Abstract:

BACKGROUND: According to European Commission guidelines, any condition affecting fewer than 5 in 10,000 people in the European Union (EU) is considered a rare disease. Orphan drugs (ODs) are medicines specifically developed to treat rare diseases. According to Article 3 of Regulation 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, orphan drug designation in Europe is granted by the European Medicines Agency (EMA), more specifically by its Committee for Orphan Medicinal Products (COMP), and then approved by the European Commission before marketing authorization is granted. Medicine with orphan designation can be granted by EMA four special statuses – two types of authorization statuses (conditional approval and approval under exceptional circumstances) and two registration requirements (additional monitoring and accelerated assessment). Equitable and universal access to treatment for patients with rare diseases is an important objective of EU drug policy. An influential aspect of pharmacovigilance, both in the pharmaceutical authorization decision and in reimbursement decisions, is the clinical effects (safety and efficacy) assessed by clinical trials. Conducting clinical trials for ODs can be challenging due to the small patient population, high patient burden due to symptoms, difficulty in collecting complete clinical da ; ta, limited scientific evidence, ethical issues (especially in pediatric trials), or limited knowledge of the condition. Due to concerns about allowing ineffective or potentially dangerous pharmacotherapies to enter the market, the clinical potential of the trial (availability and reliability of methodological data and clinical evidence) for individual ODs has a very significant impact on EMA registration decisions. Drug policy regarding the registration (authorization, market access) of ODs across the EU is joint. However, each country has a wide autonomy in developing its own reimbursement policies and studies conducted so far indicate that there is a significant difference between Central and Eastern European (CEE) and Western European countries. Health technology assessment (HTA) carried out by public advisory bodies in individual countries is an important tool to support drug policy, allowing reimbursement decisions to be rationalized. Often, HTA analyses provide a foundation for evidence-based reimbursement decisions, including those regarding ODs. However, positive recommendations from advisory agencies do not always guarantee that a medicine will be reimbursed. An assessment of the impact of different aspects, including clinical aspects, on reimbursement decisions is unknown, as no up-to-date studies are available on this topic. The results of such studies would be valu ; able given the complexity of the reimbursement decision-making process and the need to develop the most effective tools in this area applied to countries interested in optimizing their reimbursement policies. AIM: The main aim of the study was to assess drug policies for orphan drugs in selected European countries. The first specific objective was to assess the clinical potential of trials for orphan drugs in relation to the special statuses (type of authorization and registration requirements) granted by EMA. The second specific objective was to assess aspects influencing reimbursement decisions for orphan drugs in selected European countries. MATERIAL AND METHODS: The first stage of the study was to analyze clinical trial data for orphan drugs using detailed information obtained from the EMA database, collected between August 2019 and June 2020. At the same time, information on special statuses for ODs granted by the EMA was also collected. The methodological features of clinical trials for orphan drugs conducted prior to market authorization were then analyzed (e.g. number of patients included in the clinical trials, clinical phases of the trials conducted, use of randomization, type of clinical control [placebo or active comparator], duration of treatment, etc.) and the correlation between these characteristics and the special status obtained from the registration decisions ; of the EMA was assessed. In addition, a univariate analysis of the relationship between these methodological features and the status of individual drugs was conducted. The extent to which the selected methodological features of clinical trials for individual drugs affect the attainment of individual special statuses granted by the EMA was assessed. The second step was to collect and analyses information on reimbursement policies for orphan drugs in selected European countries (in the CEE and Western European country groups) using data obtained through a survey of experts from these countries; in addition, data on macroeconomic indicators for the selected countries were also obtained for analysis. The survey in the Central and Eastern European countries group was conducted from September 2021 to January 2022 (the period under review is 2021) and information was obtained for 9 countries: Bulgaria (number of experts included; n=2), Croatia (n=1), Czech Republic (n=1), Estonia (n=1), Lithuania (n=1), Poland (n=1), Romania (n=2), Slovakia (n=1) and Hungary (n=1). The survey in the Western European countries group (and again in Poland) was conducted from September 2022 to September 2023 (the review period is 2022). Responses were obtained from experts from 12 countries: Austria (n=1); Belgium (n=1); Finland (n=1); France (n=1); Greece (n=1); Spain (n=1); Netherlands (n=1); Iceland ( ; n=1); Germany (n=1); Poland (n=1); Scotland (n=2) and Italy (n=1). After data collection, descriptive and statistical analysis was carried out. The analysis of the collected data from experts enabled a comparison of reimbursement policies and procedures using health technology assessment for orphan drugs. Data on the number of medicines with positive recommendations and reimbursed in each country were subjected to descriptive analysis, and correlations were then assessed with selected aspects of: safety and clinical efficacy; other clinical aspects; dedicated legislation and reimbursement policy strategies; EMA’s authorization status and orphan designation; health technology assessment; incremental cost-effectiveness ratio (ICER) / incremental cost-utility ratio (ICUR), macroeconomic indicators and types of ODs. The types of ODs are distinguished according to the Anatomical Therapeutic Chemical (ATC) classification. RESULTS: A total of 968 clinical trials for ODs were identified. The odds of ODs receiving conditional approval were lower for