. 2020 Jan 28;7:416. doi: 10.3389/fpubh.2019.00416

Table 3.

Comparison of reimbursement systems of orphan drugs and rare diseases policies (15, 16, 29, 70–72)⁴^,²⁴, (68)³⁰^,³¹, (11, 69)³², (73–75)³³, (76–84)³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷, (67, 85, 86)¹^,⁴⁸, (87)²^,³, (88, 89)⁴^,⁵, (90, 91)⁶^,⁷^,⁸^,⁹, (92, 93).

Country	Reimbursement/HTA process
AR	No specific reimbursement process for OMP's. No defined HTA process.
DE	The AMNOG Act requires manufacturers to send in a dossier at the time of regulatory approval (and <1 month after indication change) to the Federal Joint Committee (FJC), the decision-making body of the joint healthcare representatives—HCP's, hospital association, and sickness funds) to demonstrate additional benefit of the drug over a comparator drug. After the additional benefit is granted by the G-BA, a reimbursement price is negotiated between manufacturer and GKV-SV (National Association of Statutory Health Insurance Funds). A budget cap of €50 M per active substance was introduced in 2016. After 12 months, practical benefit was assessed and reimbursement adjusted accordingly. Reimbursement prices that are negotiated on the national level are published. Afterwards, the more than 100 health insurances further negotiate discounts with the manufacturer, which are not publicly available. Except for OMPs, G-BA lets IQWiG (Institute for quality and science in healthcare) assess the proposed additional benefit with the dossier submission at the time of marketing authorization, with five benefit categories: major, considerable, minor, non-quantifiable, no additional benefit. Evidence quality is taken into account, based on the number of studies, evidential certainty and clinical outcomes, resulting in three possible scores: proof, indication or hint of benefit. Four clinical outcomes are measured: mortality, morbidity, adverse events, and health-related quality of life (HRQoL). Patient subgroups can be excluded in case of no added benefit. If projected sales are < €1 M, no full dossier is needed. Until 2019, OMPs with an EMA marketing authorization were viewed as automatically having an established additional benefit over existing therapies (i.e., the 'no additional benefit' score was excluded from OMP benefit scores). After 12 months, an early benefit assessment is performed after which prices can be renegotiated. This changed in 2019, when the GSAV bill introduced a new clause for OMPs that exceed the 50 M annual revenue threshold: in this case drug manufacturers need to perform a comparative analysis with an appropriate comparator drug within 3 months. (Hospital) Inpatient costs are now also to be included in the 50 M budget vs. only outpatient cost before 2019, increasing the likelihood for OMPs to exceed the threshold. Under G-BA can require drug manufacturers to setup data collection programs (patient registry data) according to G-BA rules, as well as require physicians and hospitals to provide OMP administration data to registries in order to be allowed to prescribe these drugs. The costs of these observational data collection activities would have to be covered by drug manufacturers. GSAV authorizes G-BA to perform periodic reassessment of the benefit analysis with new (registry) data. GSAV can lead to an increased number of price-renegotiations/reductions. Arbitration procedures can be started in case of conflicting views between manufacturer and IQWiG/GBA.
FR	No specific reimbursement criteria exist for rare diseases (standard HTA applies), however, a cost-effectiveness analysis is not needed. HAS assesses therapeutic benefit, calculated as Service Medical Rendu (SMR), which takes into account: clinical effectiveness, safety of alternatives, clinical relevance in overall treatment strategy, disease severity, population size, indication (for chronic and preventable diseases). The SMR defines the drug reimbursement level for drugs (three levels exist). The MoH is responsible for final reimbursement. For drugs which HAS considers irreplaceable, reimbursement is set at 100%. HAS also assesses the ASMR indicator (Amelioration du Service Medical Rendu), i.e., therapeutic improvement in comparison to other available treatments and sets the price level based on this value (five possible levels). No specific reimbursement criteria exist for rare diseases. The SMR defines three reimbursement levels for drugs. The MoH is a decision maker. For drugs which HAS considers irreplaceable, reimbursement is set at 100%. HAS also assesses the ASMR indicator (Amelioration du Service Medical Rendu), i.e., therapeutic improvement in comparison to available treatments and sets the price level based on this value (five levels exist). Standard HTA process applies to OMPs, however, a cost-effectiveness analysis is not required. HAS assesses therapeutic benefit, calculated as Service Medical Rendu (SMR), which into account: clinical effectiveness, safety of alternatives, clinical relevance in overall treatment strategy, disease severity, population size, indication (for chronic and preventable diseases).
