Healthcare | Free Full-Text | Navigating Gene Therapy Access: The Case of Bulgaria in the Context of the EU Regulatory Landscape

Healthcare | Free Full-Text | Navigating Gene Therapy Access: The Case of Bulgaria in the Context of the EU Regulatory Landscape

1. Introduction

1.1. Aim of the Study

This study aimed to assess the current level of accessibility of gene therapy medicinal products (GTs) in Bulgaria, with a specific emphasis on the different legal tools to access GTs and their budgetary impact, respectively. Access to GTs in Bulgaria is further compared to those in neighboring European Union (EU) member states—Greece and Romania. Finally, key factors influencing access to GTs and the main challenges for this process in Southeastern Europe are outlined and explored.

1.2. Background of the Problem

Over the past decade, GTs have become a groundbreaking approach, marking a paradigm shift in the pursuit of personalized healthcare solutions [1,2,3]. According to the official definition in the EU, a GT involves the introduction of recombinant nucleic acids into the human body with the specific aim of regulating, repairing, replacing, adding, or deleting specific genetic sequences [4]. GTs are categorized under the group of advanced therapy medicinal products (ATMPs) [5]. Most of the ATMPs are currently in the experimental stage, undergoing clinical trials to assess their safety and effectiveness. Nevertheless, the positive clinical results achieved with already-approved ATMPs drive further research developments and attract substantial investments [6]. Despite these achievements, clinical uncertainty regarding long-term benefits and potential adverse effects, combined with an extreme price tag, presents unique challenges to patient access [7,8,9].

1.3. EU Regulatory Framework

The EU’s ATMP legislation is centralized, signifying collaborative efforts among various stakeholders. The Committee for Advanced Therapies (CAT) within the European Medicines Agency (EMA) plays a crucial role in the market authorization process, evaluating safety and efficacy. The CAT’s evaluations impact the Committee for Medicinal Products for Human Use (CHMP) recommendations and, thereby, influence decisions made by the EMA. In addition, the CAT offers guidance on ATMP classification, provides scientific advice covering clinical trial designs and endpoint assessments, and contributes to efficacy follow-up and risk management procedures [10].
Regulatory mechanisms like accelerated assessment and conditional marketing authorization are often applied to ATMPs. Over half of authorized GTs underwent evaluation under the PRIME (PRIority Medicines) scheme, intensifying support for medicines targeting unmet health needs. PRIME facilitates support from the EMA and encourages early engagement with stakeholders in a submission-readiness meeting a year before the market authorization submission. As part of the PRIME benefits, a scientific coordinator is appointed, and a fee exemption for scientific advice is provided to applicants from the European Economic Area [11]. Notably, early access tools are not mutually exclusive. PRIME-designated medicines often combine accelerated assessment, compassionate use, or orphan designation [12]. Additionally, the EMA provides various financial and regulatory incentives, such as fee reductions and waivers tailored specifically for small and medium enterprises and academic institutions [13].
Despite their central role in regulating and approving GT products, the EU bodies do not influence post-authorization pricing or reimbursement decisions at the national level. These decisions are decentralized, considering the healthcare system characteristics and patient needs of each member state. Regional or national regulators and payers typically oversee access negotiations and make decisions about potential reimbursement strategies and distribution plans [14]. Health technology assessment (HTA), which takes into account factors like cost-effectiveness and budgetary impact, is frequently used to guide this process [15].

1.4. Bulgarian Pricing and Reimbursement Process

Patient access to GTs within the general reimbursement scheme in Bulgaria entails a complex procedure based on several components (Table 1). The Medicinal Products in Human Medicine Act (MPHMA) [16] sets the overall regulatory framework in the country. Key stakeholders in the general reimbursement process are the Ministry of Health (MoH), the National Council on Prices and Reimbursement of Medicinal Products (NCPRMP), and the National Health Insurance Fund (NHIF).
At the beginning, market authorization holders apply to the NCPRMP for pricing, HTA, and inclusion in the Positive Drug List (PDL). These three procedures are usually initiated at the same time. To be included in the PDL (and thus be eligible for reimbursement), an innovative therapy must already be covered by public funds in at least 5 out of 17 reference EU countries. For orphan-designated products, this list extends to all EU member states [17].
Pricing and HTA procedures are mandatory for all original medicinal products. NCPRMP applies external reference pricing based on the lowest product price from a legally defined list of ten EU countries. The final maximum price is computed by incorporating fixed margins for wholesalers and retailers, along with a 20% value-added tax. The official list price is subject to monthly updates based on the corresponding changes in the lowest price from the reference countries [17].
The NCPRMP also acts as a national HTA body in Bulgaria. Legally, the HTA stage requires additional evidence from HTA reports from the UK, France, Gerseveral, and Sweden. The incremental cost-effectiveness ratio threshold for value efficiency is set at three times GDP per capita [17].
The NHIF, being the single public healthcare payer, is responsible for the final stage of the reimbursement decision-making process. This step involves yearly reimbursement negotiations and agreements, which require a minimum 10% discount on the official list price. However, these agreements are confidential, and the exact discount rates are not publicly available. The NHIF also determines a percentage of coverage, along with additional patient eligibility criteria and outcome effectiveness monitoring if needed. Once a therapy is included in PDL, the NCPRMP conducts mandatory reviews of its reimbursement status every three years. Additionally, the NCPRMP has the authority to initiate a HTA reassessment procedure. This regulatory approach aims to ensure ongoing evaluation and alignment with evolving healthcare considerations [18].

