Background All evidence-based medical decisions rely on the assumption that the evidence being used is applicable to current populations. To date, the age of evidence is not typically measured nor reported in systematic reviews. Methods We sought to develop a method to quantify the age of evidence for medical interventions, using statins and sodium-glucose co-transporter protein 2 (SGLT-2) inhibitors as exemplars, which may facilitate evaluating its potential outdatedness. We conducted a retrospective cross-sectional study of all Cochrane reviews evaluating the effects of these drugs on cardiovascular disease (CVD) management up to August 2024, summarising the evidence and calculating the lag in time between patient enrolment in trials and current decision-making (August 2024). Results We identified 57 Cochrane reviews on statins, with 9 (15.8%) meeting our criteria, and 6 reviews on SGLT-2 inhibitors, with 2 (33.3%) being eligible. The 9 statin reviews include 153 different trials, enrolling participants from 1988 to 2017, spanning 28 years. The 2 SGLT-2 inhibitor reviews involve 67 trials from 2008 to 2021, spanning 13 years. The median age of evidence for statins is 24.1 years, compared to 8.6 years for SGLT-2 inhibitors. Among the statin review topics, evidence was most robust for statins in the context of primary prevention of CVD. Conclusions Our findings highlight the potential outdatedness of long-established treatments like statins and suggest that reporting the age of evidence in systematic reviews may facilitate outdatedness assessments. We propose that future Cochrane reviews report the age of evidence, as this could significantly enhance the decision-making process in evidence-based medicine.

Background The quality of video content published by oncology media outlets is poorly characterized. We analyzed short form videos discussing oncology trials to determine the methodological rigor of their reporting, whether content invoked shared decision-making principles, and the prevalence of relevant financial conflicts of interest (FCOIs) among speakers. Methods Videos discussing oncology trials published by Oncology Live TV [OncLive TV], Targeted Oncology, and the Video Journal Oncology [VJ Oncology] between January and April 2024 were analyzed. Abstracted data included whether study characteristics, therapy characteristics, treatment recommendations, and shared decision-making principles were discussed. Speakers’ general payment data from 2021 to 2023 were extracted from the U.S. Centers for Medicaid and Medicare Services Open Payments database. Results A majority of the 97 identified videos did not mention inclusion criteria (72%), exclusion criteria (95%), study limitations (81%), study strengths (91%), standard of care (75%), cost (96%), or shared decision-making (91%). Nearly one in five (18%) made specific treatment recommendations, of which only 13% invoked shared decision-making principles. Over half (52%) had speakers who received general payments from an entity with a financial interest in the discussed therapy. Conclusion Digital coverage of oncology trials has gaps in the transparency, methodological rigor, and disclosure of FCOIs, and rarely includes shared decision-making principles—representing a missed opportunity for outlets to disseminate patient-centered, evidence-based information to their audiences. Clear standards for reporting trial and therapy characteristics and FCOI disclosures among oncology media outlets would promote responsible dissemination of emerging evidence and further their mission to promote evidence-based and patient-centered care.

Objective To characterize the speed and nature of National Comprehensive Cancer Network (NCCN) guideline updates following Food and Drug Administration (FDA) approvals and withdrawals. Methods We conducted a retrospective observational study to measure and compare the speed of updates to the NCCN guidelines following FDA cancer approvals and withdrawals between October 2022 and July 2024. We also descriptively analyzed the frequency of specific modifications and levels of recommendations made by the NCCN. Results Of 91 drug indications analyzed, 83 were newly approved, and eight were withdrawn indications. The NCCN incorporated new indications with similar speed regardless of approval pathway (median of 16 days after accelerated approvals vs 20 days after regular approvals; p = 0.59). Notably, the NCCN added or modified 19 approved indications (22.3 %) before FDA approval. Additionally, the NCCN was faster to incorporate approvals than to remove or modify withdrawn indications from its guidelines (19 days vs. 57 days, p = 0.014). Following the official FDA withdrawal of the eight indications in our data set, the NCCN removed only three (37.5 %) from its guidelines and continued to recommend five (62.5 %). Of these five withdrawn indications, the NCCN downgraded three (37.5 %) in recommendation level and left two (25 %) unmodified, endorsing them with a Category 2 A recommendation. Conclusions & Policy Summary We found that the NCCN rapidly incorporated new FDA-approved indications but, delayed updating FDA-withdrawn indications, removing them from guidelines in only a minority of cases. This work highlights a systemic pattern that may drive financial toxicity and suboptimal patient care, underscoring the need for two bodies for the optimal practice of oncologic medicine: one that guides clinicians on all potential treatment options without informing reimbursement coverage, and one that works to usher in cost-effective, evidence-based care to the US market.

