Showing papers by "Bishal Gyawali published in 2019"
TL;DR: Confirmatory trials for one-fifth of cancer drug indications approved via the FDA's accelerated approval pathway demonstrated improvements in overall patient survival, and update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA's review.
Abstract: Importance The US Food and Drug Administration’s (FDA’s) accelerated approval pathway allows investigational cancer drugs to be approved by demonstrating a beneficial effect on a surrogate measure (eg, progression-free survival) that is expected to predict a real clinical benefit (eg, overall survival). However, these drugs must undergo postapproval confirmatory studies to evaluate their actual clinical benefits. In an assessment of the accelerated approval pathway published in 2018, the FDA concluded that this pathway was successful because only 5 (5%) of 93 accelerated drug approvals had been withdrawn or revoked over the last 25 years. Objective To compare the end points used in preapproval trials leading to accelerated approval with the end points used in the required confirmatory trials that verified clinical benefit and to update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA’s review. Design, Setting, and Participants A review of the literature on end points used in preapproval and confirmatory trials of cancer drugs that received accelerated approval and a review of the FDA’s database of postmarketing requirements and commitments focused on the outcomes of confirmatory trials that were ongoing at the time of FDA’s review of cancer drug approvals published in 2018. Main Outcomes and Measures End points used as confirmation of clinical benefit in cancer drugs that received accelerated approval, updated status of the confirmatory trials, and regulatory outcomes for cancer drugs that did not meet expectations in the confirmatory trials. Results The FDA published a review of 93 cancer drug indications for which accelerated approval was granted from December 11, 1992, through May 31, 2017. Of these approvals, the FDA reported that clinical benefit was adequately confirmed in 51 and confirmatory trials for 15 of these indications (16% of the main sample) accelerated approvals reported improvement in overall survival. For 19 approvals (37%), the confirmatory trials used surrogate measures that were the same as those used in the preapproval trials. In this updated review, confirmatory trials for 19 of 93 (20%) cancer drug approvals reported an improvement in overall survival, 19 (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 (21%) reported improvement in a different surrogate. Five confirmatory trials were delayed, 10 were pending, and 9 were ongoing. For 3 recent approvals, the primary end points were not met in the confirmatory trials; however, 1 cancer drug indication still received full approval. Conclusions and Relevance Confirmatory trials for one-fifth (n = 19 of 93) of cancer drug indications approved via the FDA’s accelerated approval pathway demonstrated improvements in overall patient survival. Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information.
157 citations
TL;DR: Most pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials, but almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials.
Abstract: Objective To examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA). Design Cross sectional analysis. Setting European regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices. Eligibility criteria Pivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016. Main outcome measures Study design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents). Results Between 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n=10) and measurement of the outcome (n=7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%) v 16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and non-preferred study endpoints, which were not disclosed as limitations in scientific publications. Conclusions Most pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.
113 citations
TL;DR: In the first-line setting, ICIs were evaluated as a single agent or in combination with chemotherapy in multiple RCTs but, again, only in patients with a PS of 0 to 1.
Abstract: Immune checkpoint inhibitors (ICIs) are now an important component of the standard of care in patients with non–small-cell lung cancer (NSCLC). ICIs have shown a survival advantage in pretreated patients in multiple randomized clinical trials (RCTs) that enrolled only patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. In the first-line setting, ICIs were evaluated as a single agent or in combination with chemotherapy in multiple RCTs but, again, only in patients with a PS of 0 to 1.
72 citations
TL;DR: PFS benefit was not strongly correlated with improvements in patients’quality of life, and, despite the palliative intent of treatments in the advanced/metastatic setting, the availability of quality of life data from clinical trials of cancer drugs was poor.