1.5. Bulgarian Induvial Access Schemes

Besides the general reimbursement scheme, patient access to GTs can also be obtained through two options, via individual schemes. Both are used in severe cases where no other therapeutic alternatives are available, and the currently applied standards of care do not result in clinical improvement (Table 1).
The first strategy, which is subject to MoH Ordinance 10 of 2011, operates on a case-by-case basis. The administrative process involves a comprehensive review by an ad hoc commission consisting of three doctors, a pharmacist, and a lawyer. This scheme enables the administration of medicinal products not listed in the PDL, non-authorized treatments, or those included in the PDL but applied in indications not included in the product characteristics (off-label use). Off-label approval is granted when available data support potential clinical benefits or when the proposed innovative treatment has been applied in similar cases in other countries. Typically, the funding for off-label treatments comes from the state budget. However, this regulation also allows pharmaceutical companies to finance products not listed in the PDL through specially designed compassionate use programs [19].
MoH Ordinance 2 of 2019 constitutes the second individual scheme in Bulgaria. This scheme enables patients under 18 years of age to access specialized medical care beyond the coverage of mandatory health insurance. The scope of this procedure includes rare diseases, cancer, and congenital hematological diseases. When that strategy is used, the case applications are assessed by an ad hoc commission, comprising a representative of the executive body of NHIF and medical experts in the relevant field. Upon approval, the price of the innovative product is negotiated directly between NHIF and the manufacturer. The NHIF covers the full payment, which is subsequently compensated by a direct transfer from the state budget [20].

2. Materials and Methods

The study applied a mixed-methods approach, combining the following steps: desk research, public data requests, and cost comparison. Data collection took place between 27 March 2023 and 10 April 2023.

2.1. Desk Research

In the initial phase of the analysis, a comprehensive list of all the EMA GTs with a valid market authorization as of 26 March 2023 was compiled. The search strategy incorporated key terms, including “gene therapy(ies)”, “gene product(s)”, “gene medicinal product(s)”, “advanced therapy medicinal product(s)”, and “ATMP(s).” Relevant information was systematically retrieved through searches on the EMA’s website, the European Public Assessment Reports (EPARs) database, and the EU’s Register of Medicinal Products for Human Use.

Subsequently, each individual medicinal product underwent scrutiny in the electronic database of the Bulgarian PDL to determine its official list price and reimbursement status. Unlike traditional static lists, the Bulgarian PDL operates in an electronic open data format (, accessed on 1 April 2023), providing a dynamic and accessible platform for stakeholders in the healthcare system. The PDL database is updated monthly. Our search utilized both the market name of the medicinal product and the international nonproprietary name (INN).

Additionally, a search of databases containing HTA reports, prepared by the NCPRMP, was conducted on 1 April 2023, to ascertain if any assessments had been conducted for the identified GTs.

2.2. Data Requests

On 27 March 2023, formal public data requests were dispatched to both the NHIF and the NCPRMP. The NHIF request sought information on payments from public funds for GT treatments under the national framework contract (a general reimbursement scheme) or the mechanisms framed under Ordinances 2 and 10 (an individual access scheme), providing real-time insights into the budgetary landscape for GTs within the national healthcare system. Simultaneously, the NCPRMP request was made to gain a thorough understanding of the regulatory aspects related to GTs, specifically accessing public information regarding the initiated procedures of HTAs and/or the registration of an official price of GT medicinal products in Bulgaria.

2.3. Comparison of Official List Prices

For the identified GTs that are currently accessible in Bulgaria (either by a general reimbursement scheme or an individual access scheme), we compared the official list prices to those in neighboring EU countries—Greece and Romania. This selection was deliberate, considering geographical proximity, epidemiological, economic, and sociocultural similarities, and comparable healthcare systems [21]. The official PDL databases [22,23,24] were screened to acquire up-to-date pricing information. The official prices in Bulgaria were converted in EUR using the fixed rate of the current currency board. The official prices in Romania were converted in EUR using the exchange rate, as set by the Romanian National Bank on 1 April 2023 [25]. The analysis did not consider the not-publicly available discount agreements between the manufacturers and the payer, which are similarly required by the corresponding Greek and Romanian legislation [26,27,28].

2.4. Analysis

The data analysis was conducted utilizing R version 4.3.2. Data visualization was performed using the ggplot2 package. The results were summarized using descriptive statistics. Categorical variables were summarized with counts and percentages. Differences in proportions were assessed using the chi-squared test. The significance level was set at 0.05. Mean cost per treatment was calculated following the EMA-approved summary of product characteristics, using identical dosage assumptions to ensure cost comparability. Only the direct GTs costs were considered. Other remaining expenditures, such as costs for diagnostics, consultations, and hospitalizations were not included. The budgetary impact for Bulgaria was estimated as a proportion of the National Health Insurance Fund Medicines Expenditure (NHIF ME) according to the NHIF’s budgets for 2021 and 2022.

3. Results

3.1. Market Authorization of Gene Therapies in the EU

A total of 25 ATMPs that have received positive market authorization via a centralized EU procedure were identified. A significant difference among the types of ATMP was observed (χ2 = 13.52, df = 2, p Figure 1).

Orphan designation varied significantly among the types of ATMPs (χ2 = 7.1014, p = 0.0287). The highest rate was found for GTs (n = 15/17, 88.2%), followed by CTs (n = 3/4, 75%), and TEPs (n = 1/4, 25%). The PRIME designation was also more commonly applied to GTs (n = 10/17, 58.8%) compared to CTs (n = 1/4, 25%), while none of the TEPs were approved under the PRIME scheme. Only one GT product (Breyanzi®) received marketing authorization exclusively under PRIME. Additionally, seven GT products benefited from both PRIME and orphan designation. Imlygic® was the only authorized GT that did not use any of the available incentives.

