To what degree are orphan drugs patient-centered? A review of the current state of clinical research in rare diseases

Abstract

Background: Over the past 30 years, the healthcare industry has increasingly turned its attention to rare diseases. Regulators have emphasized the need for clinical research in this area to be patient-centered. However, there is a lack of evidence concerning whether this need is actually met. In this paper, we aim to address this gap. Methods: First, we describe the state of patient-centricity in clinical research in rare diseases based on a targeted literature review. Second, we discuss recommendations from scientific bodies on patient-reported outcome (PRO) measures in rare diseases. Third, we analyze data collected from EMA's and FDA's websites concerning rare disease labeling claims and data from Clinicaltrials.gov concerning the use of PRO measures in rare disease pivotal trials. Fourth, we perform an exhaustive literature review on the use of PRO measures in the pharmaceutical industry, including all phases of clinical research, observational/registry studies, and instrument development and validation. Results: There is limited information on rare disease patient engagement in study design, recruitment, and retention. None of the initiatives describing methods for developing PRO measures in rare diseases provide the clear guidance clinical researchers need. Only 17.4% of orphan drug labels contain a PRO measure. Less than half of pivotal trials in orphan drugs have a PRO measure as a primary or a secondary endpoint. Although the number of publications about PRO measures in rare diseases has risen in the past fifteen years, our results indicate that substantial improvements are needed to achieve patient-centricity. Conclusions: The nature and extent of patient engagement in rare disease research is under-documented. The current paradigm for developing and using PRO measures in clinical research is failing to meet the needs of rare disease patients. 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 overallthere are too few measures for the multitude of rare diseases. We call for a clear guidance on patient engagement and suggest a realistic approach to the adaptation of PRO strategy to the specific context of clinical research in rare diseases.

Health‐related quality of life in adults with osteogenesis imperfecta

“…Over the same 15-year period, less than half of rare diseases pivotal clinical trials utilized PROMs as primary or secondary endpoints. 5 As developing a disease-specific PROM requires significant effort, one approach to overcome this limitation is to adapt and use existing PROMs for rare diseases. This approach is consistent with recommendations from large collaborative networks such as The International Rare Disease Research Consortium.…”

The Use of Patient-Reported Outcome Measures in Rare Diseases and Implications for Health Technology Assessment

“…-Development of core outcome measure set across disease, disease subtype or similar disease This requires initial upfront agreement and development; however, once developed, it is a tool that can be used sustainably with minor adjustments. In this paper, we used the term 'disease group' to refer to any methods using PROMs across similar diseases, but definitions vary in the literature: some refer to disease families [16], others relate to symptomor function-specific PROMs or PROMs that capture similar symptoms in analagous conditions [47], and still others refer to using PROMs similar to those for common diseases [60]. Thus, the parameters of such PROMs still need to be better defined.…”

Measuring health-related quality of life in patients with rare disease

“…How a concept is addressed in regulatory guidance documents, as well as how often results for a specific concept are included in label claims, can provide an insight into the level of attention devoted to the concept from the regulatory perspective. Two recent reviews examined the use of PRO measures in approved rare disease labels [24,25] demonstrating low rates of PROs in label claims.…”

“…Moreover, less than half of current clinical trials in rare disease include a PRO based on review of data from clinicaltrials.gov. [25] In addition to considerations mentioned above, the latest draft FDA guidance for rare disease [1] emphasizes the importance of patient centricity in drug development. It suggests encouraging the engagement of patients, caregivers, and advocates in the drug development process and through the inclusion of outcome measures that reflect how a patient feels and functions.…”

“…How a concept is addressed in regulatory guidance documents, as well as how often results for a specific concept are included in label claims, can provide an insight into the level of attention devoted to the concept from the regulatory perspective. Two recent reviews examined the use of PRO measures in approved rare disease labels [ 24 , 25 ] demonstrating low rates of PROs in label claims. The first examined labels of FDA-approved orphan drugs between 2002 and 2017 and revealed that, while the number of orphan drug approvals has continued to rise, only 8.3% of approved labels included results based on PRO measures.…”