Assessing Patient Risk, Benefit, and Outcomes in Drug Development: Insights From Afatinib Clinical Trials Across Diverse Cancer Indications.

PURPOSE: In 2013, afatinib was approved for non-small-cell lung cancer with subsequent indication expansion. We investigated published afatinib clinical trials to assess risk and benefit profiles for the drug in its approved indication of non-small-cell lung cancer as well as in off-label uses. Previous literature demonstrates excessive patient burden and limited benefit as afatinib has spread into more indications. A trial analysis is needed to establish efficacy and risk. METHODS: In this investigation, we screened literature databases and clinical trial registries for trials of afatinib as monotherapy or in combination interventions for cancer treatment. We extracted participant demographics, adverse event characteristics, as well as clinical and surrogate endpoints for each trial. Studies were deemed positive, negative, or indeterminate based on their achieving of primary endpoints as well as their safety. RESULTS: Our search yielded 2444 articles; we excluded 2352 articles for a final inclusion of 92 trials of 8859 patients. Our sample had 49 (53%) positive trials, 27 (29%) negative trials, and 16 (17%) indeterminate trials. The most common off-label indications for afatinib were breast cancer and squamous cell carcinoma of head and neck. The median OS for all trials was 8.4 months, median PFS 3.4 months, and the total ORR was 29.6%. Our study found that trials performed in disease states beyond the initial indications were largely negative with little patient benefit. The adverse events within our trial sample appear to be in line with expectations for toxicity. IMPLICATIONS: These results are consistent with other studies that present similar findings, such as in Carlisle et al which indicate limited efficacy in nonapproved indications. Future trials should keep this potential evidence and patient burden in mind before initiation of those trials. This study contributes to the understanding of afatinib's risk-benefit profile across many clinical applications.

Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials.

OBJECTIVE: This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. BACKGROUND: The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. METHODS: On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. RESULTS: Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. CONCLUSION: We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Lenvatinib Clinical Trials: A Systematic Review.

IMPORTANCE: Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. OBJECTIVE: This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. EVIDENCE REVIEW: On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). FINDINGS: Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. CONCLUSION AND RELEVANCE: Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

Reporting of Harms in Randomized Controlled Trials Published in Urology Journals: An Updated Analysis.

PURPOSE: Harms are often overlooked, but important, outcomes of randomized controlled trial reporting. Our goal was to determine if harms reporting has improved in high-impact urology journals. MATERIALS AND METHODS: Randomized controlled trials published in The Journal of Urology®, Urology, European Urology, and BJU International in 2012 and 2020 were analyzed. Each randomized controlled trial was evaluated by 2 authors in a masked-duplicate fashion to evaluate for adherence to harms reporting guidelines recommended by the Consolidated Standards of Reporting Trials (CONSORT) group. RESULTS: One hundred and thirty-two published studies met inclusion criteria. Between 2012 and 2020, there was a statistically significant increase in the median number of harms criteria reported between 2012 and 2020 (5.3 vs 7.2; P = .01). Methods criteria demonstrating the greatest improvements included item #3 "which harms were assessed," item #4a "when harm information was collected," and item #4b "methods to attribute harm to intervention." Results sections with the most improvement in reporting include item #6 "reasons for patient withdrawal," item #8a "effect size for harms," and item #8b "stratified serious + minor harms." CONCLUSIONS: Reporting of adverse events in randomized trials published in several top urology journals has demonstrated marked improvement. Studies published in 2020 reported approximately 70% of CONSORT-Harms criteria-an increase of nearly 40% since 2004. While these improvements mark significant change, deficits remain present and should be addressed to provide clinicians with the most complete perspective possible.

Health inequities in dialysis care: A scoping review.

MAIN PROBLEM: We aim to look at potential gaps in current dialysis literature on inequities and explore future research that could contribute to more equitable care. METHODS: Following guidelines from the Joanna Briggs Institute (JBI) and the Preferred Reporting Items for Systematic reviews and Meta Analyses extension for Scoping Reviews (PRISMA-ScR), we conducted a scoping review of health inequities in dialysis. PubMed and Ovid Embase were searched in July 2022 for articles published between 2016 and 2022 that examined at least one of the following NIH defined health inequities: race/ethnicity, sex/gender, LGBTQ+ identity, underserved rural populations, education level, income, and occupation status. Frequencies of each health inequity as well as trends over time of the four most examined inequities were analyzed. RESULTS: In our sample of 69 included studies, gaps were identified in LGBTQ+ identity and patient education. Inequities pertaining to race/ethnicity, sex/gender, underserved rural populations, and income were sufficiently reported. No trends between inequities investigated over time were identified. CONCLUSIONS: Our scoping review examined current literature on health inequities pertaining to dialysis and found gaps concerning LGBTQ+ and patients with lower levels of education. To help fill these gaps, and possibly alleviate additional burden to these patients, we recommend cultural competency training for providers and dialysis center staff as well as community-based educational programs to improve dialysis patients' health literacy.

