Base Case Study Design: the study employed a CEA to compare the effectiveness and reduction in direct and indirect costs per case of ADHD when treated with LDX and MPH from a social perspective. A one-year decision-analytic modeling approach was used to assess the value for money and financial consequences of the new health intervention (Fig. 1).

Fig. 1

Model structure as a decision tree model in Treeage pro healthcare 2022 for ADHD in patients under 18 years old in Iran

Model inputsClinical data

The target population for this research consisted of Iranian children and adolescents under 18 years old diagnosed with ADHD by a psychiatrist or neurologist based on DSM-5 guidelines. The study monitored patients who visited the psychiatric hospital in Mashhad for examination by Psychiatrists or neurologists and those who obtained ADHD medications from governmental pharmacies over 3 months. We included all the patients who had the above conditions in the study, and the requirements for excluding them from the analysis were their lack of consent to continue participating in the survey or stop taking the medicine. Eventually, a total of 197 individuals were included in the study—134 from Mashhad Psychiatric Hospital and 63 patients from governmental pharmacies. It should be mentioned that preschool patients mostly resisted behavioral therapies, and according to the guidelines, in this situation, psychiatrists started pharmacological treatments for them [19, 26]. Clinical data were collected through interviews conducted by neurologists and psychiatrists. Demographic information about the patients can be found in Table 1. During the interviews, EQ-5D questionnaires, which is one of the valid and standard questionnaires to evaluate the quality of life, were completed by patients and their parents, providing valuable clinical data. Some of these patients, who were over 7 years old, independently completed this questionnaire. The rest, who were under 7 years old and lacked the ability to read and write, or due to physical and mental conditions, were not in the circumstances to complete the questionnaire alone, had this questionnaire completed with the assistance of their parents. Additionally, the study considered the findings of relevant studies and trials conducted in other countries that demonstrated the effectiveness of LDX and MPH in treating ADHD [37,38,39,40,41]. These studies consistently showed the superiority of medicine-based treatment over placebo [41, 42]. EQ-5D questionnaires were utilized to validate the results of these studies and trials. Thus, the clinical data necessary for the CEA were collected. The target population for this research consisted of Iranian children and adolescents under 18 years old diagnosed with ADHD by a psychiatrist. The baseline transition probabilities for treatment response and discontinuation due to adverse events were obtained from the Zimovetz study, as presented in Table 2 [39].

Table 1 Frequency of some demographic characteristics (based on sex) of patients participating in the studyTable 2 Relative risks for discontinuation due to adverse events (medicine vs. placebo)CostsDirect medical costs

The study considered direct medical costs, specifically medicine acquisition costs. Unit costs were obtained from the official FDA website of Iran in June 2020 and converted to 2022 US Dollars (USD), with an exchange rate of 42,000 Iranian Rial Rates (IRR) per USD [43]. To account for potential economic fluctuations and exchange rate changes, the study used the free-market exchange rate obtained from the foreign exchange market in Iran for the statistical calculations of direct and indirect costs. The conversion rate used was 290,427 Rials per US Dollar, announced by the official exchange offices of the Central Bank of Iran at the time of the research.

The trials and studies used 30- and 50 mg dosage forms of LDX [37,38,39,40,41]. Therefore, the average price of both forms was considered. This approach was justified by the LDX Defined Daily Dose (DDD), which is 30 mg daily [44]. Regarding MPH, the trials and studies utilized a daily dose ranging from 10 to 60 mg, but the study adopted the WHO-recommended amount of 30 mg [45]. As Iran is not a member of the World Trade Organization (WTO), it does not strictly adhere to intellectual property laws for pharmaceutical patents. Consequently, pharmaceutical products in Iran are available in Original Brand (OB), Generics (Gx), and Biosimilar (BS) forms. The unit prices for general forms of MPH were 0.004US Dollars per 1 mg, while Gx forms of LDX long-acting capsules were the only available forms in Iran, with unit prices of 0.013US Dollars per 1 mg.

All costs were calculated in 2022 US Dollars, with an exchange rate of USD 1 = IRR 290,427 (Iranian Rial). The study utilized a cost-effectiveness threshold of 2450 USD, as the WHO recommended, based on the latest acceptable CEA threshold announced by the Iran FDA (Table 3).

Table 3 Direct and indirect costs applied in the base-caseDirect nonmedical costs

Direct nonmedical costs were gathered through self-declaration by patients with ADHD. Face-to-face or telephone interviews were conducted using a pre-prepared checklist to calculate these costs. Direct nonmedical prices include expenses related to transportation (within the city and long-distance), food and accommodation for the patient and their companions, purchase of medical supplies and aids (such as wheelchairs, walkers, and home care beds), home modifications due to the illness (e.g., installation of an elevator for a paralyzed patient with ADHD), and the cost of accommodation for patients' companions (Table 3).

Indirect costs

Indirect costs were derived from the productivity loss of patients or their family members due to illness, death, or treatment. The productivity loss includes the absence from the work of patients and their family members who provide care. The following factors were calculated as productivity losses in this study:

Number of disability days for patients and companions, including time spent on outpatient and inpatient services, travel time, hospitalization days, and recovery days after discharge.

Job loss resulting from illness.

