Efficacy and safety of interim oncology treatments introduced for solid cancers during the COVID-19 pandemic in England: a retrospective evidence-based analysis.

Background: The COVID-19 global pandemic placed unprecedented pressure on cancer services, requiring new interim Systemic Anti-Cancer Treatments (SACT) options to mitigate risks to patients and maintain cancer services. In this study we analyse interim COVID-19 SACT therapy options recommended in England, evaluating the evidence supporting inclusion and delineating how these have been integrated into routine cancer care. Methods: We performed a retrospective analysis of interim Systemic Anti-Cancer Treatments endorsed by NHS England during the COVID-19 pandemic. Interim therapy options were compared to baseline (replacement) therapies by comparing data from the key pivotal trial(s) in terms of clinical efficacy and potential benefits (e.g., reduced immunosuppression or improved adverse effect profile) within the context of the pandemic. Furthermore, we evaluated the evolution of these interim SACT options, exploring if these have been integrated into current treatment pathways or are no longer accessible at the pandemic end. Findings: 31 interim oncology treatment options, across 36 indications, for solid cancers were endorsed by NHS England between March 2020 and August 2021. Interim therapies focused on the metastatic setting (83%; 30/36), allowing greater utilisation of immune checkpoint inhibitors (45%; 14/31) and targeted therapies (26%; 8/31), in place of cytotoxic chemotherapy. Overall, 36% (13/36) of therapies could not have efficacy compared with baseline treatments due to a paucity of evidence. For those which could, 39% (9/23) had superior efficacy (e.g., overall survival), 26% (6/23) had equivocal efficacy and 35% (8/23) lower efficacy. 53% (19/36) of interim therapies had better or equivocal toxicity profiles (when assessable), and/or were associated with reduced immunosuppression. Almost half (47%; 17/36) of interim therapies did not have UK market authorisation, being classified as 'off label' use. Analysing access to interim options at the end of the pandemic (May 2023) identified 19 (53% 19/36) interim options were fully available, and a further four (11% 4/36) therapies were partially available. Interpretation: Interim SACT options, introduced in England, across a range of solid cancers supported delivery of cancer services during the pandemic. Most interim therapies did not demonstrate superior efficacy, but provided other important benefits (e.g., reduced immunosuppression) in the context of the pandemic. Funding: None.

The impact of transport, housing, and urban development interventions on older adults' mobility: A systematic review of experimental and quasi-experimental studies.

Background: Age-friendly cities and communities aim to enhance and preserve the functional abilities of older adults. This systematic review assesses the impact of interventions in transportation, housing, and urban development on the mobility of older adults. Methods: We systematically searched MEDLINE, Embase, CINAHL, Scopus, PsycINFO, and SocINDEX up to July 2022 to identify studies that evaluated the impact of transportation, housing, and urban development interventions on older adults' mobility. Only randomised controlled trials and quasi-experimental studies with control groups were included to establish a causal relationship between interventions and mobility outcomes. Findings: We included a total of 15 studies, of which six were randomised controlled trials. Included studies were conducted in high-income settings and employed diverse metrics to assess mobility outcomes. Among housing interventions, three studies examined the impact of assistive technology within home environments for frail older adults. Two of these interventions maintained functional status without improvement, while the third showed a significant decline in outcomes, with the control group faring even worse. Public transport interventions, focused on enhancing mobility through educational initiatives and policy revisions, consistently produced positive outcomes. Interventions related to driving training for older adults, including in-class and on-road assessments, demonstrated beneficial effects. Results from studies evaluating urban design interventions were more varied, with some enhancing mobility by making public spaces more accessible for older adults and others yielding mixed results following infrastructure changes. Interpretation: Interventions in the built environments of older adults, specifically targeting transportation, housing and urban development, have the potential to enhance mobility and related outcomes according to rigorously designed quantitative evaluations. Due to heterogeneity in how mobility is conceptualised in the literature, greater harmonisation in measurement of mobility would help us understand how the social and built environment contribute to maintaining and improving mobility in older adults. Funding: World Health Organization.

Treatment Effects in Randomized and Nonrandomized Studies of Pharmacological Interventions: A Meta-Analysis.

