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.

The impact of policy interventions to promote the uptake of biosimilar medicines in Belgium: a nationwide interrupted time series analysis.

BACKGROUND: The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake. METHODS: An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses. RESULTS: In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI -61.61 to -14.812; P < 0.001) fewer etanercept biosimilar DDDs were dispensed monthly than expected in the absence of the intervention. Two interventions were modelled for biosimilars in the hospital setting. The first intervention of 2016 includes prescription targets for biosimilars and monitoring of hospitals on adequate tendering. The second intervention involves an information campaign on biosimilars. After the first intervention, a small decrease in quarterly epoetin biosimilar uptake of 449.820 DDD (95% CI -880.113 to -19.527; P = 0.05) was observed. The second intervention led to a larger increase in quarterly epoetin biosimilar uptake of 2733.692 DDD (95% CI 1648.648-3818.736; P < 0.001). For filgrastim, 1809.833 DDD (95% CI 1354.797-2264.869; P < 0.001) more biosimilars were dispensed immediately after the first intervention and 151.639 DDD (95% CI -203.128 to -100.150; P < 0.001) fewer biosimilars each quarter after the first intervention. An immediate and sustained increase of 700.932 DDD (95% CI 180.536-1221.328; P = 0.016) in quarterly biosimilar volume was observed after the second intervention. All other parameter estimates were not statistically significant. CONCLUSIONS: The results of this study suggest that the impact of past policy interventions to increase the uptake of biosimilars has been variable and limited. A holistic policy framework is required to develop a competitive and sustainable off-patent biologicals market in Belgium.

Taking the individual bias out of examining comparability of biosimilars: A case study on monoclonal antibody therapeutics.

Biosimilar manufacturers need to perform analytical and functional similarity assessments against the reference product. Successful demonstration allows for an abbreviated clinical path, thereby translating to affordable biosimilars. Current practices for regulatory concurrence on analytical similarity data are based on chart visualization and open to individual (human) bias. Here, we present a novel, chemometric approach for assessing biosimilarity that aims to simplify assessment and eliminate individual bias from decision making through application of weighted principal component analysis. Through the proposed approach, chemical information across the analytical characterization platform and drug products can be collated into a single plot for quantitative biosimilarity assessment. The proposed one-plot analysis offers a holistic visualization of 1) inter-product variability (w.r.t reference product) in cases where multiple batches per product have been investigated and 2) intra-product variability for each critical quality attribute (CQA) wherein information from orthogonal tools can be incorporated within the same plot. This allows for numerical grading of similarity for biosimilars of any given reference product. Although the proposed statistical approach is novel, it builds on standardized measures of CQA, criticality, and analytical procedures, thus making this approach easy to incorporate within the existing regulatory framework.

Cost comparison of filgrastim versus pegfilgrastim and pegfilgrastim biosimilars for inpatient prophylaxis of febrile neutropenia.

INTRODUCTION: The Ohio State University Comprehensive Cancer Center (The James) uses daily subcutaneous filgrastim as the inpatient granulocyte colony-stimulating factor of choice. The coordination of care associated with filgrastim can often be a barrier to patient discharge. The purpose of this study was to compare the inpatient cost of daily filgrastim to single dose pegfilgrastim and biosimilars. METHODS: Adult patients admitted to The James who received at least one dose of filgrastim between June 1, 2021 and August 31, 2021 were retrospectively identified. This study compared the inpatient cost of filgrastim and biosimilars associated with one chemotherapy cycle to the potential inpatient cost of pegfilgrastim and biosimilars based on average sales price (ASP). Additionally, the number and duration of discharge prescriptions for filgrastim was determined. RESULTS: Of the 44 unique patient encounters that met inclusion criteria, 19 received 300-mcg doses of filgrastim and 25 received 480-mcg doses. The median number of doses administered per admission was eight. If each of these patients were to instead receive the most inexpensive biosimilar, pegfilgrastim reference product, the cost would be 216% higher than with filgrastim-sndz. At discharge, 15 patients (34%) received a prescription for filgrastim to be continued for a median duration of 6 days. CONCLUSION: Based on ASP, pegfilgrastim was more costly than filgrastim. Potential rebates and negotiation power may alter the financial outlook of adding pegfilgrastim to inpatient formulary. Exploration of delays in discharge due to insurance coordination for filgrastim continuation in the outpatient setting may also impact formulary decisions.