Abstract: Quality of life outcomes provide essential information for patients and physicians in oncology care. However, the validity of progression-free survival (PFS) as a surrogate for quality of life, and the inclusion and reporting of quality of life endpoints in clinical trials, is unclear. We performed a retrospective study of phase III clinical trials of drugs for advanced or metastatic solid tumors published between 2010 and 2015. Correlation coefficient (r) and area under the ROC curve (AUC) for association between PFS and positive quality of life were evaluated. Of the 352 Phase 3 trials included, 190 (54%) included a quality of life endpoint, of which 23% did not report pre-specified quality of life outcomes; a total of 125,962 patients were enrolled in studies lacking, or not reporting, quality of life outcomes. Among the 147 trials that reported quality of life outcomes, 99 (67%) reported no effect, 38 (26%) reported a positive effect and 10 (7%) reported a negative effect of treatment on patients' global quality of life. The association between PFS and improvement in global quality of life was weak (r = 0.34; AUC = 0.72), as was the association between PFS and improvement in any domain of quality of life. In conclusion, PFS benefit was not strongly correlated with improvements in patients' quality of life, and, despite the palliative intent of treatments in the advanced/metastatic setting, the availability of quality of life data from clinical trials of cancer drugs was poor.
55 citations
TL;DR: Using the Japanese version of the COST tool, various factors associated with FT in Japanese patients with cancer are identified and will have important implications for cancer policy planning in Japan.
Abstract: PURPOSEWe previously reported on the pilot study assessing the feasibility of using the Japanese translation of the Comprehensive Score for Financial Toxicity (COST) tool to measure financial toxic...
40 citations
TL;DR: The evidence is reviewed and how the digitalization affects the CHWs programmes for tackling non-communicable diseases in low- and middle-income countries (LMICs) is discussed, identifying three benefits and three challenges of digitalization.
Abstract: The use of community health workers (CHWs) has been explored as a viable option to provide home health education, counselling and basic health care, notwithstanding their challenges in training and retention. In this manuscript, we review the evidence and discuss how the digitalization affects the CHWs programmes for tackling non-communicable diseases (NCDs) in low- and middle-income countries (LMICs). We conducted a review of literature covering two databases: PubMED and Embase. A total of 97 articles were abstracted for full text review of which 26 are included in the analysis. Existing theories were used to construct a conceptual framework for understanding how digitalization affects the prospects of CHW programmes for NCDs. The results are divided into two themes: (1) the benefits of digitalization and (2) the challenges to the prospects of digitalization. We also conducted supplemental search in non-peer reviewed literature to identify and map the digital platforms currently in use in CHW programmes. We identified three benefits and three challenges of digitalization. Firstly, it will help improve the access and quality of services, notwithstanding its higher establishment and maintenance costs. Secondly, it will add efficiency in training and personnel management. Thirdly, it will leverage the use of data generated across grass-roots platforms to further research and evaluation. The challenges posed are related to funding, health literacy of CHWs and systemic challenges related to motivating CHWs. Several dozens of digital platforms were mapped, including mobile-based networking devices (used for behavioural change communication), Web-applications (used for contact tracking, reminder system, adherence tracing, data collection and decision support), videoconference (used for decision support) and mobile applications (used for reminder system, supervision, patients' management, hearing screening and tele-consultation). The digitalization efforts of CHW programmes are afflicted by many challenges, yet the rapid technological penetration and acceptability coupled with the gradual fall in costs constitute encouraging signals for the LMICs. Both CHWs interventions and digital technologies are not inexpensive, but they may provide better value for the money when applied at the right place and time.
31 citations
TL;DR: Real‐world patterns of CPI initiation near the end of life among individuals with metastatic urothelial cell carcinoma are described.
Abstract: Several immune checkpoint inhibitor therapies (CPIs) have been approved to treat metastatic urothelial cell carcinoma (mUC). Because of the favorable toxicity profile of CPI compared with chemotherapy, oncologists may have a low threshold to prescribe CPI to patients near the end of life. We evaluated trends in initiation of end-of-life systemic therapy in 1,637 individuals in the Flatiron Health Database who were diagnosed with mUC between 2015 and 2017 and who died. Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated CPI within 60 days of death increased from 1.0% to 23% during the study period (p trend < .001). After CPI approval, end-of-life CPI initiation significantly increased among patients with poor performance status (p trend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.
30 citations
TL;DR: Comparing interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD) and the prevalence of misinterpretation of the HR is compared.
30 citations
TL;DR: One year of trastuzumab for adjuvant treatment of breast cancer improves outcomes compared to shorter treatments in overall population, and cardiotoxicity is increased with the longer treatment.