Importance: Randomized clinical trials (RCTs) are widely regarded as the methodological benchmark for assessing clinical efficacy and safety of health interventions. There is growing interest in using nonrandomized studies to assess efficacy and safety of new drugs. Objective: To determine how treatment effects for the same drug compare when evaluated in nonrandomized vs randomized studies. Data Sources: Meta-analyses published between 2009 and 2018 were identified in MEDLINE via PubMed and the Cochrane Database of Systematic Reviews. Data analysis was conducted from October 2019 to July 2024. Study Selection: Meta-analyses of pharmacological interventions were eligible for inclusion if both randomized and nonrandomized studies contributed to a single meta-analytic estimate. Data Extraction and Synthesis: For this meta-analysis using a meta-epidemiological framework, separate summary effect size estimates were calculated for nonrandomized and randomized studies within each meta-analysis using a random-effects model and then these estimates were compared. The reporting of this study followed the Guidelines for Reporting Meta-Epidemiological Methodology Research and relevant portions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Main Outcome and Measures: The primary outcome was discrepancies in treatment effects obtained from nonrandomized and randomized studies, as measured by the proportion of meta-analyses where the 2 study types disagreed about the direction or magnitude of effect, disagreed beyond chance about the effect size estimate, and the summary ratio of odds ratios (ROR) obtained from nonrandomized vs randomized studies combined across all meta-analyses. Results: A total of 346 meta-analyses with 2746 studies were included. Statistical conclusions about drug benefits and harms were different for 130 of 346 meta-analyses (37.6%) when focusing solely on either nonrandomized or randomized studies. Disagreements were beyond chance for 54 meta-analyses (15.6%). Across all meta-analyses, there was no strong evidence of consistent differences in treatment effects obtained from nonrandomized vs randomized studies (summary ROR, 0.95; 95% credible interval [CrI], 0.89-1.02). Compared with experimental nonrandomized studies, randomized studies produced on average a 19% smaller treatment effect (ROR, 0.81; 95% CrI, 0.68-0.97). There was increased heterogeneity in effect size estimates obtained from nonrandomized compared with randomized studies. Conclusions and Relevance: In this meta-analysis of treatment effects of pharmacological interventions obtained from randomized and nonrandomized studies, there was no overall difference in effect size estimates between study types on average, but nonrandomized studies both overestimated and underestimated treatment effects observed in randomized studies and introduced additional uncertainty. These findings suggest that relying on nonrandomized studies as substitutes for RCTs may introduce additional uncertainty about the therapeutic effects of new drugs.

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Background: Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. Conclusion: The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Treatment methods for cervical intraepithelial neoplasia in England: A cost-effectiveness analysis.

OBJECTIVE: To compare the cost-effectiveness of different treatments for cervical intraepithelial neoplasia (CIN). DESIGN: A cost-effectiveness analysis based on data available in the literature and expert opinion. SETTING: England. POPULATION: Women treated for CIN. METHODS: We developed a decision-analytic model to simulate the clinical course of 1000 women who received local treatment for CIN and were followed up for 10 years after treatment. In the model we considered surgical complications as well as oncological and reproductive outcomes over the 10-year period. The costs calculated were those incurred by the National Health Service (NHS) of England. MAIN OUTCOME MEASURES: Cost per one CIN2+ recurrence averted (oncological outcome); cost per one preterm birth averted (reproductive outcome); overall cost per one adverse oncological or reproductive outcome averted. RESULTS: For young women of reproductive age, large loop excision of the transformation zone (LLETZ) was the most cost-effective treatment overall at all willingness-to-pay thresholds. For postmenopausal women, LLETZ remained the most cost-effective treatment up to a threshold of £31,500, but laser conisation became the most cost-effective treatment above that threshold. CONCLUSIONS: LLETZ is the most cost-effective treatment for both younger and older women. However, for older women, more radical excision with laser conisation could also be considered if the NHS is willing to spend more than £31,500 to avert one CIN2+ recurrence.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001-2020.

Background: Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and 2020. Methods: This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Findings: Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p < 0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p = 0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p = 0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. Interpretation: FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. Funding: No funding.

Availability and Coverage of New Drugs in 6 High-Income Countries With Health Technology Assessment Bodies.

This cohort study analyzes review times and approval outcomes of health technology assessments conducted in 6 high-income countries for novel therapeutic agents approved by the US Food and Drug Administration.

Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

BACKGROUND: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

Overall survival benefits of cancer drugs in the WHO Model List of Essential Medicines, 2015-2021.

INTRODUCTION: We examined overall survival (OS) benefits for targeted cancer drugs recommended for List of Essential Medicines (EMLs) since 2015. We assessed consistency of decisions in 2019 and 2021 with more specific criteria: OS benefit >4 months and high scores on European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: We identified applications for cancer drug in WHO EMLs from 2015 to 2021. We extracted evidence of OS benefit documented in WHO Technical Report Series (TRS) and compared it to evidence from pivotal trial(s) documented in Food and Drug Administration-approved labels. We retrieved published ESMO-MCBS scores. We summarised availability and magnitude of OS benefit and ESMO-MCBS scores and assessed consistency of inclusion decisions against WHO criteria. RESULTS: 22/54 targeted cancer drug indications were recommended. Among them, 68.2% and 31.8% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Among those not recommended, 59.4% and 56.3% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Of 11 cancer drug indications recommended in 2019 and 2021, 54.5% and 9.1% had evidence of OS benefit >4 months in WHO-TRS and pivotal trials, respectively; 45.5% met ESMO-MCBS criteria. Ten targeted cancer drugs had more than one application for the same indications. Five of those were eventually recommended, including three without new evidence of OS benefit. Additional factors, such as reduced cost, and increased treatment options, seemed to be important factors in the selection. CONCLUSION: While WHO has defined approval criteria for cancer drugs EML, we identified areas where adherence of these criteria and communication of the EML approval decision-making processes can be improved.

