Doctors make extremely difficult decisions every day. It is one of the hardest parts of their job. They must choose whether patients can go on living or must suffer through pain. That is why one of the greatest decisions a doctor can make is to offer a patient a chance at a longer life. Sometimes that choice can come in the form of a clinical trial. However, this choice does not come easy, and sometimes the result of this choice is unfair, as a recent story in the New York Times described.
The story involved two cousins, Thomas McLaughlin and Brandon Ryan, who last year both learned that each had a lethal skin cancer called melanoma. While the cancer was spreading rapidly through each of their bodies, “the young men found themselves with the shared chance of benefiting from a recent medical breakthrough.”
The breakthrough was a new drug, PLX4032, that only months before had shown that it could safely slow the cancer’s progress in certain patients. The cousins both had the type of tumor “almost sure to respond to it, and major cancer centers, including the University of California, Los Angeles, were enrolling patients for the last, crucial test that regulators required to consider approving it for sale.”
It would have been a simple story if both had received PLX4032 to treat the melanoma but, when Mr. Ryan was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. As the Times explained, “instead of the pills, he was to get infusions of the chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for 30 years.” Why did this happen?
In June 2009, Roche, who manufactured PLX4032, had conducted the drug’s first clinical trial, called Phase I. Using 32 patients with the form of melanoma (B-RAF) whose tumors carry a particular mutation, the results showed their tumors to shrink. This was happening just as Mr. McLaughlin awakened with what felt like an explosion under his right armpit,” which ended up later being a tumor from the melanoma.
However, a study in the New England Journal of Medicine found that most of the patients saw their tumors begin to grow again with the year. So a “second, or Phase 2, trial aiming to validate the results in more patients, was put into the works.” At the same time, oncologists were urging Roche to seek accelerated approval from the FDA because “the agency allows a manufacturer to sell a drug based on early promise so long as it proceeds with the traditional controlled trial comparing it with the standard treatment.” The use of this controlled trial subsequently created a heated debate.
Historically, controlled trials have “been considered essential for proving a drug’s value before it can go to market.” Those who support the use of controlled trials say, “They are crucial in determining whether a drug really does extend life more than competing treatments.” These defenders assert, “Without the hard proof the trials can provide, doctors are left to prescribe unsubstantiated hope — and an overstretched health care system is left to pay for it.”
To some, such as Dr. Keith Flaherty of Massachusetts General Hospital, there was not a need for this trial because they knew all they needed to know based on the results they already had from the Phase I trial. In fact, Dr. Flaherty asserted that his use of the “drug was not going to be informed by testing it against a drug we all hate and would rather never give a dose of again in our lives.” That is, doctors did not want to use “the standard chemotherapy used in melanoma, dacarbazine because it slowed tumor growth in 15 percent of patients for an average of two months whereas, PLX4032 had halted tumor growth in 81 percent of patients for an average of eight.”
Despite the fact that it was possible the tumors could start up again, doctors argued that at least PLX4032 would improve their patients’ lives. Nevertheless, there was still the issue of paying for the trial, which would cost $100 million and delay the possibility of FDA approval by at least two years. To resolve this issue, Paul B. Chapman, M.D., a medical oncologist at Memorial Sloan-Kettering Cancer Center who was chosen to lead the trial came up with a new track. He proposed, “An unconventional bid to speed the drug’s approval, rooted in the observation that patients weeks or days from death could get out of bed and off oxygen when given PLX4032, sometimes for months. The doctors working with the drug referred to this as the Lazarus effect; it was unheard of with dacarbazine.” Company officials however did not approve.
Roche feared the trial “might lead to approval for only a narrow group of the sickest patients.” Instead, they submitted a plan last year to the FDA for the traditional, randomized, controlled trial of PLX4032. It would involve 680 patients, half of them in a control group, in more than 100 sites in the United States, Europe, and Australia. Additionally, patients would know which drug they got since each was in a different form: pill (PLX4032) versus injection (dacarbazine).
When this decision was made, the controversy “spilled over at a scientific meeting sponsored by the Melanoma Research Alliance in late February.” Doctors had already been telling patients “they had been assigned to the trial’s chemotherapy control group. And some had begun to question whether an ethical code that calls for doctors to be genuinely uncertain about which of a trial’s treatments will be more effective had been breached when it came to PLX4032 versus dacarbazine.”
