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Newsletter #77–Summer 2003
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How Well Tested Are New Cancer Drugs?
by Maryann Napoli
With a certain amount of regularity a new cancer drug makes
headlines, generating an enormous amount of hope as well as pressure
to make the product swiftly available. In time, we usually learn
that the drug’s benefit is much more modest than was originally
portrayed in the media, and soon oncologists begin to prescribe the
drug for other forms of cancer without waiting for clinical trials
to prove its effectiveness.
Tumor Shrinkage
Contrary to popular belief, drug companies are not required to
prove that their drugs prolong survival. Until the mid-1980s, all
cancer drugs were approved solely on the basis of what researchers
call the “tumor response.” In other words, a drug company needed
only show that the drug caused a tumor to shrink, not necessarily to
disappear.
Years ago, a change in the approval process was recommended by
the FDA’s own Oncologic Drug Advisory Committee. The committee
members, primarily cancer experts unaffiliated with any government
agency, knew that tumor shrinkage often has little or no relation to
survival. The committee proposed the novel idea that a drug company
should be required to prove that a drug provided some benefit that
was meaningful to the patient, such as increased survival or an
improvement in symptoms. The committee argued further that the
potential benefit of tumor shrinkage did not necessarily outweigh
the substantial toxicity of cancer drugs.
This recommendation was made in the mid-1980s, but change at the
FDA comes slowly, as a recent assessment of new drug approvals has
demonstrated. From 1990 through 2001, the FDA approved 66 new cancer
drugs. Prolonged survival was not proven for 48 drugs. And tumor
response was the basis of approval for 35 drugs.
Variations in End Points
“The FDA has a certain amount of regulatory flexibility to make
an assessment of the side effects versus the efficacy of new
products,” said Richard Pazdur in a telephone interview. The
director of oncology drug products at the FDA’s Center for Drug
Evaluation and Treatment, Pazdur had been asked why so few new drugs
have been proved to prolong survival.
“The drug company must prove that its product provides a longer
life, a better life, or a favorable effect on an established end
point for a better life,” he explained. The FDA’s flexibility comes
into play on the last item, “an established end point for a better
life.” One example of an established end point, says Pazdur, is a
complete response in leukemia: that is, the bone marrow is normal
and the blood counts have normalized.
Even so, there is a hierarchy of established end points.
“Survival is the gold standard of end points because it is the most
meaningful to all people,” Pazdur said. There can be no
misinterpretation when the end point concerns survival: the patient
is either dead or alive. “Whereas the other end points, such as
tumor response rate, are usually determined by X-rays or scans,” he
continued. “There can be variations in the radiologists, the
techniques of how the X-rays or scans are obtained, which can make
it confusing and unreliable. Also, there is a subjective judgment in
reading these X-rays and scans.”
Accelerated Approval
These cautions notwithstanding, the FDA still allows the use of
tumor shrinkage as the sole end point in the approval of certain
drugs. In 1992, the agency introduced an accelerated approval (AA)
process. The idea behind AA is to get drugs quickly to
advanced-cancer patients in whom all available options have failed.
Consequently, tumor shrinkage was the sole basis of the AA for 10 of
11 new drugs. The rationale: Shrinking a lung tumor might, in the
FDA’s view, be “reasonably likely” to alleviate breathing
difficulties.
The testing for AA is minimal. The new drug is given to about 30
or so participants who have run out of options. In what is called a
phase II trial, there is no comparison group: everyone in the study
gets the new drug. Consequently, this type of trial is not likely to
provide a true picture of the drug’s toxicity or efficacy. That’s
why a drug given AA must continue to be studied to see if it
provides any benefit in terms of increased survival or symptom
improvement. “The drug companies usually do a large trial in which
the new drug is compared to the standard drug,” said Pazdur. “This
usually takes two to four years.” And what if the drug company does
not comply? “We have a process for rapidly removing the drug from
the market,” Pazdur replied.
Still, some not so well tested drugs are available for several
years following an AA, and oncologists are free to prescribe them
for cancers other than the type for which the products received
approval. Or, more often, oncologists can add the new product to a
multiple-drug regimen that in itself has never been studied. “Yes,
this is called off-label use, which is fairly common in the practice
of oncology in the U.S.,” Pazdur agreed. “But this involves the
practice of medicine, and the FDA does not control the practice of
medicine.”
Unless their oncologists tell them, cancer patients do not know
whether they are being given a drug off-label. “We would like
patients to read the drug label to see the approved indications and
contraindications,” advised Pazdur, who said that the information is
freely available at the FDA’s web site.
For More Information
- To read a drug label, go to
www.fda.gov
or to the Physicians’ Desk Reference (PDR), which is updated
yearly and available at most local libraries and large
bookstores. The label is daunting for its extensive length,
tiny type and medical jargon. It is, however, the only source
for results of the FDA-required tests. The section entitled
“Indications” will identify the purpose(s) for which the drug
has been proven beneficial. If you can’t find your type and
stage of cancer listed under “Indications,” this signals
off-label use.
Unfortunately, only the rare cancer patient well versed in
clinical trials will be able to discern whether the label is
identifying a drug that has gone through the less-rigorous AA
process. For example, capecitabine was given AA (on the basis
of tumor response) for advanced breast cancer in 1998. The
2002 Physicians’ Desk Reference describes capecitabine’s
testing as a “phase II, single-arm trial,” which signals AA.
Another clue can be found under “Indications,” where response
rate is described as the basis for the drug’s use for
metastasized breast cancer. However, the much watered-down
patient version of the capecitabine label (which appears after
the information aimed at professionals) does not include an
explanation of these terms. The patient’s label makes no
mention of the fact that the drug was approved through the
accelerated process. Capecitabine is sold under the brand name
Xeloda.
- Go to the web site of the
National
Cancer Institute, and then click into the following
succession of options: “treatment,” “chemotherapy,” and “newly
approved cancer treatments.” You will find explanations of
phase II trials, off-label drug use (complete with Q and A:
“Can off-label drug use be harmful?”), and many other relevant
terms. People without access to the Internet can call the
National Cancer Institute toll-free at 800/4-CANCER to get
this information mailed to them.
- When recommending a new cancer drug to a
patient, oncologists will often quote “response rate” without
explaining what it means. Ask. This article has addressed how
new drugs receive FDA approval. But once on the market, they
are often studied eventually in large randomized, controlled
trials as part of a multiple-drug regimen.
Ask for the evidence to support a proposed chemotherapy regimen.
Here’s one way to phrase the question: “Can you give me a citation
for the studies that show this drug or drug-combination will benefit
people with my stage and type of cancer?”
The citation will allow you to do a Medline search (ask the
librarian at your local public library) to locate the study and
determine the exact nature of the benefit. Medline is a service
available through the National Library of Medicine. It provides free
access to the abstracts, or summaries, of the studies published in a
large proportion of the world’s medical journals. Some public
libraries will retrieve the entire article at no charge, but the
article can also be purchased on-line.
Maryann Napoli is the associate director of the Center for
Medical Consumers in New York City. This article is adapted with
permission from HealthFacts, the organization’s monthly
newsletter.
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