The economic impact of living with a rare disease for children and their families: a scoping review protocol

Niamh Buckle; Orla Doyle; Naonori Kodate; Suja Somanadhan

doi:10.12688/hrbopenres.13765.1

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Study Protocol

The economic impact of living with a rare disease for children and their families: a scoping review protocol

[version 1; peer review: 1 approved with reservations, 1 not approved]

Niamh Buckle ¹, Orla Doyle², Naonori Kodate³, Suja Somanadhan^1,4

PUBLISHED 31 Aug 2023

Author details Author details

¹ School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, Leinster, D04 V1W8, Ireland
² School of Economics, University College Dublin, Dublin, Leinster, D04 N9Y1, Ireland
³ School of Social Policy, Social Work and Social Justice, University College Dublin, Dublin, Leinster, D04 N9Y1, Ireland
⁴ UCD Centre for Interdisciplinary Research, Education and Innovation in Health Systems (UCD IRIS), University College Dublin, Dublin, Leinster, Ireland

Niamh Buckle
Roles: Conceptualization, Investigation, Methodology, Project Administration, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Orla Doyle
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Naonori Kodate
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Suja Somanadhan
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Rare diseases are an often chronic, progressive and life-limiting group of conditions affecting more than 30 million people in Europe. These diseases are associated with significant direct and indirect costs to a spectrum of stakeholders, ranging from individuals and their families to society overall. Further quantitative research on the economic cost for children and their families living with a rare disease is required as there is little known on this topic. This scoping review aims to document the extent and type of evidence on the economic impacts of living with a rare disease for children and their families.
Methods: This scoping review will follow the PRISMA-ScR and Joanna Briggs Institute guidelines and follow the six-stage methodology for scoping reviews: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting the data, (5) collating, summarising and reporting results and (6) knowledge user consultation. Key inclusion criteria have been developed according to the Population-Concept-Context (PCC) framework. The databases EconLit, ABI/Inform, MEDLINE, PubMed, CINAHL, and Scopus will be searched for possible articles for inclusion. Two independent reviewers will screen titles and abstracts of potential articles using a dual review process to ensure all relevant studies are included. All included articles will be assessed using a validated quality appraisal tool. A panel of patient and public involvement representatives experiencing rare diseases and knowledge users will validate the review results.
Conclusions: This scoping review will map the current literature on the economic impact of paediatric rare diseases to understand how these impacts affect children living with rare diseases and their families. This evidence has the potential to influence policy and future research in this area and will support the future development of a cost-minimal intervention prototype to address the economic impact for families as part of this doctoral project.

Keywords

Child, cost-of-illness, economic evaluation, family, financial hardship, orphan diseases, rare diseases, ultra-rare diseases

Corresponding author: Niamh Buckle

Competing interests: No competing interests were disclosed.

Grant information: No funding was sought/ received for this scoping review proposal. The primary author is currently a recipient of a PhD scholarship from their affiliated university (University College Dublin).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Buckle N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Buckle N, Doyle O, Kodate N and Somanadhan S. The economic impact of living with a rare disease for children and their families: a scoping review protocol [version 1; peer review: 1 approved with reservations, 1 not approved]. HRB Open Res 2023, 6:41 (https://doi.org/10.12688/hrbopenres.13765.1) First published: 31 Aug 2023, 6:41 (https://doi.org/10.12688/hrbopenres.13765.1) Latest published: 08 Apr 2024, 6:41 (https://doi.org/10.12688/hrbopenres.13765.2)

Introduction

The collective incidence of rare diseases contributes to a significant global population that belies its ‘rare’ title. It is estimated that there are between 6,000 and 8,000 known rare diseases (European Commission, n.d.; Kruse et al., 2022) that affect 3.5%-5.9% of the global population (Nguengang Wakap et al., 2020). In Europe, a rare disease is one that affects less than one in 2,000 people, resulting in a rare disease population of approximately 30 million people on the continent (Kole et al., 2021). In the United States, the definition of a rare disease is one that affects less than 200,000 people; it is estimated that 10% of the US population are living with a rare disease (National Organisations for Rare Disorders (NORD), 2019). Rare diseases are often incurable, complex and are associated with a high social and economic burden that reaches from the patient to society overall (García-Pérez et al., 2021; Somanadhan et al., 2023a)

Approximately 70% of rare diseases start in childhood, and early diagnosis and treatment is critical to prevent disease progression and avoid adverse health outcomes, including disability and death (Morton et al., 2022). Eighty percent of rare diseases have a genetic component and therefore treatment is often limited or costly, and 95% of rare diseases lack an approved treatment (Somanadhan et al., 2023b). This brings challenges regarding funding for treatment research and development and treatment accessibility, as orphan drugs, which are developed specifically for rare diseases, can cost up to five times more than non-orphan drugs (Chambers et al., 2020). Few rare diseases have orphan drugs, contributing to a large unmet need (Rodriguez-Monguio et al., 2017). Other treatments for rare diseases, such as gene therapy, which involves modification of genes to treat, prevent or cure an illness or disease (White, 2019), similarly come at a high cost and are limited. It is important that treatment developments in this field balance treatment accessibility for patients, encouragement of innovation and development for researchers, clinicians and pharmaceutical companies, and creation of benefits for population health for policymakers to ensure the continued advancement and availability of treatments for the rare disease population (European Medicines Agency, 2023; UN Committee on Economic, Social and Cultural Rights (CESCR), 2000).

The lack of funding for orphan drug development stems from the limited market potential of rare diseases, as developing drugs for limited patient groups is unlikely to be cost effective and be sustainable for pharmaceutical companies (Iizuka & Uchida, 2017). However, this has both human and economic costs. High prices and reduced access to treatment can cause increased health burden and premature death for patients with rare diseases; lack of treatment access also reduces rare disease patients’ capacity to engage in society independently, incurring costs such as loss of income tax, absenteeism and presenteeism of carers, and potential increased healthcare costs due to the consequences of poor health (Hyry et al., 2013). The United Nations Resolution on Persons Living with a Rare Disease and their Families, ratified in 2021, calls on member states to cover quality essential health products, health services and quality, safe, effective, affordable and essential medicines, diagnostics, and health technologies for people living with a rare disease (United Nations General Assembly, 2022). Therefore, to achieve health equity for rare diseases, it is necessary to fund or incentivise orphan drug development. Demand-side incentive policies such as reduced patient cost-sharing can increase revenue potential and encourage innovation (Iizuka & Uchida, 2017), while supply-side incentives such as grants, protocol assistance and administrative and procedural guidance can encourage pharmaceutical companies to pursue orphan designation (Aartsma-Rus et al., 2021; Seoane-Vazquez et al., 2008).

