January 25, 2019
5 min read

Should cancer clinical trial eligibility regarding mental illness be relaxed?

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In 2017, ASCO and Friends of Cancer Research issued a joint statement calling for the expansion of clinical trial eligibility so that trial populations are more representative of all of us. They recommended liberalizing criteria in four categories: patients with brain metastases, HIV/AIDS or organ dysfunction, as well as those aged younger than 18 years.

It is now time to consider a fifth category: Patients with serious mental illness (SMI). The unmet need in health care for patients with SMI is huge. One consequence is premature mortality; these patients die at least a decade earlier than the general population. Cancer deaths make up a significant portion of this mortality excess, with the seriously mentally ill experiencing a two- to fourfold increase in cancer mortality.

Disparities in cancer care certainly account for a large part of this excess. Do barriers to clinical trial participation make matters worse? According to the FDA, 49.5% of investigational new drug applications excluded patients with “mental or psychiatric disorders,” and a survey of head and neck cancer trial listings on cancer.gov showed that 45% excluded patients with mental illness. If clinical trials are unlikely to improve outcomes, this exclusion might not matter so much, but in this era of remarkable advances in precision medicine and immuno-oncology, excluding patients with SMI from clinical trials may lead to worse outcomes for this population.

Lori J. Wirth, MD
Lori J. Wirth

Perhaps it is our duty to not take advantage of these vulnerable patients by enrolling them in clinical trials when they lack capacity to provide informed consent. Freely given informed consent is, after all, a fundamental principle in clinical research.

A diagnosis of SMI does not, however, necessarily impair an individual’s capacity to understand information relevant to his or her illness and treatment options, weigh pros and cons of options, and communicate his or her decisions. The mental health field has studied decision-making capacity in the context of mental health research at length. Analyses have shown that researchers often misjudge SMI patients’ decision-making capacity, which can remain intact in all but the most impaired. Moreover, patients with mental illness express desire to participate in clinical trials for the same reasons that patients without mental illness participate — not only to have an opportunity for better treatment for themselves, but also to help others with similar illnesses in the future.


The Common Rule defines a vulnerable population of children, prisoners, pregnant women, mentally disabled persons, or economically and educationally disadvantaged persons susceptible to coercion or undue influence. The phrase “mentally disabled persons” can be interpreted narrowly to include only people with intellectual impairment, or broadly to include people with a wide range of psychiatric illness. The mental health literature argues against defining every patient with a diagnosis of mental illness as vulnerable. Rather, it recommends that patients with SMI meet criteria for this “vulnerable population” only when specific impairment in decision-making capacity is present, or if the patient is in a situation — such as an involuntary commitment — in which he or she would be subject to coercion or undue influence.

In cancer clinical trials, a more nuanced approach to including patients with SMI may be best. Instead of excluding patients with SMI, it may be better to consider the investigational agent’s potential for psychiatric complications, potential for drug interactions and the individual’s decision-making capacity. Additional opportunities to avoid unnecessary exclusion of patients with SMI include better integration of mental health services into our cancer programs and providing investigators with support, such as psychiatric evaluation of capacity when needed. We also can adopt practices — including more flexible, patient-centered consent processes — to balance the protection of research participants with patient autonomy and desire for clinical trial participation.

In oncology, our greatest goal is to improve the lives of people with cancer. Following the guidance of ASCO and Friends of Cancer Research on broadening clinical trial eligibility, let us not forget about those of us with mental illness.


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Lori J. Wirth, MD, is associate professor in medicine at Harvard Medical School. She can be reached at lwirth@mgh.harvard.edu. Disclosure: Wirth reports no relevant financial disclosures.




Although it is desirable for patients with cancer and mental illness to be included in clinical trials, there are good reasons for why they may not be included. At the end of the day, it will come down to an individual patient-centric decision by the oncology care team, behavioral health psychology care team, the patient and their support system.

Richard L. Schilsky, MD, FACP, FASCO, FSCT
Richard L. Schilsky

There are several reasons why one may think it may not be appropriate for a patient with a mental illness to participate in a clinical trial.

First, there are ethical considerations regarding the capacity of the patient to participate in the consent process for the research study that are dependent upon the nature and severity of the patient’s mental illness. Does the patient understand the risks and benefits of participation? If we cannot conclude that they are competent to engage in the informed consent process, then it becomes difficult to offer clinical trial participation to them.

Second, we must consider the patient’s safety as a participant in a clinical trial. Clinical trials have risks and, if the investigational treatment has substantial risks associated with it and the clinical trial protocol requires that patients report adverse events, a mental illness may interfere with them monitoring for and reporting adverse events.

Third, research compliance with the protocol itself is important. The research study places demands on the care team and the patient. A patient may have to have certain evaluations done on a certain schedule and, if a patient cannot comply with those demands, this becomes an administrative and regulatory issue. There are potential risks for the research site in enrolling patients who may not be able to comply with the protocol.

Finally, there is concern that there may be strong biases on the part of treating physicians or members of the research team regarding all of the above issues, leading them to conclude that they should not offer participation in clinical trials to patients with mental illness. We know from studies of other populations that the most influential factor in whether a patient participates in a clinical trial is whether their doctor recommended that they do so. We have seen this in other populations, such as older patients.

These are all reasons to think twice about expanding enrollment criteria. We need to recognize the risks to the patients and to the research, and make a patient-centered and involved decision on a case-by-case basis as to whether an individual is a good candidate to participate in a clinical trial.

Richard L. Schilsky, MD, FACP, FASCO, FSCT, is chief medical officer of ASCO. He can be reached at richard.schilsky@asco.org. Disclosure: Schilsky reports serving as principal investigator of the TAPUR study, as well as research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Genentech/Roche, Merck and Pfizer.