This Viewpoint discusses the recent decision by the US Food and Drug Administration to eliminate Risk Evaluation and Mitigation Strategies requirements for chimeric antigen receptor (CAR) T-cell therapies for the treatment of cancer.

Pharmaceutical companies frequently explore previously approved cancer drugs for new indications, which may expose trial participants to uncertain benefit and potential harm. Sorafenib has been investigated across numerous cancer types despite limited evidence supporting many off-label uses. This study evaluates sorafenib’s reported risk–benefit profile in clinical trials published during the past decade. To assess the portfolio of sorafenib trials by examining reported efficacy and safety outcomes over the last ten years. A literature search of bibliographic databases was conducted on May 25, 2023, to identify adult clinical trials evaluating sorafenib’s antitumor activity. Eligible studies were published within the prior decade and reported objective response criteria. Screening and data extraction were performed in duplicate. Extracted variables included trial characteristics, objective response rate (ORR), grade 3–5 adverse event (AE) rates, median progression-free survival, and median overall survival. Primary endpoints were categorized as positive, negative, or indeterminate based on author-defined criteria. Since sorafenib’s most recent FDA approval in 2013, investigators have examined its activity in more than 32 off-label indications. Across 154 trials, 12,226 participants were evaluable for AE grading, with 11,003 grade 3–5 AEs reported. Cumulative trends demonstrated persistently low ORR and increasing cumulative rates of severe AEs over time across off-label indications. This descriptive portfolio review highlights that, across published trials of sorafenib monotherapy in non-FDA-approved indications, reported objective responses were infrequent while severe AEs were common. These findings underscore the importance of transparent reporting and careful consideration of the existing evidence base when designing or interpreting future sorafenib trials in off-label settings. Key words: Sorafenib, Off-label indications, Risk-benefit analysis, Clinical trial portfolio, Adverse events

e23025 Background: Since 1992, accelerated approval (AA) has become the most common pathway for initial approval of cancer drugs. AA relies on early phase studies that use surrogate endpoints, which arrive sooner. Hence, earlier approval can be beneficial for effective drugs but increases the risk that drugs without clinical benefit enter the market. This study aims to analyze the duration from enrollment to approval for the accelerated approval pathway versus regular approval. Methods: This is a retrospective cross-sectional study that analyses of all original and updated clinical trials that led to FDA accelerated or regular approval of cancer-specific drugs from 2022 through 2024. Eligible approvals were identified through FDA notifications. Clinical trials relevant to each approval indication were identified through the corresponding package insert. Total study duration and time from first enrollment to data cutoff were the primary study outcomes. Univariate linear regression was utilized to assess outcomes and results were stratified by primary tumor type, phase of trial that led to approval, and type of drug approved. Results: In total, 142 distinct indications among 136 drugs approved for treatment of solid and hematologic malignant neoplasms were identified from 2022 through 2024. Of the 136 drugs approved, 35 received AA and 101 received regular approval. Studies receiving AA required on average 250 fewer patients per trial to report a difference in primary outcome (p<0.001). Drugs receiving AA required on average 77 more months (6.4 years) to reach data cutoff from first patient enrollment than those receiving regular approval (p=0.028). When utilizing surrogate endpoints, drugs receiving AA reached data cutoff in an average of 122 months while drugs receiving regular approval reached data cutoff in an average of 45 months (difference of 76 months, p=0.059). While not statistically significant, it was noted that AA approvals took 62 fewer months to reach approval from data cutoff. Conclusions: Our findings suggest that, among clinical trials leading to FDA approval of cancer drugs from 2022 through 2024, use of surrogate endpoints was associated with a 20-day shorter length of study, and use of the AA pathway was associated with a 15 month longer total study duration. In the context of previous analyses suggesting shortened development time when utilizing the AA pathway, this reversal in recent approvals along with the greater uncertainty regarding the clinical benefit of surrogate endpoints deserves further scrutiny.

