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Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing's syndrome.

ABSTRACT: Rare diseases are often not fully understood and efforts put in investigating it from patient perspective are usually met with challenges. We performed a systematic literature review (SLR) for the last 20 years in Cushing's Syndrome (CS) to illustrate Patient-Reported Outcome (PRO) challenges, and show what solutions were found.PROs and other Clinical Outcome Assessment (COA) used with CS patients were reviewed in 36 studies. Two CS-specific Health Related Quality of Life (HRQL) measures were identified (i.e., CushingQoL, Tuebingen CD-25), as well as depression and neurocognitive measures. For CS-specific HRQL measures, the CushingQoL was the most widely used measure due in part to being the first CS-specific HRQL measure developed. With algorithms mapping the CushingQoL to both the SF-6D and EQ-5D, the CushingQoL could be used to facilitate economic modelling studies in the absence of a generic HRQL measure. While the CushingQoL offers only the global scale and two subscales compared to the six subscales of the Tuebingen CD-25, there is not yet adequate statistical validation data available for the Tuebingen CD-25 to suggest it can withstand the scrutiny of review by multiple stakeholders. Results of this review indicate that the inclusion of a measure of depressive symptoms, such as the BDI-II or similar measure, would be reasonable to include given the high level of comorbidity of depression among CS patients. A brief neurocognitive performance outcome, such as Trail Making tasks A and D or Digit Symbol, could help inform the interpretation of HRQL results. Neurocognitive differences may be an unassessed mediator of HRQL outcomes, partly accounting for the persistence of depressive symptoms and HRQL deficits despite treatment. Results suggest that HRQL improvements are possible within this population. These results are limited by small sample sizes and pre/post study design.CS showcases the difficulties encountered in measuring PROs in rare diseases. A solution for this specific case was developed in the form of dedicated PRO instruments, the CushingQOL and the Tuebingen-25. However, some aspects of CS may not be fully answered or not yet validated (e.g., depressive and cognitive symptoms). Further research needs to be done to address them.

SUBMITTER: Knoble N

PROVIDER: S-EPMC6299940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWhen assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value.ResultsRecently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic.ConclusionsGeneralized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.

Project description:BackgroundRare diseases may be life-threatening or chronically debilitating conditions. Patient care needs are often complex and challenging to coordinate and deliver effectively. Rare diseases and their clinical management may therefore substantially impact on patients' health-related quality of life (HRQOL). The use of patient-reported outcome measures (PROMs) may complement clinical assessments by elucidating patients' perspectives on their health status and care priorities. This study explored the opinions of patients and clinicians on the use of PROMs in the management of patients with rare diseases in routine clinical practice.MethodsA total of 15 semi-structured one-to-one interviews were conducted with four patients with primary sclerosing cholangitis (PSC); five renal transplant recipients; and six PSC doctors from University Hospitals Birmingham (UHB) NHS Foundation Trust. A focus group session was also conducted with 10 clinical staff members (doctors, nurses and other allied health professionals from UHB). The suitability and acceptability of the Chronic Liver Disease Questionnaire (CLDQ) and the Short Form 12 (SF12) were assessed by patients with PSC and their doctors while the Paediatric quality of life inventory Transplant Module (PedsQL-TM) and the EuroQoL-5 dimensions (EQ. 5D) were evaluated by the renal transplant recipients and their doctors. The discussions were audio recorded and transcribed verbatim. Coding of the transcripts was done using the Nvivo 11 Plus software. Thematic analysis was conducted to identify the main themes and subthemes.ResultsFour themes were identified, namely: (i) potential benefits of PROMs in the management of rare diseases; (ii) views on selected questionnaires; (iii) practical considerations for implementation; and (iv) potential facilitators and barriers of implementation. Patients and clinicians suggested that the use of ePROMs may facilitate patient-centred care by promoting patient-clinician communication, highlighting aspects of HRQOL that are important to patients and encouraging patient involvement in their care. They also felt that the disease-specific CLDQ and PedsQL-TM were more relevant than the generic SF12 and EQ-5D.ConclusionsPatients with rare diseases often experience impaired HRQOL. The use of an ePROM system may enhance the routine management of patients with rare diseases.

