Precision Medication Therapy Strategy In Crohn’s Disease: Financial Advantages
Overview
In this study, the cost-effectiveness of precision-guided dosing (PGD) of infliximab (IFX) for patients with Crohn’s disease (CD) who lose response to biologics was evaluated in comparison to two other dose intensification strategies (DIS).
A hybrid model combining Markov and decision tree elements was developed to simulate the outcomes of patients with CD who initially responded to IFX induction using precision medication therapy. The analysis was conducted from the perspective of a US payer over a 5-year time horizon, with cycles of 4 weeks. The three IFX dosing strategies compared were: PGD, which personalized dosing based on a comprehensive pharmacokinetic (PK) profile; DIS1, which intensified dosing based on symptoms, inflammatory markers, and IFX concentration; and DIS2, which relied solely on symptom-based dosing.
Transition probabilities for IFX were derived from real-world clinical PK data and patient-level data from interventional clinical trials, while other transition probabilities were sourced from published randomized clinical trials and cost-effectiveness analyses. Utility values were obtained from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries, procedures, conventional therapy, and lab testing.
The primary outcomes assessed were incremental cost-effectiveness ratios (ICERs), with sensitivity analyses conducted to test the robustness of the results. One-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA) were performed to evaluate the impact of uncertainty on the findings.
Introduction
Crohn’s disease (CD) presents a significant challenge due to its chronic inflammatory nature, often leading to recurrent intestinal inflammation and diminished quality of life for patients. Despite advancements in medical therapy, many patients experience loss of response to treatment and symptom recurrence over time, resulting in increased healthcare costs and reduced productivity. Biologic therapies, such as infliximab (IFX), have become standard for moderate-to-severe CD due to their effectiveness in reducing hospitalizations. However, a substantial proportion of patients do not respond to IFX induction therapy, and many lose response during maintenance treatment.
Loss of response to IFX is often linked to pharmacokinetic factors, such as rapid drug clearance and the development of antibodies against the drug. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize IFX dosing by measuring drug levels and antibodies in patients’ blood. Traditional TDM approaches are reactive, triggered by symptomatic recurrence, or proactive, involving scheduled monitoring regardless of symptoms. Proactive TDM has shown promise in improving clinical outcomes and reducing hospitalizations and surgeries in CD patients.
Precision-guided dosing (PGD) represents an innovative approach to proactive TDM, offering personalized dosing recommendations based on individual patient characteristics, disease factors, and pharmacokinetic data. Unlike traditional proactive TDM methods, PGD utilizes an adaptive Bayesian forecasting framework to tailor dosing regimens for optimal concentration and sustained remission.
This study aims to assess the cost-effectiveness of IFX PGD compared to two other dosing intensification strategies: DIS1, which combines symptoms, inflammatory markers, and proactive TDM, and DIS2, which relies solely on symptom-based dosing. By evaluating the economic implications of these approaches, the study seeks to inform healthcare decision-makers and optimize the management of CD in the United States.
Methods
Inclusion Criteria
– Studies or trials must pertain to Crohn’s disease (CD) management.
– Studies must adopt a US payer perspective in their analyses.
– Trials or studies must utilize a 5-year time horizon.
– The model structure should be a hybrid format, integrating Markov and decision tree components.
– Transition probabilities and dosing strategies for infliximab maintenance must be based on real-world data or patient-level interventional clinical trial data.
– Health state utility values and costs should be derived from reliable sources, preferably recent US-based studies or clinical expert recommendations.
– Direct costs, including health state-specific monitoring, drug acquisition, therapeutic drug monitoring (TDM) testing, drug administration, and event costs, should be considered.
– Transition probabilities, health-related quality of life (HRQoL) values, and costs should be accurately parameterized and validated.
Exclusion Criteria
– Studies that do not adhere to the specified inclusion criteria.
– Models or analyses lacking transparency in their methodologies or data sources.
– Studies with inadequate justification or validation of parameter assumptions.
– Trials or studies relying on outdated or unreliable data sources for transition probabilities, utility values, or costs.
– Models lacking comprehensive sensitivity analyses to assess parameter uncertainty and robustness of results.
– Analyses with significant methodological flaws or inconsistencies in the application of modeling techniques.
Analysis
The study employed multiple scenario analyses to evaluate the effects of different parameter assumptions on the outcomes. Various scenarios were explored, including different model horizons ranging from 1 to 10 years, alternative drug acquisition cost sources (Big4 or Federal Supply Schedule), and varying initial distributions of Crohn’s disease severity.
Additionally, sensitivity analyses were conducted to assess the impact of input parameters on incremental net monetary benefits (iNMBs). One-way deterministic sensitivity analysis (OWSA) and threshold sensitivity analysis (TSA) were utilized to vary parameters within predetermined ranges and observe their effects on cost-effectiveness outcomes.
To address the complexity of the model and the large number of input parameters, probabilistic sensitivity analysis (PSA) was employed. PSA allowed for the assessment of joint parameter uncertainty by utilizing parameter distributions with associated alpha (α) and beta (β) values. Transition probability parameters derived from patient-level data were fitted using a beta distribution, while the mean dosing interval, health state costs, and event costs were fitted using a gamma distribution. Assumed parameters or those lacking reliable mean and variance information were varied using a ±20% uniform distribution, with exceptions of ±10% and ±5% to prevent illogical values.
