case study

Truly Personalized Medicine?

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he patient was a fifty-year-old woman with a rare form of cancer who had failed all conventional treatment options and one experimental therapy but wished to continue to pursue aggressive treatment options. When she was diagnosed two and a half years earlier, the cancer involved the liver, lungs, stomach, and peritoneal cavity. She had recently been hospitalized numerous times for disease-related complications and was in the hospital again for a gastrointestinal bleed. The patient wished to receive an experimental drug that she was instrumental in developing. After her diagnosis, she had investigated treatments that might help her condition and discovered that a specific compound could be

commentary by Lauren B. Smith and Colin R. Cooke

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s members of the ethics committee that examined and debated this case, we argued for the administration of the drug; to do so, we needed to endorse a broad view of beneficence. In terms of therapeutic potential, the patient was very sick, and it did not appear that that there was any chance that this experimental drug would slow the progress of her cancer or prolong survival. We could not argue that it would ease her pain or ameliorate her sympJuly-August 2014

beneficial. To further the development of this potential drug, she obtained preclinical data, founded a company, and sought investment from venture capitalists. The company was about to begin phase I testing, but the clinical trial had not yet opened. In addition, she would not have been a candidate for the study, as it excluded patients with advanced disease. To be able to administer this drug to her, the patient’s team of oncologists was in the process of drafting an individual patient investigational new drug application, including the protocol for the drug’s delivery, to the Food and Drug Administration (FDA). The company developing the drug had preliminarily agreed to provide it. This protocol was also under review by the toms. As is true of any phase I clinical trial, the goal was to determine a safe dose, not symptom relief or prolonged survival. How, then, could we justify giving her this drug? We believed its administration would lead to a different sort of benefit, one derived from allowing her and her family the comfort and mental closure of knowing that she had been able to try the drug that she had spent two years developing. To deprive her of this “for her own good” struck us as paternalistic. It was true that the drug could hasten her death. However, who was in a better position than she, with her integral role in its development, to truly understand the risks and benefits of the treatment

institutional review board of the university, and the ethics committee was consulted to determine whether she should receive the drug. In discussions with the oncology team, the patient consistently expressed her desire to pursue aggressive treatment with a focus on cure; her husband and daughter confirmed that this was her steadfast position. In the past, her husband had requested aggressive care in situations when he had to act as a surrogate decision-maker. The patient actively refused hospice or palliative care consultation. In fact, during her last hospitalization, she had said that she was “hurt” by the suggestion of a possible discharge to hospice care. The patient was aware that the experimental medication had not been tested in humans and therefore that no safety information was available. However, having been involved in the development of the drug, she had a sophisticated understanding of what was known about the potential side effects. She accepted that the administration of this drug could hasten her death. The adult ethics committee was asked to consider whether the patient should be allowed access to the drug.

and provide consent? Administration of this drug was consistent with the patient’s goals of care, as she showed no interest in transitioning to a comfortcare regimen and was unwavering in her desire to forge ahead with new treatments. It is regrettable that she saw the possibility of transitioning to hospice care as a failure; however, patients in these situations often struggle with the idea of impending death and have not reached—and may never reach—the point of acceptance of their ultimate fate. In addition, discontinuing aggressive treatment at this time could have been seen as disrespecting her autonomy, as her wishes were expressed in H AS TI N GS C EN TE R RE P O RT

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such a strong and consistent manner throughout her illness. An interesting question we faced on the ethics committee was whether the patient’s premature use of the medication could lead to complications that would ultimately harm the drug trial when it opened officially. Would it be fair to future patients who may benefit from the drug in later phases of development if complications arising in this patient somehow derailed the trial? Would it be fair if other patients with similar prognoses could not obtain this drug at this time? These are valid concerns, and

our American focus on individualism and heroic end-of-life care can hamper the rigorous scientific process that is required to develop evidence-based treatments worthy of the often high price tag. However, her situation was unique. She had the idea to pursue this drug for her cancer, as an expert in this area, and invested significant personal and professional effort to ensure that it was developed. While providing access to the drug may not be entirely fair to others, it could be seen as a reasonable exception for this reason. In addition, while these efforts are not ideal and

often futile, patients in other situations are able to petition the FDA successfully for compassionate use in less compelling circumstances. We believed that the patient should receive the drug that she developed with the goal that she, and her family, would see her efforts come to fruition, even in the absence of true medical benefit. Arguing otherwise would not have honored her goals of care nor provided the closure that could benefit her family after she was gone.

