A Comparative Analysis of Pricing and Reimbursement of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Europe

Objectives: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor), have substantially improved patients’ lives yet significantly burden healthcare budgets. This analysis aims to compare pricing and reimbursement of aforementioned cystic fibrosis medicines, across European countries. Methods: Clinical trial registries, national databases, health technology assessment reports and grey literature of Austria, Belgium, Denmark, France, Germany, Ireland, Poland, Spain, Sweden, Switzerland, Netherlands, the United Kingdom were consulted. Publicly available prices, reimbursement statuses, economic evaluations, budget impact analyses and managed entry agreements of CFTR modulators were examined. Results: In Belgium, lowest list prices were observed for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €417 per defined daily dose (DDD) and €372 per average daily dose (ADD), respectively. Whereas, Switzerland had the lowest price for Orkambi® (lumacaftor/ivacaftor) listed at €309 per DDD. Spain had the highest prices for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €850 per DDD and €761 per ADD, whereas Orkambi® (lumacaftor/ivacaftor) was most expensive in Poland at €983 per DDD. However, list prices were subject to confidential discounts and likely varied from actual costs. In all countries, these treatments were deemed not to be cost-effective. The annual budget impact of the CFTR modulators varied between countries and depended on factors such as local product prices, size of target population, scope of costs and discounting. However, all modulators were fully reimbursed in ten of the evaluated countries except for Sweden and Poland that, respectively, granted reimbursement to one and none of the therapies. Managed entry agreements were confidential but commonly adopted to address financial uncertainties. Conclusion: Discrepancies concerning prices, reimbursement and access were detected for Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor) across European countries.


INTRODUCTION
Cystic fibrosis (CF) is a rare condition affecting more than 48,000 individuals in Europe. With an occurrence of 1 in 2000-3,000, it is also the continent with the highest incidence of CF (European Cystic Fibrosis Society, 2020) (Farrell, 2008;Bell et al., 2020). Over time, technological advancements such as preconception carrier screening have led to a decline in incidence rates in some countries or regions (Lopes-Pacheco, 2016;Bell et al., 2020). However, newborn screening, improved care and clinical awareness have contributed to decreased pediatric mortality, a stable and a continuously growing CF adult population, now exceeding the pediatric population (Burgel et al., 2015;Lopes-Pacheco, 2016;Balfour-Lynn and King, 2020;Bell et al., 2020).
Inheritance of the disease is autosomal recessive and caused by errors in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Rafeeq and Murad, 2017;Bell et al., 2020). Over 2000 CFTR mutations have been identified and are grouped into six classes based on the protein defect (Rafeeq and Murad, 2017). Class I mutations result in no functional CFTR and include nonsense mutations, splice mutations or deletions (De Boeck et al., 2014;Rafeeq and Murad, 2017). In Class II, characterized by the most common heterozygous or homozygous F508del mutation affecting 85% of people with CF (PWCF) in Europe, the CFTR protein is misfolded and unable to reach the cell surface (De Boeck et al., 2014;Rafeeq and Murad, 2017). Gating mutations, typically describing G551D, S549R or V520F alterations that prevent opening of the CFTR channel, are categorized in Class III (De Boeck et al., 2014;Rafeeq and Murad, 2017). Class IV describes impairment of CFTR regulation by faulty channel conformation e.g. D1152H or R117H mutations (De Boeck et al., 2014;Rafeeq and Murad, 2017). Splicing mutations of Class V, such as 3,849+10 kb C → T, result in insufficient CFTR channels and Class VI mutations cause increased degradation of the unstable protein (De Boeck et al., 2014;Rafeeq and Murad, 2017).
A dysfunctional CFTR protein generates a chloride and bicarbonate ionic imbalance while increasing influx of sodium and water (Morrison et al., 2019). This disrupts the natural pH and alters the apical liquid layer of epithelial cells and digestive fluids into accumulating thick mucus or 'mucoviscidosis'. This phenotypically manifests into persistent obstruction and inflammation of organs such as the lungs and gastrointestinal tract (NICE, 2017;Rafeeq and Murad, 2017;Morrison et al., 2019;Bell et al., 2020). Further complications can lead to deterioration of vital organs and death.
Although Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® have, moderately, while Kalydeco ® (ivacaftor) and Kaftrio ® (ivacaftor/tezacaftor/elexacaftor) have, greatly, improved quality of life for many patients, access to these medicines is not always guaranteed due to their associated high cost and burden on healthcare budgets (Chevreul et al., 2016;Lopes-Pacheco, 2019). After the adoption of CFTR modulators, a significantly higher expenditure was observed in Europe: a recent study reviewed a database of PWCF and showed that only the four percent of PWCF who were on CFTR modulators caused an increase of 27.5% in CF pharmaceutical spending (Chevreul et al., 2016). This is expected to augment further as the market uptake will grow when all eligible PWCF receive CFTR protein-targeting medicines. Additionally, new CFTR-modulators from Vertex and other companies such as Abbvie and Eloxx Pharmaceuticals are in the pipeline (Cystic Fibrosis Foundation, 2021a; Lopes-Pacheco, 2019). To illustrate, Germany noted an expenditure of €159 million in 2016 and estimates this amount to triple to €594 million if all patients would receive these modulators (Frey et al., 2019).
To inform reimbursement decisions of new medicines, many European jurisdictions perform health technology assessment (HTA) (Morel et al., 2013). For rare disease therapies such as these CFTR modulators, however, high uncertainty on medicine performance exists due to the limited and genetically heterogeneous population as well as adoption of surrogate endpoints in clinical settings (Kent et al., 2014;McLeod et al., 2020). To allow market access of Vertex' products while accounting for clinical uncertainties and high costs, some healthcare authorities closed mutual agreements with the manufacturer (Morel et al., 2013).

