## Abstract
### Introduction
Drugs for rare diseases (DRDs) offer important health benefits, but challenge traditional health technology assessment, reimbursement, and pricing processes due to limited effectiveness evidence. Recently, modified processes to address these challenges while improving patient access have been proposed in Canada. This review examined processes in 12 jurisdictions to develop recommendations for consideration during formal government-led multi-sectoral discussions currently taking place in Canada…. ### Methods
(i) A scoping review of DRD reimbursement processes, (ii) key informant interviews, (iii) a case study of evaluations for and the reimbursement status of a set of 7 DRDs, and (iv) a virtual, multi-stakeholder consultation retreat were conducted…. Budget impact is considered in all jurisdictions except Sweden. In Italy, France, Germany, Spain, and the United Kingdom, specific factors are considered for DRDs. However, in all jurisdictions opportunities for clinician/patient input are the same as those for other drugs. Of the 7 DRDs included in the case study, the number that received a positive reimbursement recommendation was highest in Germany and France, followed by Spain and Italy. No relationship between recommendation type and specific elements of the pricing and reimbursement process was found…. ### Supplementary Information
The online version contains supplementary material available at 10.1186/s13023-022-02397-4.
**Keywords:** Orphan drugs, Drugs for rare diseases, Health technology assessment, Reimbursement processes, International comparison, Canada, Patient and clinician engagement… ## Introduction
Drugs for rare diseases (DRDs), while offering important health benefits, continue to challenge traditional health technology assessment (HTA), reimbursement, and pricing processes in Canada and worldwide. Given small patient populations and disease heterogeneity, evidence supporting their clinical and cost-effectiveness is often limited, leading to significant decision uncertainty. In response to these challenges, modified processes that manage decision uncertainty while improving patient access have recently been proposed in Canada [1, 2]…. ## Objective
We compared HTA-informed reimbursement and pricing processes for DRDs in countries similar to Canada in order to develop recommendations for consideration during formal government-led multi-sectoral discussions currently taking place in Canada…. ## Methods
We conducted (i) a scoping review of HTA, reimbursement, and pricing processes for DRDs following published methodological guidelines [3], (ii) key informant interviews, (iii) a case study of the reimbursement status of a set of DRDs, and (iv) a virtual, multi-stakeholder consultation retreat…. ### Scoping review
#### Identification of relevant documents
##### Peer-reviewed literature
In consultation with an experienced medical information specialist, search strategies were developed and tested through an iterative process. They were peer-reviewed by a second information specialist prior to their application using the PRESS Checklist [4]. Strategies comprised a combination of controlled vocabulary (e.g., “Orphan Drug Production”, “Drug Approval”, “Technology Assessment, Biomedical”) and keywords (e.g., “drugs for rare diseases”, “reimbursement”, “HTA”) synonymous with concepts relating to the HTA/reimbursement review process and DRDs (Table 1)…. ###### Table 1.
Terms for literature search
|Concept 1|Concept 2|
|–|–|
|Health technology assessment ***OR***|Drugs for rare diseases ***OR***|
|Reimbursement decision-making ***OR***|Orphan drugs ***OR***|
|Coverage with evidence development ***OR***|Expensive drugs|
|Access with evidence development ***OR***|Expensive drugs|
|Conditional coverage ***OR***|Expensive drugs|
|Performance-based risk sharing arrangements ***OR***|Expensive drugs|
|Managed entry agreements ***OR***|Expensive drugs|
|Managed access programs|Expensive drugs|… ##### Grey literature
Internet searches for documents describing HTA-informed reimbursement decision-making processes for DRDs were performed using the Google search engine. Websites for reimbursement/HTA organizations in selected jurisdictions were also searched. Given the focus of the review, selected jurisdictions comprised those that had either previously reported efforts to implement processes for providing timely, appropriate access to DRDs or outranked Canada on health system performance, as measured by the Commonwealth Fund…. #### Charting the information
Two researchers independently extracted information from included documents (and interview transcripts) using a standardized data abstraction form, which was developed to categorize themes related to elements of the HTA, reimbursement, and pricing processes for DRDs and, in particular, decision options that account for uncertainty in evidence on clinical and cost-effectiveness. Information from the interviews was charted alongside data collected from peer-reviewed and grey literature using the same abstraction form…. Interview questions related to: (1) factors considered when conducting HTAs and making reimbursement decisions on DRDs; (2) the role of patient-reported outcomes (PROs) in committee deliberations; (3) involvement of patients and clinicians in assessment and review processes; (4) approaches used to manage uncertainty around clinical and cost-effectiveness (e.g., managed access programs, real-world evidence-based agreements, etc.); and, (5) opportunities for patients to provide input into those approaches…. ### Case studies