[Advances in targeted and immune therapies for hepatocellular carcinoma].

Targeted and immunotherapy drugs for hepatocellular carcinoma (HCC) have been rapidly developed. Atezolizumab in combination with bevacizumab has been recommended as the first-line standard of care for unresectable or advanced HCC in several national and international guidelines. The combination therapies with sindilizumab and bevacizumab biosimilar, apatinib and carrilizumab, dulvalizumab and tremelimumab are also recommended as first-line standard regimens for advanced HCC in the guideline of Chinese Society of Clinical Oncology. Local therapy combined with targeted drugs (such as sorafenib and lenvatinib) or immune checkpoint inhibitors can significantly improve outcomes. Therefore, some progress has also been made in the study of single-agent or combination regimens as perioperative neoadjuvant therapy.

Tapering biologics in axial spondyloarthritis: A systematic literature review.

INTRODUCTION: The emergence of biologics has improved the management of patients with rheumatic disease, mainly with spondyloarthritis (SpA). Sustained remission has become a reachable goal thanks to the treat to target strategy. Contrary to rheumatoid arthritis, data on biologic optimization among SpA patients in remission is scarce and still a subject of debate. The main objective of this systematic review was to provide the most up-to-date published literature regarding biologic tapering in axial spondyloarthritis. METHODS: This systematic review followed the preferred reporting items for systematic reviews guidelines. Original articles from Pubmed and Scopus, published until December 20th 2021, and tackling tapering strategies of the biologics in patients with axial SpA were included RESULTS: Fourteen studies met the inclusion criteria. They were published between 2008 and 2020. The most studied molecules were Etanercept (ETN) (n = 13), Infliximab (IFX) (n = 6), Adalimumab (ADA) (n = 5), certolizumab pegol (CZP) (n = 2), Golimumab (n = 1) and ETN biosimilar. There are no studies published regarding anti-IL 17 tapering strategy. Patient-tailored dose reduction of anti TNF-α agents was successful in preserving stable low disease activity in most of the studies with remission rates ranging between 20.2 % and 93.7 %. Complete treatment discontinuation is associated with a high risk of flares. CONCLUSION: To conclude, published data indicate that a progressive tapering strategy for anti TNF-α therapy is successful among axial SpA in sustained remission. However, further studies with more homogenized tapering strategies are needed in order to ascertain the specific implication of each subset for a better holistic approach.

Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. METHODS: This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). FINDINGS: Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). INTERPRETATION: In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. FUNDING: Innovent Biologics and the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Adalimumab or etanercept as first line biologic therapy in enthesitis related arthritis (ERA) - a drug-survival single centre study spanning 10 years.

OBJECTIVES: To analyse and compare drug-survival of adalimumab and etanercept (and their biosimilars) in biologic-naïve patients with ERA (Enthesitis-Related Arthritis). METHODS: In this retrospective observational study, conventional statistics and machine-learning were applied to compare drug-survival (adalimumab, etanercept and their biosimilars initiated: 2009-2019) in ERA and identify determinants. The primary outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions. RESULTS: During the observation period, 99 of 188 patients with ERA on first-line TNF inhibitors (etanercept-n=108, adalimumab-n=80) discontinued their treatment (median survival-time 3.9years, 95%CI 2.6-4.9years). Adalimumab was associated with longer drug-survival compared to etanercept especially after an initial positive response, with the median time to treatment discontinuation 4.9years (95% CI 3.9-5.7) for adalimumab, compared to 2years (95%CI 1.4-4.0) for etanercept (HR of treatment-discontinuation-0.49, 95%CI 0.32--0.75, p=0.001). Adjusted by propensity-score, adalimumab-methotrexate combination was associated with longer drug survival, compared to adalimumab-monotherapy (HR-0.41, 95%CI 0.20-0.85), etanercept-monotherapy (HR-0.28, 95%CI 0.15-0.53), and etanercept-methotrexate combination (HR-0.39, 95%CI 0.21-0.73). The presence of HLA-B27 was associated with longer drug-survival (HR-0.50, 95%CI 0.29-0.87) following an initial positive response. Higher-CRP at baseline was associated with higher rate of primary-failure (HR-1.68, 95%CI 1.08-2.62). Axial-ERA (sacroiliitis±spinal-involvement) was associated with poorer drug-survival for both primary- and secondary-failure (overall HR-2.03, 95%CI 1.22-3.40). Adjusted by propensity-score, shorter drug-survival was observed in patients with baseline-CRP≥12.15 mg/L, but only in the context of axial-ERA, not in peripheral-ERA (no sacroiliitis/spinal-involvement) (HR-2.28, 95%CI 1.13--3.64). CONCLUSION: Following an initial positive primary response, continuing methotrexate with adalimumab was associated with the longest drug-survival compared to adalimumab-monotherapy or etanercept-based regimens. Axial-ERA was associated with a poorer drug-survival. A CRP >12.15 in patients with axial-ERA was associated with a higher rate of primary-failure. Further prospective studies are required to confirm these findings.

