Therapeutic innovation & regulatory science最新文献

{"title":"Efficient Positioning of QTL and Secondary Limit Thresholds in a Clinical Trial Risk-Based Monitoring.","authors":"Vladimir Shnaydman","doi":"10.1007/s43441-024-00722-6","DOIUrl":"10.1007/s43441-024-00722-6","url":null,"abstract":"<p><p>In the high-stakes world of clinical trials, where a company's multimillion-dollar drug development investment is at risk, the increasing complexity of these trials only compounds the challenges. Therefore, the development of a robust risk mitigation strategy, as a crucial component of comprehensive risk planning, is not just important but essential for effective drug development, particularly in the RBQM (Risk-Based Quality Management) ecosystem and its component-RBM (Risk-Based Monitoring). This emphasis on the urgency and significance of risk mitigation strategy can help the audience understand the gravity of the topic. The paper introduces a novel modeling framework for deriving an efficient risk mitigation strategy at the planning stage of a clinical trial and establishing operational rules (thresholds) under the assumption that contingency resources are limited. The problem is solved in two steps: (1) Deriving a contingency budget and its efficient allocation across risks to be mitigated and (2) Deriving operational rules to be aligned with risk assessment and contingency resources. This approach is based on combining optimization and simulation models. The optimization model aims to derive an efficient contingency budget and allocate limited mitigation resources across mitigated risks. The simulation model aims to efficiently position each risk's QTL/KRI (Quality Tolerance Limits/Key Risk Indicators at a clinical trial level) and Secondary Limit thresholds. A case study illustrates the proposed technique's practical application and effectiveness. This example demonstrates the framework's potential and instills confidence in its successful implementation, reassuring the audience of its practicality and usefulness. The paper is structured as follows. (1) Introduction; (2) Methodology; (3) Models-Risk Optimizer and Risk Simulator; (4) Case study; (5) Discussion and (6) Conclusion.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"173-183"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787181","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":"Subsequent Indications in Oncology Drugs: Pathways, Timelines, and the Inflation Reduction Act.","authors":"Julie A Patterson, James Motyka, Rayan Salih, Robert Nordyke, John M O'Brien, Jonathan D Campbell","doi":"10.1007/s43441-024-00706-6","DOIUrl":"10.1007/s43441-024-00706-6","url":null,"abstract":"<p><strong>Introduction: </strong>Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act's Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.e., small molecule vs. biologic).</p><p><strong>Methods: </strong>This cross-sectional study evaluated oncology drugs first approved by the FDA from 2008 to 2018 and later approved for one or more additional indications. Numbers, types, and approval timelines of subsequent indications were recorded at the drug level, with drugs grouped by quartile based on the pacing of post-approval development (i.e., \"rapid pace\" to \"measured pace\").</p><p><strong>Results: </strong>Multi-indication oncology drugs (N = 56/86, 65.1%) had one or more subsequent indication approved in a new: cancer type (60.7%), line of treatment (50.0%), combination (41.1%), mutation (32.1%), or stage (28.6%). The median time between FDA approvals for indications increased from 0.6 years (IQR: 0.48, 0.74) in the \"rapid pace\" group to 1.6 years (IQR: 1.32, 1.66), 2.4 years (IQR: 2.29, 2.61), and 4.9 years (IQR: 3.43, 6.23) in the \"moderate,\" \"measured-moderate,\" and \"measured\" pace groups, respectively. Drugs in the \"rapid pace\" group often received their first subsequent indication approval within 9 months of initial approval (median: 0.7 years; IQR: 0.54, 1.59), whereas the \"measured pace\" group took a median of 5.7 years (IQR: 3.43, 6.98). Across all multi-indication drugs, the median time to the most recent approval for a subsequent indication was 5.5 years (IQR: 3.18, 7.95). One quarter (25%) of drugs were approved for their most recent subsequent indication after the time at which they would be DPNP-eligible.</p><p><strong>Conclusion: </strong>Approval histories of new oncology drugs demonstrate the role of post-approval indications in expanding treatment options towards new cancer types, stages, lines, combinations, and mutations. Heterogeneous clinical development pathways provide insights into potential unintended consequences of IRA-related changes surrounding post-approval research and development.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"102-111"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378334","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":"Principles for Evaluating the Efficacy and Safety of Ceramic Dental Implants in Japan.","authors":"Tomoya Hara, Yuchi Sato, Hiroyuki Tanishiro, Yukimichi Tamaki, Shunsuke Baba, Eiichi Hirose, Bunsaku Yoshida, Kiyoshi Watanabe, Genki Nishikawa, Daiju Okuda, Madoka Murakami, Yuki Niwa, Masuo Kondoh","doi":"10.1007/s43441-024-00713-7","DOIUrl":"10.1007/s43441-024-00713-7","url":null,"abstract":"<p><p>Recent progress in materials chemistry has resulted in the development of several ceramic materials that are now being used in dental implants. The advantages of ceramic materials over conventional metallic materials are that they do not induce allergic reactions in individuals with metal allergies, they do not interfere with magnetic resonance imaging, and they