Therapeutic innovation & regulatory science最新文献

{"title":"BOP2-Comb: Bayesian Optimal Phase II Design for Optimizing Doses and Assessing Contribution of Components in Drug Combinations.","authors":"Xiaohan Chi, Ying Yuan, Ruitao Lin","doi":"10.1007/s43441-025-00860-5","DOIUrl":"10.1007/s43441-025-00860-5","url":null,"abstract":"<p><strong>Background: </strong>Personalized cancer treatment using combination therapies offers substantial therapeutic benefits over single-agent treatments in most cancers. However, unmet clinical needs and increasing market competition pressure drug developers to quickly optimize combination doses and clearly demonstrate the contribution of each component when developing and evaluating new combination treatments.</p><p><strong>Methods: </strong>We propose a Bayesian optimal phase II drug-combination (BOP2-Comb) design that optimizes the combination dose and evaluates the proof-of-concept as well as the contribution of each component in two seamless stages. Our optimal calibration scheme minimizes the total trial sample size while controlling incorrect decision rates at nominal levels. This calibration procedure is Monte Carlo simulation-free and provides a theoretical guarantee of false-positive control.</p><p><strong>Results: </strong>We demonstrate the superior finite-sample operating characteristics of the proposed design through extensive simulations, achieving reduced sample sizes and improved control of both correct and incorrect decision rates compared to existing approaches. To illustrate its utility, we apply the BOP2-Comb design to redesign a real phase II trial evaluating the combination therapy of bevacizumab and lomustine.</p><p><strong>Conclusions: </strong>The BOP2-Comb design provides a valuable framework for designing future randomized phase II trials of combination therapies, particularly when both dose optimization and assessment of component contributions are required.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive Design with Bayesian Informed Interim Decisions: Application To a Randomized Trial of Mechanical Circulatory Support.","authors":"R Mukherjee, N Muehlemann, Y Gao, Gregg W Stone, C Mehta","doi":"10.1007/s43441-025-00861-4","DOIUrl":"https://doi.org/10.1007/s43441-025-00861-4","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular and oncology trials increasingly require large sample sizes and long follow-up periods. Several approaches have been developed to optimize sample size including sample size re-estimation based on the promising zone approach. With time-to-event endpoints, methods traditionally used to test for treatment effects are based on proportional hazards assumptions, which may not always hold. We propose an adaptive design wherein using interim data, Bayesian computation of Predictive Power (PP) guides the increase in sample size and/or the minimum follow-up duration.</p><p><strong>Methods: </strong>PROTECT IV is designed to evaluate mechanical circulatory support device vs. standard of care during high-risk percutaneous coronary intervention with the initial enrolment of 1252 patients and initial minimum follow-up of 12 months. The primary endpoint is the composite rate of all-cause death, stroke, durable left ventricular assist device implant or heart transplant, myocardial infarction or hospitalization for cardiovascular causes. The study will employ an adaptive increase in sample size and/or minimum follow-up at the Interim analysis. The adaptations utilize simulations to choose a new sample size up to 2500 and new minimal follow-up time up to 36 months that provides PP of at least 90%.</p><p><strong>Results: </strong>Via extensive simulations, we have examined the utility of the proposed design for situations like delayed treatment effect, early benefit only and in general crossing of survival curves. Separate Piece-wise Constant Hazard Models with non-influential (weakly-informative) Gamma-priors are fitted to the interim data for the two treatment arms, free from the proportional hazards assumptions, thus yielding more robust interim decision making. The Bayesian modeling facilitates sampling of future observations from the posterior predictive distributions with the predictive probability of trial success is computed via Monte-Carlo simulations. Simulation results show that the fitting Bayesian Piecewise Exponential models to the interim data along with the use of the posterior predictive distributions lead to more \"specific\" adaptation rules compared to the frequentist Conditional Power while the overall operating characteristics, type-I error and power, are similar.</p><p><strong>Conclusion: </strong>For clinical trials with time-to-event endpoints and where crossing of survival curves might be anticipated at the planning stage, flexible modeling along with wholesome use of patient-level data such as the calculation of predictive power as proposed here, may be more robust and efficient in making interim decisions such as sample size increase than the traditional use of the conditional power based on summary statistics and proportional hazards assumption.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Protocol Amendments, Personnel Experience and Social Determinants of Health on Study Protocol Adherence in Clinical Trials with Combination Products.","authors":"K N Cilley, A O Kaliaev, M A Malikova","doi":"10.1007/s43441-025-00859-y","DOIUrl":"https://doi.org/10.1007/s43441-025-00859-y","url":null,"abstract":"<p><strong>Introduction: </strong>The amendments to the International Council for Harmonization (ICH) Good Clinical Practice (GCP) E8 guidelines were introduced to enhance clinical trial quality, patient safety, and efficiency through a more patient-centric, risk-based approach. This study investigates the impact of various study risk factors such as protocol amendments, informed consent changes, protocol complexity, and social determinants of health (SDOH) on protocol deviations and patient retention in clinical trials involving combination products.