Heterogeneity of the pharmacologic treatment of allergic rhinitis in Europe based on MIDAS and OTCims platforms

The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems. To understand these differences and their implications, the rhinitis market was studied in some of the EU countries.


| INTRODUC TI ON
Allergic rhinitis (AR) is one of the most common chronic conditions. Available treatments include allergen avoidance, pharmacotherapy with H 1 -antihistamines or intranasal corticosteroids (INCS) and allergen-specific immunotherapy (AIT). 1 Many patients are dissatisfied with their treatment for various reasons. Management does not consider the patients' needs, no cure is available, adherence to long-term therapy is poor, and/or the patients do not fully understand their condition. Real-world data obtained via mobile technology have suggested that there are differences in medication use between countries. 2,3 MASK-air 4-6 is a Good Practice of DG Santé concerning the digital transformation of health. 7,8 The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems.
To understand these differences and their implications, it is important to have an overall view of the rhinitis market in some of the EU countries.
The goal of this paper was to assess practices in different EU countries in order to better implement the Good Practice of DG Santé (MASK-air). The secondary goal was to understand some of the differences and to propose mitigation strategies. This study will serve as a baseline status for possible future measures to be taken at the country level.

| Study design
This ARIA study evaluated the market for allergic rhinitis (AR) treatment (prescribed and over-the-counter (OTC) medications) in five EU countries in the years 2016-18. We conducted a pharmacoepidemiological database analysis to assess the medications that

Abstract
Background: The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems. To understand these differences and their implications, the rhinitis market was studied in some of the EU countries.

Methods:
We conducted a pharmaco-epidemiological database analysis to assess the medications that were being prescribed for allergic rhinitis in the years 2016, 2017 and 2018. We used the IQVIA platforms for prescribed medicines (MIDAS ®-Meaningful Integration of Data, Analytics and Services) and for OTC medicines (OTC International Market Tracking-OTCims). We selected the five most important markets in the EU (France, Germany, Italy, Poland and Spain). Discussion: There are major differences between countries in terms of rhinoconjunctivitis medication usage.

K E Y W O R D S
allergic rhinitis, costs, medications, MIDAS, units dose prescribed and treatment duration. We used manufacturing costs rather than costs for the healthcare system as, in some countries, there are rebates that are not publicly available.

| Definitions used
We used SU (Standard Units) and LEU/MNF (Local Currency Euro/ Manufacturer Price Level) to compare data between countries.
An SU is a unit defined by IQVIA to represent the smallest daily unit of consumption, for example one tablet, one vial/ampoule or 5 ml of liquid. As an example, a pack of 100 tablets with a dosage recommendation of two tablets a day will lead to Unit = 1, Counting Units = 100 and SU = 50.

LEU/MNF per year represents the total sales in Local Currency
Euro at Ex-Manufacturer Price Level per Calendar Year.
We chose Manufacturing Cost of the drugs, and it was not possible to mention healthcare system costs due to rebates that are not publicly available.

| Selection of medications
We selected medications registered for AR, as well as nasal or ocular decongestants which may also be administered for AR.
The World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classifies drugs by their active ingredients 13 and their defined daily dose (DDD), a fixed attribute that allows the conduct of national or international drug use studies. 14 This ATC system is based on the earlier Anatomical Classification System, which was intended as a tool for the pharmaceutical industry to classify pharmaceutical products (as opposed to their active ingredients). 15 This system was initiated in 1971 by the European Pharmaceutical Market Research Association (EphMRA). 16,17 In the present study, we used the EphMRA system and gave the ATC correspondence.
For prescribed medications, the study was performed by IQVIA Ltd., London, England, using de-identified prescription data from MIDAS ® for 2016, 2017 and 2018 (in € for sales) as well as numbers of treatments. MIDAS ® provides connectivity and international standardization of national-level pharmaceutical audits to allow the cross-country analysis of company and product performance, as well as additional insights and attributes not available at a local level. MIDAS ® captures and harmonizes the data from 92 countries worldwide, mainly for registered medicines (prescription and non-prescription) in pharmacy and hospital channels. MIDAS ® integrates and extends IMS National Audits that accurately detail estimated product volumes, trends and market share by product and therapy class, through retail and non-retail channels. MIDAS ® tracks the direct sales (i.e. sales invoices) of pharmaceuticals from the manufacturer to pharmacies or hospitals. MIDAS ® also tracks indirect sales (sales going through a middleman, i.e. the wholesaler) to pharmacies and hospitals. MIDAS ® tracks inflow or what these different channels are purchasing (i.e. the sales made into those outlets). It represents the full European market through representative panel projections for both retail and hospital channels.
The following subgroups include symptomatic AR drugs and ophthalmic drugs (since rhinitis is often associated with conjunctivitis).
Montelukast was not used as it is an asthma and a rhinitis treatment and is only indicated in patients with both rhinitis and asthma. The following medications were considered (Table 1)

| Allergen-specific immunotherapy
The only country where AIT is mostly delivered in pharmacies is Germany. We only provided data for AIT in Germany (allergens, V1A0).