Abstract: One year of adjuvant trastuzumab, chosen empirically, improves survival of women with early-stage, Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. Two years of trastuzumab does not improve efficacy but increases cost, inconvenience, and adverse effects. We aimed to evaluate if less than 1 year of adjuvant trastuzumab retained efficacy while reducing toxicities and cost. We performed a pooled analyses of efficacy and toxicity from Randomized Controlled Trials (RCTs) comparing 1 year of trastuzumab to shorter durations in adjuvant treatment of HER2-positive breast cancer. Hazard Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds Ratios (OR) for cardiac events with respective 95% Confidence Intervals (CI) were weighted using generic inverse variance approach and pooled in meta-analyses using random effects models with RevMan 5.3 software. Sub-group analyses of outcomes based on Estrogen Receptor (ER) and nodal status were performed. Five RCTs involving approximately 12,000 patients qualified—three assessing 6 months and two assessing 9 weeks of trastuzumab compared to 1 year. All RCTs were designed to test non-inferiority of the shorter treatment. One year of trastuzumab resulted into better OS (pooled HR 1.23, 95% CI 1.07–1.42) and DFS (pooled HR 1.21, 95% CI 1.09–1.36) in overall population, but the benefit of longer treatment was statistically insignificant in node negative (HR 1. 20, p = 0.11), and ER positive disease (HR 1.15, p = 0.09). Odds ratio for cardiac events was significantly higher with the longer duration (OR 2.48, p < 0.001). One year of trastuzumab for adjuvant treatment of breast cancer improves outcomes compared to shorter treatments in overall population. Cardiotoxicity is increased with the longer treatment.
29 citations
TL;DR: A high burden of cardio-metabolic risk factors among the migrants as well as among the populations in the home and the host countries is found, and the lack of specific focus on screening during different stages of labor migration should receive attention.
Abstract: This paper aims to explore the burgeoning burden of cardiovascular and metabolic disease (CMD) risk factors among South Asian labor migrants to the Middle East. We conducted a qualitative synthesis of literature using PubMed/Medline and grey literature searches, supplemented by a policy review of policies from the South Asian countries. We found a high burden of cardio-metabolic risk factors among the migrants as well as among the populations in the home and the host countries. For example, two studies reported the prevalence of diabetes mellitus (DM) ranging between 9 and 17% among South Asian migrants. Overweight and obesity were highly prevalent amongst South Asian male migrants; prevalence ranged from 30 to 66% (overweight) and 17–80% (obesity) respectively. The home country population had a significant CMD risk factor burden. Nearly 14 to 40% have three or more risk factors: such as hypertension (17 to 37%), diabetes (3 to 7%), overweight (18 to 41%), and obesity (2 to 15%). The host country also exhibited similar burden of risk factors: hypertension (13 to 38%), diabetes (8 to 17%), overweight (33 to 77%) and obesity (35 to 41%). Only Nepal, Bangladesh and Sri Lanka have some provisions related to screening of CMDs before labor migration. Further, analysis of policy papers showed that none of the reviewed documents had requirements for screening of any specific CMDs, but chronic diseases were used generically, failing to specify specific screening target. Given the high burden of risk factors, migrants’ health should become an urgent priority. The lack of specific focus on screening during different stages of labor migration should receive attention. The International Labour Organization and the International Office for Migration, through their country coordination teams should engage local stakeholders to create policies and plans to address this concern. Similarly, there is a need for the host country to become an equal partner in these efforts, as migrant’s better cardiometabolic health is in the benefit of both host and home countries.
21 citations
TL;DR: The number of cancer drug approvals have steadily increased over the years from 5 in 2009 to 33 in 2018, and the percentage of drugs that improved overall survival has steadily declined and reached its lowest in 2017.
Abstract: Both the speed of approval and efficacy of cancer drugs are important regulatory issues. Although the number of cancer drugs approved in a year is a marker of speed, whether it is also a marker of better outcomes remains unknown. In this study, we assess the trend in number and characteristics of 115 cancer drugs approved by the FDA over the last decade and evaluate whether they have improved patient survival. We find that the number of cancer drug approvals have steadily increased over the years from 5 in 2009 to 33 in 2018. Accelerated approvals started to rise since 2014 and peaked in 2017. The percentage of drugs that improved overall survival has steadily declined and reached its lowest (7 %) in 2017. Approval of better drugs that improve patient outcomes maybe more or at least equally important aspect for regulatory focus compared to approval of more number of drugs.