Given the incurability of many rare diseases, as well as the lack of treatment plans, most of the costs associated with rare diseases can be attributed to care management or supportive therapies. Cost-of-illness studies can be used to estimate the direct, indirect and associated costs of living with a rare disease for children and their families, as well as the impact of rare diseases on healthcare resources and labour productivity (Larg & Moss, 2011). Cost-of-illness studies explore the impact of illnesses or diseases on the health outcomes of both individuals and national populations. Overall, the goal of these studies is to evaluate the economic burden of specific illnesses from a societal perspective. Incidence of disease, resultant impacts on morbidity and quality of life, and financial consequences (direct or indirect) due to disability, injury or premature mortality are all approaches that can be explored through cost-of-illness studies (Jo, 2014). Furthermore, these studies can be conducted prospectively or retrospectively to patients’ healthcare use or treatment, or through a top-down, bottom-up or econometric approach (Jo, 2014). These approaches address economic impact in different ways: top-down estimates consider the costs of exposure to the disease or the risk factors; bottom-up estimates consider the costs through the number of health inputs used and their unit costs; econometric estimates involve cost comparisons between a cohort with a disease and an unaffected cohort (Jo, 2014). Cost-of-illness studies are the most common method of assessing the economic burden of rare diseases (Delaye et al., 2022). Similarly, economic evaluations analyse costs and outcomes of interventions to determine cost effectiveness. There are four types of economic evaluations: cost minimisation analysis; cost utility analysis; cost-benefit analysis and cost consequences analysis (Goodacre & McCabe, 2002). While cost-of-illness and economic evaluation studies can be useful in determining economic impacts of interventions, the variety of approaches for conducting these studies means that the literature around this topic lacks standardisation.

Direct costs are the healthcare and non-healthcare costs for which the health system, society, family and individuals with the illness are directly accountable for, whereas indirect costs are associated with productivity losses due to morbidity and mortality that indirectly impact the individual, family, society or employer (Jo, 2014). Economic costs associated with rare diseases arise from both direct healthcare costs, including those of specialised healthcare service provision, direct non-healthcare costs, such as those of care or education services, and indirect costs, such as loss of income at an individual level and loss of productivity on a societal level (Chung et al., 2023; Zurynski et al., 2008). Standard units of measurement for health outcomes include quality-adjusted life years (QALYs), which are years of healthy life (or life quality relative to healthy life) lived, and disability-adjusted life years (DALYs), which measure the loss of one year of healthy life due to disability or premature mortality (Feng et al., 2020; Jo, 2014).

Studies have been performed to estimate the burden and health-related quality of life for all patients (including children) with rare diseases, such as the Social Economic Burden and Health-Related Quality of Life in Patients with Rare Diseases in Europe (BURQOL-RD) study, which considered eight EU countries (Bulgaria, France, Germany, Hungary, Italy, Sweden, Spain, UK) (López-Bastida et al., 2016); and the National Economic Burden of Rare Disease study, commissioned in the US by the EveryLife Foundation (Yang et al., 2022). These studies both found a significant economic impact of rare diseases due to their high collective prevalence in their populations and high per-person costs, generated either through loss of labour productivity or the cost of formal or informal care. Children with rare diseases in particular have been associated with higher economic costs; in the US, per-person direct costs are most expensive in childhood and decrease with age; similarly, per-person indirect costs for children are higher than for adults, due to absenteeism, presenteeism and social productivity losses of family caregivers (Yang et al., 2022). In Hong Kong, children with rare diseases were also found to experience higher per-person direct and indirect costs due to experiencing a higher cost of healthcare services, medical resources, informal care support and special education (Chung et al., 2023). Similarly, families of children living with rare diseases in Spain were identified as having poorer financial situations than families of adults with rare diseases, due to the eligibility of adults for benefits such as treatment allowances or pensions, which are not available for children (Gimenez-Lozano et al., 2022). These disproportionately higher per-person costs for children have a significant impact on families. Capturing the evidence on this economic impact can aid policy makers in their decision-making, inform resource allocation and lead to the development of solutions that can benefit people living with rare diseases and their families (Yang et al., 2022).

The economic impact of rare diseases is somewhat neglected within the rare disease literature compared to other areas, e.g., clinical research, likely due to the heterogeneity and low individual incidence of rare diseases. Few cost-of-illness studies specifically related to children have been performed, and those that exist tend to focus on rare diseases for which a specific treatment exists (e.g., cystic fibrosis) (Angelis et al., 2015). As 95% of rare diseases lack an approved treatment (Kruse et al., 2022; Somanadhan et al., 2020), this means that economic evaluations are extremely limited. Previous scoping reviews on these evaluations in general have found a lack of studies on the economic impact of rare diseases (Delaye et al., 2022; García-Pérez et al., 2021). Furthermore, the quality of evidence is often below regulatory standards due to the inability to conduct quality experiments (e.g., randomised control trials) due to small sample size or the difficulty in capturing the patient experience. Therefore, standard economic evaluation procedures may not be fully appropriate for rare diseases (Armeni et al., 2021).

The goal of this scoping review is to map existing studies on the economic impact of living with a rare disease for children and their families, examine the current methodologies for collating and reporting the evidence of these impacts, and to identify any potential gaps in the literature. A preliminary search of MEDLINE and the Cochrane Library was conducted to identify any existing reviews on a similar topic. While there are reviews on the economic impact of rare diseases in all populations (Delaye et al., 2022; García-Pérez et al., 2021); these differ to this proposed review which will focus on a child and family perspective. A scoping review will be conducted, to examine how the cost of rare diseases has been explored to date, the approaches used, and to identify the gaps within this literature; this aligns with the indications for conducting a scoping review as set by the Joanna Briggs Institute (JBI) guidance (Peters et al., 2020a).

Methods

The proposed systematic scoping review will be conducted in accordance with the updated JBI methodology for scoping reviews (Peters et al., 2020b) and recommendations from Levac et al. (2010), which build on previous existing methodological guidance (Arksey & O’Malley, 2005; Peters et al., 2015). A six-stage process, including knowledge user consultation as a final stage, will be employed throughout the review process and has been used in the development of this scoping review protocol. An overview of each stage is presented below. Section headings are taken from Levac et al. (2010).

Reporting will be guided by the Preferred Reporting Items for Systematic Reviews and Meta Analyses Scoping Review extension (PRISMA-ScR) checklist, to ensure compliance with up-to-date PRISMA reporting guidance. This extension was developed to improve the methodological and quality reporting of scoping reviews (Tricco et al., 2018), and will assist in the formulation of the review and an informal quality assessment.

A panel of patient and public involvement (PPI) representatives from the rare disease community and knowledge users working in the rare disease field will be invited to validate the results and their presentation, according to the guidance on knowledge user engagement developed by Pollock et al. (2022). The review will be conducted as part of a doctoral project that was developed through public-patient involvement. The topic and a relationship with the knowledge users and PPI representatives were established prior to the commencement of this review via the Rare Disease Research Partnership (RAinDRoP) (Somanadhan et al., 2020). This protocol has been developed with and reviewed by knowledge users and PPI representatives to inform the research questions and search strategy of the review, as per the knowledge user engagement guidance (Pollock et al., 2022).

Stage 1: Identifying the research question

Research question

This scoping review aims to identify, appraise and reliably map current literature on the economic impacts of living with rare diseases for children and their families, and identify the screening and assessment tools used to identify these impacts. Therefore, the research question is “what is the economic impact for families and caregivers of children with a rare disease, and how are these impacts identified?”.

The research objectives of this scoping review are:

1. To identify, appraise, and synthesise knowledge surrounding the economic impacts of rare diseases affecting children and their families.
2. To understand how these impacts are measured.
3. To clarify what specific disease populations and disease characteristics are most researched.
4. To determine the study settings, rare conditions and geographical contexts, and the study types and organizations involved (e.g., charitable organisations, pharmaceutical companies, etc.).
5. To highlight any gaps in the literature on the economic impact of rare diseases on children and their families.

As scoping reviews summarise particular topics, the research questions are typically broad with a specific scope of inquiry, indicating the focus of the study (Levac et al., 2010). Therefore, the following sections explain the Population-Concept-Context (PCC) framework (Peters et al., 2020a) used to formulate the research questions for this study, to illustrate the origins of the research questions and the search strategy.

