Boston docs weigh in heavily in this morning’s New York Times story on the ethics of using a control arm in studies of promising drugs. The story uses the case of PLX4032, a target cancer drug that, in earlier trials, shrank tumors in some study subjects. The question is— will it save their lives, or even exend their lifes beyond a few months?
Growing up in California’s rural Central Valley, the two cousins spent summers racing dirt bikes and Christmases at their grandmother’s on the coast. Endowed with a similar brash charm, they bought each other matching hardhats and sought iron-working jobs together. They shared a love for the rush that comes with hanging steel at dizzying heights, and a knack for collecting speeding tickets.
And when, last year, each learned that a lethal skin cancer called melanoma was spreading rapidly through his body, the young men found themselves with the shared chance of benefiting from a recent medical breakthrough.
Only months before, a new drug had shown that it could safely slow the cancer’s progress in certain patients. Both cousins 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.
“Dude, you have to get on these superpills,” Thomas McLaughlin, then 24, whose melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. McLaughlin’s tumors had stopped growing after two months of taking the pills.
But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. 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.
Even if it became clear that the chemotherapy could not hold back the tumors advancing into his lungs, liver and, most painfully, his spine, he would not be allowed to switch, lest it muddy the trial’s results.
“I’m very sorry,” Dr. Bartosz Chmielowski, the U.C.L.A. oncologist treating both cousins, told Mr. Ryan’s mother, Jan. He sounded so miserable that afternoon that Mrs. Ryan, distraught, remembers pausing to feel sorry for the doctor.
Controlled trials have for decades been considered essential for proving a drug’s value before it can go to market. But the continuing trial of the melanoma drug, PLX4032, has ignited an anguished debate among oncologists about whether a controlled trial that measures a drug’s impact on extending life is still the best method for evaluating hundreds of genetically targeted cancer drugs being developed.
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Some melanoma specialists familiar with the drug would have traded the data for faster access to the drug.
“I know all that I need to know based on the results we already have,” said Dr. Keith Flaherty of Massachusetts General Hospital, who led the early clinical testing. “My use of this drug is 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.” The standard chemotherapy used in melanoma, dacarbazine, slowed tumor growth in 15 percent of patients for an average of two months. By contrast, PLX4032 had halted tumor growth in 81 percent of patients for an average of eight.
Other local docs differed over “Roche’s decision to withhold PLX4032 from many patients not eligible for the trial because they had already been treated with chemotherapy.”
The F.D.A. regularly approves such programs, known as “compassionate use,” for promising experimental drugs. But Roche feared a prospective trial candidate might undergo chemotherapy just to qualify for compassionate use and get PLX4032 with no strings attached.
In an emotional moment, Dr. Donald Lawrence of Massachusetts General Hospital e-mailed colleagues about Roche’s decision last spring, under the subject line “moral outrage.”
“Just had yet another conversation with a [patient] with a B-RAF mutation who will die in the next month or so because he can’t get PLX4032,” he wrote. “I feel we need to muster the support of our patients and lobby both Roche and the F.D.A. Compromising the Phase III trial is not justification for withholding an effective drug from dying patients.”
But Dr. Michael Atkins, director of the cancer clinical trials office at Beth Israel Deaconess Cancer Center in Boston, 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.”
It is worth noting that Mass General is advertising this type of clinical trial as treatment. The ads are carefully worded with lots of fine print. However, some ethicists call this the sale of the “therapeutic misconception.”