Therapeutic innovation & regulatory science最新文献

{"title":"Applying Aggregate Statistical Analyses to Safety Monitoring of Ongoing Clinical Studies, Issues, and Opportunities in a Test Case.","authors":"Ed Whalen, Steven Gilbert, James Buchanan","doi":"10.1007/s43441-025-00776-0","DOIUrl":"https://doi.org/10.1007/s43441-025-00776-0","url":null,"abstract":"","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987502","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":"Consideration for Assessing Data/Models/Tools Expiration Supporting Drug Development and Clinical Decision Making.","authors":"Jeffrey S Barrett, Mark A Turner","doi":"10.1007/s43441-025-00793-z","DOIUrl":"https://doi.org/10.1007/s43441-025-00793-z","url":null,"abstract":"<p><p>Decision making of any kind is informed by data and often by models, tools or other solutions built from data. Data are evaluated for such purposes within a specific context of use (COU) but implicitly we often believe the data to be relevant, accurate and of high quality. In reality, this is not always the case. The status of data for various COUs must constantly be revisited for relevance and information value over time. Using drug development as an example, we postulate that there are indeed occasions where data value diminishes over time and consideration for data expiration with respect to its relevance for decision making should be entertained and at least identified with respect to a time-dependent change in status. Other situations exist which will also necessitate periodic review and condition reassessment. For example, considerations for patient privacy and consent along with compliance to regulatory standards must factor into future recommendations as well. Actions regarding data expiration are proposed as initial thoughts to be expanded upon but this assessment is primarily an attempt to explore factors which impact opinions about data information value for both drug development and clinical decision making.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033332","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":"Patient Experience Data (PED) in 2019-2023 US FDA NME Drug Approvals: Analysis and Recommendations.","authors":"Jewell D Martin, Darcy Frear, Samantha A Roberts, Victoria A Dohnal, Cameron Kieffer, Steve L Morin, Ian Lock, Aliyah Balogun, Nimi Chhina","doi":"10.1007/s43441-025-00788-w","DOIUrl":"https://doi.org/10.1007/s43441-025-00788-w","url":null,"abstract":"<p><strong>Background: </strong>Since 2012, the United States Congress enacted several laws requiring the U.S. Food and Drug Administration (FDA) to consider the voice and perspective of patients in the regulatory review process. The goal of the paper is to evaluate the implementation and impact of this provision by assessing the inclusion of Patient Experience Data (PED) (i.e., in PED Tables and benefit-risk frameworks) in approval documents for FDA approved drugs from 2019 through 2023. It builds on previous analyses by providing a comprehensive assessment of the use of PED by sponsors and FDA.</p><p><strong>Methods: </strong>Authors assessed whether PED was submitted and reported in approval documents of 277 drugs or biologics approved by FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologic Evaluation and Research (CBER). PED reported in drug approval documents and in product labels were analyzed for each indication.</p><p><strong>Results: </strong>Of the 277 approval documents analyzed, 252 included the PED Table in some form, where 179 tables were considered complete with PED. PED was included in the benefit risk framework for 85 (30%) applications and included in the label in 75 (27%) applications.</p><p><strong>Conclusions: </strong>Efforts to standardize and improve the systematic approach to collecting and utilizing PED has been ongoing for over 10 years. Our analysis has shown that both FDA and sponsors are increasingly considering patient voice to inform drug development and decision-making; however, more transparency is needed to ensure external stakeholders understand how FDA is reviewing and considering PED to inform regulatory decision-making.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027877","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":"A Comprehensive Retrospective Analysis of Trends and Strategic Implications of 505(b)(2) Approvals (2019-2023).","authors":"Ramesh Joga, Kailas Vijay Gadekar, Kajal Gandhi, M Sowndharya, Sonali Waikar, Rajeev Singh Raghuvanshi, Saurabh Srivastava","doi":"10.1007/s43441-025-00775-1","DOIUrl":"https://doi.org/10.1007/s43441-025-00775-1","url":null,"abstract":"<p><strong>Background: </strong>The 505(b)(2) pathway, established by the USFDA, enables faster approval of new drug applications (NDAs) by allowing partial reliance on existing clinical data. This regulatory mechanism fosters innovation by encouraging new formulations, combinations, and delivery systems, accelerating the availability of advanced therapeutics.</p><p><strong>Objective: </strong>This study provides a comprehensive analysis of 505(b)(2) NDA approvals from 2019 to 2023, with an emphasis on trends, major players, therapeutic targets, and dosage form diversity. Furthermore, the impact of regulatory exclusivity strategies on market dynamics and drug pricing is explored.</p><p><strong>Methods: </strong>Approval data was gathered from the USFDA database and further classified by reformulation type, therapeutic area, primary players, and dosage form. The study also analyzed the therapeutic equivalence codes and the influence of non-patent exclusivity strategies on market competition to identify trends and the prevalence of product types across therapeutic categories.