Obesity, stigma, and person-centered language: A serial cross-sectional analysis of scientific literature.

OBJECTIVE: Language can influence societal perceptions of medical conditions. The employment of person-centered language (PCL) in health care is reflected in many scientific publications; however, the extent of this adaptation in reference to obesity is unknown. METHODS: This cross-sectional analysis included a systematic search of PubMed obesity-related articles across four cohorts spanning January 2004 through December 2006; January 2008 through December 2010; January 2015 through December 2018; and January 2019 through May 2020, respectively. Approximately 1971 publications were screened and examined for prespecified, non-PCL terminology set forth by the American Medical Association Manual of Style and the International Committee of Medical Journal Editors, of which 991 were retained. Statistical analysis demonstrating PCL and non-PCL findings was then performed. Incidence rates and cohort classifications were reported. RESULTS: Of the 991 articles examined, it was found that 24.02% of publications adhered to PCL. Similar adherence was observed across obesity-specific, general medicine, and nutrition journals. PCL adherence increased over time. The most common non-PCL label was "obese," occurring in 75.48% of articles. CONCLUSIONS: This investigation showed that non-PCL in reference to obesity is widely evident in weight-focused journals despite recommendations for adherence to PCL guidelines. Continued use of non-PCL in reference to obesity in research may inadvertently perpetuate weight-based stigma and health disparities in future generations.

Factors associated with health inequities in access to kidney transplantation in the USA: A scoping review.

BACKGROUND: The kidney is the most needed organ for transplantation in the United States. However, demand and scarcity of this organ has caused significant inequities for historically marginalized groups. In this review, we report on the frequency of inequities in all steps of kidney transplantation from 2016 to 2022. Search criteria was based on the National Institute of Health's (NIH) 2022 list of populations who experience health inequities, which includes: race and ethnicity; sex or gender; Lesbian, Gay, Bisexual, Transgender, Queer + (LGBTQ+); underserved rural communities; education level; income; and occupation status. We outline steps for future research aimed at assessing interventions and programs to improve health outcomes. METHODS: This scoping review was developed following guidelines from the Joanna Briggs Institute and PRISMA extension for scoping reviews. In July 2022, we searched Medline (via PubMed) and Ovid Embase databases to identify articles addressing inequities in access to kidney transplantation in the United States. Articles had to address at least one of the NIH's 2022 health inequity groups. RESULTS: Our sample of 44 studies indicate that Black race, female sex or gender, and low socioeconomic status are negatively associated with referral, evaluation, and waitlisting for kidney transplantation. Furthermore, only two studies from our sample investigated LGBTQ+ identity since the NIH's addition of SGM in 2016 regarding access to transplantation. Lastly, we found no detectable trend in studies for the four most investigated inequity groups between 2016 and 2022. CONCLUSION: Investigations in inequities for access to kidney transplantation for the two most studied groups, race/ethnicity and sex or gender, have shown no change in frequencies. Regarding race and ethnicity, continued interventions focused on educating Black patients and staff of dialysis facilities may increase transplant rates. Studies aimed at assessing effectiveness of the Kidney Paired Donation program are highly warranted due to incompatibility problems in female patients. The sparse representation for the LGBTQ+ population may be due to a lack of standardized data collection for sexual orientation. We recommend this community be engaged via surveys and further investigations.

What's in a P-Value? A Fragility Analysis of RCTs in the AUA Guidelines for Benign Prostatic Hyperplasia.

OBJECTIVE: To use the fragility index (FI) and fragility quotient (FQ) to assess the strength of statistically significant findings for randomized controlled trials (RCTs) cited in the American Urological Association (AUA) guidelines for benign prostatic hyperplasia. METHODS: Two investigators independently screened the AUA guidelines for management of benign prostatic hyperplasia for RCTs cited as evidence for recommendations. Investigators extracted data related to event rate per group and loss to follow-up which was compared against the FI. Stata 17.0 was used to calculate the FI and FQ which was then summarized and reported according to primary or secondary endpoints. RESULTS: Among the 373 citations in the AUA guidelines, 24 RCTs met inclusion criteria with 29 distinct outcomes analyzed. The median fragility index was 12 (IQR = 4-38), indicating that twelve alternative events to either study arm would nullify statistical significance. Six studies had a FI of ≤2, indicating that only 1-2 outcomes would need to be changed in order to render nonsignificance of results. In 10/24 RCTs, the number of patients lost to follow-up was greater than the FI. CONCLUSION: The AUA Clinical Practice Guidelines for management of benign prostatic hyperplasia cite RCTs with more robust findings when compared to previous studies assessing fragility in the field of Urology. While several included studies had high fragility, the median FI in our analysis was approximately 4-5 times higher than comparable studies of urologic RCTs. However, there are areas where improvement is necessary to support the highest quality of evidence-based medicine.

