Journal of the National Cancer Institute Advance Access originally published online on June 10, 2008
JNCI Journal of the National Cancer Institute 2008 100(12):842-844; doi:10.1093/jnci/djn197
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© Oxford University Press 2008.
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Better Prioritization May Speed Approval of Adjuvant Therapies in Breast Cancer
Improvements in detection and treatment have reduced the risk of relapse for women diagnosed with early-stage breast cancer over the last several decades. As a consequence of that success, clinical trials that aim to test new therapies in adjuvant breast cancer must include more patients and monitor them longer to detect meaningful differences. With some trials expanding to 10,000 patients, researchers are concerned that the system is at a breaking point and will not be able to test all the new agents in development—or at least not in a timely manner.
"I worry about it all the time," said Eric Winer, M.D., director of the breast oncology center at Dana-Farber Cancer Institute in Boston and cochair of the Cancer and Leukemia Group B breast cancer committee. "It takes too long. Herceptin was approved for metastatic breast cancer in 1998. It took us until 2005 before we had a result in the adjuvant setting.... The fact is, every delay has the potential to cost lives."
The challenge is what to do about the problem. Joseph Ragaz, M.D., professor of medicine and oncology at McGill University in Montreal and colleagues put forth a proposal at the San Antonio Breast Cancer Symposium last December aimed at reducing the time needed for drug testing in the adjuvant setting. Though some experts think that his overall proposal is not adequate, they applaud his effort to initiate the much-needed discussion and used the opportunity to put forth some ideas of their own.
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"We are all excited by the explosion of new agents," Ragaz said. "However, we are also aware of the bottleneck of agents waiting in the cue for clinical trials, which is [a system] built on the old infrastructure and may be unable to cope with measuring all of those trials in the next few years. Now, it takes 10–12 years to move drugs from bench to clinic. We are asking if it is possible to reduce this to less than 5 years. We believe with some proposals and some coordination it could be possible."
To begin modifying the process, Ragaz and his colleagues looked at the efficacy of drugs approved in both the metastatic and adjuvant settings in breast cancer. When they examined the results of previously reported randomized controlled trials, they found that the magnitude of response was always larger in patients with early disease than in those in the metastatic setting, and when the regimen improved progression-free survival in patients with metastatic disease, it provided substantial improvements in both disease-free survival and overall survival in the early disease setting. "Thus we could conclude that the clinical effect in stage 4 disease is a good surrogate for more activity in the adjuvant setting," he said.
On the basis of that observation, his team proposed a multistep process for moving drugs for patients with early breast cancer into the clinic more quickly by speeding and altering the types of trials carried out in the adjuvant setting. New regimens would be tested in three to four randomized controlled trials in the metastatic setting, all of which should be started soon after phase I and II data are available. Therapies that prolong both progression-free and overall survival in the metastatic setting would be moved through a rapid adjuvant testing program. In such cases, researchers would skip randomized controlled trials that compare the new regimen with standard therapy. Instead, they would use smaller randomized controlled trials to compare different doses and toxic effects of the new regimen, as well as the selection of patient cohorts or biomarkers that predict likely responders. To estimate the magnitude of benefit from the new treatment relative to standard therapy in early disease, the McGill scientists propose comparing patients in the study with patients treated with standard therapy in non–clinical trial settings that will be included in patient registries. Neoadjuvant trials could also be used to quickly assess the value of the new therapy in early breast cancer patients. Finally, to accomplish all of this, Ragaz's team proposes the establishment of a "virtual oncology leadership" consisting of representatives from North American, European, and Asian countries whose researchers belong to the American Society of Clinical Oncology or the European Society for Medical Oncology. The leadership would help prioritize which agents should be pushed through the system first and would help coordinate the studies necessary to do so.
The proposal is a bit "out of the box, but it is logical," said Ragaz. The details, of course, still need to be worked out.
Tempered Reaction
Although experts interviewed for this article uniformly agreed that something must be done to speed drug development in the adjuvant setting and to find ways around extremely large trials that require thousands of patients, they expressed skepticism about Ragaz's proposal.
