Thirty-two of 37 countries (86%) were included in the study. Vignettes for each of these were created [16]. The five non-respondent countries excluded from the study were: Australia, Croatia, Cyprus, Luxembourg, and Wales. Responses were provided by 33 country experts (two experts for the different jurisdictions in Canada) (Figure 1). Eighty percent of experts work within, or close to, HTA/reimbursement processes in the public sector, with the remaining being from academia, health care providers or private sector. Their positions are directorship-level involved in the pricing and reimbursement processes (45%), HTA scientific experts (30%), appraisal committee members (6%), academics or clinical experts (18%), or consultants (3%).
The next section provides an overview of the countries with supplemental processes, explores their key features according to the typology, and examines countries without RDT supplemental processes.
Supplemental processes for rare disease treatments
Forty one percent (13/32) of countries include supplemental processes specifically targeting rare and/or ultra-RDTs, with two of these countries (Scotland, Slovakia) each having two distinct supplemental processes for rare and ultra-RDTs, respectively (Figure 2). Integration levels of these supplemental processes within standard processes were categorised as low, medium and high. Processes with low integration are either completely (2/15) or partially separate (2/15) from the standard process. The main distinction between separate supplemental and standard processes are the different evidence submission requirements and appraisal committees. This is the case for the HST programme in England and the ultra-OMP pathway in Lithuania, both targeting ultra-RDTs. They also include different features intended to better adapt to the specificities of RDTs. Both recognise the challenges for evidence generation and tend to be more lenient with its interpretation. The HST programme in England has an explicit decision-making framework that allows for broader consideration of treatment value (nature of the condition, clinical effectiveness, value for money, impact beyond direct health benefits) and greater WTP, whereas the ultra-OMP pathway in Lithuania has different appraisal rules (therapeutic value not graded), a special reimbursement list with no waiting list, and special pricing rules.
Partially integrated supplemental processes include the ultra-OMP pathway in Scotland (where the wider decision-making framework implemented in 2016 was changed to an ultra-OMP pathway in 2019) and the OMP pathway in Germany. In Scotland, once a product is designated as an ultra-RDT by the Scottish Medicines Consortium (SMC), it is submitted for initial assessment to SMC using a special submission form and it is then made available in Scotland for three years with a data collection plan and re-assessment after three years. In Germany, the assessment and appraisal are conducted by the Federal Joint Committee (G-BA) instead of the independent Institute for Quality and Efficiency in Health Care (IQWiG). RDTs are also subject to more simplified evidentiary requirements (e.g. no need for comparative data), and their additional benefit is considered automatically proven. There is also an option for conditional approval.
Countries were defined as having adapted processes for RDTs when they include adjustments to their standard process that allow better management of the challenges with RDTs. This is the case for Norway, Sweden and Slovakia, in which the adapted process targets ultra-RDTs, and in Scotland for OMPs. The main process features common to all the countries relate to a greater understanding of the challenges to produce high quality evidence for RDTs, and more favourable reimbursement through a higher WTP. Slovakia also includes an exemption from presenting an economic evaluation. In Scotland, being an OMP has been seen as a “modifier” to the appraisal process for many years, providing more flexibility in the decision-making process [17]. Recently, there is also the possibility to hold a patient and clinician engagement (PACE) meeting for OMPs [18].
Five of the 13 countries with supplemental processes for RDTs have a high level of integration with standard processes. These are either expedited processes or processes where rarity is weighted. The three countries with expedited processes allow for an earlier start of the assessment process (and subsequently earlier access for patients to these treatments). The other two countries have points systems to determine reimbursement status (e.g. Romania) and WTP (e.g. Slovakia), where OMPs get extra points.
Two of the 13 countries with supplemental processes use alternative routes to reimburse subgroups of RDTs, through HTA exemptions. These include the separate state-reimbursement budget for children living with rare diseases in Latvia and a list of rare diseases for which medicines are automatically reimbursed in Bulgaria.
Distinction of rare versus ultra-rare disease treatments within supplemental processes
All processes with a medium to low level of integration within standard processes target ultra-RDTs, with the exception of the orphan medicines pathway in Germany and the Patient and Clinical Engagement (PACE) process and SMC modifiers in Scotland intended for OMPs (Table 1). The ultra-RDT definitions are defined using prevalence criteria ranging from less than 1 in 50,000 (Scotland, Slovakia) to less than 1 in 200,000 patients (Lithuania, Bulgaria), or are not defined (Sweden, likely to be less than 1 or 2 in 200,000 patients). Additionally, most countries limit these special processes to ultra-RDTs with specific characteristics, such as treating a severe condition with high unmet need, to potentially effective and/or high cost treatments, requiring highly specialised management. Regarding the more integrated supplemental processes, eligible medicines are those with an OMP designation.