17 May 2019
TL;DR: An overview of the role of QoL in the regulatory drug-approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care are provided.
Abstract: Historically, patient experience, including symptomatic toxicities, physical function, and disease-related symptoms during treatment or their perspectives on clinical trials, has played a secondary role in cancer drug development. Regulatory criteria for drug approval require that drugs are safe and effective, and almost all drug approvals have been based only on efficacy endpoints rather than on quality-of-life (QoL) assessments. In contrast to Europe, information regarding the impact of drugs on patients' QoL is rarely included in oncology drug labeling in the United States. Until recently, patient input and preferences have not been incorporated into the design and conduct of clinical trials. In recent years, a more in-depth understanding of cancer biology, as well as regulatory changes focused on expediting cancer drug development and approval, has allowed earlier access to novel therapeutic agents. Understanding the implications of these expedited programs is important for oncologists and patients, given the rapid expansion of these programs. In this article, we provide an overview of the role of QoL in the regulatory drug-approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care.
TL;DR: The results suggest that the prices of anticancer drugs in Italy do not reflect their therapeutic benefit and call for further efforts to establish the standard determinants of drug prices available at the time of negotiation.
Abstract: Objective To investigate whether the prices of new anticancer drugs correlated with their relative benefit despite negotiation. Design Retrospective cross-sectional study correlating new anticancer drugs prices with clinical outcomes. Setting We did a retrospective cross-sectional study including all new anticancer drugs approved by the European Medicines Agency (EMA) (2010–2016) and reimbursed in Italy. Main outcome(s) and measure(s) Information on clinical outcomes—in terms of median overall survival (OS), median progression-free survival (PFS) and objective response rate (ORR)—was extracted from pivotal trials as reported in the European Public Assessment Reports available on the EMA website. Cost of a full course treatment was estimated on negotiated official and discounted prices. Regression coefficients β, their levels of significance p and the coefficients of determination R2 were estimated adjusting by tumour type. Results Overall, 30 new anticancer drugs (with 35 indications) were available for analysis. Where data on OS were available, we observed no correlation between the improvement in median OS (in weeks) and negotiated price (R2=0.067, n=16 drugs for 17 indications). When the clinical outcomes were expressed as improvements in the median PFS or ORR, 25 drugs (29 indications) were available for the analysis, and again, there was no correlation with prices (R2=0.004 and 0.006, respectively). Conclusions and relevance Our results suggest that the prices of anticancer drugs in Italy do not reflect their therapeutic benefit. Drug price negotiations, which is mandatory by law in Italy, do not seem to ensure that prices correlate with clinical benefits provided by the cancer drugs. These results call for further efforts to establish the standard determinants of drug prices available at the time of negotiation. These findings need to be confirmed in other countries where price negotiations are in place. Moreover, further investigations may verify whether outcome data obtained after drug marketing would improve the correlation between prices and therapeutic benefit.
TL;DR: The aim of this review was to establish an overview of studies evaluating the effectiveness of community-based interventions for prevention of Type 2 diabetes in LMICs, acknowledging the community- based approach can be effective in prevention and control of Type 1 diabetes.
Abstract: Type 2 diabetes is an increasing burden in low- and middle-income countries (LMICs). Knowledge of effective prevention programs in LMICs is thus important. The aim of this review was to establish an overview of studies evaluating the effectiveness of community-based interventions for prevention of Type 2 diabetes in LMICs. A literature review with searches in the databases using MEDLINE in Ovid (Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Version (R); Embase; PsycINFO; Global Health; and Google Scholar) between 1 January 2000 and 31 December 2015 was conducted. Only 10 studies that met our selection criteria were included; 3 were randomized controlled trials, 2 non-randomized controlled trials and 5 were pre-and post-intervention studies. About 9 of 10 studies reported significant reduction in both the glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels as a result of the intervention. A majority of the studies included multicomponent interventions such as education and behavioral encompassing both individual and group work, and included health education, nutrition education, nutrition counseling, exercise and promoting physical activity, psychosocial approaches and lifestyle modification. The interventions were delivered by community health workers, volunteers, social workers, community nutritionists and community nurses. Comparisons between studies, however, was not possible due to substantial heterogeneity in study design. This review contributes to the current literature on community-based interventions for prevention of Type 2 diabetes in LMICs, acknowledging the community-based approach can be effective in prevention and control of Type 2 diabetes. Due to the heterogeneity across study designs, outcomes and in terms of variation and duration of interventions, only limited conclusions can be drawn about the effectiveness of interventions. More evidence from randomized controlled trials on culturally tailored, community-based interventions is needed to compare findings and test implementation in practice.
