Drug Program Resource Analysis: "Treatment of chronic spontaneous urticaria (ICD-10 L50.1)"

Introduction Since January 2020 treatment of patients with chronic spontaneous urticaria is possible under drug program B.107: “TREATMENT OF CHRONIC SPONTANEOUS URTICARIA.” This is the first drug program designed specifically for this group of patients. The

Results 225 patients were treated under drug program B.107 in 2020. The NFZ assigned the following amounts of money for the provision of healthcare services under this program: PLN 2,936,812 -for the medicines and PLN 452,512 -for the management of the program. The use of the aforementioned amounts was 86% for the drug in the program and 63% for the management of the program. The treatment has been carried out by 46 centers across Poland.

Conclusions
There was a strong unmet medical need indicating the necessity to provide treatment for this group of patients. A large group of medical specialists can diagnose and treat urticaria in line with Polish and international recommendations. Since this drug program includes numerous medical specialties, patients with urticaria have gained very good access to diagnostics and potential initiation of treatment within its framework. In addition, omalizumab can be dispensed to patients for use at home, which definitely increases the safety of the therapy by limiting direct contact between the patient and medical facilities.
As defined by EAACI/GA(2)LEN/EDF/WAO (European Academy of Allergy and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, World Allergy Organization) in 2013, urticaria is a disease characterized by the presence of wheals and/or angioedema. When symptoms persist for at least 6 weeks, the condition is referred to as chronic urticaria (CU), which in turn can be divided into idiopathic and induced depending on the causative agent. [1] The announcement of the Minister of Health of 20 December 2019 on the list of reimbursed medicines, foodstuffs intended for particular nutritional uses and medical devices as of 1 January 2020, included the possibility to treat patients with chronic spontaneous urticaria under drug program B.107: "TREATMENT OF CHRONIC SPONTANEOUS URTICARIA." [2] The drug program is a guaranteed healthcare benefit which involves the use of innovative, costly active substances that are not financed under other guaranteed benefits. [3] Introduction Chronic urticaria (CU) is a serious disease with complex etiopathogenesis which affects about 0.1-3% of the population. The clinical picture of urticaria consists of urticarial wheals and/or angioedema and pruritus. In severe cases, massive oedema, including swelling of the throat, may be life-threatening. Chronic spontaneous urticaria (CSU) accounts for 2/3 of all CU cases and occurs most frequently in adult women (approximately 20-40 years of age). [5] CSU presents major diagnostic and therapeutic challenges. Due to the severity of the complaints, this condition significantly impairs the patient's everyday life as well as reduces their quality of sleep and life. [6] Currently, 2018 EAACI/GA(2) LEN/EDF/WAO recommendations indicate the use of monotherapy with approved doses of the 2nd-generation non-sedative H1-antihistamines as first-line treatment. The second line of treatment consists in increasing the dose of 2nd-generation non-sedative H1-antihistamines up to four times if no improvement is seen within 2-4 weeks of follow-up. In the third line of treatment, in accordance with the current 2018 recommendations, the use of omalizumab is recommended as add-on treatment. This is a change from the previous recommendation which advocated that cyc-losporine or montelukast or omalizumab could be used in the third line of treatment. 1 The authors of the current recommendations clearly indicate that only omalizumab has been approved for use in the CSU indication and shows clinically proven efficacy. Other medicines proved ineffective in real-world setting or their use is associated with a significant risk of serious side effects. Therefore, since 2018, omalizumab has been the only recommended and approved in the European Union option for CSU patients unresponsive to antihistamines.

Material and methods
The analysis included the 2020 data published by the NFZ's Board in the NFZ Operations Report for Q4 2020 with regard to the drug program B.107: "TREATMENT OF CHRONIC SPONTANEOUS URTICARIA." [7] The following parameters were analyzed: • the number of settled settlement units divided in particular scopes of hospital treatment (drug program) for B.107 • the number of patients enrolled in the drug program • the value of program contracts • the number of healthcare providers conducting the program • the number of patients to whom the drug was dispensed for self-administered injections • the number of patients on the waiting list.

