Cannabis for medical use versus opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised clinical trials.

OBJECTIVE: The objective of this study is to evaluate the comparative benefits and harms of opioids and cannabis for medical use for chronic non-cancer pain. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: EMBASE, MEDLINE, CINAHL, AMED, PsycINFO, PubMed, Web of Science, Cannabis-Med, Epistemonikos and the Cochrane Library (CENTRAL) from inception to March 2021. STUDY SELECTION: Randomised trials comparing any type of cannabis for medical use or opioids, against each other or placebo, with patient follow-up ≥4 weeks. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently extracted data. We used Bayesian random-effects network meta-analyses to summarise the evidence and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to evaluate the certainty of evidence and communicate our findings. RESULTS: Ninety trials involving 22 028 patients were eligible for review, among which the length of follow-up ranged from 28 to 180 days. Moderate certainty evidence showed that opioids provide small improvements in pain, physical functioning and sleep quality versus placebo; low to moderate certainty evidence supported similar effects for cannabis versus placebo. Neither was more effective than placebo for role, social or emotional functioning (all high to moderate certainty evidence). Moderate certainty evidence showed there is probably little to no difference between cannabis for medical use and opioids for physical functioning (weighted mean difference (WMD) 0.47 on the 100-point 36-item Short Form Survey physical component summary score, 95% credible interval (CrI) -1.97 to 2.99), and cannabis resulted in fewer discontinuations due to adverse events versus opioids (OR 0.55, 95% CrI 0.36 to 0.83). Low certainty evidence suggested little to no difference between cannabis and opioids for pain relief (WMD 0.23 cm on a 10 cm Visual Analogue Scale (VAS), 95% CrI -0.06 to 0.53) or sleep quality (WMD 0.49 mm on a 100 mm VAS, 95% CrI -4.72 to 5.59). CONCLUSIONS: Cannabis for medical use may be similarly effective and result in fewer discontinuations than opioids for chronic non-cancer pain. PROSPERO REGISTRATION NUMBER: CRD42020185184.

Treatment outcomes for newly diagnosed, treatment-naïve TP53-mutated acute myeloid leukemia: a systematic review and meta-analysis.

BACKGROUND: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA). METHODS: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53m AML receiving first-line treatment with IC, HMA, or VEN + HMA. RESULTS: Searches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA. CONCLUSIONS: Despite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.

Theory and practice of Bayesian and frequentist frameworks for network meta-analysis.

Network meta-analysis (NMA) is an increasingly popular statistical method of synthesising evidence to assess the comparative benefits and harms of multiple treatments in a single analysis. Several automated software packages facilitate conducting NMA using either of two alternative approaches, Bayesian or frequentist frameworks. Researchers must choose a framework for conducting NMA (Bayesian or frequentist) and select appropriate model(s), and those conducting NMA need to understand the assumptions and limitations of different approaches. Bayesian models are more frequently used and can be more flexible but require checking additional assumptions and greater statistical expertise that are often ignored. The present paper describes the important theoretical aspects of Bayesian and frequentist models for NMA and the applications and considerations of contrast-synthesis and arm-synthesis NMAs. In addition, we present evidence from a limited number of simulation and empirical studies that compared different frequentist and Bayesian models and provide an overview of available automated software packages to perform NMA. We will conclude that when analysts choose appropriate models, there are seldom important differences in the results of Bayesian and frequentist approaches and that network meta-analysts should therefore focus on model features rather than the statistical framework.

Azacitidine Monotherapy in Patients With Treatment-Naïve Higher-risk Myelodysplastic Syndrome: A Systematic Literature Review and Meta-analysis.

BACKGROUND: The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes. MATERIALS AND METHODS: We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects. RESULTS: The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%. CONCLUSIONS: The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.

Reverse Total Shoulder Arthroplasty Is the Most Cost-effective Treatment Strategy for Proximal Humerus Fractures in Older Adults: A Cost-utility Analysis.

