Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study.

BACKGROUND: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator. METHODS: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1·7 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners. FINDINGS: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1·46 (95% CI 0·93-2·30). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0·71 (95% CI 0·34-1·51; p=0·38). INTERPRETATION: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching. FUNDING: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre.

Reduction of biologic pricing following biosimilar introduction: Analysis across 57 countries and regions, 2012-19.

OBJECTIVE: To evaluate the impact of the entry of biosimilars on the pricing of eight biologic products in 57 countries and regions. METHODS: We utilized an interrupted time series design and IQVIA MIDAS® data to analyze the annual sales data of eight biologic products (adalimumab, bevacizumab, epoetin, etanercept, filgrastim, infliximab, pegfilgrastim, and trastuzumab) across 57 countries and regions from January 1, 2012, to December 31, 2019. We examined the immediate and long-term changes in biologics ex-manufacturer pricing following the entry of biosimilars to the market. RESULTS: Following the entry of biosimilars, the average price per dose of biologic product was immediately reduced by $438 for trastuzumab, $112 for infliximab, and $110 for bevacizumab. The persistent effect of biosimilars' market entry led to further reductions in price per dose every year: by $49 for adalimumab, $290 for filgrastim, $21 for infliximab, and $189 for trastuzumab. Similarly, we analyzed the impact of biosimilars on four biologics' prices in the US, where the prices of three biologics significantly decreased every year, with filgrastim, pegfilgrastim, and infliximab decreasing by $955, $753, and $104, respectively. CONCLUSIONS: The introduction of biosimilars has significantly reduced the prices of biologics both globally and in the US. These findings not only demonstrate the economic benefits of increasing biosimilar utilization, but also emphasize the importance of biosimilars in controlling healthcare costs. Policies should aim to expand the availability of biosimilars to counteract the exponential growth of medical spending caused by the use of biologics.

Risk of serious infection associated with different classes of targeted therapies used in psoriatic arthritis: a nationwide cohort study from the French Health Insurance Database (SNDS).

OBJECTIVE: To assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings. METHODS: This nationwide cohort study used the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database to identify all adults with PsA who were new users of targeted therapies (adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, secukinumab, ixekizumab, ustekinumab, and tofacitinib) from 1 January 2015 to 30 June 2021. The primary outcome was a serious infection (ie, requiring hospitalisation), in a time-to-event analysis using propensity score-weighted Cox models, with adalimumab as the comparator, estimating weighted HRs (wHRs) and their 95% CIs. RESULTS: A total of 12 071 patients were included (mean age 48.7±12.7 years; 6965 (57.7%) women). We identified 367 serious infections (3.0% of patients), with a crude incidence rate of 17.0 per 1000 person-years (95% CI, 15.2 to 18.7). After inverse propensity score weighting and adjustment for time-dependent covariates and calendar year, risk of serious infection was significantly lower for new users of etanercept (wHR 0.72; 95% CI, 0.53 to 0.97) or ustekinumab (wHR, 0.57; 95% CI, 0.35 to 0.93) than adalimumab new users. This risk was not statistically modified with the other targeted therapies. CONCLUSIONS: The incidence of serious infection was low for PsA patients who were new users of targeted therapies in real-world settings. Relative to adalimumab new users, this risk was lower among new users of etanercept and ustekinumab and unmodified for the other molecules.

Use of Efficiency Frontiers to Align Prices and Clinical Benefits of Biologic Therapies for Plaque Psoriasis.

