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Background: Gliomas, originating from the most common non-neuronal cells in the brain (glial cells), are the most common brain tumors and are associated with high mortality and poor prognosis. Glioma cells exhibit a tendency to disrupt normal cell-cycle regulation, leading to abnormal proliferation and malignant growth. This study investigated the predictive potential of GJC1 in gliomas and explored its relationship with the cell cycle. Methods: Retrospective analysis of RNA-seq and single-cell sequencing data was conducted using the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The differential expression of GJC1 in gliomas with various pathological features and in different non-neuronal cell groups was analyzed. Functional data were examined using gene set variation analysis (GSVA). Furthermore, CellMiner was used to evaluate the relationship between GJC1 expression and predicted treatment response across these databases. Results: GJC1 expression was enriched in high-grade gliomas and 1p/19q non-codeletion gliomas. GJC1 enrichment was observed in classical and mesenchymal subtypes within the TCGA glioma subtype group. In single-cell subgroup analysis, GJC1 expression was higher in glioma tissues compared to other non-neuronal cells. Additionally, the TCGA classical subtype of glioma cells exhibited more GJC1 expression than the other subgroups. GJC1 emerged as an independent prognostic factor for overall survival in glioma. GSVA unveiled potential mechanisms by which GJC1 may impact cell-cycle regulation in glioma. Finally, a significant correlation was observed between GJC1 expression and the sensitivity of multiple anti-cancer drugs. Conclusion: These findings confirmed GJC1 as a novel biomarker and provided insights into the differential gene expression in non-neuronal cells and the impact of the cell cycle on gliomas. Consequently, GJC1 may be used to predict glioma prognosis and has potential therapeutic value. [ABSTRACT FROM AUTHOR]

This article discusses the high attrition rate of oncology drugs, which leads to increased costs for drug developers. The success rate for oncology drugs is relatively low, with only 1 in 20 new chemical entities receiving approval. The primary reasons for drug attrition have shifted from inappropriate pharmacokinetics to a lack of efficacy and safety. Strategies to reduce attrition include careful selection of animal models and biomarkers during early drug development stages, as well as the use of biologics, which have a higher success rate. The article also analyzes the factors contributing to drug failure and discusses potential measures to mitigate attrition, such as investment in paradigm-shifting drugs and the use of biomarkers. A survey was conducted to gather insights from experts and clinical professionals on the attrition of oncology drugs. The article highlights the increasing trend of discontinued oncology drugs and the factors that contribute to drug attrition. The number of failed drugs has doubled in the past 8 years and is projected to triple by 2023. Half of the discontinued drugs occur in Phase 1 trials, indicating that attrition can happen early in development. Reasons for drug attrition include lack of efficacy, safety issues, strategic considerations, and unspecified concerns. Small molecules have a higher attrition rate compared to biologics, and certain cancer types, such as lung cancer, have a higher number of discontinued drugs. Financial considerations also play a significant role in drug development. The study examines the factors contributing to the high attrition [Extracted from the article]

Simple Summary: The majority of oncology drugs approved by the Food and Drug Administration over the past quarter century have been targeted therapies, designed to act on cancer cells with specific molecular abnormalities. Although these newer agents have different properties compared to cytotoxic chemotherapy, the same methodology used for dose-finding during drug development has continued to be used. Growing awareness of the inadequacy of traditional dose selection processes for modern cancer drugs has been the catalyst for the creation of new regulatory guidance aimed at reforming current practices. This review summarizes six cases, illustrating different approaches to targeted therapy dose optimization. Therapeutic advances in oncology in the 21st century have contributed to significant declines in cancer mortality. Notably, targeted therapies comprised the largest proportion of oncology drugs approved by the United States (US) Food and Drug Administration (FDA) over the past 25 years and have become the standard of care for the treatment of many cancers. However, despite the metamorphosis of the therapeutic landscape, some aspects of cancer drug development have remained essentially unchanged. In particular, the dose-finding methodology originally developed for cytotoxic chemotherapy drugs continues to be implemented, even though this approach no longer represents the most appropriate strategy for modern cancer therapies. In recognition of the need to reconsider assumptions, adapt the dose selection process for newer drugs, and design alternative strategies, the FDA has undertaken several initiatives in recent years to address these concerns. These actions include the launch of Project Optimus in 2021 and the issuance of draft guidance for industry on dose optimization of oncology drugs in 2023. Amid this evolving regulatory environment, the present manuscript reviews case studies for six different targeted cancer therapies, highlighting how dose-finding challenges have been managed to date by oncologists, sponsors, and regulators. [ABSTRACT FROM AUTHOR]

Nigel SB Rawson,1– 3 David J Stewart4,5 1Macdonald-Laurier Institute, Ottawa, Ontario, Canada; 2Canadian Health Policy Institute, Toronto, Ontario, Canada; 3Centre for Health Policy Studies, Fraser Institute, Vancouver, British Columbia, Canada; 4Department of Medicine, The University of Ottawa, Ottawa, Ontario, Canada; 5Division of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, CanadaCorrespondence: Nigel SB Rawson, Email eastlakerg@gmail.comPurpose: To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs.Materials and Methods: Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH’s reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA’s webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH’s recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH’s target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated.Results: CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH’s “typical timeline” of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA’s target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023.Conclusion: CADTH’s “typical timeline” and the pCPA’s targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.Plain language summary: Canadian patients and providers are often frustrated and concerned about the timeliness of the country’s health technology assessment (HTA) and price negotiation processes, especially for cancer drugs. HTAs are carried out to evaluate the benefit of a medicine in comparison with its cost to see whether the drug is of sufficient value to add it to the benefit lists of government drug plans. HTAs are performed by the Canadian Agency for Drugs and Technologies in Health (CADTH) for all of Canada, except the province of Quebec, and price negotiations with drug developers are carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) on behalf of all government drug plans. We used data from the websites of CADTH and the pCPA on HTA reviews of cancer drugs issued between January 2014 and December 2023 and price negotiations for these drugs to assess whether CADTH and the pCPA complied with their stated target times for completing their processes. We found that CADTH’s reviews and the pCPA’s price negotiations failed to meet their targets for cancer drugs in the past 10 years and that the timeliness of their performance has, in most cases, deteriorated. HTA and price negotiation processes for cancer drugs take too long in Canada.Keywords: oncology drugs, health technology assessment, drug prices, Canada

