Health technology assessment for cancer medicines across the G7 countries and Oceania: an international, cross-sectional study.

BACKGROUND: Criticisms have emerged that cancer medicines offer modest benefits at increasingly high prices. Reimbursement decisions made by health technology assessment (HTA) agencies have become a complex endeavour for cancer medicines. Most high-income countries (HICs) use HTA criteria to identify high-value medicines for reimbursement under public drug coverage plans. We compared HTA criteria specific for cancer medicines in economically similar HICs, to understand how these criteria contribute to reimbursement decisions. METHODS: We did an international, cross-sectional analysis in collaboration with author investigators across eight HICs, from the Group of Seven (known as G7; Canada, England, France, Germany, Italy, and Japan) and Oceania (Australia and New Zealand). Publicly available data from HTA agency reports and official documentation were extracted and analysed between Aug 15, 2021, and July 31, 2022. We collected data pertaining to the decision-making criteria used by the national HTA agency; HTA reimbursement status for 34 medicine-indication pairs corresponding to 15 unique US top-selling cancer medicines; and HTA reimbursement status for 18 cancer medicine-indication pairs (13 unique medicines) with minimal clinical benefit (score of 1 on the European Society of Medical Oncology Magnitude of Clinical Benefit Scale). Descriptive statistics were used to compare HTA decision criteria and drug reimbursement recommendations (or for Germany and Japan, final reimbursement status) across the eight countries. FINDINGS: Therapeutic impact related to clinical outcomes of the new medicine was a uniform criterion across the eight countries, whereas quality of evidence (under the remit of therapeutic impact assessment) and equity were infrequently cited criteria. Only the German HTA agency mandated that surrogate endpoints be validated in therapeutic impact assessment. All countries except Germany included formal cost-effectiveness analyses within HTA reports. England and Japan were the only countries that specified a cost-effectiveness threshold. Of the 34 medicine-indication pairs corresponding to US top-selling cancer medicines, Germany reimbursed the maximum (34 [100%]), followed by Italy (32 [94%] recommended for reimbursement), Japan (28 [82%] reimbursed), Australia, Canada, England, and France (27 [79%] recommended for reimbursement), and New Zealand (12 [35%] recommended for reimbursement). Of the 18 cancer medicine-indication pairs with marginal clinical benefit, Germany reimbursed 15 (83%) and Japan reimbursed 12 (67%). France recommended nine (50%) for reimbursement, followed by Italy (seven [39%]), Canada (five [28%]), and Australia and England (three [17%] each). New Zealand did not recommend any medicine-indications with marginal clinical benefit for reimbursement. Considering the overall cumulative proportion across the eight countries, 58 (21%) of 272 indications for the US top-selling medicines and 90 (63%) of 144 marginally beneficial medicine-indications were not recommended for reimbursement or reimbursed. INTERPRETATION: Our findings indicate discordance in public reimbursement decisions across economically similar countries, despite overlapping HTA decision criteria. This suggests a need for improved transparency around the nuances of the criteria to ensure improved access to high-value cancer medicines, and deprioritisation of low-value cancer medicines. Health systems have opportunities to improve their HTA decision-making processes by learning from the systems in other countries. FUNDING: None.

GRADE Concept 7: Issues and Insights Linking Guideline Recommendations to Trustworthy Essential Medicine Lists.