BACKGROUND: Proximal humerus fractures are the second-most common fragility fracture in older adults. Although reverse total shoulder arthroplasty (RTSA) is a promising treatment strategy for proximal humerus fractures with favorable clinical and quality of life outcomes, it is associated with much higher, and possibly prohibitive, upfront costs relative to nonoperative treatment and other surgical alternatives. QUESTIONS/PURPOSES: (1) What is the cost-effectiveness of open reduction internal fixation (ORIF), hemiarthroplasty, and RTSA compared with the nonoperative treatment of complex proximal humerus fractures in adults older than 65 years from the perspective of a single-payer Canadian healthcare system? (2) Which factors, if any, affect the cost-effectiveness of ORIF, hemiarthroplasty, and RTSA compared with nonoperative treatment of proximal humerus fractures including quality of life outcomes, cost, and complication rates after each treatment? METHODS: This cost-utility analysis compared RTSA, hemiarthroplasty, and ORIF with the nonoperative management of complex proximal humerus fractures in adults older than 65 years over a lifetime time horizon from the perspective of a single-payer healthcare system. Short-term and intermediate-term complications in the 2-year postoperative period were modeled using a decision tree, with long-term outcomes estimated through a Markov model. The model was initiated with a cohort of 75-year-old patients who had a diagnosis of a comminuted (three- or four-part) proximal humerus fractures; 90% of the patients were women. The mean age and gender composition of the model's cohort was based on a systematic review conducted as part of this analysis. Patients were managed nonoperatively or surgically with either ORIF, hemiarthroplasty, or RTSA. The three initial surgical treatment options of ORIF, hemiarthroplasty, and RTSA resulted in uncomplicated healing or the development of a complication that would result in a subsequent surgical intervention. The model reflects the complications that result in repeat surgery and that are assumed to have the greatest impact on clinical outcomes and costs. Transition probabilities and health utilities were derived from published sources, with costs (2020 CAD) sourced from regional costing databases. The primary outcome was the incremental cost-utility ratio, which was calculated using expected quality-adjusted life years (QALYs) gained and costs. Sensitivity analyses were conducted to explore the impact of changing key model parameters. RESULTS: Based on both pairwise and sequential analysis, RTSA was found to be the most cost-effective strategy for managing complex proximal humerus fractures in adults older than 65 years. Compared with nonoperative management, the pairwise incremental cost-utility ratios of hemiarthroplasty and RTSA were CAD 25,759/QALY and CAD 7476/QALY, respectively. ORIF was dominated by nonoperative management, meaning that it was both more costly and less effective. Sequential analysis, wherein interventions are compared from least to most expensive in a pairwise manner, demonstrated ORIF to be dominated by hemiarthroplasty, and hemiarthroplasty to be extendedly dominated by RTSA. Further, at a willingness-to-pay threshold of CAD 50,000/QALY, RTSA had 66% probability of being the most cost-effective treatment option. The results were sensitive to changes in the parameters for the probability of revision RTSA after RTSA, the treatment cost of RTSA, and the health utilities associated with the well state for all treatment options except ORIF, although none of these changes were found to be clinically realistic based on the existing evidence. CONCLUSION: Based on this economic analysis, RTSA is the preferred treatment strategy for complex proximal humerus fractures in adults older than 65 years, despite high upfront costs. Based on the evidence to date, it is unlikely that the parameters this model was sensitive to would change to the degree necessary to alter the model's outcome. A major strength of this model is that it reflects the most recent randomized controlled trials evaluating the management of this condition. Therefore, clinicians should feel confident recommending RTSA for the management of proximal humerus fractures in adults older than 65 years, and they are encouraged to advocate for this intervention as being a cost-effective practice, especially in publicly funded healthcare systems wherein resource stewardship is a core principle. Future high-quality trials should continue to collect both clinical and quality of life outcomes using validated tools such as the EuroQOL-5D to reduce parameter uncertainty and support decision makers in understanding relevant interventions' value for money. LEVEL OF EVIDENCE: Level III, economic and decision analysis.

