Atopic dermatitis

Atopic dermatitis (AD) is an inflammatory, pruritic and chronic or chronically relapsing skin disease. AD is one of the most common non-communicable skin diseases; as a heterogeneous and intermittent condition, reported incidence rates vary. European prevalence rates are approximately 20% in children and up to 8% in adults [1]. Systemic immunosuppressant treatments including methotrexate and ciclosporin, in combination with best supportive care (BSC) (emollients and topical anti-inflammatory treatments), had been considered the standard of care for moderate-to-severe AD prior to the marketing authorisation of biological medicines in Ireland.

Dupilumab (Dupixent®) is a fully human immunoglobulin G4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signalling [2]. IL-4 and IL-13 are critical in the initiation and maintenance of the Th2 inflammatory pathway which plays a central role in the pathophysiology of AD [3]. Dupilumab was licensed for AD, by the European Medicines Agency (EMA), in 2017; the first biological medicinal product to be licensed for this indication. This approval was informed by the LIBERTY AD SOLO 1, LIBERTY AD SOLO 2 and LIBERTY AD CHRONOS clinical trial programmes [4,5,6]. A license was granted for use in moderate-to-severe AD in patients who are candidates for systemic therapy [2]. The subcutaneous injection is available in two strengths, a 200 mg formulation and a 300 mg formulation available as a pre-filled pen or pre-filled syringe [2].

At present, there are no guidelines for the treatment of AD in Ireland. The European Academy of Dermatology and Venereology (2018) recommends the use of dupilumab as a disease-modifying drug for patients with moderate-to-severe AD, in whom topical treatment is not sufficient and other systemic treatment is not advisable. Dupilumab should be combined with daily emollients and with topical anti-inflammatory treatments as needed [7].

Dupilumab in the Irish healthcare setting

Reimbursement of dupilumab by the Health Service Executive (HSE) was previously sought by Sanofi Ireland (the applicant company) [8]. To inform the HSE reimbursement decision-making processes, the National Centre for Pharmacoeconomics (NCPE) completed three Health Technology Assessment (HTA) evaluations in different populations of patients with AD. The 2019 HTA assessed the cost-effectiveness of dupilumab for the treatment of moderate-to-severe AD in adult patients, who are candidates for systemic therapy [8]. The NCPE HTA considered two populations, i.e. the full-licensed population (herein the ‘full population’) and patients with refractory disease (herein the ‘refractory population’). The full population comprises adults with moderate-to-severe AD who are candidates for systemic therapy. The refractory population (a subgroup of the full population) comprises adults who are not adequately controlled by topical therapies and who are contraindicated to, intolerant of, have had an inadequate response to or for whom it is otherwise medically inadvisable to receive treatment with a systemic immunosuppressant. The NCPE considered methotrexate and ciclosporin to be appropriate comparators [8]. Incremental cost-effectiveness ratios (ICERs) varied depending on the population assessed; plausible ICERs ranged from €103,175 to €136,062 per quality-adjusted life year (QALY) in the full population and from €74,401 to €83,424 per QALY in the refractory population [8]. The NCPE estimated that the total annual cost of dupilumab to the HSE would be €19,911 per patient per year (inclusive of rebates, fees, and VAT) based on a price to wholesaler (PTW) of €1,153.85 for 4 weeks of supply [8]. We note that in 2019, the PTW of 4 weeks of supply of methotrexate at the maximum dose of 25 mg once weekly was about €5.24 and the PTW of ciclosporin at a dose of 200 mg twice daily was approximately €95.77 [9]. The NCPE estimated that the 5-year cumulative gross budget impacts would be about €51.9 million in the full population and approximately €38.3 million in the refractory population. The NCPE recommended that dupilumab not be reimbursed, at the submitted price, for the treatment of AD in adult patients [8].

In 2021, the HSE led the confidential price negotiations with the applicant company; these negotiations were informed by the NCPE HTA evaluation. As a result, the applicant company offered a confidential discount on the original submitted price of dupilumab. The NCPE concluded that the cost effectiveness of dupilumab had been improved as a result of this price discount. The HSE subsequently approved reimbursement of dupilumab for the treatment of moderate-to-severe AD in the refractory population (as defined within the NCPE HTA evaluations) [10]. This approval extends to two cohorts; adult patients aged 18 years and older (herein the ‘adult cohort’) and adolescent patients aged 12 to 17 years old (herein the ‘adolescent cohort’). The approval was subject to a HSE Managed Access Protocol (MAP) being implemented that would limit approval of treatment to patients with refractory disease only. The MAP was an initiative aimed at approving treatment for those patients in which the medicine was expected to be the most effective and cost-effective (versus standard of care) and also as a cost containment measure. The HSE-Medicines Management Programme (MMP) was tasked with developing and implementing this MAP. As per standard processes, the HSE-Primary Care Reimbursement Service (PCRS) is responsible for the High Tech (HT) ordering and management system which provides for the supply, dispensing and reimbursement of HT treatments (high-cost medicines which are initiated in a hospital setting) such as dupilumab through community pharmacies [11].