To examine the relationship between different review processes for DRDs and access, reimbursement recommendations for a set of seven DRDs were explored using a case study approach…. Publicly reported reimbursement recommendations were obtained through the websites of considerably transparent review processes in the following countries: Australia, Spain (Catalonia), France, Germany, Italy, the Netherlands, Scotland, Sweden, and the United Kingdom. They were then tabulated to identify qualitatively patterns in recommendations across and within countries. Where a pattern was noted, review processes were compared to identify any corresponding potentially explanatory elements (e.g., inclusion of disease specific clinical experts on review committee)…. ### Stakeholder retreat
A half-day virtual retreat involving a broader group of stakeholders (patients, payers, HTA specialists, industry, and academia) was held. Prior to the retreat, participants were given a copy of a synthesis of information obtained from parts (i) through (iii) above, along with a set of questions, which took the form of a consultation document. Their responses were used to facilitate discussions during the retreat. Based on feedback received during breakout and plenary sessions, as well as the results of the scoping review, a set of recommendations for HTA-informed reimbursement and pricing processes for DRDs in Canada was developed…. ## Results
### HTA-informed pricing and reimbursement processes for DRDs
The following section combines findings from the scoping review and key informant interviews. Three hundred documents were selected for inclusion in the review (Additional file 1: Appendix 1 describes the results using the Preferred Reporting Items for Systematic Reviews and Meta-analyses [PRISMA] flowchart)…. In most jurisdictions, no separate processes or programs for making reimbursement and pricing decisions on DRDs have been introduced. Submission requirements, review committees, decision-making criteria, and decision options remain the same as those for drugs that target more prevalent conditions. However, some jurisdictions have modified steps within their processes to facilitate quicker access to therapies awarded orphan drug status at regulatory approval *and* whose annual budget impact per indication falls under an explicit threshold…. In Australia, DRDs receiving a negative reimbursement decision following a review through standard processes may be considered by the Life Saving Drugs Program (LSDP) [5, 6]. Drugs listed on the LSDP do not meet cost-effectiveness requirements but are considered clinically effective and treat a clearly definable disorder for which no alternative non-drug therapeutic modality exists. In addition, their annual cost constitutes an unreasonable burden on the patient and his/her guardian…. Of the jurisdictions included in this review, only one has a separate process through which certain DRDs are reviewed from the outset (i.e., without consideration by a standard process first)…. The Highly Specialized Technologies Programme (HSTP) within the National Institute for Health and Clinical Excellence (NICE) evaluates the benefits and costs of a limited number of drugs for very rare conditions that meet the following criteria for reimbursement in NHS England: (1) the target population is so small that treatment is concentrated within a… In most jurisdictions, requirements for economic evaluations or budget impact analyses are the same for all drugs, including DRDs. Submissions to HTA-informed reimbursement review processes in Sweden [23], the Netherlands [20], Scotland [20], England, and Wales [73, 82, 84] must include cost-effectiveness (typically cost-utility) analyses…. With few exceptions, where DRDs require a full assessment and review, neither processes nor committees differ from those involved in making reimbursement decisions for non-DRDs. The exceptions are Australia and the UK (NICE and SMC). Based on advice issued following review through standard processes, certain DRDs may be recommended for inclusion in Australia’s Life Saving Drugs Program and forwarded to the Department of Health and Aging (DoHA) [6]…. #### Decision factors/criteria
Decision factors or criteria guiding deliberations by review committees are, for the most part, the same for DRDs and non-DRDs. Moreover, all processes/jurisdictions share the following criteria or factors: disease severity/clinical burden, unmet need/lack of active treatment alternatives, therapeutic value (clinical efficacy/effectiveness and significance of additional benefit), strength/robustness/quality of evidence, value for money, and budget impact (except Sweden)…. For highly specialized technologies (some DRDs), that threshold range is £100,000 to £300,000 per quality-adjusted life year (QALY). The UK (NICE and SMC) and Spain [53] consider system capacity for appropriate use/infrastructure and staffing requirements/feasibility. Regarding additional DRD specific criteria, only Sweden excludes ‘budget impact’ from reimbursement decisions on therapies with orphan drug status [58]…. #### Pricing
In most jurisdictions, pricing procedures for DRDs are the same as those for non-DRDs. They comprise multiple strategies, which commonly include reference pricing (e.g., Au