Towards Transparency in the Selection of Published Health Utility Inputs in Cost-Utility Analyses: The Health Utility Application Tool (HAT).

BACKGROUND: Evaluating the relevance of published health utilities to the context of a cost-utility analysis (CUA) remains an essential, yet often overlooked, task. OBJECTIVE: The objective of this study was to provide guidance on this process through the development of the Health utility Application Tool (HAT). METHODS: We conducted semi-structured telephone interviews with Canadian stakeholders from reimbursement bodies, academia, and the pharmaceutical industry to identify current practices and perspectives of the application of the health utility literature to CUAs. An online survey with international members of the general health economics and outcomes research community was also conducted to gather opinions on key concepts. RESULTS: Based on the themes emerging from the interviews and online questionnaire, the HAT includes questions prompting investigators to consider the following constructs: similarity of the clinical condition in the health utility study and the CUA; similarity of health utility study participant demographics and the demographics of the CUA's target population; similarity of the health state descriptions in the health utility study and the CUA; and the method of assigning utility weights. Considerations of transparency prompted additional items, including: means by which the health utility study was identified; type of respondents; study design; and measure used to collect health utility estimates. CONCLUSION: The HAT is intended to guide the evaluation of the applicability of published health utilities for a CUA, thus promoting transparency and accountability in the selection of model inputs.

Evaluating the conduct and application of health utility studies: a review of critical appraisal tools and reporting checklists.

BACKGROUND: Published health utility studies are increasingly cited in cost-utility analyses to inform reimbursement decision-making. However, there is limited guidance for investigators looking to systematically evaluate the methodological quality of health utility studies or their applicability to decision contexts. OBJECTIVE: To describe how health utility concepts are reflected in tools intended for use with the health economic literature, particularly with respect to the evaluation of methodological quality and context applicability. METHODS: We reviewed the critical appraisal and reporting tools described in a 2012 report published by the Agency for Healthcare Research and Quality (AHRQ), supplemented with a keyword search of MEDLINE and EMBASE, to identify existing tools which include health utility constructs. From these tools, a list of relevant items was compiled and grouped into domain categories based on the methodological or applicability aspect they were directed toward. RESULTS: Of the 24 tools we identified, 12 contained items relevant to the evaluation of health utilities. Sixty-five items were considered relevant to the evaluation of quality, while 44 were relevant to the evaluation of applicability. Items were arranged into four domains: health state descriptions; selection and description of respondents; elicitation and measurement methods; and other considerations. CONCLUSION: As key inputs to cost-utility analyses, health utilities have the potential to significantly impact estimates of cost-effectiveness. Existing tools contain only general items related to the conduct or use of health utility studies. There is a need to develop tools that systematically evaluate the methodological quality and applicability of health utility studies.

Comparing the use of aggregate data and various methods of integrating individual patient data to network meta-analysis and its application to first-line ART.

BACKGROUND: The 2018 World Health Organization HIV guidelines were based on the results of a network meta-analysis (NMA) of published trials. This study employed individual patient-level data (IPD) and aggregate data (AgD) and meta-regression methods to assess the evidence supporting the WHO recommendations and whether they needed any refinements. METHODS: Access to IPD from three trials was granted through ClinicalStudyDataRequest.com (CSDR). Seven modelling approaches were applied and compared: 1) Unadjusted AgD network meta-analysis (NMA) - the original analysis; 2) AgD-NMA with meta-regression; 3) Two-stage IPD-AgD NMA; 4) Unadjusted one-stage IPD-AgD NMA; 5) One-stage IPD-AgD NMA with meta-regression (one-stage approach); 6) Two-stage IPD-AgD NMA with empirical-priors (empirical-priors approach); 7) Hierarchical meta-regression IPD-AgD NMA (HMR approach). The first two were the models used previously. Models were compared with respect to effect estimates, changes in the effect estimates, coefficient estimates, DIC and model fit, rankings and between-study heterogeneity. RESULTS: IPD were available for 2160 patients, representing 6.5% of the evidence base and 3 of 24 edges. The aspect of the model affected by the choice of modeling appeared to differ across outcomes. HMR consistently generated larger intervals, often with credible intervals (CrI) containing the null value. Discontinuations due to adverse events and viral suppression at 96 weeks were the only two outcomes for which the unadjusted AgD NMA would not be selected. For the first, the selected model shifted the principal comparison of interest from an odds ratio of 0.28 (95% CrI: 10.17, 0.44) to 0.37 (95% CrI: 0.23, 0.58). Throughout all outcomes, the regression estimates differed substantially between AgD and IPD methods, with the latter being more often larger in magnitude and statistically significant. CONCLUSIONS: Overall, the use of IPD often impacted the coefficient estimates, but not sufficiently as to necessitate altering the final recommendations of the 2018 WHO Guidelines. Future work should examine the features of a network where adjustments will have an impact, such as how much IPD is required in a given size of network.

