In accordance with the Law on Medicinal Products in Human Medicine (LMPHM), medicinal products can be placed on the market only after they have received authorization for use in the relevant order and have a price registration, i.e., a medicinal product can be defined as available only if it is authorized for use and has a registered price. The same medicinal product is defined as affordable if it is available and included in the reimbursement system from the public fund. Therefore, we sought information on the original TKIs, marketing authorization holders, and manufacturers, as well as the date of expiry of patent protection, the availability of generic MPs for those TKIs whose patent protection has expired, and the costs that the NHIF reimbursed for a 5-year period (2018–2022). The data are presented in Tables 1–3. As can be seen from the Table 1 on the pharmaceutical market in our country there are already a large number of generic products of Imatinib and Dasatinib after the patents of the two original products, Glivec and Sprycel have expired. Delaying the first generic imatinib in the United States by about 6 months after the patent expiration of Gleevec, and in the EU Glivec (INN-imatinib), as well as pricing the generic product very close to the price of the patented drug for the next 6 months, has raised serious concerns that the advent of affordable generic drugs will be delayed in the US. Potential solutions specific to generics include:

• monitoring and sanctioning anti-competitive late payment strategies;
• monitoring potential buyouts by generic firms of competing companies in order to establish a monopoly in small markets;
• reducing the procedures and costs of abbreviated applications for new drugs to encourage the availability of more generic drugs to prevent or alleviate shortages;
• establishing price limits for generic drugs to prevent their prices from increasing (e.g., the highest price of the first generic drug is less than 50% of the price of the original drug in the 6-month exclusivity period. According to the Bulgarian normative regulation, the price of the biosimilar medicinal products (BSMP) cannot exceed 80% of the registered price of the BSMP with the same INN due to the same considerations).

The prices of the original TKIs vary widely - the lowest is the price of Glivec (BGN 1120.38), and the highest is the price of Iclusig 45mg (BGN 18163.08) for 1 month of treatment, which continues non-stop until the end of the patients‘ lives (Table 2). Table 3 shows that the price of the generic versions of Imatinib varies from BGN 197.16 to BGN 980.80, and that of Dasatinib from BGN 1571.11 to BGN 3130.25, i.e., generic products are significantly cheaper than original products, but even for them the prices of a one-month therapeutic course significantly exceed the average income of Bulgarian citizens; therefore, these products, although available, can be considered affordable only after the inclusion in the reimbursement system. Based on this analysis, we can summarize that, in theory, all medicinal products, original and generic, once authorized for use could be considered available on the market in Bulgaria from the date of the authorization. In practice, this is not the case, because the Ordinance on the conditions, rules, and procedure for regulating and registering the prices of medicinal products, introduces a mandatory condition that a „medicinal product can be sold on the territory of the country only after the entry into force of a decision on approval of a price issued by the National Council for Pricing and Reimbursement of Medicinal Products (NCPRMP)“ (Council Directive 2020; EMA 2020; National Council of Price and Reimbursement of Medicinal Products 2020; National Health Insurance Fund 2021; Lex.bg 2020a, 2020b) and in case of non-compliance with this condition, the National Law on Medicinal Products in Human Medicine provides administrative penalties.

We requested from the NHIF with an application for access to public information (entry no. 24-01-90/ 21. 07.2023) data at the national level on the number of health insured patients with CML for the period 2018–2022 and on the costs incurred for their treatment. With the decision RD -19-245/3.08.2023 of the NHIF, we received the information we requested, presented in Tables 4–9. Table 4 presents information on the number of patients with CML and the costs of their drug therapy outside the value of the Clinical Pathway (CP) for the period 2018–2022.

