The Ups and Downs of Adaptive Clinical Trial Design

A reduction in drug development timelines, lower clinical trial costs, improved efficacy and better trial design – all things the pharmaceutical industry constantly strives to achieve and many believe adaptive clinical trial design can offer.

Explained in the simplest way, adaptive clinical trial design involves using an interim analysis to determine whether any changes need to be made to the research.

A more comprehensive definition, laid out in draft guidance on the subject published by the United States Food and Drug Agency (FDA), describes an adaptive clinical trial as a "prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data".

This analysis takes place at specific pre-planned points within the study and can be performed either blinded or unblinded.

However, for all its potential benefit, the pharmaceutical industry and regulatory authorities are still reserved about the use of adaptive clinical trial design in future drug development.

Optimising trial design

Researchers at the University of Michigan were recently granted funding from the National Institutes of Health and the FDA to conduct a three year study into the field.

The department highlighted how there is no way of telling how quickly a clinical trial will show results, meaning traditional designs prevent necessary changes taking place to improve the results of the trial.

William Barsan, chair and director of the U-M Department of Emergency Medicine, explained the objective of the research is to "optimise the design of four large, neurological emergency trials at various stages of development."

"We'll use modeling and mathematical simulation to really kick the tires on a number of potential adaptive designs with the hope of gaining efficiency in the ultimate trial design," he explained.

Hurdles for wider use

However, research conducted by Perceptive Informatics in 2009, before the FDA's draft guidance was published, suggested there are a number of hurdles currently preventing more widespread use of clinical trials.

In a survey of 500 biopharmaceutical professionals, including those involved in clinical, statistical and regulatory roles, 35 percent claimed regulatory concerns were the main barrier to the implementation of adaptive clinical trial design, although the company predicted this may change when guidance was made available.

Some 33 percent said there remained a lack of understanding about the new technologies used within such trial designs, while 28 percent cited concerns about "rapid access to clinical end point data."

The FDA also spoke on some of the pitfalls of adaptive clinical trial design in its guidance on the subject, where it said "major concerns about study integrity" were presented by revisions which had not been previously planned, or which had been made after an unblended interim analysis.

It stressed one of the major issues is the potential for adaptive clinical trials to produce a positive bias to results. "In the case of some of the more recently developed adaptive methods, the magnitude of the risk of bias and the size of the potential bias, and how to eliminate these effects, are not yet well understood," the FDA explained.

There are also concerns adaptive clinical trial design could be "counterproductive" as the final analysis of results is not likely to produce data which can be used to influence and improve the design of further studies.

Real world applications

Despite these reservations, adaptive clinical trial designs recently experienced what some are describing as a promising real world success.

Researchers at theUniversity of Texas M.D. Anderson Cancer Center are currently undertaking a clinical trial, called Battle, to find biomarkers related to certain types of lung cancer which would better enable medical professionals to more effectively target therapies.

After 40 percent of those involved in the trial were enrolled, researchers conducted an interim analysis, which allowed them to then weight the remaining patients in favour of the most promising therapies based on their biomarkers, the Wall Street Journal reported.

While the success rate for those participants involved in the adapted trial was not higher than the initiation stages, this was not said to be due to a problem with the trial design, but rather issues in the definition of biomarkers.

The uses for adaptive clinical trials are likely to increase in the future, industry experts predict.
Bill Byrom, senior director, product strategy, Perceptive Informatics, said: "A growing area for adaptive trials is the ability to include more dose levels in Phase II dose-finding studies without significantly increasing the number of study participants or timeline required."

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