RARE Daily

Study Finds Real-World Data Comparable to Placebo Control in DMD

September 16, 2020

The early wave of clinical trials for therapies in Duchenne muscular dystrophy were plagued with failure as study after study showed experimental therapies unable to meet the endpoints and demonstrate a statistically significant benefit relative to a placebo.

In hindsight, said Susan Ward, founder and executive director of the collaborative Trajectory Analysis Project (cTAP), even though some of the trials enrolled a large number of patients, the studies were underpowered.

When a phase 2b study of the drug ataluren was published in 2014, it showed for the first time the individual patient trajectories and what the placebo arm of the study looked like. “What you see is kids’ ability to walk in that particular example is all over the map. The reason for that is not that the trial was conducted poorly or that the test systems were not administered in a consistent manner. None of that,” said Ward. “The reason is that some kids progress in this disease much more rapidly than others.”

The wide variation in the progression of the disease made it challenging to do studies that would demonstrate when a drug was providing benefit given the small population of a rare disease. “When you have a very noisy population like this, you simply throw patients at the problem. You run a bigger trial,” said Ward. “That works just fine for blood pressure and many of the prevalent disorders where you can run the 20,000-patient trial. But in rare disease, that is simply not an option.”

Ward, who spent most of her professional life on the research side of pharmaceutical companies and as an advisor to pharmaceutical company executives, founded the multi-stakeholder research coalition cTAP in 2015 to address critical problems in drug development in Duchenne muscular dystrophy. Now, a recent study by cTAP and its collaborators, published in the journal Neurology, show for the first time that real-world data and natural history data could augment or replace placebo controls in clinical trials in Duchenne muscular dystrophy (DMD).

Though regulators are working to incorporate real-world evidence into the drug review process, the use of natural history studies as an alternative to a placebo control arm has only been done in a limited number of circumstances. Among the concerns of regulators is the potential for bias to skew data and the quality standards under which data are collected. Nevertheless, the cTAP study provides validation for this approach, which could help accelerate rare disease drug trials, many of which must rely on smaller populations than the Duchenne community.

For the study, cTAP brought together researchers from around the world who analyzed disease progression in 383 patients from placebo arms in six clinical trials and compared results to data observed in a real world setting for 430 DMD patients from five clinical registries in the United States and Europe.  The study sought to determine whether natural history study data was consistent with placebo arm study data by looking at all of the published clinical trial studies that had used the six-minute walk test. Using their inclusion / exclusion criteria, it then applied them to a number of different natural history databases. The findings showed that patient outcomes were similar, indicating that real world data could be used effectively in DMD clinical research in lieu of a placebo-control arm as a comparator to determine the effectiveness of an experimental drug versus standard of care treatment.

By rare disease standards, DMD is more common than most rare diseases and Ward said the Duchenne community has been astute in having invested in formal natural history studies early. Even though it can be difficult to access the needed data, there is adequate data available, which makes Duchenne a good subject for this kind of study, but the findings suggest a path forward for other rare disease communities.

“The principle here is that the solutions we find in Duchenne should be applicable to other rare diseases,” said Ward, “And that’s precisely what we’d like to do.”

Photo: Susan Ward, founder and executive director of the collaborative Trajectory Analysis Project (cTAP)

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