A bold proposal to streamline clinical trials

SAN ANTONIO—If therapeutic agents are documented to be more effective than standard therapies in the advanced breast cancer setting, they will also be effective in the adjuvant setting. This renders randomized phase III adjuvant trials unnecessary in many cases, and means that undue delays in moving new agents up-front are costing lives, Joseph Ragaz, MD, professor of medicine and oncology, McGill University, Montreal, said at the 2007 San Antonio Breast Can-cer Symposium (abstract 14).

Dr. Ragaz projected, for example, that the 5-year delay between the observation of tamoxifen's efficacy and its inclusion in adjuvant guidelines could have saved up to 100,000 lives. Along with his co-author, John J. Spinelli, PhD, senior biostatistician, British Columbia Cancer Agency, Vancouver, he took issue with the clinical trials process and proposed some changes.

In their study, all pivotal trials of hormonal, chemotherapy, and biological agents that have been tested in the same design, first in stage IV and then in the adjuvant setting, were reviewed. The data have confirmed that all those commonly used systemic agents that were efficacious, though not curative, in stage IV disease were more efficacious, and in many cases curative, in the adjuvant setting.

For instance, for tamoxifen, CMF, anthracyclines, taxanes, and aromatase inhibitors, as compared to the standards of care in pivotal trials, high response rates were achieved, but there were no cures. In the adjuvant setting, however, not only was risk of relapse reduced by about 20% to 40%, but mortality was also reduced by 15% to 40%. Population studies have also shown that the incorporation of systemic therapies results in mortality reductions, he said.

"If introduction of systemic therapies does cure disease, does withholding of systemic therapy due to delays [in the clinical trial process] prevent the materialization of survival gains?" Dr. Ragaz asked.

The answer, he said, is yes. "It is estimated that 400,000 women are alive today as a result of tamoxifen therapy," Dr. Ragaz said. "In the adjuvant setting, tamoxifen saves about 20,000 breast cancer deaths worldwide each year. The projections show that if tamoxifen had been activated in 1980 instead of 1985, it could have saved 100,000 more lives."

Similarly, for adjuvant trastuzumab (Herceptin), the median number of recurrences avoided per 1,000 new patients is 15 in low-risk patients, 38 in intermediate-risk patients, and 53 in high-risk patients. If adjuvant trastuzumab had been included in the guidelines in 2001 rather than 2006, close to 50,000 breast cancer recurrences could have been avoided over those 5 years, he estimated.

"These agents have very powerful curative effects. Any delay of implementation of potentially curative agents translates into a delay in saving lives," Dr. Ragaz emphasized.

He noted that the new agent lapatinib (Tykerb) plus capecitabine (Xeloda), compared to capecitabine alone, reduced the risk of progression by 50% in stage IV disease, but the first adjuvant trial has just begun, and "with the present infrastructure, it could be 5 years or more before lapatinib becomes available in the adjuvant setting," he said. Furthermore, there are 40+ new targeted agents to be tested within the current clinical trials process, only accentuating the delays, he said.

Dr. Ragaz offered more than criticism. He provided a set of "outside the box" proposals that he believes will streamline and hasten the clinical trials process and make effective drugs available sooner.

His first proposal was to "tighten" the description of clinical benefit in advanced stage disease to include the following outcomes:

• Type I, minimum benefit—no improvement in progression-free survival (PFS) or overall survival (OS).

• Type II, medium benefit—improved PFS but not OS.

• Type III, maximum benefit—high response rate and improved PFS and OS.

Only trials with type III benefits would qualify for this immediate "transfer" to the adjuvant setting, he said.

He would further "tighten" the process by rapidly moving from phase I-II trials to phase III trials within 2 years, and conducting three to four clinical trials simultaneously. Currently, he noted, only one pivotal trial of an agent is being conducted at any one time.

"We would move to the adjuvant setting if a type III effect is seen in the stage IV setting," he said. "And type III agents from metastatic trials should be studied without a placebo arm. The focus would be on short- and long-term toxicity, dose response, biomarkers, and selection of appropriate patient cohorts."

This would furthermore be complemented with data from the neoadjuvant setting, ideally obtained via needle biopsy, which gives the best in vivo assessment of therapeutic effect, he noted.

"A neoadjuvant trial is an ideal model for in vivo activity, producing both pathological and molecular response data. Neoadjuvant trials should follow soon after stage IV trials, with answers produced within 1 year," Dr. Ragaz said.

He also proposed new study designs for phase II adjuvant trials to allow completion in less than 2 years. Patients would come from many centers registered in an identical database. One registry group of 10,000 patients would receive standard therapy and another group of 10,000 would receive standard therapy plus the new agent under study—a major expansion of sample size permitting detection of small differences more quickly.

Finally, greater international coordination among trialists is necessary, he maintained. He called for coordinated efforts to produce trials that are simultaneous, prioritized, evaluated early, and coordinated internationally. "This is a detailed outline of a concept with only the start of conceptual details. The rest, I hope, will come," he said.