KAZ	Healthcare is generally funded by the State and is free for all citizens. Treatment of rare diseases is covered within the national healthcare budget, and no special reimbursement rules exist for OMP's. However, OMP funding needs to be applied for by the regions, after which budget is granted by the State, based on individual patient characteristics (e.g., body mass/dosing). OMP's need to be registered in Kazakhstan or elsewhere and be on the official orphan drug list to be eligible for reimbursement. All medical interventions are monitored under supervision of the MoH. No specific HTA process for OMPs.
LV	Drugs listed on the national reimbursement drug list are reimbursed, based although individual patient reimbursement decisions can be made a by the medical council (limit: 14,229 Euro per patient/year). The national reimbursement list has three sections: List A with therapeutically equivalent drugs (generic drugs); List B with drugs without therapeutic equivalent; List C with drugs costing more than 4,269 Euro per patient per year. The manufacturer must reimburse at least 10% of the costs of drugs on list C for a defined number of patients. Other OMP's can be reimbursed on an individual basis in medical need (life-threatening situations) if costs are < €14,229 per year, which is assessed by the National Drug Agency. Co-payment is needed in case of additional costs, by patient or manufacturer. This does not limit access substantially. Between 2008–2011, 300+ patients had successful individual negotiations. Pediatric rare disorders can receive special reimbursement rules. The NHS evaluates therapeutic value, price, expected budget impact and cost-effectiveness for each drug before it is included in the reimbursement list. No specific HTA rules for OMPs. List C decisions are made annually, depending on budget and total budget impact of the treatment.
NL	OMP's go through the same HTA process as all other “specialist drugs,” which are assessed based on the “risk” they pose to the overall Dutch basic insurance coverage, taking into account budget impact, lack of control over the use of the product, doubts on the quality of evidence, etc. If the risk is considered high, a formal HTA assessment is done. A price >€25,000 per patient per year is also defined as a risk factor, however, if total budget impact is small (< €2.5 M per year), ZiN will likely not do an assessment. Due to a frequent lack of evidence for OMP's, the rarity, severity, and societal impact of the disease will be considered. Hospital drugs (mainly specialty care) that either are expected to have a high per patient cost, or a high total budget impact, can be put into a “sluice” (waiting room) by the minister of health. This means a delay in reimbursement until a positive evaluation, restrictions for use have been put in place and/or a successful price negotiation has been done by the MoH (undisclosed).
PL	No special reimbursement rules for OMPs. A reimbursement application is sent to the MoH, which transfers it to AOTMiT for evaluation (containing clinical effectiveness, cost-effectiveness, and budget impact analyses). AOTMiT gathers and assesses information on health, social, economic, and ethical aspects of medicinal technology. The Transparency Council (part of AOTMiT) gives its recommendation on pricing and reimbursement and the final recommendation is issued by the President of AOTMiT. Final approval is given by the Healthcare Minister. Most OMPs are reimbursed within “Drug Programs” (DPs), introduced by the MoH in 2012 for expensive medical technologies replacing previous “therapeutic programs.” DPs are mainly designed to control consumption of the most expensive drugs.