PCC Framework

Population

This scoping review focuses on the economic impact of having a child with a rare disease on family units, recognising that children will not bear the economic burden of living with a rare disease themselves. Therefore, studies that consider the economic impact from the perspective of families, parents, (informal) caregivers that are part of the family unit or guardians will be included. This includes the direct and indirect impacts of having a child with a rare disease which commonly affect family members.

Concept

The concept is the economic impact of rare diseases for children and/or their families. This is assumed to mean any financial experiences or effects directly or indirectly incurred due to the rare disease. How these experiences/ effects are measured (e.g., using validated screening or measurement tools) will also be mapped. The economic impact of rare diseases is typically assessed through cost-of-illness studies or economic evaluations, as these studies explore the impact of illnesses or diseases via their associated costs (García-Pérez et al., 2021). Therefore, these types of studies are highlighted in the search strategy. Other studies, e.g., intervention or health impact studies that discuss economic burden or impact for families, are also captured in the search strategy.

Context

The context differs to the population, as this scoping review will focus on the phenomenon of children with rare diseases. Therefore, the context is rare diseases in childhood, and is thus divided into two parts. The United Nations Convention on the Rights of the Child definition is used to understand a ‘child’ as anyone under the age of 18 years (UNICEF, n.d.). Other relevant terms, such as adolescent, infant and variations on these are included to capture relevant literature. Studies that discuss siblings will also be included, to reflect the impact of living with a rare disease on this population.

The US and European definitions of rare diseases will be adhered to, dependent on the context of the articles. Studies that consider individual rare diseases will be included; however, studies that consider chronic or complex conditions that are not rare will be excluded. Studies that discuss a range of complex conditions, including rare disease(s), will be included if they clearly delineate their results and data can be charted according to the rare disease(s) considered. Due to variation in definitions, illnesses or diseases that are conceptualised as rare diseases by researchers in particular countries where these diseases are considered rare will be included, even if different to the authors’ home country. For example, sickle cell disease is considered rare in the Republic of Ireland but is the most common genetic condition in the world (Rare Disease Taskforce, 2020).

Types of sources

All study designs, whether quantitative and qualitative, will be considered for the review. This will include both experimental and quasi-experimental study designs including randomised controlled trials, non-randomised controlled trials, before and after studies and interrupted time-series studies. Analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies will also be considered for inclusion, as will descriptive observational study designs including case series, individual case reports and descriptive cross-sectional studies.

Qualitative studies will also be considered including, but not limited to, designs such as phenomenology, grounded theory, ethnography, qualitative description, action research and feminist research.

Studies that are not primary research, e.g., reviews or conference materials, or non-peer-reviewed articles, e.g., dissertations or theses, will be excluded, as will studies that have not been peer-reviewed. A publication date limit of 1983 until the present will be applied to ensure relevance to current economic contexts. The start date of 1983 reflects the introduction of the United States Orphan Drug Act in the same year, which aimed to advance development of drug treatments for rare diseases and thus stimulated research in this area (Dawkins et al., 2018). There are no limits on geographical location. Articles in languages other than English will be excluded due to lack of funding for translation services; however, this restriction will not be imposed on the search strategy, and it may be reviewed if there are a small number of results in another language, to reduce the possibility of language bias (Stern & Kleijnen, 2020). Results excluded due to language will be reported transparently. The corresponding authors of articles for which the full-text is not available online will be contacted to source a copy of the article; however, if it is not possible to retrieve the full-text, the article will be excluded. The inclusion and exclusion criteria are presented in Table 1.

Table 1. Inclusion and exclusion criteria.

	Inclusion	Exclusion
Population	Studies that discuss costs of rare diseases to the family unit, including parents, informal caregivers and/ or guardians.	Studies that only focus on populations outside the family unit, e.g., caregivers or guardians not related to the child with a rare disease (e.g., formal/ professional caregivers), healthcare providers, healthcare systems, society.
Concept	Studies that discuss the economic impacts of having a rare disease on children and their families, including direct and indirect impacts.	Studies that discuss the impacts of rare diseases on children and their families, but do not focus on economic impacts.
Context	Any geographical location. Studies that focus on rare diseases in childhood.	Studies that do not differentiate their study population between children or adults. Studies that discuss complex or chronic conditions that are not rare diseases.
Language	Articles in English.	Articles in languages other than English.
Publication Date	1983 to present.	Articles published prior to 1983.
Types of Evidence Sources	Peer-reviewed cost-of-illness studies, economic evaluations or other studies that discuss the economic impacts of living with a rare disease for children and their families. Peer-reviewed primary research sources e.g., research studies.	Secondary research sources, e.g., reviews (systematic, scoping, meta-analyses, etc.). Conference materials, editorials, commentaries, opinion papers, dissertations/theses. Studies for which the full text is not available following contact with the corresponding author. Non-peer-reviewed research.

Stage 2: Identifying relevant studies

Databases to be included in this scoping review were chosen to reflect the nature of the research questions. Therefore, the databases searched will include EconLit (EBSCO), ABI/Inform Global (Proquest), MEDLINE (Ovid), PubMed, CINAHL Plus, and Scopus (Elsevier).

The search strategy was developed by the primary author in consultation with a university librarian. An initial search was performed on 13 March 2023 to establish common terms and subject headings relevant to the topic. These terms and headings were used to develop the search strategy. Boolean operators, and truncation markers will be used in the search strategy, which will be altered to meet the requirements of each database. A sample search strategy is provided in Table 2. This search strategy is subject to change during the review process, as the reviewers become more familiar with the literature (Peters et al., 2020a).

Table 2. Sample search strategy.

Search	Search Terms
1	((famil) OR (parent) OR (caregiver) OR (guardian))
2	((cost of illness) OR (economic evaluation) OR (economic burden) OR (burden of illness) OR (economic cost) OR (economic impact*) OR (financial hardship))
3	((paediatric) OR (child) OR (adolescen) OR (sibling) OR (newborn) OR (infan*))
4	((rare disease) OR (rare condition) OR (orphan disease) OR (orphan condition) OR (ultra-rare disease) OR (ultra-rare condition) OR (ultra-orphan disease) OR (ultra-orphan condition))
5	S3 AND S4
6	S1 AND S2 AND S5

Stage 3: Study selection

Studies yielded by the search strategy will be uploaded to EndNote 20 (Clarivate Analytics, 2023) and duplicates will be removed. The remaining articles will be screened by title and abstract first, followed by a full-text review to determine their suitability for inclusion in the review. This part of the proposed review will be supported through the use of Covidence, a web-based collaboration software platform that streamlines the production of systematic and other literature reviews (Covidence, n.d.). Screening will be performed by the primary author and another independent reviewer and validated through peer debriefing. Disagreements on whether to include or exclude articles will be addressed by a third researcher. A pilot test will be completed with a sample of studies (n=25) to ensure consistent decision-making between the reviewers and the clarity of the inclusion and exclusion criteria, and facilitate possible necessary refinements, as recommended by the JBI Manual for Evidence Synthesis (Peters et al., 2020a).

Following title and abstract screening, included articles will go through a full-text review to determine their inclusion eligibility according to the inclusion and exclusion criteria. As in the previous study selection step, this will be conducted by the primary author and another independent reviewer and validated through peer debriefing, with any disagreements resolved by a third researcher. Reasons for exclusion of sources of evidence at full text that do not meet the inclusion criteria will be recorded and reported in the scoping review. As discussed in the previous section, authors of papers will be contacted to request missing or additional data, where required. The reference lists of included articles will also be searched to identify other potential studies not captured by the search strategy, and these will undergo a similar full text screening process by two researchers.

