Mapping  the evidence  on patient-centred outcome measures used in orphan medicinal product reimbursement frameworks: Protocol for a scoping review

Introduction

A rare disease (RD) is a seldomly-occurring health condition. In Europe a RD is defined as a condition affecting less than 5 in 10,000 people (European Commission). More than 30 million people in Europe live with a RD (European Commission). About 80% are genetic in origin, while 20% result from infections, environmental factors, allergies, and proliferative and degenerative causes (Rare Diseases Europe [EURORDIS]). Seventy-five percent of people living with RD are children, and more than 3 of 10 children with a RD will not survive past the age of five years (U.K. Department of Health and Social, 2021). The rarity of their health conditions is a challenge because there is limited general awareness about the disease and low levels of physician training (Ramalle-Gómara et al., 2020). The heterogenous nature of health conditions is a challenge because it is more difficult to accurately and promptly recognize disease symptoms. The average total diagnosis time is about five years in Europe (Faye et al., 2024).

The management of RD can negatively impact people physically (McGovern et al., 2017), cognitively (Hart et al., 2013), and emotionally/psychologically, such as anxiety and depression (Uhlenbusch et al., 2019). It may also diminish a person’s ability to perform activities of daily living (ADLs) (Brown et al., 2023). RD can also lead to lower quality of life (QOL) for caregivers (Boettcher et al., 2021), social isolation (Currie & Szabo, 2020), and burnout (Mengel et al., 2021). Another challenge is the high cost associated with travel to see specialists and undergo genomic testing (Mordaunt et al., 2024) and pay for medical treatments (Jovanovic et al., 2024) and related investments (e.g., construction of wheelchair ramps) (Landfeldt et al., 2014). The Rare Barometer Program, launched by EURORDIS, is a global survey initiative aimed at assessing the above challenges faced by people with RD and their families (EURORDIS).

Of the more than 7,000 known RDs, there are no treatments available for approximately 95% of RDs (The Lancet Global Health, 2024). To increase the availability of medicines for rare diseases in Europe, the European Commission implemented Regulation (EC) No 141/2000 in 2000, providing incentives for pharmaceutical companies to develop Orphan Medicinal Products (OMPs). To qualify for orphan designation, a medicine must meet a number of criteria (European Medicines Agency):

Medicines that are considered to be OMPs are only those that have received an) orphan designation per Regulation (EC) No 141/2000 and b) a European Marketing Authorization (Orphanet). As of 2024, the European Commission has approved more than 200 orphan medicines (European Commission). A further 2,000 products in development have received orphan designation, but have not yet received European marketing authorization.

While OMP regulation is centralized at the European Medicines Agency (EMA) and results in simultaneous marketing authorization for all EU member states, decisions about pricing and reimbursement take place at the national level. This has led to differences in patient access to OMPs across EU member states (Czech et al., 2020). Several factors influence how OMPs are priced and reimbursed, including the healthcare budget, systems of healthcare and insurance, co-payment rules, reimbursement timelines, and evidence requirements (Czech et al., 2020).

The World Health Organization (WHO) has recognized the importance of placing people at the center of healthcare to achieve integrated health systems that are equitable, of high quality, responsive, participatory, efficient, and resilient (WHO, 2016). Patient-centered outcome measures (PCOMs) are a type of clinical outcome assessment (COA) that play a key role in the delivery of patient-centered care because they can be used to capture information on health outcomes that matter to patients’ lived experiences. PCOMs are tools for measuring health indicators that put the perspective of people living with disease rather than clinicians at the forefront. PCOMs prioritize patients’ experiences and views, providing a more holistic understanding, compared to clinical metrics alone, of how illness and the systems designed to manage it impact patients.

According to the International Rare Diseases Research Consortium (IRDiRC) (2016), a number of instruments fall under the PCOM umbrella: patient-reported outcomes (PRO), observer-reported outcomes (ObsRO), clinician-reported outcomes (ClinRO), and performance outcomes (PerfO). The instrument type with the greatest number of occurrences is patient-reported outcome measures (PROMs) (IRDiRC, 2016). For the purposes of this protocol, we will use the term “PCOM” so as to be as inclusive as possible when searching for available evidence (Table 1).

PCOMs can be used for a broad group of diseases or specific diseases and can include clinical and nonclinical indicators. PCOM data can be provided by patients themselves or by proxies, that is, patient-reported outcome measures (PROMs), or by non-patients such as parents, caregivers, and healthcare professionals. PCOMs can be useful for monitoring symptoms and reporting them to clinicians (Govindaraj et al., 2023); identifying and reporting adverse events (Peipert et al., 2024); assessing therapy adherence (Efficace et al., 2024) and treatment response (Im et al., 2023). There are numerous benefits of PCOMs: promotion of patient involvement, improvement of the focus of consultations, improved healthcare quality, facilitation of standardized outcome monitoring, and improvement of the patient-clinician relationship (Campbell et al., 2022). PCOMs are associated with improved QOL and decreased risk of overall mortality (Balitsky et al., 2024). PCOMs are useful in the management of various chronic diseases, but they are especially valuable for managing RD. In 2015, the IRDiRC created a taskforce for PCOMs. The taskforce concluded that it is necessary to develop PCOMs for RDs. PCOMs are instruments that can be used to measure real benefits for patients and from their perspective” (IRDiRC, 2016).

