In many cases, the researchers conducting the phase II effort knew beforehand that, due to financial or other constraints, a phase III trial was unlikely.
According to experts, that raises the troubling question of why the phase II study was done at all.
"If all of this effort in supporting phase II trials doesn't go anywhere, it means that the patients included -- and the efforts of their doctors -- could have been spent in finishing potentially practice-changing phase III studies," said the study's lead author, Ian Tannock, professor of medical oncology at Princess Margaret Hospital and the University of Toronto, Canada.
The bench-to-bedside evolution of any new cancer treatment occurs in three stages once a drug clears animal testing. First, a small phase I trial assesses the therapy's safety and calibrates the best dose. Next, a phase II trial (usually less than 100 patients) looks at how effective the therapy might be against a particular type of tumor.
If those results are positive, the drug should next go on to a much larger -- and expensive -- randomized trial comparing the new agent against the current standard of care. Positive results from phase III trials are required for U.S. Food and Drug Administration approval of most new agents.
Given the scarcity of both money and willing volunteers for cancer research, "a phase II trial shouldn't even be started unless there is an intention -- if the phase II results look promising -- to take it forward," said Tannock, who presented the study findings in June at the American Society of Clinical Oncology annual meeting.
And yet, for years, he and his colleagues had noticed a troubling trend: An overabundance of phase II trials presented at ASCO and other meetings that claimed promising results but then went nowhere.
In their study, the Canadian researchers reviewed the post-presentation histories of 200 phase II trials with "encouraging results" for breast, lung, gastrointestinal, genitourinary, and gynecological cancers. One hundred of the trials were presented at ASCO's 1995 and 1996 annual meetings, while the other 100 were presented at the society's 2006 conference.
They found that just 13 percent of the trials did, in fact, go on to a phase III study, despite results that had shown a positive response of the therapy against the targeted tumor.
Many of the trials reached a dead end, because the researchers couldn't get financial backing or enough patients for a phase III look at the treatment.
However, the study also found that "many of these limitations are known [to the researchers] when planning the phase II study, implying that many phase II trials are not planned as precursors of phase III trials."
So, why the wasted time, money, and effort for research that the investigators suspect will go nowhere? Tannock believes that, in many cases, the researchers' career goals may have come first.
"There's a lot of young oncologists out there, and they are encouraged to publish," he explained. "Their promotion at academic centers is dependent on publication. So, many of them may be encouraged to put together a protocol in which they take new drugs and treat a small number of patients with a certain disease in a phase II trial."
Because the teams that conduct phase II trials are smaller, a young researcher is more likely to be listed as the prestigious "lead researcher." This gains researchers more recognition than if their name is buried among the much-longer list of authors that typically accompanies phase III studies, Tannock explained.
Most phase III trials are headed by seasoned leaders in the field. "It is clearly impossible for a young investigator to run a large phase III study," Tannock noted. "And they just don't get the academic kudos for entering patients into a potentially practice-changing phase III study that they do from running a 20-patient phase II study."
Tannock believes that most young researchers do not "consciously" seek to begin a dead-end phase II trial, "but I think the system encourages it." He believes the same paradigm may exist in other areas of medical research, such as heart disease or other illnesses.
Another expert agreed that the preponderance of phase II trials is troublesome.
Dr. Bruce Hillner, a professor of medicine at Virginia Commonwealth University, has researched the issue on a global scale. In a study published in 2003 in the Journal of Clinical Oncology, Hillner found that phase II trials are much more common in the United States than Europe, where more resources are poured into practice-changing phase III trials.
"One of the pressures may be the 'publish-or-perish' that's disproportionately felt by American junior faculty," he said. "The other is the depth of financial entanglements with the pharmaceutical industry."
In some cases, Hillner said, drug companies use promising results from small phase II trials to encourage doctors to use an already FDA-approved drug 'off-label' for another purpose. In this way, he said, the company boosts drug sales while sparing itself the expense of the multimillion-dollar phase III trial that's required for new agency approvals.
Hillner also believes that, in many cases, phase II trials simply aren't presented well enough to garner the wider interest that's needed to take them to the next level.
In many cases, he said, researchers simply label their results "encouraging" or "positive," but never compare them to outcomes seen with currently available drugs or treatments.
"They compare it to a straw man, just saying 'this looks great,' " Hillner said. "This failure to define a benchmark is a major reason why many of these reports are just short-term fireworks."
Another expert agreed.
"While a phase II study might be 'positive,' it may not be as positive as something that's already been tested in a similar patient population," said Dr. Richard Schilsky, ASCO's president-elect and associate dean of clinical research at the University of Chicago.
He called the overabundance of dead-end phase II trials "a tough academic and cultural issue," and agreed that much of the problem is caused by the "publish-or-perish" phenomenon.
"As an academic community, we have to develop a better reward system for people who play important roles in developing these large, multi-center [phase III] trials," Schilsky said. Such a move would give young researchers a way of gaining peer recognition besides heading a phase II trial.
The message for the public is also clear, the experts said.
"The public should also be very cautious about 'exciting' results from phase II trials," Tannock said. "The literature is replete with things that looked very good in phase II but did not prove to be any better than standard treatment in phase III. You have to be careful."
More information
There's more on the clinical-trials process at the U.S. National Cancer Institute.
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