Importance: The US lacks a systematic approach for aligning drug prices with clinical benefit, and traditional cost-effectiveness analysis (CEA) faces political obstacles. The efficiency frontier (EF) method offers policymakers an alternative approach. Objective: To assess how the EF approach could align prices and clinical benefits of biologic medications for plaque psoriasis and estimate price reductions in the US vs 4 peer countries: Australia, Canada, France, and Germany. Design and Setting: This health economic evaluation used the EF approach to compare the prices and clinical benefits of 11 biologics and 2 biosimilars for plaque psoriasis in the US, Australia, Canada, France, and Germany. Data were collected from February to March 2023 and analyzed from March to June 2023. Main Outcome Measures: EFs were constructed based on each biologic's efficacy, measured using the Psoriasis Area and Severity Index (PASI) 90 response rate, and annual treatment cost as of January 2023; US costs were net of estimated manufacturer rebates. Prices based on the EF were compared with traditional CEA-based prices calculated by the Institute for Clinical and Economic Review at a threshold of $150 000 per quality-adjusted life-year gained. Results: Among 13 biologics, PASI 90 response rates ranged from 17.9% (etanercept) to 71.6% (risankizumab); US net annual treatment costs ranged from $1664 (infliximab-dyyb) to $79 277 (risankizumab). The median (IQR) net annual treatment cost was higher in the US ($34 965 [$20 493-$48 942]) than prerebate costs in Australia ($9179 [$6691-$12 688]), Canada ($15 556 [$13 017-$16 112]), France ($9478 [$6637-$11 678]), and Germany ($13 829 [$13 231-$15 837]). The US EF included infliximab-dyyb (PASI 90: 57.4%; annual cost: $1664), ixekizumab (PASI 90: 70.8%; annual cost: $33 004), and risankizumab (PASI 90: 71.6%; annual cost: $79 277). US prices for psoriasis biologics would need to be reduced by a median (IQR) of 71% (31%-95%) to align with those estimated using the EF; the same approach would yield smaller price reductions in Canada (41% [6%-57%]), Australia (36% [0%-65%]), France (19% [0%-67%]), and Germany (11% [8%-26%]). Except for risankizumab, the EF-based prices were lower than the prices based on traditional CEA. Conclusions and Relevance: This economic evaluation showed that for plaque psoriasis biologics, using an EF approach to negotiate prices could lead to substantial price reductions and better align prices with clinical benefits. US policymakers might consider using EFs to achieve prices commensurate with comparative clinical benefits, particularly for drug classes with multiple therapeutic alternatives for which differences can be adequately summarized by a single outcome measurement.

Access to biologics and Janus kinase inhibitors for treatment of rheumatic diseases in the biosimilars era in Poland: a nation-level study.

INTRODUCTION: By reducing treatment costs, biosimilars provide an opportunity to improve accessibility to highly effective drugs. OBJECTIVES: This study aimed to evaluate access to biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKis) among patients with rheumatic musculoskeletal diseases within a 10 year timeframe in Poland. PATIENTS AND METHODS: We performed a retrospective analysis using a nationwide public payer database. RESULTS: By 2022, 11 102, 6602, and 4400 patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were treated with bDMARDs or JAKis. Peak drug utilization was observed for adalimumab, followed by etanercept and tocilizumab. Within the study timeframe, the estimated access to innovative drugs increased from 0.8%, 1.4%, and 0.8% to 3.2%, 8.7%, and 3.5% for RA, PsA, and axSpA patients, respectively. Affordable tumor necrosis factor inhibitors (TNFis) still predominate among innovative therapeutics, but their market share declined from 87% to 46%. The number of patients treated with other bDMARDs/JAKis almost doubled within the prespecified timeframe. Overall, the average annual treatment cost per patient decreased by 60%, from 7315 EUR to 2886 EUR. Despite recent safety warnings, JAKis appear to be increasingly utilized. Additional analyses regarding the COVID­19 pandemic showed impaired access to intravenous therapies, but not subcutaneous or oral formulations. CONCLUSIONS: In Poland, biosimilars­related savings improved availability of higher­priced innovative drugs rather than less costly TNFis. Data­driven resource allocation and dedicated policy solutions facilitating access to affordable biologics are recommended.

Identifying therapeutic alternatives in Medicare drug price negotiation: The case of etanercept.