Smoldering multiple myeloma (SMM) represents a biological continuum between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), and not all individuals with smoldering disease will progress to symptomatic multiple myeloma. The AQUILA trial compared daratumumab with active monitoring in high-risk SMM and led to regulatory approvals and guideline updates. However, several challenges complicate interpretation of contemporary trials, including QuiRedex (lenalidomide-dexamethasone) and ECOG E3A06 (lenalidomide). Progression definitions differ across studies. Progression-free survival (PFS) in SMM reflects progression to MM using the hypercalcemia, renal dysfunction, anemia, and bone disease (CRAB) criteria, but AQUILA uniquely included the "SLiM" biomarkers. Presymptomatic disease constituted most progression events, and the clinical benefit of delaying progression to SLiM multiple myeloma remains unknown. Imaging frequency and modality also vary, with advanced imaging in AQUILA increasing detection of asymptomatic lesions and limiting comparability with prior trials. AQUILA is further affected by concerns about informative censoring. In open-label trials, patient dropouts may not occur at random, and reconstructed Kaplan-Meier analyses and sensitivity analyses indicate that modest changes in censoring assumptions could eliminate the appearance of an OS advantage. Additionally, OS was a secondary endpoint in AQUILA and in previous trials, and none of which were powered for survival. Overall, before stronger clinical evidence showing otherwise, observation including appropriate surveillance should remain the standard of care for high-risk smoldering multiple myeloma.

Preexisting health conditions complicate post–COVID condition diagnosis in children and adolescents, while the lack of standardized clinical phenotypes challenges its definition and epidemiological estimates. Prospective studies with robust methodologies are needed to minimize bias and confounders, yet they remain scarce in high-impact factor journals. To review, characterize, and assess the methodology used in studies examining post–COVID condition in children and pediatric populations in highly cited studies, which have greater visibility and are likely to be used in informing policy. Studies on PubMed and studies with high citations on Web of Science published through July 2024 were reviewed. Pediatric studies from journals with an impact factor of 5 or higher were included if they employed observational or risk-benefit designs. Studies were classified based on whether they included a SARS-CoV-2 test-negative control group or a non–test-negative group, which included studies with either no comparator or a different type of comparator. Joanna Briggs Institute and Risk of Bias in Nonrandomized Studies of Exposures tools assessed the risk of bias. Of 426 publications, 24 were analyzed; 9 studies (38%) used test-negative controls, while 15 studies (63%) did not (P < .001). Among studies with test-negative groups, 4 (44%) used prospective cohort designs vs 5 (33%) studies without a test-negative group. Demographic reporting of post–COVID condition cases varied. Sex was reported in 12 studies (50%), but the median (IQR) sample size was small (27 female patients [14-110]; 21 male patients [10-79]). Psychiatric history was often not reported (20 patients [83%]), as well as a lack of history of comorbidities (16 patients [67%]) or body mass index (15 patients [63%]). Among 9 test-negative control studies, 4 (44%) used matched control design, while only 1 (11%) accounted for confounders by sex-stratifying results. These findings highlight the need for rigorous study designs that minimize bias and confounding, ensuring a clearer definition of pediatric post–COVID condition and its sequelae. Employing true test-negative matched controls is essential for distinguishing common symptoms and assessing risk factors, while standardizing demographic reporting strengthens comparability and ensures consistency in patient selection.

Though vascular endothelial growth factor receptor (VEGFR)-targeting drugs have been approved in the past and are known for their potential off-site action, fruquintinib is a possible new, specific inhibitor of VEGFR-1, 2, and 3. The US Food and Drug Administration (FDA) recently approved fruquintinib based on the FRESCO-2 trial results. However, the FRESCO-2 trial is potentially problematic given the suboptimal choice of placebo in the trial, and the poor cost-effectiveness of fruquintinib. Firstly, we argue that fruquintinib should have been tested against regorafenib, and only offered a moderate benefit despite being tested against a suboptimal placebo. Secondly, fruquintinib is likely cost ineffective (measured in quality-adjusted life years (QALY)), with a crude estimation placing its value over a million USD per QALY. Lastly, we show that the use of a suboptimal placebo is unfortunately not new.