METHODS
We conducted a comparative analysis of list prices, reimbursement statuses, economic evaluations, BIAs and MEAs of Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) in selected European countries. Kaftrio ® (ivacaftor/tezacaftor/elexacaftor) was not included in the analysis due to limited information availability as it was recently authorized. Twelve countries were selected based on publicly accessible data and consisted of Austria, Belgium, Denmark, France, Germany, Ireland, Poland, Spain, Sweden, Switzerland, the Netherlands, the United Kingdom. If information was confidential or not available for a specific country, the country was not analyzed further.
Official list prices and reimbursement status of the CFTR modulators were recovered from public sources and grey literature, namely, medicinal products databases, formularies and/or pharmaceutical registries and government-specific healthcare or reimbursement databases. The latter comprised of Belgian National Institute for Health and Disability Insurance To conduct a comparison between countries, we converted list prices to prices per defined daily dose (DDD) which represents the assumed average maintenance dose per day for a medicine used for its main indication in adults (World Health Organization, 2021). If no DDD of the CFTR modulator was available for a specific dose, instead, we converted list price to price per average daily dose (ADD) as indicated in the package leaflet. For Kalydeco's ® (ivacaftor) dose of 150 mg, a DDD of 0.3g was specified (WHO, 2020). Only for Orkambi's ® (lumacaftor/ ivacaftor) tablet dose of 200 mg/125 mg, a DDD of four tablets was stated (WHO, 2021). For the other tablet dose of 100 mg/ 125 mg of Orkambi ® (lumacaftor/ivacaftor), we adopted an ADD of four tablets instead (European Medicines Agency, 2015). For Symkevi ® (tezacaftor/ivacaftor), no DDD was released thus the ADD was defined as one 100mg/150 mg Symkevi ® (tezacaftor/ ivacaftor) tablet combined with one 150 mg Kalydeco ® (ivacaftor) tablet. (European Medicines Agency, 2018). List prices comprised of pharmacist fee and value added tax (VAT). If the price was listed without pharmacist fee, it was specified, or without tax, it was recalculated with the VAT rate on prescription-only medicines from the corresponding country (Bundesverband der Pharmazeutischen Industrie (BPI), 2020). Currencies were subsequently converted to 2021 € with Belgium as the target country using the 'CCEMG -EPPI-Centre Cost Converter' online tool (The Campbell and Cochrane Economics Methods Group and the Evidence for CCEMG, 2021). It was assumed that original data related to the year of the data source. Finally, prices were rounded to the unit.
To compare economic evaluations, we considered following design parameters; model, perspective, comparator, time horizon, costs and discounting. The incremental cost-effectiveness ratio (ICER) or cost per quality-adjusted life years (QALY) and sensitivity analyses were also included.
Furthermore, publicly available BIAs were reviewed on their design including perspective, time horizon, target population (size), costs, discounting and uncertainty. The results of BIAs were also reported. This information was gathered from reimbursement applications or health technology appraisal reports from the respective agencies.
We determined whether a financial or performance-based MEA, between the company and national healthcare payers for Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ivacaftor) and

List Prices
List prices for Kalydeco ® (ivacaftor) ranged from €417 to €850 per DDD in Belgium and Spain, respectively (see Figure 1).

