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FDA Encourages New Study Designs
  "FDA Signals It's Open To Drug Trials That Shift Midcourse"
Wall St Jnl
July 10, 2006; Page B1
Clinical trials of medicines are traditionally performed in a "blinded" fashion so that the findings will remain secret until the studies are completed. But regulators and the pharmaceutical industry are increasingly interested in starting to use a very different model that lets studies change as they go along, based on early results.
Drug companies have begun to perform such adaptive trials for their new medicines, hoping for more efficient tests that could save millions of dollars. The Food and Drug Administration, meanwhile, is sending increasingly encouraging signs that it is open to considering the results of such trials. In a move that could lay the groundwork for greater future use of such studies, Scott Gottlieb, an FDA deputy commissioner, is set to announce today plans to develop regulatory guidelines for adaptive trials. The FDA has also put together an internal team to work with its drug-review divisions on the adaptive designs, which are statistically complex.


"We think it's time to start exploring the appropriate use of these designs in the appropriate situations," says Robert T. O'Neill, director of the FDA drug center's office of biostatistics. Over the past year, all of the FDA drug-review divisions have seen at least one adaptive trial submitted by companies, he says.
The most ambitious adaptive designs would represent a big change from traditional clinical-trial practices, and the idea has sparked controversy among researchers. Now, once trials are set in motion, they are supposed to be left largely untouched until they are finished and the drug company finds out the results. One exception: The studies often have an independent data-monitoring board that has the power to shut a trial down for ethical or safety reasons.
Adaptive trials have aspects that are "fundamentally different from what we currently do," says Michael Krams, who joined Wyeth in April as assistant vice president for adaptive trials. The results of an ongoing study are watched closely, and changes to the design occur as it continues, guided by a complex plan developed in advance, typically through computer simulations. If one treatment looks more effective, a greater proportion of patients may be funneled to it. If one group of patients appears to be benefiting more, the trial might start adding a larger share of that type of person.
Pharmaceutical companies hope such approaches hold the potential for major savings, though so far they are largely focused on early-stage trials. Advocates of adaptive designs say they can involve a reduction of 30% or more in the number of patients needed in a trial, and can save time as well. They also say that adaptive trials carry major benefits for patients, who have reduced odds of getting a less-effective treatment.
"It helps us pick the winners and losers faster," says Steve Ruberg, director of global medical information sciences at Eli Lilly & Co. The company has three ongoing early-stage adaptive drug trials in areas including oncology and diabetes, he says.
Bristol-Myers Squibb Co. is planning a migraine-drug trial that will use adaptive principles to help determine how much medicine to give. The study will start with 10 to 15 different doses, far more than the three or four the company would typically give in a traditional trial. As data comes in, new patients will be routed to the doses showing the best results, so by the end only a few doses will remain active.
But researchers and regulators say that such trials also raise serious questions. Perhaps the biggest concern is that allowing access to ongoing trial results could introduce bias if the sponsor or the doctors running the trial -- or the patients taking part in it -- learn about them and consciously or unconsciously change their conduct on an ad hoc basis. Another worry is that preliminary findings could leak out to investors. Adaptive designs can work, but they are also "much more open to abuse," says Bruce Turnbull, a professor of statistics at Cornell University in Ithaca, N.Y.
One possible solution is to have independent experts examine ongoing results and execute design changes. But "that's going to be a tough pill for companies to swallow, putting potentially important decisions about trial design in the hands of totally independent bodies," says Paul Gallo, a director of biostatistics at Novartis AG. Novartis is suggesting that a few of its employees who aren't working on the trials gain access to the trial data on the condition that they not disclose the data to Novartis.
Adaptive trials also carry major logistical and statistical challenges. For one thing, an early signal from a study "is not always a reliable clue," potentially sparking premature design changes that will cause a trial to be less efficient and harder to interpret, says Thomas Fleming, a statistics professor at the University of Washington in Seattle. He says the use of adaptive designs in late-stage trials used to confirm that drugs work raises "very serious ethical and scientific concerns." But Donald Berry, chairman of the biostatistics department at the M.D. Anderson Cancer Center in Houston and an adaptive-design advocate, says that statisticians can correct for the risk of using the emerging data, and that adaptive trials still often increase efficiency.
The FDA's Dr. O'Neill says the agency hopes to address such issues, including the independent data-monitoring committees and the proper role for data generated by adaptive trials. The FDA is gathering examples of adaptive designs it has reviewed, and it will develop a "concept paper," likely followed by draft guidelines sometime next year, he says. The FDA sees benefits in adaptive designs, he adds, but "the last thing we want to have happen is for the enthusiasm for these designs to run ahead of the ability to carry them out with integrity."
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