Research evaluating the effectiveness of dementia interventions in low- and middle-income countries: A systematic mapping of 340 randomised controlled trials.

OBJECTIVES: More people with dementia live in low- and middle-income countries (LMICs) than in high-income countries, but best-practice care recommendations are often based on studies from high-income countries. We aimed to map the available evidence on dementia interventions in LMICs. METHODS: We systematically mapped available evidence on interventions that aimed to improve the lives of people with dementia or mild cognitive impairment (MCI) and/or their carers in LMICs (registered on PROSPERO: CRD42018106206). We included randomised controlled trials (RCTs) published between 2008 and 2018. We searched 11 electronic academic and grey literature databases (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, World Health Organization Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit) and examined the number and characteristics of RCTs according to intervention type. We used the Cochrane risk of bias 2.0 tool to assess the risk of bias. RESULTS: We included 340 RCTs with 29,882 (median, 68) participants, published 2008-2018. Over two-thirds of the studies were conducted in China (n = 237, 69.7%). Ten LMICs accounted for 95.9% of included RCTs. The largest category of interventions was Traditional Chinese Medicine (n = 149, 43.8%), followed by Western medicine pharmaceuticals (n = 109, 32.1%), supplements (n = 43, 12.6%), and structured therapeutic psychosocial interventions (n = 37, 10.9%). Overall risk of bias was judged to be high for 201 RCTs (59.1%), moderate for 136 (40.0%), and low for 3 (0.9%). CONCLUSIONS: Evidence-generation on interventions for people with dementia or MCI and/or their carers in LMICs is concentrated in just a few countries, with no RCTs reported in the vast majority of LMICs. The body of evidence is skewed towards selected interventions and overall subject to high risk of bias. There is a need for a more coordinated approach to robust evidence-generation for LMICs.

Marketing authorisation and pricing of FDA-approved cancer drugs in Brazil: a retrospective analysis.

Background: Most cancer drugs enter the US market first. US Food and Drug Administration (FDA) approvals of new cancer drugs may influence regulatory decisions in other settings. The study examined whether characteristics of available evidence at FDA approval influenced time-to-marketing authorisation (MA) in Brazil, and price differences between the two countries. Methods: All new FDA-approved cancer drugs from 2010 to 2019 were matched to drugs with MA and prices approved in Brazil by December 2020. Characteristics of main studies, availability of randomised controlled trials (RCTs), overall survival (OS) benefit, added therapeutic benefit, and prices were compared. Findings: Fifty-six FDA-approved cancer drugs with matching indications received a MA at the Brazilian Health Regulatory Agency (Anvisa) after a median of 522 days following US approval (IQR: 351-932). Earlier authorisation in Brazil was associated with availability of RCT (median: 506 vs 760 days, p = 0.031) and evidence of OS benefit (390 vs 543 days, p = 0.019) at FDA approval. At Brazilian marketing authorisation, a greater proportion of cancer drugs had main RCTs (75% vs 60.7%) and OS benefit (42.9% vs 21.4%) than that in the US. Twenty-eight (50%) drugs did not demonstrate added therapeutic benefit over drugs for the same indication in Brazil. Median approved prices of new cancer drugs were 12.9% lower in Brazil compared to the US (adjusted by Purchasing Power Parity). However, for drugs with added therapeutic benefit median prices were 5.9% higher in Brazil compared to the US, while 17.9% lower for those without added benefit. Interpretation: High-quality clinical evidence accelerated the availability of cancer medicines in Brazil. The combination of marketing and pricing authorisation in Brazil may favour the approval of cancer drugs with better supporting evidence, and more meaningful clinical benefit albeit with variable degree of success in achieving lower prices compared to the US. Funding: None.

Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe.

OBJECTIVE: To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe. DESIGN: Document content analysis. SETTING: European Medicines Agency. PARTICIPANTS: Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19. MAIN OUTCOME MEASURES: Whether written information on a product addressed patients' commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports). RESULTS: 29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public. CONCLUSIONS: The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians.

Characteristics of Prior Authorization Policies for New Drugs in Medicare Part D.

This cross-sectional study examines the characteristics of prior authorization policies for new drugs in Medicare Part D to understand whether they are consistent with US Food and Drug Administration indications.

Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway.

This study examines the Food and Drug Administration's accelerated approval pathway and whether preapproval initiation was associated with faster conversion to traditional approval or withdrawal for drugs with nononcology indications.

Negotiating Drug Prices in the US-Lessons From Europe.

This Viewpoint describes European drug price negotiation practices and compares them with practices in the US.