Analysis of the availability of bronchodilators and anti-inflammatory drugs for patients with chronic obstructive pulmonary disease

INTRODUCTION / ВВЕДЕНИЕ

Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity, disability and mortality worldwide [1]. More than 80% of COPD-related deaths occur in low- and middle-income countries In these countries, where tobacco smoking, air pollution were identified as major risk factors of COPD [2]. Despite recent advances in pharmacotherapy for COPD, it remains inaccessible to many patients. Coupled with the high prevalence of the disease, it results in a high clinical and economic burden.

Ensuring the availability of medicines for patients is also an urgent problem for domestic healthcare system. Measures to improve it are one of the main directions of reforming the healthcare system in the Russian Federation (RF). For this purpose, a federal program for additional drug provision has been developed [3, 4]. However, a medical and sociological study on the provision of pulmonological care for patients with COPD in the RF, conducted by O.A. Rizakhanova et al., showed that 40.1% of patients, require medication provision, but are not classified as preferential categories of citizens [5]. The lack of adequate benefits for a significant proportion of COPD patients the frequency of hospital admissions, premature death and leads to increased economic losses for the state. A survey of COPD patients in the Astrakhan Region revealed that only 72.3% of respondents received basic therapy, and this also indicates its insufficiency [6].

So in most cases, the cost of purchasing drugs is passed on to patients, resulting in a significant financial burden for them. This burden is the most frequent among low- and middle-income individuals, and costs may increase if a patient has multiple chronic conditions [7]. According O.A. Rizakhanova et al., 41.58% of COPD patients had a monthly income below the average level, and 50.2% – within the average level [5]. High drug costs result in to non-compliance with the treatment regimen (taking smaller doses, skipping and delaying medications), the choice of drugs that provide only symptom relief in order to save money, which worsens health and leads to hospitalization [7, 8]. Ultimately, the transfer of drug expenses from the state to patients lead to high healthcare cost by increasing the use of medical services in hospitals [7]. Because access to medicines is an important component of the management of chronic noncommunicable diseases, both research and regular data collection are needed to monitor the availability and affordability of medicines. They should include all medications, and not be limited only to short-acting bronchodilators, as presented in many studies [9].

Thus, studying the availability of medications for patients with COPD seems to be one of the priority tasks in organizing effective COPD management in the RF.

Objective: to assess drug prices, affordability, and availability for COPD patients.

MATERIAL AND METHODS / МАТЕРИАЛ И МЕТОДЫ

A pharmacoepidemiological analysis of the availability of various pharmacological drug classes used to achieve the main goals of COPD therapy (symptoms control and reducing risk of exacerbations) was performed. The assessment was carried out on both original and generic medications with the minimal price. The study was one-stage. Data collection was carried out on the basis of information on the availability of study drugs in 357 pharmacies in Astrakhan.

Drug classes / Классы препаратов

In the clinical guidelines on COPD developed in 2021 by the Russian Respiratory Society [10], and in the report of the working group of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2023 [11], therapy was presented with different drug classes: short-acting beta-2-agonists (SABA), long-acting beta-2-agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic antagonists (LAMA), inhaled glucocorticoids (IGC), as well as fixed combinations of LAMA + LABA, IGC + LABA, LAMA + LABA + IGC.

WHO/HAI methodology // Методика ВОЗ/HAI

An analysis of the price, affordability and physical availability of drugs for patients with COPD was carried out according to the methods of the World Health Organization (WHO) and the international non-governmental organization Health Action International (HAI) [12].

Price availability assessment

The price availability of each drug was evaluated using the median price ratio (MPR) determined by the formula [12]:

MPR = P_reg / P_ref,

where P_reg – regional median price; P_ref – international reference price.

Median prices from the 2015 International Drug Price Guide prepared by the Management Sciences for Health (MSH) organization were used as a reference price [12]. The MPR shows the correspondence or the multiple of the excess of regional prices over the reference ones. The regional price is considered equivalent to the reference price when the MPR=1. The MPI=2 means that the regional price exceeds the reference price by 2 times [13]. According to WHO recommendations, the price of a drug is considered acceptable for patients if the MPR≤1.5 and MPR≤2.5 in the public and private sectors, respectively [14].

