Background

The European Union (EU) regulation on orphan medicinal products (OMPs) (Regulation No. 141/2000) (1) granted a unified EU approach to orphan drug designation and marketing authorization; it ensured 10-year marketing exclusivity (with a possible 2-yr extension for pediatric indications) or fee waivers (Reference Gammie, Lu and Babar2). Even though the OMP registration process has been harmonized across all EU member states, the pricing and reimbursement (P&R) processes remain fragmented and unpredictable (Reference Czech, Baran-Kooiker and Atikeler3), impeding patient access to treatment (Reference Gammie, Lu and Babar2;Reference Annemans, Aymé and Le Cam4).

The assessment of OMP must reflect the characteristics of rare diseases. Typical difficulties stem from the limited experience with the disease and small population of affected individuals, which results in significant uncertainty regarding clinical outcomes (Reference Dupont and Van Wilder5). The limited number of patients eligible for treatment also severely limits the market potential and consequently raises the price of OMP to cover research costs. Thus, the cost-effectiveness willingness-to-pay (WTP) thresholds are seldom fulfilled to ensure adequate return on investment for pharmaceutical companies (Reference Czech, Baran-Kooiker and Atikeler3;Reference Drummond and Towse6).

In the past few years, considerable attention has been paid to designing general recommendations for value assessment and funding processes for rare diseases (ORPH-VAL) (Reference Annemans, Aymé and Le Cam4). In addition, an ISPOR Special Task Force recently redefined elements of value that should be incorporated in value assessments, in addition to those conventionally included and considered (Reference Lakdawalla, Doshi and Garrison7). Inspired by this recent scientific research, Czechia designed a unique and innovative P&R strategy to reflect current best practices. The resulting health policy approach is a real-world application of the proposed recommendations and can inspire other countries.

Several publications have described OMP access in specific countries in the Central–Eastern European (CEE) region (Reference Logviss, Krievins and Purvina8;Reference Iskrov, Miteva-Katrandzhieva and Stefanov9) or surveyed a larger number of countries in Europe (Reference Czech, Baran-Kooiker and Atikeler3). However, Czechia has scarcely been investigated, and due to the adoption of new orphan legislation in 2022, the prior information is no longer valid.

This paper presents a unique and innovative P&R process for OMP, as stated in Act No. 48/1997 Coll. (10). The description is preceded by a thorough analysis of OMP availability and an explanation of the rationale behind the policy design. The novel approach takes into account specific aspects of rare diseases, assesses OMP value from the societal perspective, and includes patient representatives in the assessment and appraisal process.

Previous OMP reimbursement process and unmet need

Many countries still do not have any specific P&R process for OMP (Reference Czech, Baran-Kooiker and Atikeler3). Until recently, this was also the case of Czechia, where patient access was usually granted by non-orphan-specific drug programs, that is, temporary or exceptional reimbursement (Figure 1). The situation was too complex, time-consuming, and uncertain for drug suppliers (Reference Skoupá11;Reference Vostalová, Mazelová, Samek and Vocelka12). Since the external price referencing system pushes prices to the lowest acceptable level, pharmaceutical companies often completely avoid or at least postpone entering the Czech market due to the consecutive price-drop effect in other countries.

Figure 1. Reimbursement in Czechia.

Therefore, out of 185 OMPs registered by European Medicines Agency (EMA) from 2015 to 2021, a mere 110 (59 percent) were available to Czech patients, and only 54 (29 percent) were officially reimbursed (Figure 2) (13–15). Moreover, the proportion of officially reimbursed OMP has steadily decreased over time (Reference Ornstová, Sebestianova and Paris16).

Figure 2. Availability of OMP (2015–2021).

The situation is even worse in other countries in the CEE region, with the proportion of reimbursed OMP varying from 6.3 percent in Latvia to 27.4 percent in Poland, as shown in the analysis by Malinowski et al. (Reference Malinowski, Kawalec and Trąbka17). On the other hand, the proportion of OMP reimbursed in Western-European countries varies from 33 to 93 percent (Reference Garau and Mestre-Ferrandiz18;Reference Zamora, Maignen, O’Neill, Mestre-Ferrandiz and Garau19). Orphan drug availability is thus more restricted in lower-income European countries with budget limitations (Reference Szegedi, Zelei and Arickx20).

It is clear that even though therapies are available for many rare conditions, access to care is often heavily restricted. Thus, Czechia had to respond to this urgent public health issue by updating the decision-making process and the whole legal framework to provide safe and effective therapies for patients suffering from rare diseases.