TL;DR: To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer trial.
Abstract: Background In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial. Methods The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study. Results Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P = .01), but not sorafenib (P = .10). Conclusions Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.
02 Aug 2019
TL;DR: Greater regulatory attention should be paid to randomized noninferiority trials of cancer drugs, especially regarding the justification for using such a design.
Abstract: Importance Noninferiority trials test whether a new intervention is not worse than the comparator by a given margin. Objectives To study the characteristics of published randomized noninferiority trials in oncology with overall survival as an end point, to assess the association of justification and success in achieving noninferiority with the funding of these trials, and to evaluate the association of such trials with patient survival. Data Sources A systematic search of PubMed and Google Scholar databases was conducted in March 2018, with no date restrictions. Study Selection Randomized noninferiority trials of cancer drug therapies with overall survival as an end point were included. Trials of decision support, supportive care, and nondrug treatment in both arms were excluded. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for meta-epidemiological studies. Studies were screened for eligibility criteria, and data on criteria for noninferiority, funding, success (achieving noninferiority), and hazard ratios with confidence intervals for overall survival were extracted. Hazard ratios for overall survival were pooled across trials using a random-effects model. Main Outcomes and Measures Associations of the justification for using a noninferiority design and success in achieving noninferiority with the source of funding were assessed. Overall pooled hazard ratios and confidence intervals for overall survival were calculated. Results Among 74 noninferiority trials of cancer drug therapies, 23 (31%; enrolling 21 437 patients) used overall survival as the primary end point. The noninferiority margins for the hazard ratio of overall survival ranged from 1.08 to 1.33. Noninferiority design was justified in 14 trials (61%) but not in 9 (39%). Overall, 18 trials (78%) concluded with a finding of noninferiority. Industry funding was associated with lack of justification for noninferiority design (P = .02, assessed using the Fisher exact test) but not with success in proving noninferiority (P = .80, assessed using the Fisher exact test). When the hazard ratios across the trials were pooled, there was no beneficial or detrimental association with overall survival, with a pooled hazard ratio of 0.97 (95% CI, 0.92-1.02). Conclusions and Relevance The findings suggest that a substantial fraction of noninferiority trials in oncology, most of which are industry funded, lack justification for such a design. Greater attention to the use of noninferiority designs in randomized clinical trials of cancer drugs from local and national regulators is warranted.
TL;DR: It is concluded that continued real-world surveillance of patients treated with eradication therapy as well as longer-term follow up of these RCTs are necessary to further confirm that no such mortality risk exists in real- world.
Abstract: Infection with Helicobacter pylori has been linked to 78% of gastric cancer cases, prompting the International Agency for Research on Cancer to classify H. pylori as a Group 1 carcinogen. Thus, H. pylori eradication therapy is recommended to prevent gastric cancer. In 2014, a meta-analysis of randomized controlled trials (RCTs) found a substantially reduced risk of gastric cancer but also a non-significant 9% increase in the risk of all-cause mortality among patients randomized to eradication therapy (Risk Ratio 1.09, 95% CI 0.86-1.38). A more recent RCT also demonstrated a reduced risk of gastric cancer, but again showed a non-significant increased risk of all-cause mortality among patients randomized to eradication therapy (Hazard Ratio 1.95, 95% CI, 0.72 to 5.27; P = 0.19). The possibility that there could also be an association with an increased risk of all-cause mortality is an important public health concern. Thus, we performed an updated systematic review and meta-analysis of RCTs evaluating H. pylori eradication therapy to evaluate the risk of all-cause mortality. Our updated meta-analysis still did not find a statistically significant increase in the risk of all-cause mortality with H. pylori eradication therapy, which should be reassuring for patients and physicians. Since the pooled RR remained over 1, we conclude that continued real-world surveillance of patients treated with eradication therapy as well as longer-term follow up of these RCTs are necessary to further confirm that no such mortality risk exists in real-world. This article is protected by copyright. All rights reserved.