Withdrawals were observed for two GTs (Skysona® and Zynteglo®), one CT (Zalmoxis®), and one TEP (MACI®). In addition, the first approved GT product in the EU, Glybera®, authorized in 2012, was withdrawn in 2018 following the marketing-authorization holder’s decision not to apply for a renewal.

Excluding withdrawn products, the final list consisted of 14 GT products with a valid market authorization by the time of the study, with 12 (84%) tailored specifically for rare diseases (Table 2).

3.2. Gene Therapies in the Bulgarian Positive Drug List

Only one GT (Kymriah®) underwent a pricing procedure with a NCPRMP decision on 2 July 2020. The official list price for the product was not changed from the pricing procedure to the research date and was EUR 335,636.94 per package (and subsequently, this was also the cost per patient since one package covers the whole treatment course). However, Kymriah® is currently not included on the PDL and therefore is not eligible for reimbursement by the NHIF. For all the remaining 13 GTs, we can not find any evidence of pricing or inclusion in the PDL, leading us to the conclusion that the market authorization holder did not start any such procedures in Bulgaria.

3.3. HTA Reports for Gene Therapies

The Bulgarian HTA agency’s databases (NCPRMP) include publicly available information on positive and negative HTA reports dating back to 2019. However, a comprehensive search revealed that none of the 14 GTs have completed this process. In response to a public data request, the official answer from NCPRMP stated that the agency initiated both HTA assessment and pricing for Zolgensma® on 28 September 2021. However, no final decisions are publicly available yet.

3.4. Alternative Funding Strategies and Budjetary Impact

The NHIF data obtained through a public request revealed that four patients were treated with Zolgensma® under the framework of the MoH Ordinance 2 of 2019, with a total cost of EUR 11,402,550.16, or EUR 2,850,637.54 per patient. The direct medicinal expenditures were EUR 5,601,942.61 for two patients treated in 2021 and EUR 5,800,607.55 for two patients treated in 2022. These four payments accounted for 0.8% and 0.7% of all NHIF budgets allocated for medicinal treatment in the respective years. There was no available data for the remaining 13 GTs, implying that they have not been funded through the NHIF or the state budget (under either the MoH Ordinance 2 or MoH Ordinance 10).

3.5. Official List Prices

The pricing and reimbursement status of the identified 14 GTs with a valid market authorization were searched and checked in the PDL databases of Greece and Romania. Five out of the fourteen GTs (Luxturna®, Zolgensma®, Yescarta®, Tecartus®, and Kymriah®) were included in Greece’s PDL, resulting in a 36% inclusion rate, while only one (Kymriah®) was found in Romania’s PDL (7%) (Table 1). Comparison was made between the list price for Zolgensma® in Greece and the negotiated price disclosed by the NHIF as well as the list price for Kymriah® in both Greece and Romania.

Up to 1 April 2023, Zolgensma’s list price in Greece was EUR 2,134,478 per dose. A direct comparison resulted in an absolute difference of EUR 716,159, with the product’s price being higher in Bulgaria. This difference is remarkable due to the fact that the treatment costs in Greece can be expected to be even lower considering the applicable discount agreements. Moreover, Bulgarian expenditures might be inflated due to direct market negotiations under the MoH Ordinance 2 of 2019 and the lack of formal pricing procedure. For Kymriah®, a direct comparison indicated a Bulgarian list price 1.05 times higher than Greece, with an absolute difference of EUR 16,270.17. Compared to Romania, the estimated absolute difference was EUR 3029.37.

4. Discussion

Our study identified a smaller number of accessible GTs in Bulgaria in comparison to Greece and Romania. Furthermore, the implementation of tools for individual patient access to GTs in Bulgaria seemed to result in elevated purchase expenses. Nevertheless, our research is limited, and no overall conclusions about the uptake of GTs and ATMPs should be drawn.

On the other hand, the main health policy question here should not be about the uptake of these innovative therapies but rather the availability of legal mechanisms for patients to access this kind of treatment [28]. Patients, regardless of their diagnosis, should be able to obtain timely, adequate, and effective therapy. The lack of therapies or implementation of access schemes that are not optimal exacerbates health inequalities and leads to excess costs.

4.1. Balancing Cost, Access, and Ethical Responsibilities

GTs deviate significantly from traditional medicinal products, exhibiting unique characteristics in development, production, therapeutic mechanism, and clinical benefits [1,29]. As a form of personalized medicine, large-scale production is often impractical, justifying their elevated costs [2]. This uniqueness not only adds complexity but, when combined with inherent long-term clinical uncertainties, makes patient access to GTs highly problematic [30,31]. On one hand, denying access to these pioneering treatments not only poses a risk for patients but also raises ethical concerns [32], emphasizing the moral obligation to ensure fair access, especially in cases where GTs are the only therapeutic option in place [33]. On the other hand, manufacturers grapple with delicately balancing shareholder interests and societal responsibilities. As a convincing return on investment becomes pivotal for sustainable development [34,35], often a paradigm shift in pricing and reimbursement models is needed [36].

