social benefit of knowing they contributed to the greater good of the community. I believe physicians, beleaguered though we often feel in this political climate, must also devote ourselves to the greater good of the community through tireless efforts to enhance health care for the entire community— not just those with insurance or financial means. We must not be in the position of allowing the desperately ill patient to make the sacrifice to benefit others, including perhaps our own research career, if we are not prepared to make sacrifices to benefit others as well.

Additional Reading

Gazzaniga, Michael S. The Ethical Brain: The Science of Our Moral Dilemmas. New York: Dana Press; 2005.
Damasio, Antonio. Looking for Spinoza: Joy, Sorrow, and the Feeling Brain. Orlando: Harcourt, Inc.; 2003.

An Option When Current Therapy Fails

Anthony W. Tolcher, MD, FRCP
Director of Clinical Research, South Texas Accelerated Research Therapeutics (START)

Far too many of our patients face the prospect of non-curative therapies for metastatic disease. Despite conventional frontline treatment, disease recurrence, ever-evolving resistance to therapy, and accompanying symptoms of progressive disease is the natural history for most of our patients with advanced malignancies. This results in the clinical dilemma of whether a patient should continue on approved but marginal therapies in the third- or fourth-line setting, be considered for hospice care, or if well enough, be referred for clinical studies that will accommodate the patient.

Since phase I studies accommodate patients with extensive prior therapy and diverse malignancies, many find this the only outlet for participation in a clinical trial. Although viewed by many as non-therapeutic and dose-finding, it is important to differentiate phase I clinical studies in oncology from those of other therapeutic areas. In standard phase I studies performed in normal healthy volunteers, single-dose exposure with detailed pharmacokinetics is considered the custom as no therapeutic effect is needed. In contrast, phase I studies in oncology frequently incorporate the detection of antitumor activity as a secondary objective, permit patients to receive repetitive doses of the investigational therapy to maximize the potential for benefit, and permit patients to continue on in the absence of progressive disease or doselimiting toxicity. Furthermore, in most circumstances, even those patients who experience toxicity are not automatically withdrawn from treatment but can continue on study at reduced doses to ensure that the “all pain, no gain” quandary does not occur.

In an ideal world, dose escalation would be unnecessary as allometric scaling from preclinical models would predict both therapeutic and safe dose levels. Unfortunately, as in all things, we do not live in an ideal world. Dose escalation, from the conservative beginning dose levels to those that induce toxicity, creates the uncertainty that patients and doctors alike feel when considering participation in a phase I study. Is the dose too low for therapeutic benefit or is it going to give side effects that are severe? Most phase I clinicians address these uncertainties up front and directly with the patients, and it is critical for not only patient participation but also the informed consent process. Remarkably, and in contrast to widely held perception, patients generally recognize and accept the inability for anyone to predict benefit, the low likelihood of response, and the risk for toxicity. Patients frequently state reasons for their participation with phrases such as, “If it doesn’t benefit me, maybe it will benefit someone else,” or, “I am not ready to give up.”

The widely reported low response rate notwithstanding, benefit is increasingly observed in phase I targeted therapies from prolonged and durable stable disease, and of course the occasional impressive response. Phase I studies frequently identify activity in tumor types that eventually lead to future approvals. Examples of activity and durable static disease (SD) in phase I studies include gefitinib and erlotinib in non-small cell lung cancer, temsirolimus and everolimus in clear cell carcinoma of the kidney and hepatocellular carcinomas, bevacizumab in breast carcinoma, sunitinib in renal cell carcinoma, and more recently IG FR1 therapies in Ewing sarcoma. Furthermore, despite the perception that these low response rates encountered in phase I studies indicate little benefit, we have seen a forward migration of the same low objective response rates (<10%) in phase II studies, although these same agents lead to progression-free and overall survival in later randomized phase III studies (e.g., erlotinib, temsirolimus, everolimus, sorafenib).1-11

In conclusion, the consideration of a patient’s participation in a phase I study for someone with advancing metastatic disease is one of a number of options that physicians and their patients encounter during the natural history of their disease. Realistic expectations, altruistic characteristics of individual patients, and frank and open discussion of risk and benefit make phase I studies reasonable options for our patients.


  1. Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res. 2006;12:6049-6055.

  2. Jackman DM, Yeap BY , Lindeman NI , et al. Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007;25:760-766.

  3. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.

  4. Atkins MB , Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918.

  5. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.

  6. Amato RJ, Jac J, Giessinger S, et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RA D001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer. 2009;115:2438-2446.

  7. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.

  8. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505-2512.

  9. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.

  10. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293-4300.

  11. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.

Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the editor or of the American Society of Clinical Oncology.


Kelly Marline Willenberg, PhD, BSN

Jun, 30 2010 11:43 AM

I read with interest Current Controversies in Oncology [“Ethical Considerations for Phase I Clinical Trials,” April 2010] as I work with numerous sites who are dealing with ethical considerations in phase I trials. But I was surprised that at no time in the article did either physician mention the controversy of billing phase I trials to Medicare. With the Centers for Medicare and Medicaid Service’s continued non-commitment to defining therapeutic intent for cancer trials and whether or not phase I studies are “qualifying” under the guidelines, it has been left up to the decision of the Fiscal Intermediaries (FIs) of the Medicare Contractors.

There is much disagreement among them, and sites have to make decisions on whether to even open phase I trials that are not properly funded if their FI has denied payment for all phase I trials. This adds another layer to the continued controversy of treatment decisions based on funding. It becomes even more of a dilemma when other payers will cover these costs so the Medicare recipient is denied coverage as a beneficiary based on region.

If it was my family member who was facing this decision, it is not only the risk vs. benefit that our family would discuss, but whether or not our decision would mean lack of coverage from the government payer that we are a beneficiary of. I think that is as much of an ethical dilemma for oncologists as fidelity, autonomy, and communitarian values as a human being. I would hate to have to make that decision based on my payer in today’s economy.

Kelly Willenberg, BSN, MBA, CHRC
President, Synergism, LLC
Chesnee, SC

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