TL;DR: A high prevalence of all single and combined cardiometabolic risk factors in Nepal is found, which underlines the need to managerisk factors in aggregate and plan prevention activities targeting multiple risk factors.
Abstract: This study assessed the burden and correlates of three cardiometabolic risk factors, (hypertension, diabetes, and overweight/obesity), and their possible clustering patterns in a semi-urban population of Nepal. Data were obtained from a community-based management of non-communicable disease in Nepal (COBIN) Wave II study, which included 2,310 adults aged 25–64 years in a semi-urban area of Pokhara Metropolitan City of Nepal, using the World Health Organization-STEPS questionnaire. Unadjusted and adjusted binary logistic regression models were used to study the correlates of the individual risk factors and their clustering. The prevalence of hypertension, diabetes, and overweight/obesity was 34.5%, 11.7%, and 52.9%, respectively. In total, 68.2% of the participants had at least one risk factor and many participants had two risks in combination: 6.8% for ‘hypertension and diabetes’, 7.4% for ‘diabetes and overweight/obesity’ and 21.4% for ‘hypertension and overweight/obesity’. In total, 4.7% had all three risk factors. Janajati ethnicity (1.4–2.1 times), male gender (1.5 times) and family history of diabetes (1.4–3.4 times) were associated with presence of individual risk factors. Similarly, Janajati ethnicity (aOR: 4.31, 95% CI: 2.53–7.32), current smoking (aOR: 4.81, 95% CI: 2.27–10.21), and family history of diabetes (aOR: 4.60, 95% CI: 2.67–7.91) were associated with presence of all three risk factors. Our study found a high prevalence of all single and combined cardiometabolic risk factors in Nepal. It underlines the need to manage risk factors in aggregate and plan prevention activities targeting multiple risk factors.
TL;DR: Although the data needed for biomarker validation has traditionally been hard to access, new research initiatives can ease this process and encourage more formal validation efforts.
Abstract: Biomarkers can be powerful tools to guide diagnosis, treatment, and research. However, prudent use of bio-markers requires formal validation efforts. Although the data needed for biomarker validation has traditionally been hard to access, new research initiatives can ease this process.
TL;DR: How ESCAT can be further improved to increase its utility in clinical and policy decisions is highlighted.
Abstract: The ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) will be useful as a common language to harmonize discussions in precision oncology and could also guide policy and reimbursement decisions, but it is far from perfect. Herein, we highlight how ESCAT can be further improved to increase its utility in clinical and policy decisions.
03 May 2019
TL;DR: This analysis of 67 studies found that both industry and academia conducted negative phase 3 trials of cancer drugs, and no association was found between trial sponsorship and lack of a positive phase 2 trial; there was no association with patient overall survival.
Abstract: Importance Only 3.4% of cancer drugs evaluated in phase 1 trials are approved by the US Food and Drug Administration, with most failing in phase 3 trials. Objective To investigate whether an association exists between the sponsorship and conduct of a negative phase 3 randomized clinical trial (RCT) investigating a cancer drug that lacked supporting phase 2 trial evidence for that drug, and to evaluate the association with overall survival among patients randomized to the experimental arm of such phase 3 trials. Data Sources Articles in theLancet,Lancet Oncology,JAMA,JAMA Oncology, andJournal of Clinical Oncologypublished between January 2016 and June 2018 were searched. Study Selection Phase 3 RCTs of cancer drugs that failed to improve the primary end point were selected and any prior phase 2 trial of the same drug that supported the phase 3 trial was selected without any date or journal restrictions. Data Extraction and Synthesis Percentages of negative phase 3 RCTs of cancer drugs that lacked any phase 2 evidence, had a negative phase 2 trial, or had a positive phase 2 study were extracted. Associations were assessed using the Fisher exact test. Pooled hazard ratios and 95% CIs for the overall survival of patients enrolled in these negative phase 3 RCTs were estimated using a random-effects model. Main Outcomes and Measures Negative phase 3 RCTs with a lack of a phase 2 trial or the presence of a negative phase 2 trial and overall survival of enrolled patients in the phase 3 RCTs. Results In this meta-epidemiological study, 67 negative phase 3 RCTs on cancer drugs, which included 64 600 patients, met the criteria of being sponsored by industry or academic groups, of which 42 RCTs (63%) were industry sponsored and the remaining 25 RCTs (37%) were academic. A phase 2 trial was not available for 28 of these trials (42%). Of 29 trials (43%) with a phase 2 trial available, 8 trials (28%) failed to meet their primary end points and 5 of those were industry sponsored. There was no association with overall survival for patients participating in these negative phase 3 RCTs (pooled hazard ratio, 0.99; 95% CI, 0.96-1.02). When the pooled analysis was limited to the 27 RCTs with a hazard ratio above 1.00, the overall pooled hazard ratio for overall survival was 1.11 (95% CI, 1.06-1.16). No association between having a negative or undefined phase 2 trial and trial sponsorship was found using the Fisher exact test. Conclusions and Relevance More than 40% of the negative phase 3 RCTs in oncology published in these 5 journals were conducted without a supporting phase 2 trial and were sponsored by both academia and industry. Running such trials not only may risk loss of resources owing to a failed trial but also may be associated with decreased patient survival. Further research and regulations in this area appear warranted.
