Budget impact analysis of the novel PD-1 inhibitor toripalimab versus pembrolizumab in recurrent or metastatic nasopharyngeal carcinoma.

AIM: To estimate the budget impact of adding a toripalimab regimen as a treatment option to the existing pembrolizumab regimen, both including gemcitabine and cisplatin, in untreated recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) using the published wholesale acquisition cost (WAC) and average sales price (ASP). METHODS: Budget impact analysis comparing a treatment mix "without" versus "with" the toripalimab regimen in the US eligible annual incident R/M NPC population, a 3-year time horizon, toripalimab/pembrolizumab market splits of 60/40 (Y1) and 80/20 (Y2/3), and medication adjustments for discontinuation or progression. Cost inputs included drugs, administration, and adverse event (AE) management. The models were replicated for a hypothetical 1-million-member health plan in which costs per-member-per-month (PMPM) and per-member-per-year (PMPY) were estimated. One-way (OWSA) and probabilistic sensitivity analyses (PSA) as well as scenario analyses were performed. RESULTS: In the "without" scenario, the 3-year WAC-based costs for the pembrolizumab regimen total $1,449,695,333 ($1,305,632,448 for treatment and $144,062,885 for managing AEs). In the "with" scenario, total 3-year costs for pembrolizumab decline to $380,012,135 with toripalimab adding $885,505,900 ($779,206,567 for treatment and $106,299,333 for AE management). Annual net savings range from $46,526,152 in 2024 to $71,194,214 in 2026, for 3-year savings of $184,177,298. Associated net savings in a 1-million-member health plan are $543,068 over 3 years with savings of $0.045 PMPM and $0.543 PMPY. The ASP-based model shows similar patterns with 3-year net savings of $174,235,983 in the US incident population and savings of $0.043 PMPM and $0.514 PMPY in a 1-million-member health plan. The PSA support base case findings; OWSA and scenario analyses reveal how parameter variability impacts results. CONCLUSION: Savings between $174 million and $184 million can be achieved from treating 60% of R/M NPC patients in year 1 and 80% in years 2 and 3 with the toripalimab regimen over a similar pembrolizumab regimen.

Toripalimab, a human monoclonal anti-body that targets PD-1, was recently approved by the US Food and Drug Administration (FDA) for the first-line treatment of adults with metastatic or recurrent, locally advanced nasopharyngeal carcinoma (NPC), in combination with gemcitabine and cisplatin. We evaluated how much it would cost a payor to cover the FDA-approved toripalimab plus gemcitabine and cisplatin regimen (the toripalimab regimen) to a non-FDA-approved pembrolizumab plus gemcitabine and cisplatin regimen (the pembrolizumab regimen). With no trial data available for such pembrolizumab regimen, we assumed that it would be comparable to the toripalimab regimen in efficacy and safety. Our model adopted a 3-year time horizon and assumed a 60/40 market share split in year 1 and an 80/20 market split in years 2 and 3. It included two US cost inputs: the wholesale acquisition cost (WAC) or "list price" at market entry and, as no average sales price (ASP) will be available for toripalimab for several quarters, a toripalimab price point of 80% of the pembrolizumab ASP. We adjusted for patients whose cancer progressed or who discontinued treatment to determine the number of fully-treated-patient-equivalents. We found that treating 60% of NPC patients in year 1 and 80% in years 2 and 3 with the toripalimab regimen instead of the pembrolizumab regimen generates, for the entire adjusted patient population, savings ranging from $174 million when using ASP to $184 million when using WAC.

Manuka combinations with nigella sativa and hydroxyurea in treating iron overload of pediatric ß-thalassemia major, randomized clinical trial.

