It's not only what it does but how you feel when taking it
In an important change, cancer patients' own assessments of how a drug is working, called patient-reported outcomes or PROs, are increasingly part of the drug-approval process at the Food and Drug Administration. The agency says PROs have been integral for the approval of a number of cancer drugs in recent years, including Amgen Inc.'s Kepivance for severe mucositis, mouth sores that are a side effect of cancer treatment, and Axcan Scandipharm Inc.'s Photofrin, an agent used in treating precancerous lesions in Barrett's esophagus.
There have been calls by researchers to add PROs to reports of drug toxicity that are used during clinical trials, something traditionally reported only by clinicians. There is even emerging evidence that, for patients with advanced cancer, a patient's self-report about how he is feeling is a better predictor of how long a patient will live than other standard clinical data.
Traditionally, patients' quality of life or well-being while on a drug has been a secondary consideration, rated and reported by researchers. But one recent study demonstrated that clinicians tend to underestimate subtle signs of problems that patients can pick up on earlier; patients reporting numbness in the hands or feet, a symptom caused by some anticancer drugs, were able to detect the problem months before the clinician reports did.
The shift toward PROs is important for cancer patients, whose opinions now play a much more significant role in determining the success of a drug. It is driven in part by the growing influence of the patient-advocacy movement. But it can also be valuable for drug companies, which often invest huge sums of money in drugs that fail because they can't demonstrate that the drugs extend a patient's life. With the emerging role of PROs, drugs that don't necessarily extend life but make the patient feel and function better have a better chance of winning approval.
PROs have long been an integral part of trials testing new drugs to treat conditions such as arthritis, where patients are the most accurate source on whether a product relieves pain. In cancer trials, though, whether a patient lives longer has long been the central measure by which a drug is judged. However, in recent years, the reality began to sink in that there weren't many new cancer drugs that dramatically extended people's lives. The FDA increasingly began to acknowledge that giving someone a higher quality of life offered clinical benefits that could lead to an approval.
What drug companies and FDA both realized is that "changes in tumor size do not always conform with improvement as perceived by the patient," says Laurie Burke, director of study endpoints and label development in the Office of New Drugs at FDA.
Eli Lilly & Co. has used PROs in the regulatory process for its drug Gemzar, approved for pancreatic cancer in 1996 and ovarian cancer in 2006. In the 2004 approval of its Alimta drug for lung cancer, PRO data were critical in showing that the new drug not only shrank tumors as effectively as the existing treatment, but had fewer patient-reported side effects. "PROs are now a standard part of our Phase III cancer drug trials," says Astra Lipa, senior health outcomes scientist at Lilly.
Patient-reported data are also becoming more important in determining which approved drugs oncologists will prescribe -- especially important given the high price of cancer drugs. At a meeting of American Society of Clinical Oncology in Atlanta last year, Bayer Pharmaceuticals Corp. and Onyx Pharmaceuticals Inc. made a point of presenting patient-reported data on their new kidney-cancer drug Nexavar, demonstrating the drug improved the way patients perceived their own health-related quality of life. (In the case of Nexavar, the PROs weren't submitted for the FDA approval process because the trial had early success and there wasn't time to evaluate those data. The drug, the first new kidney-cancer treatment approved in a decade, was shown to double the time before the disease got worse, compared with a placebo.)
Last year, the
FDA issued a set of guidelines as to how the
agency will evaluate PROs during drug approval;
the final version is expected to be issued in the
coming months. The guidelines emphasize that
patient responses should be relevant measures of
whatever is being tested, and raised concerns
about the credibility of the PROs in cases when
patients know they are getting an active drug,
because patient responses are subjective.
In a 2005 paper published in the Journal of the
National Cancer Institute, a group of researchers
associated with the Radiation Oncology Therapy
Group studied whether short-term radiation
therapy was as effective in alleviating pain in
patients with cancer that had spread to their
bones as the standard course, which was longer
and involved higher doses. By asking patients to
rate how much pain they felt and how much pain
medicine they needed, doctors concluded that
shorter and lower doses of radiation were just as
effective. Deborah Watkins Bruner, one of the
authors of the study and a professor of nursing
at the University of Pennsylvania, says the trial
was a case study in the way PROs "can provide
evidence for important clinical changes."
The trial also demonstrated some of the
challenges of using patient information: 160 of
the 845 patients died or were too ill to fill out
questionnaires after three months of therapy.
Even of the patients who were able to provide the
data, only 84% participated.
Ms. Burke at the FDA, says the problem of
"missing PRO data can't be ignored," and is
especially challenging in a disease like cancer
where many of the patients on a trial are likely
to die. She said the agency was asking companies
to start working with FDA on finding ways to deal
with this issue as early as Phase I of drug
trials, when companies are still only testing a
drug in small numbers of patients for safety
issues.
Patricia Ganz, the director of the division of
cancer prevention and control in UCLA's cancer
center, says that all measures of how patients
are faring have problems. Blood-pressure readings
can be different depending on who is taking them.
X-ray results may be interpreted differently by
various radiologists. It isn't always easy to
calculate exactly how much a tumor has grown
using CT scans. In her own research and clinical
experience, she says, "physicians are very poor
at predicting how long someone will live" using
standard clinical information. In a study she and
her colleagues conducted of patients with
advanced lung cancer, she said that patient
self-reports of their quality of life were a more
accurate predictor of survival outcome than
physician or laboratory assessments of prognosis.
David Cella, executive director of the Center on
Outcomes, Research and Education at Evanston
Northwestern Healthcare in Evanston, Ill., says
drug companies aren't going to be able to stray
too far from the issue of whether a drug has an
impact on a tumor. But Dr. Cella, who helped
develop the questionnaire used by Bayer and Onyx
in the Nexavar trials, says he noticed that
patients and physicians often had different
priorities in assessing a drug.
Known as the Functional Assessment of Cancer
Therapy-Kidney Symptom Index, the questionnaire
included questions chosen by both patients and
clinicians. In the final list of questions, the
top eight chosen by patients included whether
they were able to work and whether they lacked
energy. Questionnaire items chosen by clinicians
-- and not ranked highly by patients -- included
treatment side effects, bone pain, shortness of
breath and coughs. Dr. Cella's group has created
10 other patient questionnaires targeted to
specific cancers.
At Bayer, which supplied a grant to help develop
the new index, Kathleen Gondek, the head of
Global Health Economics and Outcomes Research at
the company, says that "traditional measures" are
necessary in evaluating drug efficacy. But, she
adds, "what we have embraced is the understanding
that how a patient feels and functions may be
equally important."
The experience of Robert Eppinger, 72,
demonstrates how important quality of life can be
to patients. He enrolled in the Nexavar trial in
2005 for advanced kidney cancer. On the drug, his
tumors have either shrunk or held stable, and
although Mr. Eppinger, a retired office-furniture
developer in Stamford, Conn., said he would
prefer a "cure," he still feels well enough to
continue activities such as going to the theater.
"To find out that I could maintain a relatively
normal life began to make me feel a lot better,"
says Mr. Eppinger.