Number of hospitalizations, nursing days at home, and days of disability for family members, relatives, and friends due to patient care.

Percentage decrease in patient income due to illness.

The study employed the human capital approach based on the minimum wage to calculate indirect costs. The data necessary for this calculation were obtained through self-reporting by patients and their companions via face-to-face or telephone interviews.

The formula used to calculate the indirect cost for each individual and disease status is as follows: Minimum daily wage * Total number of disability days for patients and companions = Indirect cost.

The average national wage for laborers in Iran was determined to be 885,165 Iranian Rials (USD 1 = IRR 279,199) per day, multiplied by the number of days lost [46]. The minimum monthly wage was 41,797,500 Rials (USD 149.70), and the minimum daily wage was 1,390,000 Rials (USD 4.97) [46].

Model assumptions

Patients are included in the model when they start treatment with either LDX or MPH. They undergo a 28-day titration period to reach the optimal treatment dose. Patients who experience intolerable side effects during titration (within the first 14 days of treatment) discontinue therapy. For those who stop treatment during titration, the utilities and costs during this period (28 days) are a combination of 50% respondent and non-respondent values. The costs are also a mixture of 50% respondent costs and 50% non-respondent medicine costs. This assumption is based on the average observation that patients discontinue treatment halfway through the first month across different treatments. Alternative assumptions were explored where these patients were assumed to have the same utility as respondents and non-respondents during titration.

Patients who discontinue treatment due to intolerable side effects do not start any further pharmacological treatment. Like non-respondents, they are assumed to receive behavioral therapy. This assumption is primarily driven by the need for more relevant clinical evidence on follow-up therapies. In the model, the behavioral therapies are the same for both LDX and the comparison group, so the model results do not differentiate between them. Therefore, it is assumed that patients who drop out have the same utilities and costs as non-respondents for the remaining 1-year model horizon.

At the end of the titration period, patients who do not respond to treatment discontinue it without pursuing other pharmacological therapies. They are assigned the non-response costs and utilities for the titration period and the remaining time horizon of the model. Patients who respond to treatment at the end of the titration period continue with it for the rest of the model's time horizon, maintaining their level of response. Patients who respond to and tolerate treatment are assumed to be fully adherent and persistent throughout the model's time horizon, based on observations from pivotal trials. This dichotomous response framework is utilized. In the base-case evaluation, costs and outcomes are not discounted since the time horizon is 1 year.

Treatment strategies

In the medical approach for ADHD patients, two pharmacological treatment options were considered: LDX and MPH. The initial dose for LDX was 30 mg, followed by a maintenance dose of 30 to 70 mg once daily [47]. For MPH, the initial amount was 5 mg twice daily, which could be adjusted to a maximum of 60 mg daily [48]. The medicines were intended to be used for 1 year only.

Model outputs

The study’s primary outcome was the ICER. This ratio represents the additional cost of pharmacological treatment to achieve a designated clinical outcome (QALY) within 1 year. The effectiveness and cost-effectiveness of interventions were calculated and compared using monetary units, QALYs, and the cost per QALY for all treatments. The ICER was estimated using the formula [36]: ICER = (Cost of intervention A—Cost of intervention B)/(Increase in quality-of-life A—Increase in quality-of-life B).

Scenario analysis

The decision tree model used in the study considered two treatment strategies for patients receiving LDX and MPH. In each strategy, patients could either tolerate the medications or discontinue treatment. After the titration stage, patients had two conditions: they either responded to treatment or did not respond. Clinical guidelines such as NICE, the American Academy of Pediatrics (AAP), and the European ADHD Guidelines Group (EAGG) and expert opinions guided the selection of treatment comparators [49,50,51]. Non-pharmacological interventions, such as parent training, cognitive behavioral therapy (CBT), cognitive training, play therapy, and Biofeedback and Neurofeedback, were included as part of the non-medicine costs and were assumed to vary based on treatment response [52]. The target population for the analysis was children and adolescents with ADHD. Health outcomes included "tolerate," "unable to tolerate," "response," and "non-response." The impact of using LDX instead of MPH in terms of costs and health outcomes was assessed based on treatment response and discontinuation rates.

Sensitivity analysis

Deterministic and probabilistic sensitivity analyses were conducted to address uncertainties in model inputs. In DSA, ± 20.0% variation in necessary information such as average cost of ADHD care, prices of LDX and MPH, and 5.0% variation in the probability of ADHD in the first year were considered. PSA was utilized using Monte Carlo simulation with 5000 iterations to generate a scatter plot and acceptability curve, capturing the uncertainties in the model.

Budget impact analysis

The DDD of LDX and MPH were obtained from the WHO website for the budget impact analysis. The number of people with ADHD and the prevalence rate among individuals under 18 years old in Iran was considered. Market share calculations were performed using official pharmaceutical statistics from the Food and Medicine Organization of the Ministry of Health in Iran. Three scenarios were designed to calculate the budget impact of adding LDX:

1.

LDX is not covered by insurance, and treatment continues with MPH.

2.

LDX is not covered by insurance, but the medicine is available in the market.

3.

LDX is covered by insurance, and both LDX and MPH are used for treatment, considering changes in market share. The market size of MPH and other competitors was estimated.