Current state, control, impact and management of rheumatoid arthritis according to patient: AR 2020 national survey.

OBJECTIVES: To analyse current status, control and impact of RA on patients' lives as well as the management of RA symptoms. METHODS: A structured anonymous online questionnaire was designed and sent to patients with RA, aged 18 years or above living in Spain. Participants were invited though different strategies: 1) ConArtritis and related patients associations; 2) Patients participating in the platform www.in-pacient.es; 3) Links from ConArtritis website and open social networks. Sociodemographic and clinical variables, as well as others related to the objectives were collected. A descriptive analysis was performed. RESULTS: We analysed 882 RA patients, 89% women, with a median age of 52 years, 31.9% disease duration <5 years. They reported a mean pain and patient global disease score (0-10) of 5.1 and 4.9 respectively. The rate of patients with many difficulties or inability to perform daily tasks varied from 6.4% to 49.2%. Based on the activity index 56.8% of patients reported high activity. We found a great or severe impact on the emotional well-being in 31.5% of patients, and of 29.2% in the workplace or academic setting. A total of 87.9% are taking some medication for RA, and 17.3% are little/not satisfied with them. In addition, 67.1% take conventional synthetic disease modifying drugs (DMARDs), and 45.9% biological therapies including biosimilars and small molecules. CONCLUSIONS: The current impact of RA on patients' daily lives remains very high. A significant number of patients are not taking DMARDs (conventional synthetic and/or biologics) despite high activity.

Advancing Biologic Therapy for Refractory Autoimmune Hepatitis.

Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.

Immunotherapy or targeted therapy as the first-line strategies for unresectable hepatocellular carcinoma: A network meta-analysis and cost-effectiveness analysis.

Introduction: The existence of many phase III randomized controlled trials (RCTs) of first-line treatment for unresectable hepatocellular carcinoma (HCC) puzzle doctors and patients in choosing the most effective treatment strategies. We aimed to assess the efficacy, safety, and cost-effectiveness of immunotherapy or targeted therapy as the first-line strategy for unresectable HCC. Methods: The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and Web of Science databases, in which immunotherapy or targeted therapy was regarded as the first-line treatment for unresectable HCC, published in English between January 1, 2010, and September 20, 2022. We conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) from the Chinese payer's perspective. Overall survival (OS), progression-free survival (PFS), the ranks of different treatments using P-score, and adverse events (AEs) were evaluated by NMA. Total costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-benefit ratio (ICER) were estimated from 15-year Markov models developed by CEA. Results: We identified 2,825 records, including 11,796 patients, from 15 RCTs. The NMA revealed that sintilimab plus a bevacizumab biosimilar (HR, 0.57; 95% CI, 0.43 to 0.75; P = 0.96) and camrelizumab plus rivoceranib (HR, 0.56; 95% CI, 0.41 to 0.66; P = 0.94) could lead to great improvements in OS and PFS compared with sorafenib-related survival. The CEA indicated that tislelizumab increased by 0.220 QALYs (0.312 LYs) and decreased by $1,938 compared with sorafenib, which yielded ICERs of -$8,809/QALY (-$2,612/LY). Sensitivity analysis showed that the model was stable. Conclusion: Sintilimab plus a bevacizumab biosimilar and camrelizumab plus rivoceranib significantly prolonged OS and PFS, respectively. Further considering the pharmacoeconomics factors, tislelizumab is the most cost-effective first-line treatment strategy for unresectable HCC in China.

The formulary process for biosimilar additions at a comprehensive cancer center.