The analysis of the data from Table 4 shows that the number of health insured persons with ICD diagnosis C 92.1 – CML increased in 2019 and 2020 by more than 40 patients, which is the average annual number of newly diagnosed CML patients. In 2021 the increase was only by 5 patients, and in the last year of the period it even decreased by 9 people. The NHIF spent for the entire 5-year period the sum of BGN 137,659,851.92, and recalculated in US dollars at an average annual exchange rate of BGN 1.861798 for 1 US dollar, the costs of drug therapy amounted to $73,939,197. The annual costs for the same period (2018–2022) for all TKI drugs with international non-proprietary names (INN): Imatinib, Dasatinib, Nilotinib, Bosutinib, and Ponatinib are presented in Table 5. The analysis of the data in Table 5 shows that the total costs for TKI therapies remain around $27.5 million per year with slight fluctuations according to the number of patients. However, there is a serious trend of decreasing costs for Imatinib from nearly BGN 4 million in the first year of the period to around BGN 1.5 million in the second year, and with a continued decrease in the next 3 years, costs fall below BGN 400,000. This major change can be explained by the lack of data on the reimbursed costs of Glivec c INN Imatinib for the last 2 years and the introduction of cheaper generic versions compared to the price of the original Glivec, with the development of mutations and intolerance to this therapy, as well as the fact that second-generation TKIs are approved for use as a first treatment strategy for CML-CP patients and as replacement therapy after failure of Imatinib therapy. Therefore, the total amount of costs for the last 3 years of the period decreased, a trend that did not correspond to the increased number of patients with CML due to increased survival and better therapeutic strategies. A minor fluctuation is observed in the costs of MPs with INN Nilotinib, which remains around BGN 20 million with a slight downward trend, and with Dasatinib, which increased from BGN 3,200,000 in 2018 to over BGN 4 million in the following years. The most significant increase is in the costs of Bosutinib, which, from nearly 1 million at the beginning of the period already exceed 1.5 million BGN. However, a real spike in costs was seen with Ponatinib, the highest-priced 3^rd-generation TKI but the only MP approved by the EMA in 2013 for use as Second-line treatment for CML with the T315I mutation, which data show from the literature is often found (National Statistical Institute in Bulgaria 2023).

In our country, this product was proposed for inclusion in the positive list at the end of 2017, but was approved in 2018. According to the authors of the PACE study (Council Directive 2020; EMA 2020; Lex.bg 2020a, 2020b; NCPRMP 2020; National Health Insurance Fund 2021), the use of Рonatinib in the earliest stages of the disease can prevent the emergence of resistance caused by mutations. The costs for this МP which were a little over BGN 300,000 in 2018, will reach nearly BGN 2 million in 2022 with a tendency to increase. (EMA, Availability of medicines, for regulators-on-public-communicationsection, 2020; Electronic registers of National Council of Price and Reimbursement of Medicinal Products. Bulgaria, 2020; Website of the National Health Insurance Fund, Bulgaria, 2021; Lex.bg. Bulgarian Law on Medicinal Products in Human Medicine, in force since 13. Apr. 2007, 2020; Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures regulating the prices of medicinal products for human use and their inclusion in the scope of national health insurance systems, 2020; Ordinance on terms, rules, and procedure for regulation and registration of prices for medicinal products, in force since 30. Apr. 2013, 2020).

The analysis of the data from Table 6 shows that only two codes according to the National Health Insurance Fund were present during the 5 years of the period LH 401 (Imatinib Teva Pharma) and LH 324 (Imatinib Meaxin) as generic drugs. It lacks cost data for the original Glivec (INN Imatinib) for the past several years, as well as the cost of generic products with the INN Dasatinib. The total costs of treatment with TKI MPs, distributed by INN for the five-year period, are BGN 133,874,624.62. Of them, the share of original TKI MPs is 97.32%, while the share of generic medicinal products is only 2.68% (Table 7 and Fig. 1)

Figure 1. 

Graphic presentation of the costs of the NHIF for original and generic medicinal products for the period 2018-2022. as a total amount and distribution by INN in BGN. Legend: TM-trademark, GN- generic name, INN- international non-proprietary name.