TL;DR: The results suggest that opportunistic screening can identify significant numbers with hypertension, and there is a strong imperative to scale up hypertension prevention, screening, and management programmes in Nepal.
Abstract: Hypertension is the leading risk factor of mortality in Nepal accounting for ∼33 000 deaths in 2016. However, more than 50% of the hypertensive patients are unaware of their status. We participated in the May Measurement Month 2017 (MMM17) project initiated worldwide by the International Society of Hypertension to raise the awareness on the importance of blood pressure (BP) screening. In this paper, we discuss the screening results of MMM17 in Nepal. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017 following the standard MMM protocol. Data were collected from 18 screening sites in 7 districts covering 5 provinces. Screenings were conducted either in health facilities, public places, or participants' homes. Trained volunteers with health science background and female community health volunteers were mobilized to take part in the screening. A total of 5972 individuals were screened and of 5968 participants, for whom a mean of the 2nd and 3rd readings was available, 1456 (24.4%) participants had hypertension; 908 (16.8%) of those not receiving treatment were hypertensive; and 248 (45.2%) of those being treated had uncontrolled BP. MMM17 is the first nationwide BP screening campaign undertaken in Nepal. Given the suboptimal treatment and control rates identified in the study, there is a strong imperative to scale up hypertension prevention, screening, and management programmes. These results suggest that opportunistic screening can identify significant numbers with hypertension. Mobilization of existing volunteer networks and support of community stakeholders, would be necessary to improve the overall impact and sustainability of future screening programmes.
TL;DR: Prevalence of ideal cardiovascular health is low in the semi-urban population in Nepal and Concerted efforts are needed to develop a population-based intervention to improve cardiovascular health in Nepal.
Abstract: Background The aim of this study was to assess the status of cardiovascular health among a semi-urban population of Nepal, and determine factors associated with ideal cardiovascular health. Methods A population-based, cross-sectional study using a systematic random sample was conducted among 2310 adults aged ≥ 25 years in a semi-urban area of the Pokhara Metropolitan City previously named Lekthnath in Nepal. The ideal, intermediate and poor cardiovascular health were defined as the presence of 6-7, 4-5 or 1-3 health metrics, among a list of 7 health behaviours and healthfactors, namely smoking, body mass index, physical activity, fruits and vegetables intakes, harmful alcohol consumption, blood pressure, and fasting blood glucose. We used univariate and multivariate Poisson regression models adjusting for sex, age groups, ethnicity, educational level and socioeconomic status, and calculated the prevalence ratios with 95% CIs. Results Only 14.3 % of the participants had ideal cardiovascular health, whereas 67.0% and 18.7% of the participants had intermediate and poor cardiovascular health, respectively. Age groups 45-54 years (prevalence ratio 0.88, 95% CI: 0.83 to 0.94, p<0.001) and 55-64 years (prevalence ratio 0.84, 95% CI: 0.79 to 0.90, p<0.001) were significantly associated with low prevalence of ideal cardiovascular health compared with the age group 35-44 years. Ethnic groups, including Janajati (prevalence ratio 0.89, 95% CI: 0.85 to 0.93, p<0.001) and Dalit (prevalence ratio 0.9, 95% CI: 0.84 to 0.95, p=0.001), were significantly associated with low prevalence of ideal cardiovascular health. Conclusions Prevalence of ideal cardiovascular health is low in the semi-urban population in Nepal. Concerted efforts are needed to develop a population-based intervention to improve cardiovascular health in Nepal.