(Table 1)
In 2020, which was the first year of implementation of the B.107 drug program, the following operations were carried out: • 450 one-day hospitalizations related to the implementation of the program for a total of PLN 219,024; • 340 outpatient admissions related to the program implementation for a total of PLN 36,774. The highest number of patients was treated at the centers in Łódzkie Province.
No center in Lubuskie Province has concluded the contract for the implementation of the B.107 drug program; therefore no treatment was reported in that region in 2020. (Table 3) In 2020, the NFZ allocated the following amounts to the implementation of the B.107 drug program: • PLN 2,936,812 -for the medicines, • PLN 452,512 -for the management of the program.
The use of the aforementioned amounts is 86% for the drug in the program and 63% for the management of the abovementioned program.
(  The largest number of healthcare providers implementing the B.107 program was noted in Śląskie Province. None of the sites in Lubuskie Province has concluded the contract for the provision of the above-mentioned benefit.
The highest contract values were noted in Mazowieckie Province, while the lowest -in Wielkopolskie Province.
( Table 5) Omalizumab was dispensed to patients for use at home in only 3 provinces. The procedure of dispensing the medicine for use at home under the B.107 drug program was most common in the Mazowieckie Province. The University Clinical Centre of the Medical University of Warsaw has completed this procedure fourteen times between June and October.
( Table 6) A total of 68 patients awaited the implementation of the benefit under the B.107 programme in 2020. However, waiting time was relatively short -up to 2 months.

Discussion
Chronic spontaneous urticaria (CSU) manifests with cyclic, at least 6-weeks long presence of wheals and/or angioedema, and in contrast to induced urticaria, there is no triggering factor. CSU can be divided into urticaria of unknown causes (chronic idiopathic urticaria, CIU) and urticaria of known origin (infection-related urticaria). 3 In approximately one-third of patients with CIU it is suspected that the condition may be associated with autoimmune processes. [8] According to the latest studies in Poland, CSU may account for up to 42% of cases of all chronic urticaria. Less than 50% of patients achieve control of CSU symptoms with the use of antihistamines (AH1). The remaining patients require increased doses of AH1; however, every third or fourth CSU patient is resistant to such a therapy. 6 The symptoms of CSU significantly reduce the patient's quality of life and make normal, everyday functioning difficult due to troublesome itching, pain and indirect effect on the patient's emotional well-being.
Xolair, omalizumab, humanized monoclonal anti-IgE antibody has been approved by the EMA and FDA for use in the treatment of adults and adolescents (≥ 12 years of age) with chronic spontaneous urticaria who remain symptomatic despite treatment with anti-H1 antihistamines. The recommended dose for the treatment of CSU, according to the Summary of Product Characteristics, is 300 mg by subcutaneous injection every 4 weeks. [9] The approval of omalizumab in chronic spontaneous urticaria (CSU) in 2014 was based on efficacy and safety data from Phase III clinical trials [ASTERIA I (NCT01287117), ASTERIA II (NCT01292473) and GLA-CIAL (NCT01264939)]. These studies showed that omalizumab at a dose of 300 mg significantly improved disease control and significantly reduced pruritus severity (Itch Severity Score, ISS) as compared to placebo. [

10] [11] [12] [13]
In 2019, the Minister of Health decided on the reimbursement of omalizumab under the drug program B.107 "Treatment of chronic spontaneous urticaria." This decision was long-awaited by both physicians and patients. The treatment has been carried out by 46 centers across Poland. There is no healthcare facility providing treatment under this program only in Lubuskie Province. In other provinces the program was implemented by allergology, dermatology and pediatric facilities. As specified in the appendix to the Regulation of the President of the National Health Fund (NFZ) No 162/2020/DGL, the aforementioned program may be implemented by: outpatient clinics and departments of allergology, pediatric allergology, dermatology, pediatric dermatology, pulmonology, pediatric pulmonology, pediatrics and internal diseases. The dosage specified in the description of the drug program indicates that treatment with omalizumab should be suspended 24 weeks after the initiation of the therapy (administration of the first dose). During the treatment the patient receives 7 doses in weeks: 0, 4, 8, 12, 16, 20, 24. The patient should not discontinue the treatment with an antihistamine. During the period when the patient's participation in the drug program is suspended, the use of antihistamines remains at the discretion of the physician. In patients who restart treatment with omalizumab, therapy should be continued at the dose specified in the Summary of Product Characteristics for a period of consecutive 24 weeks, i.e. 300 mg administered subcutaneously every 4 weeks.
In 2020 the treatment was provided to 225 patients. The highest number of treatments is provided by centers in Łódzkie Province. In the majority of cases the healthcare benefit is settled as "hospitalization related to the program" -for a unit amount of PLN 486.72.
The total value allocated for the implementation of B.107 was PLN 3,389,323.2. At the same time, healthcare providers completed the above-mentioned drug program in 86% as regards the drug dispensed in the program and in 63% as regards the program management.
In light of the COVID-19 epidemic in 2020, the President of the National Health Fund (NFZ) decided that omalizumab can be dispensed to patients for use at home. Undoubtedly, it was a step towards increasing the patient's safety by limiting their direct contact with medical facilities. This benefit was provided 23 times in only 3 provinces over 6 months.
In 2020 the number of patients awaiting participation in the B.107 drug program was 68. Waiting time was less than 2 months.