From the reports presented (Tables 8, 9) on the number of cases of patients with a diagnosis of C2.1 and the amounts paid for their treatment in outpatient and in-hospital medical care, it can be seen that the economic burden of CML is increasing progressively. Regardless of the fact that in out-of-hospital care the number of cases increased by 22% over the 5-year period, but the amounts paid increased by 44%, and in in-hospital care due to the good quality of life of patients treated on an outpatient basis at home with the new TKI tablets and hard capsules, easy to take, the cases have almost halved in the same period, but the amounts have increased more than 6.5 times.

Under the terms of Bulgaria‘s membership in the EU, Bulgarian citizens have guaranteed availability of quality, safe, and efficient modern medicinal products, equal to other EU citizens. Regardless of the fact that Bulgaria has been a member of the EU since January 1, 2007, our population has the lowest incomes; the number of pensioners is over 2 million, and half of them receive pensions of less than BGN 1,000 (about 500 euros), which is why all approved TKI МPs are included in the positive list and their costs are fully covered by the National Health Insurance Fund/ NHIF/ with public funds. This gives clinicians the opportunity to prescribe the most suitable therapy for the patient, even when the disease is diagnosed. All TKIs are prescribed every month according to a protocol issued by a specialized hematology center. Although they fall into a higher price range, the original МPs are preferred for prescribing, dispensing, and treatment in Bulgaria, even when generic alternatives are available. In accordance with the established rules for prescribing and dispensing in our country, prescribing is still by trade name and not by INN, even when a protocol for expensive treatment is issued by special order. Bulgarian pharmacists do not have the right to replace the prescribed drug with another cheaper one with the same INN, as is the case in most developed countries in the world. It is not surprising to find that the share of generic TKI МPs is at a negligible low level. On the other hand, many medical specialists lack confidence and knowledge about the quality and effectiveness of generic drugs in order to achieve rational drug use for the benefit of patients. In Bulgarian therapeutic practice, there is a lack of uniform and adequate standards for the replaceability and interchangeability of commercial drugs with generic drugs and of biological drugs with biosimilar drugs, which are of equal quality, safety, and efficacy. We are fully convinced that it is imperative to introduce the criteria for rational drug use in clinical practice as a mandatory element of our national drug policy (WHO Resolution 2020)

At the local level, we calculated the costs for all 188 patients with CML treates in CP, AP, and BC for the period 2005–2022. On the Table 10 presents the data on the number of patients diagnosed in a 5-year interval, the phase of the disease and the number of deaths. As can be seen from the data in Table 10, at the beginning of the period, the new targeted therapy was prescribed to only 6 patients, and in 2006–2010, their number gradually increased by 42 patients to reach 188 patients included in the study, of which during the period 2009–2022, 40 patients died, including 8 out of 10 patients in the CML blast crisis (CML-BC). The first patient was diagnosed with CML-CP on 1 March 2000, at the age of 55, received the first TKI therapy in 2005, and, as included in the present study, underwent four lines of TKI therapies, but failed to achieve MR. He died at the age of 74 in 2019, when he finally lost the battle with the disease. The youngest of the last 8 patients included in the study in the second half of 2022 is a newly diagnosed 22-year-old patient with a diagnosis of CML-CP, who has the chance to soon be put into long-term remission if he complies with the prescribed therapy and manages to achieve a large and deep molecular response.

BGN 18,792,814 was spent for the treatment of all 188 first-line patients with various TKIs for 12,691 months; BGN 6,749,213 was spent for second-line treatment over 2,398 months; and BGN 6,749,213 for 3+ lines amounts to BGN 2,404,925 for 417 months, or only for the tyrosine kinase inhibitor drugs; the total amount is BGN 22,946,040. Adding to it are the costs of laboratory tests, molecular response monitoring, and other tests. According to clinical path 242 for CML, the total costs are worth BGN 31,458,542 for the entire period of their treatment from the start of TKI therapy until the end of 2022. Fig. 2 presents the cumulative incidence of progression-free survival of patients on the 1^st, 2^nd, and 3^rd lines of treatment.