In 2020, the EMA launched a strategy to promote patient-centered drug development, including incorporating PROs into risk-benefit assessments for medicines (EMA, 2020). A review of medicines for RD approved by the EMA and the United States of American Food and Drug Administration (U.S. FDA) from 2002 to 2017 found that of 258 medicines that received orphan designation, only 45 (17.4%) had PRO-based labelling (Lanar et al., 2020). The labels focused more on clinical symptoms (e.g., fatigue and pain) than on indicators of functioning or QOL (Lanar et al., 2020). A study of 60 OMPs approved by the EMA between 2012 and 2017 found that only 12 products (21.7%) had PRO language in the Clinical Studies section of the Summaries of Product Characteristics (SmPC) (Jarosławski et al., 2018).

Another factor is the small cohort size of patients with RD, which is problematic due to the resulting lack of evidence. Research on orphan medicinal products (OMPs) or substances intended for the prevention, diagnosis, or treatment of an RD often lacks the large-scale clinical trial data typically required for reimbursement. Thus, OMPs may be challenging to evaluate because of the small patient population and variability in disease progression. Thus, patient-centered outcome measures (PCOMs) are particularly crucial for OMPs because they demonstrate value for RD treatments, where conventional clinical measures may be insufficient.

PCOMs for RD may be challenging to validate for a number of reasons: 1) many companies involved in developing treatments for RD are small in size and lack the capacity to undertake labor-intensive validation processes; 2) low awareness, the RD community has low awareness about defining new outcome measures and limited experience with outcome measurement development and evaluation (Consortium, 2016). Despite these challenges, the use of PCOMs in RD medicine development is growing because the data provided can help policy makers make decisions not only based on morbidity and mortality but also on QoL, socioeconomic impacts, and other social consequences. This is an important advantage because it provides more visibility to people living with rare chronic/complex medical conditions and highlights the broad range of hurdles they and their families face during the entire life course.

Although PCOMs are increasingly used in the development of OMPs, knowledge about their role in OMP reimbursement decision-making processes remains limited. Specifically, there is limited understanding of how many PCOMs are available for use in reimbursement frameworks, their impact on the reimbursement process, and the barriers and facilitators to incorporating PCOMs in reimbursement decision-making. This highlights a critical gap in the current understanding and practice regarding their application in the OMP reimbursement decision-making processes.

Methods

We will conduct a scoping review based on the Joanna Briggs Institute (JBI) methodology (JBI, 2024) updated by Peters and others (Peters et al., 2020). The JBI methodology for scoping reviews includes a template for the study protocol comprised of steps such as developing a research question, identifying inclusion and exclusion criteria, creating a search strategy and approach for data extraction, and outlining how to analyse and report evidence (JBI, 2024). The methodology update introduced by Peter and others (Peters et al., 2020) involves using a systematic and structured approach to promote rigor and transparency, as well as ensure that findings are trustworthy. We use the conceptual framework of Arksey and O’Malley, which is comprised of six steps: 1) identifying the research question, 2) identifying relevant studies, 3) selecting studies, 4) charting the data, 5) collating, summarizing and reporting the results, and 6) consulting knowledge users (Arksey & O'Malley, 2005). We use Levac and others’ recommendations for improving the clarity of scoping reviews and enhancing each of the above six steps (Levac et al., 2010). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension (PRISMA-ScR) checklist will be used to document findings (Tricco et al., 2018).

Dissemination

We intend to submit a scoping review for publication in a peer-reviewed academic journal. Additionally, we will develop an evidence summary to disseminate our findings to a broad audience through social media. We plan to present the results at national and international conferences, as well as at meetings and events with relevant stakeholders.

Study status

Currently, we are in stage two: locating relevant studies. We are formulating and pilot-testing a search strategy and searching databases.

Conclusions

Reimbursement for OMPs is often complex and delayed, with significant uncertainty surrounding the availability and role of PCOMs in this process. These factors limit access to treatment for individuals with RD. The scarcity of evidence further impedes the development of policies and practices aimed at improving the quality of life of people living with RD and their families. Our scoping review seeks to map the current literature on PCOMs and OMP reimbursements, offering valuable insights to the field. The findings will guide the next phase of the study, which will explore the experiences of patients and caregivers with PCOMs and OMP reimbursements in the Republic of Ireland.

Ethics and consent

Ethical approval and consent were not required.