Streamlining Clinical Trials

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Coming Soon: Faster, Yet Still Safe, Clinical Trials

03.29.06, 12:00 AM ET

WEDNESDAY, March 29 (HealthDay News) -- In an ideal world, new, effective and safe medications would sail through clinical trials in just a couple of years.

But the drug-approval process in this country is far from ideal: In the whole of 2005, the U.S. Food and Drug Administration approved just 20 new agents, down from 36 approvals the year before.

And while everyone wants effective drugs marketed as soon as possible, the Vioxx debacle in 2004 has regulators and drug developers leery of releasing medications to market too soon.

That's why something called surrogate markers -- a kind of clinical trials "crystal ball" -- has everyone in drug development so excited.

"We're hoping that it will be the impetus to change clinical trials from five-year trials, for example, to just one-year trials," said Dr. Jerry Radich, a noted leukemia researcher in the clinical research division of the Fred Hutchinson Cancer Research Center, in Seattle.

Radich is very familiar with the issue: He's leading the first-ever federally approved, phase 3 clinical trial of a cancer agent in which a surrogate marker will be the primary criterium by which researchers will judge each drug's effectiveness.

That trial, which is still recruiting patients, will compare two doses of imatinib (Gleevec) against the experimental drug dasatinib, for patients with chronic myeloid leukemia (CML).

Surrogate markers are essentially tests or patient milestones that researchers can use as stand-ins to predict longer-term patient results, such as survival. They include patterns such as tumor shrinkage, time-to-disease-relapse, findings on a MRI or PET scan, or molecular or genetic changes in blood or tissue samples.

The important thing is that these findings can predict, with a fair amount of accuracy and years in advance, who is going to benefit from a particular therapy, and by how much.

Right now, "patient survival remains the gold standard as the endpoint for any large clinical trial," explained Dr. James Doroshow, director of the division of cancer treatment and diagnosis at the U.S. National Cancer Institute (NCI). "There's no question that if something significantly enhances a patient's survival, then that therapy -- if it has an acceptable toxicity profile -- will often, if not always, be approved by the FDA."

But there's a big problem with using survival as a study's main endpoint: Final results can take many years, even decades, to come in as researchers count up who lived and who died.

It's part of the reason why the average FDA-approved drug now takes at least a decade to make it from the laboratory to the marketplace, if not longer.

So, experts have recently focused on the development of tests that "might predict, with a very high likelihood, whether a treatment provides a survival benefit or not," Doroshow said.

In the case of Radich's trial, the test in question measures post-treatment changes in a blood-borne genetic marker that predicts the "depth" of a CML patient's response to drug therapy. Because his team won't have to wait for survival outcomes, results from this trial of 600 patients should be ready within months, not years, of initial treatment, Radich said. "It's a pretty nifty way of moving things up and getting drugs that might be potentially better out there more quickly," he said.

But won't speeding things up raise the risk that long-term side effects will go unnoticed? Not so, according to experts.

First of all, "with all the drug trials that we are talking about right now, there is enough phase 1 and 2 [safety] data, so that people are already pretty comfortable about the side effects," Radich said.

And Doroshow noted that most phase 3 trials -- which focus on efficacy -- don't end when initial results are published. "Especially for new therapies, we follow patients for a long time after that, looking for long-term effects," he said.

The NCI expert cautioned, however, that any move to surrogate markers needs to be done cautiously, first making sure that a particular marker does, in fact, predict patient survival. A joint NCI/FDA initiative to test one such theory -- that PET scan findings predict survival after lung cancer treatment -- is currently being assembled, Doroshow said. The FDA is also investigating whether time-to-disease-relapse might be a good predictor of survival for patients battling metastatic colon cancer.

If either of those efforts ends positively, the result could be much shorter -- yet still accurate -- clinical trials for drugs to fight two leading cancer killers. And experts believe surrogate markers might also serve as endpoints for trials for other forms of disease, including autoimmune disorders and infections such as HIV.

The usually conservative FDA has been unusually proactive when it comes to surrogate endpoints, said Radich, who has recently attended agency-sponsored symposiums on the topic as it relates to leukemia research.

In fact, in a statement released March 16, the agency listed "biomarkers" as one of the key planks in its "Critical Path Initiative" (CPI), which is aimed at speeding up clinical trials.

In the statement, Dr. Janet Woodcock, FDA's deputy commissioner for operations and head of the initiative, said that "most researchers agree that a new generation of predictive markers would dramatically improve the efficiency of product development, help identify safety problems before a product is on the market (and even before it is tested in humans), and facilitate the development of new types of clinical trials that will produce better data faster."

So, are surrogate endpoints the future of medical research?

"The short answer is, 'yes,' " Doroshow said. And clinical trials are just the beginning, he added.

Eventually, he said, doctors will use predictive biomarkers as "crystal balls" at the bedside to make crucial decisions as to "whether we should continue useful therapy in the appropriate patients, or discontinue therapy that may well have bad side effects in patients and in whom it can be predicted the therapy won't be useful."