Design
For Kalydeco ® (ivacaftor) an economic evaluation was provided by the company and/or the country-specific healthcare authorities in the indications of G551D in children above six, gating class III children above two and/or R117H mutations in adults over 18 (see Table 3). A patient-level micro-simulation model, payer perspective, ivacaftor plus standard of care with standard of care only comparison and a lifetime horizon were adopted in most countries. However, differences were detected for: the Netherlands where the company carried out an evaluation based on a Markov model and the health authorities adopted a societal perspective; Poland and Sweden for which, respectively, the company and health authority adopted a societal perspective next to the payer's perspective; Scotland and Sweden, for which early ivacaftor treatment (initiated at 2 years of age) was additionally compared to standard of care and late ivacaftor treatment (initiated at 6 years of age); Wales, for which the perspective in G551D and gating class III mutations indications were not reported. Adjustments to the economic evaluation design made by local health authorities were claimed to be more adaptive to their population's characteristics. Reported costs often included medicine costs but also direct condition-related costs and indirect nonmedical costs assessed in Poland. Furthermore, a discount rate for costs and/or health outcomes and sensitivity analyses, scenario or probabilistic, were generally considered.
In all countries, Orkambi ® (lumacaftor/ivacaftor) was evaluated for people homozygous for the F508del CFTR mutation (see Table 4). In every economic evaluation, a patient-level micro-simulation model, third-party payer perspective and/or societal perspective was adopted. The treatment combined with the standard of care was compared to standard of care only. A lifetime horizon and medicine costs but also direct medical costs were generally considered. Poland and the Netherlands were the sole countries to also include indirect costs in their evaluation. When reported, a discount rate was applied to costs and health outcomes.
Frontiers in Pharmacology | www.frontiersin.org November 2021 | Volume 12 | Article 746710   CF, cystic fibrosis; ICER, incremental cost-effectiveness ratio; NA, not applicable, NHS, National Health Service; ppFEV 1 , per cent predicted forced expiratory volume in one second; PSA, probabilistic sensitivity analysis; QALY, quality adjusted life years; SoC, standard of care. a As of June 2021. b ICER in regular font indicates the results in the currency and reference year used in the study (third column from the right). The number in bold indicates the ICER in euros (Belgium, 2020 values).
Frontiers in Pharmacology | www.frontiersin.org November 2021 | Volume 12 | Article 746710 standard of care was compared to either standard of care only or standard of care and lumacaftor in the case of Sweden. Lifetime was generally considered as a time horizon. Furthermore, medicine costs, direct medical costs, and additionally, for the Netherlands, indirect costs were integrated in the economic evaluations. A discount rate on costs and/or outcomes was also applied.

Cost-Effectiveness (Incremental Cost-Effectiveness Ratio)
Kalydeco ® (Ivacaftor) The ICERs varied greatly per indication and across the analyzed countries (see Table 3).