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients’ access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival. [ABSTRACT FROM AUTHOR]

Evidentiary requirements for relative effectiveness assessment vary among European health technology assessment (HTA) bodies, affecting the time to HTA decision-making and potentially delaying time to patient access. Improved alignment may reduce this time; therefore, we aim to analyze the differences in evidentiary requirements for oncology drug assessments among European HTA bodies and provide recommendations toward an increased alignment. Interviews were conducted with stakeholders in drug assessments of Italy, the Netherlands, Poland, Portugal, England and Wales, and Sweden about evidentiary requirements for several subdomains to identify differences and obtain recommendations for addressing differences. The interview results were analyzed on degrees of evidence acceptability per HTA body and alignment on evidentiary requirements among HTA bodies. Subdomains demonstrating noteworthy differences concerned the acceptability of extrapolation to other populations, class effects, progression-free survival and (other) surrogate endpoints as outcomes, the absence of quality-of-life data, single-arm trials, cross-over trial designs, short trial duration, and the clinical relevance of effect size. Alignment can be enhanced to reduce time to decision-making and to improve equity in patient access. Proposed recommendations to achieve this included joint early dialogues, intensified collaboration and exchange between countries, joint relative effectiveness assessments, and the use of access agreements. [ABSTRACT FROM AUTHOR]

Objective: The lack of anticancer drugs for curative and supportive purposes is the critical reason for the low survival rate in low-and-middle-income countries. This study aims to analyze whether the National Essential Medicines List (NEML) and Registered Essential Medicines List (REML) are in concordance with the World Health Organization (WHO) Essential Medicines List (EML) and whether the formularies prevalent in the country are parallel to each other and to the NEML. Method: An observational study design was used in which antineoplastic drugs from the 2021 NEML and REML were compared with 2021 WHO EML to evaluate their availability in Pakistan. Market access was determined. Moreover, the formularies of six different hospital types were compared with each other and with the NEML, and REML to estimate the availability within hospitals. Results: There were 66 anticancer drugs in 2021 WHO EML and all were found in Pakistan's 2021 NEML but only 48 drugs (73%) were found in the REML. Hydroxycarbamide and dasatinib were two registered drugs absent in all hospitals' formularies. The market access for anticancer medicines was 73% (48 of 66). Semigovernment hospital (86%) has the highest availability, followed by the government hospital (80%). All the hospitals have unregistered drugs including bortezomib, lenalidomide, and mesna. Conclusion: Pakistan's NEML adopts WHO EML abruptly but all medicines are not registered. The hospitals are trying their best to increase availability but optimum drug regulations to revise NEML based on the country's requirements and emphasizing registration of anticancer medicines are needed to improve the country's availability of antineoplastic agents. [ABSTRACT FROM AUTHOR]

New oncology drugs undergo detailed review prior to public funding in a single-payer healthcare system. The aim of this study was to assess how cancer drug review times impact funding recommendations. Drugs reviewed by the pan-Canadian Oncology Drug Review (pCODR) between the years 2012 and 2020 were included. Data were collected including Health Canada approval dates, initial and final funding recommendations, treatment intent, drug class, clinical indications, and incremental cost-effectiveness ratios (ICER). Univariable and multivariable analyses were used to determine the association between funding recommendations and review times. Of the 164 applications submitted, 130 received a positive final recommendation. Median time from Health Canada (HC) approval to final recommendation was longer for drugs indicated for the treatment of gastrointestinal (GI) and lung cancer compared to breast, genitourinary (GU), and other tumours (205 vs. 198 vs. 111 vs. 129 vs. 181 days, respectively; Kruskal–Wallis p = 0.0312). Drugs with longer review times were more likely to receive a negative pCODR recommendation, even when adjusting for tumour type, drug class, and intent of therapy (157 vs. 298 days; Wilcoxon p = 0.0003, OR 1.002 95% CI [1.000–1.004].). There was no association between funding recommendation and tumour type or class of drug. The exploration of factors associated with variance in review times will be important in ensuring timely patient access to cancer drugs.