Background: ß-thalassemia major is microcytic hypochromic anemia disorder inherited from parents, resulting from a mutation in the ß-globin locus. As a result, a quantitative defective hemoglobin synthesis and relative excess in α-globin is occurred. As such, frequent blood transfusion is required, that leads to iron overload. Iron overload results in several pathological complications, including cell death, tissue injury, organ dysfunction, and liver fibrosis. The present study examined the effectiveness of nigella Sativa and manuka honey combination or manuka honey alone to the conventional therapy (Deferasirox + blood transfusion) used for preventing and managing iron overload in pediatric ß-thalassemia major patients. Methods: One hundred sixty-five patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 500 mg nigella sativa oil combined with manuka honey lozenge (344 mg) daily or manuka honey alone plus the conventional therapy for ten treatment months. Ferritin level, serum iron, transferrin saturation, total iron binding capacity, alanine transaminase, and aspartate transaminase were determined at baseline and month 10. Results: Eventually, serum ferritin and iron were decreased significantly in the nigella sativa + manuka honey group as compared with the control group. Other clinical parameters were significantly impacted. The level of alanine transaminase and aspartate transaminase were significantly decreased in the nigella sativa plus manuka honey group compared with the control group. Conclusion: Results showed that nigella sativa plus manuka honey was more effective than manuka alone or the conventional treatment alone in managing iron overload of ß-thalassemia major patients.

Cost-efficiency and budget-neutral expanded access modeling of pembrolizumab versus the novel PD-1 inhibitor toripalimab in locally advanced or metastatic nonsquamous non-small cell lung cancer.

AIMS: To estimate in a panel of patients with locally advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with a programmed death receptor-1 inhibitor in the US in 2024 (1) the cost-efficiency of toripalimab regimens compared to pembrolizumab regimens; and (2) the budget-neutral expanded access to additional toripalimab cycles and regimens from accrued savings. METHODS: Simulation modeling of toripalimab + pemetrexed + carboplatin in nonsquamous NSCLC to a similar pembrolizumab regimen in a panel of 49,647 patients; utilizing two cost inputs (wholesale acquisition cost (WAC) at market entry and an estimated ex ante toripalimab price point of 80% of pembrolizumab average sales price (ASP)) plus administration costs over one and two years of treatment with treatment rates from 1%-10%. Scenario analyses with treatment durations equivalent to toripalimab and pembrolizumab trials' median PFS were also conducted. RESULTS: In the WAC-based models, toripalimab saves $2,223 per patient per cycle and $40,014 over 1 year of treatment ($77,805 over 2 years). Extrapolated to the 49,647-patient panel, estimated 1-year savings range from $19,865,840 (1% treatment rate) to $198,658,399 (10% rate). Reallocating these savings permits budget-neutral expanded access to an additional 1,753 (1% rate) to 17,533 (10% rate) toripalimab maintenance cycles or to an additional 97 (1% rate) to 972 (10%) full 1-year toripalimab regimens with all agents. Two-year savings range from $38,628,022 (1% rate) to $386,280,221 (10%). Reallocating these efficiencies provides expanded access ranging from 3,409 (1% rate) to 34,093 (10%) additional toripalimab cycles or to 97 to 973 full 2-year regimens. The ex ante ASP model showed similar results as did the scenario analyses but at a lower magnitude than the base case. CONCLUSION: Toripalimab generates significant savings that enable budget-neutral funding for up to 17,533 [34,093] additional maintenance cycles over one year [two years] with toripalimab + pemetrexed in nonsquamous NSCLC, or 972 [973] full one-year [two-year] regimens.

An estimated 49,647 patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) will be treated with a PD-1 inhibitor in the US in 2024. Toripalimab, a PD-1 inhibitor recently approved by the US Food and Drug Administration for the treatment of nasopharyngeal carcinoma, has also been found to be beneficial in patients with nonsquamous NSCLC when used in combination with chemotherapy. We conducted an economic simulation of the costs of toripalimab + pemetrexed + carboplatin versus the costs of a similar regimen with the PD-1 inhibitor pembrolizumab in the treatment of patients with nonsquamous NSCLC. Our simulation models used two US cost inputs for toripalimab: the wholesale acquisition cost or "list price" at market entry and, as no average sales price (ASP) will be available for toripalimab for several quarters, a hypothetical toripalimab price point of 80% of the pembrolizumab ASP. We compared the savings in each scenario when between 1% and 10% of the 49,647 nonsquamous NSCLC patients are treated with the toripalimab regimen. We then evaluated how these savings could be re-allocated, without requiring extra funding, to provide more patients with access to toripalimab treatment on a budget-neutral basis. We found that, if 1% of new cases of advanced/metastatic nonsquamous NSCLC were treated with toripalimab for 1 year, these savings are enough to purchase up to 1,753 additional toripalimab maintenance cycles; or these savings could provide up to an additional 97 patients with full one-year regimens with all agents (toripalimab + chemotherapy). If 10% of new cases were treated with toripalimab for 1 year, the savings are enough to purchase up to 17,533 additional toripalimab maintenance cycles; or these savings could provide up to an additional 972 patients with full one-year regimens with all agents.

