Yoram Unguru, MD, MS, MA
Improvements in protocol-driven clinical trials and supportive care for children and adolescents with cancer have markedly reduced mortality rates over the past 5 decades. Yet, along with clinical advances, oncologists and their young patients with cancer face a host of ethical issues, made more complex by the tender age of the population. To shed light on this challenging sector of the oncology community, The ASCO Post spoke with Yoram Unguru, MD, MS, MA, a pediatric hematologist/oncologist with joint faculty appointments at The Herman and Walter Samuelson Children’s Hospital at Sinai and The Johns Hopkins Berman Institute of Bioethics, Baltimore, where he is a Core Faculty member.
Family-Specific Decision-Making Model
Please give the readers a sense of the ethical challenges in pediatric oncology, especially in difficult discussions about treatment options.
In many ways, these issues overlap with the adult cancer population faced with life-threatening illness. Of course, the caveat is that we must balance the needs and wishes of parents with those of our patients who include young children, school-aged children, adolescents, and young adults, and who by virtue of their developmental station have varying levels of capacity, maturity, and life experiences.
The basic approach for shared decision-making is a “triangle.” The focus is on the child, accounting for age, developmental maturity, and emotional intelligence while simultaneously engaging in a meaningful manner with the parent or guardian who is an integral participant. Most pediatric hematology/oncology clinicians appreciate the need to include the child to the extent that he or she is able and willing to participate in clinical decision-making, which takes on many forms depending on the physical and mental status of the child.
“I’m a firm believer in bringing kids into the heart of the discussion. Often when they don’t have a grasp of what’s happening, it can lead to greater anxiety.”— Yoram Unguru, MD, MS, MA
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I’m a firm believer in bringing kids into the heart of the discussion. Often when they don’t have a grasp of what’s happening, it can lead to greater anxiety. The wrinkle is in the nuances of these discussions. Over the years, I’ve been humbled by the experience; I continue to modify my approach, using a family-centric model that accounts for each family’s culture, religion, experience with decision-making, and related issues.
You’ve written about the drug shortages that affect pediatric oncology. It seems beyond the pale that the world’s richest country could run low on life-saving drugs for children. How did we get to this troubling place?
It is a jaw-dropping realization that more than any other wealthy industrialized nation, we have created a situation where U.S. drug shortages are the new normal. Although drug shortages have existed in one form or another for a long time, for the past 10-plus years, they have been omnipresent. Shortages are a reflection of our unique for-profit health-care system. If you scour the literature on this issue, leading health-care policy experts and honest insiders, agree that the primary driver behind drug shortages is about economics and business decisions.
To understand this conundrum, you have to look at the drugs that are in short supply. For example, right now, and on-and-off for years, we have and have had shortages of the leukemia drug asparaginase Erwinia chrysanthemi, which is made by a single company. In 2018 and again in 2019, we saw terrible shortages of vincristine, probably the single most used chemotherapy agent in childhood cancer. In February 2018, we experienced a vincristine shortage; at the time, two companies manufactured vincristine and each had difficulty meeting demand. In October 2019, vincristine became scarce again, but this time, only a single company was responsible for its production.
This is one of the key problems of shortages, an over-consolidated marketplace with little, if any redundancy or backup. As far as the vincristine shortage, through the good work of patients, patient-advocates, clinicians, and professional organizations, the company which had stopped making vincristine was publicly shamed into bringing vincristine back into the marketplace.
Drugs that are in short supply largely come from the class of sterile generic injectables, which have been around for decades. These drugs are not easy to make and they are not hugely profitable, so there is little financial incentive to produce them. Consequently, often only one or two companies make drugs like vincristine; so, along with the economic disincentives, if there’s a manufacturing issue, the supply chain dries up, a shortage ensues, and it takes time for supply to be reestablished. You don’t see shortages of profitable blockbuster drugs with names ending in “mab” (ie, monoclonal antibodies). Another problem relates to the manufacturing model, so-called “just-in-time” production. Companies produce just enough drug for here and now with little backup. From a regulatory perspective, when a glitch in manufacturing results in shortages, by law, companies are not required to disclose to the public where they get their ingredients or where individual products are made. Moreover, companies are expected to verify that imported ingredients meet necessary quality controls, but this isn’t a legal requirement and some companies do a better job than others in this regard. We need a more transparent system. When it comes to childhood cancers, we have very few alternative agents to substitute when faced with a scarce lifesaving drug. The result: kids with cancer, our most vulnerable patients, end up needlessly suffering.
Stirring Emotion Into Action
What are we doing to cope with cancer drug shortages?