BACKGROUND:The risk of cancer increases as people age, and yet, participants in oncology clinical trials have historically been younger than those in the general population with the respective tumor type, thus limiting our understanding of the safety and efficacy of trial results in the real world. The US Food and Drug Administration (FDA) has issued guidance on multiple occasions on the inclusion of older adults in clinical trials. We sought to evaluate whether there has been progress in the representativeness of older adults in oncology trials. METHODS:For oncology drug approvals since 2002, we searched for registration trials and collected data on the median age of study participants. We then searched SEER*Explorer to find the median age of the general population with the respective cancer type. We assessed linear trends to see if there were age gaps between the median ages of trial participants and SEER participants, and we assessed differences in time frames when guidance was issued. RESULTS:The age gap between registration trials and SEER data for all 22 years was 5 years (62 years for registration trials vs. 67 years for SEER). The age gap has declined over time (Beta = -0.22, p = 0.004) but still persists. Between 2002 and 2012, the age gap between registration trials and the SEER population was 7 years (59 vs. 66 years, p < 0.001); between 2013 and 2019, it was 5 years (62 vs. 67 years, p < 0.001); and between 2020 and 2024, the age gap was 4 years (63 vs. 67 years, p < 0.001). CONCLUSION:We found that the age gap between registration trial participants and the general population with the respective tumor type has declined over time, but the age-gap persists, despite guidance issued by the FDA. Efforts to include more representative study participants in clinical trials should be intensified, possibly through greater enforcement through regulatory oversight.

On 12 April 2024, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted (12-0) in support of minimal residual disease (MRD) as an accelerated approval endpoint for newly diagnosed multiple myeloma. MRD negativity in myeloma, defined by the IWMG, refers to bone marrow flow cytometry at specified time points after treatment which fail to detect malignant cells below some threshold (The ODAC discussed below < 10-5). The committee's rationale was based on data showing that MRD is prognostic- i.e. patients who achieve MRD negativity do better than those who do not- and that this endpoint is demonstrated months or years before progression free survival- the current criteria for FDA approval. While MRD promises to bring more drugs to patients sooner and earlier in the course of disease, we outline five open questions. Ultimately, providers and patients will have to consider whether they are willing to alter treatments based on MRD negativity or if further safety or efficacy data is desired.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have transformed the landscape of tumor therapy. Yet, little is known about the collective long-term survival from these therapies. We sought to characterize long-term survival. METHODS:In a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we retrieved data from supporting registration trials. We examined the percentage of study participants surviving at 12-, 24-, 36-, and 60-months follow-up; the American Society of Clinical Oncology (ASCO) Value Framework Tail of the Curve calculation; and the correlation between the longest time with 10 % of patients still at-risk and the difference in the percentage of patients in each treatment group alive. RESULTS:Out of 88 included approvals, 20 (22.7 %) qualified for ASCO's tail of the curve bonus. Twenty-seven studies (30.7 %) did not report OS at 12 months; 44 (50.0 %) did not report OS at 24 months; 60 (68.2 %) did not report OS at 36 months; and 78 (88.6 %) did not report OS at 60 months. We found no correlation between the last time that at least 10 % of patients were still at-risk and the difference in the percentage of patients in each group still alive at that time-point (R2=0.1; p = 0.30). Among 81 studies that reported an OS curve, the longest time with at least 10 % of participants at-risk was a median of 30 months. The median difference in survival was 8 %. CONCLUSIONS:Few registration trials testing ICI oncology therapies report long-term overall survival data. The gathering and reporting of this information should be incentivized so that the value of these drugs for patients can be more readily assessed.

Patient visitor restrictions were implemented in unprecedented ways during the COVID-19 pandemic and included bans on any visitors to dying patients and bans separating mothers from infants. These were implemented without high quality evidence they would be beneficial and the harms to patients, families and medical personnel were often immediately clear. Evidence has also accumulated finding strict visitor restrictions were accompanied by long-term individual and societal consequences. We highlight numerous examples of restrictions that were enacted during the COVID-19 pandemic, including some that continue to be in place today. We outline six specific concerns about the nature and effects of the visitor restrictions seen during the COVID-19 pandemic. These considerations may help provide both an ethical and science-based framework, through which healthcare workers, families and government entities can work towards safeguarding patient and family rights and well-being.

Newspaper journalists are viewed as important purveyors of information—information that should be unbiased, especially in times of uncertainty. We sought to examine the corrections in the New York Times (NYT) and assess if there is an imbalance towards overstating the pandemic severity, which may support more extreme measures. In our cross-sectional analysis of COVID-19 articles that had corrections reported in the NYT “corrections page”, we assessed the number and type of corrections by author type (NYT reporter, NYT other, and independent author) and number and percentage of corrections indicating an over- or under-statement of the COVID-19 situation. Compared to non-COVID-19 corrections, COVID-19 corrections were less likely to result in an equivocal tone, but they were more likely to both overstate and understate the situation in the original text . Multiple reporters accounted for one-quarter of corrections. Differential tone of the corrections suggests bias in the reporting of COVID-19 topics in a top news outlet. The reporting of unbiased information is a first step in addressing issues of misinformation in public health messaging.