Figure 2. 

Cumulative rate of progression-free survival of CML patients on first-, second-, and third- line TKI therapy.

Obviously, the earlier the disease is detected in the chronic phase and, based on a personalized approach, the patient is assigned the appropriate TKI therapy, to which he achieves a rapid MMR and a subsequent long-term DMR, the more he will feel “cured” and the quality of his life will be close to 1. In the message we quoted above (Li et al. 2018) the unit QALY, which combines two indicators at the same time (year, prolonged life with improved quality) for CML-CP is 0.92, and for CML-AP and CML-BC is much lower. Progression of the disease in a higher line of therapy and/or phase of the disease (AP and BC) leads to an increase in costs due to switching to more expensive drugs, a deterioration in the quality of life, a decrease in survival, and an increase in mortality (Table 10 and Fig. 2).

A study conducted in Bulgaria evaluated the quality of life of patients with three rare diseases, among them CML (Kamusheva et al. 2013).

Only 10 patients with CML, without an established disease phase, with a mean age of 50 years were surveyed, and based on their responses to the SF 36 short form (WHO) their estimated quality of life was 67.7 out of a maximum value of 100. A statistical relationship was sought between the domains of health-related quality of life and the costs incurred for the treatment of these patients, including co-payments by the patients themselves. The authors conclude that the study is not a long-term analysis, but only a snapshot of the current state, and further studies should be done to assess the long-term HQoL for patients with these three rare diseases in Bulgaria (Kamusheva et al. 2013).

On October 29, 2021, the US Food and Drug Administration granted accelerated approval of asciminib (Scemblix, Novartis AG) for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors (TKIs) and approved asciminib for adult patients with Ph+ CML in CP with the T315I mutation. Over the past 20 years, the development of TKIs has changed the treatment paradigm for patients with CML; accordingly, the survival outcomes of CML patients have also improved dramatically. However, a significant proportion of patients still experience resistance or intolerance to TKI treatment, resulting in a discontinuation rate of approximately 30% for 1^st-line TKI, which gradually increases with treatment lines (Bonifaciо et al. 2022; Yeung et al. 2022).

Because patients who fail to respond to multiple lines of TKIs show poorer outcomes, more effective therapy is needed for CML patients with treatment failure. Asciminib is a first-in-class allosteric inhibitor that binds to the myristoyl pocket of ABL1. Preclinical data support the specificity and potent efficacy of asciminib in CML cells with or without BCR:ABL1 mutations, as well as the synergistic effects of asciminib and conventional TKIs, particularly in overcoming resistance. In phase 1 and phase 3 clinical trials, asciminib showed a significantly improved and durable response with a favorable safety profile, even when enrolled patients were pretreated with multiple TKIs. It is also effective in patients with the T315I mutation. Research efforts today aim to determine whether the use of asciminib as a first-line treatment compared to conventional TKIs, as add-on therapy to achieve DMR, or as consolidation therapy for successful TFR can improve patient outcomes in various clinical scenarios, including CML (Cortes et al. 2013; Kim et al. 2019; Yeung et al. 2022).

The distribution of CML-CP patients (whose numbers are respectively 151 patients for the first line and 40 patients for the second line) according to the line and type of TKI therapy is presented in Figs 3, 4, and the results for the achieved molecular response to the respective therapies are presented in Table 11.

Figure 3. 

Distribution of patients with CML-CP in the first line according to therapy (INN).

Figure 4. 

Distribution of second-line CML-CP patients according to therapy (INN).

