Sujata Purja

Background: Adaptive designs are increasingly employed to improve trial efficiency; however, their benefits over fixed designs in late-phase oncology trials remain underexplored. We aimed to determine whether adaptive designs in phase 3 cancer trials are associated with primary completion time and primary endpoint success compared with fixed designs. Methods: This cross-sectional study analyzed phase 3 randomized lung and breast cancer trials initiated between 2000 and 2020 using Aggregate Analysis of ClinicalTrials.gov database (static version downloaded April 15, 2025). Eligible trials had time-to-event primary endpoints and were completed or terminated. Trials were classified as adaptive or nonadaptive based on preplanned design modifications. Associations between trial design and primary completion time were examined using Kaplan–Meier curves and multivariable cause-specific Cox regression, while associations between trial design and primary endpoint success were examined using multivariable logistic regression. Results: Of 421 eligible trials, 210 employed adaptive designs. Adoption of adaptive designs increased over time, with group-sequential designs being the most common adaptive approach. Adaptive designs showed earlier primary completion, but no statistically significant association was observed after multivariable adjustment. Adaptive trials had higher hazards of early stopping for efficacy or futility and lower hazards of administrative termination. Among 396 trials with available results, 163 achieved primary endpoint success. Adaptive trials had higher odds of success than nonadaptive trials (66.26% vs 33.74%; odds ratio [OR] = 2.363, 95% CI = 1.491 to 3.778; P < .001). Conclusions: Adaptive designs were associated with higher primary endpoint success but not shorter primary completion time. Given high failure rates in late-phase oncology, adaptive designs may improve efficiency primarily by facilitating data-driven decisions rather than accelerating trial timelines.

Vancomycin is the standard therapy for suspected or confirmed Methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI). Although newer anti-MRSA agents claim improved efficacy and safety, evidence in microbiologically confirmed MRSA-SSTI remains limited and heterogenous. Thus, this study aimed to systematically compare the efficacy and safety of alternative agents versus vancomycin in adults with confirmed MRSA-SSTI. Three databases were searched until August 05, 2025, to retrieve randomized controlled trials (RCTs) from published meta-analyses evaluating vancomycin versus alternatives involving patients with MRSA-confirmed SSTI. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using random-effects model. The study is registered in PROSPERO (CRD420251119756). From 28 meta-analyses, 39 RCTs (n = 20,285; 2,662 patients with MRSA-confirmed SSTI receiving alternative agents and 2,322 receiving vancomycin) were included. No significant difference in clinical success was observed between groups (RR: 1.012, 95% CI: 0.992-1.032; prediction interval: 0.994-1.030). Although alternatives showed modestly higher microbiological success (RR: 1.058, 95% CI 1.001-1.119; prediction interval: 0.895-1.250), the effect lost significance after publication bias adjustment. Alternative agents had significantly lower dermatologic but higher gastrointestinal and hematological risk. Tigecycline had higher adverse events (RR: 1.090, 95% CI: 1.019-1.166), and telavancin had higher drug discontinuation (RR: 1.405, 95% CI: 1.105-1.786). Despite the growth of newer anti-MRSA agents, vancomycin remains clinically comparable for MRSA-confirmed SSTI, with apparent microbiological advantages of alternatives tempered by potential publication bias. Varying safety and pharmacological profiles of these agents emphasize the importance of individualized treatment selection.

Objective: To evaluate the efficacy and safety of tegoprazan (TPZ) compared to conventional proton pump inhibitors (PPIs) for Helicobacter pylori eradication as first‐ and second‐line therapies.Methods: Four databases were searched for randomized controlled trials (RCTs) and retrospective studies comparing TPZ‐ and PPI‐based regimens for H. pylori eradication published until October 15, 2024. A random‐effects model was used to calculate pooled odds ratio (OR) and 95% confidence interval (CI) based on intention‐to‐treat and per‐protocol analyses. The PROSPERO registration number of the study is CRD42024622705.Results: Nine studies (three RCTs and six retrospective studies) involving 5228 treatment‐naïve patients were included. TPZ was non‐inferior to PPIs as a first‐line therapy (intention‐to‐treat: odds ratio [OR] 1.066, 95% confidence interval [CI] 0.929–1.224; per‐protocol: OR 1.142, 95% CI: 0.967–1.349). Subgroup analyses showed no significant differences based on study design, therapeutic regimen, or treatment duration. In patients with clarithromycin‐resistant strains confirmed by 23S rRNA sequencing, TPZ achieved a higher eradication rate (OR 4.961, 95% CI 1.024–24.030). TPZ was associated with significantly lower odds of abdominal discomfort compared to PPIs (OR 0.490, 95% CI 0.268–0.897). Regarding treatment duration, a 14‐day regimen was linked to a lower risk of diarrhea, while a 7‐day regimen was associated with a higher risk of abdominal pain. No significant differences were observed in second‐line therapeutic outcomes.Conclusions: TPZ represents a non‐inferior alternative to PPIs for H. pylori eradication, with potential benefits in clarithromycin‐resistant infections and favorable safety profiles. Future studies are warranted to assess higher dosages and address pharmacokinetic limitations.