Results
The base case analysis, along with scenario analyses, provided comprehensive insights into the cost-effectiveness of precision-guided dosing (PGD) in comparison to other dosing strategies for Crohn’s disease (CD) management. These analyses, conducted over varying time horizons ranging from 1 to 10 years, considered different aspects such as drug acquisition costs, disease severity distribution, and testing costs associated with PGD.
In the base case scenario, PGD exhibited an incremental cost-effectiveness ratio (ICER) relative to dose intensification strategy 1 (DIS1) of $122,932 per quality-adjusted life year (QALY). This suggests that, compared to DIS1, PGD comes at an additional cost to gain an additional QALY. However, when compared to DIS2, both PGD and DIS1 were found to be more favorable options, with PGD showing dominance over DIS2 in terms of costs and QALYs gained.
Moreover, the analysis explored various sensitivity scenarios to understand the robustness of the results. One-way deterministic sensitivity analysis (OWSA) highlighted the impact of different parameters on the incremental net monetary benefits (iNMBs) of PGD relative to DIS1. Parameters such as the PGD mean dosing interval were identified as having a substantial influence on the cost-effectiveness outcomes.
Threshold sensitivity analysis further identified parameters that could alter the cost-effectiveness decision, with PGD TDM cost being one of the key factors. This analysis indicated the threshold values at which PGD would remain cost-effective compared to other strategies.
Probabilistic sensitivity analysis (PSA) introduced the element of uncertainty into the analysis by considering joint parameter uncertainty. Despite this uncertainty, the dominance of both PGD and DIS1 over DIS2 was consistently observed, indicating higher QALYs at lower costs.
Overall, the analyses provided valuable insights into the cost-effectiveness of PGD in the management of CD, highlighting its potential as a favorable dosing strategy, particularly when compared to traditional approaches like DIS1 and DIS2.
Discussion
The results of this cost-effectiveness analysis confirm the efficacy of therapeutic drug monitoring (TDM) strategies in managing Crohn’s disease (CD) patients transitioning to infliximab (IFX) maintenance therapy post-induction. Specifically, TDM approaches, such as precision-guided dosing (PGD), were found to be cost-effective compared to strategies solely based on symptomatic response (DIS2), in line with previous research findings.
PGD emerged as a potentially cost-effective option relative to dose intensification strategy 1 (DIS1) at a willingness-to-pay (WTP) threshold of $150,000 per quality-adjusted life year (QALY). Moreover, both PGD and DIS1 demonstrated dominance over DIS2, indicating superior outcomes in terms of cost and QALYs gained. Over a 5-year horizon, PGD exhibited significant worth, with $2140 and $65,036 more per patient compared to DIS1 and DIS2, respectively, reinforcing its value in CD management.
Insights from scenario analyses further elucidated the impact of varying parameters on cost-effectiveness outcomes. Notably, drug acquisition costs, particularly for IFX, exerted substantial influence, emphasizing the importance of biosimilar use in enhancing cost-effectiveness. Additionally, scenarios exploring initial disease severity distribution highlighted the effectiveness of PGD, especially for patients with mild CD, underscoring its role as a personalized TDM approach crucial for preventing disease progression and hospitalization.
One-way deterministic sensitivity analysis (OWSA) and threshold sensitivity analysis (TSA) identified key parameters affecting cost-effectiveness decisions, including the PGD mean dosing interval, remission quality of life (QoL) values, and DIS1 transition probabilities. These analyses underscored the robustness of PGD as a cost-effective strategy, particularly when considering its ability to maintain remission effectively.
Probabilistic sensitivity analysis (PSA) confirmed the favorable cost-effectiveness profile of TDM strategies, with both PGD and DIS1 demonstrating a high probability of being cost-effective relative to DIS2. While PGD showed slightly lower mean incremental net monetary benefits (iNMBs) compared to the base case, the right skew in PGD costs influenced outcomes, emphasizing the importance of parameter variation in PSA.
Despite its contributions, the model has limitations, including reliance on small sample sizes for parameter estimation and the memory-less nature of Markov cohorts. Future models could overcome these challenges by incorporating more objective disease severity markers and conducting microsimulations for a nuanced understanding of CD treatment pathways.
Conclusion
According to the simulation results, therapeutic drug monitoring (TDM) strategies present a high likelihood of being cost-effective compared to reactive dose intensification strategies (DIS) for patients with Crohn’s disease (CD) initiating infliximab (IFX) maintenance therapy. This holds particularly true for patients with mild disease severity. Precision-guided dosing (PGD) emerges as a promising approach, offering both clinical and quality of life (QoL) benefits by effectively maintaining clinical remission and preventing IFX failure. In comparison to DIS1, especially among patients with mild CD, PGD is expected to be cost-effective. By adopting personalized TDM approaches, US payers can enhance QoL outcomes for CD patients while also realizing cost savings, particularly as IFX and its biosimilars become more affordable to acquire.