The HSE-MMP is a multi-disciplinary National Clinical Programme comprising clinicians, pharmacists and data analysts [12]. Against the backdrop of concerns regarding the affordability of medicines, the HSE-MMP has become the steward of Health Technology Management (HTM) in Ireland. HTM has been defined as ‘measures put in place to enhance the safe, effective, and cost-effective use of medicines thereby controlling utilisation and expenditure’ [13]. The HTM approach that Ireland has adopted, for the reimbursement of dupilumab, is comparable to the approach taken in other jurisdictions such as Canada, England and Scotland [14,15,16,17].

The eligibility criteria for patient-specific approval of dupilumab through the HSE were informed by European clinical guidelines, clinical trial efficacy data and the NCPE HTA evaluations [1, 4, 5, 7, 8, 18]. These eligibility criteria are outlined in the HSE-Managed Access Protocol for High Tech Medicines for the treatment of moderate-to-severe atopic dermatitis and include that patients [19]:

Are aged 12 years or older at the time of application

Have moderate-to-severe AD confirmed by an Eczema Area Severity Index (EASI) score of ≥ 16 at the time of application

Previous immunosuppressant treatment:

Has failed or

Is not tolerated or

Is contraindicated

Are in receipt of BSC for AD

Applications for individual patient approval of treatment with dupilumab, through the HT arrangement, are only considered when submitted by a HSE-approved prescriber [19]. Consultant dermatologists, in Ireland, who have read and formally agree to the terms of the MAP are eligible to be approved prescribers. All applications are reviewed on a case-by-case basis by the HSE-MMP. Once a patient is deemed eligible, by the HSE-MMP, for treatment with dupilumab, the approved prescriber is authorised to issue a prescription for the patient which can be dispensed by a community pharmacist through the HT arrangement.

Prior to the HSE reimbursement of dupilumab, the marketing authorisation holder (MAH) initiated an ‘early access programme’ (EAP). EAPs are operated at the discretion of the MAH. Here, the clinician would seek approval, from the MAH, for access to the drug for an individual patient. The MAH would approve access for that individual only if certain eligibility criteria (pre-defined by the MAH) are met. Applications to the HSE-MMP for individual supply of dupilumab for patients who are already on dupilumab, via the EAP, are processed according to the same HSE-MMP eligibility criteria applicable to all other patients.

Database descriptions

There were two sources of data pertaining to the same cohort of patients included in this analysis.

Firstly, analysis was carried out on the data provided by consultant dermatologists in application forms submitted for the individual supply of dupilumab through the HT arrangement from 01 April 2021 to 31 March 2022 inclusive. This time frame represents the first year that dupilumab was available to patients in Ireland through the HT arrangement. The data analysed were anonymised and included information about the patient, their condition and previous treatments. Specifically, information captured and utilised included patient sex, patient date of birth, the duration since the patient diagnosis of AD, the EASI score and Children’s Dermatology Quality Life Index (CDLQI)/Dermatology Quality Life Index (DLQI) at the time of application, systemic immunosuppressant treatments previously received by the patient, the rationale for cessation of previous systemic immunosuppressant treatment and information regarding any contraindications the patient had for immunosuppressant treatment.

Furthermore, an evaluation of pharmacy claims data for dispensed items from the HSE-PCRS claims databases during the same time period as specified above was conducted. The HSE-PCRS claims databases comprise numerous databases. These include the General Medical Services (GMS) Scheme and Drugs Payment Scheme (DPS) databases which are of relevance here. Dupilumab is available to patients through the PCRS HT arrangement through their individual GMS or DPS eligibility. Patients with GMS scheme eligibility may access HT drugs for free at the point of care through this means-tested HSE community prescription drug scheme [11]. All other patients can access HT drugs through their DPS eligibility; here patients and their families have their monthly spend on approved prescribed drugs, medicines and medical and surgical appliances (including HT drugs) capped at a threshold value, currently €80 per calendar month [20]. Anonymised patient-level data, from both the GMS and DPS databases, were analysed from all claims submitted through the HT arrangement. The PCRS pharmacy claims database records details including age and sex of patient, and the cost, quantity, strength and form of drugs dispensed to patients eligible for the scheme.

Aims of study

The aim of this study is to analyse the applications received during the first year of HSE reimbursement of dupilumab to determine:

The percentage of patients (for whom an application to the HSE-MMP was made) who were eligible for HSE reimbursement and

Certain characteristics (age, sex, time since first diagnosis and disease severity at the time of application) of this population.