Table 1. Country definitions for rare and ultra-rare disease treatments, and their use as eligibility criteria within supplemental processes for rare disease treatments
PROCESS TYPE
|
COUNTRY
|
PROCESS DESCRIPTION
|
ELIGIBILITY
|
DEFINITION
|
Rare disease
|
Ultra-rare disease
|
Separate
|
England
Highly Specialised Technology Programme (HST)
|
Main differences with standard process: willingness to pay threshold, specialised appraisal committee, more holistic perspective of value, managed access agreements possible
|
High cost technologies for ultra-rare conditions - see HST prioritisation criteria
|
-
|
No prevalence criteria, based on HST eligibility criteria
|
Lithuania
Ultra-rare disease treatment pathway
|
Very rare disease committee: special appraisal committee decides on inclusion in special list. Main differences with standard process: therapeutic value not graded, no waiting list in case of positive decision, special pricing rules. Decision can be individual-case (yearly revised fixed budget) or generalised-case approach (general budget)
|
(1) ultra-rare, (2) life-threatening or significant disability, (3) subject to effective aetiology or pathogenic treatment, (4) effective treatment (increases survival or reduces disability)
|
-
|
<1:200,000
|
Partially separate
|
Scotland
Ultra-rare disease treatment pathway
|
Assessment based on ultra-orphan drug decision-making criteria, routine use for 3 years after which re-assessment.
Option for Patient and clinician engagement programme (PACE). Disease-specific experts describe treatment benefit not captured within original assessment
|
URDT: (1) ultra-rare, (2) chronic and severely disabling condition, (3) highly specialised management
PACE: OMPs (and end of life treatments) not considered cost-effective - after NDC decision (after 3-year monitoring)
|
-
|
<1:50,000
|
Germany
|
Different reimbursement status: additional benefit guaranteed, strong negotiation power and reasonable reimbursement. Assessment by G-BA (instead of IQWIG), different evidence requirements
|
(1) OMP, (2) revenues from statutory health insurance < 50 million/last 12 months
|
OMP
|
-
|
Adapted
|
Norway
|
Greater willingness to pay
|
(1) ultra-rare, (2) effective treatment (>2 QALY gain), (3) severe condition (>30 QALYs lost)
|
-
|
<1:100,000
|
Slovakia
|
Exempt from economic evaluation
|
Ultra-rare
|
-
|
<1:50,000
|
Sweden
|
Greater willingness to pay
|
(1) ultra-rare, (2) good potential for effective drug, (3) very severe condition
|
-
|
no fixed limit
~<1-2:100,000
|
Scotland
Standard pathway with PACE and modifiers
|
PACE: disease-specific experts describe treatment benefit not captured within original assessment.
Modifiers: standard assessment for OMPs, but SMC recognises limitation in evidence generation and will accept greater uncertainty in the economic case
|
PACE: OMPs (end of life treatments) not cost-effective, manufacturer can request a PACE to get additional insights
Modifiers: OMPs, life-threatening, substantial increase in quality of life/life expectancy, can reverse the condition, bridges gap to a definitive therapy.
|
OMP
|
-
|
Expedited
|
Belgium
|
Earlier pricing: after positive CHMP opinion, before marketing authorisation. Exemption from economic model
|
OMP
|
OMP
|
-
|
Italy
|
Earlier pricing and reimbursement: after positive CHMP opinion, before marketing authorisation
|
OMP (and hospital or exceptionally therapeutic and social medicinal products)
|
OMP
|
-
|
New Zealand
|
Earlier reimbursement: before marketing authorisation
|
Rare disease (as per country definition)
|
Cum prevalence <1:50,000
|
-
|
Rarity weighted
|
Romania
|
Reimbursement status based on points cumulated (unconditional, conditional reimbursement etc.): OMPs get extra points
|
OMP
|
OMP
|
-
|
Slovakia
|
Willingness to pay threshold based on points system: OMPs get extra points
|
OMP
|
OMP
|
-
|
Exempt from HTA
|
Bulgaria
|
All drugs to treat those rare diseases included in special list of rare diseases are 100% reimbursed
|
Drugs with indication included on special list of rare diseases
|
OMP
|
-
|
Latvia
|
Separate state-reimbursement budget for children with rare diseases
|
OMP for use in children
|
OMP
|
-
|
Legend: HTA: Health technology assessment; OMP: orphan medicinal product (refers to drugs with an orphan designation from the European Medicines Agency); RDT: rare disease treatment; HST: Highly Specialised Technology programme; SMC: Scottish Medicines Consortium; PACE: Patient and Clinical Engagement programme; G-BA: Federal Joint Committee; IQWIG: Institute for Quality and Efficiency in Health Care; CHMP: Committee for Medicinal Products for Human Use of the European Medicines Agency; NDC: New Drugs Committee; QALY: Quality of Life Adjusted Life Years
Key process features for appraisal of rare disease treatments
The distinctions between supplemental and standard processes have been characterised as features occurring throughout the HTA process, and are discussed in this section (Figure 3).