Country-Specific Outcomes
Belgium does not consider cost-effectiveness for orphan medicines (Denis et al., 2009   to bring the ICER below the thresholds and be deemed costeffective. Orkambi ® (lumacaftor/ivacaftor) was given negative advice for reimbursement due to failed cost-effectiveness, insufficient clinically proven effect, lack of long-term data on lung function but also a limited patient eligibility (Zorginstituut Nederland, 2016a;Zorginstituut Nederland, 2019a). Symkevi ® (tezacaftor/ivacaftor) was negatively advised for heterozygotes but positively advised for homozygotes with the condition that the price would not be set higher than Orkambi ® (lumacaftor/ ivacaftor)'s price given that it has a similar therapeutic value (Zorginstituut Nederland, 2019b;Zorginstituut Nederland, 2020a). In Sweden, cost-effectiveness is flexible, influenced by disease severity and usually determined based on a range of €35,000 to €100,000 per QALY (Denis et al., 2009). However, costeffectiveness is not a primary criterium and no official threshold is defined. Kalydeco ® (ivacaftor)'s and Symkevi ® (tezacaftor/ivacaftor)'s costs were not deemed reasonable compared to their clinical benefit and therefore not funded for any of their indication (Tandvårds-och läkemedelsförmånsverket TLV, 2019). In contrast, Orkambi ® (lumacaftor/ivacaftor) was funded with the requirement to register specific effect parameters and a reduced cost.
For England, Kalydeco ® (ivacaftor) was shown not to be costeffective unless a discount would be agreed and ICER would fall within the increased ultra-orphan medicines threshold margin of £100,000 to £300,000 per QALY (Whiting et al., 2014;NHS England, 2015; National Institute for Health and Care Excellence (NICE), 2017; Kelly et al., 2018). Orkambi ® (lumacaftor/ivacaftor) had zero percent chance of being costeffective compared to the standard of care at their official threshold of £30,000 per QALY and was given a negative recommendation.
The Scottish Medicines Consortium (SMC) does not specify a formal ICER cut off but NHS' threshold of £20,000 per QALY is often used as a reference (Scottish Medicines Consortium, 2021a). In some cases, a higher cost per QALY may be accepted and additional factors are assessed to determine value for money (Denis et al., 2009). SMC did not advise Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ivacaftor) nor Symkevi ® (tezacaftor/ ivacaftor) for reimbursement within NHS Scotland because of insufficient justification of the cost in relation to the health benefit and a lack of robust economic and clinical analysis (Scottish Medicines Consortium (SMC), 2013; SMC, 2016a; SMC, 2016b; Kelly et al., 2018;Scottish Medicines Consortium, 2019).
In Poland, cost-effectiveness with an ICER threshold of three times their GDP per capita of that year, is considered (Kolasa et al., 2018). The Polish HTA Agency (AOTMiT) gave a negative recommendation for Kalydeco ® (ivacaftor) In Wales, the English NHS threshold of £100,000 to £300,000 per QALY for the economic evaluation of ultra-orphan medicines was adopted (Denis et al., 2009; National Institute for Health and Care Excellence (NICE), 2017). Kalydeco ® (ivacaftor) was negatively recommended by their health technology assessment body (AWMSGs) as issues surrounding cost-effectiveness and clinical uncertainties were defined (Drakeford, 2013; All Wales Medicines Strategy Group (AWMSG), 2019).

Kalydeco ® (Ivacaftor)
For most countries a BIA was provided in the indication of gating class III mutations and/or G551D mutations (see Table 6). In addition, England, Scotland and Wales also analyzed the budget impact in the indication of R117H mutations. In terms of design, payer's perspective was adopted in all cases, except for Wales that did not report their perspective. Budget impact results were depicted over an annual, 3-year, 5-year and/or life time horizon. Population size varied per country and depending on the indication. An open population was considered in Ireland, Scotland and Wales, in the indications G551D and R117H mutations. In Scotland, market uptake of Kalydeco ® (ivacaftor) for the gating class III and for G551D mutations were estimated to be 100 and 90%, respectively. For the Netherlands a market expansion with a treatment uptake of 100% was predicted. Medicine only costs were considered in Belgium, Poland, Sweden and the Netherlands, disaggregated costs were not reported for Ireland and all other countries considered costs beyond medication costs. Discount rates were generally not adopted or confidential, except for England and for Ireland in the indications of gating class III and R117H mutations. Overall, detailed information on handling uncertainty was confidential, however, England, Poland and the Netherlands performed deterministic sensitivity analyses and Wales performed a probabilistic sensitivity analysis of patient number and disease management costs. Some countries reported one gross or net budget impact per indication, while others disaggregated their estimates and stated the first and last year budget impact over the chosen horizon.
Orkambi ® (Lumacaftor/Ivacaftor) A BIA was conducted for patients homozygous for the F508del mutation in all selected countries (see Table 7). Calculations were done from the perspective of the payer and the chosen time frame differed, from a 1-year to a 3-year and a 5-year horizon, respectively in Poland, Belgium and the remaining countries. An open population was only considered in   Scotland, where patient number dynamically changed with discontinuation and in England, where they accounted for adherence and a yearly incremental market uptake. Other countries considered a closed population. Additionally, Belgium and the Netherlands reported a possible larger population size, in case Orkambi ® (lumacaftor/ivacaftor) would expand the current treatment market and be entirely adopted by all ages. Direct medical costs beyond medicineassociated costs, such as hospitalization and adverse events costs, were included in the analyses of England and Ireland only. No information on discount rates was publicly released. Only Poland reported on the use of sensitivity analysis and patient number influencing the potential budget impact. Belgium, the Netherlands and England disaggregated budget impact results and reported yearly amounts. In England, both budget estimates of the company and the national health service were reported, with the latter being slightly higher. One total budget impact estimation over the analyzed time horizon was reported for England, Ireland and Poland.
For all countries the payer's perspective was adopted to estimate the impact while time horizons included 3-year horizons for the Netherlands and Sweden, a 5-year horizon for Scotland and a lifetime horizon in the case of Sweden. An open population was considered in France and Scotland with the latter country also reporting a 100% market uptake while changes in population size incur partly due to discontinuation. Sweden and the Netherlands studied a closed population. Netherlands predicted market expansion and an alternative population size in case of full market uptake of Symkevi ® (tezacaftor/ ivacaftor) across all ages in the heterozygous indication. With respect to the scope of costs, medicine-only costs were generally considered while direct medical costs beyond medicine-costs, such as follow-up and maintenance costs, were reported in France only. Discount rates were generally not reported and uncertainty in the analyses for France and the Netherlands was addressed by scenarios. The latter, particularly for the Netherlands, was done by alternating treatment compliance rate. Budget impact results were generally confidential, only Sweden and the Netherlands published one total annual estimate over their respective time horizons.