BackgroundThis study examined multiple aspects about the approval of new drugs: the characteristics of the drugs, the quality and quantity of information that Health Canada discloses about the demographics of patients enrolled in clinical trials, the characteristics of the trial, and the type of review that it uses. It examines whether there have been changes in these measures between 1 September 2012 and 31 March 2022.MethodsA list of all new drugs approved, type of review used, and drug characteristics was generated from Health Canada annual reports. Therapeutic categories were identified from the World Health Organization Collaborating Center for Drugs Statistics Methodology. The Summary Basis of Decision documents of Health Canada were used to identify patient demographics in clinical trials and clinical trial characteristics.ResultsHealth Canada approved 326 new drugs for 407 indications. The percent of orphan drugs approved increased from 35.6 to 51.3%. The number of indications per drug decreased (p = 0.0817) as did the number of pivotal trials per drug (p = 0.0091). The percent of Phase 3 trials dropped from 76.3% in 2012–2015 to 64.8% in 2019–2022 (p = 0.005). There was also a statistically significant decrease in the percent of trials that were randomized, controlled, and blinded. The clinical trial characteristics of orphan drugs and the type of review used were both significantly different compared with non-orphan drugs. The percent of trials which had information about the number of patients enrolled, the percent of trials that provided the age of the patients, and the sex breakdown all significantly increased.ConclusionThe results show that there has been a change in regulatory standards that may be due to them becoming less rigorous, because of an adaptation to the number of orphan drugs being submitted or a combination of both reasons. At the same time, there has been some improvement in the transparency of data. Health Canada has recently embarked on a series of reforms in drug regulation and clinical trial management. These changes need to be closely evaluated to be sure that they enhance the efficacy and safety of new drugs.

Simple Summary: Cancer is one of the leading causes of death in Canada and worldwide, and there is ongoing discovery of new cancer medicines. However, before these drugs are publicly funded, they undergo a rigorous review process. In a single-payer health system, additional reviews are necessary to balance clinical benefit with cost effectiveness, which can cause delays in the public availability of these lifesaving treatments. Our study aimed to examine the factors that impact these drug review times and, ultimately, public funding recommendations. Interestingly, we found that longer drug review times (time from Health Canada approval to pCODR final recommendations) were associated with negative funding recommendations, with drugs for lung and gastrointestinal cancers undergoing more lengthy review processes. New oncology drugs undergo detailed review prior to public funding in a single-payer healthcare system. The aim of this study was to assess how cancer drug review times impact funding recommendations. Drugs reviewed by the pan-Canadian Oncology Drug Review (pCODR) between the years 2012 and 2020 were included. Data were collected including Health Canada approval dates, initial and final funding recommendations, treatment intent, drug class, clinical indications, and incremental cost-effectiveness ratios (ICER). Univariable and multivariable analyses were used to determine the association between funding recommendations and review times. Of the 164 applications submitted, 130 received a positive final recommendation. Median time from Health Canada (HC) approval to final recommendation was longer for drugs indicated for the treatment of gastrointestinal (GI) and lung cancer compared to breast, genitourinary (GU), and other tumours (205 vs. 198 vs. 111 vs. 129 vs. 181 days, respectively; Kruskal–Wallis p = 0.0312). Drugs with longer review times were more likely to receive a negative pCODR recommendation, even when adjusting for tumour type, drug class, and intent of therapy (157 vs. 298 days; Wilcoxon p = 0.0003, OR 1.002 95% CI [1.000–1.004].). There was no association between funding recommendation and tumour type or class of drug. The exploration of factors associated with variance in review times will be important in ensuring timely patient access to cancer drugs. [ABSTRACT FROM AUTHOR]

Aims patients & methodsIn this retrospective review, we sought to estimate the proportion of patients in the USA with advanced or metastatic cancer who are eligible for and may respond to recommended first-line cytotoxic chemotherapy based on National Comprehensive Cancer Network treatment guidelines.ResultsAmong 609,640 patients, we estimate 479,823 (78.7%, 95% CI: 78.6-78.8%) may be eligible for cytotoxic chemotherapy while 189,159 out of 609,640 patients (31.0%, 95% CI: 30.9-31.1%) may have achieved treatment response. The average objective response rate from these regimens was 48.6% (range 9.2 to 90.6%).ConclusionGiven the large role of cytotoxic agents in cancer, drug development in this space may remain of interest in specific cancer types, and regulatory approval of novel oncology drugs may justify head-to-head comparisons against cytotoxic regimens.

Abstract Purpose To assess the reporting quality of published economic evaluations of the negotiated oncology drugs listed for China’s 2020 National Reimbursement Drug List (NRDL). Methods A comprehensive search was conducted to identify economic evaluation studies of negotiated oncology drugs listed in China’s 2020 NRDL using the PubMed/MEDLINE, Embase, Web of Science, CNKI, SinoMed, and WanFang Database up to March 31, 2021. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist scored the reporting quality between 0 and 100. A linear regression analysis was employed to examine the influence of various characteristics on the reporting quality scores. Results Eighty papers were included in the study, with the majority published during the past decade. Furthermore, more than half of the articles (57.5%, or 46 out of 80) were written in English. The average CHEERS score was 74.63 ± 12.75 and ranged from 43.48 to 93.75. The most inadequately reported items included choice of model, characterization of heterogeneity, and discussion, as well as currency, price date and conversion. Higher scores were associated with articles published from 2019 to 2021 and English publications. Conclusion The economic evaluation studies of negotiated oncology drugs listed in 2020 NRDL had moderate reporting quality. The Chinese economic evaluation publications could improve the reporting quality if the CHEERS checklist is consistently implemented. Also, the Chinese journals maybe explore introducing a reporting standard for economic evaluations.