TL;DR: It is shown that the vast majority of cancer cells will not mutate following chemotherapy, and any mutation introduced in a single cancer cell and hence would likely go undetected by the immune system.
TL;DR: The sponsorship and funding of RCTs demonstrating life-extending outcomes in non-small cell lung cancer can help identify the greatest drivers of public health benefit and inform the allocation of scarce health care resources.
Abstract: Bishal Gyawali, Gauthier Bouche, Pan Pantziarka, Aaron S. Kesselheim, and Ameet Sarpatwari Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide.1 Although overall survival rates among patients with the disease remain low,2 modest improvements have been reported in recent decades.3 These improvements have been achieved in large part due to practice-changing randomized controlled trials (RCTs), some related to drug products and others to interventions such as surgery and radiotherapy. Understanding which interventions have yielded overall survival gains and which institutions have contributed to the RCTs revealing these benefits can help identify the greatest drivers of public health benefit and inform the allocation of scarce health care resources. Accordingly, we reviewed the sponsorship and funding of RCTs demonstrating life-extending outcomes in non-small cell lung cancer. We used the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC (v.5.2017) to identify the cohort of interventions for this study. We chose the NCCN guidelines because they are the most widely used multi-disciplinary guidelines in cancer and include drug and non-drug interventions. For each intervention, we assessed its supporting evidence, selecting only interventions that were tested in at least one RCT. We collected the report of the RCT from PubMed and evaluated whether it found overall survival gains related to the intervention. Interventions for which RCTs did find overall survival gains were categorized as taking place in the curative (non-metastatic) or non-curative (advanced or metastatic) setting. For each RCT, we recorded the overall survival gains (5-year overall survival rates were available in the curative setting, and median overall survival was available in the non-curative setting; hazard ratios were obtained for each setting), the sponsor (defined as the person or entity that takes responsibility for a clinical investigation), and the funder (defined as the organization providing financial support for a study). We categorized sponsors into industry, academia, or both; and funders into industry, public, or mixed. When this information was not available from the published literature, we searched Clinicaltrials.gov; if unavailable there, we contacted the corresponding author. Results were analyzed descriptively. Among 57 NCCN-recommended interventions, 39 (68%) were based on at least one RCT, of which 19 (49%) showed an improvement in overall survival in 26 RCTs published between 1990 and 2017 (Table). These 19 interventions included the same drug in different settings (e.g., pembrolizumab as first-line and second-line treatment). Combining these, there were 17 distinct intervenLung Cancer Survival Gains: Contributions of Academia and Industry
TL;DR: In patients with aUC, there has been a dramatic rise in CPI initiation at the end of life particularly among pts with poor performance status, driven largely by end-of-life CPI use.
Abstract: 395Background: National guidelines recommend against chemotherapy use at the end of life. Five CPIs are now approved for aUC. We hypothesized that oncologists may have a lower threshold to initiate...
01 Jan 2019
TL;DR: This chapter explores the causes and consequences of high cancer drug prices in detail and will also walk the readers through different strategies that have been proposed to control these costs.
Abstract: We have seen a sharp increase in cancer drug prices in recent years, far exceeding the rates of inflation. This increasing cost of cancer drugs has many adverse consequences not only for the economy of the country but also in clinical outcomes of cancer patients, a phenomenon referred to as “financial toxicity.” Indeed, the increasing cost of cancer drugs is no longer just a policy issue; it is also a clinical issue with clinical consequences such as increased risk of mortality, poor quality of life, and lack of adherence to medications among others. In this chapter, I explore the causes and consequences of high cancer drug prices in detail and will also walk the readers through different strategies that have been proposed to control these costs. Indeed, each solution strategy has its own challenges, but not doing anything is no longer a sustainable strategy. We owe it to our patients that they are able to take the cancer drugs that help them live longer or live better without having to worry about being bankrupt during the course of treatment.