Managed Entry Agreements
To have CF products reimbursed, the company and some European countries have set up a unique portfolio-deal agreement (Bruce, 2018;Vertex Pharmaceuticals Incorporated, 2018c). The concept was introduced to pay for the company's CF products considered expensive, not cost-effective and clinically uncertain in many jurisdictions. These portfolio deals aim to facilitate entry of the company's current products and those in the pipeline for the treatment of CF, while mitigating potential risks for their reimbursement (Rawson, 2018). To that end, a confidential discounted price based on caps, is agreed upon and, in many instances, this   products (Vertex Pharmaceuticals Incorporated, 2017;Vertex Pharmaceuticals Incorporated, 2018c). This agreement, with HSE, formed the blueprint for similar subsequent contracts between the company and Swedish TLV and county councils but also the Danish pharmaceutical and procurement body, Amgros (Nawrat, 2018;Vertex Pharmaceuticals Incorporated, 2018c;Vertex Pharmaceuticals Incorporated, 2018b;Vertex Pharmaceuticals Incorporated, 2018a). A recent study claims that the agreements in Sweden are mostly cost-sharing to address affordability whereas clinical uncertainties usually remain unsolved (Andersson et al., 2020). In Denmark, the price caps in the agreement are linked to the number of patients adopting the treatments (Bruce, 2018). In 2019, the company managed to bring its portfolio approach to England, Northern Ireland and Wales (Vertex Pharmaceuticals Incorporated, 2019c; National Institute for Health and Care Excellence (NICE), 2021). This agreement is performance based and supersedes any previous agreement between the company and NICE (National Institute for Health and Care Excellence (NICE), 2021). Under this deal, the company is required to deliver answers to clinical uncertainties that arose after health technology appraisal. These a priori defined elements and data are collected in the UK CF registry, that is monitored by NICE and funded by the company.
In other markets where reimbursement of the CF products exists, the company has agreed on other proposals.
In Scotland, a 5-year interim deal for Orkambi ® (lumacaftor/ ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) was realized in 2019, requiring to collect real-world evidence and to resubmit the medicines to the Scottish Medicines Consortium during the contract period (Vertex Pharmaceuticals Incorporated, 2019b; Cystic Fibrosis Trust, 2019). In 2020, a deal for the triple-therapy, Kaftrio ® (ivacaftor/tezacaftor/elexacaftor) was reached even before market authorization in Europe (Cystic Fibrosis Trust, 2020). In 2016, a pay-for-performance agreement was set up between the company and NIHDI due to remaining concerns about high budget impact and effectiveness, in terms of disease progression, survival rates and hospitalization rates (Comissie voor Gezondheid en Gelijke Kansen, 2019; Comissie voor Gezondheid en Gelijke Kansen, 2021). This allowed for a 3year temporary inclusion of Kalydeco ® (ivacaftor) on the Belgian reimbursement list. In return, the company was required to collect data and resolve established clinical uncertainties (Fair Healthdata, 2015;Sectoraal Comité, 2017). To account for the budgetary risks, a yearly amount based on profits and number of treated patients was refunded to NIHDI (Rijksinstituut voor ziekte-en invaliditeitsverzekering (RIZIV, 2016a;RIZIV, 2016b). Since the end of the agreement, it has been amended, renewed and is still ongoing (Rijksinstituut voor ziekte-en invaliditeitsverzekering (RIZIV, 2019). An agreement for the reimbursement of cystic fibrosis medicines, Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® (tezacaftor/ivacaftor), was reached in March of 2021 (Mucovereniging, 2021; Vlaamse Radio-en Televisieomroeporganisatie (VRT), 2021). That same month, the company applied for reimbursement of their most recent innovative therapy, Kaftrio ® (ivacaftor/tezacaftor/ elexacaftor).
In the Netherlands, although not cost-effective, Orkambi ® (lumacaftor/ivacaftor) was added to their reimbursement list (van Rijn, 2016). Currently, a confidential price-agreement with conditions is set up between the company and the government for all three modulators (Zorginstituut Nederland, 2019a;Zorginstituut Nederland, 2019b;Zorginstituut Nederland, 2021a). Likewise, for Orkambi ® (lumacaftor/ivacaftor), a straight reimbursement deal was achieved in Austria but also Kalydeco ® (ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) are found on their specialty list (Pinto, 2018;Rawson, 2018;Vertex Pharmaceuticals Incorporated, 2018a;Österreichische Sozialversicherung, 2020 Since the market authorization of the cystic fibrosis medicines by the European Commission, the modulators are available in Germany (GKV-Spitzenverband, 2012;GKV-Spitzenverband, 2015;Vertex Pharmaceuticals Incorporated, 2016; GKV-Spitzenverband, 2018a). However, a reimbursement agreement between the German National Association of Statutory Health Insurance Funds (GKV) and the company was founded on the obligation of the pharmaceutical company to automatically report the CF modulators' price and product information through electronic data transmission, in accordance with legal Section 131 (4) SGB V (GKV-Spitzenverband, 2018b).

