Advances made in cancer care in recent years have been made possible by the willingness of patients to participate in clinical trials, including phase I trials, which are generally the first time investigational agents are used in humans. These early-phase trials raise unique concerns because they have a therapeutic intent, and can provide clinical and psychological benefits, but they are not primarily designed to establish efficacy.1
Other ethical issues to consider in the enrollment of patients to oncology trials include how to better incorporate older adults, who comprise the majority of patients in oncology practice but are underrepresented in clinical trials,1 andfactors related to the conduct of clinical trials in resource-constrained regions of the world, where logistical, ethical, and cultural differences must be considered.
To further explore some of these issues, experts in various areas of clinical trial conduct are joining together to hold the Education Session, “Enrolling Patients in Early-Phase Clinical Trials: An Ethical Dilemma,” to be held Sunday, March 31 (11:30 AM-12:45 PM, in room E450). The session will be chaired by Steven Joffe, MD, MPH, vice chair of medical ethics and the Emanuel and Robert Hart Associate Professor at the University of Pennsylvania.
Ethics of Phase I Trial Enrollment
To open the session, Dr. Joffe will discuss pertinent issues, key evidence, and future directions related to the ethics of phase I trials. Potential benefits of phase I trials, as outlined in a 2015 ASCO Position Statement Update, include improved quality of life, positive psychological effects, and the potential for a direct medical benefit.1 Thus, “objections to phase I trials based on the arguments that participants are especially vulnerable, and on the fact that the trials’ primary objectives address toxicity and dose-finding, are misguided,” Dr. Joffe said.
Evidence indicates that more recent phase I trials, which are more likely to include targeted agents and immunotherapy than older trials, are associated with rates of response that are higher than those reported in older phase I studies.1 The overall risk–benefit ratio for patients has also been improving, as targeted agents may induce responses with less toxicity than is often seen with cytotoxic therapy.1
On the whole, current data “support the contention that phase I trials in oncology offer a prospect of benefit, although we must acknowledge that it’s limited,” Dr. Joffe said.
However, patients may have misconceptions about the potential benefit they may gain by participating in a phase I trial. Intervening in the informed consent process has been shown to improve patients’ comprehension about the objectives of phase I trials.1 Dr. Joffe concurred that improvements in the process for obtaining informed consent are needed. “We can do better,” he said.
Considerations for Older Patients
The second speaker, Stuart M. Lichtman, MD, FACP, is an attending physician at Memorial Hospital for Cancer and Allied Diseases, professor of medicine at Weill Cornell Medical College and president-elect of the International Society of Geriatric Oncology (SIOG). Dr. Lichtman, an internationally renowned leader in the field of geriatric oncology, will discuss the role of geriatric oncology and palliative care in clinical trials.
Older adults comprise the majority of patients with cancer but are in the minority when it comes to clinical trial enrollment. “Older patients are underrepresented in trials compared to their proportion in the population,” Dr. Lichtman said, “even in curative therapies.” This leads to clinicians needing to extrapolate data from younger and healthier populations to their older patients.
Potential barriers to participation in clinical trials among older adults include restrictive eligibility criteria (because of performance status, end-organ function, or health-related factors), as well as study design. It has been proposed that current clinical trials do not typically include endpoints relevant to older adults.2 Lack of referral by treating physicians is also a substantial driver of lack of participation. In a Cancer and Leukemia Group B retrospective study of patients with breast cancer, age was significantly associated with a physician’s decision to offer a clinical trial, after controlling for physical function and comorbidity.3 Dr. Lichtman postulated that this situation may be changing.
Fear of toxicities is another reason that older individuals may not enroll on clinical trials. Comorbidities and drug interactions, given the polypharmacy common in older patients, are also considerations. In some cases, this hesitation is warranted, Dr. Lichtman explained. “We have to be realistic,” he said, adding, “if there is fear of vulnerability, the patient shouldn’t enroll.”
In general, there is a lack of data about the safety, efficacy, and appropriate dosing of cancer therapies in older adults, Dr. Lichtman added. Even if trials do enroll some older patients, they often do not provide adequate information about the study population and the efficacy and safety of an agent according to age. “Many studies do not report age distribution and other clinical information,” he noted, and oftentimes safety information is not broken down by age. For example, it would be very helpful to know if a specific adverse event is occurring predominately in older individuals.
Changes to clinical trial design could make trials more amenable to older populations. Perhaps eligibility criteria should be redesigned and more relevant endpoints, including cognition, independence, and preservation of function, could be incorporated.2
Dr. Lichtman also suggested that small studies using drugs that have already received U.S. Food and Drug Administration approval are one way to obtain information on the dosing, safety, and efficacy of new therapies in older adults. Such studies conducted in older or more vulnerable patient populations could provide valuable insight on the effects of a drug in a more “real-world” setting.
(For more information on the care of older patients with cancer, view the infographic Preparing for an Aging Nation: The Rise of Older Adult Patients with Cancer in the United States.)
The Globalization of Cancer Research
The third speaker will be Carlos H. Barrios, MD, professor of internal medicine and director of the oncology research unit at Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Su, in Porto Alegre, Brazil. As director of the Latin American Cooperative Oncology Group, Dr. Barrios brings a unique perspective on the conduct of clinical trials outside the United States.
Over the past few decades, the nature of cancer clinical research has changed substantially, from a strategy centered almost exclusively in high-resource countries to one that is increasingly involving resource-constrained regions of the world, Dr. Barrios said. The increasingly global nature of clinical trials is primarily seen in confirmatory phase III trials. In a 2007 estimate, one third of all phase III trials (across all disciplines) sponsored by the 20 largest pharmaceutical companies were being conducted exclusively outside the United States, and 55% of all phase III study sites were located outside the United States.4 In contrast, early-phase trials continue to be concentrated largely in the United States and Western Europe.
Dr. Barrios noted that the inclusion of resource-constrained countries in global cancer studies is justified by the epidemiological changes occurring in recent decades in resource-constrained regions, with fewer people dying from avoidable diseases and more people facing cancer and chronic illness. The globalization of clinical research does have potential benefits for persons living in resource-constrained regions, including improvements in medical care and early access to new drugs and advances. However, conducting clinical trials in resource-constrained regions also presents new challenges, and both the logistic and ethical implications should be considered.
For example, the conduct and analysis of clinical trials can be affected by multiple cultural factors that differ geographically, including variations in perceptions of clinical research, dietary habits, use of herbal products or alternative treatments, adherence to treatment, reporting of adverse events, and the doctor–patient relationship. Geographically distinct populations also have different lifestyles, ethnicities, and genetic profiles, and the inclusion of these different populations can affect both the safety and efficacy of drugs, Dr. Barrios explained.
Regulatory aspects of clinical trial conduct also vary geographically and present significant challenges regarding monitoring, auditing, and inspecting to ensure trials are being conducted appropriately and consistently. In regard to ethical considerations, Dr. Barrios notes that participation in a clinical trial “may represent the best therapeutic alternative for a specific patient, as the available standard of care or access to the health care system may be suboptimal.” Important to consider, Dr. Barrios added, is that for patients in high-resource countries, the standard of care may be available outside a clinical trial.
The issue of informed consent is also a key consideration, particularly in areas where significant barriers may include access to care, illiteracy, and language issues, Dr. Barrios said. He concluded that, “efforts to integrate academic research at a global level are vital if we are going to succeed in advancing the science of medicine and improve health for all.”