Objectives: National health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies' evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.Methods: Interviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.Results: Acceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.Conclusions: Differences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed. [ABSTRACT FROM AUTHOR]

Cancer remains the leading cause of death worldwide with approved oncology drugs continuing to have heterogenous patient responses and accompanied adverse effects (AEs) that limits effectiveness. Here, we examined >100 FDA-approved oncology drugs in the context of stemness using a surrogate model of transformed human pluripotent cancer stem cells (CSCs) vs. healthy stem cells (hSCs) capable of distinguishing abnormal self-renewal and differentiation. Although a proportion of these drugs had no effects (inactive), a larger portion affected CSCs (active), and a unique subset preferentially affected CSCs over hSCs (selective). Single cell gene expression and protein profiling of each drug's FDA recognized target provided a molecular correlation of responses in CSCs vs. hSCs. Uniquely, drugs selective for CSCs demonstrated clinical efficacy, measured by overall survival, and reduced AEs. Our findings reveal that while unintentional, half of anticancer drugs are active against CSCs and associated with improved clinical outcomes. Based on these findings, we suggest ability to target CSC targeting should be included as a property of early onco-therapeutic development. • Half of the tested oncology drugs target and effect cancer stem cells (CSCs). • A unique subset preferentially affected CSCs over healthy stem cells (hSCs) (selective drugs). • Molecular correlation to functional oncology drug responses was identified. • Drugs selective for CSCs are associated with better clinical efficacy. • Stemness response represents a key factor in efficacy of oncology drugs. [ABSTRACT FROM AUTHOR]

Abstract Background We examined if oncology drug indications with high clinical benefit, as measured by the American Society of Clinical Oncology Value Framework (ASCO‐VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS), received public reimbursement status faster than those with lower clinical benefit from the time of pan‐Canadian Oncology Drug Review (pCODR) recommendation. Methods Oncology drug indications submitted to pCODR between July 2011 and October 2018 were examined. Included indications had a regulatory approval date, completed the pCODR review process, received a positive pCODR recommendation, and been funded by at least one province. Trials cited for clinical efficacy were used to determine the clinical benefit (per ASCO‐VF and ESMO‐MCBS) of drug indications. Results Eighty‐four indications were identified, yielding 65 ASCO‐VF and 50 ESMO‐MCBS scores. The mean ASCO‐VF and ESMO‐MCBS scores were 44.9 (SD = 21.1) and 3.3 (SD = 1.0), respectively. The mean time to provincial reimbursement from pCODR recommendation was 13.2 months (SD = 9.3 months). Higher ASCO‐VF and ESMO‐MCBS scores had low correlation with shorter time to reimbursement, (ρ = −0.21) and (ρ = 0.24), respectively. In the multivariable analyses, ASCO‐VF (p = 0.40) and ESMO‐MCBS (p = 0.31) scores were not significantly associated with time to reimbursement. Province and year of pCODR recommendation were associated with time to reimbursement in both ASCO and ESMO models. Conclusions Oncology drug indications with higher clinical benefit do not appear to be reimbursed faster than those with low clinical benefit. This suggests the need to prioritize oncology drug indications based on clinical benefit to ensure quicker access to oncology drugs with the greatest benefits.

Background: Gliomas, originating from the most common non-neuronal cells in the brain (glial cells), are the most common brain tumors and are associated with high mortality and poor prognosis. Glioma cells exhibit a tendency to disrupt normal cell-cycle regulation, leading to abnormal proliferation and malignant growth. This study investigated the predictive potential of GJC1 in gliomas and explored its relationship with the cell cycle., Methods: Retrospective analysis of RNA-seq and single-cell sequencing data was conducted using the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The differential expression of GJC1 in gliomas with various pathological features and in different non-neuronal cell groups was analyzed. Functional data were examined using gene set variation analysis (GSVA). Furthermore, CellMiner was used to evaluate the relationship between GJC1 expression and predicted treatment response across these databases., Results: GJC1 expression was enriched in high-grade gliomas and 1p/19q non-codeletion gliomas. GJC1 enrichment was observed in classical and mesenchymal subtypes within the TCGA glioma subtype group. In single-cell subgroup analysis, GJC1 expression was higher in glioma tissues compared to other non-neuronal cells. Additionally, the TCGA classical subtype of glioma cells exhibited more GJC1 expression than the other subgroups. GJC1 emerged as an independent prognostic factor for overall survival in glioma. GSVA unveiled potential mechanisms by which GJC1 may impact cell-cycle regulation in glioma. Finally, a significant correlation was observed between GJC1 expression and the sensitivity of multiple anti-cancer drugs., Conclusion: These findings confirmed GJC1 as a novel biomarker and provided insights into the differential gene expression in non-neuronal cells and the impact of the cell cycle on gliomas. Consequently, GJC1 may be used to predict glioma prognosis and has potential therapeutic value., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ji, Chen, Lin, Ma, Yang, Zhao, Chen and Yang.)

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) is not yet performed routinely in the standard care of oncology patients, although it offers a high potential to improve treatment outcome and minimize toxicity. TKIs are perfect candidates for TDM as they show a relatively small therapeutic window, a wide inter-patient variability in pharmacokinetics and a correlation between drug concentration and effect. Moreover, most of the available TKIs are susceptible to various drug-drug interactions and medication adherence can be checked by performing TDM. Plasma, obtained via traditional venous blood sampling, is the standard matrix for TDM of TKIs. However, the use of plasma poses some challenges related to sampling and stability. The use of dried blood microsamples can overcome these limitations. Collection of samples via finger-prick is minimally invasive and considered convenient and simple, enabling sampling by the patients themselves in their home-setting. The collection of small sample volumes is especially relevant for use in pediatric populations or in pharmacokinetic studies. Additionally, working with dried matrices improves compound stability, resulting in convenient and cost-effective transport and storage of the samples. In this review we focus on the different dried blood microsample-based methods that were used for the quantification of TKIs. Despite the many advantages associated with dried blood microsampling, quantitative analyses are also associated with some specific difficulties. Different methodological aspects of microsampling-based methods are discussed and applied to TDM of TKIs. We focus on sample preparation, analytics, internal standards, dilution of samples, external quality controls, dried blood spot specific validation parameters, stability and blood-to-plasma conversion methods. The various impacts of deviating hematocrit values on quantitative results are discussed in a separate section as this is a key issue and undoubtedly the most widely discussed issue in the analysis of dried blood microsamples. Lastly, the applicability and feasibility of performing TDM using microsamples in a real-life home-sampling context is discussed. [ABSTRACT FROM AUTHOR]