International Collaborations
Several countries were hesitant to adopt Orkambi ® (lumacaftor/ ivacaftor) due to its high price and clinical uncertainties. To mitigate these uncertainties, Belgium and the Netherlands performed a joint price negotiation as part of the Beneluxa initiative in 2015 (O'Donnell, 2015;Paun, 2018;Rawson, 2018; Beneluxa Initiative on Pharmaceutical Policy, 2021). The negotiation was a pilot study of a larger international collaboration, additionally involving Luxembourg, Austria and Ireland, which was set up to jointly assess highly priced and innovative medicines often intended for a small population (De Block, 2015). In the case of Orkambi ® (lumacaftor/ivacaftor), Belgian and Dutch negotiations resulted in a negative decision to reimburse the medicine as no agreement could be established (Allen, 2017). The Ministers of Health deemed the medicine to be overpriced and not cost-effective (van Rijn, 2016;De Block, 2017). A price reduction of 82% was requested to make Orkambi ® (lumacaftor/ivacaftor) cost-effective. Ultimately, Netherlands managed to strike a deal with the company alone.

Prices and Efficacy
Although, prices are closely relatable in some countries, our findings show that Kalydeco ® (ivacaftor) is generally the most expensive CFTR modulator, followed by Symkevi ® (tezacaftor/ ivacaftor) and, lastly, by Orkambi ® (lumacaftor/ivacaftor). This price relation may be reflective of the effectiveness of the modulators, as Kalydeco ® (ivacaftor) has proven to be of highest clinical added value. At the launch of Kalydeco ® (ivacaftor) unmet medical need for PWCF was high and no alternative was available. The modulator showed significant lung improvement in gating mutations but was indicated for a small population. (Lopes-Pacheco, 2019; European Medicines Agency, 2021b). More recently, an observational study confirmed the ability of treatment with Kalydeco ® (ivacaftor) to be disease modifying (Bessonova et al., 2018). With the introduction of Orkambi ® (lumacaftor/ivacaftor), the most common mutation in PWCF was able to be treated and clinical studies showed moderate lung function amelioration, however the tolerability of this treatment in patients with low baseline lung function was poor and interactions with other medication had been reported. With Symkevi ® (tezacaftor/ivacaftor) a more extensive population is able to be treated with comparable but fewer side effects than Orkambi ® (lumacaftor/ivacaftor) (Lopes-Pacheco, 2019). Health authorities might have had greater negotiation power and might have been stricter on price depending on clinical added value and unmet medical need with the second and third generation of medicines, namely Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® (tezacaftor/ ivacaftor).
Furthermore, our results highlight apparent intra-variability when it comes to pricing of the same medicine in different European countries. As price-setting and HTA in Europe is determined nationally by the member states, price differences are inevitable (Young et al., 2017). It should also be noted that reported list prices may differ from the actual paid price subject to a discount determined in a confidential contract with the company. This discount differs among countries and is dependent on factors such as the country's negotiation power and use of external reference pricing (Rémuzat et al., 2015). Additionally, prices for individuals may vary from these averages, as dosage differs according to weight and age group. Underlying price differences may also be influenced by the included pharmacist fees, wholesale quotas and the national VAT on prescription-only medicines.