BACKGROUND:Vemurafenib (Zelboraf®, Roche), approved by the FDA in 2011 for unresectable and metastatic melanoma and Erdheim-Chester Disease, has been explored in trials for other BRAF-mutated cancers. Despite 12 years of clinical use, the risk-benefit profile for off-label indications remain unclear. RESEARCH DESIGN AND METHODS:This study systematically reviewed clinical trials utilizing vemurafenib in adult malignancies, with responses assessed using RECIST or similar criteria. On May 25, 2023, we searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov. Screening and data extraction were performed in a masked, duplicate fashion, collecting data on trial characteristics, adverse events, progression-free survival, overall survival, and objective response rates. RESULTS:Vemurafenib was tested in 15 cancers beyond its FDA-approved indications. A 0% complete response rate was observed in colorectal cancer, non-small cell lung cancer, and papillary thyroid cancer. Adverse events were more frequent in non-melanoma cancers, with 5,205 grade 3-5 events reported, equating to two severe events for every three participants. Only metastatic melanoma consistently demonstrated efficacy, aligning with its FDA approval. CONCLUSIONS:Although vemurafenib showed efficacy in metastatic melanoma, off-label use resulted in limited benefit and increased adverse events. Unclear endpoints and underreported adverse events highlight the need for improved clinical trial design.

BackgroundProfessional medical organizations publish policy statements that are used to impact legislation or address societal issues. Many organizations are nonpartisan, yet it is uncertain whether their policy statements balance liberal and conservative values. ObjectiveThis study aims to evaluate the political viewpoint of policy statements from 6 influential medical organizations, including the American Academy of Pediatrics, American College of Surgeons, American Psychiatric Association, American College of Obstetricians and Gynecologists, American College of Physicians, and American Academy of Family Physicians. MethodsBetween December 2023 and February 2024, policy statements from the 6 organizations were identified and evaluated using ChatGPT with GPT-4 to reduce bias. Each statement was pasted into a new ChatGPT session following the phrase “Does this text align with a liberal or conservative viewpoint?” Two authors reviewed each response and categorized the statement as liberal, probably liberal, neutral, probably conservative, or conservative. ResultsOne-third of policy statements (529/1592, 33.2%) were found to be aligned with a political ideology. Among these 529 statements, 516 (97.5%) were liberal or probably liberal and 13 (2.5%) were conservative or probably conservative. For each organization, among policy statements with a political leaning, the percentage of liberal or probably liberal statements was as follows: 100% (69/69) for the American Academy of Pediatrics, 100% (24/24) for the American College of Obstetricians and Gynecologists, 100% (12/12) for the American College of Surgeons, 99% (72/73) for the American Psychiatric Association, 97% (174/180) for the American Academy of Family Physicians, and 96% (165/171) for the American College of Physicians. ConclusionsOne in 3 policy statements from these 6 professional organizations align with a partisan political viewpoint. Among these, positions are 40 times more likely to be liberal or probably liberal than conservative or probably conservative. Whether or not organizations are politically neutral and seek viewpoint diversity warrants further exploration.

In 2018, we estimated that eligibility for and response to immune checkpoint inhibitor (ICI) therapies were 44% and 12%, respectively. Since these estimates were published, there have been additional approvals. We sought to provide updated estimates of the percentage of patients with advanced and/or metastatic cancers in the US who are eligible for and respond to immune checkpoint inhibitors (ICIs). Using a cross-sectional analysis (2011-2023) of US Food and Drug Administration approvals (FDA) and deaths reported by the American Cancer Society, we estimated the percentage of patients in the US with advanced or metastatic cancers who are eligible and respond to ICI therapies and the long-term response of ICI drugs. Eleven ICI drugs have been approved for 20 tumor types in the metastatic setting. The estimated eligibility for ICIs increased from 1.54% in 2011 to 56.55% in 2023. The estimated response to ICIs increased from 0.14% in 2011 to 20.13% in 2023. The tumor types with the highest contribution to response and eligibility estimates in 2023 were non-small-cell lung cancer with PD-L1 expression ≤50% and PD-L1 expression >50%. Sixteen drug approvals had long-term progression-free survival (PFS) data available at 3 years follow-up, and 2 had PFS data at 5 years follow-up. Estimated eligibility and response have increased over time, but many people with advanced or metastatic cancers are currently ineligible for ICIs. Only about one-fifth of the patients will respond. Given the wide range of uses, the cost implications of ICIs globally are large.