OBJECTIVES: Guidelines and essential medicine lists (EMLs) bear similarities and differences in the process that lead to decisions. Access to essential medicines is central to achieve universal health coverage. The World Health Organization (WHO) EML has guided prioritization of essential medicines globally for nearly 50 years, and national EMLs (NEMLs) exist in over 130 countries. Guideline and EML decisions, at WHO or national levels, are not always coordinated and aligned. We sought to explore challenges, and potential solutions, for decision-making to support trustworthy medicine selection for EMLs from a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group perspective. We primarily focus on the WHO EML; however, our findings may be applicable to NEML decisions as well. STUDY DESIGN AND SETTING: We identified key challenges in connecting the EML to health guidelines by involving a broad group of stakeholders and assessing case studies including real applications to the WHO EML, South Africa NEML, and a multiple sclerosis guideline connected to a WHO EML application for multiple sclerosis treatments. To address challenges, we utilized the results of a survey and feedback from the stakeholders, and iteratively met as a project group. We drafted a conceptual framework of challenges and potential solutions. We presented a summary of the results for feedback to all attendees of the GRADE Working Group meetings in November 2022 (approximately 120 people) and in May 2023 (approximately 100 people) before finalizing the framework. RESULTS: We prioritized issues and insights/solutions that addressed the connections between the EML and health guidelines. Our suggested solutions include early planning alignment of guideline groups and EMLs, considering shared participation to strengthen linkage, further clarity on price/cost considerations, and using explicit shared criteria to make guideline and EML decisions. We also provide recommendations to strengthen the connection between WHO EML and NEMLs including through contextualization methods. CONCLUSION: This GRADE concept article, jointly developed by key stakeholders from the guidelines and EMLs field, identified key conceptual issues and potential solutions to support the continued advancement of trustworthy EMLs. Adopting structured decision criteria that can be linked to guideline recommendations bears the potential to advance health equity and gaps in availability of essential medicines within and between countries.

Conflict of Interest Disclosure in Oncology: Preliminary Insights From the Global ONCOTRUST-1 Cross-Sectional Study.

PURPOSE: Conflicts of interest (COIs) between oncologists and industry might considerably influence how the presentation of the research results is delivered, ultimately affecting clinical decisions and policy-making. Although there are many regulations on reporting COI in high-income countries (HICs), little is known about their reporting in low- and middle-income countries (LMICs). Oncology Transparency Under Scrutiny and Tracking (ONCOTRUST-1) is a pilot global survey to explore the knowledge and perceptions of oncologists regarding COI. MATERIALS AND METHODS: We designed an online 27-question-based survey in the English language to explore the perceptions and knowledge of oncologists regarding COI, with an emphasis on LMICs. Descriptive statistics and the Consensus-Based Checklist for Reporting of Survey Studies guidelines were used to report the findings. RESULTS: ONCOTRUST-1 surveyed 200 oncologists, 70.9% of them practicing in LMICs. Median age of the respondents was 36 (range, 26-84) years; 47.5% of them were women. Of the respondents, 40.5% reported weekly visits by pharmaceutical representatives to their institutions. Regarding oncologists' perceptions of COI that require disclosure, direct financial benefits, such as honoraria, ranked highest (58.5%), followed by gifts from pharmaceutical representatives (50%) and travel grants for attending conferences (44.5%). By contrast, personal or institutional research funding, sample drugs, consulting or advisory board, expert testimony, and food and beverage funded by pharmaceutical industry were less frequently considered as COI. Moreover, only 24% of surveyed oncologists could correctly categorize all situations representing a COI. CONCLUSION: These findings underscore the importance of clear guidelines, education, and transparency in reporting COI in oncology. This hypothesis-generating pilot survey provided the rationale for ONCOTRUST-2 study, which will compare perceptions of COI among oncologists in LMICs and HICs.

Expensive Drug Prices for Rare Cancers: Are Patients Truly Benefitting?

Cancer medicines comprise the largest proportion of expensive drugs for rare diseases (EDRDs). The US Orphan Drug Act (ODA) (Office of Inspector General, Department of Health and Human Services 2001) encourages pharmaceutical manufacturers to develop medicines for rare diseases through a range of financial incentives, which has shifted the development of cancer medicines to rare cancer subtypes. Although certain medicines approved through the ODA have revolutionized cancer treatment, only half demonstrate added therapeutic benefit compared to existing alternatives. Canadian regulators should ensure that cancer medicines that receive fast-track approval through the Health Canada Notice of Compliance with conditions offer benefit to Canadian patients. Furthermore, payers might engage in methods for reassessment and renegotiations over the medicines' lifespan.

Characteristics of clinician input in Canadian funding decisions for cancer drugs: a cross-sectional study based on CADTH reimbursement recommendations.