Clinical Trial Data Sharing for COVID-19-Related Research.

This paper aims to provide a perspective on data sharing practices in the context of the COVID-19 pandemic. The scientific community has made several important inroads in the fight against COVID-19, and there are over 2500 clinical trials registered globally. Within the context of the rapidly changing pandemic, we are seeing a large number of trials conducted without results being made available. It is likely that a plethora of trials have stopped early, not for statistical reasons but due to lack of feasibility. Trials stopped early for feasibility are, by definition, statistically underpowered and thereby prone to inconclusive findings. Statistical power is not necessarily linear with the total sample size, and even small reductions in patient numbers or events can have a substantial impact on the research outcomes. Given the profusion of clinical trials investigating identical or similar treatments across different geographical and clinical contexts, one must also consider that the likelihood of a substantial number of false-positive and false-negative trials, emerging with the increasing overall number of trials, adds to public perceptions of uncertainty. This issue is complicated further by the evolving nature of the pandemic, wherein baseline assumptions on control group risk factors used to develop sample size calculations are far more challenging than those in the case of well-documented diseases. The standard answer to these challenges during nonpandemic settings is to assess each trial for statistical power and risk-of-bias and then pool the reported aggregated results using meta-analytic approaches. This solution simply will not suffice for COVID-19. Even with random-effects meta-analysis models, it will be difficult to adjust for the heterogeneity of different trials with aggregated reported data alone, especially given the absence of common data standards and outcome measures. To date, several groups have proposed structures and partnerships for data sharing. As COVID-19 has forced reconsideration of policies, processes, and interests, this is the time to advance scientific cooperation and shift the clinical research enterprise toward a data-sharing culture to maximize our response in the service of public health.

Heterogeneity in renal end points of cardiovascular outcomes trials in Type 2 diabetes.

Composite renal end points and end stage renal disease (ESRD) are frequently included as prespecified secondary end points in the cardiovascular outcomes trials (CVOTs) of diabetes medications. We examined the heterogeneity in the definitions of composite renal end point and ESRD in CVOTs. Five criteria (macroalbuminuria, doubling of serum creatinine, estimated glomerular filtration rate [GFR], ESRD and renal death), were considered for the renal composite end point across the trials. Only three of the 12 trials included all five criteria, whereas the other trials included different combinations of four, three and two criteria. ESRD definition also showed considerable heterogeneity across the trials. Heterogeneity exists in the definitions of renal composite and ESRD end points in CVOTs making it challenging to assess comparative efficacy of the active treatments for reimbursement purposes.

Efficacy of Treatments for Polycystic Ovarian Syndrome Management in Adolescents.