Evidence submissions
The countries with separate or partially separate processes have different clinical and/or economic evidence submission requirements. This is done through use of different submission forms as seen for the HST in England and ultra-OMP pathways in Lithuania and Scotland, or with the possibility of presenting a simplified version of the standard submission in Germany (exempt from presenting comparative data). In all other countries, evidentiary requirements are the same as for standard processes with the exception of Lithuania, Slovakia and Belgium, which don’t require economic models for ultra-RDTs.
Assessment
The inclusion of disease-specific input is being achieved by involving patient and clinical experts in different ways across the HTA process, starting from the assessment phase. First, through the stand-alone PACE process in Scotland, where the SMC assessors discuss the added benefit of the treatment not captured within conventional clinical and cost-effectiveness assessments with those who have experience of the disease and/or treatment being assessed. This meeting can be requested by the manufacturer if a negative opinion is initially given by the assessment committee. A PACE statement is then drafted and becomes part of the evidence submitted to the appraisal committee. Secondly, the process may allow for clinical (and in some cases patient) experts to provide input about the condition, the care pathway in the country and impacts of treatment in standard clinical practice, which supports understanding and interpretation of the evidence and assumptions. Most countries, including countries with standard processes for RDTs, allow this. Third, some countries have established committees with rare disease experts that support decision-making around pricing, reimbursement and use of the medicine. This is the case in Bulgaria with their rare disease expert committee that decides on inclusion of diseases on the special positive formulary (for which all treatments are reimbursed), and in New Zealand with their clinical advisory committee.
Additionally, some processes may allow for an earlier start in the assessment process to guarantee more timely access to RDTs. This is seen in Belgium, Italy and New Zealand in their expedited processes targeting RDTs, which allow for the assessment process to start before marketing authorisation is granted.
Appraisal
The greatest number of features implemented in the supplemental processes relate to the appraisal phase. The main distinction seen within separate supplemental processes for ultra-RDTs is the existence of different appraisal committees, which provides a standing group with rare disease expertise who only assess RDTs. One of the main distinctions seen in England is in membership composition with the inclusion of rare disease clinical specialists (adult and paediatric), ethicists, geneticists, and rare disease expert centre representatives.
Broader consideration of value is another feature adopted in England’s and Scotland’s supplemental processes for ultra-RDTs (within their ultra-OMP decision frameworks), where context and specification of issues specific to rare diseases are considered as evidence. This is done by more detailed consideration about the nature of the condition (including consideration of severity, unmet need and existence of alternative treatments), and accounting for indirect costs and benefits on patients, carers and health system.
The most common feature in supplemental processes relates to allowing more leniency in the quality of the evidence. This is done through less stringent requirements for demonstrating added benefit (e.g. acceptance of non-comparative data), and/or willingness to accept surrogate endpoints or non-randomised controlled trials (RCTs). Generally, this is done on a case-by-case basis, if appropriate justification is provided or if the evidence is considered to be of best possible quality. Greater leniency may also be more acceptable for medicines with a high level of unmet need or those that have a high media profile.
In those countries where cost-effectiveness needs to be proven (e.g. where an economic submission is required), there may be more flexibility in the interpretation of the economic evidence. This is done by accepting natural outcome measures instead of QALYs or cost-consequence analyses, and including sensitivity analyses that reflect wider costs and benefits (Scotland) [19].