4.2. Market Authorization and Reimbursement Challenges

Two critical points stand out in the complex journey of patient access to GTs: market authorization and reimbursement decision-making. Market authorization serves as the regulatory stamp of approval, confirming the safety and efficacy of these therapies [37]. The small number of participants in GT clinical trials, however, can pose a challenge to this process and raise questions about the generalizability of the results [8]. The growing number of individuals turning to compassionate use programs compels regulators to base extrapolated safety data on N-of-1 study designs, introducing a dynamic shift from traditionally approved randomized trials [6,38]. Further methodological issues, including the utilization of single-arm trials and historical cohorts, as well as inappropriate comparators, additionally induce uncertainty about the effectiveness and durability of therapeutic effects [7,39].
To overcome these hurdles, the EMA has implemented strategic measures like the PRIME and Orphan Designation programs [11,40,41]. The CAT and scientific adversity communities add specialized expertise, helping to facilitate the evaluation of advanced therapeutic medicinal products. Financial incentives also streamline the regulatory process, facilitating innovative treatment development [11]. This collaborative effort has yielded tangible results, as explored in the current research with 25 market-authorized ATMPs. Notably, the majority of them (68%) are GTs, with 88% receiving an orphan designation and 58% approved under the PRIME scheme. Nevertheless, the EU does not hold the forefront in GT development, as China and the United States have a higher number of market-approved GTs [42,43].
The second challenge to achieving GT access lies in reimbursement decision-making, a decentralized process within the EU that fragments the common market and leads to significant health inequalities [7,44]. Our study revealed that in Bulgaria, only one GT product, Kymriah®, has undergone a pricing procedure, but it is not yet included in the PDL, rendering it ineligible for public funds reimbursement. A second GT (Zolgensma®) has initiated pricing and HTA procedures, but official decisions are still pending, despite this process starting over a year ago [45]. Even among neighboring countries that are comparable in terms of health systems and health resources, such as Bulgaria and Greece [46], notable discrepancies in these reimbursement decisions are observed. For instance, in Greece, five out of fourteen GTs are listed on the PDL, indicating a 36% inclusion rate. The official list price of Zolgensma® is 1.48 times lower in Greece than in Bulgaria, a finding that persists even when potential discount agreements are not considered. This emphasizes the intricate nature of reimbursement decisions and highlights the need for a more transparent approach to ensure equitable access to GTs across diverse healthcare systems [47,48].

4.3. Innovative Reimbursement Models

Typically, reimbursement decisions are based on the HTA results [15]. However, several studies emphasize that traditional HTA methods cannot quantify the overall patient benefits provided by GT [49]. Furthermore, substantial heterogeneity exists in the clinical indications of GTs [50]. While some are categorized as life-saving medications, often intended for children, the majority of these products are formulated to address rare cancers in adults [2,51]. In those cases, the scarcity of survival data poses a significant challenge in determining the appropriate time frame for benefit, particularly given the heightened sensitivity of cost-effectiveness analysis to the applied discount rates [30,42,50].
Reimbursement models that involve risk-sharing, such as pay-for-performance arrangements and outcome-based rebates, offer innovative solutions to traditional challenges in reimbursement [52]. These models, like product performance agreements that link payments to clinical outcomes, effectively distribute the financial responsibility associated with high gene therapy prices. They promote a balanced risk-sharing approach between payers and manufacturers. This approach enhances patient access without significantly escalating budgetary impact [53]. Annuity payments, akin to risk-sharing agreements, offer reimbursements in annual installments based on specific clinical results [54]. Payments linked to therapeutic outcomes (an alternative model), involves payers compensating manufacturers upon achieving pre-negotiated treatment results. These strategies are meant to reduce budgetary impact and uncertainty, as well as to stimulate GT development and access [53]. These goals suggest why there is a need to refine value assessment frameworks from a broader societal perspective. Such steps have been taken by several EU member states not only for GTs like Yescarta® and Kymriah® [55,56,57,58] but also for other personalized medicine interventions, such as genomic testing [59].
However, these innovative reimbursement models are not without limitations. The administrative burden due to lack of unified implementation strategies can be substantial [60]. Risk-sharing models can be particularly challenging, as they require additional resources for monitoring and data collection [61]. Often these models lead to increased transaction costs, which can be a significant barrier for SMEs and academic institutions. Furthermore, the lack of transparency and the potential for conflicts of interest can undermine the credibility and increase health inequalities [62].

4.4. Limitations

There are several limitations to our study’s findings. First, we only focused on public fund reimbursement and did not explore any options for private funding of GT access. This is reasonable because of the extremely high official prices of GTs. Except for GT treatment provided within clinical trials, it might be very unlikely for patients to access GTs outside the scope of public funds.

Second, we compared the official list prices of GTs. Those prices, however, are not the ones that are actually used for reimbursement decisions. Instead, regulators and payers nowadays require certain discounts and rebates. The latter are confidential and therefore not publicly available. The latter restriction ultimately makes international comparisons very difficult.

Third, while we can request public data about alternative individual access schemes in Bulgaria, we were not able to do the same regarding Greece and Romania. It is realistic to expect that similar access mechanisms exist and are applied in these jurisdictions as well.

Fourth, we analyzed GT access in three neighboring EU member states. Our sample was limited, and any extrapolations from this research must be cautious. Nevertheless, our findings suggest very limited access to GTs in Southeastern Europe, thus ringing the bell for targeted policy measures to address these significant health inequalities.

Finally, we explored whether and how GTs and ATMPs benefit from the various incentives that the EU applies to foster the research and development of these innovative health technologies. There is a lot of variability between and within the three main types of ATMPs. Furthermore, the sample size was relatively small. Therefore, no general conclusions can be drawn about the pattern of use of those legal instruments and their impact on the progress of ATMPs.

5. Conclusions

Bulgaria is currently applying a combination of general reimbursement and individual schemes to provide access to GTs. While, on paper, these tools should secure a GT-friendly regulatory environment, we found a lower scope in terms of the number of accessible treatments compared to neighboring Greece and Romania. Additionally, individual access schemes in Bulgaria were associated with higher purchasing costs. This is a particularly troublesome situation considering the country’s limited resources.