Background and research question: Loss of exclusivity of oncology drugs causes an important drop in their price due to the marketing of generic medicines. In this article we study how the price of certain oncology drugs evolves throughout time after the loss of their patent, both in terms of the notified price and at a level of the public tenders for the purchase of medicines. Methods: The variation in the price of oral oncology drugs was assessed from the public information provided by the Interministerial Medicinal Products Pricing Committee (Comisión Interministerial de Precios de los Medicamentos, CIPM) and the data from public tenders for the purchase of medicines. Results: The data show a significant drop in price of the medicines assessed after the expiry of their patent, both at a notified price level (70% of average drop in price in 2.6 years) and at the level of the public tenders (drops exceeding 90% in a year for the most innovative drugs). Discussion: The drop in the price of the oncology drugs after the expiry of their patent is seen in all the medicines assessed. The trends seen allow to predict the evolution of the price of another innovative medicine that is nearing the expiry of its patent (Lenalidomide), with an expected drop in price by 90% with respect to the current price of the innovative drug.

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) is not yet performed routinely in the standard care of oncology patients, although it offers a high potential to improve treatment outcome and minimize toxicity. TKIs are perfect candidates for TDM as they show a relatively small therapeutic window, a wide inter-patient variability in pharmacokinetics and a correlation between drug concentration and effect. Moreover, most of the available TKIs are susceptible to various drug-drug interactions and medication adherence can be checked by performing TDM. Plasma, obtained via traditional venous blood sampling, is the standard matrix for TDM of TKIs. However, the use of plasma poses some challenges related to sampling and stability. The use of dried blood microsamples can overcome these limitations. Collection of samples via finger-prick is minimally invasive and considered convenient and simple, enabling sampling by the patients themselves in their home-setting. The collection of small sample volumes is especially relevant for use in pediatric populations or in pharmacokinetic studies. Additionally, working with dried matrices improves compound stability, resulting in convenient and cost-effective transport and storage of the samples. In this review we focus on the different dried blood microsample-based methods that were used for the quantification of TKIs. Despite the many advantages associated with dried blood microsampling, quantitative analyses are also associated with some specific difficulties. Different methodological aspects of microsampling-based methods are discussed and applied to TDM of TKIs. We focus on sample preparation, analytics, internal standards, dilution of samples, external quality controls, dried blood spot specific validation parameters, stability and blood-to-plasma conversion methods. The various impacts of deviating hematocrit values on quantitative results are discussed in a separate section as this is a key issue and undoubtedly the most widely discussed issue in the analysis of dried blood microsamples. Lastly, the applicability and feasibility of performing TDM using microsamples in a real-life home-sampling context is discussed.

Background: We examined if oncology drug indications with high clinical benefit, as measured by the American Society of Clinical Oncology Value Framework (ASCO‐VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS), received public reimbursement status faster than those with lower clinical benefit from the time of pan‐Canadian Oncology Drug Review (pCODR) recommendation. Methods: Oncology drug indications submitted to pCODR between July 2011 and October 2018 were examined. Included indications had a regulatory approval date, completed the pCODR review process, received a positive pCODR recommendation, and been funded by at least one province. Trials cited for clinical efficacy were used to determine the clinical benefit (per ASCO‐VF and ESMO‐MCBS) of drug indications. Results: Eighty‐four indications were identified, yielding 65 ASCO‐VF and 50 ESMO‐MCBS scores. The mean ASCO‐VF and ESMO‐MCBS scores were 44.9 (SD = 21.1) and 3.3 (SD = 1.0), respectively. The mean time to provincial reimbursement from pCODR recommendation was 13.2 months (SD = 9.3 months). Higher ASCO‐VF and ESMO‐MCBS scores had low correlation with shorter time to reimbursement, (ρ = −0.21) and (ρ = 0.24), respectively. In the multivariable analyses, ASCO‐VF (p = 0.40) and ESMO‐MCBS (p = 0.31) scores were not significantly associated with time to reimbursement. Province and year of pCODR recommendation were associated with time to reimbursement in both ASCO and ESMO models. Conclusions: Oncology drug indications with higher clinical benefit do not appear to be reimbursed faster than those with low clinical benefit. This suggests the need to prioritize oncology drug indications based on clinical benefit to ensure quicker access to oncology drugs with the greatest benefits. [ABSTRACT FROM AUTHOR]