I’ve been dealing with this issue for 8 or 9 years, and while I’m an optimist and want to believe that the work done by so many people and organizations will result in change, over the past several months, the drug shortages have made me a bit more cynical. That said, the 2019 U.S. Food and Drug Administration report, Drug Shortages: Root Causes and Potential Solutions,1 and several initiatives that followed such as the U.S. Department of Homeland Security report on prescription drugs and the MEDS Act offer a glimmer of hope. We in the medical community, and those in media, must keep this issue front and center. We need to think outside the proverbial box and not be afraid to stir peoples’ emotions so they take action.
Let’s be honest: there are few things that are more unfair than a child denied a life-saving cancer drug because it isn’t profitable. We need to call out the companies and their culture and hold them responsible. There is nothing wrong with pharmaceutical companies making a profit, but at what cost to patients? Only by keeping this issue in the public and governmental consciousness can we make substantial and lasting change.
Ethical Dilemmas in Clinical Trials
Please describe the phenomenon called “therapeutic misconception” and how it might affect the accrual of children on clinical trials.
Therapeutic misconception is an interesting concept; it occurs when participants in clinical trials conflate the goals of clinical care and research. Specifically, trial participants fail to appreciate that the goal of research is to produce generalizable knowledge to help future patients and not aimed for their direct benefit. In therapeutic misconception, the patient on a trial inaccurately believes that the trial is designed for therapeutic intent.
It’s important to distinguish benefit from intent. A patient who agrees to participate in a trial must understand the goal or purpose of the trial. Each potential trial participant brings unique abilities to the table, and it is necessary to adapt the presentation of the information to the subject’s capabilities. I’ve engaged with parents who, after getting a complete rundown of what to expect on a phase III clinical trial, appreciate the nuances of the trial and are interested in the experimental agent but ultimately reject enrollment because they don’t want their sick child to be randomly assigned to a treatment arm—the notion doesn’t fit with them.
“It is a jaw-dropping realization that more than any other wealthy industrialized nation, we have created a situation where U.S. drug shortages are the new normal….”— Yoram Unguru, MD, MS, MA
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One interaction stands out: I discussed trial enrollment with the mother of a patient, and after hours of listening to me and taking notes, she stated she wasn’t interested. She had as good a grasp on the trial as one could have. The next day, she said she’d changed her mind and wanted her child to go on study. At the time, there was a methotrexate shortage; digging a bit deeper, she shared she thought her daughter would stand a better chance of getting the drug if she were on trial. I told her that wasn’t the case and for this exact reason, guidance on drug shortages that colleagues and I published specifically notes that trial participants should not be prioritized to receive a scarce drug. We don’t want to create a situation wherein the trial serves as undue inducement. People should enroll in trials because it’s consistent with their values and preferences and they believe in the particular study in question. This example illustrates just how desperate people are when faced with a drug shortage. This mother who had a strong grasp of the trial and was against enrolling was nonetheless willing to do so because of the methotrexate shortage.
Euthanasia and Culture
You were coauthor of a paper in the AMA Journal of Ethics with the highly provocative title, “Should Euthanasia Be Considered Iatrogenic?”2 What motivated that work?
I wrote that piece with a very bright postdoctoral fellow, Silvana Barone, MD, who had done quite a bit of research on the subject. I’ve studied decision-making for some time, and recently, I’ve been very interested not just in how families make decisions, but also in the role of culture. The idea of physician-assisted suicide or active euthanasia is inextricably enmeshed with culture and societal views of family. Looking where this practice is more accepted, such as Belgium and the Netherlands, to a degree, these are morehomogeneous populations with more similar mores. The United States on the other hand is so heterogeneous both culturally and religiously. For this, and other reasons, even though physician-assisted suicide is legal in some states, as a country, I don’t think we’ll ever fully accept it.
Although major American medical associations reject euthanasia, as a last resort in terminal patients with refractory pain, palliative sedation to unconsciousness is considered an appropriate intervention. Palliative sedation is ethically distinguished from euthanasia as the physician’s intent is to relieve unbearable suffering, not to kill his or her patient.
Although pediatric euthanasia is an emotionally charged and controversial issue for the public and for medical and legal communities, open discourse about medical issues fosters an environment where we can mature as a medical community. Discussion need not result in a sea change. Rather, debate is healthy; it’s how we grow and become better practitioners. At the end of the day, what it means to cause harm or act in the best interest of a patient isn’t always straightforward.
DISCLOSURE: Dr. Unguru reported no conflicts of interest.
1. U.S. Food and Drug Administration Drug Shortages Task Force: Drug Shortages: Root Causes and Potential Solutions. Originally published October 2019; updated February 2020. Available at https://www.fda.gov/media/131130/download. Accessed July 20, 2020.
2. Barone S, Unguru Y: Should euthanasia be considered iatrogenic? AMA J Ethics 19:802-814, 2017.