We call for policy actions at both the EU and national levels. We recommend exploring EU-wide incentives for market authorization holders and manufacturers to undergo national pricing procedures in all the EU member states. At the national level, we suggest considering novel financial models, including annuity payments, in order to mitigate the budgetary risks that are associated with GTs. Addressing all these challenges is vital to establishing a more uniform and equitable landscape for GT access within the EU, fostering a supportive environment for patients and their families, and encouraging further innovations in this transformative field of medicine.

Author Contributions

Conceptualization, K.K. and Y.M.; methodology, G.I.; software, E.H.-A.; validation, K.K., Y.M., and K.D.; formal analysis, R.S.; investigation, Y.M.; resources, K.K.; data curation, E.H.-A.; writing—original draft preparation, K.K. and Y.M.; writing—review and editing, K.K. and E.H.-A.; visualization, K.K. and K.D.; supervision, G.I. and R.S.; project administration, K.K. and Y.M.; internal funding acquisition, Y.M. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Conflicts of Interest

The authors declare no conflicts of interest.


  1. Wirth, T.; Parker, N.; Ylä-Herttuala, S. History of gene therapy. Gene 2013, 525, 162–169. [Google Scholar] [CrossRef]
  2. Allen, J.; Berry, D.; Cook, F.; Hume, A.; Rouce, R.; Srirangam, A.; Wellman, J.; McCombs, C. Medicaid coverage practices for approved gene and cell therapies: Existing barriers and proposed policy solutions. Mol. Ther.-Methods Clin. Dev. 2023, 29, 513–521. [Google Scholar] [CrossRef]
  3. Carvalho, M.; Sepodes, B.; Martins, A.P. Regulatory and Scientific Advancements in Gene Therapy: State-of-the-Art of Clinical Applications and of the Supporting European Regulatory Framework. Front. Med. 2017, 4, 182. [Google Scholar] [CrossRef]
  4. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use. The Official Journal of the European Union; European Parliament, Council of the European Union. Available online: (accessed on 12 December 2023).
  5. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation (EC) No 726/2004. The Official Journal of the European Union. Available online: (accessed on 12 December 2023).
  6. Sopena, L.; English, B.; Munetsi, R. PBI—48 Overview of gene therapy pricing policies and reimbursement models in the EU-5 (Gerseveral, UK, France, Italy and Spain). Value Health 2020, 23, S418. [Google Scholar] [CrossRef]
  7. Tunis, S.; Hanna, E.; Neumann, P.J.; Toumi, M.; Dabbous, O.; Drummond, M.; Fricke, F.-U.; Sullivan, S.D.; Malone, D.C.; Persson, U.; et al. Variation in market access decisions for cell and gene therapies across the United States, Canada, and Europe. Health Policy 2021, 125, 1550–1556. [Google Scholar] [CrossRef] [PubMed]
  8. Ermacora, P.; Meszarosova, D.; Ong, A.D.; Carr, D. PBI 47—Innovative Approaches for Patient Access to Gene Therapies in Haemophilia. Value Health 2020, 23, S418. [Google Scholar] [CrossRef]
  9. Baas, L.; van der Graaf, R.; van Hoorn, E.S.; Bredenoord, A.L.; Meijer, K. The ethics of gene therapy for hemophilia: A narrative review. J. Thromb. Haemost. 2023, 21, 413–420. [Google Scholar] [CrossRef] [PubMed]
  10. Celis, P. CAT—The new committee for advanced therapies at the European Medicines Agency. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2010, 53, 9–13. [Google Scholar] [CrossRef] [PubMed]
  11. Aguilera-Cobos, L.; Rosario-Lozano, M.P.; Ponce-Polo, A.; Blasco-Amaro, J.A.; Epstein, D. Barriers for the evaluation of advanced therapy medicines and their translation to clinical practice: Umbrella review. Health Policy 2022, 126, 1248–1255. [Google Scholar] [CrossRef] [PubMed]
  12. European Parliament, Council of the European Union. Development Support and Regulatory Tools for Early Access to Medicines. 2015. Available online: (accessed on 12 December 2023).
  13. Kondo, H.; Shibatsuji, M.; Yasuda, N. Regulatory/Scientific Supports for Micro-, Small-, and Medium-Sized Enterprises (SMEs) With Medicinal Products Provided by the PMDA and EMA. Ther. Innov. Regul. Sci. 2019, 53, 193–198. [Google Scholar] [CrossRef]
  14. Pimenta, C.; Bettiol, V.; Alencar-Silva, T.; Franco, O.L.; Pogue, R.; Carvalho, J.L.; Felipe, M.S.S. Advanced Therapies and Regulatory Framework in Different Areas of the Globe: Past, Present, and Future. Clin. Ther. 2021, 43, e103–e138. [Google Scholar] [CrossRef]
  15. Coyle, D.; Durand-Zaleski, I.; Farrington, J.; Garrison, L.; Graf von der Schulenburg, J.-M.; Greiner, W.; Longworth, L.; Meunier, A.; Moutié, A.-S.; Palmer, S.; et al. HTA methodology and value frameworks for evaluation and policy making for cell and gene therapies. Eur. J. Health Econ. 2020, 21, 1421–1437. [Google Scholar] [CrossRef]
  16. Ministry of Health. Medicinal Products in Human Medicine Act. 2007. Available online: (accessed on 12 December 2023).
  17. Ministry of Health. Ordinance on the Terms, Rules and Procedure for Regulation and Registration of Prices for Medicinal Products. 2013. Available online: (accessed on 12 December 2023).