Project description:IntroductionRare disease patient data are typically sensitive, present in multiple registries controlled by different custodians, and non-interoperable. Making these data Findable, Accessible, Interoperable, and Reusable (FAIR) for humans and machines at source enables federated discovery and analysis across data custodians. This facilitates accurate diagnosis, optimal clinical management, and personalised treatments. In Europe, twenty-four European Reference Networks (ERNs) work on rare disease registries in different clinical domains. The process and the implementation choices for making data FAIR ('FAIRification') differ among ERN registries. For example, registries use different software systems and are subject to different legal regulations. To support the ERNs in making informed decisions and to harmonise FAIRification, the FAIRification steward team was established to work as liaisons between ERNs and researchers from the European Joint Programme on Rare Diseases.ResultsThe FAIRification steward team inventoried the FAIRification challenges of the ERN registries and proposed solutions collectively with involved stakeholders to address them. Ninety-eight FAIRification challenges from 24 ERNs' registries were collected and categorised into "training" (31), "community" (9), "modelling" (12), "implementation" (26), and "legal" (20). After curating and aggregating highly similar challenges, 41 unique FAIRification challenges remained. The two categories with the most challenges were "training" (15) and "implementation" (9), followed by "community" (7), and then "modelling" (5) and "legal" (5). To address all challenges, eleven types of solutions were proposed. Among them, the provision of guidelines and the organisation of training activities resolved the "training" challenges, which ranged from less-technical "coffee-rounds" to technical workshops, from informal FAIR Games to formal hackathons. Obtaining implementation support from technical experts was the solution type for tackling the "implementation" challenges.ConclusionThis work shows that a dedicated team of FAIR data stewards is an asset for harmonising the various processes of making data FAIR in a large organisation with multiple stakeholders. Additionally, multi-levelled training activities are required to accommodate the diverse needs of the ERNs. Finally, the lessons learned from the experience of the FAIRification steward team described in this paper may help to increase FAIR awareness and provide insights into FAIRification challenges and solutions of rare disease registries.

Project description:BACKGROUND:Since the implementation of the Regulation on Patient Integration (2003), the Act on the Reorganization of the Pharmaceutical Market (2011), and the Patient Rights Law (2013), the inclusion of patient perspectives has been further anchored in the German early benefit assessment process. During the assessment of rare disease interventions, patient perspectives are particularly important, as clinical studies are often designed acknowledging small samples and patients suffering from severe symptoms and the chronic course of the disease. Therefore, our research question is whether patient perspectives are considered as part of early benefit assessments for rare diseases. We also strive to examine how patient perspectives are methodologically elicited and presented. METHODS:Our empirical evidence comes from a systematic review of orphan drug value dossiers submitted to the German Federal Joint Committee as well as the corresponding evaluations conducted between January 1, 2011 and March 1, 2019 (n?=?81). Data on patient perspective integration were extracted using the following patient-reported outcome subcategories: clinical patient-reported outcomes, health-related quality of life, patient preferences, and patient satisfaction. RESULTS:The analysis demonstrates the specific relevance of patient-reported outcomes raised as part of the medical data set and presented during the early benefit assessment process. They are predominantly presented in the form of health-related quality of life data (n?=?75%) and clinical outcomes (n?=?49%). Preferences (n?=?2%) and satisfaction (n?=?1%) are still rarely presented, although the heated methodological discussion in Germany would suggest otherwise. While various methodologies for the integration of clinical outcomes and quality of life data were found, presenting data on satisfaction and preferences still lacks methodological rigor. The German Federal Joint Committee has not yet integrated these data in their decision text. Clinical outcomes and quality of life have been included in 46% and 73% of the cases, respectively. CONCLUSIONS:The underlying analysis demonstrates that there is still a relative high potential for the regular and systematic inclusion of patient perspectives within the early benefit assessment process for rare diseases. In particular, patient preferences and patient satisfaction are still rarely included suggesting the need for a clear-cut methodological foundation and incentives.

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Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing's syndrome.

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