The actions of screening and full-text review will be reported according to the PRISMA-ScR guidance (Tricco et al., 2018). A Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 flow diagram template (Figure 1) for systematic reviews (Page et al., 2021) will be used to illustrate the screening process for transparency and replicability. The JBI Template source of evidence details, characteristics and results extraction instrument (Peters et al., 2020a) will be amended to the concept of this scoping review and used to describe the included articles for transparency.

Figure 1. PRISMA 2020 Flow Diagram Template for Systematic Reviews, taken from Page et al. (2021).

A quality appraisal will be performed on included articles to determine the trustworthiness of the results. While not an essential step in scoping reviews (Arksey & O’Malley, 2005; Levac et al., 2010), this step will be performed due to the evidence of quality concerns within the field of economic evaluations of rare diseases, as discussed in a previous section. The Mixed Methods Appraisal Tool (MMAT) (Hong et al., 2018) will be used due to its versatility for appraising quantitative, qualitative or mixed methods studies. The results of the quality appraisal will be reported in the final scoping review.

Stage 4: Charting the data

The data extracted will include specific details about the participants, concept, context, study methods and key findings relevant to the review questions. A draft data charting extraction table developed (Table 3) will be trialled at the pilot test stage and will be modified and revised as necessary both prior and during the process of extracting data from each included evidence source. This draft data extraction table has been developed using guidance from the JBI Manual for Evidence Synthesis (Peters et al., 2020a) and amended to the focus of the proposed scoping review. Modifications will be detailed in the scoping review. Any disagreements that arise between the reviewers will be resolved through discussion, or with an additional reviewer/s. If appropriate, authors of papers will be contacted to request missing or additional data, where required.

Table 3. Sample data charting table.

Heading	Description of Data
Author(s)	The authors responsible for the source.
Year of Publication	When the source was published.
Origin/ Country of Origin	Where the source was published or conducted.
Aims	What the source set out to do.
Sample	The sample used within the source, including characteristics e.g., size, age, gender, etc.
Methodology	The research design and procedures or techniques used to identify, select, process, and analyse the data obtained by the authors.
Economic Impacts	What economic impacts were discussed by the source, and how these were measured.
Interventions	Where the source discusses the introduction of an intervention, what type of intervention it was, its comparator and the details of its introduction.
Other Key Findings	Any other key points related to the scoping review research questions.

Knowledge users and PPI representatives will be provided the opportunity to participate in Stage 3 and Stage 4 of the scoping review process. If interested in participating, they will receive training on the software used for data screening and extraction.

Stage 5: Collating, summarising and reporting the results

Data charting will be completed and collated on Microsoft Excel and will be shared among the team for review and sign off. The results of the review will be presented as a map of the data from the included studies according to the aims of the review, as recommended by the JBI Manual for Evidence Synthesis (Peters et al., 2020a). This will involve two aspects: reporting of the overall results, which will be presented in tabular form and include aspects such as number of studies included, types of study design, etc; and a basic descriptive analysis, which will apply meaning to the results (Levac et al., 2010). Thematic analysis will not be undertaken as it is outside the remit of scoping reviews (Peters et al., 2020a); however, a table according to the PAGER framework will be provided. This framework, which looks at the patterns (P), advances (A), gaps (G), Evidence for practice (E) and research recommendations (R), provides a consistent approach for the reporting of scoping review findings (Bradbury-Jones et al., 2022). Explicit details of the methodology for analysis will be provided to ensure transparency and rigour in the analysis process. The results of the review will be validated through peer debriefing and PPI representative and knowledge user consultation, discussed in the next section. Gaps in the literature will be highlighted as areas for future research.

Stage 6: Consultation

The results of the review will be presented to PPI representatives and knowledge users working in the rare disease field for validation and to ensure the implications of the findings are meaningful to their community. For the purposes of this review, a knowledge user is defined as:

“one in a position of authority to influence and/or make decisions about health policy or the delivery of services and can act to ensure that the findings of the research will be translated to influence decision making and change within their (or other) organisations” (Health Research Board, 2023, p.7).

Dissemination of the research findings will also be developed through knowledge user engagement. The same knowledge users and PPI representatives will be invited to participate in the development of an evidence summary for dissemination on social media. This is to ensure knowledge translation and impact is accessible and meaningful to the communities it is targeted at and is in line with the guidance for knowledge user engagement developed by Pollock et al. (2022).

As the PRISMA-ScR tool currently does not include the reporting of knowledge user engagement (Pollock et al., 2022), the participation of knowledge users in the consultation process will be reported using the ACTIVE framework, developed by Pollock et al. (2019) for use in systematic reviews. This framework is appropriate for use in this review due to the similarities in conduct processes between systematic and scoping reviews (Pollock et al., 2022).

Knowledge users in clinical practice and policy, and PPI representatives have been consulted in the development of this scoping review protocol and have validated the research questions proposed. These knowledge users and PPI representatives will be involved in the review process through consultation and review.

Dissemination

The proposed scoping review will be submitted for publication in peer-reviewed academic journals. As previously discussed, an evidence summary will be developed for social media through knowledge user engagement, to ensure the meaningful transmission of results. In addition, the results will be presented at conferences and shared with relevant stakeholders and policymakers where appropriate.

Study Status

This review is currently in the stage three: study selection phase. Database searches have been performed and the results are being screened by title and abstract by two reviewers.

Conclusions

Rare diseases are associated with significant economic impacts for families of children living with rare diseases; however, the literature in this area is sparse and as a topic, it remains underexplored. The results of this scoping review will map existing work on the economic impacts of living with a rare disease for children and their families, contributing to the literature on this topic. The results will also be used to develop a survey measuring the economic and psychosocial costs of living with a rare disease in Northern Ireland and the Republic of Ireland, and to develop a cost-minimal intervention prototype around these economic impacts in the future, as part of this doctoral project.

Data availability

No data are associated with this article.

Acknowledgements

The proposed scoping review is part of a larger PhD project currently being undertaken by the first author (NB). The authors acknowledge the support from Diarmuid Stokes, librarian at University College Dublin, for supporting the development of the search strategy of the proposed review.