  18. Ministry of Health. Ordinance No 10 on the Conditions, Procedure, Mechanism and Criteria for Payment by the National Health Insurance Fund of Medicinal Products, Medical Devices and Dietary Foods for Special Medical Purposes and of Auxiliary Aids, Devices, Equipment and Medical Devices for People with Disabilities, Negotiation of Discounts and Reimbursement of Excess Funds in Application of a Mechanism Guaranteeing Predictability and Sustainability of the NHIF Budget. 2009. Available online: (accessed on 12 December 2023).
  19. Ministry of Health. Ordinance No. 10 on the Conditions and Procedure for the Treatment with Medicinal Products not Authorised for Use in the Republic of Bulgaria, Medicinal Products Administered Outside the Terms of the Authorisation for Use and Medicinal Products for Compassionate Use, as Well as on the Conditions and Procedure for the Inclusion, Modification, Exclusion and Supply of Medicinal Products from the List Referred to in Article 266a, Paragraph 2 of Medicinal Products in Human Medicine Act. 2011. Available online: (accessed on 12 December 2023).
  20. Ministry of Health. Ordinance No. 2 on the Medical and Other Services Referred to in Article 82, Paragraphs 1a and 3 of the Health Act and the Procedure for Their Approval, Use and Payment. 2019. Available online: (accessed on 12 December 2023).
  21. Kamusheva, M.; Turcu-Stiolica, A.; Gierczyński, J.; Subtirelu, M.-S.; Czech, M.; Petrova, G. Do Advanced Therapies Have a Future in the Low- and Middle-Income Countries—The Case of Bulgaria, Romania, and Poland. Front. Public Health 2021, 9, 729847. [Google Scholar] [CrossRef]
  22. Ministry of Health. National Council on Prices and Reimbursement. Positive Drug List. 2023. Available online: (accessed on 12 December 2023).
  23. Ministry of Health. Positive Drug List. Available online: (accessed on 12 December 2023).
  24. National Health Insurance House. List of Fully and Partially Reimbursed Medicines. 2023. Available online: (accessed on 12 December 2023).
  25. National Bank of Romania. Exchange Rates, Daily Series. 2023. Available online: (accessed on 12 December 2023).
  26. Yfantopoulos, J.N.; Chantzaras, A. Drug Policy in Greece. Value Health Reg. Issues 2018, 16, 66–73. [Google Scholar] [CrossRef]
  27. Paveliu, M.S.; Radu, P. PCP37—The confidentiality regarding drugs pricing and reimbursement in Romania. Value Health 2018, 21, S87. [Google Scholar] [CrossRef]
  28. Pejcic, A.V.; Iskrov, G.; Jakovljevic, M.M.; Stefanov, R. Access to orphan drugs—Comparison across Balkan countries. Health Policy 2018, 122, 583–589. [Google Scholar] [CrossRef]
  29. Mansnérus, J. Encountering Challenges with the eu Regulation on Advance Therapy Medical Products. Eur. J. Health Law 2015, 22, 426–461. [Google Scholar] [CrossRef]
  30. Drummond, M.F.; Neumann, P.J.; Sullivan, S.D.; Fricke, F.-U.; Tunis, S.; Dabbous, O.; Toumi, M. Analytic Considerations in Applying a General Economic Evaluation Reference Case to Gene Therapy. Value Health 2019, 22, 661–668. [Google Scholar] [CrossRef] [PubMed]
  31. Iskrov, G.; Vasilev, G.; Stefanov, R. What can gene therapies learn from orphan drugs’ post-regulatory approval access in the EU? Expert Opin. Orphan Drugs 2019, 7, 407–414. [Google Scholar] [CrossRef]
  32. Neuhaus, C.P.; Zacharias, R.L. Compassionate use of gene therapies in pediatrics: An ethical analysis. Semin. Perinatol. 2018, 42, 508–514. [Google Scholar] [CrossRef] [PubMed]
  33. Cuende, N.; Ciccocioppo, R.; Forte, M.; Galipeau, J.; Ikonomou, L.; Levine, B.L.; Srivastava, A.; Zettler, P.J. Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products. Cytotherapy 2022, 24, 686–690. [Google Scholar] [CrossRef] [PubMed]
  34. Colasante, W. PMU75—Is adopting a low price strategy to gain market access compatible with a viable gene/cell therapy business? Value Health 2018, 21, S320. [Google Scholar] [CrossRef]
  35. Thielen, F.W.; Heine, R.J.S.D.; van den Berg, S.; ten Ham, R.M.T.; Groot, C.A.U. Towards sustainability and affordability of expensive cell and gene therapies? Applying a cost-based pricing model to estimate prices for Libmeldy and Zolgensma. Cytotherapy 2022, 24, 1245–1258. [Google Scholar] [CrossRef] [PubMed]
  36. Grosvenor, A.; Ermacora, P. PBI-19 Gene therapies: How will indication-based pricing affect patient access and cost-containment mechanisms for payers? Value Health 2019, 22, S420. [Google Scholar] [CrossRef]
  37. Detela, G.; Lodge, A. EU Regulatory Pathways for ATMPs: Standard, Accelerated and Adaptive Pathways to Marketing Authorisation. Mol. Ther.-Methods Clin. Dev. 2019, 13, 205–232. [Google Scholar] [CrossRef] [PubMed]
  38. Kirmani, S.; Akbar, F.; Mehboobali, A.; Kaleem, S. P214: Experience in delivering free of cost gene therapy for spinal muscular atrophy using the managed access program in Pakistan. Genet. Med. Open 2023, 1, 100242. [Google Scholar] [CrossRef]
  39. Kearns, L.; Chapman, C.R.; Moch, K.I.; Caplan, A.L.; Watson, T.; McFadyen, A.; Furlong, P.; Bateman-House, A. Gene therapy companies have an ethical obligation to develop expanded access policies. Mol. Ther. 2021, 29, 1367–1369. [Google Scholar] [CrossRef] [PubMed]
  40. Salzman, R.; Cook, F.; Hunt, T.; Malech, H.L.; Reilly, P.; Foss-Campbell, B.; Barrett, D. Addressing the Value of Gene Therapy and Enhancing Patient Access to Transformative Treatments. Mol. Ther. 2018, 26, 2717–2726. [Google Scholar] [CrossRef]
