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.

The top sports medicine influencers on X (formerly Twitter).

BACKGROUND: With increasing sports medicine content on social media, we sought to identify the top sports medicine influencers on X (formerly Twitter) and analyse their common characteristics. METHODS: X influence scores for "Sports Medicine" were collected in November 2021 from Right Relevance. Accounts were then screened in a blind, duplicate manner for personal and X profile characteristics. RESULTS: Physical therapists/physiotherapists made up 48% of the top sports science and medicine influencers. Locations in the U.S. and U.K. were listed for half of the influencers. The mean h-index was 30.2 (95% CI = [24.8-35.6]) with a median of 22.0 (range = 1-101). Most individuals reported multiple practice settings (63%), with 60% associated with an academic setting. Professional (62%) and Olympic (49%) level athletics were most frequently mentioned, with soccer (48%) and rugby (30%) as the most common sports. Among 76 profiles with URLs, most were linked to personal websites (57.9%). CONCLUSION: The top influencers on X consisted of accredited sports science and medicine professionals across various locations and occupations, providing ample networking and collaboration opportunities. The relatively high h-index in this study suggests sports science and medicine influencers on X are notable contributors to academic literature.

Suburban firefighter perceptions of health and wellness using patient-reported outcome measures.

BACKGROUND: Firefighting is among the most dangerous professions and requires exceptional physical fitness and focus while working. Patient-reported outcomes are a commonly used method to evaluate subjective health information and may be utilized by fire departments to identify the health status of firefighters and provide insight to promote their health and wellness. OBJECTIVE: This study is a novel analysis of firefighters' self-reported health to potentially identify musculoskeletal dysfunction, assist in therapeutic intervention, and improve overall health and wellness. METHODS: Firefighters were evaluated using seven different self-reported health surveys to assess various physical capabilities and quality of life. The questionnaires were delivered via online format and administered once to provide a snapshot of a suburban Oklahoma fire department. RESULTS: Using the Disablement in the Physically Active Scale, 14 of the 35 firefighters answered "slight, moderate, or severe" for the pain and motion variables. Only two of the firefighters indicated no stiffness or soreness after activity on the Nirschl Phase Rating Scale. The firefighters mean rating for "energy/fatigue" via the RAND-36 was 54.14 out of 100. CONCLUSION: Firefighters frequently report pain, impaired motion, and soreness, indicating areas in which health and wellness interventions may be helpful. The incorporation of periodic health surveys into firefighter health and wellness programming can highlight the presence of concerns, as well as intervention effectiveness by subjective health status reporting. By combining the health surveys with aerobic and core strength exercises, fire departments may be able to monitor and improve firefighter health.

Evaluating reporting of patient-reported outcomes in randomized controlled trials regarding inflammatory bowel disease: a methodological study.

Patient-reported outcomes (PROs) in randomized controlled trials pertaining to inflammatory bowel disease are important in identifying patients' perspective of treatment. Incompletely reported PROs within trials could misrepresent information for clinicians and may contribute to treatment which lacks accommodation of patient input. Our study evaluates completeness of reporting of PROs and risk of bias (RoB) to identify how well trialists are adhering to known resources for trials. We used MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify eligible trials from 2006 to 2020 with at least 1 PRO measure related to inflammatory bowel disease. The trials were screened in duplicate using Rayyan. We then compared trial completion of reporting to the Consolidated Standards of Reporting Trials (CONSORT)-PRO adaptation, and assessed RoB using the Cochrane Collaboration RoB 2.0 tool. To measure trial and reporting characteristics, we performed bivariate regression analyses. Among a sample of 29 trials, the mean completion percentage for CONSORT-PRO was 46.77%. We found PROs as a secondary outcome had significantly lower CONSORT-PRO reporting (p<0.05). In addition, per cent completeness of reporting was significantly higher with both a 'therapy' intervention, and trials published following the development of CONSORT-PRO (p<0.05). Incomplete PRO reporting is common in trials focused on inflammatory bowel disease. This suboptimal reporting indicates the need for adherence to reporting guidelines. Trialists should use the CONSORT-PRO checklist, as endorsed by Patient-Reported Outcomes Tools: Engaging Users and Stakeholders, to assess their studies in order to enhance reporting adherence.