As the Centers for Medicare & Medicaid Services (CMS) navigates the process of negotiating drug prices, it plans to compare the cost, safety, and effectiveness of each drug with its therapeutic alternatives. How CMS selects therapeutic alternatives is a consequential decision, and there remains uncertainty about their methodology. To understand the challenges CMS will face in selecting therapeutic alternatives, we developed a methodology that leverages clinical guidelines by US medical professional associations to identify potential therapeutic alternatives for etanercept, one of the first 10 drugs selected for Medicare price negotiation. For each of etanercept's 5 US Food and Drug Administration-approved indications, we identified all drugs with the same mechanism of action as etanercept and considered drugs with different mechanisms if they were recommended in place of etanercept at the same treatment stage, or if there was no strong comparative safety or effectiveness evidence that the drug differed from etanercept. We identified 22 potential therapeutic alternatives to etanercept, including 4 drugs with the same mechanism, 10 biologics with different mechanisms, and 8 small-molecule drugs. We faced several challenges in selecting therapeutic alternatives using clinical guidelines, such as how to reconcile strong recommendations that were based on weak evidence and how to consider combination therapies. This exercise demonstrates the complex considerations that CMS will face as it negotiates drug prices based on therapies' cost, safety, and effectiveness relative to therapeutic alternatives.

Anti-tumor necrosis factor α: originators versus biosimilars, comparison in clinical response assessment in a multicenter cohort of patients with inflammatory arthropathies.

OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy.

OBJECTIVES: The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. METHODS: The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab.Adult subjects with Rheumatoid Arthritis were considered in the analysis.In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. RESULTS: Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. CONCLUSIONS: This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

Availability of comparative real-world evidence research in Medicare patients: implications for Centers for Medicare and Medicaid Services drug price negotiations.

Aim: To evaluate the availability of published comparative real-world evidence (RWE) studies in Medicare patients for the ten drugs set to undergo Centers for Medicare and Medicaid Services (CMS) price negotiations in 2026. Materials & methods: A scoping review was completed in MEDLINE/PubMed to evaluate the availability of comparative RWE investigations conducted among Medicare-eligible patient populations in the US for the following drugs: apixaban, rivaroxaban, sitagliptin, ibrutinib, empagliflozin, etanercept, dapagliflozin, sacubitril/valsartan, ustekinumab and insulin aspart. Results: Of the 170 real-world comparative studies identified, 55 (32.4%) used Medicare real-world data (RWD) while 34 (20.0%) used commercial claims data in conjunction with either Medicare Advantage or Medicare Supplementary databases. The number of studies varied considerably by drug with apixaban and rivaroxaban studies accounting for the majority (i.e., 67.1%) of comparative RWE studies. Approximately a third or less of the comparative RWE studies were conducted in CMS RWD per drug. Conclusion: Our results demonstrate there is a considerable amount of comparative RWE for apixaban, rivaroxaban, and etanercept but limited comparative RWE for the other drugs set to undergo CMS price negotiations in 2026; additionally, our findings set up a number of next steps (e.g., risk of bias assessments) for further exploration of the available evidence base. Overall, CMS and manufacturers should consider proactively generating high-quality comparative RWE studies in the Medicare population to ensure that future price negotiations are based on robust evidence.

Expenditure of biological drugs for rheumatoid arthritis treatment in the Brazilian public health system.

OBJECTIVE: This work aims to analyze the quantity and expenses related to biological drugs used for the treatment of rheumatoid arthritis (RA) in outpatient public care within the Brazilian Unified Health System (SUS). METHODS: It is a cross-sectional descriptive study based on secondary data from a historical series, referring to the purchase, volume, and the number of patients treated with different biological drugs (infliximabe, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab, and certolizumab pegol) for RA treatment in outpatient care from 2012 to 2017. The data were extracted from the SUS Outpatient Information System database-SIA/SUS and included ten drugs used for RA treatment. The study assessed the quantity and expenditure of these drugs, the number of RA patients treated, and the expenditure by RA subtypes. The National Broad Consumer Price Index was used to adjust the expenditures for December 2017. RESULTS: The Ministry of Health allocated approximately $500 million to provide about 2 million units of biological drugs for RA patients from 2012 to 2017. The supply of adalimumab 40 mg and etanercept 50 mg accounted for 68.3% of the total expenditure. The subtypes "other rheumatoid arthritis with rheumatoid factor" (ICD-10 M05.8), "rheumatoid arthritis without rheumatoid factor" (ICD-10 M06.0), and "Felty's syndrome" (M05. 0) represented 84.5% of the total expenditures. The proportion of patients treated with biological drugs increased by 33.0%. There was a significant 83.0% increase in the number of patients using biological drugs compared to the overall number of RA patients treated during the study period. CONCLUSIONS: The results obtained allow us to draw a more recent profile of expenditure on RA treatment and indicate trends in the use of biological drugs for this condition, generating data that can support management decisions in public health policies.

Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database.

BACKGROUND AND OBJECTIVE: Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database. METHODS: We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events. RESULTS: In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy. CONCLUSIONS: This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results.

What About Offering a Financial Incentive Directly to Clinical Units to Encourage the Use of Biosimilars? Results of a Two-Year National Experiment in France.

BACKGROUND: Regarding the low penetration of biosimilars in the French market, in 2018, the government introduced two mutually exclusive financial incentives to increase biosimilar use. They redirect 20% (general case) or 30% (experimental case) of the price difference between the reference product and its biosimilar to hospitals for every biosimilar delivered in retail pharmacies from these hospital prescriptions. The experimental case specifically targets prescribing clinical units. OBJECTIVES: Our study aimed to assess whether the new payment scheme closer to physicians (experimental case) improved etanercept biosimilar penetration after 25 months. METHOD: We evaluated hospital prescriptions using IQVIA Xponent data. The monthly number of etanercept boxes delivered in retail pharmacies was linked to the corresponding hospital prescription. The impact of the experimental case on the etanercept biosimilar rate was assessed by a difference-in-difference method. RESULTS: Among the 39 hospitals studied in the experimental case compared with the 169 belonging to the general case, a similar growing trend of etanercept biosimilar use was observed before October 2018. At the start of the experiment, there was an acceleration of biosimilar penetration in the experimental group, until both groups reached a plateau. A significant double difference estimator of 9.72 percentage points in favor of the experiment confirmed this (p < 2.2.10-16). CONCLUSION: The French experimental incentive appeared to be more effective at increasing biosimilar use. As it is expected to be implemented in all hospitals, the knowledge gained during this testing phase should allow adjustment of some of its terms and increase physician engagement.

Eficacia y seguridad de adalimumab en pacientes adultos con artritis reumatoide activa moderada a grave con intolerancia y/o falla a terapia convencional e infliximab / Efficacy and safety of adalimumab in adult patients with moderately to severely active rheumatoid arthritis with intolerance and/or failure to conventional therapy and infliximab

ANTECEDENTES: El presente dictamen expone la evaluación de la eficacia y seguridad de adalimumab en pacientes adultos con artritis reumatoide activa moderada a grave con intolerancia y/o falla a terapia convencional e infliximab. Esta evaluación se realiza en respuesta a la solicitud de la médica especialista en reumatología Ana Karina La Madrid Barreto del Hospital III José Cayetano Heredia de Piura, quien siguiendo la Directiva N° 003-IETSIESSALUD-2016, envió al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico adalimumab no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La artritis reumatoide (AR) es una enfermedad crónica inflamatoria de etiología desconocida, que inicialmente afecta las articulaciones sinoviales (England 2022; SSR 2021). La AR es una enfermedad típicamente simétrica y, usualmente, si no es ontrolada, ocasiona la destrucción de las articulaciones debido a la erosión del cartílago el hueso, causando deformaciones en

Cost Effectiveness of Rituximab Therapy for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Cost-Utility Studies.