Faculty Opinions recommended

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Version 2

VERSION 2 PUBLISHED 31 Aug 2023

Author details Author details

Niamh Buckle
Roles: Conceptualization, Investigation, Methodology, Project Administration, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Orla Doyle
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Naonori Kodate
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Suja Somanadhan
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

No funding was sought/ received for this scoping review proposal. The primary author is currently a recipient of a PhD scholarship from their affiliated university (University College Dublin).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

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Published: 08 Apr 2024, 6:41

https://doi.org/10.12688/hrbopenres.13765.2

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Published: 31 Aug 2023, 6:41

https://doi.org/10.12688/hrbopenres.13765.1

© 2023 Buckle N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Buckle N, Doyle O, Kodate N and Somanadhan S. The economic impact of living with a rare disease for children and their families: a scoping review protocol [version 1; peer review: 1 approved with reservations, 1 not approved]. HRB Open Res 2023, 6:41 (https://doi.org/10.12688/hrbopenres.13765.1)

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Reviewer Report 24 Oct 2023

Andrew Dwyer, Boston College, Massachusetts, USA

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15057.r36287

Buckle and colleagues present a protocol for a scoping review that aims to map the current literature on the economic impact of pediatric rare diseases. Specifically the scoping review will examine how costs for pediatric rare diseases have been explored, what approaches have been employed, and what gaps remain in our understanding of the economic impact of rare pediatric conditions on families. This is a timely and important topic that merits investigation. A relative strength of the protocol include the rigor of the approach. Authors propose to: follow the PRISMA-ScR guidelines to guide the process, utilize the PCC model to guide article identification, search 6 databases, use supporting software (EndNote, Covidence) and have public and patient involvement (PPI). After carefully reviewing the protocol I have a number of questions that I feel merit consideration:

Authors appropriately cite the PRISMA-ScR yet I feel it would be useful to consider using an economic evaluation guideline from the EQUATOR network (i.e., CHEERS reporting guideline) to aid in identifying gaps in the literature and guide future reporting efforts for consistency and comparability.
The protocol describes cost of illness analysis as well as direct and indirect healthcare costs. Given that rare disease patients are geographically dispersed and have difficulty accessing specialized care I feel that noting travel costs is a relevant and key consideration.
The protocol cites recent economic evaluations for rare diseases (i.e., Delaye et al., 2022 and Garcia-Perez et al., 2021) yet it is not completely clear how the proposed scoping review will differ from the recent analysis or what gap this study will fill. Did these prior studies include (at least to some extent) a focus on pediatrics? This could be clarified for precision.
I applaud the PPI but there is relatively scant description of this. Have PPI stakeholders already been identified? If so, who are they and what perspectives do they bring? Similarly, it is not exactly clear at what stages they will be involved. Having a separate section detailing PPI would be beneficial. Similarly, who are the “knowledge users in clinical practice and policy” stakeholders?
When describing the population the term “economic impact” is not clearly defined. Is it direct costs? Indirect costs? Both? Other? Please clarify for precision.
The protocol correctly states that definitions of what makes a condition rare varies by country. I would appreciate more clarity on how rarity will be defined. Presumably by the country the investigators hail form. How will this be handled in international (cross-border) collaborative studies?
Under “types of sources” it is stated that “Results excluded due to language will be reported transparently”. This seems vague, please clarify.
I was confused by the inclusion criteria. Shouldn’t this include an inclusion criteria specifying articles that report on healthcare costs for rare diseases?
The “Stage 2: Identifying relevant studies” was not entirely clear. I understand that titles and abstracts as well as full text will undergo independent dual review. Will data extraction also be independently done by two investigators then compared?
In Table 2, please define abbreviations (i.e., S1, S2, S3, S4).
In the section on “Stage 5”, what does the sentence “Explicit details of the methodology for analysis will be provided to ensure transparency and rigour in the analysis process”? Would not this be part of the quality appraisal? Please clarify.
In Table 3, health finance and healthcare system structures vary widely between countries. For example, the U.S. has health insurance tied to employment with largely a fee-for-service structure, while the U.K. has nationalized healthcare (i.e., NHS) and Switzerland has a mandatory insurance program. I feel that it is important to extract and describe information on the respective health systems.
In the conclusions section it would be helpful to operationally define terminology that is introduced. Specifically, what is a “cost-minimal intervention”?

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Rare diseases

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

08 Apr 2024

Author Response

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and ... Continue reading We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and lack of highlighted focus in the introduction of the protocol. The introduction has been edited to clearly highlight how this scoping review differs from other scoping reviews on the topic.
We acknowledge the lack of clarity provided on the possible development of a ‘cost-minimal’ intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool. The PRISMA guidance will be retained, as it reports the scoping review process.
We thank the reviewer for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided. Further information on the PPI representatives and knowledge users is included in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the unclear definition of ‘economic impact’. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs that will be used to illustrate economic impact.
We thank the reviewer for their request for clarity on the inclusion and exclusion criteria. The vague statement has been addressed. Regarding the inclusion criteria, this paper will focus on studies considering all the costs associated with rare diseases, not only healthcare costs. The types of costs to be included have been more clearly defined. The wording has been changed regarding if any studies will be excluded due to language barriers. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We acknowledge the reviewer’s concerns around stage 5 of the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. However, the analysis methodology will be reported to ensure transparency and rigour in the analysis process and assist in future replication.
We thank the reviewer for their thoughts on the data extraction component of this review. Travel costs have been included in Table 1 of costs to be included. A section for defining the relevant health system for each included article has been included in the data extraction chart.
We thank the reviewer for their request for clarity on how rarity will be defined. Rare diseases will be defined according to Orphanet classifications, which has been cross-referenced across contexts and databases, and therefore should be acceptable across any contexts included in the review.
We thank the reviewer for their request for clarity on Stage 2. More information on the data extraction process has been provided to address their query.
We thank the reviewer for their request for clarity on abbreviations included in Table 2. The abbreviations in the relevant table are now defined.
We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and lack of highlighted focus in the introduction of the protocol. The introduction has been edited to clearly highlight how this scoping review differs from other scoping reviews on the topic.
We acknowledge the lack of clarity provided on the possible development of a ‘cost-minimal’ intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool. The PRISMA guidance will be retained, as it reports the scoping review process.
We thank the reviewer for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided. Further information on the PPI representatives and knowledge users is included in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the unclear definition of ‘economic impact’. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs that will be used to illustrate economic impact.
We thank the reviewer for their request for clarity on the inclusion and exclusion criteria. The vague statement has been addressed. Regarding the inclusion criteria, this paper will focus on studies considering all the costs associated with rare diseases, not only healthcare costs. The types of costs to be included have been more clearly defined. The wording has been changed regarding if any studies will be excluded due to language barriers. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We acknowledge the reviewer’s concerns around stage 5 of the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. However, the analysis methodology will be reported to ensure transparency and rigour in the analysis process and assist in future replication.
We thank the reviewer for their thoughts on the data extraction component of this review. Travel costs have been included in Table 1 of costs to be included. A section for defining the relevant health system for each included article has been included in the data extraction chart.
We thank the reviewer for their request for clarity on how rarity will be defined. Rare diseases will be defined according to Orphanet classifications, which has been cross-referenced across contexts and databases, and therefore should be acceptable across any contexts included in the review.
We thank the reviewer for their request for clarity on Stage 2. More information on the data extraction process has been provided to address their query.
We thank the reviewer for their request for clarity on abbreviations included in Table 2. The abbreviations in the relevant table are now defined.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