  41. Drago, D.; Foss-Campbell, B.; Wonnacott, K.; Barrett, D.; Ndu, A. Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs. Mol. Ther.-Methods Clin. Dev. 2021, 21, 524–529. [Google Scholar] [CrossRef]
  42. Chen, W.; Wang, Y.; Zemlyanska, Y.; Butani, D.; Wong, N.C.B.; Virabhak, S.; Matchar, D.B.; Teerawattananon, Y. Evaluating the Value for Money of Precision Medicine from Early Cycle to Market Access: A Comprehensive Review of Approaches and Challenges. Value Health 2023, 26, 1425–1434. [Google Scholar] [CrossRef]
  43. Mycka, J.; Dalal, N.; Dellamano, R. HPR149 Global Pricing, Reimbursement and Market Access Trends for Regenerative Medicines, ATMPs, Cell, & Gene Therapies. Value Health 2022, 25, S259. [Google Scholar] [CrossRef]
  44. Cornetta, K.; Patel, K.; Wanjiku, C.M.; Busakhala, N. Equitable Access to Gene Therapy: A Call to Action for the American Society of Gene and Cell Therapy. Mol. Ther. 2018, 26, 2715–2716. [Google Scholar] [CrossRef]
  45. Djambazov, S.; Vutova, Y.; Dacheva, A.; Koleva-Kolarova, R.; Encheva-Malinova, M. HPR30 Reimbursement Pathway for Advanced Therapy Medicinal Products in Bulgaria. Value Health 2022, 25, S472. [Google Scholar] [CrossRef]
  46. Exadaktylos, N.M. Organisation and financing of the health care systems of Bulgaria and Greece—What are the parallels? BMC Health Serv. Res. 2005, 5, 41. [Google Scholar] [CrossRef] [PubMed]
  47. Ylä-Herttuala, S. The Need for Increased Clarity and Transparency in the Regulatory Pathway for Gene Medicines in the European Union. Mol. Ther. 2012, 20, 471–472. [Google Scholar] [CrossRef] [PubMed]
  48. Kerpel-Fronius, S.; Baroutsou, V.; Becker, S.; Carlesi, R.; Collia, L.; Franke-Bray, B.; Kleist, P.; Kurihara, C.; Laranjeira, L.F.; Matsuyama, K.; et al. Development and Use of Gene Therapy Orphan Drugs—Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society. Front. Med. 2020, 7, 608249. [Google Scholar] [CrossRef] [PubMed]
  49. Meyer-Acs, M.; Loke, L.; Esser, M. HTA—177 Current Developments in the Market Access Conditions for Gene Therapies in Gerseveral. Value Health 2022, 25, S331. [Google Scholar] [CrossRef]
  50. Vellekoop, H.; Versteegh, M.; Huygens, S.; Ramos, I.C.; Szilberhorn, L.; Zelei, T.; Nagy, B.; Tsiachristas, A.; Koleva-Kolarova, R.; Wordsworth, S.; et al. The Net Benefit of Personalized Medicine: A Systematic Literature Review and Regression Analysis. Value Health 2022, 25, 1428–1438. [Google Scholar] [CrossRef] [PubMed]
  51. Arabi, F.; Mansouri, V.; Ahmadbeigi, N. Gene therapy clinical trials, where do we go? An overview. Biomed. Pharmacother. 2022, 153, 113324. [Google Scholar] [CrossRef] [PubMed]
  52. Koleva-Kolarova, R.; Buchanan, J.; Vellekoop, H.; Huygens, S.; Versteegh, M.; Mölken, M.R.; Szilberhorn, L.; Zelei, T.; Nagy, B.; Wordsworth, S.; et al. Financing and Reimbursement Models for Personalised Medicine: A Systematic Review to Identify Current Models and Future Options. Appl. Health Econ. Health Policy 2022, 20, 501–524. [Google Scholar] [CrossRef]
  53. Drummond, M.; Federici, C.; Busink, E.; Apel, C.; Kendzia, D.; Brouwer, W. Performance-based risk-sharing agreements in renal care: Current experience and future prospects. Expert Rev. Pharmacoeconomics Outcomes Res. 2021, 21, 197–210. [Google Scholar] [CrossRef] [PubMed]
  54. Barlow, J.F.; Yang, M.; Teagarden, J.R. Are Payers Ready, Willing, and Able to Provide Access to New Durable Gene Therapies? Value Health 2019, 22, 642–647. [Google Scholar] [CrossRef] [PubMed]
  55. Horgan, D.; Metspalu, A.; Ouillade, M.-C.; Athanasiou, D.; Pasi, J.; Adjali, O.; Harrison, P.; Hermans, C.; Codacci-Pisanelli, G.; Koeva, J.; et al. Propelling Healthcare with Advanced Therapy Medicinal Products: A Policy Discussion. Biomed. Hub 2020, 5, 1–23. [Google Scholar] [CrossRef]
  56. Jørgensen, J.; Kefalas, P. Annuity payments can increase patient access to innovative cell and gene therapies under England’s net budget impact test. J. Mark. Access Health Policy 2017, 5, 1355203. [Google Scholar] [CrossRef]
  57. Jørgensen, J.; Kefalas, P. The use of innovative payment mechanisms for gene therapies in Europe and the USA. Regen. Med. 2021, 16, 405–422. [Google Scholar] [CrossRef] [PubMed]
  58. Sharpe, M.; Barry, J.; Kefalas, P. Clinical Adoption of Advanced Therapies: Challenges and Opportunities. J. Pharm. Sci. 2021, 110, 1877–1884. [Google Scholar] [CrossRef]
  59. Singer, D.R.J.; Marsh, A. Challenges and solutions for personalizing medicines. Health Policy Technol. 2012, 1, 50–57. [Google Scholar] [CrossRef]
  60. Inotai, A.; Kaló, Z. Risk sharing methods in middle income countries. Acta Pharm. Hung. 2012, 82, 43–52. [Google Scholar]
  61. Gonçalves, F.R.; Santos, S.; Silva, C.; Sousa, G. Risk-Sharing Agreements, Present and Future. Ecancermedicalscience 2018, 12, 823. [Google Scholar] [CrossRef]
  62. Adamski, J.; Godman, B.; Ofierska-Sujkowska, G.; Osińska, B.; Herholz, H.; Wendykowska, K.; Laius, O.; Jan, S.; Sermet, C.; Zara, C.; et al. Risk sharing arrangements for pharmaceuticals: Potential considerations and recommendations for european payers. BMC Health Serv. Res. 2010, 10, 153. [Google Scholar] [CrossRef]