The new national pricing and reimbursement strategy

After years of debate induced by unsatisfactory OMP access, the national viewpoint shifted toward creating a special status for the reimbursement of OMP. The updated legislation followed the ORPH-VAL recommendations (Reference Annemans, Aymé and Le Cam4), for example, assessing the OMP value on patient/healthcare system/societal level, including its uncertainty. The methodology of including these principles in the P&R procedure is described in detail.

The initial appraisal/assessment of OMP is performed by the governmental health technology assessment (HTA) agency, that is, the State Institute for Drug Control (“the Institute”). It critically reviews and assesses the clinical and economic evidence, then formulates its opinion in the form of an assessment report. The complete process is depicted in Figure 3.

Figure 3. Schematic of the administrative procedure.

[1] The application with clinical and cost-effectiveness evidence and budget impact analyses is submitted to the Institute by the Marketing Authorization Holder (MAH) or by one of the health insurance funds; thus, initiating the proceeding.

[2] In addition to the MAH and insurance funds, the relevant professional associations and relevant patients’ organizations also participate in the administrative proceeding. Therefore, they are entitled to present evidence and make comments during the 30 days after the initiation of administrative proceedings. This ensures the essential involvement of healthcare professionals and affected patients in the P&R process.

[3] Within 110 days from the initiation of the proceedings, the Institute shall issue an assessment report summarizing available information on the efficacy and safety of the OMP, the disease for which it is indicated, the current treatment of the disease, and the effects of treatment on the patient’s quality of life (QoL), the impact on health insurance and social security systems, and/or the overall impact from a societal perspective.

For this purpose, the Institute is entitled to request any necessary information from the Institute of Health Information and Statistics, the Czech Statistical Office, public health insurance funds, relevant social security bodies, relevant medical professional societies, and patient organizations.

[4] All the participants have the right to comment on the assessment report within 15 days from its publication.

[5] The Institute then publishes the final assessment report and forwards it together with a summary of the participants’ statements and possible managed entry agreements (MEAs) to the Ministry of Health and its advisory body (described further in the article).

[6] Based on these documents, the ministry should issue a binding opinion within 30 days. The binding opinion results from discussions within the advisory body established beforehand by the Minister of Health.

The advisory body consists of four stakeholders: (i) patients (not with the given disease, i.e., from a different patient organization), (Reference Gammie, Lu and Babarii) clinical experts (not from the given disease area), (Reference Czech, Baran-Kooiker and Atikeleriii) public health insurance funds, and (Reference Annemans, Aymé and Le Camiv) the State. Each stakeholder has two representatives, and the binding opinion has to be agreed to by the majority of voters (five out of eight votes). The advisory body members are appointed and dismissed by the Minister of Health with the term of office set to 3 years. A member of the advisory body can be reappointed repeatedly. Proposals for the appointment and dismissal of members of the advisory body are submitted to the Minister of Health by (i) the Patient Council of the Minister of Health after consultation with the Czech Association for Rare Diseases, (Reference Gammie, Lu and Babarii) the Czech Medical Society of Jan Evangelista Purkyně, (Reference Czech, Baran-Kooiker and Atikeleriii) public health insurance funds, and (Reference Annemans, Aymé and Le Camiv) the Deputy Minister for Economics and Health Insurance, respectively. At least four representatives are nominated for each sector. The nomination shall be accompanied by a written declaration of the nominee’s conflict of interest. In the case of medical society or patients, the nominees should be members of a different medical society or patient organization (i.e., not related to the assessed condition due to conflict of interest). From these nominees, the Minister of Health chooses two representatives for each stakeholder, that is, eight in total. The members shall have no conflict of personal or professional interests, and they shall not misuse any information obtained through their service on the advisory body.

Evaluation criteria specified by law and assessed by the advisory body are summarized in Table 1. These criteria are in line with other multicriteria decision analyses (MCDA) criteria used to evaluate orphan drugs (Reference Lasalvia, Prieto-Pinto and Moreno21) and with the ORPH-VAL framework (Reference Annemans, Aymé and Le Cam4). There are no specific value thresholds or weights for individual criteria, but a summary of each criterion’s justification and anonymous voting results shall be publicly available. This ensures the transparency and legitimacy of the decision and the whole process.

Table 1. Criteria and parameters for OMP assessment (according to Order n. 53/2021 from the Minister of Health)

Abbreviations: MEAs, managed entry agreements; OMP, orphan medicinal products; QALYs, quality-adjusted life-years; QoL, quality of life; RWE, real-world evidence.