</p><p><strong>Results: </strong>Our findings reveal a strong presence of reformulations, with new dosage forms (Type 3) and new formulations or other differences (Type 5) accounting for a substantial portion of approvals. Cancer (16.7%), CNS disorders (16.2%), and anti-infective treatments emerged as key therapeutic areas. Teva Pharmaceuticals USA Inc. was the leading entity by approval count. Parenteral dosage forms dominated at 40.3%, followed by tablets at 20.6%. Exclusivity strategies, notably three year's new clinical investigation exclusivity, impacted drug pricing and competitive positioning.</p><p><strong>Conclusion: </strong>The 505(b)(2) pathway proves instrumental in advancing pharmaceutical innovation and expediting access to therapies targeting unmet needs. These insights offer value for regulatory professionals, drug developers, and policymakers in optimizing development and market strategies to enhance drug accessibility. Companies must remain vigilant and proactive in anticipating potential blocking exclusivities to secure successful approvals.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998788","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":"Has FDA's Drug Development Tools Qualification Program Improved Drug Development?","authors":"Felix Yang, Imein Bousnina, Anne Madej, Rasika Kalamegham","doi":"10.1007/s43441-025-00790-2","DOIUrl":"https://doi.org/10.1007/s43441-025-00790-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The Drug Development Tools (DDTs) Qualification program creates a pathway to evaluate Clinical Outcome Assessments (COAs) that capture a specific concept of interest (COI) in a specified Context of Use (COU). If successfully qualified, a COA can be relied upon to measure a COI that has an application in drug development and regulatory decision-making. Thus, qualified COAs are important DDTs. This analysis aims to assess the Food and Drug Administration's (FDA's) performance reviewing applications in the COA Qualification Program, as well as the uptake of qualified COAs in drug development to date.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In order to assess the use of qualified COAs in drug development, we analyzed the Summary Basis of Approvals (SBA) retrieved from Drugs@FDA and the COA compendium. The submission and review dates for the Letter of Intent (LOI), Qualification Plan (QP), and Full Qualification Package (FQP) steps were retrieved from Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research's (CBER) database, as well as the FDA COA Qualification Program website.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our analysis showed that 86 COAs were listed on the FDA COA website, with a majority of them being Patient Reported Outcomes (PRO). Completeness Assessment (CA) for each portion of submission, as well as review times for the LOI, QP, and FQP steps vary widely, with 46.7% of submissions having a review time exceeding the published targets. To date, 7 COAs (8.1%) have achieved qualification, and one (1.1%) has been denied after undergoing all steps for qualification. On average, it takes 6 years for a COA to be qualified. Our analysis of FDA's approval documents shows that the Agency has relied on qualified COAs to support benefit-risk assessment of 11 medicines. Only three of the seven qualified COAs have been used to support benefit-risk assessment of medicines. The three qualified COAs that have been used are KCCQ, E-RS, and EXACT. Each of these has been used to support multiple indication claims. KCCQ - cardiomyopathy for 2 medicines, heart failure for 6 medicines; E-RS - chronic obstructive pulmonary disease (COPD) for 1 medicine; and EXACT - COPD for 3 medicines. Note: E-RS and EXACT were both used in aclidinium bromide/formoterol/fumarate. In each case they were used as secondary or exploratory endpoints, none as primary endpoints. Only 1 qualified COA was included in drug labels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The lengthy and unpredictable nature of the COA Qualification Program review timelines poses a risk for tool developers and sponsors intending to qualify a new COA, to use an existing COA or sponsors intending to qualify and use a new COA in the drug development process. Our findings show that, to date, the DDT Qualification Program has not significantly improved the inclusion of qualified COAs in clinical development plans to support regulatory decision-making and labe","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987611","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":"Evaluation of United Kingdom (UK)-Windsor Framework and Comparison Against European Union (EU) Regulations for Medicines Regulation.","authors":"R B Ankitha, Shailee Dewan, Francis Fernandes, Sharad Verma, Gowri M Bhat, Pradeep M Muragundi","doi":"10.1007/s43441-025-00753-7","DOIUrl":"10.1007/s43441-025-00753-7","url":null,"abstract":"<p><p>The United Kingdom (UK)'s regulatory profile is changing following the UK's exit from the European Union (EU). As a consequence, the Medicines and Healthcare products Regulatory Agency (MHRA) became more independent. Since then, numerous attempts have been made to ease the separation of the UK from the European Union, focusing mainly on Northern Ireland (NI), which is part of the UK but shares a land border with the EU. The Windsor Framework facilitates the relationship between the EU and the UK, including the role of the European Medicines Agency (EMA) and MHRA in NI. The review throws light on the implementation of the Windsor Framework detailing the key aspects, and the pre- and post-implementation changes in Northern Ireland, Great Britain and the Republic of Ireland. The Framework is useful for industries such as pharmaceuticals where regulatory approval and an uninterrupted supply chain are critical. Evaluating the Framework illuminate's areas for improvement, threats, and scope for cooperation between the UK and EU authorities. The review details efficiency, costs, and market accessibility of medicines, to give a better representation of the regulatory position in NI. The study reveals the pros and cons of the Framework, to assist stakeholder evaluation of Marketing Authorisation Holders (MAHs) that have registered both in UK and EU markets.