Background and research question: Loss of exclusivity of oncology drugs causes an important drop in their price due to the marketing of generic medicines. In this article we study how the price of certain oncology drugs evolves throughout time after the loss of their patent, both in terms of the notified price and at a level of the public tenders for the purchase of medicines. Methods: The variation in the price of oral oncology drugs was assessed from the public information provided by the Interministerial Medicinal Products Pricing Committee (Comisión Interministerial de Precios de los Medicamentos, CIPM) and the data from public tenders for the purchase of medicines. Results: The data show a significant drop in price of the medicines assessed after the expiry of their patent, both at a notified price level (70% of average drop in price in 2.6 years) and at the level of the public tenders (drops exceeding 90% in a year for the most innovative drugs). Discussion: The drop in the price of the oncology drugs after the expiry of their patent is seen in all the medicines assessed. The trends seen allow to predict the evolution of the price of another innovative medicine that is nearing the expiry of its patent (Lenalidomide), with an expected drop in price by 90% with respect to the current price of the innovative drug. [ABSTRACT FROM AUTHOR]

utcome-based agreements (OBAs) are occasionally deployed to relieve the burden of high drug prices on healthcare budgets. However, it is not clear when manufacturers are willing to collaborate in establishing such agreements. Therefore, we explored the feasibility of OBAs from the manufacturer's point of view. Dutch market-access experts from eight major pharmaceutical companies, globally active in the field of oncology, were interviewed. Opinions were compiled, and interviewees and their colleagues were then given the chance to review the manuscript for additional comments. Most interviewees believe that OBAs can be useful in providing access to off-label use of authorised medicines, especially when no alternative treatment is available for seriously ill patients. For the licenced indications, manufacturers seem to be more inclined to collaborate when there is a potential incentive to improve market-access (e.g., if the product is not used because of concerns regarding its effectiveness). However, manufacturers are less likely to collaborate when there are greater financial risks for the company. Further concerns were definition of outcome or performance, the impact of compliance on the effectiveness of a drug, administrative burden, uncertainty regarding revenue recognition and the challenges of reimbursing combination therapies. Market-access interviewees were generally positive about OBAs, however they were more reluctant towards OBAs for registered indications with low response-rate. The definition of performance or outcome and its clinical relevance and validity, the feasibility of OBAs and their administrative burden are relevant aspects that need to be addressed in advance. Ideally, countries should collaborate to share the outline of OBAs and create shared databases to accumulate evidence. [ABSTRACT FROM AUTHOR]

Background Oncology drugs are frequently approved on the basis of surrogate outcomes that require further trials to confirm the benefits, but at times these trials fail and regulators need to decide whether to withdraw approval for the indication and/or to remove the drug from the market. This study compares decisions by the Food and Drug Administration and Health Canada about oncology drugs that were approved using either Accelerated Approval (FDA) or Notice of Compliance with conditions (NOC/c, Health Canada) and that failed confirmatory trials. Methods Drug/indications approved by the FDA through its Accelerated Approval Pathway and that later failed confirmatory studies were identified from a published study and additional information on these drugs was collected from Drugs@FDA. Health Canada websites were searched on September 11, 2021 for the same group of drugs to determine if they were approved in Canada under the NOC/c pathway for the same indication as in the US. Information from both the FDA and Health Canada about these products was entered into an Excel spreadsheet. Decisions about whether to withdraw the drugs or remove the failed indication for the drug and requirements for confirmatory studies were compared. In addition, the dates of decisions by the two agencies were compared. Results Ten drug/indications were available for comparison. Regulatory decisions were similar in 4 cases, different in 1 case and could not be determined in the remaining 5, in 1 case because decisions were pending in both countries and in the other 4, because the NOC/c had not been fulfilled in Canada. The requirements for the confirmatory studies were similar in both countries. Decisions were made earlier in the United States. Conclusions This study shows that decisions made by Health Canada and the FDA about whether to withdraw a drug or remove a failed indication when drug/indications fail a confirmatory trial are usually similar, although the sample size on which this conclusion is made is small. The clinical implications of these similarities and differences should be explored.

Background: Oncology drugs are frequently approved on the basis of surrogate outcomes that require further trials to confirm the benefits, but at times these trials fail and regulators need to decide whether to withdraw approval for the indication and/or to remove the drug from the market. This study compares decisions by the Food and Drug Administration and Health Canada about oncology drugs that were approved using either Accelerated Approval (FDA) or Notice of Compliance with conditions (NOC/c, Health Canada) and that failed confirmatory trials. Methods: Drug/indications approved by the FDA through its Accelerated Approval Pathway and that later failed confirmatory studies were identified from a published study and additional information on these drugs was collected from Drugs@FDA. Health Canada websites were searched on September 11, 2021 for the same group of drugs to determine if they were approved in Canada under the NOC/c pathway for the same indication as in the US. Information from both the FDA and Health Canada about these products was entered into an Excel spreadsheet. Decisions about whether to withdraw the drugs or remove the failed indication for the drug and requirements for confirmatory studies were compared. In addition, the dates of decisions by the two agencies were compared. Results: Ten drug/indications were available for comparison. Regulatory decisions were similar in 4 cases, different in 1 case and could not be determined in the remaining 5, in 1 case because decisions were pending in both countries and in the other 4, because the NOC/c had not been fulfilled in Canada. The requirements for the confirmatory studies were similar in both countries. Decisions were made earlier in the United States. Conclusions: This study shows that decisions made by Health Canada and the FDA about whether to withdraw a drug or remove a failed indication when drug/indications fail a confirmatory trial are usually similar, although the sample size on which this conclusion is made is small. The clinical implications of these similarities and differences should be explored. [ABSTRACT FROM AUTHOR]