Limited evidence on treatment options for polycystic ovarian syndrome (PCOS) has led to considerable variation in health care practices. We aimed to compare the effects of metformin and/or oral contraceptive pills (OCP) in combination with pioglitazone, spironolactone, flutamide, and lifestyle interventions among adolescents aged 11 to 19 years with PCOS. Literature searches were performed in Medline, Embase, and the Cochrane Central Register of Controlled Trials from database inception through December 2018, with no language restriction. Two reviewers screened titles and abstracts, assessed full text eligibility, and extracted information from eligible trials. Evidence was synthesized through network meta-analyses (NMA) using a Bayesian random-effects approach. We identified 37 randomized controlled trials, in which 2400 patients were randomized. NMA showed no statistically important difference among all interventions to improve menstrual regulation or body mass index. Moderate-quality evidence showed hirsutism scores were reduced by multiple interventions that included single and combination medications namely; lifestyle intervention, metformin, OCP, spironolactone, pioglitazone, metformin-OCP, metformin-spironolactone, and metformin-flutamide against placebo. Moderate-quality evidence showed OCP results in more dysglycemia compared to metformin (odds ratio, 2.98; 95% credible interval, 1.02-8.96), no intervention resulted in dysglycemia reduction. In conclusion, metformin and OCP as monotherapy or in combination with other interventions compared with placebo can reduce hirsutism scores, but none of these medications lead to effective menstrual cycle regulation or weight reduction. However, the use of OCP leads to worse cardiometabolic risk factors. Further research into new treatment options is urgently needed. PROSPERO REGISTRATION NUMBER: CRD42015016148.

Reporting and design of randomized controlled trials for COVID-19: A systematic review.

BACKGROUND: The novel coronavirus 2019 (COVID-19) pandemic has mobilized global research at an unprecedented scale. While challenges associated with the COVID-19 trial landscape have been discussed previously, no comprehensive reviews have been conducted to assess the reporting, design, and data sharing practices of randomized controlled trials (RCTs). PURPOSE: The purpose of this review was to gain insight into the current landscape of reporting, methodological design, and data sharing practices for COVID-19 RCTs. DATA SOURCES: We conducted three searches to identify registered clinical trials, peer-reviewed publications, and pre-print publications. STUDY SELECTION: After screening eight major trial registries and 7844 records, we identified 178 registered trials and 38 publications describing 35 trials, including 25 peer-reviewed publications and 13 pre-prints. DATA EXTRACTION: Trial ID, registry, location, population, intervention, control, study design, recruitment target, actual recruitment, outcomes, data sharing statement, and time of data sharing were extracted. DATA SYNTHESIS: Of 178 registered trials, 112 (62.92%) were in hospital settings, median planned recruitment was 100 participants (IQR: 60, 168), and the majority (n = 166, 93.26%) did not report results in their respective registries. Of 35 published trials, 31 (88.57%) were in hospital settings, median actual recruitment was 86 participants (IQR: 55.5, 218), 10 (28.57%) did not reach recruitment targets, and 27 trials (77.14%) reported plans to share data. CONCLUSIONS: The findings of our study highlight limitations in the design and reporting practices of COVID-19 RCTs and provide guidance towards more efficient reporting of trial results, greater diversity in patient settings, and more robust data sharing.

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

BACKGROUND: To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. METHODS: We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. FINDINGS: We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48-2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04-0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48-0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50-0·92). INTERPRETATION: The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. FUNDING: WHO.

The Landscape of Emerging Randomized Clinical Trial Evidence for COVID-19 Disease Stages: A Systematic Review of Global Trial Registries.

