Title
DARWIN EU® – Trends in utilisation of Attention-Deficit Hyperactivity Disorder (ADHD) Medications
Rationale and background
A first off-the-shelf study has been performed in 2024 at the request of the SPOC Working Party (responsible for monitoring and reporting events that could affect the supply of medicines in the EU) that has been monitoring shortages of different medicines to treat Attention-Deficit Hyperactivity Disorder (ADHD), mainly due to an increased demand in multiple markets, production constraints related to raw material availability, new regulatory approvals for some medicines, and changes in the competitive
landscape. The main products under monitoring are lisdexamfetamine and methylphenidate, but three more have the indication in Europe (atomoxetine, dexamfetamine and guanfacine). Currently, the situation has improved slightly in the EU and there are no critical shortages. However, it is anticipated that constraints in the supply will continue throughout 2024. The initial study was conducted to better anticipate potential shortages and its impact on appropriate patient management, as it is important to assess the evolution of prescriptions over time and get an overview of how these ADHD medicines are used across Europe. The Spanish Regulatory Authority (AEMPS) after having seen the results of the initial study has asked the EMA if we could repeat the study with additional data partners, especially Spanish ones as the network expanded in this country since the first FA request.
Research question and objectives
The overall aim of this study is to characterise the use of ADHD medications in the period of 2010 to 2023.
The specific objectives are:
1. To estimate the monthly and yearly period prevalence of use of each ADHD medicine, overall and stratified by age and sex in each database.
2. To estimate the monthly and yearly incidence of use of each ADHD medicine, overall and stratified by age and sex in each database.
3. Among new users of each ADHD medicine, to identify the indication at the time of the initial of the prescribing/dispensing, overall and stratified by age and sex.
4. Among new users of each ADHD medicine, to estimate the initial dose, cumulative dose, and time on treatment of the initial medication, overall and stratified by age and sex.
5. Among new users of any ADHD medicine, to estimate the total treatment duration, number of prescriptions overall and by medicine, stratified by initial medicine, age, and sex.
6. To identify the treatment pathway of each individual who initiated an ADHD medicine, including treatment add-on, switch, and concurrent medication/co-prescribing, stratify by calendar time of initiation, age, and sex.
Methods
Study design
Population-level drug utilisation study (Objectives 1 and 2)
Patient-level utilisation study (Objectives 3 – 6, new user cohort study)
Population
In the population-level utilisation of ADHD medications (prevalence, incidence), all people aged 3 years and older, registered in the respective databases since 1st of January of 2010 to the latest available data, with at least 365 days of prior data availability, will be included.
In the patient-level utilization of ADHD medications, new users will be identified using the first record of any of the ADHD medications of interest within the study period, having no previous records for the study medication during the 12 months before cohort entry.
Variables
Drugs of interest: Five approved medications for the treatment of ADHD in Europe: methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine and guanfacine.
Data source
• SIDIAP, covering primary care and linked hospital data from Catalonia, Spain
• BIFAP, covering Spanish primary care
• DK-DHR, linked national registries from Danmark
• NLHR, linked national registries from Norway
• InGef RDB, national wide claims data with primary and secondary care from Germany
• SMPA-GU, linked national registries from Sweden
Statistical analysis
Objectives 1 to 2 are population-level drug utilisation study, monthly and yearly period prevalence and incidence use of each ADHD medications will be estimated, overall and stratified by age group and sex.
Objectives 3 to 6 are patient-level drug utilisation study. In Objectives 3 and 4, new user cohorts will be constructed for each ADHD medicine with pre-defined washout period, characteristics of user will be described, indication for the initial prescribing/dispensing will be estimated, overall and stratified by age and sex. Initial dose, cumulative dose, and length of the treatment will be calculated. In Objectives 5 and 6, we will construct new user cohorts of any ADHD medicine, estimate the total treatment duration and number
of prescriptions. Treatment pathways will be defined and proportion of individuals in each path and the length of each treatment stage will be reported.
For all analyses, a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as “<5”.