The most controversial point was forgoing randomized controlled trials that compare the new therapy with standard therapy in the adjuvant setting. "The importance of a randomized trial is that it takes into account prognostic factors that you are not aware of," said Richard Pazdur, M.D., director of the office of oncology drug products at the U.S. Food and Drug Administration. "The issue here is that we may think we know everything about a disease, but I doubt we do."
Randomized controlled trials are particularly important when the endpoint is disease-free survival, which can be heavily influenced by the time of scans, for example. Also, most regimens provide only modest benefits, and these are particularly likely to be obscured by the use of historical databases because of unknown variations between the populations, Pazdur said.
Also, Ragaz's proposal is based on the assumption that metastatic and early breast cancer are the same disease, a point that not everyone thinks is necessarily the case. For example, women with early disease have reported relatively substantial trouble with neuromuscular and skeletal pain when they take aromatase inhibitors. Researchers, however, were not aware of the magnitude of the problem in women with metastatic disease. "If, in fact, we really believed a new therapy would absolutely work, one could argue we could do without adjuvant trials," Winer said. "They are not only necessary to document efficacy, but we also need long-term toxicity data in the adjuvant setting."
Neoadjuvant Trials
Both Pazdur and Donald Berry, Ph.D., professor and head of the division of quantitative sciences at the University of Texas M. D. Anderson Cancer Center in Houston, agreed with Ragaz that an increase in the use of neoadjuvant trials could help speed approval, but they differ in how they propose using such trials. Instead of using the data from neoadjuvant trials directly in a regulatory application for a new therapy, Pazdur and Berry both suggested that these data may be best used to guide the adjuvant trials themselves, which might be more efficient and faster as a result.
For example, neoadjuvant trials may identify patients that are most likely to derive long-term benefit from a new regimen or indicate which combinations will be most effective. If that information leads to an increase either in the proportion of patients that respond in an adjuvant trial or in the magnitude of benefit, then the adjuvant trial can be smaller or shorter—and still show a statistically significant outcome.
Moreover, neoadjuvant data can be used to help prioritize therapies for further clinical testing. For example, if a drug or therapy shows a large effect in the neoadjuvant setting, researchers may want to put their effort into testing it in the adjuvant setting rather than some other regimen. "This strategy is enormously promising, and the breast cancer research community is aggressively pursuing it," Berry said. "The sample sizes to show treatment effect on pathologic complete response are relatively modest in the hundreds of patients."
Whether clinical benefit in the neoadjuvant setting would be enough to gain regulatory approval in the adjuvant setting is unknown. Pazdur emphasized that although the patients involved all have early disease, neoadjuvant and adjuvant therapy are really distinct settings. However, "it might be a way to get a drug approved initially," he said. "I think that could be a consideration," pending discussions with the FDA's Oncology Drug Advisory Committee.
Better Coordination
One point that everyone agreed on is that better prioritization and better coordination in selecting and running trials would greatly improve the system. Ragaz proposed assembling a formal headquarters linking the oncology communities in Europe, Asia, and North America, which would coordinate the effort to quickly move promising therapies through adjuvant trials.
But even without building a new organizational structure, Winer thinks that there is too much complacency in the system and that dealing with that issue could speed drug development. "We need a sense of urgency that we just need to get studies up and running and we cannot tolerate delays," he said. Some delays, such as scientific analyses and safety and regulatory reviews, cannot be avoided. But other delays are due to complacency within the community. Though individual people are passionate about moving things forward, there is an acceptance that the system is slow. And delays accumulate if no one pushes hard to prevent them or move past them once they occur. "I will tell you as an investigator, when I really want something to happen, it is amazing how quickly I can get people moving at times. That makes me think—apart from the delays required to answer necessary scientific questions, which is very important—there are steps we can take to get past some of the delays" without altering the whole system.
As the chief scientific officer for the Susan G. Komen Breast Cancer Foundation, Winer says that the group has thought about putting conditions on their grants, requiring researchers to get a trial up and running within a certain amount of time or losing the financing. "We haven't implemented it yet, but we've thought about trying to put some real teeth to this."
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