Among the treated 151 first-line CML-CP patients, of 98 (64.9%) patients receiving Glivec (Imatinib) 400 mg, 11 (11.2%) patients achieved a major molecular response /MMR 3logs/, 46 (46.9%) patients had deep and very deep molecular response/DMR 4logs and 4.5logs and VDMR 5logs/ and 41 (41.9%) patients had no response. A total of 58.1% of patients treated with first-line Imatinib in chronic phase CML achieved the primary goal of therapy. The remaining 53 (35.1%) first-line patients were treated with 2^nd generation TKI therapies, with the following results: 5 (9.4%) patients achieved MMR, 32 (60.4%) patients had DMR and VDMR and 16 (30.2%) - had no molecular response. Among the 44 (29.1%) first-line patients treated with nilotinib, 5 (11.4%) patients achieved MMR and 28 (63.6%) patients - DMR and VDMR, and 11 (25%) - had no response. Among dasatinib-treated 9 (6%) patients, 4 (44.4%) achieved DMR and VDMR, and 5 (55.6%) patients had no response. Thus, nilotinib administered to 44 patients in the first line, i.e. over twice as many patients as those on imatinib had better outcomes-33 (75%) patients achieved MMR, DMR, and VDMR versus 57 (58.1%) patients on imatinib and only 11 (25%) patients vs. 41 (41.9%) treated with imatinib had no response. The total contribution of the 2^nd generation TKI MPs in the first line is two times greater compared to that of imatinb; 37 (69.8%) patients achieved a molecular response and 16 (30.2%) did not while 57 (58.1%) patients on imatinib achieved MR and 41 (41.9%) had no response. In summary, of 151 CML-CP patients on first-line therapy, 94 (62.3%) patients achieved a large and deep molecular response, but 57 (37.7%) patients did not respond to therapy.

40 patients were treated on the second line of therapy, of which 3 (7.5%) patients received Imatinib (2 patients × 400 mg daily and 1 patient × 600 mg daily), 26 (65%) patients - Nilotinib, 8 (20%) patients - Dasatinib and 3 (7.5%) patients - Bosutinib. The results for the achieved MR for the respective therapies are as follows:

• 3 (7.5%) imatinib-treated patients achieved MR: 1 patient achieved MMR, 1-DMR and 1-VDMR; Among 26 (65%) Nilotinib-treated patients, 2 (7.5%) achieved MMR, 14 (54%) patients had DMR and VDMR, and 10 (38.5%) had no response;
• Among 8 (20%) patients treated with Dasatinib, 6 (75%) patients had DMR and VDMR and 2(25%) had no response;
• Among the 3 (7.5%) patients treated with bosutinib, 1 patient had a DMR and 2 had no response. There are 8 patients in the third line of therapy, as MR data is available for only 2 of them, and in the fourth line, there are two patients who have not achieved MR. Overall, second-line outcomes were slightly better than first-line outcomes - 65% of patients achieved MR and 35% did not.

For the treatment of all 151 patients with CML-CP in the first line with various TKIs during 11066 months, 16 106 444 BGN were spent for their drug therapy with TKIs. For the treatment of all 40 patients with CML-CP on the second line during 2315 months, BGN 6,475,294 was spent on drug therapy with TKI medicinal products, or only on TKI MPs. The total amount for the first and second lines is BGN 22,581,738. We add to it the costs of laboratory tests, monitoring of the molecular response, and other tests. According to clinical path 242 for CML, the total costs are worth BGN 23,274,501 for the entire period of their treatment from the start of TKI therapy for each patient until 31 Dec. 2022.

Cost data included the following items: costs of diagnostic procedures, costs of drug therapy, costs of laboratory tests, and costs of monitoring the molecular response to therapy. The prices of TKI MPs were taken from the Register of the National Council for Prices and Reimbursement of MPs in the Republic of Bulgaria/NSCRRB/ (Electronic registers of National Council of Price and Reimbursement of Medicinal Products. Bulgaria 2020) and from the Positive Drug List, and the costs for laboratory tests and monitoring of the molecular response were taken from Clinical Pathway 242 for ICD diagnosis C2.1.-CML.