[7] The binding opinion is then forwarded back to the Institute, which then issues a final decision on the P&R in line with the opinion. If the applicant disagrees with the conditions proposed by the binding opinion, the Institute will not grant reimbursement from health insurance funds. In case of a negative binding opinion, the applicant may submit a new application no earlier than 6 months after the administrative proceeding.

After 3 years, the Institute shall re-examine the maximum price according to the current external reference prices. Moreover, after at least 1 year, a health insurance company or the Institute can apply for a reassessment of the reimbursement price for the OMP in case it exceeds the estimated budget impact, there is a change in effectiveness, safety in clinical practice did not meet the preconditions set for reimbursement, or the relevant guidelines have changed. If the Institute cancels the reimbursement, the health insurance company is obliged to reimburse additional treatment costs for up to 12 months. The option of future reassessment decreases the uncertainty and offers the possibility of changing the decision in light of new evidence.

Other P&R strategies

Figure 1 presents four types of reimbursement in Czechia, formulated in Act No. 48/1997 Coll. and related decrees (10).

[1] For permanent reimbursement, the use of medicinal products needs to be cost-effective with a WTP threshold of 1.2 million CZK per QALY (approx. €49,000). The threshold was defined in relation to the incremental cost-effectiveness ratios for already reimbursed technologies and corresponded to approximately three times the gross domestic product per capita (Reference Robinson, Hammitt, Chang and Resch22). This particular WTP threshold is relatively generous compared to other CEE as well as several western countries (e.g., UK) but is still generally too high for OMP. Moreover, OMP are generally unable to prevail in the rigorous evaluation process (23) due to the inherent clinical/economic uncertainty.

[2] The temporary reimbursement for highly innovative drugs (HIDs) was previously described by Ornstova et al. (Reference Ornstova, Sebestianova, Mlcoch, Lamblova and Dolezal24) and Vostalova et al. (Reference Vostalová, Mazelová, Samek and Vocelka12). However, the HID program has changed slightly, together with the new OMP legislation. This type of reimbursement is now granted for a minimum of 3 years and can be prolonged for another 2 years without the need of being cost-effective below a fixed WTP threshold. Then, the product must transition to permanent reimbursement with the fulfillment of its rigorous cost-effectiveness criteria. Nevertheless, in the case of OMPs, the uncertainty and high costs usually last for the whole 5-year period, and the strict cost-effectiveness criteria still cannot be met. This scheme is therefore not attractive or widely acceptable for OMP.

Furthermore, the innovative product has to fulfill at least one of the HID criteria, that is, (a) the primary endpoint in the clinical study demonstrated at least a 30 percent improvement compared to SoC and the endpoint must affect QoL, or (b) the innovative product increases the median overall survival by at least 30percent and by a minimum of 3 months compared to standard of care. For OMP, the evidence is usually not strong enough to meet these criteria since there is often limited comparative data and overall uncertainty.

Another drawback compared to permanent reimbursement [1] is the enforced budget cap for the entire temporary reimbursement period and the mandatory risk-sharing agreement. Nevertheless, the orphan pathway also strongly favorites applications with a MEA proposal. The applicable MEAs are simple discount, budget cap, pay-back, price–volume, or outcomes-based agreement (Table 1).

Another disadvantage of temporary reimbursement is the risk linked to re-evaluating the “highly innovative status” if another drug enters permanent reimbursement with the same indication. However, this usually is not the case with OMP since multiple products are generally not in development at the same time.

[3] If the medicinal product is not permanently reimbursed, in cases where it is the only treatment available, the product can still be covered based on an individual patient request (Section 16 of the Act No. 48/1997 Coll., on Public Health Insurance (10)). This exceptional reimbursement is assessed individually on a case-by-case basis, and it is only valid for 3 months, after which the application has to be resubmitted. This puts a substantial bureaucratic burden both on patients and healthcare professionals as well those assessing the application. Generally, continuous patient access to the product cannot be granted through this application process since it is unpredictable, burdensome, and generally obscure.

It is necessary to stress that the HTA process in Czechia is currently implemented only for pharmaceuticals used in outpatient (ambulatory) care. The reimbursement of inpatient drugs used in hospital care lacks full transparency. Hospital budgets cover these drugs without a transparent decision-making process and public oversight. Only two stakeholders are involved in the process, that is, hospitals and health insurance funds, with no representation from other healthcare professionals, professional associations, or patients; additionally, it lacks a thorough and transparent HTA process.