OBJECTIVE: To examine characteristics of clinician input to the pan-Canadian Oncology Drug Review (pCODR) for cancer drug funding recommendations from 2016 to 2020. DESIGN, SETTING AND PARTICIPANTS: Descriptive, cross-sectional study including 62 reimbursement decisions from pCODR from 2016 to 2020. INTERVENTIONS: pCODR recommendations were analysed for the number of clinicians consulted on each submission, affiliation, number of submissions per clinician, declared financial conflicts of interest (FCOIs), randomisation, type of blinding, primary endpoint, study phase, and whether the study demonstrated improvement in overall survival (OS) and progression-free survival (PFS). MAIN OUTCOME MEASURES: The main outcome was clinician support for the initial funding recommendation. Secondary outcome measures were the association between clinician FCOIs and clinical benefit in positive recommendations. RESULTS: The study consisted of 62 submissions, in which 48 included clinician input. A total of 129 unique clinicians provided 342 consultations. The majority (59%) provided input on less than 5 submissions; however, a small proportion (4%) consulted on over 10. Nearly all clinicians were physicians (125; 96%). From the 342 consultations, 228 declared financial conflicts (67%). The most common conflicts were payments for advisory roles (51%) and honorariums (23%). Of the 48 cancer drugs under review, clinicians recommended funding 46 (96%). Only 12 (25%) demonstrated substantial benefit, according to the European Society for Medical Oncology Magnitude of Clinical Benefit Scale score. Drugs recommended for funding were more likely to have improved PFS and OS data. However, most cancer drugs supported by clinicians demonstrated no change in health-related quality of life (HRQoL), including one that demonstrated worsened HRQoL. There was no statistically significant difference between FCOI status and recommending drugs with health gains. CONCLUSION: Clinicians offer crucial information on funding decisions. However, we found clinicians strongly supported funding nearly all cancer drugs under review, despite most not offering substantial benefit to patients nor gains in quality of life. While these drugs might be helpful options in clinical practice, funding numerous cancer drugs may be unsustainable for public health systems.

What drives cancer clinical trial accrual? An empirical analysis of studies leading to FDA authorisation (2015-2020).

OBJECTIVE: To examine factors associated with accrual rate in industry sponsored clinical trials supporting US Food and Drug Administration (FDA) cancer drug approvals from 2015 to 2020. DESIGN, SETTING AND PARTICIPANTS: Retrospective cross-sectional study included 194 pivotal trials supporting cancer drug approvals by the US FDA from 2015 to 2020. INTERVENTIONS: Clinical trials were analysed for the type of blinding, primary endpoint, whether crossover was specified in the publication, study phase, line of therapy, response rate, investigational sites, manufacturer and randomisation ratio. MAIN OUTCOME MEASURES: The main outcome was the rate of accrual, which is the number of patients accrued in the study per open month of enrolment. RESULTS: The study consisted of 133 randomised (68%) and 61 (32%) non-randomised clinical trials. In randomised studies, we found the accrual rate was higher in trials investigating first and second line drugs (adjusted rate ratios (aRR): 1.55, 95% CI 1.18 to 2.09), phase III trials (aRR: 2.13, 95% CI 1.48 to 2.99), and for studies sponsored by Merck (aRR: 1.47, 95% CI 1.18 to 2.37), adjusting for other covariates. In contrast, the primary endpoint of a study, presence of crossover, single agent response rate, the number of investigational sites, population disease burden and skewed randomisation ratios were not associated with the rate of accrual. In the non-randomised adjusted model, the accrual rate was 2.03 higher (95% CI 1.10 to 3.92) for clinical trials sponsored by manufacturer, specifically Merck. Primary endpoint, crossover, trial phase, response rate, the number of investigational sites, disease burden or line of therapy were not associated with the rate of accrual. CONCLUSION: In this cross-sectional study, line of therapy, study phase and manufacturer were the only factors associated with accrual rate. These findings suggest many proffered factors for speedy trial accrual are not associated with greater enrolment rates.

Cancer medicines on the WHO Model List of Essential Medicines: processes, challenges, and a way forward.