Health inequities in human papillomavirus prevention, diagnostics and clinical care in the USA: a scoping review.

BACKGROUND: Human papillomavirus (HPV) represents the most common STI in the USA. HPV inequities in prevention, diagnostics and clinical care persist. We define inequities as systematic, avoidable and unfair differences in health outcomes. OBJECTIVES: The objectives of this scoping review are to chart existing data on HPV-related inequities, identify gaps in existing literature and guide future research to reduce these inequities. METHODS: We completed a scoping review following guidelines from the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping reviews extension. We performed a literature search on PubMed and Ovid Embase in July 2022 for articles pertaining to HPV and evaluating populations within the USA. We included English language publications from 2018 to 2022 evaluating at least one health inequity outlined by the National Institutes of Health. General publication characteristics and health inequity data were charted in a masked, duplicate fashion using a pilot-tested Google Form. We analysed frequencies of health inequities and summarised main findings from included studies. RESULTS: Our final sample included 170 publications. The most common inequities examined were race/ethnicity (140 studies), sex or gender (97 studies), and income (69 studies). Many historically marginalised racial/ethnic groups had lower rates of HPV-related knowledge, vaccination and worse overall outcomes related to HPV. Compared with women, men had lower rates of HPV vaccination and provider recommendation, and higher rates of HPV-infection. Results regarding income were largely conflicting. CONCLUSION: Findings from our review demonstrate clear gaps in HPV-related inequity research. Vaccine completion, provider recommendation and intersectionality should continue to be evaluated to implement targeted interventions.

Evaluating The Reporting of Patient-Reported Outcomes in Surgical Management of Stress Urinary Incontinence in Women: An Analysis of Randomized Controlled Trials.

BACKGROUND: Stress urinary incontinence (SUI) significantly reduces women's quality of life (QoL). Use of patient-reported outcomes (PROs) is increasing in randomized controlled trials (RCTs), thus standardization is important to ensure reporting completeness. We aim to evaluate completeness of reporting of RCTs for surgical management of SUI in women based on an adaptation of the Consolidated Standards of Reporting Trials statement with PRO extension (CONSORT-PRO). STUDY DESIGN: A literature search was conducted and all RCTs meeting inclusion criteria were evaluated using the CONSORT-PRO adapted checklist and the Cochrane Collaboration risk of bias assessment tool (RoB). We calculated a completion percentage score for each trial's adherence to the CONSORT-PRO adapted checklist and used bivariate regression analysis to examine associations between trial characteristics and completion percentage scores. RESULTS: Forty-three RCTs underwent data extraction and analysis. Mean completion percentage of the CONSORT-PRO was 50.53% (SD = 15.63). A total of 38 (of 43; 88.37%) RCTs received an RoB 2.0 rating of "some concern." RCTs with follow-up longer than 3 months had statistically significantly higher CONSORT-PRO completion: 3-6 months (p = .049), 6-12 months (p = .009), more than 12 months (p = .021). Compared with studies without a conflict of interest statement, studies reporting a conflict of interest (p < .001) or reporting no conflict of interest (p = .048) had higher reporting completeness. CONCLUSIONS: Our results suggest many RCTs addressing surgical management of SUI in women have poor adherence to CONSORT-PRO reporting guidelines. Improving reporting completeness through adherence to the CONSORT-PRO checklist can better inform clinical decision making and improve QoL.

An Analysis of the Evidence Underpinning the American Urologic Association Clinical Practice Guidelines.

OBJECTIVE: To evaluate the reporting quality of systematic reviews (SRs) underpinning the American Urologic Association (AUA) clinical practice guidelines (CPGs). METHODS: We searched the AUA for CPGs from 2015-2021. We extracted all SRs from the reference sections and two independent investigators evaluated eligible SR/meta-analysis using the PRISMA (Preferred Reporting Instrument for Systematic Reviews and Meta-Analyses) and AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews 2) instruments. We compared SRs conducted by the Cochrane group to non-Cochrane SRs using a Mann-Whitney test. A multivariate regression was used to compare study characteristics. RESULTS: Eighteen CPG's met inclusion criteria. We extracted 120 unique SRs, which accounted for 5.1% (n = 120/2346) of all citations. Mean percent adherence to PRISMA and AMSTAR-2 was 65.4% -d 55.2% respectively. SRs conducted by the Cochrane Collaboration scored higher on AMSTAR-2 compared to non-Cochrane (z = -4.41, P <.01) and a positive correlation between PRISMA and AMSTAR-2 scores (r = 0.56, P <.001) was determined. CONCLUSION: Our study indicated the quality of SRs used to develop AUA CPGs across both PRISMA and AMSTAR-2 was variable. Despite higher evaluations, Cochrane SRs accounted for less than 15% of SRs underpinning CPG recommendations. Given the importance placed on CPGs within clinical practice, we recommended a synergistic relationship between the AUA and the Cochrane Collaboration to increase the number of quality urologic SRs.