Rare Disease Clinical Trials Need Patient-Centered Outcome Measures, European Researchers Argue

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by Magdalena Kegel |

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To develop meaningful therapies for rare diseases such as Alport syndrome, scientists need to take into account what those with the conditions consider important, two European researchers argued in an opinion piece promoting patient-centered outcomes.

Although doctors increasingly consider patients’ perspectives in assessing treatment outcomes, the article argues that scientists have yet to make patient-centered outcomes an important part of rare disease clinical trials.

Those scientists that do need to come up with ways to measure these outcomes during clinical trials, the authors said.

The article, published in the Orphanet Journal of Rare Diseases, is titled “Measuring what matters to rare disease patients – reflections on the work by the IRDiRC taskforce on patient-centered outcome measures,” 

Current clinical-trial yardsticks often fail to show the benefits that some patients receive from therapies,  according to Thomas Morel of KU Leuven in Belgium and Stefan J. Cano of Modus Outcomes in Britain. This leads to increasing difficulty obtaining regulatory approval of new treatments, they contended.

“Has the rare disease voice been lost in translation?” they asked.

The U.S. Institute for Clinical and Economic Review also agrees that clinical trials often fail to cover issues that patients deem important.

Many of the outcome measures that researchers use in trials are unable to capture the benefits that patients obtain from the therapies being tested, Morel and Cano contended. This leads to many failed trials, they argued.

“Core to these failures is the inability to demonstrate statistical significance and meaningful benefit,” they wrote. “Failed therapies or flawed outcome measurement?”

The situation is further fueled by a poor understanding of many rare diseases, and patient populations that are small and too similar, they contended.

A meager evidence base can prompt those paying for healthcare to balk at reimbursing patients for treatments that are approved, Morel and Cano added.

In 2011, the European Commission and the U.S. National Institutes of Health started an initiative known as the International Rare Diseases Research Consortium to foster global collaboration and investment in rare disease research. The consortium set up a task force on Patient-Centered Outcome Measures in 2015.

The task force has made it clear that it believes patient-centered outcome measures are necessary to advance rare disease drug development. Several hurdles must be overcome for such measures to be introduced, however.

To start with, researchers need to agree on what outcomes to measure. Patient-centered outcomes do not necessarily mean patient-reported outcomes, they underscore. These can also include doctor or observer-reported outcomes or therapy performance ratings.

Still, patients need to identify issues that matter most to them, Morel and Cano maintained. Outcomes that doctors consider important are not necessarily the ones that patients consider important.

“Because a rare disease affects every aspect of their daily life, patients and their caregivers become experts of the rare condition and of the important outcomes of diseases that need to be addressed,” they wrote.

Gathering patient voices is made difficult by the small number who have rare and ultra-rare conditions. Such groups are often spread over large geographical regions.

Moreover, half of rare disease patients are children, making it difficult to assess the reliability and relevance of both self-reported and observer-reported outcomes.

More qualitative research would help get around these problems, the authors said. Instead of asking “how much” — which would yield an answer that was quantifiable — researchers should ask “what” and “how” questions, they said.

A variety of methods can be used in qualitative research, including focus groups, interviews, and social media, Morel and Cano said. Patient organizations can play a key role in this mission as well, they said. That’s because they can “steer, or even lead,” the work in partnership with other players, including academic researchers.

Identifying the issues important to patients is only the first step of the process, Morel and Cano said. Researchers must then develop tools to measure patient-identified outcomes.

Considering the thousands of rare diseases, it might be wise to adapt existing tools to the measuring challenge, or develop new tools that can be used to measure a range of conditions with similar features, the authors said.

Patients also need to be involved in the yardstick-development process, they said. Only patients can provide the proper perspective on how a measure ought to be interpreted, they noted.

As an example, they said, patients need to answer questions such as“What does a 2-point change on a 0- to 10- point scale mean? Is a 2-point change from 10 to 8 saying the same as a change from 4 to 2?”

Morel and Cano said developing patient-centered outcome measures should not be viewed as a competitive activity. Expertise and resources should be pooled to advance research in this domain, they said.

“A multi-stakeholder collaboration should emerge, with the rare disease patient community at its center, to promote the development and use of Patient-Centered Outcomes Measures to help achieve Patient-Centered Care across all rare diseases,” they concluded.


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