</p><p><strong>Methods: </strong>A retrospective analysis of 14 clinical trials with 202 enrolled subjects was conducted. Key risk indicators (KRIs) such as protocol amendments, amendments triggering informed consent changes, study staff experience, and clinical trial phase were evaluated for their association with protocol deviations. The analysis also explored the influence of social factors, including age, gender, race, insurance type, and travel distance on protocol adherence.</p><p><strong>Results: </strong>Study revealed that longer study participation was associated with an increased number of protocol deviations (p = 0.0003), while no significant associations were found between protocol deviations and demographic factors (p = 0.4039 for gender; p = 0.40650 for age), insurance type (p = 0.0640), or complexity scores (p = 0.7798). The findings highlight the importance of effective informed consent processes, study staff training, and risk management strategies to minimize protocol deviations and enhance data integrity in clinical trials.</p><p><strong>Conclusion: </strong>while larger numbers of participant were associated with more deviations, site preparedness and patient compliance can mitigate these risks, underscoring the need for robust quality management systems in clinical trials.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter To the Editor \"Strengthening the Use of International Collaborative Regulatory Assessments and Regulatory Alignment- Implications for Global Convergence\".","authors":"Zilin Zhao, Fei Xu, Hejia Wan","doi":"10.1007/s43441-025-00862-3","DOIUrl":"https://doi.org/10.1007/s43441-025-00862-3","url":null,"abstract":"","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Leveraging Multi-National Observational Study in Post-Marketing Safety Assessment: Challenges and Strategies.","authors":"Li-An Lin, Tarek A Hammad, Wei Liu, Yong Ma, Ed Whalen, Ranjeeta Sinvhal, Melvin Munsaka, William Wang","doi":"10.1007/s43441-025-00858-z","DOIUrl":"https://doi.org/10.1007/s43441-025-00858-z","url":null,"abstract":"","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights on Clinical Development of Cell and Gene Therapy for Rare Diseases-by DahShu Innovative Design Scientific Working Group (IDSWG).","authors":"Chenkun Wang, Junrui Di, Mercedeh Ghadessi, Rui Tang, Caroline Mulatya, Daoyuan Shi, Tu Xu, Wenquan Wang, Chaoqun Mei, Susan Wang, Bryan McComb, Robert A Beckman, Gianna McMillan","doi":"10.1007/s43441-025-00853-4","DOIUrl":"https://doi.org/10.1007/s43441-025-00853-4","url":null,"abstract":"<p><p>The rapid advancement of cell and gene therapies (CGT) in the past ten years has inspired biopharmaceutical companies, biotechnologies, and nonprofits to tackle diseases that have traditionally been challenging to treat. Rare diseases, where roughly 80% have a genetic basis, have enjoyed this scrutiny, but the complexity of CGT trial design and implementation have proven challenging. This manuscript offers general guidance for CGT clinical development, current regulatory requirements and guidelines governed by FDA and EMA, considerations around preclinical development, safety monitoring and the need for long-term monitoring and follow up.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal Trends in the Prescription of Biosimilars and the Status of Switching from Original Biologics to Biosimilars at Individual and Institutional Levels in Japan.","authors":"Minako Matsumoto, Ryosuke Kumazawa, Akiko Ishii-Watabe, Itsuko Horiguchi, Hiroaki Mamiya, Hiroko Shibata, Yoshiro Saito, Motohiko Adomi, Yuta Taniguchi, Jun Komiyama, Ryoko Sakai, Masao Iwagami","doi":"10.1007/s43441-025-00850-7","DOIUrl":"https://doi.org/10.1007/s43441-025-00850-7","url":null,"abstract":"<p><strong>Purpose: </strong>To describe the temporal trends in the prescription of biologics in Japan, with additional analysis focusing on switching from original biologics to biosimilars at the individual and institutional levels.</p><p><strong>Methods: </strong>Using the JMDC claims database from January 2005 to May 2024, we identified patients who received at least one prescription for 17 biologics (original biologics or biosimilars). We elucidated the monthly trends in the proportions of original biologics and biosimilars. We also estimated the proportion of patients receiving original biologics only, those receiving biosimilars only, and those switching from original biologics to biosimilars (and vice versa) during the study period. Finally, we estimated the proportion of medical institutions that started prescribing biosimilars during the study period based on the type of medical institution.</p><p><strong>Results: </strong>Temporal trends in the proportions of original biologics and biosimilars varied widely. In May 2024, the proportion of biosimilar prescriptions was 13.6% for somatropin and 92.5% for filgrastim. At the individual level, the proportion of patients switching from original biologics to biosimilars was low (1.2-14.0%), indicating that switches do not often occur within the same patient, while more recent new users of biologics start biosimilars. At the institutional level, university-related hospitals and clinics were more and less likely, respectively to introduce biosimilars than public and other types of hospitals.