By Deborah Borfitz
April 28, 2008 | The management and monitoring of adaptive clinical trials can present some new challenges to study sponsors and exacerbate some old ones. Meeting those challenges may or may not get a drug to market faster, but it likely will have some secondary benefits for investigators and study subjects.
So says Michael Krams, MD, assistant vice president, adaptive trials, clinical development at Wyeth, the industry leader in adaptive dose-ranging studies. “The major attraction for investigators and patients to participate in these types of trials is the higher information value for the research investment. For investigators, adaptive clinical trials are a more intelligent way to interpret the data. From the individual patient’s perspective, there’s a higher probability of getting a good treatment or not being allocated to a bad treatment.”
This is especially meaningful when it comes to adaptive randomization in trials for life-threatening conditions, including most cancers, says Trevor Mundel, MD, global director of the immunology and infectious disease business franchise of Novartis Pharmaceuticals. “If you can do this and you start to see a subgroup respond better to your drug, aren’t you obliged to put more patients in that subgroup?”
This serves as compensation to investigators engaged in adaptive clinical trials who face “an additional level of uncertainty” regarding study length and subject enrollment, as well as higher expectations in terms of timely data entry, says Krams. With adaptively designed studies, how long a study will run and how many patients will be involved “is not known at the beginning, but emerges as data accrues.”
Most investigators have never conducted an adaptive clinical trial and are understandably skeptical, says Krams. “But once they’ve gone through the experience, they clearly want to do it again.”
From sponsors’ perspective, it is important to ensure that patients entering the trial are “exchangeable,” says Krams. “For instance, if there are likely to be regional differences on a primary endpoint, this needs to be taken into account when designing the trial.”
Study monitoring also needs to happen in an adaptive manner, with site visits occurring “whenever there’s data to look at,” says Krams. Because data queries happen “without any delay,” they double as an educational tool for adaptive clinical trial investigators.
There is a “clear need” for additional information sharing with institutional review boards and ethics committees regarding the intention of an adaptive clinical trial, says Krams. “Some ethics committees have asked if we could share interim results with them whilst the trial is still ongoing. We believe that the only body which should see the data from interim analyses is the independent data monitoring committee.”
Informed consent documents also need to “clearly explain to which treatments a patient could get allocated and how the probability of treatment allocation can change during the course of the trial,” says Krams. This can be easily accomplished in a short paragraph.
For drug companies, adaptive clinical trials may be a convenient way to size up questionable compounds, according to Professor Donald Berry, head of the division of quantitative sciences and chairman of the department of biostatistics at the University of Texas MD Anderson Cancer Center. “Most of the ones we’ve done [at MD Anderson] so far have been very successful in the sense that they’ve killed off a drug very early. One possibility is that most drugs are duds. The other possibility, which worries me, is that companies use standard [trial] designs if they have a highly positive drug and do an adaptive clinical trial if they’re not sure the drug is any good. Proving a drug doesn’t work is a great service, but it’s not making us famous.”
Part of an eCliniqua series on adaptive clinical trials. Previous articles in this series can be found here.