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.

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.