On-body injector pegfilgrastim for chemotherapy-induced neutropenia prophylaxis: Current Status.

INTRODUCTION: Myelosuppression, a challenge in cancer treatment, often results in severe complications. Prophylactic granulocyte colony-stimulating factors, particularly pegfilgrastim, mitigate chemotherapy-induced neutropenia. This narrative review evaluates the role of on-body injector (OBI) devices for pegfilgrastim administration. A comprehensive search strategy of PubMed and AI-powered intuitive search tools, complemented by authors' contributions, yielded a body of papers presenting evidence on OBI devices, their effectiveness and safety, the benefits and challenges of OBI versus pre-filled syringe administration, patient preferences for pegfilgrastim administration, and economic considerations. DISCUSSION: OBI devices prove effective and safe, with advantages such as reduced clinic visits and enhanced adherence. Studies highlight cost-efficiency and expanded access, emphasizing the socioeconomic context. Patient and provider preferences underscore the potential of OBI devices in cancer care, with implications for healthcare resource utilization and pharmacoeconomics. CONCLUSION: The value proposition of OBI devices lies in improving patient outcomes, convenience, resource optimization, and enhancing the overall cancer care experience. As biosimilar OBIs enter the market, they may offer cost savings, further influencing their adoption and their positioning as a cost-efficient alternative in cancer care. Ongoing research and technological advancements are expected to contribute to the broader acceptance of OBI devices in cancer care delivery.

Comparative efficacy of later-line therapies for metastatic colorectal cancer: a network meta-analysis of survival curves.

INTRODUCTION: We evaluated the comparative efficacy of 6 later-line (≥3) therapies for metastatic colorectal cancer (mCRC) over placebo. We applied a novel statistical method of reconstructing pseudo patient-level data (pseudo-IPD) to inform a network meta-analysis of survival curves that considers shape in addition to scale parameters. METHODS: A literature search yielded 10 phase II/III trials. We digitized all survival curves and applied a novel method incorporating curve coordinates, patients-at-risk, and events reported to generate pseudo-IPD. Using fitted random effects lognormal distributions, we estimated the survival proportions and HRs(95CrI) of progression-free (PFS) and overall survival(OS) over 12 months of follow-up. RESULTS: Compared to placebo, in ascending order, 12-month OS HRs were 0.50(95%CrI = 0.35, 0.69; PFS = 0.11(95%CrI = 0.06, 0.14)) for TAS+bevacizumab; 0.71(95%CrI = 0.51, 0.97; PFS = 0.26(95%CrI = 0.16, 0.41)) for regorafenib; 0.75(95%CrI = 0.61, 0.91; (PFS = 0.24(95%CrI = 0.17, 0.31)) for TAS-102; 0.80(95%CrI = 0.79, 0.90; PFS = 0.18(95%CrI = 0.13, 0.24)) for fruquintinib; 0.83(95%CrI = 0.50, 0.99; PFS = 0.42(95%CrI = 0.20, 0.75)) for atezolizumab+cobimetinib; and 1.03(95%CrI = 0.55, 1.65; PFS = 0.67(95%CrI = 0.29, 1.01)) for atezolizumab. CONCLUSION: In this independent NMA of survival data all later-line mCRC therapies but atezolizumab monotherapy exhibited superiority in 12-month PFS and OS over placebo. TAS+bevacizumab emerged as the most dominant option and may be the preferred choice; with fruquintinib, regorafenib and TAS-102 monotherapy showing statistically significant but lower PFS and OS benefits. REGISTRATION: PROSPERO: CRD42022371953.

Polytomous Rasch Analyses of Surgeons' Decision-Making on Choice of Procedure in Endoscopic Lumbar Spinal Stenosis Decompression Surgeries.

BACKGROUND: With the growing prevalence of lumbar spinal stenosis, endoscopic surgery, which incorporates techniques such as transforaminal, interlaminar, and unilateral biportal (UBE) endoscopy, is increasingly considered. However, the patient selection criteria are debated among spine surgeons. OBJECTIVE: This study used a polytomous Rasch analysis to evaluate the factors influencing surgeon decision-making in selecting patients for endoscopic surgical treatment of lumbar spinal stenosis. METHODS: A comprehensive survey was distributed to a representative sample of 296 spine surgeons. Questions encompassed various patient-related and clinical factors, and responses were captured on a logit scale graphically displaying person-item maps and category probability curves for each test item. Using a Rasch analysis, the data were subsequently analyzed to determine the latent traits influencing decision-making. RESULTS: The Rasch analysis revealed that surgeons' preferences for transforaminal, interlaminar, and UBE techniques were easily influenced by comfort level and experience with the endoscopic procedure and patient-related factors. Harder-to-agree items included technological aspects, favorable clinical outcomes, and postoperative functional recovery and rehabilitation. Descriptive statistics suggested interlaminar as the best endoscopic spinal stenosis decompression technique. However, logit person-item analysis integral to the Rasch methodology showed highest intensity for transforaminal followed by interlaminar endoscopic lumbar stenosis decompression. The UBE technique was the hardest to agree on with a disordered person-item analysis and thresholds in category probability curve plots. CONCLUSION: Surgeon decision-making in selecting patients for endoscopic surgery for lumbar spinal stenosis is multifaceted. While the framework of clinical guidelines remains paramount, on-the-ground experience-based factors significantly influence surgeons' selection of patients for endoscopic lumbar spinal stenosis surgeries. The Rasch methodology allows for a more granular psychometric evaluation of surgeon decision-making and accounts better for years-long experience that may be lost in standardized clinical guideline development. This new approach to assessing spine surgeons' thought processes may improve the implementation of evidence-based protocol change dictated by technological advances was endorsed by the Interamerican Society for Minimally Invasive Spine Surgery (SICCMI), the International Society for Minimal Intervention in Spinal Surgery (ISMISS), the Mexican Spine Society (AMCICO), the Brazilian Spine Society (SBC), the Society for Minimally Invasive Spine Surgery (SMISS), the Korean Minimally Invasive Spine Society (KOMISS), and the International Society for the Advancement of Spine Surgery (ISASS).

Cost-efficiency and budget-neutral expanded access modeling of the novel PD-1 inhibitor toripalimab versus pembrolizumab in recurrent or metastatic nasopharyngeal carcinoma.

AIMS: To estimate, in the setting of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) for an assumed 1,207 incident US cases in 2024, (1) the cost-efficiency of a toripalimab-gemcitabine-cisplatin regimen compared to a similar pembrolizumab regimen; and (2) the budget-neutral expanded access to additional toripalimab cycles and regimens afforded by the accrued savings. METHODS: Simulation modeling utilized two cost inputs (wholesale acquisition cost (WAC) at market entry and an ex ante toripalimab price point of 80% of pembrolizumab average sales price (ASP)) and drug administration costs over 1 and 2 years of treatment with treatment rates ranging from 45% to 90%. In the absence of trial data for pembrolizumab-gemcitabine-cisplatin in R/M NPC, it is assumed that such a regimen would be comparable to toripalimab-gemcitabine-cisplatin in efficacy and safety. RESULTS: In the models utilizing the WAC, toripalimab saves $2,223 per patient per cycle and $40,014 over 1 year of treatment ($77,805 over 2 years). Extrapolated to the 1,207-patient panel, estimated 1-year savings range from $21,733,702 (45% treatment rate) to $43,467,404 (90% rate). Reallocating these savings permits budget-neutral expanded access to an additional 2,359 (45% rate) to 4,717 (90% rate) toripalimab maintenance cycles or to an additional 126 (45% rate) to 252 (90%) full 1-year toripalimab regimens with all agents. Two-year savings range from $42,259,976 (45% rate) to $84,519,952 (90% rate). Reallocating these efficiencies provides expanded access, ranging from an additional 4,586 (45% rate) to 9,172 (90% rate) toripalimab cycles or to an additional 128-257 full 2-year toripalimab regimens. The ex ante ASP model showed similar results. CONCLUSION: This simulation demonstrates that treatment with toripalimab generates savings that enable budget-neutral funding for up to an additional 252 regimens with toripalimab-gemcitabine-cisplatin for one full year, the equivalent of approximately 21% of the 2024 incident cases of R/M NPC in the US.

An estimated 1,207 patients will be diagnosed with late-stage nasopharyngeal cancer in the US in 2024. Toripalimab is a novel PD-1 inhibitor drug approved by the US Food and Drug Administration on October 27, 2023 as first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer when used in combination with gemcitabine and cisplatin. We conducted economic evaluations of the costs of this toripalimab regimen versus the costs of a similar regimen with the PD-1 inhibitor pembrolizumab. Our simulation models used two pricing scenarios: the wholesale acquisition cost (WAC) or "list price" at market entry and, as no average sales price (ASP) will be available for toripalimab for several quarters, an estimated toripalimab price point of 80% of the pembrolizumab ASP. We compared the savings in each scenario when between 45% and 90% of the 1,207 patients are treated with the toripalimab regimen. We then evaluated how these savings could be re-allocated, on a budget-neutral basis and without requiring extra cash outlays, to provide more patients with access to toripalimab treatment; specifically, how many toripalimab doses and how many full toripalimab regimens could be purchased to provide more patients with treatment. We found that, if 90% of new cases of recurrent or metastatic nasopharyngeal cancer were treated with toripalimab over 1 year, these savings are enough to purchase up to 4,717 additional doses on a budget-neutral basis, which could provide up to an additional 252 newly diagnosed patients with 1 year of treatment with toripalimab. In combination with gemcitabine and cisplatin, toripalimab can markedly improve access to care for patients with recurrent or metastatic nasopharyngeal cancer in a cost-responsible way.

Disability-adjusted life years from bone and joint infections associated with antimicrobial resistance: an insight from the 2019 Global Burden of Disease Study.

PURPOSE: Bone and joint infections, complicated by the burgeoning challenge of antimicrobial resistance (AMR), pose significant public health threats by amplifying the disease burden globally. We leveraged results from the 2019 Global Burden of Disease Study (GBD) to explore the impact of AMR attributed to bone and joint infections in terms of disability-adjusted life years (DALYs), elucidating the contemporary status and temporal trends. METHODS: Utilizing GBD 2019 data, we summarized the burden of bone and joint infections attributed to AMR across 195 countries and territories in the 30 years from 1990 to 2019. We review the epidemiology of AMR in terms of age-standardized rates, the estimated DALYs, comprising years of life lost (YLLs) and years lived with disability (YLDs), as well as associations between DALYs and socio-demographic indices. RESULTS: The GBD revealed that DALYs attributed to bone and joint infections associated with AMR have risen discernibly between 1990 and 2019 globally. Significant geographical disparities and a positive correlation with socio-demographic indicators were observed. Staphylococcus aureus infections, Group A Streptococcus, Group B Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter-related bone and joint infections were associated with the highest DALYs because of a high proportion of antimicrobial resistance. Countries with limited access to healthcare, suboptimal sanitary conditions, and inconsistent antibiotic stewardship were markedly impacted. CONCLUSIONS: The GBD underscores the escalating burden of bone and joint infections exacerbated by AMR, necessitating urgent, multi-faceted interventions. Strategies to mitigate the progression and impact of AMR should emphasize prudent antimicrobial usage and robust infection prevention and control measures, coupled with advancements in diagnostic and therapeutic modalities.

The economic burden of Ebola virus disease: a review and recommendations for analysis.

BACKGROUND: Ebola virus disease (EVD) continues to be a major public health threat globally, particularly in the low-and-middle-income countries (LMICs) of Africa. The social and economic burdens of EVD are substantial and have triggered extensive research into prevention and control. We aim to highlight the impact and economic implications, identify research gaps, and offer recommendations for future economic studies pertaining to EVD. METHOD: We conducted a comprehensive librarian-led search in PubMed/Medline, Embase, Google Scholar, EconLit and Scopus for economic evaluations of EVD. After study selection and data extraction, findings on the impact and economics of EVD were synthesized using a narrative approach, while identifying gaps, and recommending critical areas for future EVD economic studies. RESULTS: The economic evaluations focused on the burden of illness, vaccine cost-effectiveness, willingness-to-pay for a vaccine, EVD funding, and preparedness costs. The estimated economic impact of the 2014 EVD outbreak in Guinea, Liberia, and Sierra Leone across studies ranged from $30 billion to $50 billion. Facility construction and modification emerged as significant cost drivers for preparedness. The EVD vaccine demonstrated cost-effectiveness in a dynamic transmission model; resulting in an incremental cost-effectiveness ratio of about $96 per additional disability adjusted life year averted. Individuals exhibited greater willingness to be vaccinated if it incurred no personal cost, with a minority willing to pay about $1 for the vaccine. CONCLUSIONS: The severe impact of EVD puts pressure on governments and the international community for better resource utilization and re-allocation. Several technical and methodological issues related to economic evaluation of EVD remain to be addressed, especially for LMICs. We recommend conducting cost-of-sequelae and cost-of-distribution analyses in addition to adapting existing economic analytical methods to EVD. Characteristics of the affected regions should be considered to provide evidence-based economic plans and economic-evaluation of mitigations that enhance resource allocation for prevention and treatment.

Ebola virus disease (EVD) is a serious health problem, not only in Africa where there have been outbreaks but in other parts of the world as well. In addition to its severe health implications and resultant death, EVD also poses significant impact across several sectors, including food and agriculture, transportation, education, among others, ultimately impacting the economies of affected countries. While some studies have estimated the economic burden of EVD, there remains questions that need addressing. We conducted a review of published studies to estimate what is known about the economic burden of EVD, identified research gaps. Studies looked at how much money EVD costs in terms of prevention and treatment, while others reported on people's willingness to pay for a vaccine. The estimated economic impact of the 2014 EVD outbreak in Guinea, Liberia, and Sierra Leone ranged from approximately $30 billion to $50 billion across studies. Healthcare facility construction and modification were significant cost factors for response preparedness for EVD outbreaks. While the EVD vaccine showed cost-effectiveness, surveys of people across various regions revealed that more individuals were willing to get vaccinated if it was free, with a minority willing to pay a median of about $1 for the vaccine. The severe impact of EVD puts pressure on governments and the international community to use resources more efficiently. We recommend conducting analyses on the costs of long-term effects of EVD and costs of vaccine and treatment distribution, as well as adapting existing economic methods to the specific characteristics of affected regions. This would help create evidence-based economic plans and evaluations of strategies to enhance resource allocation for EVD prevention and treatment.

Optimizing Postpartum Care in Rural Communities: Insights from Women in Arizona and Implications for Policy.

OBJECTIVES: Optimal postpartum care promotes healthcare utilization and outcomes. This qualitative study investigated the experiences and perceived needs for postpartum care among women in rural communities in Arizona, United States. METHODS: We conducted in-depth interviews with thirty childbearing women and analyzed the transcripts using reflexive thematic analysis to gauge their experiences, needs, and factors affecting postpartum healthcare utilization. RESULTS: Experiences during childbirth and multiple structural factors, including transportation, childcare services, financial constraints, and social support, played crucial roles in postpartum care utilization for childbearing people in rural communities. Access to comprehensive health information and community-level support systems were perceived as critical for optimizing postpartum care and utilization. CONCLUSIONS FOR PRACTICE: This study provides valuable insights for policymakers, healthcare providers, and community stakeholders in enhancing postpartum care services for individuals in rural communities in the United States.

Network meta-analysis of second line and beyond treatment options in metastatic clear cell renal cell carcinoma.

INTRODUCTION: Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents. PATIENTS AND METHODS: We identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0. RESULTS: All therapies demonstrated some benefits over placebo. Lenvatinib + everolimus ranked first for OS (HR = 0.44; 95%CI = 0.24-0.82; p-score = 0.92), PFS (HR = 0.13; 95%CI = 0.07-0.24, p-score = 0.98), and ORR (OR = 35.95; 95%CI = 11.55-111.87; p-score = 0.93) compared to placebo, though with a higher SAE (OR = 5.27; p-score = 0.23). Cabozantinib ranked second for OS (HR = 0.57, p-score = 0.80), PFS (HR = 0.19; p-score = 0.86), and ORR (OR = 27.24, p-score = 0.84). Nivolumab was third for ORR (p-score = 0.79), fourth for OS (p-score = 0.69), fifth for PFS (p-score = 0.61), and last for SAE (p-score = 0.83). Lenvatinib monotherapy ranked worst SAE (OR = 5.89, p-score = 0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinib + everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo. CONCLUSION: Based on OS and PFS, the lenvtatinib + everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs.

Cost-effectiveness of intravenous resuscitation fluids in sepsis patients: a patient-level data analysis in Jordan.

AIM: Albumin role as fluid resuscitation in sepsis remains understudied in low- and middle-income countries. This study aimed to evaluate the cost-effectiveness of intravenous (IV) Albumin compared to Crystalloids in sepsis patients using patient-level data in Jordan. METHODS: This was a retrospective cohort study of sepsis patients aged 18 or older admitted to intensive care units (ICU) at two major tertiary hospitals during the period 2018-2019. Patients information, type of IV fluid, and clinical outcomes were retrieved from medical records, and charges were retrieved from the billing system. A 90-day partitioned survival model with two health states (alive and dead) was constructed to estimate the survival of sepsis patients receiving either Albumin or Crystalloids as IV fluids for resuscitation. Overall survival was predicted by fitting a Weibull model on the patient-level data from the current study. To further validate the results, and to support the assessment of uncertainty, time-dependent transition probabilities of death at each cycle were estimated and used to construct a state-transition patient-level simulation model with 10,000 microsimulation trials. Adopting the healthcare system perspective, incremental cost-effectiveness ratios(ICERs) of Albumin versus Crystalloids were calculated in terms of the probability to be discharged alive from the ICU. Uncertainty was explored using probabilistic sensitivity analysis. RESULTS: In the partitioned survival model, Albumin was associated with an incremental cost of $1,007 per incremental1% in the probability of being discharged alive from the ICU. In the state-transition patient-level simulation model, ICER was $1,268 per incremental 1% in the probability of being discharged alive. Probabilistic sensitivity analysis showed that Albumin was favored at thresholds >$800 per incremental 1%in the probability of being discharged alive from the ICU. CONCLUSION: IV Albumin use in sepsis patients might not be cost-effective from the healthcare perspective of Jordan. This has important implications for policymakers to readdress Albumin prescribing practice in sepsis patients.

Sepsis is a life-threatening complication of infection, which usually requires resuscitation with intravenous fluids. Still, no conclusive evidence is available about the best fluid resuscitation to be used in sepsis patients especially in low- and middle-income countries. This study compared the costs and effectiveness of intravenous Albumin versus Crystalloids in sepsis patients. Findings from this study showed that resuscitation with Albumin is much more expensive compared to resuscitation with Crystalloids with no significant difference in mortality but with prolonged length of stay in the hospital and the intensive care unit. Decision makers are advised to change Albumin prescribing practices in a way that mitigates the associated clinical and financial burdens without compromising quality of care or resuscitate with Crystalloids.

The economics of biosimilars and challenges to biosimilar adoption in low- and middle-income countries.

INTRODUCTION: Biologics have shown marked success over the past decades in disease areas as cancer, immunology and diabetes. However, elevated costs of innovative biologic medicines have led to an inequity in accessibility across the world. While 85% of the world's population lives in low- and middle- income countries (LMIC), 80% of the sales of monoclonal antibodies are attributed to Western countries, highlighting the pronounced market imbalance. AREAS COVERED: This perspective paper draws some analogies as well as differences between biosimilars and generics, aims to address the unmet need for treatment with biologics in LMICs by reviewing possible causes, economic and social, of low access, displaying the disparity between LMICs and HIC, and suggets countermeasures for this unmet medical need in LMICs. EXPERT OPINION: It is up to all stakeholders to capitalize on the opportunity that biosimilars provide, mostly by committing to transparent collaboration, to make biotherapeutics accessible to all, regardless of region or country of residence.

The role of cytokines and Indolamine-2.3 dioxygenase in experiencing a psycho-neurological symptom cluster in hematological cancer patients: IL-1alpha, IL-1beta, IL-4, IL-6, TNF-alpha, kynurenine, and tryptophan.

OBJECTIVE: This study examined (a) whether there are a subgroup of cancer patients experiencing the selected psycho-neurological symptoms as a cluster (depression, cognitive impairment, fatigue, sleep disturbance, and pain); (b) whether demographic and clinical characteristics and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-4, IL-6, TNF-alpha) are associated with subgroup membership; and (c) whether the activity of indolamine-2.3 dioxygenase(IDO) is associated with pro-inflammatory cytokine activity and psycho-neurological symptom cluster experience. METHODS: This was a prospective cohort study where 149 hematologic patients were recruited from a university hospital and 65 healthy volunteers provided control data. Latent profile analyses were conducted to identify subgroups at two time points: the last day of chemotherapy and 1 week after chemotherapy completion. Influencing factors of subgroup membership were examined by logistic regression. RESULTS: A substantial number of patients (33%, 34% at each time point) experienced the selected psycho-neurological symptoms as a cluster. Older age and elevated IL-1α and IL-6 were associated with experiencing the psycho-neurological symptom cluster. IDO activity was higher in the patients experiencing psycho-neurological symptom cluster; and was positively associated with IL-6. Symptom severity, IL-1α, IL-6, and IDO activity were all significantly higher in cancer patients than in the healthy controls. The findings were preserved across time points. CONCLUSIONS: The activation of pro-inflammatory cytokines and their cross-talk with IDO may be a common biological mechanism, underlying a psycho-neurological symptom cluster experience. The novel approaches for symptom assessment and management can be developed by assessing multiple psycho-neurological symptoms as a cluster and by targeting their common biological pathway.

Randomized Clinical Trials and Observational Tribulations: Providing Clinical Evidence for Personalized Surgical Pain Management Care Models.

Proving clinical superiority of personalized care models in interventional and surgical pain management is challenging. The apparent difficulties may arise from the inability to standardize complex surgical procedures that often involve multiple steps. Ensuring the surgery is performed the same way every time is nearly impossible. Confounding factors, such as the variability of the patient population and selection bias regarding comorbidities and anatomical variations are also difficult to control for. Small sample sizes in study groups comparing iterations of a surgical protocol may amplify bias. It is essentially impossible to conceal the surgical treatment from the surgeon and the operating team. Restrictive inclusion and exclusion criteria may distort the study population to no longer reflect patients seen in daily practice. Hindsight bias is introduced by the inability to effectively blind patient group allocation, which affects clinical result interpretation, particularly if the outcome is already known to the investigators when the outcome analysis is performed (often a long time after the intervention). Randomization is equally problematic, as many patients want to avoid being randomly assigned to a study group, particularly if they perceive their surgeon to be unsure of which treatment will likely render the best clinical outcome for them. Ethical concerns may also exist if the study involves additional and unnecessary risks. Lastly, surgical trials are costly, especially if the tested interventions are complex and require long-term follow-up to assess their benefit. Traditional clinical testing of personalized surgical pain management treatments may be more challenging because individualized solutions tailored to each patient's pain generator can vary extensively. However, high-grade evidence is needed to prompt a protocol change and break with traditional image-based criteria for treatment. In this article, the authors review issues in surgical trials and offer practical solutions.

The status and preparation for the next decade of biosimilars in the Middle Eastern and North African region.

INTRODUCTION: Little is known about the status and the future potential of biosimilars in the Middle East and North Africa (MENA) region. AREAS COVERED: This perspective provides insights into the current regulatory landscape of some MENA countries, currently available biosimilars, the potential of biosimilars in the next decade, and challenges to overcome. EXPERT OPINION: Given the economic and demographic heterogeneity across the MENA countries, biosimilars could reduce significant economic unmet needs in these countries. In the next decade, biosimilars may witness higher approval rates and market share over their originators in the MENA countries. We argue that the regulatory bodies in the MENA countries should adopt the new policies of the FDA, the EMA, and the WHO, that aim to ease the biosimilar approval process. These policies are to adopt technology in the process of approval; engage health technology assessment bodies in price assessment; provide educational materials to increase awareness among providers, patients, and payers. Further, MENA countries should upgrade the external-reference pricing systems to more sophisticated ones that consider the heterogeneity in economics and needs.