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"438-449"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward an Extensible Regulatory Framework for N-of-1 to N-of-Few Personalized RNA Therapy Design.","authors":"Mélissa Bou-Jaoudeh, Gabriele Piaton-Breda, Florian Pereme, Stephen Gilbert","doi":"10.1007/s43441-025-00752-8","DOIUrl":"10.1007/s43441-025-00752-8","url":null,"abstract":"<p><p>The emergence of personalized RNA therapeutics, tailored to individual patients' genetic profiles, offers new hope for treating both common and rare diseases. This review explores regulatory aspects of N-of-1 and N-of-few approaches, providing promising treatments for ultra- or nano-rare diseases that lack established therapies. These diseases present unique challenges, as patients may represent the sole individual or a small group worldwide with a specific mutation, necessitating personalized approaches to treatment development, validation, and approval. While progress is promising, the regulatory landscape remains nascent, raising challenges in ensuring safety and industry sustainability. Artificial intelligence (AI) and automated systems, coupled with real-world evidence (RWE) monitoring, offer significant potential to address these challenges by optimizing development, manufacturing, and regulatory compliance. Drawing parallels from other regulatory domains, this review presents a design envelope framework, integrated with AI tools, to streamline the approval process and enhance the adaptability of RNA-based treatments. Case studies of individualized RNA-based treatments highlight successes and setbacks, underscoring the need for regulatory alignment. Collaborative efforts from stakeholders and regulatory authorities are essential to refine this framework for real-world application. Overall, this review emphasizes the transformative potential of personalized RNA therapeutics in advancing precision medicine.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"505-518"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Beginning of a \"Regulatory Renaissance\": Positioning Regulatory Coverage at the Interface of Human Expertise and Digital Support.","authors":"James Jones, Robert M Califf","doi":"10.1007/s43441-025-00745-7","DOIUrl":"10.1007/s43441-025-00745-7","url":null,"abstract":"<p><p>Following the largest reorganization in its history, the U.S. Food and Drug Administration (FDA) is now working to modernize how it defines and engages in regulatory oversight of the quality of products that the agency regulates. However, the volume and complexity of these tasks, coupled with the size and interdependent nature of the global supply chains that generate and distribute these products, raise questions about how the agency can keep up with the pace of change. This dilemma, together with the FDA's recent reorganization, create an opportunity to rethink the FDA's strategy for regulatory coverage and usher in a \"regulatory renaissance.\" In this article, we examine how the agency is working to develop a more quantitative, comprehensive approach to ensuring that the wide arrays of FDA-regulated commodities are produced and distributed in systems that meet societal expectations for safety and quality in a global digital environment. We discuss a number of tools and methods that the agency can bring to bear to achieve this goal, including leveraging internal FDA data and information from third-party audits; utilizing information from foreign regulators; incorporating data and findings from state and local inspections; and applying sophisticated data technologies including AI systems. The underlying concept for this regulatory renaissance is for the agency to focus on leveraging multiple sources of data, information, and analysis to inform its actions in order to optimize the quality of products produced by regulated industries, including the dimensions of safety, effectiveness, and reliability of manufacturing, as well as distribution and instructions for use throughout their product lifecycle. The degree of success of this approach will depend upon a broad recognition of similar opportunities across the regulated industries, sister federal and state agencies, and academia working on regulatory science.