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JULY / AUGUST 2014 :: 75(4)
Cancer in North Carolina

Cancer is the leading cause of death in North Carolina. This issue of the NCMJ discusses cancer prevention, screening, treatment, and survivorship; disparities in incidence and mortality; and ethics of clinical trials. Highlighting the importance of comprehensive data for understanding cancer, original articles in this issue address how medical homes can reduce health care utilization among breast cancer patients and how distance to care affects receipt of radiation therapy.


The Ethics of Clinical Trials for Cancer Therapy

Lynn J. Howie, Jeffrey M. Peppercorn

N C Med J. 2014;75(4):270-273.PDF | TABLE OF CONTENTS

Cancer clinical trials are intended to evaluate novel interventions and to improve outcomes. Such research depends on the participation of patients seeking the best options for care. The design, conduct, and analysis of trials must therefore be grounded in an ethical framework that respects and protects the interests of clinical trial participants.

Despite advances in treatment, cancer continues to cause substantial morbidity and mortality in the United States, with more than 1.5 million cases of cancer diagnosed each year [1]. It is estimated that 57,000 new cases of cancer will be diagnosed in North Carolina in 2014 [2]. Clinical trials are central to the development of new treatments to improve cancer care and outcomes. However, clinical trials are designed to answer questions about treatments that do not yet have clearly demonstrated benefits. Therapies tested in clinical trials can have unexpected toxicities, and by definition, the risk-to-benefit ratios of these interventions have not yet been determined. In addition, clinical trials can involve tests or procedures that are performed solely for research purposes and are not otherwise necessary for the care of the patient.

Patients often want to enroll in clinical trials in order to obtain cutting-edge therapy or to gain a chance of clinical improvement that is unlikely with conventional therapy. Physicians may discuss a clinical trial with a patient for these same reasons. However, clinical trials are designed to advance knowledge and to improve care for future generations, and thus they are distinct from routine clinical practice, where the sole goal is to care for the patient. For this reason, cancer clinical trials must consider and adhere to core ethical values—including voluntary informed consent, minimization of harm, and equipoise—and they must take into account researchers’ obligations to both participants and science. By doing so, such trials can lead to improvements in clinical care and advancement of new therapeutics for future patients.

Patient Participation
Patients participate in clinical trials for a variety of reasons. The primary reasons include interest in a new treatment that may provide direct benefit, desire to help others, and trust in the physicians and institutions conducting the research [3, 4]. Despite these motivations, fewer than 2% of cancer patients participate in clinical research [5]. Studies have demonstrated that elderly individuals, those with comorbid conditions, ethnic minorities (including African Americans and Latinos), and those with lower socioeconomic status tend to be underrepresented in cancer clinical trials [5-7]. Barriers to enrollment include concern about adverse effects of unstudied therapies, mistrust of research, financial constraints, lack of availability of trials for treatment of a particular condition, or lack of access to trials [8-10]. In addition, although randomized trials typically test the interventions that appear most promising based on preliminary efficacy and safety data, patients may be confused by the concept of randomization, they may not like the fact that their doctor will not be directly determining which intervention they receive, or they may be unwilling to risk being assigned to a control arm.

Amid the general concern about low rates of participation in adult oncology trials, there have been recent calls to reinvigorate and reemphasize the recruitment of ethnic minorities to participate in cancer clinical trials, because the persistently low participation rates among these groups is thought to be associated with ongoing disparities in outcomes [11]. In pediatric oncology, rates of clinical trial participation have historically been very high, and the ability to learn from virtually every patient is credited with being part of the reason for the high cure rates achieved in pediatric cancers over the past several decades [12].

Types of Clinical Trials
Studies evaluating new therapies occur in several phases to determine whether these agents or interventions merit continued evaluation in larger groups of participants (see Table 1). It is important to understand the phases of cancer trials and to consider the distinct ethical issues that can arise at each step of the process of trying to bring a new intervention to the clinic.