Biological products may be used to diagnose, prevent, treat, and cure diseases and medical conditions, including cancer. Biosimilar agents, approved under an abbreviated 351(k) pathway, continue to increase in number and market share for biologic agents, especially for cancer care. Although biosimilars offer the potential for improved access to care, their introduction to the marketplace has created significant disruption. It is imperative that health systems providing care to patients with cancer develop a well-defined process to address the challenges associated with biosimilars. This descriptive article outlines pharmacy considerations for biosimilars and describes the current practices at The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University. Biosimilars have and will continue to significantly impact oncology care. Organizations must understand the clinical, operational, and financial challenges associated with the use of these products.

Evaluation of adalimumab biosimilar candidate (HS016) in Chinese patients with active ankylosing spondylitis based on a health survey: sub-analysis of a phase 3 study.

OBJECTIVE: The equivalence of the biosimilar HS016 to adalimumab (Humira) for the treatment of active ankylosing spondylitis (AS) patients has been previously validated. The aim was to compare the efficacy of HS016 and adalimumab in stratified subgroups at different time points using Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S) and short form 36 (SF-36) questionnaires. METHODS: We carried out a multicenter, randomized, double-blind, parallel, positive control, phase 3 trial of patients with active AS. They were selected randomly to be subcutaneously administered 40 mg HS016 or adalimumab every 2 weeks for a total treatment period of 24 weeks in a 2:1 ratio. A health surveys were used to assess mental and physical improvements of patients as well as other factors. RESULTS: HAQ-S revealed that changes in scores from baseline in both groups were time dependent until 14 weeks and that during the first 4 weeks of treatment the changes declined rapidly. The SF-36 health survey revealed that both HS016 and adalimumab produced rapid beneficial effects against AS during the first 2 weeks of therapy, which gradually declined between 2 and 12 weeks and flattened out after 12 weeks until 24 weeks. CONCLUSION: This trial demonstrated that both HS016 and adalimumab produced rapid improvements in symptoms during the first 2 weeks of treatment. These findings suggest that HS016 is an alternative economical treatment for Chinese AS patients producing a rapid amelioration of symptoms, aiding them to recover their lifestyle satisfaction. TRIAL REGISTRATION: http://www.chictr.org.cn/enindex.aspx , ChiCTR1900022520, retrospectively registered. Key points • HS016 and adalimumab produced rapid AS symptom improvements during the first 2 weeks followed by a slowdown of improvements until week 4 with afterwards few improvements evaluated by HAQ-S • The improvements according to the short form of the 36 (SF-36) questionnaires revealed similar trends as for HAQ-S • There was no significant difference in HAQ-S and SF-36 scores between HS016 and adalimumab.

AMCP Partnership Forum: Biosimilars-policy, practice, and postmarketing surveillance to support treatment and coverage decisions.

With the dual goals of identifying key actions that can support the further development and use of biosimilars in the United States and providing consistent and accurate messages about the value of biosimilars, AMCP held a virtual multidisciplinary stakeholder forum December 15-16, 2020. The participants, including payers, pharmacists, integrated delivery system leaders, health economists and analysts, academicians, patient advocates, pharmaceutical manufacturers, and other key decision makers, spent the 2 days (1) identifying challenges with biosimilar adoption within the US health care system; (2) determining clear and unbiased scientific messaging to support broader acceptance of biologics as valid therapeutic options and to facilitate faster time to biosimilar adoption; and (3) discussing needs and opportunities related to real-world evidence to help with adoption of biosimilars. Participants identified various challenges, including approval-related nuances and other regulatory considerations; general information about biosimilars and lack of consistent, positive messaging; clinical and administrative barriers; and economic complexities and variation. They also highlighted areas of opportunity, such as demystifying information and developing strong, positive messaging around biologics and biosimilars, and improving confidence in biosimilars by using tools such as education and real-world evidence, organizational strategies to ease biosimilar adoption, and updates to legislation and regulation to reduce barriers related to biosimilars. DISCLOSURES: This forum was sponsored by Amgen, the Association for Accessible Medicines, Boehringer Ingelheim, Fresenius Kabi, Johnson & Johnson, Novo Nordisk, Pfizer, Sandoz, and Takeda. These proceedings were prepared as a summary of the forum to represent common themes; they are not necessarily endorsed by all attendees, nor should they be construed as reflecting group consensus.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A health economic guide to market access of biosimilars.