Affordability assessment

Affordability is considered to be the possibility of purchasing drugs for the money of citizens who do not belong to preferential categories at acceptable prices [4, 15]. The affordability ratios (AR) was calculated as the number of one-day wages of the lowest paid unskilled government sector worker needed to pay for drugs in the amount of monthly requirements, prescribed at a standard dosage [12]. The minimum wage used in the analysis for the Astrakhan Region in 2023 amounted to 546 rubles per day [16]. According to the WHO/HAI methodology, a drug can be considered affordable if its monthly treatment course only costs one day’s wage or less [12].

Availability assessment

The physical availability of drugs was calculated as the proportion of pharmacies, in which a drug was available at the time of data collection, out of the total number of pharmacies. Data were collected on the availability of the original drug and the corresponding generic drugs in the same dosage forms. The following ranges were used to interpret availability: very low (<30%), low (30–49%), high enough (50–80%), and high (>80%) [14].

ATC/DDD analysis // Анализ ATC/DDD

Additionally, we were interested in the demand for medications of COPD basic therapy in the region. For this purpose, an analysis of the volume of consumption of bronchodilators and anti-inflammatory drugs was carried out using the pharmacoepidemiological ATC/DDD methodology (Anatomical Therapeutic Chemical classification, defined daily dose) over a three year period (from 2020 to 2022) [17, 18].

We analyzed sales volume using data of two large pharmacy chains in Astrakhan, including a total of 53 pharmacies. Medications were сategorized according to ATC classification. For each international nonproprietary name, taking into account all trade names, the number of DDDs used per 1000 inhabitants per day was calculated. The number of residents was estimated based on data from the marketing agency DSM Group on the population per pharmacy (1932 people). DDDs were calculated based on the WHO DDD, including for combination drugs (Table 1) [17]. The information obtained was adjusted in accordance with the instructions for use in case of discrepancy between the DDD and the daily dose of a drug.

DU90% analysis / DU90%-анализ

The methodology of drug utilization 90% (DU90%) was used to analyze the consumption of bronchodilators and anti-inflammatory drugs, considering their proportion in the total DDD structure. This analysis allowed us to identify the number of drugs making up 90% of drug prescriptions [18].

For each purchased medicationsin pharmacies, the calculated DDDs per 1000 inhabitants per day were sorted from largest to smallest, followed by determination of the proportion of each drug in the total quantity of all calculated DDDs taken as 100%. As a result, the DU90% group was identified, comprising 90% of DDDs consumed in pharmacies.

Statistical analysis / Статистический анализ

Statistical processing of obtained data was performed by MS Excel 2010 (Microsoft, USA) and the statistical analysis package StatPlus 7.0 (StatSoft Inc., USA). Qualitative indicators are presented as relative frequencies (%). Student's t-test was used to compare two independent samples. Pearson's χ² test was used for comparing qualitative variable. The strength of association between qualitative characteristics was calculated using Cramer's V test (interpretation of values according to Rea and Parker recommendations). Significance of differences was determined at p<0.05.

RESULTS / РЕЗУЛЬТАТЫ

Physical availability / Физическая доступность препаратов

The analysis demonstrated a specific picture of the physical availability of bronchodilators and anti-inflammatory drugs for patients with COPD in Astrakhan pharmacies (Table 2).

The group of drugs with high availability (>80%) was represented by the generic form of salbutamol (96.4%) in a metered-dose aerosol inhaler (MDAI), while the original drug was available only in 9.8% of cases. The group of drugs with fairly high availability (50–80%) included budesonide (74.8%), “ipratropium bromide + fenoterol” combination (63.6%), fenoterol (51%), presented in the original form. The group of drugs with low availability (30–49%) included drugs from the IGC group. Thus, beclomethasone in the original MDAI form was in demand only in 40.6% of cases, and in 18.8% of cases in the generics form. The “budesonide + formaterol” fixed combination under the trade name Symbicort^® Turbuhaller (AstraZeneca, Sweden) had an availability of 32.8%.

It should be noted that the majority of basic therapy drugs were in the group of very low availability (<30%). All representatives of this group were original drugs, except for the “fluticasone + salmeterol” combination, which are generic drugs in MDAI form and a metered-dose powder inhaler (MDPI) form with low availability of 0.3%. The “beclomethasone + formoterol”, “fluticasone + formoterol” combinations and tiotropium bromide had the greatest availability in this group (19.6%, 14%, 17%, respectively), and more often were used in regional healthcare practice. Among fixed combinations of bronchodilators, the availability of “tiotropium bromide + olodaterol” combination predominated (12%). The remaining medications in this group had a very low level of physical accessibility. Notably, there was a statistically significant predominance of physical accessibility of original drugs, except salbutamol (p<0.005).