	As a tailored approach to HTA for OMPs does not currently exist in Poland, standard HTA rules for “standard” medicinal products apply, which take into account: health priorities, results of sequelae of disease, public health significance, social preferences, organizational, legal aspects, and ethical aspects. The cost-effectiveness threshold is based on an ICER (Incremental cost-effectiveness ratio) that needs to be lower or equal to 3×GDP per capita to consider a medical technology cost-effective (3 × 41.985 PLN = 125.955 PLN~29.989 EUR in 2016, EUR rate from 16.03.2018 1EUR = 4.2PLN).
RO	OMP's are reimbursed within the National Program for rare disorders and National Program for treatment of chronic disorders (list C2), and provided for free. HTA was introduced in 2014, with separate rules for reimbursement of OMPs. In order to be included in the reimbursement list, medicinal products need to gain a minimum of 60 points (out of 80) during HTA. Results between 60 and 79 ensure conditional reimbursement, with price negotiation and by using risk-sharing tools (agreements on cost-volume, cost-volume-outcome). Drugs with an orphan designation assigned by EMA automatically get 55 points and depending on the reimbursement status in other EU countries points are added: 0 points if the drug is reimbursed in up to 2 EU countries 10 points if the drug is reimbursed in 3–7 EU countries 20 points if the drug is reimbursed in 8–13 EU countries 25 points if the drug is reimbursed in at least 14 EU countries.
RU	The reimbursement system is quite complex, consisting of many lists, programs and levels of reimbursement. OMP's can be reimbursed on federal and regional levels. Federal reimbursement is based on the Vital and Essential Drug List (VEDL)—a list of reimbursed drugs with price limits. Federal benefits are available if rare disease patients belong to one of the “privileged categories” of citizens such as veterans, invalids or victims of the Chernobyl and Mayak disasters. Orphan drugs are mainly reimbursed within two programs, the high-cost Nosologies List and the orphan diseases list. Within the seven nosologies program, funded on the federal level, the treatment for those diseases is reimbursed: hemophilia, cystic fibrosis, pituitary nanism, Gaucher disease, lymphoid malignant neoplasms, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, juvenile arthritis with systemic onset, mucopolysaccharidosis type I, II, and VI. Although the reimbursed treatments on the 24 orphan diseases list are defined on the federal level, funding is done regionally. If budget allows, treatment for other rare disorders (not on one of the lists) can be reimbursed. There is no special HTA for OMPs, the same rules apply as for other medicinal products.
TR	All OMP reimbursement applications are assessed by the Medical and Economic Evaluation Commission, which informs the Reimbursement Commission that will make a final decision. The TITCK, SGK, and the Ministry of Finance are part of the Medical and Economic Evaluation Commission and the Reimbursement Commission. Orphan drugs are exempt from submitting pharmacoeconomic analyses in contrast to other medicinal products, which allows OMP's to enter the market faster (if budget impact is within limits).
UA	In 2016 the new legislation on HTA was implemented. The new regulation introduced criteria (such as morbidity level, disease prevalence, evidence on comparative effectiveness, safety) which are taken into consideration in order to include medicinal products to National essential medicines list (NLEM). In addition a pharmacoeconomic analysis must be provided while applying for the reimbursement. An expert Committee on the Selection and Use of Essential Medicines was appointed by the MoH for decision making concerning the inclusion of medicinal products to NLEM. No specific reimbursement and HTA processes for OMPs exist. In January 2019 HTA Department was established at the State an Expert Centre of the MoH to prepare recommendations and inform decisions on medical technologies financed by the state funds. The main stakeholders are the central government (Cabinet of Ministers), the MoH, the Ministry of Finance and local governments. In 2019 there are 41 national programs that are approved annually for public (state) procurements for diseases, rare diseases in particular, through which OMP's are procured annually via international organizations (UNDP, Crown agents, UNICEF). Currently there are clinical protocols approved by the MoH for treatment of mucopolysaccharidosis, Gaucher disease, epidermolysis bullosa, cystic fibrosis, phenylketonuria, Wilson's disease.