PURPOSE: A multitude of randomized controlled trials (RCTs) have emerged in response to the novel coronavirus disease (COVID-19) pandemic. Understanding the distribution of trials among various settings is important to guide future research priorities and efforts. The purpose of this review was to describe the emerging evidence base of COVID-19 RCTs by stages of disease progression, from pre-exposure to hospitalization. METHODS: We collated trial data across international registries: ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Registry; Chinese Clinical Trial Registry; Clinical Research Information Service; EU Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; German Clinical Trials Register (up to 7 October 2020). Active COVID-19 RCTs in international registries were eligible for inclusion. We extracted trial status, intervention(s), control, sample size, and clinical context to generate descriptive frequencies, network diagram illustrations, and statistical analyses including odds ratios and the Mann-Whitney U-test. RESULTS: Our search identified 11503 clinical trials registered for COVID-19 and identified 2388 RCTs. After excluding 45 suspended RCTs and 480 trials with unclear or unreported disease stages, 1863 active RCTs were included and categorized into four broad disease stages: pre-exposure (n=107); post-exposure (n=208); outpatient treatment (n=266); hospitalization, including the intensive care unit (n=1376). Across all disease stages, most trials had two arms (n=1500/1863, 80.52%), most often included (hydroxy)chloroquine (n=271/1863, 14.55%) and were US-based (n=408/1863, 21.90%). US-based trials had lower odds of including (hydroxy)chloroquine than trials in other countries (OR: 0.63, 95% CI: 0.45-0.90) and similar odds of having two arms compared to other geographic regions (OR: 1.05, 95% CI: 0.80-1.38). CONCLUSION: There is a marked difference in the number of trials across settings, with limited studies on non-hospitalized persons. Focus on pre- and post-exposure, and outpatients, is worthwhile as a means of reducing infections and lessening the health, social, and economic burden of COVID-19.

Conservative Intervention Strategies for Adult Cancer-Related Lymphedema: A Systematic Review and Network Meta-Analysis.

PROBLEM IDENTIFICATION: The comparative effectiveness of available management options for cancer-related secondary lymphedema is unknown. LITERATURE SEARCH: CINAHL®, Embase®, and MEDLINE® were searched for randomized trials comparing conservative treatment strategies. DATA EVALUATION: A network meta-analysis was conducted for lymphedema volume, along with pairwise meta-analyses for remaining outcomes. Evidence certainty was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. SYNTHESIS: Overall, 36 studies with a total of 1,651 participants were included. Compared to standard care, conservative treatments did not significantly reduce lymphedema volume. There was low to very low certainty evidence of benefit for several treatments on secondary outcomes. IMPLICATIONS FOR PRACTICE: There is insufficient evidence to suggest important differences between standard care and conservative treatment strategies for reducing lymphedema volume and improving lymphedema-related symptoms. SUPPLEMENTAL MATERIAL CAN BE FOUND AT HTTPS: //onf.ons.org/supplementary-material-conservative-intervention-strategies-adult-cancer-related-lymphedema.

An Exploratory Analysis of Predictors of Concordance between Canadian Common Drug Review Reimbursement Recommendations and the Subsequent Decisions by Ontario, British Columbia and Alberta.

BACKGROUND: Concordance between Common Drug Review (CDR) recommendations and provincial plans has been studied previously. However, no study has, to the best of the authors' knowledge, examined the characteristics of CDR recommendations that may be associated with concordance. METHODS: Recommendation-decision pairs were collected from the CDR and the provincial plans of Ontario, British Columbia and Alberta. Concordance was evaluated by province. Characteristics of each CDR recommendation were collected, and associations with concordance were evaluated by logistic regression. RESULTS: Recommendation-listing concordance was high. Positive references to cost and clinical outcomes compared to placebo were statistically associated with concordance. Negative references to cost and to the consistency and certainty of economic evidence were statistically associated with discordance. However, these findings were inconsistent across the jurisdictions studied. CONCLUSION: Although concordance was high, the ability of recommendation characteristics to explain the relationship between province and CDR listing decisions was limited. This exploratory study highlights the complexity of the reimbursement process and possible reasons for drug listing differences across jurisdictions.

Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis.

