Treatments for relapsing-remitting Multiple Sclerosis (RMS) have been available commercially since 1993—and since that time, patients have developed an increasingly sophisticated and accurate understanding of RMS. While this is obviously good news for individual patients, it poses certain challenges for researchers attempting to develop and evaluate new and more effective treatments for RMS; for example, patient populations in recent studies typically have a lower disease activity level at the time of entry into clinical trials in comparison to the past, so it’s difficult to compare contemporaneous or planned studies to historical data for the purposes of estimating sample size and study duration for key outcome measures. Additionally, it’s even more difficult to find treatment-naïve patients, as standards of care recommend patients begin treatment for RMS at a very early stage of the disease.
What this means for interventional MS research, and in particular, RMS research, is that the traditional clinical endpoints for a study may not be sensitive enough to demonstrate that a new drug is more effective than an existing standard treatment, particularly in earlier phase exploratory research characterized by limited sample sizes, and demands for efficient exploration of dose, exposure, and response. In addition, in an RMS research population with low disease activity, it’s difficult to detect differences with respect to placebo, given similar constraints.
It’s clear that new design strategies including patient enrichment maneuvers, potential exploitation of composite endpoints and the use of adaptive trial designs offer promise —but what strategies will be most effective?
Adaptive Trials: The Key to Success
Certain contract research organizations (CROs), Worldwide Clinical Trials among them, have begun to embrace adaptive design clinical trials across a mosaic of different indications, which are designed to be able to change on-the-go as data is collected using prespecified analyses. While the studies continue, adaptive clinical trials can modify sample size, adaptively change dosage levels to be evaluated, modify the randomization across those dosages, rearrange hierarchical approaches to analyses and combine different clinical phases of drug development, and more.
As an example, one adaptive clinical trial in RMS research was the BOLD study, in which three doses of study drug and placebo were tested for MRI-supported efficacy in the first period of Phase II of the study. After three months of treatment, investigators added two additional active doses for Phase II’s second period—a prespecified study design option that expanded the range of dosages to be explored prior to determining the optimal dose for later Phase III studies, while keeping placebo exposure to a minimum.
Researchers have begun to consider innovative study endpoints as well, particularly in exploratory clinical research characterized by limited sample size and durations of exposure. Recognized benefits and limitations of a composite, which includes MRI, the absence of sustained disease progression, and the absence of clinical relapse reflect different aspects of disease severity as a unitary construct. This delivers a new outcome measurement of “no-evidence-of-disease-activity” (NEDA), which is the treatment goal for MS in daily clinical practice.
Choosing NEDA as a study endpoint allows investigators to increase statistical precision and efficiency while benefiting the study’s participants—an attractive and plausible program option even for pivotal Phase III trials provided that potential asymmetries in the frequency of each parameter of the composite are adequately addressed. With NEDA as an endpoint for adaptive clinical trials that pivot upon adaptive dose ranging or sample size reestimation, Worldwide and other CROs can reduce the sample size and the time it takes to evaluate a promising new treatment for MS.
To learn more on this topic, read this article, titled “Evolving landscapes in multiple sclerosis research: adaptive designs and novel endpoints.”
Dr. Michael Murphy, M.D., Ph.D., is Chief Medical & Scientific Officer at Worldwide Clinical Trials.