UK	England NICE performs HTA assessment using (incremental) cost-effectiveness ratios, with thresholds for medicines (incl. orphan drugs): below the £20,000 limit NHS reimbursement is based mainly on cost-effectiveness data, between £20,000–£30,000 more data is needed e.g., degree of ICER certainty, innovativeness, whether or not the drug is life-extending at end of life, etc. Above £30,000 evidence needs to be stronger. For very rare disorders (1 <50,000) the HST (Highly Specialized Technologies) programme is used, which uses an ICER QALY limit of £100,000. If costs remain below that the assessment will be based on standard cost-effectiveness analysis. Above the limit evidential certainty, the innovation level and actual effectiveness increase (QALY gains) will be taken into account and a QALY modifier can raise the cost limit up to £300,000 per incremental QALY. In 2017 NICE introduced a “budget impact test” with a limit of £20 million (over 3 years), set by the NHS. If the limit is exceeded a commercial negotiation is triggered, special arrangements need to be made and reimbursement can be delayed or phased in over a longer period. Expensive OMP's can also be procured via the Cancer Drug Fund (budget £340 M in 2016), a dedicated budget for innovative costly treatments too expensive for common NHS reimbursement (after NICE recommendation), and also via an Individual Funding Request to the NHS. Wales Wales is generally following NICE' reimbursement recommendations, but has its own agency All-Wales Medicines Strategy Group (AWMSG) which can approve drugs for reimbursement. A special treatment fund for high-cost drugs has been introduced in 2017. Scotland The Scottish Medicines Consortium (SMC), the Scottish equivalent of NICE, reviews all newly approved medicines, including orphan and ultra-orphan drugs. The HTA process is similar to England, with similar ICER QALY thresholds (£20 and £30 k). The Scottish NHS boards are not obliged to follow SMC's advice. A separate fund exists dedicated to funding expensive medicines, including rare disease treatments, called the New Medicines Fund. Since 2014 manufacturers can ask SMC to convene a Patient and Clinician Engagement (PACE) group, if their drug is not recommended for reimbursement by the New Drug Committee (NDC). PACE was setup after the realization that existing cost-effectiveness thresholds were not always suitable for (ultra)rare diseases and end-of-life conditions. PACE is aimed at enlarging the role of expert physicians and patients in the decision-making process. Orphan drugs for ultra-rare diseases can receive additional flexibility in the process. Northern Ireland The Department of Health (DH) in Northern Ireland assesses all NICE recommendations for local implementation. Very rare drugs approved via NICE HST assessment will be approved for reimbursement.

¹https://www.gkv-spitzenverband.de/english/statutory_health_insurance/amnog_evaluation_of_new_pharmaceutical/amnog_english.jsp (accessed September 18, 2019). ²Interview with French key opinion leader (accessed July 26, 2019). ³https://www.has-sante.fr/portail/upload/docs/application/pdf/2014-03/pricing_reimbursement_of_drugs_and_hta_policies_in_france.pdf (accessed September 18, 2019). ⁴https://www.zorginstituutnederland.nl/over-ons/programmas-en-samenwerkingsverbanden/horizonscan-geneesmiddelen/sluis-voor-dure-geneesmiddelen (accessed September 18, 2019). ⁵http://www.korektorzdrowia.pl/wp-content/uploads/3.-wojciech-matusewicz-1.pdf (accessed September 30, 2019).

⁶Order of MOH No. 84 dated 11.02.2016, Order of MoH No. 1050 dated 07.10.2016. Available online at: http://www.apteka.ua/article/362317 (accessed September 30, 2019). ⁷http://www.apteka.ua/article/390509 (accessed September 30, 2019). ⁸Order of MOH No. 778 dated 27.10.2014 http://zakon3.rada.gov.ua/laws/show/160-2015-%D0%BF (accessed September 30, 2019). ⁹https://www.scottishmedicines.org.uk/how-we-decide/pace/ (accessed September 30, 2019).