Phase I clinical trials are the first test of an intervention in humans; these trials are performed following preclinical work in cancer cells and in animals. The primary goals of phase I trials are to evaluate dosing and to study the safety of novel therapies; the secondary goal is to determine whether there is evidence of anticancer activity that merits further evaluation in subsequent studies. These relatively small studies raise large ethical issues, because the participants are often relatively healthy patients who have few or no other therapeutic alternatives, who face death in a matter of months without treatment, and who participate with the hope of improved survival [13]. However, these studies involve interventions that are the least tested, and the study may not expose patients to the dose of the drug that will be used in later studies. The difference between the participants’ goals and the scientific goals of phase I cancer trials has created concern regarding therapeutic misconception [14], which is defined as the failure of trial participants to understand that the primary purpose of clinical trials is to produce generalizable scientific knowledge [15]. Behind these ethical concerns is the idea that, if patients truly understood the nature and design of a phase I trial, they might choose not to enroll.

Much has been written about the concept and validity of therapeutic misconception, but as Agrawal and Emmanuel pointed out [16], it may be perfectly reasonable for an informed patient to participate in a phase I trial, given the limited alternatives. The researcher’s ethical obligation is to ensure that participants in a phase I oncology trial understand that the study is research and that drugs tested in phase I clinical trials often have limited efficacy and unexpected toxicities; researchers should also make sure patients know what is and what is not known about the intervention. A systematic review of phase I oncology trials from 1991 through 2002 [17] demonstrated that agents evaluated in phase I trials had an objective tumor response rate of 10.6%; this rate ranged from 4.4% among trials of a single agent to 17.8% among trials that include at least 1 anticancer agent that was already approved by the US Food and Drug Administration (FDA). Of the participants for whom grade 4 toxicity data were available, 14.3% experienced at least 1 such toxic event. The highest toxicity-related death rate was found in trials involving multiple chemotherapeutic agents (both investigational and FDA-approved) [17]. Thus there is need for a thorough discussion of the risks, benefits, and alternatives to participation in a phase I trial, including palliative care [13].

Once a phase I trial has proven that an intervention is relatively safe (and ideally that it has potential for disease response), then additional phases of clinical trials are conducted; these are designed to better define safety and effectiveness in larger populations. Phase II clinical trials are typically single-arm studies that test interventions at a dose defined as tolerable by the phase I trial; the goal of phase II trials is to further evaluate safety and to determine whether an agent is effective at controlling disease or symptoms for a specific cancer.

If an intervention still appears safe and effective in phase II trials, then a larger, randomized phase III trial will be conducted to evaluate the novel intervention in comparison with an existing standard of care. In oncology, phase III trials typically test a proven therapy, such as cytotoxic chemotherapy, with or without the addition of a novel intervention (in recent years, the novel therapy is often a molecularly targeted intervention). A placebo can be used in a phase III trial when patients in the control arm and those in the experimental arm both receive standard chemotherapy, or a placebo alone can be given to patients in the control arm when there is no clear standard of care or when the existing standard of care is known to have little efficacy and/or has excessive toxicity [18].

Although participation in a clinical trial at any phase may benefit the subject, such studies are designed to determine the best treatment for future patients. Given the uncertainty associated with any experimental intervention, there are potential benefits but also risks associated with participation in clinical trials, including toxicity, lack of efficacy, adverse events from study procedures, financial costs, time burdens, and privacy concerns. As a result, how patients are informed about potential risks and benefits is a central component of the ethical conduct of these trials.

Informed Consent
Informed consent is a necessary, but not sufficient, component of ethical research conduct. For participation in clinical research to be voluntary, patients must understand several aspects of the study: its purpose, the visits and procedures that will take place as a part of the study, the risks and benefits of the study and of the potential interventions, their right to withdraw from study participation at any time, and the alternative treatments that are available if they choose not to participate in the study [19]. Important elements of informed consent are described in the US Code of Federal Regulations [20]. Recent efforts have sought to improve the quality of informed consent through the use of plain language and by having prospective research participants watch videos that enhance their understanding of the study and of the consent process [21, 22].

Scientific Considerations
In addition to considerations pertaining to respect for research subjects as individuals, the scientific aspects of clinical trials also play a role in determining whether a clinical research study is ethical. Study design, study conduct, scientific validity, contribution to scientific knowledge, and communication and dissemination of results are all parts of ethical research conduct [23]. Ethical research studies must be scientifically rigorous and designed in such a way that they will be able to answer the questions they pose; fulfilling these criteria helps to justify patients’ participation in the study and the risks that they accept in exchange for contributing to scientific knowledge.