| Selection of countries
The market for prescribed medications (in costs for patients) for 2018 in all EU countries was ranked in order to choose the markets with the highest sales (Table S1). OTC medications were not considered in the country selection because a single database cannot be used in all countries. AIT was not considered in the country selection since large variations exist between countries in terms of supply (pharmacies, hospitals, Named-Patient Products, etc.).
The first six countries with the highest sales for AR medications and nasal decongestants were France, Germany, Italy, Spain, Poland and the UK. There was a big gap between UK N°6 and Sweden N°7. Thus, we considered only the first six countries. In the UK, a significant proportion of sales took place in supermarkets and these were not considered by IQVIA. Thus, the country had to be excluded.
The 'Sell-Out' (Medication dispensed in pharmacies) data and, if not available, the 'Sell-In' (Medication delivered in pharmacies) data were obtained from IQVIA. For the countries selected, the databases were from different origins, and the data type differed taking into account the country specificities on drug dispensing (Table 3).

| Collection of information
There are different methods of collecting the information, and we needed to make assumptions.
It is possible to compare 'Sell-in' (from wholesaler to retail pharmacy, effects like stocking are included) and 'Sell-out' (from retail pharmacy to patient) data, bearing in mind some biases. Therefore, for one quarter, the 'Sell-in' data might be higher when compared to 'Sell-out' due to stock, but these effects are minimized for yearly data. In the countries tested, 'hospital' means hospital consumption from hospital to patient.
For the OTCims Panel, all panels are 'Sell-out'.

| Analyses
We conducted a descriptive analysis to evaluate the medications used in different countries. To derive figures for anti-rhinitis consumption per person over the three years, we linked consumption by SU to population estimates.
Stratification: The analyses were performed separately for prescription data and OTC data. In some countries, the same products could be prescribed and were also available OTC. Thus, in order to prevent multiple counts, a complex merger process between prescriptions and OTC was necessary. Analyses were performed once at the same time.
Projection: The results were projected yearly per country.

| Intranasal decongestants (R1A7 and 01B2)
Intranasal decongestant sales (R1A7 and 01B2) are extremely variable, with low sales in France (from 612,073 to 751,739 kSU per year, 12.6%-14.8% of total sales) and high sales in Germany (from 6,586,460 to 6,890,822 kSU per year, 71.6%-79.6%) ( Table 4). We checked the monthly variation of R1A7 in Germany in 2018 and found that they were purchased less often during the pollen season than outside ( Figure S4). In Germany, although the majority of products were available in pharmacies, they were non-prescribed. We therefore excluded R1A7 and 01B2 from further analyses as they are unlikely to represent patients with allergic rhinitis.

| Overall results without intranasal decongestants (R1A7 and 01B2)
The results are presented in Table S2,

| Rhinoconjunctivitis medication consumption per person in Europe
There are very large differences in medication consumption (SU) per person in Europe depending on the country (Table 6). In France, there are 4.3 times more INCS sold per inhabitant than in Germany.
On the other hand, in Germany, there are 9.25 times more nasal decongestants sold per inhabitant than in France.
Although the proportion of reimbursement/out of pocket differs between countries, and even in the same country, for different classes of drugs, reimbursement and OTC availability of medications differ in EU countries (Table S3).

| DISCUSS ION
The present paper shows that there is a great heterogeneity in AR medications across Europe. Some explanations may be proposed including reimbursement strategies. general practitioners to also do so. These molecules were prescribed very early by pediatricians, also to children of atopic families who present nasal signs. These children are used to these methods from the age of 3.

TA B L E 3 Origin of the databases
In Germany, the situation is more complex than in other countries. The general reimbursement strategy is outlined in it is likely that AR severity is similar between countries. However, the reimbursement strategies of some countries may impair the implementation of guidelines. Moreover, although most AR patients consulting a physician have moderate to severe rhinitis, the low level of ICNS prescribed is surprising. These data may at least partly explain the poor satisfaction of AR patients.
There are also very large differences between countries in intranasal decongestants. Although the indications cannot be assessed using the IQVIA database, it is likely that many patients in Germany use intranasal decongestants for AR. This does not accord with guidelines. In ARIA, 'in adults with AR and severe nasal obstruction, we suggest a very short course (no longer than 5 days, and preferably shorter) of intranasal decongestants while co-administering other drugs (conditional recommendation, very low-quality evidence)'. 20

| CON CLUS IONS
With the limitations discussed, this study is of great interest for assessing the heterogeneity of pharmacotherapy in some European countries and can be used as a baseline for future studies to show treatment trends.

CO N FLI C T O F I NTE R E S T
CB reports personal fees from Meda. JB reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan,