Exploring the impact of the national tender system on the use of costly drugs treating rheumatoid arthritis patients in ten rheumatology centers in Norway (2010-2019).

BACKGROUND: Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are highly effective in treating rheumatoid arthritis (RA), albeit high drug cost has restricted their use in many countries. As a countermeasure, Norway implemented pharmaceutical tendering as a cost-reducing strategy. The aim of this study was to assess the annual proportion of different b/tsDMARDs registered to treat RA patients under the influence of a Norwegian pharmaceutical tendering between 2010 and 2019. METHOD: The data is collected from ten Norwegian outpatient centers. The included patients are categorized as naïve, non-naïve, and current b/tsDMARD users. 13 individual b/tsDMARDs are assessed and compared with the tender rankings from each year. Overview of subcutaneous (sc) with per oral vs. intravenous (iv) and biosimilars vs. non-biosimilar are also described. RESULT: The tender-winning b/tsDMARD was the most or second most used drug in nine out of ten years for naïve users, seven for non-naïve users, and twice for current users. The average sum of the highest and second highest proportion among naïve, non-naïve, and current b/tsDMARD users were 75%, 53%, and 50% during the ten years, respectively. The tender-winning drug was iv in eight out of ten years. However, the average total proportion of sc and per oral b/tsDMARDs was about 70% for naïve b/tsDMARD users, 50% for non-naïve b/tsDMARD users, and 60% for current b/tsDMARD users. The main contributors to sc and per oral b/tsDMARD were etanercept (reference and biosimilar) and certolizumab pegol. The main contributors to iv b/tsDMARD were rituximab reference and infliximab biosimilar. Despite low-ranking offers, rituximab reference (offered as a second-line drug) often achieved a high proportion among non-naïve and current b/tsDMARD users. After the introduction of biosimilars, their average proportion was about 40%, 40%, and 20% for naïve, non-naïve, and current b/tsDMARD users, respectively. CONCLUSION: Based on observed data, a higher tender rank was associated with a higher proportion among naïve and non-naïve b/tsDMARD users. However, in most cases, sc b/tsDMARDs achieved a higher proportion with lower tender ranks than iv b/tsDMARDs with higher tender ranks.

Exploring drug cost and disease outcome in rheumatoid arthritis patients treated with biologic and targeted synthetic DMARDs in Norway in 2010-2019 - a country with a national tender system for prescription of costly drugs.

BACKGROUND: In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system. METHODS: RA patients monitored in ordinary clinical practice were recruited from 10 Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process. RESULTS: The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39% in 2010 and 45% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 42 to 67%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47%, from 13.1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75% (13.0 thousand EUR in 2010 and 3.2 thousand EUR in 2019). CONCLUSIONS: In the period 2010-2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities' intention to reduce treatment costs by implementing a tender system has been successful.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). Main Outcome and Measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures: The primary end point was clinical remission at week 30. Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.