Study design. For a clinical trial to be ethical, it must possess the quality of clinical equipoise, meaning that there is no existing evidence suggesting that participation in one treatment arm will result in inferior results compared with participation in another treatment arm [24]. This equipoise should be present throughout the trial; if it becomes evident that one of the treatment arms is inferior to the other, then the design of the trial should be modified to eliminate the inferior treatment. This modification, which can be done through adaptive clinical trial designs or interim analyses, should ensure that subjects enrolled in a study are not exposed to treatments that have been demonstrated to be worse than alternatives within the trial design.

As data are collected and evaluated for interim safety and efficacy analyses, researchers may face decisions about discontinuing a trial early due to evidence of harm, evidence of futility, or evidence of superior efficacy. The ethical need to not harm current research subjects, whether by exposing them to risky medications or by preventing them from receiving therapies that appear to be clearly superior, can conflict with the need to better understand the risks and benefits of the treatment over time [25]. However, given that participants have the right to withdraw, there should be established ways of notifying them of new information obtained during the trial, particularly information about potential treatment risks, so that informed consent is present throughout the subject’s participation [26].

Scientific obligations. When a clinical trial is completed, researchers have a duty to report the results so that the study can inform oncologists and patients about the suitability of the experimental intervention as a possible addition to standard cancer care. Unfortunately, a significant number of trials are not reported in journal publications, which results in biased reporting of available data [27]. Additionally, preliminary data that are reported at scientific meetings are often not followed by journal publications, suggesting that analysis of additional data changed the magnitude and/or direction of the impact of the therapy [28]. This lack of published studies has substantial implications for the way that new therapeutics are incorporated into routine clinical practice and how information about safety or efficacy is understood.

Ethical Issues With Emerging Research Practices
While our focus has been on the ethical issues associated with traditional cancer clinical trials, we should also acknowledge the increased interest in using “real world” data from electronic health records (EHRs) and administrative data to better understand the effectiveness and safety of cancer interventions in clinical practice. This is of particular interest in oncology, where patients enrolled in trials are often younger and healthier than the average cancer patient, and because there is considerable off-label treatment in settings where a large randomized trial may never be done [29]. Given that EHRs are used in routine clinical practice, issues concerning consent to data usage and patient privacy are of central concern when data are used for research. The ethical frameworks to address these concerns are developing, with a central focus on the balance between protecting patient privacy and the potential public good that might result from this research, such as safety data and comparative effectiveness evidence, which could lead to improved outcomes and reduced societal costs of care [30].

Clinical trials are essential to improving outcomes for future generations of patients with cancer. Such trials also offer participating patients access to a treatment within a carefully regulated environment with an emphasis on safety. A clinical trial participant may be among the first to benefit from a novel intervention that is not otherwise available. However, given the uncertain nature of the outcomes for individual participants in these trials, adherence to ethical principles in study design and conduct is needed to ensure that participants are being treated with autonomy and respect, and that the study is contributing to knowledge that will help guide care for future patients.

Advances in cancer care over the past 50 years have come primarily through clinical trials. Further research, conducted on a solid ethical foundation, is essential to continue this progress. Patients with cancer should be offered the opportunity to consider participation in clinical trials whenever possible, and they should be provided with the information they need to make an informed choice about whether enrollment in such a trial is right for them.

Potential conflicts of interest. J.M.P. has received research funding from Novartis and is a consultant for Genentech; his spouse is an employee of GlaxoSmithKline. L.J.H. has no relevant conflicts of interest.

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Lynn J. Howie, MD fellow, Division of Medical Oncology, Duke Cancer Institute; fellow, Duke Clinical Research Institute; Durham, North Carolina.
Jeffrey M. Peppercorn, MD, MPH associate professor, Duke Cancer Institute, Durham, North Carolina.

Address correspondence to Dr. Jeffrey M. Peppercorn, Division of Medical Oncology, Duke Cancer Institute, Box 3446, DUMC, Durham, NC 27710 (