In fact, Dr. Neal Rosen, a Sloan-Kettering colleague, stood up at the meeting during a speech by Dr. Chapman and said, “Excuse me. But if it was your life on the line, Doctor, would you take dacarbazine?” Dr. Chapman responded that his goal was “to find out as quickly as possible in as few patients as possible whether this works because if we never know, then we’re never going to be able to build on anything.” He further stated that he is in the business of making people live longer, not just making tumors go away.
On the other hand, many oncologists argued that there was an ethical obligation to push both the FDA and Roche to make the drug more immediately available. Some of this urging came from laboratory researchers “who studied the biology of the disease and saw the drug as fundamentally different from its predecessors.” They asserted that since previous drugs “never had such a high response rate, and few other drugs had shrunk tumors in as high a percentage of patients with melanoma or any other solid tumor as PLX4032 had in its first human trial,” there should be an exception.
Dr. David E. Fisher, a leading melanoma biologist at Massachusetts General agreed. He noted that he did not know “anyone who hasn’t shuddered at the concept that we can’t let patients on the control arm cross over because we need them to die earlier to prove this point.”
Finally, the “debate grew even more heated when Roche decided to withhold PLX4032 from many patients not eligible for the trial because they had already been treated with chemotherapy.” Sometimes, FDA regularly approves such programs, known as “compassionate use,” for promising experimental drugs. In this case however, “Roche feared a prospective trial candidate might undergo chemotherapy just to qualify for compassionate use and get PLX4032 with no strings attached.”
This led one oncologist, Dr. Donald Lawrence of Massachusetts General Hospital, to e-mail colleagues about his “moral outrage” of Roche’s decision last spring. He explained to his colleagues that he had just advised another patient he could not get PLX4032 because of Roche’s decision. As a result, he urged his colleagues to “muster the support of our patients and lobby both Roche and the FDA because compromising the Phase III trial was not justification for withholding an effective drug from dying patients.” Dr. Michael Atkins, director of the cancer clinical trials office at Beth Israel Deaconess Cancer Center in Boston, did not feel the same way.
Dr. Atkins “urged him to consider what he thought was the greater good: “Even though it is painful, I think completing a clean Phase III trial and determining if there truly is a survival benefit for PLX would have major value for the field and future patients.” In other words, Dr. Atkins wanted to let people die, and in fact watch them as it happened, to prove that this drug could help other people live. To Mr. Ryan’s mother, this explanation was unacceptable, and it left the cousins asking, “Who the hell was making these decisions?” Who decided that one of them lives and watches the other one die?
It turned out to be a computer. Mr. Ryan eventually found out that a computer had decided his fate and chose him for the chemotherapy. His mother asked if there was someone higher up she could talk with. She asked who else had the drug because to her, this was her son, not just some statistic.
Unfortunately, shortly after Mr. Ryan began his chemotherapy, he passed away. Mr. McLaughlin, his cousin, was there to help carry his casket. He is now going through treatment on the PLX4032.
In the end, the story of PLX4032 demonstrates that “the new science behind certain drugs has eclipsed the old rules — and ethics — of testing them.” Since drugs under development like PLX4032 may “be so much more effective than their predecessors, it is argued that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering.” This begs the question, “Why do we have to be so rigorous,” when drugs like PLX4032 that have minimal side effects and dramatic response rates?
For some like Dr. Charles L. Sawyers, chairman of human oncology at Sloan-Kettering, he hopes that PLX4032 could be one of those defining cases where we say, “Look, our system has to change.” Interestingly, there may be signs of such change already.
Dr. Richard Pazdur, director of the cancer drug office at the FDA, said in a recent interview that the “new wave of drugs in development — especially for intractable cancers like melanoma — might require individual evaluation.” He recognized that “This is an unprecedented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion.”
Whatever the case may be, “the new wave of cancer drugs is intensifying the conflict between a doctor’s responsibility to their patients and their commitment to gathering scientific knowledge for generations of the critically ill.” To resolve this conflict, researchers, industry, government, and physicians must work together to achieve the regulatory flexibility that is necessary to save lives now as well as the future.
There is no question that regulations regarding the safety and effectiveness of clinical trials are paramount for public health. Nevertheless, we are watching people die in the interest of safety, and when we start letting computers decide who gets to live and who gets to die, we as a society must give a voice to the patients and doctors that must live with these decisions.
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