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"403-408"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606385","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":"Sponsor- vs. FDA-Initiated Changes to Pediatric Clinical Trial Protocols: A Comparison of Associated Participant Burden.","authors":"Susan Abdel-Rahman, Zoe Sund, Cheryl Alderman, Karylle Abella, Phyllis Kennel","doi":"10.1007/s43441-025-00760-8","DOIUrl":"10.1007/s43441-025-00760-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Risks associated with clinical trial participation are a foremost consideration during protocol development whereas trial-associated burdens receive less focus despite their measurable impact on enrollment and retention. Of late, the U.S. Food and Drug Administration (FDA) has elevated discussions on barriers to research participation resulting from overly burdensome trials. Given the agency's role in shaping clinical protocol design, this study examined the perceived burden associated with FDA-proposed study changes in the context of pediatric, off-patent, labeling studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;Pediatric Trials Network (PTN) studies conducted between 2013 and 2023 for which there existed a record of formal communication between the PTN and FDA were evaluated. All protocol versions and regulatory communications were reviewed, and every protocol change with the potential to alter participant burden was extracted and attributed to the PTN Sponsor or FDA. Changes were grouped into 11 themes (e.g. change in the number of visits, change in invasive procedures) and each change assigned a perceived burden score on an 11-point Likert scale by pediatric clinical trialists who were blinded to attribution. An abbreviated list of protocol changes were reviewed and scored by children to examine their concordance with adult scores. Quantitative and qualitative differences between changes introduced by Sponsors and the FDA were compared.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Twenty-one studies (94 protocol versions) met the criteria for inclusion (18 drug, 3 device). Half of the protocol versions incorporated changes (n = 123) that could perceivably affect participant burden (77 initiated by the sponsor, 46 proposed by the FDA). Changes classified as introducing, increasing, or extending protocol features occurred almost twice as often (64%) as changes that reduced, removed, or restricted features of the protocol (36%), the latter also occurring later in the life of the protocol (1.2 vs. 2.0 year, p &lt; 0.01). Changes recommended by the FDA were primarily related to ensuring safety (77%), optimizing trial design (16%) and adequately capturing effectiveness (7%) and, on average, were associated with statistically higher burden scores. Modifications driven by sponsors reflected trial design refinements (34%), safety assessment (32%), expansion of primary/secondary scientific questions (22%), and effectiveness evaluation (12%). Burden scores demonstrated strong concordance between trialists and children (r = 0.7).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Half of all protocol amendments are associated with changes that conceivably alter the burden of clinical trial participation, and these changes are twice as likely to add to (vs. reduce) participant burden. Given the time and effort involved with protocol amendments, we suggest that modifications to trial protocols be accompanied by a reassessment of the role and util","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"558-565"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484012","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":"A Proposed Confidence Ellipse Approach for Benefit-Risk Assessment in Clinical Trials.","authors":"Yinuo Zhang, Xiaofang Zhang, Peijin Wang, Yangfeng Wu, Shein-Chung Chow","doi":"10.1007/s43441-025-00762-6","DOIUrl":"10.1007/s43441-025-00762-6","url":null,"abstract":"<p><p>In clinical development, an independent data safety monitoring committee (IDMC) is often established to ensure the test treatment's integrity, quality, safety, and efficacy under investigation. In clinical trials, IDMC may recommend stopping the trial early due to safety, futility/efficacy, or both after reviewing observed data in the interim based on pre-specified stopping boundaries. In practice, the interim data is often too small to reach clinically meaningful differences with statistical significance (i.e., the observed clinically meaningful difference is reproducible and not purely by chance alone). To provide an overall assessment (or complete clinical picture) of the performance of the test treatment under investigation, the FDA (2023) published guidance on the benefit-risk assessment (BRA) framework to facilitate IDMC decision-making. Several methods have been studied in the literature following the FDA's recommended framework. However, these methods did not consider the uncertainties and heterogeneities. Alternatively, a BRA approach is proposed based on a confidence ellipse of primary safety and efficacy endpoints. The proposed confidence ellipse approach was evaluated both theoretically and via a clinical trial simulation. The results indicate that the proposed confidence ellipse provides consistent and stable metrics, particularly as sample sizes increase. The derived metrics of Benefit-Risk Difference (BRD) and Benefit-Risk Ratio (BRR) showed favorable performance across different scenarios and thresholds. Applied to the TESTING trial data (Lv et al. JAMA. 327(19):1888-98, 2022), our method confirmed and extended the original finding that a reduced methylprednisolone dose offered a more favorable benefit-risk profile. Specifically, the confidence ellipse method highlighted that the reduced dose consistently provided a better balance between efficacy and safety, particularly under stricter criteria for clinical significance. This method validated the original conclusions and provided additional insights into how different dosing regimens perform across various clinical scenarios, potentially offering a more refined tool for optimizing treatment decisions in complex therapeutic contexts.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"606-618"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543626","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}