If a tree falls in a forest and nobody is there to hear it, does it make a noise?  How about if an experimental therapy is tested on a patient, and no results are published, does it advance scientific understanding?

An estimated 60 million people in the United States and Europe suffer from one of approximately 7,000 rare diseases, but less than 10 percent of those conditions have an approved therapy.

Though regulatory and financial incentives have increased drug developers interests in rare diseases, some 94 percent of those conditions are without an approved therapy, and as little as 22 percent have ever been the subject of a clinical trial.

The challenges in conducting clinical trials for rare disease therapies are well known. They include the difficulty of running trials with small and geographically dispersed patient populations, the heterogeneity of these conditions in patients, inaccurate diagnostic measures, a lack of validated clinical endpoints, and limited disease expertise in the medical community, among others.

A study at the end of November published in PLOS Medicinesought to determine how often clinical trials for rare disease therapies are not completed and do not result in publication. It found that more than half of clinical trials initiated for rare diseases were either discontinued or not published four years after completion, resulting in large numbers of rare disease patients exposed to interventions that did not lead to informative findings.

“Given the critical need for therapeutic development for rare diseases and the small patient populations available to generate robust clinical evidence,” the authors wrote, “it is essential that clinical trials initiated for these conditions are completed and trial results disseminated in a timely fashion.”

The researchers analyzed rare disease trials registered in a clinical trial registry from 2010 to 2012 and determined the frequency of trial noncompletion and nonpublication through 2018. Among 659 randomized controlled trials, 199 (30.2 percent) were discontinued, most often because of difficulties with patient recruitment.

There were 306 (66.5 percent) trials that were not published two years after completion and 142 (31.5 percent) that remained unpublished four years after trial completion.

In all, more than 18,000 participants were enrolled in trials that were not completed or remained unpublished four years after completion.

The authors note that the rate of nonpublication aligns with previous studies evaluating nonpublication rates across a number of other cohorts, including surgical trials, vaccine trials, trials of neurodegenerative diseases, pediatric trials, and trials with specific types of funding sources. Reasons for nonpublication included industry funding, early trial phase, and certain clinical trial design features.

Two points the authors make speak to ethical considerations. The first involves patient recruitment. Given the difficulties of enrolling patients for rare disease trials, they argue that collaborations with rare disease experts and patient groups should be prioritized. But they go further to suggest that stakeholders should take a disease-focused approach “to ensure patient participation in the most promising trials, as opposed to diffuse enrollment based on sponsor needs.” They also say that to avoid futile patient enrollment, trials should not commence until there is reasonable certainty that the required sample size can be achieved.

The other point they make is that policies from the Declaration of Helsinki to the U.S. Federal Policy for the Protection of Human Subjects emphasize the responsibility investigators have to make timely publication of accurate and complete trial results.

“Timely publication of trial results, particularly for diseases with a scarcity of treatment options, is imperative,” the authors write. “Beyond the scientific mandate for knowledge dissemination, trial investigators and sponsors have an ethical obligation to study participants to maximize the benefit derived from their participation in research studies.”

It’s easy to dismiss rare disease patient involvement in clinical trials as being driven by their lack of therapeutic options, but part of the risk they are subjecting themselves to is with the expectation of advancing scientific knowledge and helping other rare disease patients get to treatments that work. When studies aren’t published, participants are deprived of having their sacrifices benefit others, and patients more broadly lose out.

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