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Review Calls For Clear Guidance to Ensure Patient Centricity in Orphan Drug Trials


Researchers called for new guidance to address the underreporting of patient engagement in rare disease clinical trials after finding a dismal amount of patient-reported outcome measures listed in orphan drug labeling claims.

New guidance is needed to address the underrepresentation of patient-reported outcomes (PROs) in rare disease research, according to a review published in the Orphanet Journal of Rare Disease.

“Not only are PROs rarely used as high-level endpoints in clinical trials or taken into account in labeling claims, they are also under-researched overall—there are too few measures for the multitude of rare diseases,” wrote the authors.

Currently, there are an estimated 6000 to 8000 identified rare diseases worldwide, with another estimated 250 to 280 new ones being discovered each year.

The review revealed that despite an increase in interest surrounding the use of PRO measures (PROMs) in rare disease trials over the past 15 years, the trend appears to be too slow to keep up with the rise in rare diseases that are discovered per year. Additionally, the authors noted that none of the current initiatives describing methods for developing PROMs in rare diseases provide clear guidance for clinical researchers.

Using data collected from the European Medicines Agency (EMA) and FDA websites and the US government website for clinical trial information, researchers were able to compile a total of 109 rare disease articles addressing 81 therapeutic indications where only 34 rare disease specific PROMs were found.

“The current paradigm for developing and using PRO measures in clinical research is failing to meet the needs of rare disease patients,” wrote the authors.

Overall, PROs are rarely used as high-level endpoints in clinical trials, with less than half of the reviewed pivotal orphan drug trials having a PROM as a primary or secondary endpoint. Additionally, only 17.4% of orphan drug with a labeling claim EMA or FDA contained a PROM in their label.

“This low percentage may make it difficult for prescribing clinicians to know the impact that authorized orphan medications may have on the HRQoL [health-related quality of life] of their patients,” wrote the authors.

Furthermore, among the trials the included a PROM that measured HRQoL, a majority were considered generic PROMs and not disease specific. Only 1 study used a PROM as the primary outcome.

Authors said that the data they collected demonstrated “that there remains a gap between the importance given to these constituencies and the extent of patient-centricity in orphan drug development.”

In 2009, FDA released guidance on the development of PROs. However, there are very few examples of orphan drug labels of PROMs developed and used in compliance with that guidance, showing that the time and resources needed for development prevented them from being available in a timely fashion to inform regulatory decisions.

“These delays underscore the need for faster, innovative methods for the development and validation of PROMs for rare diseases that are acceptable to regulators,” wrote the authors.

The authors also noted that it is not efficient to create individual questionnaires for every rare disease. However, it is also not adequate to use a generic questionnaire in place of a rare disease specific 1 as they often do not assess concept important to those patients.

In response, the authors developed a potential solution based on the assumption that stakeholders should address 4 types of outcomes in order to assess treatment benefits for patients:

  1. Disease burden and level of unmet needs
  2. Treatment impact and specific hypotheses on drug activity
  3. Patient perception of change
  4. Meaningfulness of perceived change

“The combination of these four types of outcomes and the use of mixed methods will enable sponsors to capture the specificity of a rare disease and to view that disease through a large lens in comparison to other diseases,” wrote the authors.


Lanar S, Acquadro C, Seaton J, Savre I, Arnould B. To what degree are orphan drugs patient-centered? A review of the current state of clinical research in rare diseases. Orphanet J. Rare Dis. 2020; 15(134): 1-18. Doi: 10.1186/s13023-020-01400-0.

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