BACKGROUND: Recent approval and adoption of pangenotypic direct acting antivirals (DAAs) necessitated a revision of the 2015 World Health Organization guidelines for the management of persons with hepatitis C virus (HCV) infection. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and relevant conference proceedings to identify randomized and non-randomized trials, as well as prospective observational studies of DAAs. The proportions of persons with events were pooled for sustained virological response at 12 weeks post-treatment (SVR12), discontinuations due to adverse events (DAEs), serious adverse events (SAEs), and all-cause mortality. Analyses were stratified by HCV genotype and antiviral treatment experience, with subgroup analyses based on presence of cirrhosis and HIV-HCV coinfection. FINDINGS: The evidence base consisted of 238 publications describing 142 studies. In the overall analysis, which included all persons irrespective of treatment experience or comorbidities, the pooled proportion achieving SVR12 exceeded 0.94 for all pangenotypic regimens across genotypes 1, 2, and 4. Some heterogeneity may have led to lower SVR rates in persons with genotype 3 infection. High SVR12 (>0.90) was observed in persons with genotype 1 infection with cirrhosis, though evidence varied and was limited for genotypes 2-4. Evidence was sparse for persons with HIV-HCV coinfection. All regimens were associated with small proportions of persons with DAEs, SAEs, or all-cause mortality. INTERPRETATION: Based on this and other supporting evidence, the WHO issued updated guidelines with a conditional recommendation, based on moderate quality evidence, for the use of pangenotypic DAA regimens for persons with chronic HCV infection aged 18 years and older (July 2018). FUNDING: This study was funded by the World Health Organization.

Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.

BACKGROUND: Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. METHODS: We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. RESULTS: We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500-90 = 410), and the median study duration was 22.3 (IQR: 74.1-42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565-252 = 313), and the median study duration was 60.9 (IQR: 81.3-46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6-4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835-255 = 1580), and the median study duration was 58.9 (IQR: 101.3-36.9 = 64.4) months. CONCLUSIONS: We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Health Utility Book (HUB)-Cancer: Protocol for a Systematic Literature Review of Health State Utility Values in Cancer.

Background. Treatment options in oncology are rapidly advancing, and public payer systems are increasingly under pressure to adopt new but expensive cancer treatments. Cost-utility analyses (CUAs) are used to estimate the relative costs and effects of competing interventions, where health outcomes are measured using quality-adjusted life years (QALYs). Health state utility values (HSUVs) are used to reflect health-related quality of life or health status in the calculation of QALYs. To support reimbursement agencies in the appraisal of oncology drug submissions, which typically include a CUA component, we have proposed a systematic literature review of published HSUV estimates in the field of oncology. Methods. The following databases will be searched: MEDLINE, EMBASE, EconLit, and CINAHL. A team of reviewers, working independently and in duplicate, will evaluate abstracts and full-text publications for eligibility against broad inclusion criteria. Studies using a direct, indirect, or combination approach to eliciting preferences related to cancer or cancer treatments are eligible. Data extraction will capture details of study methodology, participants, health states, and corresponding HSUVs. We will summarize our findings with descriptive analyses at this stage. A pilot review in thyroid cancer is presented to illustrate the proposed methods. Discussion. This systematic review will generate a comprehensive summary of the oncology HSUV literature. As a component of the Health Utility Book (HUB) project, we anticipate that this work will assist both health economic modelers as well as critical reviewers in the development and appraisal of CUAs in oncology.

Reporting of master protocols towards a standardized approach: A systematic review.

BACKGROUND: In September 2018 the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and may be further categorized as basket, umbrella, and platform trials. However, inconsistencies in reporting persist in the literature. We conducted a systematic review to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from inception to April 25, 2019 for English articles on master protocols. This was supplemented by hand searches of trial registries and of the bibliographies of published reviews. We used the FDA's definitions of master protocols as references and compared them to self-reported master protocols. RESULTS: We identified 278 master protocol publications, consisting of 228 protocols and 50 reviews. Sixty-six records provided unique definitions of master protocol types. We observed considerable heterogeneity in definitions of master protocols, and over half (54%) used oncology-specific language. The majority of self-classified master protocols (57%) were consistent with the FDA's definitions of master protocols. CONCLUSION: The terms 'master protocol', 'basket trial', 'umbrella trial', and 'platform trial' are inconsistently described. Careful treatment of these terms and adherence to the definitions set forth by the FDA will facilitate better understanding of these trial designs and allow them to be used broadly and to their full potential in clinical research. We encourage trial methodologists to use these trial designations when applicable.