Objective: To summarize the evidence on the efficacy and safety of vancomycin compared with those of alternative treatments in adult patients with methicillin‐resistant Staphylococcus aureus (MRSA) infection.Methods: PubMed, Embase, and Web of Science were searched up to December 15, 2023, for systematic reviews and meta‐analyses comparing vancomycin with alternative MRSA treatments. Primary outcomes included clinical cure and microbiological eradication rates. Organ‐specific safety outcomes were assessed. Summary estimates were recalculated using a random‐effects model. Evidence was graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. This study was registered in PROSPERO (CRD42022340359).Results: This umbrella review included 19 studies and 71 meta‐analyses (46 efficacy and 25 safety) comparing vancomycin with 10 alternative treatments across different MRSA infection types and populations. GRADE assessment showed that 29.58% of the meta‐analyses were of high quality. Linezolid and daptomycin showed higher efficacy in MRSA‐induced skin and soft tissue infections and pneumonia (moderate evidence quality) and bacteremia (very low evidence quality), respectively, compared with that of vancomycin. Cephalosporins had a higher risk of nausea, whereas linezolid had a higher risk of nausea, diarrhea, and thrombocytopenia than that of vancomycin. Vancomycin posed a higher risk of rash, pruritus, red man syndrome, and nephrotoxicity than that of alternatives.Conclusions: The quality of evidence supporting the higher efficacy of alternative treatment over vancomycin for MRSA infection was not high. Given varying safety profiles and advancements in therapeutic monitoring, careful consideration of patient‐specific factors and pharmacokinetics is crucial when selecting treatment alternatives to vancomycin.

Background Breast cancer (BC) presents persistent challenges due to subtype-specific limited efficacy and potential resistance to standard therapy, influenced by the dynamic reversible nature of epigenetic plasticity. This study aims to comprehensively explore the evolving BC epigenetic landscape, analyzing trends and evaluating the therapeutic potential of epigenetic drugs (epi-drugs) for BC treatment. Methods We conducted a cross-sectional study of BC epigenetic trials using ClinicalTrials.gov until July 18, 2023. Additionally, results from randomized controlled trials were retrieved from the registry or PubMed using trial registration numbers. Results In total, 22 epi-drugs were investigated in 100 trials, with 11 currently being studied in 38 ongoing trials for BC. Over the years, epigenetic clinical trials for BC have notably increased, with histone deacetylase inhibitors constituting 45.45% of the candidate agents in the development pipeline. All ongoing trials are enrolling human epidermal growth factor receptor2 (HER2)-negative BC patients. Epi-drugs are commonly explored in combination with multiple anti-cancer therapies, such as aromatase or microtubule inhibitors, using an intermittent sequential administration approach. Emerging strategies include new-generation epi-drugs and combination involving immunotherapy or targeted therapy. Among candidate drugs, tucidinostat and entinostat, in combination with exemestane, demonstrated significant improvements in progression-free survival in phase III trials for hormone receptor-positive, HER2-negative BC patients. Conclusion This study highlights the growing interest in BC epigenetics, suggesting a potential shift from a one-size-fits-all approach to precision medicine, and emphasizes the necessity for robust evidence on their efficacy and safety to support continuous development and approval, addressing the unmet needs in BC treatment.

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. Objective: This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. Methods: In this retrospective study, trials were collected by searching clinicaltrials.gov using the term “Alzheimer”. Primary and secondary outcomes were analyzed separately for each phase. Results: Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials ( p = 0.001) and secondary endpoints in phase 3 trials ( p = 0.001). Conclusions: The growing recognition of the importance of biomarkers in AD trial’ design and drug development is evident by the significant steady increase in biomarkers’ utilization in phases 2 and 3.

Gene therapy products (GTPs) used for incurable diseases can be expedited for early commercialization to fulfill unmet needs. This study analyzed the expedited programs available for GTPs in the US, EU, Japan, and South Korea using their regulatory authorities’ websites, related regulations, and documents. In total, there were five expedited programs available for GTPs in the US, four in the EU, and three in both Japan and South Korea, of which four are tailored for GTPs. These programs, sharing similar objectives, can be categorized as those expediting drug development, review, and approval. However, variations are observed in eligibility criteria, specific benefits, and post-marketing study conditions across regulatory authorities. Additionally, the criteria for orphan drug designation for a rare disease differs in prevalence thresholds, incentive offered, and marketing exclusivity period. Overall, 19 GTPs were approved–13 in the US, 14 in the EU, eight in Japan, and three in South Korea–with majority obtaining regulatory approval through at least one expedited program. Therefore, future studies can analyze whether acquiring multiple expedited programs accelerates the drug development and commercialization of GTPs compared with when only one expedited program is processed. Additionally, inter-authority scientific discussion is encouraged for harmonization of expedited program requirements.

Spin, defined as the misrepresentation of the results of a study, could negate the validity of scientific findings. We aimed to evaluate spin in early published RCTs on pharmacotherapy for COVID-19 with nonsignificant primary outcomes, explore the manifestation of spin, and identify the factors affecting spin in COVID-19 RCTs. A systematic review was performed through a search of RCTs from PubMed/Medline, National Institutes of Health, EMBASE, Cochrane, and Web of Science. RCTs on pharmacotherapy for COVID-19 with nonsignificant primary outcomes published in 2020 were included. Of the included articles, 21 abstracts (33.9%) and 28 main texts (45.2%) were found to contain spin in at least one section. In the conclusion section, other spin strategies beautifying their findings that were not included in the abstract were found in the main texts. Although specialized medical journals and the small sample size of the included RCTs were common factors that were associated with higher odds of spin in both abstracts in univariate analysis, they were not significant predictors of spin in the multivariate analysis. More factors influencing the level of spin were found in abstracts than in the main texts, but most of the levels of spin in abstracts were comparable to those in the main texts. Although common factors that affected the manifestation of spin in the main texts and abstracts were the sample size and type of journal, further research to determine multicollinearity between significant factors and the manifestation of spin is required.