The selection of cancer medicines for national procurement requires deliberate evaluation of population benefit, budget impact, sustainability, and health system capacity. However, this process is complicated by numerous challenges, including the large volume and rapid pace of newly developed therapies offering marginal gains at prohibitively high prices. The WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) have undergone a series of evidence-based updates to ensure recommended cancer medicines offer meaningful clinical benefit. This Health Policy paper describes how cancer medicines are listed on the EML and EMLc, including two updated WHO processes: (1) the formation of the Cancer Medicines Working Group, and (2) additional selection principles for recommending cancer medicines, including a minimum overall survival benefit of 4-6 months with improvement to quality of life compared with standard treatment. These updates, along with proposals to include formal price considerations, additional selection criteria, and multisectoral collaboration (eg, voluntary licensing) promote procurement of high-value essential cancer medicines on national formularies in the context of supporting sustainable health systems to achieve universal health coverage.

Describing Sources of Uncertainty in Cancer Drug Formulary Priority Setting across Canada.

Over the years, there have been significant advances in oncology. However, the rate that therapeutics come to market has increased, while the strength of evidence has decreased. Currently, there is limited understanding about how these uncertainties are managed in provincial funding decisions for cancer therapeutics. We conducted qualitative interviews with six senior officials from four different Canadian provinces (British Columbia, Alberta, Quebec, and Ontario) and a document review of the uncertainties found in submissions to the pan-Canadian Oncology Drug Review (pCODR). Participants reported considerable uncertainty related to a lack of solid clinical evidence (early-phase clinical trials: generalizability, immature data, and the use of unvalidated surrogate outcomes). Proposed strategies to deal with the uncertainty included risk-sharing agreements, collection of real-world evidence (RWE), and ongoing collaboration between federal groups and provinces. The document review added to the reported uncertainties by classifying them into five main categories: trial validity, population, comparators, outcomes, and intervention. This study highlights how decision makers must deal with significant amounts of uncertainty in funding decisions for cancer drugs, most of which stems from methodological limitations in clinical trials. There is a critical need for transparent priority-setting processes and mechanisms to reevaluate drugs to ensure benefit given the high level of uncertainty of novel therapeutics.

Experiences and perspectives of individuals accessing CAR-T cell therapy: A qualitative analysis of online Reddit discussions.

INTRODUCTION: Several chimeric antigen receptor (CAR-T) T-cell therapies have been approved for use for haematological malignancies. Despite known safety, access, and cost issues, little is known about how patients and caregivers understand novel treatments such as CAR-T and their associated uncertainties. METHODS: We gathered data from Reddit, an online public social media site. We performed a keyword search in three relevant subreddit threads: r/cancer, r/lymphoma, r/leukemia. We systematically extracted threads and associated comments and reviewed against our inclusion criteria. RESULTS: We identified a total of 186 posts and 87 were included in the qualitative analysis from March 1, 2013, to April 15, 2021. Qualitative content analysis was used to identify themes. Of those excluded, 88 contained discussions of other immunotherapies and 11 were scientific profiles. We identified four themes: 1) navigating uncertainty with community, 2) finding a cure, 3) managing treatment-related uncertainties, and 4) overcoming uncertainties related to access. We found patients experience numerous barriers when seeking access to novel therapeutics, such as CAR-T therapies. CONCLUSIONS: The perceptions and struggles of patients and their families are relevant for developing technology assessments that are sensitive to patient experiences, as well as to inform policies for equitable resource allocation. POLICY SUMMARY: Our study underscores the importance of balanced decision making between patients and physicians to ensure patients understand the risk and benefits of cancer treatments. Study investigators might evaluate trial participants based on patient demographics to ensure equitable access to studies for individuals in settings where internet access is less common.

Challenges with sex-specific subgroup analyses in oncology clinical trials for drug approvals between 2015-2020.