08 Apr 2024

Author Response

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and ... Continue reading We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and lack of highlighted focus in the introduction of the protocol. The introduction has been edited to clearly highlight how this scoping review differs from other scoping reviews on the topic.
We acknowledge the lack of clarity provided on the possible development of a ‘cost-minimal’ intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool. The PRISMA guidance will be retained, as it reports the scoping review process.
We thank the reviewer for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided. Further information on the PPI representatives and knowledge users is included in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the unclear definition of ‘economic impact’. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs that will be used to illustrate economic impact.
We thank the reviewer for their request for clarity on the inclusion and exclusion criteria. The vague statement has been addressed. Regarding the inclusion criteria, this paper will focus on studies considering all the costs associated with rare diseases, not only healthcare costs. The types of costs to be included have been more clearly defined. The wording has been changed regarding if any studies will be excluded due to language barriers. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We acknowledge the reviewer’s concerns around stage 5 of the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. However, the analysis methodology will be reported to ensure transparency and rigour in the analysis process and assist in future replication.
We thank the reviewer for their thoughts on the data extraction component of this review. Travel costs have been included in Table 1 of costs to be included. A section for defining the relevant health system for each included article has been included in the data extraction chart.
We thank the reviewer for their request for clarity on how rarity will be defined. Rare diseases will be defined according to Orphanet classifications, which has been cross-referenced across contexts and databases, and therefore should be acceptable across any contexts included in the review.
We thank the reviewer for their request for clarity on Stage 2. More information on the data extraction process has been provided to address their query.
We thank the reviewer for their request for clarity on abbreviations included in Table 2. The abbreviations in the relevant table are now defined.
We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and lack of highlighted focus in the introduction of the protocol. The introduction has been edited to clearly highlight how this scoping review differs from other scoping reviews on the topic.
We acknowledge the lack of clarity provided on the possible development of a ‘cost-minimal’ intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool. The PRISMA guidance will be retained, as it reports the scoping review process.
We thank the reviewer for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided. Further information on the PPI representatives and knowledge users is included in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the unclear definition of ‘economic impact’. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs that will be used to illustrate economic impact.
We thank the reviewer for their request for clarity on the inclusion and exclusion criteria. The vague statement has been addressed. Regarding the inclusion criteria, this paper will focus on studies considering all the costs associated with rare diseases, not only healthcare costs. The types of costs to be included have been more clearly defined. The wording has been changed regarding if any studies will be excluded due to language barriers. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We acknowledge the reviewer’s concerns around stage 5 of the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. However, the analysis methodology will be reported to ensure transparency and rigour in the analysis process and assist in future replication.
We thank the reviewer for their thoughts on the data extraction component of this review. Travel costs have been included in Table 1 of costs to be included. A section for defining the relevant health system for each included article has been included in the data extraction chart.
We thank the reviewer for their request for clarity on how rarity will be defined. Rare diseases will be defined according to Orphanet classifications, which has been cross-referenced across contexts and databases, and therefore should be acceptable across any contexts included in the review.
We thank the reviewer for their request for clarity on Stage 2. More information on the data extraction process has been provided to address their query.
We thank the reviewer for their request for clarity on abbreviations included in Table 2. The abbreviations in the relevant table are now defined.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 23 Oct 2023

Yvonne Zurynski, Professor of Health System Sustainability, Macquarie University, Sydney, New South Wales, Australia

Not Approved

https://doi.org/10.21956/hrbopenres.15057.r35969

An interesting protocol for a scoping review.

The introduction is excessively long and reads like a literature review for a thesis rather than the background for a peer-reviewed publication. I would suggest shortening the background to include a very clear rationale that supports the need for this scoping review.

In the abstract, the authors mention that the review will support a cost-minimal intervention - there is no rationale provided as to why this might be suggested before the review has even been done! If you are going to use terms such as "cost-minimal" these need to be clearly defined.

I would suggest that the main research question is revised to include how the economic impacts are measured, the types and magnitude of these impacts rather than just how impacts are "identified".

The methods rely on the JBI 6-step process and PRISMA-ScR which is a good basis for this type of review.

The involvement of patient and public is commendable, however, it's not clear whether the PPI panel has already been established, what kinds of representatives are included in the PPI and exactly how they have contributed to the development of this protocol - some additional clarification would be good to include.

In the methods please provide clear definitions of direct and indirect costs that will be included and/or excluded in the review, is loss of income included or excluded? Is travel to appointments included or excluded? What about the cost of medical equipment (wheelchairs etc.) and medical consumables (e.g. dressings, oxygen tubing and masks, etc...).

Please be clear on what study designs are included and excluded - for example the methods say that "case-control studies and analytical cross-sectional studies will also be considered" - it's not clear what this means - will you include such studies or exclude them?

Justification to use the MMAT tool is required. Why are you not using quality assessment tools specifically developed for health economic studies e.g. CHEC, QHES or HEE?

Stage 5 seems to have been a little glossed over when actually this is extremely important for a review such as this. It is very likely that there will be high levels of heterogeneity among the included studies and yet this is not addressed. For example the economic outcomes and impacts are likely to differ depending on the country of origin and factors such as the degree of universal coverage, access to private health insurance and social security supports will need to be considered - how will you deal with these very different socio-economic contexts?

What exactly is meant by "financial experiences"?

There is likely to be a significant level of heterogeneity of rare diseases included in the identified studies - what will be the strategy for interpreting the economic impact for families who have a child with for example a developmentally disabling disease such as Rett Syndrome compare with for example Fabry disease where the impacts are different?

Including an empty PRISMA chart as a figure holds little value for the reader of this protocol.

I would suggest that the authors think through a little bit more carefully about what details they may wish to extract in their data charting to ensure that they extract adequate detail for synthesis and interpretation.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Health services and systems research; models of care, impacts on families, chronic and complex disease including rare diseases

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Report a concern

Author Response 08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

08 Apr 2024

Author Response

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction ... Continue reading We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction has been edited for clarity as per the reviewer’s suggestion.
We acknowledge the lack of clarity provided on the possible development of an intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
Following the reviewer’s suggestion, the research question has been amended to better reflect the aims of the review.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool.
We thank the reviewer’s for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided, including further information on the PPI representatives and knowledge users, in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the direct and indirect costs to be included, which was unclear. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We thank the reviewer for requesting clarity on the types of sources to be included. Additional text has been inserted clarifying the types of sources to be included. The focus of the review on any design that provide information on the economic costs (direct and/ or indirect) of paediatric rare diseases and meet the inclusion criteria is highlighted.
We acknowledge the reviewer’s concerns around stage 5 and the likely high heterogeneity of included studies in the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. Furthermore, the review does not aim to evaluate the economic impact of each rare disease, but rather understand what types of costs are evaluated in the included studies. The likely high levels of heterogeneity will be addressed following data extraction and analysis according to the articles retrieved. The data extraction table will include the country of origin of the articles, the rare diseases evaluated by the articles, and the types of costs evaluated by the articles, therefore allowing the mapping of these types of costs according to country and disease.
We thank the reviewer for pointing out the lack of clarity of the term ‘financial experiences’. This term has been removed in favour of ‘direct and indirect costs’.
We thank the reviewer for their comment on Figure 1. This figure has been removed.
We thank the reviewer for their thoughts on the data extraction component of this review. The data extraction chart has been updated to address the reviewers’ concerns and provide further detail.
We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction has been edited for clarity as per the reviewer’s suggestion.
We acknowledge the lack of clarity provided on the possible development of an intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
Following the reviewer’s suggestion, the research question has been amended to better reflect the aims of the review.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool.
We thank the reviewer’s for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided, including further information on the PPI representatives and knowledge users, in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the direct and indirect costs to be included, which was unclear. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We thank the reviewer for requesting clarity on the types of sources to be included. Additional text has been inserted clarifying the types of sources to be included. The focus of the review on any design that provide information on the economic costs (direct and/ or indirect) of paediatric rare diseases and meet the inclusion criteria is highlighted.
We acknowledge the reviewer’s concerns around stage 5 and the likely high heterogeneity of included studies in the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. Furthermore, the review does not aim to evaluate the economic impact of each rare disease, but rather understand what types of costs are evaluated in the included studies. The likely high levels of heterogeneity will be addressed following data extraction and analysis according to the articles retrieved. The data extraction table will include the country of origin of the articles, the rare diseases evaluated by the articles, and the types of costs evaluated by the articles, therefore allowing the mapping of these types of costs according to country and disease.
We thank the reviewer for pointing out the lack of clarity of the term ‘financial experiences’. This term has been removed in favour of ‘direct and indirect costs’.
We thank the reviewer for their comment on Figure 1. This figure has been removed.
We thank the reviewer for their thoughts on the data extraction component of this review. The data extraction chart has been updated to address the reviewers’ concerns and provide further detail.
Competing Interests: No competing interests were disclosed. Close
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Author Response 08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