Figure 1.
Time distribution of gene therapies garnering positive market authorization.

Figure 1.
Time distribution of gene therapies garnering positive market authorization.

Healthcare 12 00458 g001

Table 1.
Comparison of gene therapy access schemes in Bulgaria.

Table 1.
Comparison of gene therapy access schemes in Bulgaria.

Framework Component
General Scheme Individual Scheme
Ordinance 10
Individual Scheme
Ordinance 2
Regulator MoH, NCPRMP, NHIF MoH, BDA
Ad hoc commission (three doctors, a pharmacist, and a lawyer)
Ad hoc commission (a representative of the executive body of NHIF and medical experts)
Scope General reimbursement Off-label
Compassionate Use
Age limitation (applicable only to patients under 18 years)
Reimbursement of non-authorized products No Yes No
PDL inclusion procedure Yes No No
Pricing procedure Yes
Mandatory external reference pricing
(Monthly update based on the lowest external reference price)
Direct negotiation process
Direct negotiation process
HTA procedure Yes
(Reappraisal every 3 years if deemed necessary)
No No
Discounts Yes
(Mandatory confidential discounts of at least 10%)
No No
Funding source NHIF
(Review of the reimbursement status and PDL inclusion every 3 years)
State budget
Market authorization holders (if applicable)
State budget transfer to NHIF

Table 2.
Official list prices (in EUR) for gene therapy products authorized by the EMA up to 26 March 2023.

Table 2.
Official list prices (in EUR) for gene therapy products authorized by the EMA up to 26 March 2023.

GT Product Therapeutic Area Date of MA Orphan Designation PRIME Bulgaria Greece Romania
Imlygic® Melanoma 16 December 2015
Strimvelis® Severe Combined Immunodeficiency 26 May 2016
Yescarta® Lymphoma 23 August 2018 321,818
Kymriah® Lymphoma/Leukemia-Lymphoma 22 August 2018 335,637 319,367 332,490
Luxturna® Leber Congenital Amaurosis/
Retinitis Pigmentosa
22. November 2018 378,609
Zolgensma® Muscular Atrophy, Spinal 18 May 2020 2,850,638 * 2,134,478
Tecartus® Lymphoma, Mantle-Cell 14 December 2020 367,416
Libmeldy® Leukodystrophy, Metachromatic 17 December 2020
Abecma® Multiple Myeloma 18 August 2021
Breyanzi® Lymphoma/
Mediastinal Neoplasms
4 April 2022
Carvykti® Multiple Myeloma 25 May 2022
Upstaza® Aromatic L-amino acid decarboxylase deficiency 18 July 2022
Roctavian® Haemophilia A 24 August 2022
Hemgenix® Hemophilia B 20 February 2023

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Disasters Expo USA, is proud to be supported by Inergency for their next upcoming edition on March 6th & 7th 2024!

The leading event mitigating the world’s most costly disasters is returning to the Miami Beach

Convention Center and we want you to join us at the industry’s central platform for emergency management professionals.
Disasters Expo USA is proud to provide a central platform for the industry to connect and
engage with the industry’s leading professionals to better prepare, protect, prevent, respond
and recover from the disasters of today.
Hosting a dedicated platform for the convergence of disaster risk reduction, the keynote line up for Disasters Expo USA 2024 will provide an insight into successful case studies and
programs to accurately prepare for disasters. Featuring sessions from the likes of The Federal Emergency Management Agency,
NASA, The National Aeronautics and Space Administration, NOAA, The National Oceanic and Atmospheric Administration, TSA and several more this event is certainly providing you with the knowledge
required to prepare, respond and recover to disasters.
With over 50 hours worth of unmissable content, exciting new features such as their Disaster
Resilience Roundtable, Emergency Response Live, an Immersive Hurricane Simulation and
much more over just two days, you are guaranteed to gain an all-encompassing insight into
the industry to tackle the challenges of disasters.
By uniting global disaster risk management experts, well experienced emergency
responders and the leading innovators from the world, the event is the hub of the solutions
that provide attendees with tools that they can use to protect the communities and mitigate
the damage from disasters.
Tickets for the event are $119, but we have been given the promo code: HUGI100 that will
enable you to attend the event for FREE!

So don’t miss out and register today:

And in case you missed it, here is our ultimate road trip playlist is the perfect mix of podcasts, and hidden gems that will keep you energized for the entire journey


This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More