Economic Evaluations
Overall, Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) were considered not cost-effective in the studied countries. HTA bodies unanimously reported clinical uncertainties on long-term lung function and requested a price reduction of the modulators for the ICER to fall below the adopted threshold or comply with their cost-effectiveness requirements. Some countries (Netherlands, England, Sweden, France) questioned the accuracy of the ICER values determined by the company and requested additional data to support their outcome or delivered a recalculated ICER value showing the company's initial ICERs to be a considerable underestimation. Apparent discrepancies between ICER values internationally could be explained by differences in methodological guidelines for economic evaluations (Hay et al., 2010). The chosen simulation model, patient-level microsimulation or Markov, but also differences in perspective, payer or society, could affect the outcome (Schuller et al., 2015). Furthermore, differing ICERs could be influenced by the source for retrieval, from clinical trial or country-specific data, of input values such as QALYs or costs, particularities in healthcare system and the applied discount rate.
Cost-effectiveness might also be influenced by the approach adopted for the assessment of these CFTR modulators. In Poland and Ireland, Kalydeco ® (ivacaftor) and Symkevi ® (tezacaftor/ ivacaftor) were assessed in their general HTA process for medicines and under the same criteria and threshold as nonorphan medicines (Caban et al., 2016; National Centre for Pharmacoeconomics (NCPE), 2017b; Vaithyanathan et al., 2018;Malinowski et al., 2019). It was shown that with these conditions, orphan medicines are most likely not to be costeffective due to typical characteristics of a small population and limited clinical data availability. Some states, such as England, Scotland and Wales, established a HTA process specific to orphan medicines and others, like Sweden and the Netherlands, rely on a process dependent on disease severity, which allowed Kalydeco ® (ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) to be measured against a higher or more flexible ICER threshold (Denis et al., 2009;NHS England, 2015; National Institute for Health and Care Excellence (NICE), 2017; Kelly et al., 2018;Tandvårds-och läkemedelsförmånsverket TLV, 2019). Other countries like Belgium, France and Germany do not rely on ICER values to determine the value of (orphan) medicines (Denis et al., 2009). In Belgium, the company was exempt of delivering a costeffectiveness analysis and only a BIA for both orphan medicines was requested. In France, the CF modulators were evaluated according to their clinical added value or service medical rendu (SMR) and similarly in Germany, the assessment was based on additional medical benefit (Denis et al., 2009;IHS Global, 2013

Budget Impact Analyses
Budget impacts varied amongst countries and were dependent on the country's CF patient number, medication prices, included or excluded treatment-related costs and discounting. Comparison of budget impact between countries and interventions was complicated as results were reported over varying time horizons and numerical outcomes were not depicted in a consistent form. Some countries such as England and Germany, considered a budget impact threshold (Ollendorf et al., 2017; Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG), 2020; IQWIG, 2021). In England this meant that commercial discussions were mandatory for reimbursement of Kalydeco ® (ivacaftor) and Orkambi ® (lumacaftor/ivacaftor). Germany did not release information on their budget impact calculations, however benefit reassessment by their health authority, G-BA, meant that both orphan medicines Kalydeco ® (ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) breached their €50 million budget impact benchmark (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG), 2020; IQWIG, 2021). Overall, countries unanimously considered budget impact to be high. The accuracy of the budget estimates is not guaranteed as analyses did not always methodologically adhere to BIA guidelines, information was missing and some parameters were Frontiers in Pharmacology | www.frontiersin.org November 2021 | Volume 12 | Article 746710 unspecified (Sullivan et al., 2014). Lack of transparency due to confidentiality also prevents insight into the actual budget impact.
Assuring the methodological quality of future BIA could allow a more in-depth analysis and better informing of decision-makers on affordability (Abdallah et al., 2021).