BACKGROUND AND OBJECTIVES: Depletion of B cells is shown to be clinically effective for rheumatoid arthritis (RA) treatment. Although B-cell depletion therapy with rituximab is indicated for RA patients who have failed to other disease-modifying anti-rheumatic drugs (DMARDs), primary cost-effectiveness evidence is inconsistent. We aimed to provide synthesised cost-effectiveness evidence of rituximab in the treatment of RA compared to other DMARDs, since the published cost-effectiveness evidence is mixed. METHODS: We identified economic evaluation studies reporting cost-utility of rituximab compared to other DMARDs by searching PubMed, Embase, Scopus, and Tufts Cost-Effective Analysis registry. Using random-effects meta-analysis, we pooled incremental net benefit (INB) in (purchasing power parity) adjusted US$ with 95% confidence intervals. We used the modified economic evaluations bias checklist and Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) instrument for quality appraisal. The study protocol was pre-registered with PROSPERO, CRD 42021222541. RESULTS: Of the selected 18 studies, the majority were from high-income countries (n = 14) followed by upper middle-income countries (n = 3) and lower middle-income countries (n = 1), with minimal risk of bias. Rituximab is significantly cost effective with a pooled INB (95% CI) of $8767 (720 to 16,814). On subgroup analysis, rituximab is significantly cost effective from a health system perspective [$12,832 (3392 to 22,272)], for studies using 3.5% discount rate [$15,468 (5973 to 24,963)] and a for a time horizon of less than 5 years [$8496 (1547 to 15,445)]. In a separate analysis, rituximab as third-line therapy (for conventional synthetic DMARDs followed by any other biologic DMARD failed patients) was not cost effective compared to DMARDs [$5314 (-2278 to 12,905)]. Further, the GRADE assessment indicated very-low confidence in the pooled results. CONCLUSION: Rituximab is cost effective compared to other DMARDs but not if used as third-line therapy after failure of biologics. There is a need to generate context-specific evidence for the lower income settings.

Assessment of the influence of Fc-γ receptor polymorphisms on biologics' pharmacokinetics in Tunisian rheumatoid arthritis patients.

AIMS: This study aims to determine whether a modification in Fc-γ receptors' (FcgRs) affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus serum drug levels and the development of anti-drug antibodies. METHODS: A cross sectional, multicentral and noninterventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the 3 FcgR single nucleotide polymorphisms. RESULTS: A total of 81 patients were included: 47 were under tumour necrosis factor inhibitors (18 ETA, 13 ADL and 16 IFX), and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%), of whom only 1 was treated with RTX. Fourteen patients (22.2%) developed ADA, but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FcgR polymorphisms. However, the high affinity FcgR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (P = .018). The same result was obtained in the monoclonal antibody tumour necrosis factor inhibitor subgroup (n = 29, P = .022) as well as in patients treated only with IFX (n = 16, P = .029). CONCLUSION: Our work supports the hypothesis of an impact of FcgR single nucleotide polymorphisms on biologics' immunogenicity, particularly FcgR R131H polymorphism, but further studies with larger cohorts need to be undertaken to confirm these results.

Cost-effectiveness analyses of biologic and targeted synthetic disease-modifying anti-rheumatic diseases in patients with rheumatoid arthritis: Three approaches with a cohort simulation and real-world data.

OBJECTIVE: To assess the cost-effectiveness of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in rheumatoid arthritis. METHODS: We conducted three analyses: a lifetime analysis with a cohort model (Study A) and two short-term analyses (Studies B and C). Study A evaluated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained from costs of standard treatments. Study B evaluated yearly costs per person achieving American College of Rheumatology (ACR) response (ACR20, ACR50, and ACR70), and Study C evaluated costs per person achieving previously defined claims-based effectiveness (equivalent to 28-joint Disease Activity Score ≤ 3.2). The proportion of ACR responders to the drugs of interest were determined by mixed treatment comparisons. Studies B and C estimated costs using a claims database. RESULTS: In Study A, ICERs of all b/tsDMARDs were lower than 5.0 million Japanese yen (JPY) per QALY. In Study B, yearly costs per person with ACR50 response were lower for subcutaneous tocilizumab (TCZ-SC; 1.9 million JPY) and SC abatacept (2.3 million JPY). In Study C, costs per person were lower for TCZ-SC (1.3 million JPY) and intravenous TCZ (1.6 million JPY) and effectiveness rates were higher for intravenous TCZ (45.3%) and infliximab (43.0%). CONCLUSION: The b/tsDMARDs with lower prices showed higher cost-effectiveness.