08 Apr 2024

Author Response

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction ... Continue reading We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction has been edited for clarity as per the reviewer’s suggestion.
We acknowledge the lack of clarity provided on the possible development of an intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
Following the reviewer’s suggestion, the research question has been amended to better reflect the aims of the review.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool.
We thank the reviewer’s for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided, including further information on the PPI representatives and knowledge users, in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the direct and indirect costs to be included, which was unclear. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We thank the reviewer for requesting clarity on the types of sources to be included. Additional text has been inserted clarifying the types of sources to be included. The focus of the review on any design that provide information on the economic costs (direct and/ or indirect) of paediatric rare diseases and meet the inclusion criteria is highlighted.
We acknowledge the reviewer’s concerns around stage 5 and the likely high heterogeneity of included studies in the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. Furthermore, the review does not aim to evaluate the economic impact of each rare disease, but rather understand what types of costs are evaluated in the included studies. The likely high levels of heterogeneity will be addressed following data extraction and analysis according to the articles retrieved. The data extraction table will include the country of origin of the articles, the rare diseases evaluated by the articles, and the types of costs evaluated by the articles, therefore allowing the mapping of these types of costs according to country and disease.
We thank the reviewer for pointing out the lack of clarity of the term ‘financial experiences’. This term has been removed in favour of ‘direct and indirect costs’.
We thank the reviewer for their comment on Figure 1. This figure has been removed.
We thank the reviewer for their thoughts on the data extraction component of this review. The data extraction chart has been updated to address the reviewers’ concerns and provide further detail.
We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction has been edited for clarity as per the reviewer’s suggestion.
We acknowledge the lack of clarity provided on the possible development of an intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
Following the reviewer’s suggestion, the research question has been amended to better reflect the aims of the review.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool.
We thank the reviewer’s for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided, including further information on the PPI representatives and knowledge users, in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the direct and indirect costs to be included, which was unclear. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We thank the reviewer for requesting clarity on the types of sources to be included. Additional text has been inserted clarifying the types of sources to be included. The focus of the review on any design that provide information on the economic costs (direct and/ or indirect) of paediatric rare diseases and meet the inclusion criteria is highlighted.
We acknowledge the reviewer’s concerns around stage 5 and the likely high heterogeneity of included studies in the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. Furthermore, the review does not aim to evaluate the economic impact of each rare disease, but rather understand what types of costs are evaluated in the included studies. The likely high levels of heterogeneity will be addressed following data extraction and analysis according to the articles retrieved. The data extraction table will include the country of origin of the articles, the rare diseases evaluated by the articles, and the types of costs evaluated by the articles, therefore allowing the mapping of these types of costs according to country and disease.
We thank the reviewer for pointing out the lack of clarity of the term ‘financial experiences’. This term has been removed in favour of ‘direct and indirect costs’.
We thank the reviewer for their comment on Figure 1. This figure has been removed.
We thank the reviewer for their thoughts on the data extraction component of this review. The data extraction chart has been updated to address the reviewers’ concerns and provide further detail.
Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 31 Aug 2023

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Reviewer Reports

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	1	2	3
Version 2 (revision) 08 Apr 24		read	read
Version 1 31 Aug 23	read	read

Yvonne Zurynski, Macquarie University, Sydney, Australia
Andrew Dwyer, Boston College, Massachusetts, USA
Genevieve Currie, Mount Royal University, Calgary, Canada

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Reviewer Report

20 Views

19 Jun 2024 | for Version 2

Genevieve Currie, School of Nursing and Midwifery, Mount Royal University, Calgary, AB, Canada

20 Views Cite this report Responses(0)

Approved

Thank you for the opportunity to provide this review. This is a strong scoping review protocol paper. However, I have highlighted some things I think you could still focus on with in your paper to make your paper stronger.

Please do not use the word patient to describe a person with a rare disease. Use the word person or child instead as you are not describing someone receiving an intervention or care in this manuscript.
You could also include as therapy as direct costs therapy for children with rare diseases (physio, occupational, speech and behavioral), educational supports with aides and educational assistants and indirect costs for parents could be respite for caregiver support. I see some of these in table one but in the literature review these are not mentioned.
Since this scoping review is focused on children and their families, I think this should be explicitly stated early in the third paragraph of the literature review. The manuscript also describes costs for adults with rare diseases but this should be only for context and not figure so prominently in the literature review as this is not the focus of this paper.
I don’t understand research question #4: “To determine the study settings, rare conditions and geographical contexts, and the study types and organizations involved (e.g., charitable organisations, pharmaceutical companies, etc.). “What do you mean by determine study settings? Are you asking to determine where other research studies have occurred and who was studied and who was involved in conducting the study? Just needs to be clearer. You could use the concepts you list under table 4 with charting the data.
You mention indirect costs to siblings in the context. I think you could add siblings earlier in the background when you say children and their families, including siblings as they are in important family members to understand the impacts.
Consultation: Will the PPI parents be parents of the same child i.e. a mother and father of the same child? I think it would increase diversity of the consultation if they were 4 parents of 4 different children. This could be stated in this section.

Consultation: policymakers is misspelled.
I would put this sentence earlier in the manuscript under methods to demonstrate you had engagement with representatives much earlier than the consultative stage: “This scoping review protocol was presented to the PPI representatives and knowledge users working in the rare disease field and the research questions and search strategy were validated through separate discussion and consultation to understand the priorities of the two groups.”
Well designed and supported from multiple frameworks and theories.
Excellent to include parents as consultants as well as knowledge users. Great to give the definition of a knowledge user that you are using.

Is the rationale for, and objectives of, the study clearly described?

Partly
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

24 Views

13 Apr 2024 | for Version 2

Andrew Dwyer, Boston College, Massachusetts, USA

24 Views Cite this report Responses(0)

Approved

The authors have responded appropriately to the points raised in the initial review.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Rare diseases