Introduction: utcome-based agreements (OBAs) are occasionally deployed to relieve the burden of high drug prices on healthcare budgets. However, it is not clear when manufacturers are willing to collaborate in establishing such agreements. Therefore, we explored the feasibility of OBAs from the manufacturer’s point of view. Methods: Dutch market-access experts from eight major pharmaceutical companies, globally active in the field of oncology, were interviewed. Opinions were compiled, and interviewees and their colleagues were then given the chance to review the manuscript for additional comments. Results: Most interviewees believe that OBAs can be useful in providing access to off-label use of authorised medicines, especially when no alternative treatment is available for seriously ill patients. For the licenced indications, manufacturers seem to be more inclined to collaborate when there is a potential incentive to improve market-access (e.g., if the product is not used because of concerns regarding its effectiveness). However, manufacturers are less likely to collaborate when there are greater financial risks for the company. Further concerns were definition of outcome or performance, the impact of compliance on the effectiveness of a drug, administrative burden, uncertainty regarding revenue recognition and the challenges of reimbursing combination therapies. Discussion: Market-access interviewees were generally positive about OBAs, however they were more reluctant towards OBAs for registered indications with low response-rate. The definition of performance or outcome and its clinical relevance and validity, the feasibility of OBAs and their administrative burden are relevant aspects that need to be addressed in advance. Ideally, countries should collaborate to share the outline of OBAs and create shared databases to accumulate evidence.

Background: Regulatory agencies now recognize single-arm trials with external historical controls, particularly common in oncology, to assess promising treatments for rare or specific indications. When a new treatment indication depends on events over time, such as treatment failures, this design can introduce time-related biases in comparisons with external controls.Methods: We describe two potential biases resulting from calendar time and choice of time zero. We illustrate these biases using simulated data, emulating those from a single-arm trial of the effectiveness of blinatumomab in treating relapsed or refractory acute lymphoblastic leukemia on the outcome of mortality.Results: The trial compared 189 patients treated with blinatumomab with 1112 external historical control patients. First, calendar time was not concurrent, with the blinatumomab arm diagnosed during 2010-2014 and the control cohort during 1990-2013. The median survival under blinatumomab was 6.1 months compared with 3.3 months in the control arm, though for the latter it increased from 2.4 to 4.2 months over the 24-year period. Second, using the latest line of salvage treatment as cohort, entry for the control cohort introduces selection bias. The corresponding hazard ratio of death with blinatumomab compared with control was 0.56 (95% CI = 0.47, 0.67) but became 0.98 (95% CI = 0.83, 1.15) after redefining cohort entry by the matched line of salvage treatment rather than the latest line.Conclusion: While single-arm trials with external historical controls are gaining recognition, a proper understanding of time-related sources of bias is essential if such trials will be used to provide valid evidence for drug approval from regulatory agencies. [ABSTRACT FROM AUTHOR]

Aims, patients & methods: In this retrospective review, we sought to estimate the proportion of patients in the USA with advanced or metastatic cancer who are eligible for and may respond to recommended first-line cytotoxic chemotherapy based on National Comprehensive Cancer Network treatment guidelines. Results: Among 609,640 patients, we estimate 479,823 (78.7%, 95% CI: 78.6–78.8%) may be eligible for cytotoxic chemotherapy while 189,159 out of 609,640 patients (31.0%, 95% CI: 30.9–31.1%) may have achieved treatment response. The average objective response rate from these regimens was 48.6% (range 9.2 to 90.6%). Conclusion: Given the large role of cytotoxic agents in cancer, drug development in this space may remain of interest in specific cancer types, and regulatory approval of novel oncology drugs may justify head-to-head comparisons against cytotoxic regimens.

Ankur Arora,1,2 Rajinder K Jalali,1,2 Divya Vohora1 1School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; 2Medical Affairs and Clinical Research, Sun Pharmaceutical Industries Limited, Gurgaon, Haryana, India Background: Numerous reporting biases have been known to affect spontaneous reporting databases. The Weber effect, which constitutes a peak in adverse event (AE) reporting of a drug at the end of second year after regulatory approval followed by a continuous decline thereafter, has been considered an important bias for a long time. The existence of this bias in AE reporting of oncology drugs remains an underevaluated area, prompting a targeted examination.Methods: The US Food and Drug Administration (USFDA) Adverse Event Reporting System (FAERS) was studied for AE reporting patterns of 5 years of 15 new molecular entities (NMEs) and biologics used in oncology. This 5-year period started from the USFDA date of approval for the NMEs and biologics. The number of AEs reported for each of the drugs was plotted against time (years). The AE reporting patterns were specifically examined for the existence of the Weber effect. In addition, AE reporting rate patterns of 5 years of seven NMEs and biologics used in oncology were examined.Results: A total of 50,630 AE reports were logged in to the FAERS for all 15 drugs examined for AE reporting patterns. We observed five distinct AE reporting patterns for 15 drugs; however, none of the AE patterns were identical to the Weber effect. We did not observe a consistent AE reporting rate pattern for the seven drugs examined for AE reporting rates. With the exception of one drug (cetuximab), none of the drugs exhibited a second-year peak in AE reporting rates. This peak was not followed by continuous decline in AE reporting rate thereafter.Conclusion: This study does not support the existence of the Weber effect in AE reporting of oncology drugs. The contemporary AE reporting of oncology drugs does not exhibit a consistent pattern. Keywords: Weber effect, adverse event reporting patterns, oncology drugs, USFDA, FAERS

The never-ending explosion in the cost of new oncology drugs is reducing in many countries the access to the most recent, effective anticancer therapies and represents a significant obstacle to the design and realization of combinatorial trials. Already approved, anticancer and nonanticancer drugs can be considered for in silico, preclinical, and clinical repurposing approaches and offer the significant advantages of a potentially cheaper, faster, and safer validation. This review discusses recent advances and challenges in the field. [ABSTRACT FROM AUTHOR]

