Author: Jon Merz
Date: 07-08-04 14:34
Source: Boston Globe
URL: http://www.boston.com/news/nation/articles/2004/07/04/placebos_break_taboo_in_cancer_drug_tests/
Date published: July 4th 2004
from Haavi Morreim:
Placebos break taboo in cancer drug tests
Study seeks hope for desperately ill
By Raja Mishra, Globe Staff | July 4, 2004
For 10 years, drugs and surgeries kept Betty Rosenbluth alive, but the
cancer in her gut persisted and soon the 73-year-old woman could scarcely
make her beloved Sunday stroll up the road to Mt. Zion Lutheran Church.
As a last resort, she journeyed from her home in York, Pa., to the
Dana-Farber Cancer Institute here to participate in a medical experiment on
a cutting-edge cancer drug that has pushed the envelope of research ethics.
As part of the experiment, her doctors explained that she could get an
inactive pill called a placebo. They said giving a placebo at random to some
of the patients, who all were dying, was the only foolproof method for
showing that the drug worked and thereby convincing the federal government
to approve its use for many thousands of desperate patients.
The ongoing experiment and a few other clinical trials of cancer drugs are
breaking what had been a taboo in cancer medicine: Denying dying patients
promising though unproven drugs that may prolong their lives.
Many physicians say the increasingly successful war on cancer depends on
these sorts of experiments. But the practice has riled some in the cancer
research community, with two leading medical centers refusing to participate
and some patient-advocate groups lodging complaints. They say the
experiments jeopardize the well-being of patients in the trials for the
benefit of future patients. Yet placebo use in cancer trials is expected to
increase because the new generation of precision cancer drugs works through
subtle biological means that often elude the more crude methods of drug
testing typically used with dying patients.
Supporters of the Dana-Farber trial, which is testing a drug called SU11248
for a rare but lethal digestive tract cancer, defend it as ethical, saying
patients are fully informed of the risks and that, ultimately, thousands of
patients worldwide will benefit.
''I'm trying to put patients' interest up front -- my patients now, my
patients later, and patients who won't be my patients but someone else's,"
said Dr. George D. Demetri, who is running the experiment. ''This is
probably the best way for American patients to get this drug."
As it turned out, Rosenbluth got a placebo. Despite the advance warning, it
still haunts her.
''If they would have offered me a choice, I would have gone on the drug
right away," said Rosenbluth, who was allowed to start taking the real drug
in June after her cancer worsened during the three months she took a
placebo. It is too soon to tell whether the drug is helping her.
Another patient in the same trial, Sandi Merriman, took a differing view.
''I knew it was about trying to get the drug to market to help other
patients," said Merriman, 56, an auto marketing consultant from Minneapolis.
''I knew I was making a sacrifice."
Placebo-controlled experiments are considered the gold standard by federal
regulators, who must approve new treatments before they can be widely
distributed. Demetri was initially wary of using placebos. But when he
brought his early-stage data to the US Food and Drug Administration last
summer, he said, regulators questioned the drug's effectiveness against
gastrointestinal stromal tumor, or GIST. The problem was that SU11248 does
not shrink the tumors of most patients, which the FDA considers strong proof
that a cancer drug works, he said. Instead, it seems to halt the progression
of disease. But patients' tumors stay put.
The drug may be holding GIST in check in some more subtle biological way. Or
these patients could be getting lucky, with something other than the drug
helping them. The only way to know reliably whether the drug is the cause is
testing with a placebo, so researchers can make detailed biological
comparisons between those on the drug and those on the placebo.
Also, without a placebo wing, Dana-Farber researchers said they lacked
patients to compare with their SU11248 patients. In many cancer trials,
doctors give all patients a drug, then measure how they do against similar
patients elsewhere that did not get the drug. But there are few GIST
patients around the country that have also failed on Gleevec, as all the
SU11248 trial patients have.
''Without the placebo arm, the FDA would question if this drug was doing
anything," Demetri said.
FDA spokeswoman Kathleen Quinn said: ''The FDA has developed accelerated
approval processes to speed drugs to patients without placebo-based trials.
We have not insisted that trials be placebo controlled." She would not
comment specifically on the Dana-Farber trial.
Between 5,000 and 10,000 Americans develop GIST annually, and only a third
live five years after being diagnosed. Surgery can help some patients, and a
drug called Gleevec is the only non-surgical treatment now, shrinking some
tumors. But many patients eventually fail on Gleevec.
But S11248 disrupts cancer cells' ability to multiply and cuts off their
blood supply, a powerful combination far more targeted than most cancer
treatments.
Last month, Demetri unveiled new SU11248 data: In 92 GIST patients who
failed on Gleevec, seven had their tumors shrink and 53 had stable disease,
meaning their health stabilized, though its unclear how much longer they
will live. Sixty five percent of patients got some benefit from the drug,
enough evidence to launch a bigger, final-stage trial with about 400
patients at 60 hospitals worldwide.
But two prestigious medical centers, MD Anderson Cancer Center in Houston
and the University of Michigan medical center, refused to join in.
''When patients have an advanced cancer and the cancer is growing, there
isn't any way the placebo can be helpful" to the patient, said Dr. Laurence
Baker, associate director of Michigan's cancer center. ''To argue that a
placebo trial is in society's interests has nothing to do with helping these
patients."
Some patient advocates, after initially championing SU11248 trials, have
become sharp-elbowed critics of the placebo trial used to test it.
''That drug is the only option they have to live. Under those circumstances,
we think a placebo is unnecessary and dangerous and unethical," said Norman
Scherzer, executive director of the Life Raft Group, a GIST advocacy
organization.
The SU11248 experiment was carefully reviewed by a Harvard ethics panel
before it began. One panel member, Dr. Steven Joffe of Dana-Farber, said,
''I can understand the desire of patients with this terrible cancer to have
these drugs now, but at the same time if ineffective drugs get out there,
it's the patients that pay the price."
As a safeguard, Demetri insisted on a provision that ''unblinds" patients
who continue to deteriorate past a certain threshold, revealing if they are
taking the drug or a placebo. Those on placebos get the drug, as Rosenbluth
eventually did.
''I said I will not run a placebo-controlled trial without a crossover.
Period," Demetri said. ''If you sneeze, I'll do a CAT scan. And if you're
getting worse, you'll have access to the drug."
Some GIST patient-advocates have argued that Pfizer, which makes SU11248,
insisted on a placebo trial to get the drug to market quicker.
Of that allegation, Pfizer's vice president for cancer drug development, Dr.
Bill Slichenmyer, said: ''Absolutely not . . . the expedient thing would be
to do no trial at all. Pfizer is not going to make money off this drug." He
explained that GIST is a relatively rare cancer representing a small market.
The Dana-Farber researchers have no investments in Pfizer, they said.
George Annas, a medical ethicist at Boston University, understood the desire
for placebo data. ''Placebo-controlled trials are the gold standard," he
said. ''From the scientific point its what you want to do, but you can't
always do it.
''You have to give people in that situation something that might help them,"
he said. ''I don't see any justification for withholding that drug from
someone."
Rosenbluth said she still holds her Dana-Farber doctors in high esteem but
wishes she had received the drug from the outset. ''I would have had three
months under my collar with the drug. Definitely, if I had a choice I'd have
taken the pill right away," she said. ''I don't know why they do this with
things as serious as cancer."
Raja Mishra can be reached at rmishra@globe.com.
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