The Influence of US Drug Price Dynamics on Cost-Effectiveness Analyses of Biologics.

OBJECTIVES: This study aimed to evaluate the influence of drug price dynamics in cost-effectiveness analyses. METHODS: We evaluated scenarios involving typical US drug price increases during the exclusivity period and price decreases after the loss of exclusivity (LOE). Worked examples are presented using the Institute for Clinical and Economic Review's assessments of tezepelumab for the treatment of severe asthma and targeted immune modulators for rheumatoid arthritis. RESULTS: Tezepelumab case: yearly 2% price increases during the period of exclusivity and a post-LOE price decrease of 25% yielded an incremental cost per quality-adjusted life-year (QALY) gained that increased over the base case from $430 300 to $444 600 (+3.2%). Yearly 2% price increases followed by a steeper post-LOE price reduction of 40% resulted in a cost per QALY gained of $401 400 (6.8% reduction vs the base case). Rheumatoid arthritis case: incorporating post-LOE price reductions for etanercept (intervention) and adalimumab (comparator) ranging from 25% to 40% yielded an incremental cost per QALY of $121 000 and $122 300, respectively (< 3% increase from the base case of $119 200/QALY). Including a 2% yearly price increase during the projected exclusivity periods of both intervention and comparator increased the cost per QALY gained by > 60%. CONCLUSION: Two biologic treatment cases incorporating price dynamics in cost-effectiveness analyses had varied impacts on the cost-effectiveness ratio depending on the magnitude of pre-LOE price increase and post-LOE price decrease and whether the LOE also affected the comparator. Yearly price increase magnitude during the period of exclusivity, among other factors, may counterbalance the effects of lower post-LOE intervention prices.

The Price and Market Share Evolution of the Original Biologics and Their Biosimilars in Finland.

BACKGROUND: Biological drugs are generally expensive and produce a continuously growing share of drug costs. Yet they are essential in the treatment of many chronic diseases. Biosimilars, clinically equivalent to biological originator products, are expected to restrain drug costs in the biological market. OBJECTIVE: This study aimed to examine the impact of the biosimilar market entry on the prices of the reference products in outpatient care in Finland, investigate the impact of biosimilar market entries on price competition among biological medicinal products, and examine how the prices and market shares of outpatient biosimilars have developed in Finland during 2009-2020. METHODS: This retrospective register study applied data from IQVIA covering national community pharmacy wholesale data between 1 January, 2009, and 31 August, 2020, for somatropin, epoetin, filgrastim, follitropin, insulin glargine, insulin lispro, etanercept, pegfilgrastim, adalimumab, teriparatide, and enoxaparin biosimilars and their reference products, in addition to two relevant insulin products. We determined the monthly wholesale amounts in defined daily doses and wholesale weighted average prices (excluding value-added tax) per defined daily dose for each product. We analyzed the evolution of the price and market shares. We performed a linear segmented regression analysis to examine the impact of the market entry of biosimilars on the prices of reference products. RESULTS: The prices of the reference products mainly decreased after the biosimilar entered the market. If the reference product price was not reduced, it was no longer reimbursable after evaluation under the Health Insurance Act, leading to marginal market shares. The changes in the prices of biosimilars were not as remarkable as the changes in the prices of reference products after the biosimilar market entry. For most active substances, biosimilar prices were stable or decreased. The utilization of biosimilars varied widely between different active substances at the end of the observation period. CONCLUSIONS: Changes in pricing policy and the public reimbursement scheme related to the market entry of biosimilars were the main reasons for the decrease in the prices of reference products. Therefore, biosimilars did not generate genuine price competition between biological products. In many of the drug groups examined, the market shares of biosimilars have growth potential in the future.