Managed Entry Agreements
The reimbursement of the CF products was possible through MEAs between specific countries and the company. HTA reports emphasized not only the need to reduce prices substantially to increase affordability but also to address uncertainty around long-term clinical efficacy. To resolve uncertainties, some countries conditioned the reimbursement by requiring the company to monitor medicine administration and collect data on agreed efficacy measures in a register. Conventionally, these agreements are temporary, revised periodically and put in place for one product. In this case, the company pioneered with their portfolio-deal agreement for all their current and future CF products. The impact of this type of agreement on affordability and evidence collection is still uncertain, but arguably, agreeing to reimburse all future CF products without a rigorous HTA might have critical implications in the future.

Cross-Border Collaboration
Although the Netherlands and Belgium joined forces in price negotiations for reimbursement as a pioneer project under the Beneluxa initiative, an agreement could not be reached (Allen, 2017). To accommodate a seamless market access process for high cost and innovative medicines in the future, efforts towards information sharing and joint assessment such as done by Beneluxa and the International Horizon Scanning Initiative, should be maintained and further developed (Natsis, 2019; Beneluxa Initiative on Pharmaceutical Policy, 2021). Expansion in terms of number of countries participating in such initiatives should be further encouraged, as coalitions for negotiations with pharmaceutical companies have proven to be successful (Government of the Netherlands, 2018; Sheet, 2019). Moreover, to circumvent intricacies relating to various HTA processes amongst countries, performing assessments aggregately in an independent, joint network such as EUnetHTA could promote a more streamlined process. In turn, this could equip countries with more reliable, transparent and qualitative information to accurately perform their national HTA and increase their bargaining power with companies (O'Mahony, 2019; European Network For Health Technology Assessment, 2021). Our study shows that despite failed cost-effectiveness, high budget impact and negative recommendations, Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® (tezacaftor/ivacaftor) are reimbursed in the majority of analyzed countries. MEAs and portfolio deals allowed for the adoption of these CF medicines but also other decision criteria such as equity and equal access, disease severity, innovation, patients' and clinicians' views, patient advocacy, media attention but also prevalence seem to have played a role in final reimbursement decisions (Denis et al., 2009;Drakeford, 2013; National Institute for Health and Care Excellence (NICE), 2017; Ollendorf et al., 2017;Kelly et al., 2018;Tandvårds-och läkemedelsförmånsverket TLV, 2019;Andersson et al., 2020;Smith and Barry, 2020;Scottish Medicines Consortium, 2021b).

Strengths and Limitations
Our study sheds light on the market access of CFTR modulators in European countries based on a comprehensive analysis of pricing information, economic evaluations, BIAs, MEAs and reimbursement decisions. However, our findings were limited by public availability of data and confidentiality of reports. Depicted prices are facial prices and do not reflect the actual medicine price with discount. Critical information on costeffectiveness and budget impact was often blacked-out or assessment reports were incomplete. Thus, the selection of countries in this study was based on availability of HTA documents. Little insight of MEAs was possible, therefore, details on considered clinical uncertainties and their influence on the final agreed discount is unknown.

CONCLUSION
This study shows that the CFTR modulators Kalydeco ® (ivacaftor), Orkambi ® (lumacaftor/ivacaftor) and Symkevi ® (tezacaftor/ ivacaftor) are generally considered to be expensive, not costeffective and with a high budget impact in selected European countries. Reimbursement of these medicines was dependent on the ability of respective countries to form an agreement with the company. Even though most analyzed countries offered full reimbursement of treatments, some only selectively reimbursed certain treatments (Sweden) or none at all (Poland). Our findings point to unequal access, differential pricing and delayed availability of cystic fibrosis modulators in Europe.

AUTHOR CONTRIBUTIONS
KA and SS contributed to conception and design of the study. KA acquired the necessary data for the review that was analysed and interpreted by all authors. KA drafted the manuscript under supervision of KDB, MD and SS. All authors critically revised the manuscript, read and approved the submitted version. Funding was obtained by SS.

ACKNOWLEDGMENTS
With special consideration to Sevengul Car, Enid Froeyen, Jordi Gombert and Sofie Vannuffelen for initiating this study.