commentary

difference. Requesting it meant asking her caregivers to provide a medication about which they had inadequate knowledge. And access could have been quite dangerous for the patient. There are legal rules for compassionate use (available at www.cancer.org), for how a patient not otherwise eligible for a study can access a study drug. Those rules are based not on what the patient desires but rather on scientific principles about what access could reasonably provide. Access can be allowed only after there is reliable information about proper dosing, safety, and potential effectiveness of a drug from ongoing or completed clinical trials. Why? As the FDA explains on its website, “to avoid exposing patients to unnecessary risks.” Thus, while informed choice is important, it is not an absolute. Patients also need to form therapeutic alliances with their caregivers. And caregivers, with proper attention to the patient’s values, need to consider the best interests of the patient. In this case, since the drug was not being used in any research study with human subjects, the rules of compassionate use did not apply. There was not yet any evidence even of possible efficacy. The exception for compassionate use applies only if there is a study for which the patient is not eligible. Patients must meet criteria to be involved in drug studies. What would it mean for reliable research and scientific advancement if patients could demand and receive drugs that have not gone through trials? This would completely negate the purpose, reliability,

and quality of studies. Public opinion and pressure have led to many disasters, including bone marrow transplants to treat breast cancer, which occurred because patients were willing to try anything in the hope for a cure. Allowing access at the request of the patient can also falsely promote the idea that phase I trials are designed for treatment, when, in fact, they are designed only to assess safety and dosing. All too often, desperate patients think of research as proven therapy—a problem known as “therapeutic misconception.” When the scientific method is ignored, it is not possible to adequately assess the potential of new drugs. If patient autonomy were a trump card, what would that do to the validity of research studies, to the rules of research designed to protect patients from harm, to best evidence, and to the scientific method? Respecting autonomy is important but cannot be the only important goal in patient care. We frequently encounter patient requests that are not seen as medically appropriate (antibiotics for viral illness or unproven drugs like laetrile for terminal illness), and these are properly not honored by caregivers. In the given case, provision of the unproven drug most likely would have provided false hope, could have led to an unnecessarily painful death, and could have undermined phase I drug studies.

by Edward B. Goldman

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was also part of the ethics committee that considered this case and was certainly sympathetic to the wishes of the patient; here, however, I consider the case in light of broader issues. The patient’s request to be administered unproven drugs—for pharmaceutical access outside the normal research protocol—required the ethics committee to consider how the case related to what is known as compassionate access. The case also pushes us to consider its larger implications for research ethics and to question the limits of patient autonomy. In this case, the principle of “First, do no harm” bumped up against the principle of respect for persons and the patient’s desire to “try everything.” In Tom Wolfe’s 1979 book The Right Stuff, a pilot in a malfunctioning plane radios that he has tried options A, B, and C but has not restarted the engine. He asks about option D and is told to jump. This means “giving up.” Like a trained pilot, this patient hated to give up. She was dying, and her physicians wanted her to avoid needless pain. They suggested hospice, but the patient wanted a drug that had not yet, and might never, demonstrate any efficacy and whose side effects were not yet known. Access simply to satisfy the patient might have allowed her to feel that everything was being done, but there was little reason to expect that the drug at this very early stage would make a 12 HASTI N G S C E N T E R R E P ORT

DOI: 10.1002/hast.325

July-August 2014

Case study. Truly personalized medicine? Commentary.

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