INTRODUCTION: Women continue to be underrepresented in oncology clinical trials, leading to poor, underpowered subgroup analyses that cannot be generalized to cancer patients in practice. In 2014, the US Food and Drug Administration (FDA) released an Action Plan, which included actions to improve the quality and reporting of demographic subgroup data. We sought to evaluate the five-year progress since the release of this report by assessing the credibility of sex-specific subgroup analyses in oncology clinical trials. METHODS: We reviewed the FDA Hematology/Oncology Approvals website for New Molecular Entities (NMEs) that were approved for adults from 2015 to 2020. Publications and their supplementary indexes were reviewed by two authors (K.J. & A.R.) against ten criteria that gauge the credibility of subgroup analyses by assessing factors related to study design, analysis, and context. One point was awarded for each criteria met, for a maximum score of 10. RESULTS: We identified a total of 73 NMEs approved for cancer treatment between 2015-2020, of which 61 met our eligibility criteria. Of these, 32 studies (52 %) reported a subgroup analysis by sex and were included in our analysis. Phase 2 (41 %) and Phase 3 (53 %) studies represented most studies. No study met ≥3 credibility criteria. CONCLUSION: Only half the studies included in our analysis reported outcomes by sex, which suggests the activities stipulated in the 2014 US FDA Action Plan might be ineffective. This is concerning as uncredible sex-specific subgroup analyses can lead to wrongful clinical decision-making and poor patient outcomes. POLICY SUMMARY: Our findings suggest sex-specific subgroup analyses in oncology are not credible and users of these data should interpret results with caution. Regulatory bodies, such as the US FDA, ought to mandate subgroup analyses by demographic groups in drug applications. Peer-reviewed journals could ensure investigators disclose study results by sex as a condition for publication.

Evaluation of the Clinical Benefit of Cancer Drugs Submitted for Reimbursement Recommendation Decisions in Canada.

Importance: Cancer drugs approved by the US Food and Drug Administration have come under scrutiny for marginal clinical benefits; however, the clinical benefits of cancer drugs recommended for reimbursement in Canada have not been adequately studied. Objective: To assess the differences in the clinical evidence and benefit of cancer drugs that received a positive vs a negative recommendation for provincial reimbursement in Canada. Design, Setting, and Participants: This cohort study obtained publicly available regulatory documents from the pan-Canadian Oncology Drug Review (pCODR) and corresponding clinical trial documentation. All cancer drugs with a solid tumor indication that were submitted from the inception of the pCODR (July 2011) to February 2020 were evaluated. To be included, submissions had to have a final reimbursement recommendation; submissions that were incomplete, were withdrawn, or had a pending decision were excluded. Exposures: A completed reimbursement recommendation decision from the pCODR. Main Outcomes and Measures: Final reimbursement recommendation (positive vs negative); trial characteristics; and relevant clinical outcomes (ie, overall survival [OS] and progression-free survival [PFS]), including the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores available at the time of pCODR assessment. Results: Between 2011 and 2020, the pCODR issued 104 reimbursement recommendation decisions for cancer drugs with a solid tumor indication. Among these drug submissions, 78 (75.0%) received a positive recommendation, of which 72 (92.3%) were conditional. Drugs that received a positive recommendation compared with those with a negative recommendation were more likely to have phase 3 randomized clinical trial design (92.3% [72 of 78] vs 53.8% [14 of 26]; P < .001) and have substantial benefit according to the ESMO-MCBS scores (61.5% [48 of 78] vs 19.2% [5 of 26]; P < .001). The most common primary end points associated with the successful submissions were PFS (53.9%) and OS (32.1%). Overall, 39 of 78 submissions (50.0%) that received a positive recommendation had shown OS benefit, with median (interquartile range) OS gains of 3.7 (2.7-6.5) months. Conclusions and Relevance: This cohort study found that, although the pCODR takes into account the magnitude of clinical benefit, only half of the cancer drugs that received a positive recommendation had evidence of improved OS and the survival gains were usually modest. These results suggest that, although the pCODR helps filter out some cancer drugs with low quality of evidence and low magnitude of benefit, cancer drugs without meaningful patient benefit continue to enter the Canadian market; these findings are important for making reimbursement policy decisions globally.

Correction to: Challenges and opportunities for graduate students in public health during the COVID-19 pandemic.

This article was updated was to correct the spelling of Chenoa Cassidy-Matthews' name: it is correct as displayed here.

Assessment of Price and Clinical Benefit of Cancer Drugs in Canada, 2011-2020.

This cohort study examines the association between approval characteristics, clinical benefit, and prices of cancer drugs recommended for reimbursement by the Canadian Agency for Drug and Technology in Health.