In 2001, it is estimated that 1,268,000 people in the United States alone will be diagnosed with cancer. Many of these people will seek what they consider "the latest and greatest" in cancer treatment, demanding the state of the art from their health care providers.
The good news: according to the Pharmaceutical Research and Manufacturers of America, there are 402 medicines in the pipeline for cancer. The bad news: many of these therapies still need to be rigorously tested in clinical trials, the results of which may not be available for decades.
The rationale for clinical trials is clear. As one of the final stages of a long and careful cancer research process, trials determine if promising approaches to cancer prevention, diagnosis, and treatment are safe and effective in humans. Clinical trial results provide the benchmark for which procedures or drugs are moved from an "experimental" designation to one of "standard care." Patients and physicians are encouraged to simply wait out the trial results.
It can take anywhere from months to years to conduct one individual clinical trial. Bringing a drug or test from bench to bedside, through phase I, II, and III trials and approval by the U.S. Food and Drug Administration, takes a minimum of 8 years, and the average is 15 years, according to data from PhRMA.
The Waiting Game
"Im very concerned that the clinical trials mechanism may become a serious bottleneck in our ability to translate new knowledge and treatment approaches into standards of patient care," said Charles M. Balch, M.D., executive vice president of the American Society of Clinical Oncology, based in Alexandria, Va.
|
|
"Its not a valid premise that laboratory advances are inherently good for people," said Steven H. Woolf, M.D., of Virginia Commonwealth University in Richmond, and a member of the U.S. Preventive Services Task Force, an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. "If you actually do studies and look at the promising interventions at the laboratory stage, youll find that the vast majority ultimately fail."
Indeed, according to a June 2000 report by PhRMA, of every 5,000 medicines tested in the laboratory, on average, only five are tested in clinical trials and only one of those is ultimately approved for patient use.
Proposing Change
This love-hate relationship with clinical trialsneeding the outcome yet disliking the time it takes to generate those resultsleads some researchers to hypothesize about what could be done to optimize the system.
"I think that one has to proceed fairly carefully here," noted Meinert. "We curse about how long it takes, but I also worry about the risks on the other side with regard to going too fast." Meinert points to a reduction in bureaucracy, specifically in the review process, as one way to reduce the time from laboratory discovery to clinical trial result. Especially in the case of large, multicenter trials, when each individual institutional review board must review and approve the protocol in question, he sees reciprocity among institutional review boards as a possible step toward simplification. "If that ever came about, that would simplify some of the things that one has to do; instead of dealing with 30 IRBs youd deal with one, which would be a step forward."
Meinert also foresees a system in which information is pooled from multiple sources and centers for real-time meta-analysis. "I think presently there isnt a very integrated system. So perhaps one could benefit there, leading to better or more focused trials, provided you didnt create more bureaucracy with that."
Balch sees the lag time in clinical trials as a complicated and multi-dimensional problem. "The issues have to do with having the sufficient protocols that cover all the range of cancer presentations; it has to do with the practicing oncologists being able to incorporate clinical trials into their practice, having sufficient staffing and funding to do that; and it has to do with the public not asking or demanding about clinical trials when they go to see the cancer specialists. And all of those issues need to be addressed."
Balch feels passionately about the "unacceptably low rate" of participation in clinical trials, often cited as 2% to 3%. He believes that researchers should work at a national level to address the barriers to clinical trial participation. "The process right now for patient accrual into clinical trials is simply too slow and is unacceptable in terms of the fact that it takes too long to accrue patients into clinical trials to prove whether a treatment approach is worthwhile."
Putting patient accrual rates aside, Woolf points to several changes in the clinical trials framework that could be made methodologically, including demonstrating the benefits of interventions through intermediate outcomes; altering patient sampling methods to achieve a statistically significant effect by selectively doing studies in high-risk populations; and, as Meinert mentioned, pooling data from multiple centers to boost sample size.
"There are a number of innovations that could be made to move the process along," said Woolf. "But, again, I think its important to not undercut the quality of the trials in the process."
Barnett S. Kramer, M.D., director of the NIH Office of Medical Applications of Research and editor in chief of the Journal of the National Cancer Institute, sees two ways that clinical trials can change. First, multiple hypotheses could be tested within the same trial to increase efficiency by asking and answering more than one question within the same large trial. Second, he said, "When were designing any given trial, we should be thinking about the molecular tools we have and incorporate ancillary molecular studies."
Such molecular studies have led to the discovery of biomarkers, substances sometimes found in an increased amount in the blood, other body fluids, or tissues that may suggest the presence of some types of cancer. Biomarkers include CA 15-3 for breast cancer; CEA for ovarian, lung, breast, pancreas, and gastrointestinal tract cancers; and PSA for prostate cancer.
The discovery of these biomarkers has opened up the question of surrogate end points, or intermediate outcomes. If researchers can demonstrate that there is a direct correlation between biomarker level and specific health outcome, it might be possible to shorten the duration of some clinical trials.
"But the bottom line will always be that the health benefits of an intervention, whether it is molecular, genetic, or any other, cannot be proven until its effect on patients health outcomes is shown," Woolf said.
Meinert is cautious about the use of biomarkers. "You have to be wary about surrogate outcome measures; they are often intuitively appealing. But treatments have lots of effects. Its not only the effect on the biomarker, but its the effect on all sorts of other things and on morbidity and mortality. And if youre concentrating on a biomarker or surrogate outcome to the exclusion of more important clinical measures, I think youre going to get blindsided a lot of the time."
So what can cancer specialists tell their patients when asked if the newest test or drug, still undergoing clinical trials, is better than the current gold standard?
Paul Frame, M.D., of the University of Rochester School of Medicine and Dentistry in Rochester, N.Y., and a member of the USPSTF, is a full-time family practitioner with expertise in evaluating evidence for clinical preventive services. He sees nothing wrong with patients having diagnostic tests that are still considered experimental, such as spiral CT scans for lung cancer, "as long as physicians and patients are honest...as long as the patient understands that we dont know whether this test works or not...as long as the patient understands all that and still wants to go ahead," he said.
Kramer summarized: "The underlying clinical trials methods are tried and true. Theres a lot of gruntwork and just hard work in arriving at medical answers. But, when it affects the health of so many people, both for the good and the bad, its important to get it right."
According to Balch, until clinical trials are completed and the results are known, doctors must be able to say three simple words: "We dont know."
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |