What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.

BACKGROUND: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. METHODS: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. RESULTS: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12-$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. CONCLUSION: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. PATIENT OR PUBLIC CONTRIBUTIONS: The patient partner coauthor informed protocol development, identified data items, and interpreted findings.

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Quality of life and cost-effectiveness of convalescent plasma compared to standard care for hospitalized COVID-19 patients in the CONCOR-1 trial.

BACKGROUND: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.

Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Cost-Effectiveness Study.

BACKGROUND: Clinical practice guidelines recommend indefinite anticoagulation for a first unprovoked venous thromboembolism (VTE). OBJECTIVE: To estimate the benefit-harm tradeoffs of indefinite anticoagulation in patients with a first unprovoked VTE. DESIGN: Markov modeling study. DATA SOURCES: Systematic reviews and meta-analyses for the long-term risks and case-fatality rates of recurrent VTE and major bleeding. Published literature for costs, quality of life, and other clinical events. TARGET POPULATION: Patients with a first unprovoked VTE who have completed 3 to 6 months of initial anticoagulant treatment. TIME HORIZON: Lifetime. PERSPECTIVE: Canadian health care public payer. INTERVENTION: Indefinite anticoagulation with direct oral anticoagulants. OUTCOME MEASURES: Recurrent VTE events, major bleeding events, costs in 2022 Canadian dollars (CAD), and quality-adjusted life-years (QALYs). RESULTS OF BASE-CASE ANALYSIS: When compared with discontinuing anticoagulation after initial treatment in a hypothetical cohort of 1000 patients aged 55 years, indefinite anticoagulation prevented 368 recurrent VTE events, which included 14 fatal pulmonary emboli, but induced an additional 114 major bleeding events, which included 30 intracranial hemorrhages and 11 deaths from bleeding. Indefinite anticoagulation cost CAD $16 014 more per person and did not increase QALYs (-0.075 per person). RESULTS OF SENSITIVITY ANALYSIS: Model results were most sensitive to the case-fatality rate of major bleeding and the annual risk for major bleeding during extended anticoagulation. LIMITATION: The model assumed that risks for recurrent VTE and major bleeding measured in clinical trials at 1 year remained constant during extended anticoagulation. CONCLUSION: Clinicians should use shared decision making to incorporate individual patient preferences and values when considering treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

A systematic assessment of preclinical multilaboratory studies and a comparison to single laboratory studies.

Background: Multicentric approaches are widely used in clinical trials to assess the generalizability of findings, however, they are novel in laboratory-based experimentation. It is unclear how multilaboratory studies may differ in conduct and results from single lab studies. Here, we synthesized the characteristics of these studies and quantitatively compared their outcomes to those generated by single laboratory studies. Methods: MEDLINE and Embase were systematically searched. Screening and data extractions were completed in duplicate by independent reviewers. Multilaboratory studies investigating interventions using in vivo animal models were included. Study characteristics were extracted. Systematic searches were then performed to identify single lab studies matched by intervention and disease. Difference in standardized mean differences (DSMD) was then calculated across studies to assess differences in effect estimates based on study design (>0 indicates larger effects in single lab studies). Results: Sixteen multilaboratory studies met inclusion criteria and were matched to 100 single lab studies. The multicenter study design was applied across a diverse range of diseases, including stroke, traumatic brain injury, myocardial infarction, and diabetes. The median number of centers was four (range 2-6) and the median sample size was 111 (range 23-384) with rodents most frequently used. Multilaboratory studies adhered to practices that reduce the risk of bias significantly more often than single lab studies. Multilaboratory studies also demonstrated significantly smaller effect sizes than single lab studies (DSMD 0.72 [95% confidence interval 0.43-1]). Conclusions: Multilaboratory studies demonstrate trends that have been well recognized in clinical research (i.e. smaller treatment effects with multicentric evaluation and greater rigor in study design). This approach may provide a method to robustly assess interventions and the generalizability of findings between laboratories. Funding: uOttawa Junior Clinical Research Chair; The Ottawa Hospital Anesthesia Alternate Funds Association; Canadian Anesthesia Research Foundation; Government of Ontario Queen Elizabeth II Graduate Scholarship in Science and Technology.

Phlebotomy resulting in controlled hypovolemia to prevent blood loss in major hepatic resections (PRICE-2): study protocol for a phase 3 randomized controlled trial.

INTRODUCTION: Blood loss and red blood cell (RBC) transfusion in liver surgery are areas of concern for surgeons, anesthesiologists, and patients alike. While various methods are employed to reduce surgical blood loss, the evidence base surrounding each intervention is limited. Hypovolemic phlebotomy, the removal of whole blood from the patient without volume replacement during liver transection, has been strongly associated with decreased bleeding and RBC transfusion in observational studies. This trial aims to investigate whether hypovolemic phlebotomy is superior to usual care in reducing RBC transfusions in liver resection. METHODS: This study is a double-blind multicenter randomized controlled trial. Adult patients undergoing major hepatic resections for any indication will be randomly allocated in a 1:1 ratio to either hypovolemic phlebotomy and usual care or usual care alone. Exclusion criteria will be minor resections, preoperative hemoglobin <100g/L, renal insufficiency, and other contraindication to hypovolemic phlebotomy. The primary outcome will be the proportion of patients receiving at least one allogeneic RBC transfusion unit within 30 days of the onset of surgery. Secondary outcomes will include transfusion of other allogeneic blood products, blood loss, morbidity, mortality, and intraoperative physiologic parameters. The surgical team will be blinded to the intervention. Randomization will occur on the morning of surgery. The sample size will comprise 440 patients. Enrolment will occur at four Canadian academic liver surgery centers over a 4-year period. Ethics approval will be obtained at participating sites before enrolment. DISCUSSION: The results of this randomized control trial will provide high-quality evidence regarding the use of hypovolemic phlebotomy in major liver resection and its effects on RBC transfusion. If proven to be effective, this intervention could become standard of care in liver operations internationally and become incorporated within perioperative patient blood management programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651154 . Registered on August 29 2018.

Protocol for a modelling study to assess the clinical and cost-effectiveness of indefinite anticoagulant therapy for first unprovoked venous thromboembolism.

INTRODUCTION: Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE. METHODS AND ANALYSIS: We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal.

Engaging Patients and Caregivers in an Early Health Economic Evaluation: Discerning Treatment Value Based on Lived Experience.

BACKGROUND: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment. OBJECTIVE: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. METHODS: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data. RESULTS: Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration. CONCLUSIONS: Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models.

Epidemiology of intravenous immune globulin in septic shock: a retrospective cohort analysis of the Premier Healthcare Database.

PURPOSE: Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock. METHODS: We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use. RESULTS: Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5-1.8] g·kg-1 for a median [IQR] of 1 [1-2] day. Receipt of IVIG was less likely for Black patients (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.41 to 0.72) and patients without private insurance (Medicare OR, 0.73; 95% CI 0.59 to 0.90; Medicaid OR, 0.41; 95% CI 0.30 to 0.57) and more likely for patients with immunocompromise (OR, 6.83; 95% CI 5.47 to 8.53), necrotizing fasciitis (OR, 9.78; 95% CI 6.97 to 13.72), and toxic shock (OR, 56.9; 95% CI 38.7 to 83.7). CONCLUSIONS: Intravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed.

RéSUMé: OBJECTIF: L'immunoglobuline intraveineuse (IGIV) peut améliorer la survie chez les personnes atteintes de choc septique. Les pratiques actuelles d'utilisation de l'IGIV sont inconnues. Nous avons cherché à caractériser les patients adultes en état de choc septique et nécessitant des vasopresseurs qui ont reçu de l'IGIV, à décrire les dosages administrés d'IGIV, et à évaluer les causes déterminantes d'une utilisation d'IGIV chez ces patients. MéTHODE: Nous avons réalisé une étude rétrospective de base de données portant sur des patients adultes atteints de choc septique admis dans des hôpitaux américains et inclus dans la base de données Premier Healthcare (de juillet 2010 à juin 2013). Nous avons décrit la proportion de patients en choc septique recevant de l'IGIV, examiné les posologies utilisées d'IGIV à travers les sites et employé des techniques de régression multivariable à effets aléatoires pour identifier les prédicteurs de l'utilisation d'IGIV. RéSULTATS: L'IGIV a été administrée à 0,3 % (n = 685) des patients présentant un choc septique, avec une dose médiane [écart interquartile (ÉIQ)] de 1 [0,5­1,8] g·kg-1 pour une médiane [ÉIQ] de 1 [1­2] jour. L'administration d'IGIV était moins probable chez les patients noirs (rapport de cotes [RC], 0,54; intervalle de confiance [IC] à 95 %, 0,41 à 0,72) et les patients sans assurance privée (RC Medicare, 0,73; IC 95 %, 0,59 à 0,90; RC Medicaid, 0,41; IC 95 %, 0,30 à 0,57) et plus probable chez les patients immunodéprimés (RC, 6,83; IC 95 %, 5,47 à 8,53), atteints de fasciite nécrosante (RC, 9,78; IC 95 %, 6,97 à 13,72), et en choc toxique (RC, 56,9; IC 95 %, 38,7 à 83,7). CONCLUSION: L'IGIV est rarement utilisée aux États-Unis chez les patients en choc septique. Les dosages d'IGIV utilisés en cas de choc septique pourraient être moins intensifs que ceux associés à un effet bénéfique en matière de survie dans les méta-analyses. L'utilisation peu fréquente observée appuie une équivalence clinique apparente, peut-être secondaire aux limites de la littérature princeps. Une étude clinique évaluant le rôle de l'IGIV dans le choc septique est nécessaire.

Stakeholder engagement in economic evaluation: Protocol for using the nominal group technique to elicit patient, healthcare provider, and health system stakeholder input in the development of an early economic evaluation model of chimeric antigen receptor T-cell therapy.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy is a class of immunotherapy. An economic evaluation conducted at an early stage of development of CAR-T therapy for treatment of adult relapsed or refractory acute lymphoblastic leukaemia could provide insight into factors contributing to the cost of treatment, the potential clinical benefits, and what the health system can afford. Traditionally, stakeholders are engaged in certain parts of health technology assessment processes, such as in the identification and selection of technologies, formulation of recommendations, and implementation of recommendations; however, little is known about processes for stakeholder engagement during the conduct of the assessment. This is especially the case for economic evaluations. Stakeholders, such as clinicians, policy-makers, patients, and their support networks, have insight into factors that can enhance the validity of an economic evaluation model. This research outlines a specific methodology for stakeholder engagement and represents an avenue to enhance health economic evaluations and support the use of these models to inform decision making for resource allocation. This protocol may inform a tailored framework for stakeholder engagement processes in future economic evaluation model development. METHODS AND ANALYSIS: We will involve clinicians, healthcare researchers, payers, and policy-makers, as well as patients and their support networks in the conduct and verification of an early economic evaluation of a novel health technology to incorporate stakeholder-generated knowledge. Three stakeholder-specific focus groups will be conducted using an online adaptation of the nominal group technique to elicit considerations from each. This study will use CAR-T therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia as a basis for investigating broader stakeholder engagement processes. ETHICS AND DISSEMINATION: This study received ethics approval from the Ottawa Hospital Research Institute Research Ethics Board (REB 20200320-01HT) and the results will be shared via conference presentations, peer-reviewed publications, and ongoing stakeholder engagement.

Lack of Cost-Effectiveness of Preoperative Erythropoiesis-Stimulating Agents and/or Iron Therapy in Anaemic, Elective Surgery Patients: A Systematic Review and Updated Analysis.

OBJECTIVES: For anaemic elective surgery patients, current clinical practice guidelines weakly recommend the routine use of iron, but not erythrocyte-stimulating agents (ESAs), except for short-acting ESAs in major orthopaedic surgery. This recommendation is, however, not based on any cost-effectiveness studies. The aim of this research was to (1) systematically review the literature regarding cost effectiveness of preoperative iron and/or ESAs in anaemic, elective surgery patients and (2) update existing economic evaluations (EEs) with recent data. METHODS: Eight databases and registries were searched for EEs and randomized controlled trials (RCTs) reporting cost-effectiveness data on November 11, 2020. Data were extracted, narratively synthesized and critically appraised using the Philips reporting checklist. Pre-existing full EEs were updated with effectiveness data from a recent systematic review and current cost data. Incremental cost-effectiveness ratios were expressed as cost per (quality-adjusted) life-year [(QA)LY] gained. RESULTS: Only five studies (4 EEs and 1 RCT) were included, one on intravenous iron and four on ESAs + oral iron. The EE on intravenous iron only had an in-hospital time horizon. Therefore, cost effectiveness of preoperative iron remains uncertain. The three EEs on ESAs had a lifetime time horizon, but reported cost per (QA)LY gained of 20-65 million (GBP or CAD). Updating these analyses with current data confirmed ESAs to have a cost per (QA)LY gained of 3.5-120 million (GBP or CAD). CONCLUSIONS: Cost effectiveness of preoperative iron is unproven, whereas routine preoperative ESA therapy cannot be considered cost effective in elective surgery, based on the limited available data. Future guidelines should reflect these findings.

Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer.

A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.

Patient Participation in Clinical Trials of Oncology Drugs and Biologics Preceding Approval by the US Food and Drug Administration.

Importance: Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. Objective: To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. Design, Setting, and Participants: This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. Main Outcomes and Measure: The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. Results: A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). Conclusions and Relevance: The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Implementation of the Canadian Cardiovascular Society guidelines for perioperative risk assessment and management: an interrupted time series study.

PURPOSE: The Canadian Cardiovascular Society (CCS) guidelines for patients undergoing non-cardiac surgery address the lack of standardized management for patients at risk of perioperative cardiovascular complications. Our interdisciplinary group evaluated the implementation of these guidelines. METHODS: We used an interrupted time series design to evaluate the effect of implementation of the CCS guidelines, using routinely collected hospital data. The study population consisted of elective, non-cardiac surgery patients who were: i) inpatients following surgery and ii) age ≥ 65 or age 45-64 yr with a Revised Cardiac Risk Index ≥ 1. Outcomes included adherence to troponin I (TnI) monitoring (primary) and adherence to appropriate consultant care for patients with elevated TnI (secondary). Exploratory outcomes included cost measures and clinical outcomes such as length of stay. RESULTS: We included 1,421 patients (706 pre- and 715 post-implementation). We observed a 67% absolute increase (95% confidence interval, 55 to 80; P < 0.001) in adherence to TnI testing following the implementation of the guidelines. In patients who had elevated TnI following guideline implementation (n = 64), the majority (85%) received appropriate follow-up care in the form of a general medicine or cardiology consult, all received at least one electrocardiogram, and half received at least one advanced cardiac test (e.g., cardiac perfusion scan, or percutaneous intervention). CONCLUSIONS: Our study showed the ability to implement and adhere to the CCS guidelines. Large-scale multicentre evaluations of CCS guideline implementation are needed to gain a better understanding of potential effects on clinically relevant outcomes.

RéSUMé: OBJECTIF: Les lignes directrices de la Société canadienne de cardiologie (SCC) concernant les patients subissant une chirurgie non cardiaque ont été conçues pour pallier l'absence de standardisation dans la prise en charge des patients à risque de complications cardiovasculaires périopératoires. Notre groupe interdisciplinaire a évalué la mise en œuvre de ces lignes directrices. MéTHODE: Nous avons utilisé une méthodologie de série chronologique interrompue pour évaluer l'effet de la mise en œuvre des lignes directrices de la SCC, à l'aide des données hospitalières habituellement recueillies. La population à l'étude se composait de patients de chirurgies non cardiaques non urgentes qui étaient : i) hospitalisés après leur chirurgie et ii) âgés de ≥ 65 ans ou de 45 à 64 ans avec un Indice de risque cardiaque révisé ≥ 1. Les critères d'évaluation comprenaient l'observance du monitorage de la troponine I (TnI) (critère d'évaluation primaire) et l'observance des soins spécialisés appropriés aux patients présentant un taux élevé de TnI (critère secondaire). Les critères exploratoires comprenaient des mesures de coûts et des résultats cliniques tels que la durée de séjour. RéSULTATS: Nous avons inclus 1421 patients (706 avant et 715 après la mise en œuvre). Nous avons observé une augmentation absolue de 67 % (intervalle de confiance de 95 %, 55 à 80; P < 0,001) de l'observance des tests de la TnI suite à la mise en œuvre des lignes directrices. Parmi les patients présentant un taux élevé de TnI suite à la mise en œuvre des lignes directrices (n = 64), la majorité (85%) a reçu des soins de suivi appropriés sous la forme d'une consultation en médecine générale ou en cardiologie; tous ont subi au moins un électrocardiogramme, et la moitié ont passé au moins un examen cardiaque subséquent (p. ex., évaluation de la perfusion myocardique par scintigraphie ou cathétérisme percutané). CONCLUSION: Notre étude a montré qu'il est possible de mettre en œuvre et d'adhérer aux nouvelles lignes directrices de la SCC. Des évaluations multicentriques à grande échelle portant sur la mise en œuvre des lignes directrices de la SCC sont nécessaires pour mieux comprendre ses effets potentiels sur les devenirs cliniquement pertinents.

Benefits and obstacles to cell therapy in neonates: The INCuBAToR (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research).

Cell-based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard-earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell-based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence-based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence-based fashion.

Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study.

OBJECTIVES: To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls. DESIGN: Propensity-matched population-based cohort study using administrative data. SETTING: Ontario, Canada. PATIENTS: We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63-1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50-1.55 and hazard ratio, 1.41; 95% CI, 1.40-1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568-$29,913) for severe and $9,475 (95% CI, $9,150-$9,727) for nonsevere sepsis. CONCLUSIONS: Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors.

Value of mesenchymal stem cell therapy for patients with septic shock: an early health economic evaluation.

BACKGROUND.: This study estimates the maximum price at which mesenchymal stem cell (MSC) therapy is deemed cost-effective for septic shock patients and identifies parameters that are most important in making treatment decisions. METHODS: We developed a probabilistic Markov model according to the sepsis care trajectory to simulate costs and quality-adjusted life years (QALYs) of septic shock patients receiving either MSC therapy or usual care over their lifetime. We calculated the therapeutic headroom by multiplying the gains attributable to MSCs with willingness-to-pay (WTP) threshold and derived the maximum reimbursable price (MRP) from the expected net monetary benefit and savings attributable to MSCs. We performed scenario analyses to assess the impact of changes to assumptions on the study findings. A value of information analysis is performed to identify parameters with greatest impact on the uncertainty around the cost-effectiveness of MSC therapy. RESULTS: At a WTP threshold of $50,000 per QALY, the therapeutic headroom and MRP of MSC therapy were $20,941 and $16,748, respectively; these estimates increased with the larger WTP values and the greater impact of MSCs on in-hospital mortality and hospital discharge rates. The parameters with greatest information value were MSC's impact on in-hospital mortality and the baseline septic shock in-hospital mortality. CONCLUSION: At a common WTP of $50,000/QALY, MSC therapy is deemed to be economically attractive if its unit cost does not exceed $16,748. This ceiling price can be increased to $101,450 if the therapy significantly reduces both in-hospital mortality and increases hospital discharge rates.

Pragmatic Strategy Empowering Paramedics to Assess Low-Risk Trauma Patients With the Canadian C-Spine Rule and Selectively Transport Them Without Immobilization: Protocol for a Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: Each year, half a million patients with a potential neck (c-spine) injury are transported to Ontario emergency departments (EDs). Less than 1.0% (1/100) of these patients have a neck bone fracture. Even less (1/200, 0.5%) have a spinal cord injury or nerve damage. Currently, paramedics transport all trauma victims (with or without an injury) by ambulance using a backboard, cervical collar, and head immobilizers. Importantly, prolonged immobilization is often unnecessary; it causes patient discomfort and pain, decreases community access to paramedics, contributes to ED crowding, and is very costly. We therefore developed the Canadian C-Spine Rule (CCR) for alert and stable trauma patients. This decision rule helps ED physicians and triage nurses to safely and selectively remove immobilization, without x-rays and missed injury. We successfully taught Ottawa paramedics to use the CCR in the field in a single-center study. OBJECTIVE: This study aimed to improve patient care and health system efficiency and outcomes by allowing paramedics to assess eligible low-risk trauma patients with the CCR and selectively transport them without immobilization to the ED. METHODS: We propose a pragmatic stepped-wedge cluster randomized design with health economic evaluation, designed collaboratively with knowledge users. Our 36-month study will consist of a 12-month setup and training period (year 1), followed by the stepped-wedge trial (year 2) and a 12-month period for study completion, analyses, and knowledge translation. A total of 12 Ontario paramedic services of various sizes distributed across the province will be randomly allocated to one of three sequences. Paramedic services in each sequence will cross from the control condition (usual care) to the intervention condition (CCR implementation) at intervals of 3 months until all communities have crossed to the intervention. Data will be collected on all eligible patients in each paramedic service for a total duration of 12 months. A major strength of our design is that each community will have implemented the CCR by the end of the study. RESULTS: Interim results are expected in December 2019 and final results in 2020. If this multicenter trial is successful, we expect the Ontario Ministry of Health will recommend that paramedics evaluate all eligible patients with the CCR in the Province of Ontario. CONCLUSIONS: We conservatively estimate that in Ontario, more than 60% of all eligible trauma patients (300,000 annually) could be transported safely and comfortably, without c-spine immobilization devices. This will significantly reduce patient pain and discomfort, paramedic intervention times, and ED length of stay, thereby improving access to paramedics and ED care. This could be achieved rapidly and with lower health care costs compared with current practices (possible cost saving of Can $36 [US $25] per immobilization or Can $10,656,000 [US $7,335,231] per year). TRIAL REGISTRATION: ClinicalTrials.gov NCT02786966; https://clinicaltrials.gov/ct2/show/NCT02786966. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16966.

Cost analysis of using Magee scores as a surrogate of Oncotype DX for adjuvant treatment decisions in women with early breast cancer.

Breast cancer is the most common cancer in women worldwide. Most current guidelines recommend using multigene profiling assays to aid the decision on the addition of chemotherapy to adjuvant hormone therapy for women who present with early-stage, hormone receptor-positive, HER2-negative disease. One of these assays is the Oncotype DX, which predicts the disease recurrence risk and adjuvant chemotherapy benefits. Given its high cost, there is an economic incentive to evaluate its surrogates, such as the Magee equations. We assessed health system costs associated with the use of the Magee scores. A probabilistic decision tree was used to calculate the difference in mean health system costs based on data obtained from a randomized trial and the published literature. Costs were calculated from a perspective of Canada's publicly funded health care system. A series of sensitivity analysis was conducted to assess the robustness of the study findings. The Magee equations were associated with a total cost savings of C$100 per patient (95% CI, -C$3068 to C$5022) compared with standard of care. The difference in costs was highly sensitive to the extent that the Magee scores could reduce the frequency of adjuvant chemotherapy and Oncotype DX requests.