</p><p><strong>Conclusion: </strong>Temporal trends in the prescription of biosimilars and switching patterns varied widely by the type of biologics. The type of medical institution should be considered when assessing and promoting the use of biosimilars. Further research and strategies to increase the use of biosimilars in clinics may be needed.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Global Harmonization: Implementing Global Dose Form Attributes for Medicinal Products Identification.","authors":"Emelie Ahnfelt, Olof Lagerlund, Jenny Klint, Malin Fladvad, Christopher Jarvis, Ta-Jen Chen, Panagiotis Telonis, Ronald Fitzmartin","doi":"10.1007/s43441-025-00838-3","DOIUrl":"https://doi.org/10.1007/s43441-025-00838-3","url":null,"abstract":"<p><p>The global pharmaceutical market includes a wide range of medicinal products, which makes it difficult to achieve consistent identification and classification across different regions. To address this, the International Organization for Standardization (ISO) developed five standards that together create a framework for the Identification of Medicinal Products (IDMP). Implementing the ISO IDMP standards globally necessitates collaboration to ensure consistent data. As part of these efforts, investigations were conducted to explore the feasibility of introducing global dose form attributes, which aim to standardize dose forms worldwide. These characteristics, defined by the European Directorate for the Quality of Medicines (EDQM), include the administrable basic dose form, administration method, intended site, and release characteristics. The global dose form attributes were successfully applied to data from nine countries, representing six dose form terminologies or lists, and were successfully assigned to over 99% of medicinal products. The process of assigning global dose form attributes was improved by mapping local dose form terminologies to global dose form attributes. The results from these studies were used to develop business rules for assigning the global dose form attributes.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Multi-National Observational Study in Post-Marketing Safety Assessment: Challenges and Strategies.","authors":"Li-An Lin, Tarek A Hammad, Wei Liu, Yong Ma, Ed Whalen, Ranjeeta Sinvhal, Melvin Munsaka, William Wang","doi":"10.1007/s43441-025-00836-5","DOIUrl":"10.1007/s43441-025-00836-5","url":null,"abstract":"<p><p>The use of multi-national observational study in post-marketing safety assessment has been rising in recent years in parallel with the rapid development and adoption of electronic healthcare data (e.g., administrative claims, electronic health records) and novel statistical analysis methods to handle these data. Secondary use of routinely collected electronic health information has long been available to conduct pharmacoepidemiologic studies using data from millions of patients. Certain observational studies or surveillance activities, especially those investigating rare exposure or outcome or those designed to study specific patient subgroups (e.g., elderly, pediatric) or newly approved medical products, necessitate a multi-national approach. Other instances utilizing such study design include but not limited to (1) postmarketing study requested by multiple regulatory authorities; (2) multiple data systems chosen to complement each other (e.g., databases with long-term clinical outcome data combined with another that includes lab and radiology findings to allow case adjudication and/or algorithm validation); (3) multiple data sources needed to verify and replicate study findings. In this article, we share examples of multi-national postmarketing studies and discuss key pitfalls related to the design and analysis of such studies as well as strategies to mitigate biases.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ensuring Quality and Interpretability of Progression Free Survival and Overall Survival in Oncology Clinical Trials.","authors":"Philip He, Haijun Ma, Chengxing Cindy Lu, Revathi Ananthakrishnan, Gu Mi, Thomas Gwise, Laura Fernandes, Hui Yang, David Leung, Natalie Ren, Sohail Chaudhry","doi":"10.1007/s43441-025-00848-1","DOIUrl":"https://doi.org/10.1007/s43441-025-00848-1","url":null,"abstract":"<p><p>Time-to-event endpoints, such as progression free survival (PFS) and overall survival (OS), are critical in assessing therapeutic efficacy in oncology drug development. However, their quality and interpretability are frequently challenged by a range of factors, from protocol design and intercurrent events (ICE) to inconsistent data collection and missing follow-up data. These methodological and operational complexities can obscure the true treatment effect. Discontinuation of study treatment, initiation of subsequent anticancer therapy, lost to follow-up and withdrawal of consent can introduce significant bias, limiting the robustness of survival endpoints and complicating regulatory decision making. Adopting a prospective ICH E9(R1) estimand framework helps mitigate risks associated with data collection, analysis methodology and interpretability. This facilitates clearer discussions with regulators and stakeholders. Although both the FDA guidance on oncology endpoints and the EMA guideline on anticancer medicinal product evaluation outline key principles in evaluating PFS and OS endpoints, integration of ICH E9(R1) offers a harmonized strategy that is important for the design and conduct of randomized late phase oncology clinical trials. In this article, we investigate the quality and interpretability of the endpoints of PFS and OS according to the ICH E9(R1) framework and present some practical recommendations for designing and conducting robust oncology clinical trials.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}