Quality of reporting among systematic reviews underpinning the ESC/ACC guidelines on ventricular arrhythmias and sudden cardiac death.

OBJECTIVES: The main objective of this study was to assess the methodological and reporting quality of the systematic reviews (SRs) supporting the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) clinical practice guidelines (CPGs) recommendations for the management of patients with ventricular arrhythmias and sudden cardiac death (SCD). As a secondary objective, we sought to determine: (1) the proportion of Cochrane SRs were cited; and (2) whether Cochrane SRs scored higher on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) appraisals. DESIGN: Cross-sectional analysis. MAIN OUTCOME MEASURES: We searched for CPGs published by the ESC and the ACC from 2010 to 2020. We selected the CPGs for ventricular arrhythmias and the prevention of SCD. The reference sections were searched for SRs. Two independent investigators evaluated eligible SR using the PRISMA checklist and the AMSTAR-2 assessment tool. RESULTS: Two CPGs for ventricular arrhythmia and SCD were included in this study. Fifty-five SRs were included in our analysis. Across all SRs, the mean PRISMA score was 0.70. The lowest scoring PRISMA item related to the presence of a pre-published protocol (item 5, score 0.17). Overall, 40% of included SRs were found to have 'critically low' AMSTAR-2 ratings. One of the lowest scoring items for AMSTAR-2 was reporting of sources of funding (item 10). The 4 Cochrane SRs that were included scored higher on both assessment tools than non-Cochrane studies, specifically in PRISMA overall completion (88.7% vs 69.7%). CONCLUSION: Our study suggests the methodological and reporting quality of SRs used within ESC and ACC CPGs is insufficient, as demonstrated by the lack of adherence to both AMSTAR-2 and PRISMA checklists. Given the importance of CPGs on clinical decision making, and ultimately patient care, the methodological rigour and quality reporting within SRs used in CPGs should be held to the highest standard within the field of cardiology.

An Evaluation of Evidence Underpinning Management Recommendations in Tobacco Use Disorder Clinical Practice Guidelines.

INTRODUCTION: Clinical practice guidelines(CPGs) are important tools for medical decision-making. Given the high prevalence and financial burden associated with tobacco use disorder(TUD), it is critical that recommendations within CPGs are based on robust evidence. Systematic reviews(SRs) are considered the highest level of evidence, thus, we evaluated the quality of SRs underpinning CPG recommendations for TUD. METHODS: We used PubMed to search for CPGs relating to TUD published between January 1, 2010 and May 21, 2021. SRs were extracted from CPG references and evaluated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) and A MeaSurement Tool to Assess Systematic Reviews(AMSTAR-2) tools. We then compared SRs conducted by the Cochrane Collaboration with non-Cochrane SRs using a Mann-Whitney U test and determined associations between PRISMA and AMSTAR-2 extracted characteristics using multiple regression. RESULTS: Our search generated 10 CPGs with 98 SRs extracted. Mean PRISMA completion was 74.7%(SD = 16.7) and mean AMSTAR-2 completion was 53.8%(SD = 22.0) across all guidelines. Cochrane SRs were more complete than non-Cochrane studies in the PRISMA and AMSTAR-2 assessments. The regression model showed a statistically significant association between PRISMA completion and AMSTAR-2 rating, with those classified as "low" or "moderate" quality having higher PRISMA completion than those with "critically low" ratings. CONCLUSION: We found substandard adherence to PRISMA and AMSTAR-2 checklists across SRs cited in TUD CPGs. A lack of recent SRs in CPGs could lead to outdated recommendations. Therefore, frequent guideline updates with recently published evidence may ensure more accurate clinical recommendations and improve patient care. IMPLICATIONS: Systematic reviews used to underpin clinical practice guideline recommendations influence treatment decisions and, ultimately, patient outcomes. We found that many systematic reviews underpinning tobacco use disorder guideline recommendations were out of date and unsatisfactory in reporting and quality. Thus, including newer systematic reviews containing more recently conducted trials and better reporting could alter recommendations and improve the rate of successful tobacco cessation attempts.