Some of the features included in supplemental processes allow for different decision rules. The first relates to different WTP, where a higher ICER than would be admissible in common conditions (Scotland, Norway, Sweden), or a higher adjusted WTP that increases with magnitude of benefit and QALY gained (England) would be accepted, or through a points-system calculation of the WTP threshold where OMPs get extra points (Slovakia). The second relates to alternative reimbursement rules, where the therapeutic benefit of the medicine would be considered proven (Germany), or would not be graded (Lithuania). In Romania, reimbursement status is based on a points system, where OMPs get extra default points. Third, the process features also include decision modifiers in the appraisal framework, which impact deliberation about WTP or reimbursement status. While most processes, including the standard ones, are mainly interested in severity, unmet need and existence of treatment alternatives, some of the processes explicitly account for rarity or other criteria that may favour appraisal of RDTs (e.g. children, equality or the innovative nature of treatment [20]). Rarity is accounted for in Scotland as part of its decision modifiers. Other criteria that may influence the decisions are equality (England, New Zealand), children (Germany), ethical considerations (Bulgaria, Latvia), or innovative nature of treatment (England, Italy).
Pricing and reimbursement
Many countries include different forms of conditional approval agreements or MEAs, aiming to collect additional data to facilitate later re-assessment of added benefit or cost-effectiveness. This is the case for England’s HST programme, Scotland’s ultra-OMP pathway, Germany, Norway, Slovakia, Italy and Belgium. A few countries also include alternative routes to pricing and reimbursement for a group of RDTs, where they would be exempt from HTA as a whole. This is the case in Bulgaria, where all medicines used to treat conditions included on a special list of rare diseases would be automatically reimbursed, and in Latvia, with their separate state-budget for children with rare diseases.
Impact and proposed changes
Country experts were asked to state the impacts of their supplemental processes for RDTs. Increased acceptance rate was the most common response, resulting in the reimbursement of medicines that otherwise would not be reimbursed. The assumption of proven added benefit was considered to ensure a stronger negotiating position for the manufacturer and more flexibility in pricing. Some countries stated that these processes are more adapted to dealing with specificities in appraisal of RDTs. These processes allow special approaches to be taken for reimbursement of RDTs with clinical and/or budgetary issues in a consistent way, rather than on a case-by-case basis, supporting fairness in the decision-making system.
Changes in four of the 13 countries with supplemental processes are also being discussed, including refinement of processes (Sweden), potential legislative changes (Romania), implementation of a separate budget for adult rare disease patients (Latvia) and establishment of a therapy monitoring process (Bulgaria).
What are countries with standard processes doing?
In total, 19 countries (out of 32) do not have supplemental processes targeting RDTs, but may have features in their standard processes that might work to the advantage of RDTs. Ten (out of 19) adopt one or more of the features identified, but these are not specific to RDTs. Nine countries (of the 10 countries adopting one or more of the features) have a process that allows more leniency around quality of evidence (Austria, Canada, France, Estonia, Hungary, Poland, Portugal, Czech Republic, and Netherlands). Two (out of 10) countries have different clinical and economic submission requirements (Estonia, Czech Republic). Two (out of 10) countries have a process that allows for more flexibility in the use of the economic model in decision-making (Estonia, Slovenia). For example, Estonia has a process for accepting different WTP. Six (out of 10) countries can implement conditional approval schemes (Austria, Canada, Ireland, Czech Republic, Netherlands). Two (out of 10) have separate budgets (Italy has a separate fund for innovative and cancer medicines and Austria has specific funds for political solutions). Ireland has a Rare Diseases Technology Review Committee enabling clinicians and other stakeholders to provide input in the post-HTA phase, and review MEA proposals (was not included as a country with a supplemental appraisal process, since this applies to post-HTA/appraisal). Some of these 10 countries and two without process adaptations (Finland and Greece) have appraisal criteria likely to favour RDTs. These relate to rarity (Netherlands), equality (Netherlands), children (Netherlands), ethical considerations (Netherlands, Slovenia, Finland), or innovative nature of treatment (Greece).
Some countries include additional processes that are not specifically for RDTs, but might work to their advantage. In the Czech Republic, highly innovative medicines are eligible for conditional reimbursement, and do not need to prove cost-effectiveness. Switzerland automatically grants reimbursement for diseases included in the national list of birth defects and congenital disorders [21]. In France, their expedited processes target medicines with high unmet need.
Eleven of the 19 countries without supplemental processes are engaged in ongoing discussions about implementing changes in their processes for RDTs. Discussions revolve around general process changes in the standard pathway, or process changes for orphan medicines, including implementing exemptions for economic models or including bespoke patient involvement processes.