studies with randomization (p=0.002) and active-controlled trials (p=0.010), but they increased with a treatment duration of 3 to 12 months (p=0.002) and a safety and efficacy follow-up of 2 to 6 months (p=0.008 and p=0.035, respectively). Approval under exceptional circumstances was less likely for each additional 1000 patients (p=0.002), r ; andomization (p=0.024), double blinding (p=0.033), and active-controlled trials (p=0.006). However, it was more likely for phase II/III trials (p=0.039), a treatment duration of 3 to 12 months (p=0.03), and safety and efficacy follow-up longer than 6 months (p=0.022 and p=0.047, respectively). In the second stage of the study, results were obtained for selected European countries on reimbursement aspects for ODs. Within the group of CEE countries, the percentage of reimbursed ODs varied and ranged from 17.7% in Estonia to 49.6% in Hungary (p<0.001). ODs with ATC classification L (antineoplastic and immunomodulating agents) received the highest number of positive recommendations in the CEE countries (35.2%; p<0.001) and reimbursement decisions (42.3%; p=0.011) compared to all ATC categories. The odds of ODs receiving a positive recommendation were lower in CEE countries where the impact of the safety and clinical efficacy assessment on reimbursement decisions was assessed as ‘high’ (p<0.001); where other (besides efficacy and safety profile) clinical aspects influencing reimbursement decisions were considered (p<0.001) and in countries with a higher gross domestic product (GDP) (p=0.048). It was also shown that the probability of a positive recommendation was higher in CEE countries with dedicated ODs legislation and reimbursement policy strategy (p=0.036); when reimbursement de ; cisions depended on the authorization status and orphan designation granted by the EMA (p<0.001); when a positive recommendation (from HTA agency or advisory body) guaranteed reimbursement (p<0.001) and for oncology drugs (ATC class L) (p=0.034). ODs were less likely to be reimbursed in CEE countries, where the impact of clinical safety and efficacy on reimbursement decisions was rated as ‘high’ (p=0.018); other (besides efficacy and safety profile) clinical aspects influencing reimbursement decisions were present (p<0.001); and clinical safety assessment was mandatory (p=0.004). The likelihood of ODs reimbursement increased in countries with a ‘moderate’ influence of drug safety and efficacy on reimbursement decisions (p=0.018); when reimbursement decisions depended on EMA’s authorization status and orphan designation (p<0.001); when a positive recommendation (from HTA agency or advisory body) guaranteed reimbursement (p<0.001); and in countries with higher GDP (p=0.003) and higher levels of healthcare expenditure (p<0.001). Within the group of Western European countries, the proportion of reimbursed ODs varied from 23.5 % in Iceland to 86.03 % in Germany (p<0.001). The most numerous groups of drugs by ATC classification were ATC group L (n=49) (p<0.001). Additionally, ODs from specific ATC classifications (C, L, M, N and R) were statistically significantly more likely to be p ; ositively recommended and reimbursed in the selected group of studied countries. Statistical analysis did not show that. selected aspects (safety and clinical efficacy; other clinical aspects; dedicated legislation and reimbursement policy strategies; impact of EMA authorization status and orphan designation; HTA and ICER/ICUR;) were significantly correlated with ODs’ reimbursement policy. Despite the lack of correlation, differences in reimbursement policy between Western European countries were described; clinical safety assessment of ODs was mandatory in 10 countries, optional in one (Italy) and not required in one (Iceland). In contrast, the assessment of clinical efficacy was mandatory in 10 countries; optional/informative in one country (Germany) and not required in one country (Iceland). The impact of safety and efficacy on reimbursement decisions was assessed as ‘high’ in 10 countries; ‘low’ in one (Germany) - and in one (Iceland) no assessment was performed. CONCLUSIONS: The study provided the missing scientific evidence on the impact of different aspects (clinical and non-clinical) on reimbursement policy in selected European countries and the impact of the clinical potential of trials for ODs in the decision-making process of the EMA. The results allow us to conclude that, in some cases, randomized, double-blinded and active comparator studies reduce the likelihood o ; f ODs obtaining EMA special status. In contrast, clinical phase II/III studies, treatment lasting no longer than one year, and longer follow-up time for safety and efficacy increased this probability. After interpreting some of the results, it seems reasonable to conclude that clinical trials with low clinical validity (e.g. without randomization) were positively correlated with the probability of receiving EMA’s special status. The assessment of clinical safety and efficacy with a high impact on reimbursement decisions; the mandatory assessment of clinical safety in the reimbursement process and the presence of other clinical aspects reduced the likelihood of ODs reimbursement. In contrast, the moderate level of influence of the assessment of safety and clinical efficacy on reimbursement decisions; the authorization status and orphan designation granted by EMA; and the principle that ‘a positive recommendation of the assessment (from HTA or an advisory body) guarantees the reimbursement of the drug’ increased the probability of ODs reimbursement. It was shown that in most countries included, health technology assessment was mandatory, (exceptionally it could be only informative), but often ODs were reimbursed regardless of its recommendation. The most common HTA analyses for ODs in the CEE group were budget impact analysis and cost-effectiveness analysis, while in the Western ; European group only cost-effectiveness analysis. A higher GDP per capita and higher healthcare expenditure per capita increased the likelihood of reimbursement for ODs. Drug groups by ATC classification (e.g. ATC L, antineoplastic and immunomodulating agents) were significantly positively correlated with the chance of a positive recommendation and reimbursement decision.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

system ochrony zdrowia ; farmacja

Degree grantor:

Rada Dyscypliny Nauki o zdrowiu

Promoter:

Kawalec, Paweł

Date issued:

2024

Identifier:

oai:dl.cm-uj.krakow.pl:5248

Call number:

ZB-141628

Language:

pol

Access rights:

tylko w bibliotece