Sponsors, others trying new trial methodology

This could soon be a trend

Clinical trial sites may soon see more studies with adaptive designs, reflecting the industry's movement toward a more efficient clinical trial process and a growing trend of treatments targeted to specific groups and populations.

While there are a variety of ways clinical trial methodology can be made more flexible and adaptive, one definition is as follows: "Basically, what it means is you have upfront defined criteria of how you monitor the trial, and based on emerging data from the trial, you modify it to the duration of the trial, size of trial and, possibly, to the importance of end points," says P. K. Tandon, PhD, a senior vice president of BioMedical Operations for Genzyme Corporation in Cambridge, MA.

Tandon is scheduled to offer a half-day tutorial on the subject on June 16, 2007. His lecture, titled, "The Scientific and Economic Benefits of Flexible Adaptive Trial Methodology Designed to Achieve Early Registration and Robust Results: Raptiva and Fabrazyme as Case Studies," is part of the 43rd Annual Meeting of Drug Information Association (DIA), which will be held June 17-21, 2007, in Atlanta.

The way the adaptive methodology works could be of significant benefit in a phase II clinical trial, for example, Tandon says.

"In a phase II trial setting there are some diseases where you don't know what the primary end point should be," Tandon explains. "And when looking at the data it might say that 'This end point is not working, but this one is working.'"

Biologically this might make sense, and a researcher could use that new end point as some kind of inference-based decision, Tandon says.

"But your trial is basically important for learning how to interpret the data," he adds. "This could be used in designing future studies."

The same flexibility could be applied to finding the best dose during a phase II trial, Tandon says.

In the typical drug development scenario, investigators will complete the trial and have a negative outcome, which could result in the sponsor abandoning the intervention or starting over with something new, Tandon says.

"But the beauty of flexibility and adaptive design is there is still some hope for the product," he says. "We can use existing data to understand what is going on in some diseases."

One example can be found in biomarkers. "We may be looking at biomarkers where it turns out that a particular biomarker is not really doing what you hope for," Tandon says.

"Sometimes what happens is the patient population used for that phase II study is showing something different than what you expected," Tandon says.

Or maybe the sponsor underestimated or overestimated the efficacy of a particular drug, he notes.

Designing clinical trials with flexibility and adaptability built-in could help improve investigators' and sponsors' understanding of the drug and disease, especially in certain patient populations, Tandon says.

"At the same time you want to be very careful and acquire pretty sophisticated timing and methodology," he adds.

"In phase II settings, you can see how some patients of a decent number are really behaving differently [with treatment], although the overall results are not that impressive," Tandon says. "But maybe this one patient population we can go after and start recruiting more patients in this particular subgroup."

Since mid-2005 when the Food and Drug Administration (FDA) approved the drug hydralazine/isosorbide dinitrate (BiDil), which treats heart failure, as the first drug ever approved for one specific ethnic group, the door was opened for targeted medicine and treatment.

Hydralazine/isosorbide dinitrate was approved by the FDA on June 23, 2005, for use in African Americans.

There were 2 clinical trials of hydralazine/isosorbide dinitrate among the general population, and these found no benefit from the drug, an FDA media release says.

The FDA-approved hydralazine/isosorbide dinitrate is based on results from the African-American Heart Failure Trial (A-HeFT), which involved 1050 self-identified black patients with severe heart failure who had already been treated with the best available therapy.

Black patients in the A-HeFT study had a 43% reduction in death and a 39% decrease in hospitalization for heart failure when compared with placebo, the FDA notice says.

Although targeted treatments are possible, they'll continue to be challenging to study because of the regulatory requirements, Tandon notes.

"One has to be careful in changing a trial that is ongoing because you need IRB approval; you have to change the case report forms," he says. "It's not easy — not a slam dunk."

It requires very careful planning in the same way as a football game strategy, Tandon says.

"You have a plan A, B, and C," he adds.

Nonetheless, adaptive methodology is catching on and could become a trend because of the financial pressures inherent in drug development, Tandon says.

"If you can make a decision faster, then it benefits the scientific community and companies," he says.

To do it right requires a strong investigative team, including statisticians who are very careful, Tandon says.

"The consequences are very severe because it could be that you killed a product that is very good, or it could be you say a product works well, but down the road you find that you had a false positive," Tandon explains. "You need to make sure you have the right methodology and that appropriate caution is taken into account."