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

• Reporting of benefit–risk assessments by regulators vary along multiple dimensions. • Standard of evidence for benefit–risk assessments have diversified over time. • Despite policy goals there is rare inclusion of patient experience or real-world data. The European Medicines Agency (EMA) and FDA have policy goals of strengthening benefit–risk (B–R) capabilities; but how this has been translating into regulatory practice is unclear. A systematic review of oncology drug approvals between 2015 and 2020 was conducted with approvals identified through review of FDA and EMA annual reports, with extraction of information on submission, clinical program and B–R assessment from publicly available review documents. Data were extracted from 236 reviews (EMA: 66 new submissions, 100 label extensions; FDA: 70 new submissions). The standard of evidence for B–R assessments seems to have diversified over time; yet, despite policy targets to extend their use, these assessments rarely include patient experience or real-world data. [ABSTRACT FROM AUTHOR]

Background: Healthcare horizon scanning systems, have become one of the main components of health technology assessment. We conducted a horizon scanning exercise to identify new oncology drugs that may have a high impact on cancer patients and the health system in Iran. Methods: We reviewed existing health technology horizon scanning systems, and selected and weighted criteria for prioritizing oncology drugs, including 1) clinical efficiency and effectiveness, 2) incidence and prevalence of cancer types, 3) potential costs, 4) availability of alternative treatment, 5) having variable indications, 6) quality of evidence, and 7) being a first, second or third line drug. We reviewed horizon scanning reports in other countries and prepared a list of new oncology drugs to be ranked. We summarized clinical and epidemiological information about the drugs and presented them to a member of our expert panel who ranked them based on a structured checklist. Eventually, the drugs were categorized into four groups from low to high impact, based on their effect on patients and the health system of Iran in the future Results: We identified 158 new oncology drugs, most of which were in their phase III clinical trials, and had been approved by the US Food and Drug Administration (FDA). Finally, we selected 18 medicines as having the highest impact on patients and the health system of Iran. Conclusion: The results of this study can be used for several purposes, including research and drug development. These results suggest the need for periodical horizon scanning in Iran and other low and middle-income countries.

Background: This study examined multiple aspects about the approval of new drugs: the characteristics of the drugs, the quality and quantity of information that Health Canada discloses about the demographics of patients enrolled in clinical trials, the characteristics of the trial, and the type of review that it uses. It examines whether there have been changes in these measures between 1 September 2012 and 31 March 2022., Methods: A list of all new drugs approved, type of review used, and drug characteristics was generated from Health Canada annual reports. Therapeutic categories were identified from the World Health Organization Collaborating Center for Drugs Statistics Methodology. The Summary Basis of Decision documents of Health Canada were used to identify patient demographics in clinical trials and clinical trial characteristics., Results: Health Canada approved 326 new drugs for 407 indications. The percent of orphan drugs approved increased from 35.6 to 51.3%. The number of indications per drug decreased ( p  = 0.0817) as did the number of pivotal trials per drug ( p  = 0.0091). The percent of Phase 3 trials dropped from 76.3% in 2012-2015 to 64.8% in 2019-2022 ( p  = 0.005). There was also a statistically significant decrease in the percent of trials that were randomized, controlled, and blinded. The clinical trial characteristics of orphan drugs and the type of review used were both significantly different compared with non-orphan drugs. The percent of trials which had information about the number of patients enrolled, the percent of trials that provided the age of the patients, and the sex breakdown all significantly increased., Conclusion: The results show that there has been a change in regulatory standards that may be due to them becoming less rigorous, because of an adaptation to the number of orphan drugs being submitted or a combination of both reasons. At the same time, there has been some improvement in the transparency of data. Health Canada has recently embarked on a series of reforms in drug regulation and clinical trial management. These changes need to be closely evaluated to be sure that they enhance the efficacy and safety of new drugs., Competing Interests: Between 2019–2023, JL received payments for writing briefs on the role of promotion in generating prescriptions for two legal firms. JL is a member of the Board of Canadian Doctors for Medicare. JL receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. JL is participating in research funded by the Canadian Institutes of Health Research., (Copyright © 2023 Lexchin.)

Summary: Brentuximab vedotin (Bv) is becoming increasingly important in the treatment of Hodgkin lymphoma (HL), with improved outcomes and an overall favourable toxicity profile. However, Bv is associated with severe pulmonary toxicity when combined with bleomycin, suggesting that additive toxicity may be an important consideration. Furthermore, little has been published on tolerability in paediatric patients. We retrospectively evaluated the occurrence of pulmonary toxicity of Bv in 19 paediatric and young adult patients with relapsed or refractory HL. Patient characteristics, baseline health status, treatment regimens including cumulative doses of Bv, bleomycin, gemcitabine, radiation and carmustine, and the occurrence of pulmonary toxicity were collected. Seven (36·8%) of the 19 patients were treated with Bv. The odds of pulmonary toxicity were 4·0‐fold higher (95% confidence interval 0·55–29·18) in patients exposed to Bv compared to unexposed patients in univariate analysis (P = 0·17). Similar results were found in multivariable analysis. Pulmonary toxicity occurred frequently in our cohort and was more common in patients who received Bv than in patients who did not receive Bv, although this was not statistically significant. Because patients with HL are exposed to a myriad of therapies with potential for pulmonary toxicity, continuing to evaluate the risk associated with Bv is critical. [ABSTRACT FROM AUTHOR]