Introduction: Little is known about market access to biosimilars from a health economic perspective, except for studies that compute the budget impact of biosimilar use. Areas covered: This comprehensive health economic guide to the market access of biosimilars focuses on the role of biosimilars in pharmaceutical innovation and competition, the objective of biopharmaceutical policy, the budget impact of biosimilars, and the cost-effectiveness of biologic therapy in the presence of biosimilars. Expert opinion: We argue that the objective of biopharmaceutical policy in a health system should be to create a competitive and sustainable market for off-patent reference biologics, biosimilars, and next-generation biologics that makes biologic therapy available to patients at the lowest cost. Market access of biosimilars can contribute to this objective as a result of the lower price of biosimilars and price competition with alternative therapies. The resulting improvement in the cost-effectiveness of biologic therapy needs to be accounted for by revisiting reimbursement decisions and conditions. When examining the cost-effectiveness of biologic therapy following patent expiry, stakeholders need to consider residual uncertainties at the time of biosimilar marketing authorization, the nocebo effect, market entry of a second-generation reference biologic with a different administration form than the biosimilar, and value-added services.

[Immunotherapies in the German healthcare system : Economic aspects of established antibodies and recently available therapies]. / Immuntherapien im deutschen Gesundheitswesen : Ökonomische Aspekte etablierter Antikörper und neuerer Therapien.

In the German healthcare system, immunotherapies have been well established for years. Currently there are over 100 registrations of monoclonal antibodies (MABs). In recent years, new immunotherapeutic approaches became available, amongst them checkpoint inhibitors and CAR­T cells in oncology. Increasing expenditures of the German statutory health insurance (SHI) system are regarded with concerns. This article presents an overview of the development and status of prescriptions and sales of selected immunotherapeutics in Germany. Data from 2015-2019 were analyzed, primarily from the GKV-Arzneimittel-Schnellinformation (GAmSi) and the consultancy IQVIA.In the group of older MABs, such as immunosuppressive and antineoplastic agents, biosimilars led to a (temporary) increase of applications, but reimbursement amounts are decreasing. Instruments of the SHI system like drug agreements, reference prices, and individual discount contracts intervene as expenditure control. Checkpoint inhibitors clearly show increasing prescriptions and expenditures. Finally, the CAR­T cells are indeed very expensive treatments, but are currently not that important due to the limited number of applications. In addition, the exemption from VAT of 19% and the signed discount agreements between suppliers and sickness funds reduce the burden. In 2015 and 2019, the net expenditures on drugs and surgical dressings accounted for 17.2% of the total expenditures on benefits of the SHI system. Should the expenditures on drugs increase overproportionately in the future, the German SHI system will be able to counteract with already available or new instruments, supported by the legislator. Manufacturers and the SHI system should develop joint actions to achieve solutions for new treatment approaches.

Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study.

PURPOSE: The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial. METHODS: This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months. RESULTS: After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P < 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P < 0.01 for non-inferiority). CONCLUSION: There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

Unified approaches to assessing treatment effect of traditional Chinese medicine based on health profiles.

Two dissimilarity indices are introduced to measure the disharmony of a human body system by mimicking the population bioequivalence and the individual bioequivalence concepts. Hypotheses for the treatment effect of a traditional Chinese medicine are formulated based on the two indices and then tested under the proposed designs by reverting an approximate confidence upper bound. The proposed methods can also be used when a drug product has multiple components or a trial has multiple endpoints.

Current and Future Therapies for Psoriasis with a Focus on Serotonergic Drugs.

Psoriasis is a chronic immune-mediated skin disease, with a pathogenesis resulting from a combination of genetic and environmental factors. The pathogenesis of psoriasis is driven by the interaction between innate and adaptive immune cells and keratinocytes, in a complex process mediated by cytokines and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis, and infiltration of white cells in the skin, which cause the characteristic psoriasis plaques. Several studies have suggested that the neurotransmitter serotonin, a key mediator between the skin and the neuroendocrine system, also plays an important role in the pathogenesis of psoriasis. Psoriasis often needs long-term treatment, which can be a burden. Thus, the choice of the treatment is crucial to increase the patients' adherence and quality of life. This review addresses the currently available systemic and topical treatments for psoriasis, used by themselves or combined with phototherapy. It particularly focuses on the importance of advanced drug delivery systems as a way to increase the drug penetration and retention in the skin, while also enhancing its solubility and stability. Finally, we discuss the role of the serotonin system in psoriasis, and summarize what is known about the effects of antidepressants, in particular specific serotonin reuptake inhibitors, on the physical symptoms of this disease.