Economic affordability / Экономическая доступность препаратов

Analysis of the economic affordability of drugs revealed higher rates (AR≤1) for SABA and SAMA compared to drugs of basic bronchodilator and anti-inflammatory therapy (Table 3).

Thus, the lowest AR was recorded for salbutamol and amounted to 0.25 for Ventolin^® (GlaxoSmithKlein Trading JSC, Russia), and for generic form for MDAI and solution for inhalation – 0.26 and 0.21, respectively. For the rest of short-acting bronchodilators, the AR was also less than 1. Similar indicators of economic affordability were found for IGC. In the case of pulmicort, AR was 0.84 for MDPI. For beclomethasone, it did not exceed one-day wages, both for the original drug (0.84) and for generics (0.88). The cost of IGC + LABA fixed combinations significantly exceeded one-day wages of the lowest paid unskilled government sector worker in Astrakhan.

However, the extremely low availability of drugs used for basic COPD therapy is cause for concern. Thus, tiotropium bromide (Spiriva^® Respimat – Boehringer Ingelheim Pharma GmbH and Co.KG, Germany) and “tiatropium bromide + olodaterol” combination (Spiolto^® Respimat – Boehringer Ingelheim Pharma GmbH and Co.KG, Germany) had AR of 3.58 and 5.31, respectively. LAMA + LABA combinations represented by “umeclidinium bromide + vilanterol”, “glycoperonium bromide + indacaterol”, “fluticasone furoate + vilanterol”, and “aclidinium bromide + formaterol”, had AR ranging from 4.28 to 5.37. The “fluticasone furoate + vilanterol + umeclidinium bromide” fixed combination, used as a triple form of basic therapy in the most severe COPD patients, had the highest AR of 8.53.

We did not find a statistically significant difference between AR of original and generic drugs (p=0.026), except for “fluticasone + salmeterol” combination.

The correlation analysis of the relationship between the physical and economic availability of drugs for basic COPD treatment revealed a relatively strong correlation (V=0.446; p<0.05).

Price availability / Ценовая доступность препаратов

The MPR was determined only for four drugs that have an international reference price. For all drugs, regional prices were found to exceed reference prices, but not more than 2.5 times, with the exception of “fluticasone + salmeterol” combination in the original form (Table 4).

DU90% analysis / DU90%-анализ

The most purchased drugs for bronchodilator and anti-inflammatory therapy according to the results of DU90% analysis for all studied years were drugs from the group of short-acting bronchodilators (salbutamol, fenoterol, “ipratropium bromide + fenoterol”) and IGC (budesonide, becomethasone (in 2020)) (Fig. 1).

The highest level of consumption (55%, 58% and 56% in 2020, 2021 and 2022, respectively) was found for salbutamol. The DU10% segment included beclomethasone (2021, 2022), ipratropium bromide, tiotropium bromide, formoterol, fluticasone, indacaterol as well as “budesonide + formoterol”, “beclomethasone + formoterol”, “tiotropium bromide + olodaterol”, “fluticasone + salmeterol”, “fluticasone furoate + vilanterol”, “beclomethasone + salbutamol”, “fluticasone furoate + vilanterol + umeclidinium bromide” combinations.

DISCUSSION / ОБСУЖДЕНИЕ

An analysis of bronchodilators and anti-inflammatory drug sales volume over 3 years revealed a significant predominance of short-acting bronchodilators from the SABA group and their combination with SAMA, as well as IGC. These drugs are not specific for COPD patients and can be used to treat various bronchopulmonary pathologies.

Drugs for basic COPD therapy had low sales volumes and entered the DU10% segment. Combinations of LABA with IGC prevailed, of which the leading position was occupied by “budesonide + formoterol” combination. A lower frequency of consumption was observed for “beclomethasone + formoterol”, “fluticasone + salmeterol”, “fluticasone furoate + vilanterol” combinations. Fixed combinations of LABA + LAMA, which are preferred according to current clinical guidelines, had low demand among buyers. Among them, the most frequently purchased combination was “tiotropium bromide + olodaterol” (Spiolto^® Respimat). Tiotropium bromide was used with similar frequency without combination with LABA. The “glycopyrronium bromide + indacaterol” and “umeclidinium bromide + vilanterol” combinations as well as “fluticasone furoate + vilanterol + umeclidinium bromide” triple combination had low demand and were purchased in isolated cases.