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

47 Views

24 Oct 2023 | for Version 1

Andrew Dwyer, Boston College, Massachusetts, USA

47 Views Cite this report Responses(1)

Approved With Reservations

Authors appropriately cite the PRISMA-ScR yet I feel it would be useful to consider using an economic evaluation guideline from the EQUATOR network (i.e., CHEERS reporting guideline) to aid in identifying gaps in the literature and guide future reporting efforts for consistency and comparability.
The protocol describes cost of illness analysis as well as direct and indirect healthcare costs. Given that rare disease patients are geographically dispersed and have difficulty accessing specialized care I feel that noting travel costs is a relevant and key consideration.
The protocol cites recent economic evaluations for rare diseases (i.e., Delaye et al., 2022 and Garcia-Perez et al., 2021) yet it is not completely clear how the proposed scoping review will differ from the recent analysis or what gap this study will fill. Did these prior studies include (at least to some extent) a focus on pediatrics? This could be clarified for precision.
I applaud the PPI but there is relatively scant description of this. Have PPI stakeholders already been identified? If so, who are they and what perspectives do they bring? Similarly, it is not exactly clear at what stages they will be involved. Having a separate section detailing PPI would be beneficial. Similarly, who are the “knowledge users in clinical practice and policy” stakeholders?
When describing the population the term “economic impact” is not clearly defined. Is it direct costs? Indirect costs? Both? Other? Please clarify for precision.
The protocol correctly states that definitions of what makes a condition rare varies by country. I would appreciate more clarity on how rarity will be defined. Presumably by the country the investigators hail form. How will this be handled in international (cross-border) collaborative studies?
Under “types of sources” it is stated that “Results excluded due to language will be reported transparently”. This seems vague, please clarify.
I was confused by the inclusion criteria. Shouldn’t this include an inclusion criteria specifying articles that report on healthcare costs for rare diseases?
The “Stage 2: Identifying relevant studies” was not entirely clear. I understand that titles and abstracts as well as full text will undergo independent dual review. Will data extraction also be independently done by two investigators then compared?
In Table 2, please define abbreviations (i.e., S1, S2, S3, S4).
In the section on “Stage 5”, what does the sentence “Explicit details of the methodology for analysis will be provided to ensure transparency and rigour in the analysis process”? Would not this be part of the quality appraisal? Please clarify.
In Table 3, health finance and healthcare system structures vary widely between countries. For example, the U.S. has health insurance tied to employment with largely a fee-for-service structure, while the U.K. has nationalized healthcare (i.e., NHS) and Switzerland has a mandatory insurance program. I feel that it is important to extract and describe information on the respective health systems.
In the conclusions section it would be helpful to operationally define terminology that is introduced. Specifically, what is a “cost-minimal intervention”?

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Rare diseases

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Author Response

08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We thank the reviewer for their comments and acknowledge their thoughts on the length and lack of highlighted focus in the introduction of the protocol. The introduction has been edited to clearly highlight how this scoping review differs from other scoping reviews on the topic.
We acknowledge the lack of clarity provided on the possible development of a ‘cost-minimal’ intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool. The PRISMA guidance will be retained, as it reports the scoping review process.
We thank the reviewer for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided. Further information on the PPI representatives and knowledge users is included in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the unclear definition of ‘economic impact’. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs that will be used to illustrate economic impact.
We thank the reviewer for their request for clarity on the inclusion and exclusion criteria. The vague statement has been addressed. Regarding the inclusion criteria, this paper will focus on studies considering all the costs associated with rare diseases, not only healthcare costs. The types of costs to be included have been more clearly defined. The wording has been changed regarding if any studies will be excluded due to language barriers. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We acknowledge the reviewer’s concerns around stage 5 of the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. However, the analysis methodology will be reported to ensure transparency and rigour in the analysis process and assist in future replication.
We thank the reviewer for their thoughts on the data extraction component of this review. Travel costs have been included in Table 1 of costs to be included. A section for defining the relevant health system for each included article has been included in the data extraction chart.
We thank the reviewer for their request for clarity on how rarity will be defined. Rare diseases will be defined according to Orphanet classifications, which has been cross-referenced across contexts and databases, and therefore should be acceptable across any contexts included in the review.
We thank the reviewer for their request for clarity on Stage 2. More information on the data extraction process has been provided to address their query.
We thank the reviewer for their request for clarity on abbreviations included in Table 2. The abbreviations in the relevant table are now defined.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

53 Views

23 Oct 2023 | for Version 1

Yvonne Zurynski, Professor of Health System Sustainability, Macquarie University, Sydney, New South Wales, Australia

53 Views Cite this report Responses(1)

Not Approved

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Health services and systems research; models of care, impacts on families, chronic and complex disease including rare diseases

Respond to this report

Responses (1)

Author Response

08 Apr 2024

Niamh Buckle, School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland

We thank the reviewer for their comments and considered feedback on this scoping review protocol.
We acknowledge their thoughts on the length of the introduction of the protocol. The introduction has been edited for clarity as per the reviewer’s suggestion.
We acknowledge the lack of clarity provided on the possible development of an intervention following completion of the scoping review as part of this multiphase project. Mention of a ‘cost-minimal’ intervention has been removed. The results of this review will instead inform further research on this topic.
Following the reviewer’s suggestion, the research question has been amended to better reflect the aims of the review.
We thank the reviewer for acknowledging the strength of the scoping review through its reliance on methodology framework, and for their thoughtful comments on aspects we should consider further. We have incorporated the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) into the quality assessment of the included studies, instead of the MMAT tool.
We thank the reviewer’s for their comments and considered suggestions. More detail on the PPI aspects of the review have been provided, including further information on the PPI representatives and knowledge users, in the Consultation section of the review. Information on the relationships between the PPI representatives and the research team is also provided.
We thank the reviewer for their thoughts on methods, specifically around the direct and indirect costs to be included, which was unclear. An additional table is provided with examples of direct and indirect healthcare and non-healthcare costs.
We thank the reviewer for requesting clarity on the types of sources to be included. Additional text has been inserted clarifying the types of sources to be included. The focus of the review on any design that provide information on the economic costs (direct and/ or indirect) of paediatric rare diseases and meet the inclusion criteria is highlighted.
We acknowledge the reviewer’s concerns around stage 5 and the likely high heterogeneity of included studies in the review. As this is a scoping review, the method of analysis will not be as in-depth as a systematic review or meta-analysis. Furthermore, the review does not aim to evaluate the economic impact of each rare disease, but rather understand what types of costs are evaluated in the included studies. The likely high levels of heterogeneity will be addressed following data extraction and analysis according to the articles retrieved. The data extraction table will include the country of origin of the articles, the rare diseases evaluated by the articles, and the types of costs evaluated by the articles, therefore allowing the mapping of these types of costs according to country and disease.
We thank the reviewer for pointing out the lack of clarity of the term ‘financial experiences’. This term has been removed in favour of ‘direct and indirect costs’.
We thank the reviewer for their comment on Figure 1. This figure has been removed.
We thank the reviewer for their thoughts on the data extraction component of this review. The data extraction chart has been updated to address the reviewers’ concerns and provide further detail.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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The economic impact of living with a rare disease for children and their families: a scoping review protocol

Abstract

Keywords

Introduction

Methods

Stage 1: Identifying the research question

Table 1. Inclusion and exclusion criteria.

Stage 2: Identifying relevant studies

Table 2. Sample search strategy.

Stage 3: Study selection

Figure 1. PRISMA 2020 Flow Diagram Template for Systematic Reviews, taken from Page et al. (2021).

Stage 4: Charting the data

Table 3. Sample data charting table.

Stage 5: Collating, summarising and reporting the results

Stage 6: Consultation

Dissemination

Study Status

Conclusions

Data availability

Acknowledgements

References

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The economic impact of living with a rare disease for children and their families: a scoping review protocol

Abstract

Keywords

Introduction

Methods

Stage 1: Identifying the research question

Table 1. Inclusion and exclusion criteria.

Stage 2: Identifying relevant studies

Table 2. Sample search strategy.

Stage 3: Study selection

Figure 1. PRISMA 2020 Flow Diagram Template for Systematic Reviews, taken from Page et al. (2021).

Stage 4: Charting the data

Table 3. Sample data charting table.

Stage 5: Collating, summarising and reporting the results

Stage 6: Consultation

Dissemination

Study Status

Conclusions

Data availability

Acknowledgements

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Competing Interests Policy

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Are you a HRB-funded researcher?

Thank you!