The results obtained were confirmed by the results of studying physical availability. The highest percentage of physical availability was also shown for SABA (salbutamol). Quite high (50–80%) availability was observed for another representative of the SABA group (fenoterol), SABA+ SAMA combination (“ipratropium bromide + fenoterol”), and IGC (budesonide). The drugs for basic COPD therapy had a low percentage of physical availability.

In the RF, studies of drug availability using the WHO/HAI methodology have been conducted since 2011. The availability of drugs for the treatment of cardiovascular pathology and palliative patients was studied [4, 13, 15, 19, 20]. We did not find similar works on the availability of drugs for the treatment of respiratory diseases in the RF. The results of our study coincided with data obtained in other countries. Thus, in Vietnam, the highest physical availability was also observed for salbutamol: in 77.1% of pharmacies the drug was available to customers in its original form, and in 17.9% – in a generics form [14]. But it should be noted that in our study, the availability of salbutamol in a generic form predominated.

In a systematic review including 29 studies with data from 60 low- and middle-income countries, an availability rate of 80% for SABA was observed in 6 of 58 countries. For IGC, a similar indicator was observed in three of 48 countries [21]. Despite the fact that regional prices were found to exceed international reference prices (MRP>1), according to WHO methodology, prices were considered acceptable for patients, except of the original drug “fluticasone + salmeterol”. According to the results of a study conducted in Vietnam, the salbutamol MRP also exceeded 1, but was less than the permissible limit of 2.5 and was 2.26 and 1.76 for the original and generic drugs, respectively [14].

When studying economic accessibility, it turned out that the only drugs available (AR≤1) were SABA and IGC. Drugs for basic therapy had AR higher than 1. The highest AR was observed in the triple fixed combination. According to a systematic review, the cost of SABA inhalers was usually about 1–4 days' wage, IGC – 2–7 days, and IGC + LABA – at least 6 days. Availability of LAMA ranged from 4 days' wages in Jordan, a third of monthly income in Brazil, up to 75 days in Nigeria and 95 days in Gambia [21].

Our study did not reveal a statistically significant difference between AR of original and generics drugs. Perhaps this explains the predominance of physical availability of original drugs. In contrast, in a study to set WHO targets for the availability and affordability of essential drugs for the treatment of noncommunicable diseases in countries with different income levels, original brands were less accessible than the cheapest generics in both sectors in all three groups of countries [22]. The low percentage of physical availability of drugs for basic COPD treatment can be explained by their high AR, which was confirmed by the identification of a relatively strong correlation between physical and economic availability (V=0.446; p<0.05).

The inability to purchase drugs in accordance with current clinical guidelines leads to progression of the disease, frequent hospitalizations, and disability, which ultimately causes an increase in the economic costs. K.E.H. Florman et al. showed that only 6% of patients with COPD received recommended treatment based on disease severity. Such results were explained by the availability of SABA alone in all countries studied [23].

Various studies demonstrated that COPD was associated with a significant economic burden in terms of both direct costs to healthcare systems and indirect costs to society [24]. For example, an observational cohort study conducted in the United States showed that patients who received delayed maintenance therapy were 68% more likely to have a subsequent exacerbation requiring hospitalization and 80% more likely to have an exacerbation requiring an emergency room visit compared with patients receiving maintenance therapy [25].

CONCLUSION / ЗАКЛЮЧЕНИЕ

Analysis of bronchodilators and anti-inflammatory drugs consumption over 3 years showed a greater demand for short-acting bronchodilators from the SABA group and their combination with SAMA, as well as IGC, compared to drugs for the basic COPD therapy. For these drugs, a low percentage of physical accessibility was also determined due to high AR, which confirms the identified inverse, relatively strong correlation between physical and economic accessibility.

Low economic accessibility of basic drugs contributes to an increase in the burden of COPD. This fact dictates the need to improve the mechanisms of drug provision for patients, especially those with low material income, which in the long term will significantly reduce the costs of the healthcare system for the treatment of such diseases by reducing the severity and frequency of exacerbations.