provide improved esthetics. In addition, some ceramic materials are tougher than metallic materials and less brittle. However, despite these advantages, few ceramic dental implant materials are currently approved for use in Japan. In FY2022, the Ministry of Health, Labour and Welfare of Japan commissioned a project called the \"Project for the Development of a Guideline for the Evaluation of Ceramic Dental Implants,\" the goal of which was to consider how best to facilitate swift clinical development and approval of emerging ceramic dental implant materials. At a meeting of experts from professional societies, related industry organizations, and government agencies, the issues related to evaluation of the efficacy and safety of ceramic implant were discussed. Here, we summarize the outcomes of that meeting as a set of principles for the premarketing evaluation of ceramic dental implant materials in Japan.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"3-8"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583904","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":"Review of the European Union Clinical Trials Regulation: Key Early Learnings from the United Kingdom Drug Information Association Medical Writing Committee.","authors":"Dicken D H Koo, Eve Taylor, Iain T Hooper, Saman F Khaled, Vivien Fagan, Helen Turner, Harriet L Buttery","doi":"10.1007/s43441-024-00726-2","DOIUrl":"10.1007/s43441-024-00726-2","url":null,"abstract":"<p><p>The European Union Clinical Trials Regulation (EU CTR) provides new regulatory requirements for the preparation and submission of clinical trial documents. The United Kingdom Drug Information Association Medical Writing (UK DIA MW) Committee, with members from across the pharmaceutical industry, have reviewed the EU CTR and in this report, provide expert guidance on writing documents for submission in the EU CTR Clinical Trials Information System (CTIS) portal. Medical writers should be aware that the Investigator's Brochure containing the Reference Safety Information (RSI) must align with the annual safety report, and the RSI format must comply closely with the EU CTR. For clinical study protocols, medical writers should prepare a single integrated EU protocol that receives consolidated approvals from all participating EU member states, with different versions of a protocol for different EU member states no longer permitted. This report also provides details of experiences and recommendations on protocol synopses from the UK DIA MW Committee. In addition, plain language summaries are new EU CTR documents required for each study presenting summaries of clinical trial results for laypersons. Some of these documents will be published in the publicly accessible CTIS portal which has created concerns amongst many companies who are keen to protect commercially confidential information (CCI). Medical writers may help reduce CCI through lean writing, but specifically identifying CCI may require specialist legal evaluation. This report by the UK DIA MW Committee highlights the key processes for medical writers to ensure compliance with the EU CTR when preparing documents for submission to the CTIS portal.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"190-198"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751671","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":"Hypocalcemia Event Associated with Denosumab: A Real-World Study from FDA Adverse Event Reporting System (FAERS) Database.","authors":"Siyuan Gao, Guanhao Zheng, Zhichao He, Lishi Chen, Dengfeng Yan, Zhisheng Lai, Tingfeng Cai, Shijie Hu","doi":"10.1007/s43441-024-00712-8","DOIUrl":"10.1007/s43441-024-00712-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Denosumab is widely used for osteoporosis and cancer treatment. However, hypocalcemia induced by denosumab is a frequent adverse event. The objective of this study is to comprehensively investigate the safety signals and the occurrence of hypocalcemia in real-world patient cases reported through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).</p><p><strong>Methods: </strong>Reports from January 1, 2017 to December 31, 2021 were extracted from the FAERS. Only cases of hypocalcemia suspected to denosumab were eligible in pharmacovigilance study. Denosumab-related hypocalcemia safety signal were identified to characterize their clinical features. A safety signal for hypocalcemia was evaluated using reporting odds ratios (ROR).</p><p><strong>Results: </strong>Among the 102,413 cases related to denosumab, 1042 cases were reported with denosumab-related hypocalcemia. The affected patients were mainly elderly (median age 70 years) and male (n = 568, 63.5%). In available data, the median onset time of 23 (range 0-1601) days. Most patients required drug interruption (n = 226, 72.9%) and can achieve a recovered-resolved state (n = 318, 62.1%). For the whole database, denosumab exhibited a safety signal for hypocalcemia (ROR = 14.09, 95% Cl 13.18, 15.06). In the sensitivity analyses, denosumab also showed a safety signal for hypocalcemia in cancer (ROR = 21.28, 95% Cl 18.79, 24.11) and osteoporosis (ROR = 9.29, 95% Cl 6.80, 12.59). Compared with bisphosphonates, denosumab still has safety signal for hypocalcemia (ROR = 1.88, 95% Cl 1.67, 2.11).</p><p><strong>Conclusions: </strong>This pharmacovigilance database analysis indicates a high safety signal for hypocalcemia associated with denosumab, particularly in cancer patients.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"135-141"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508547","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":"Research on Core Competency Elements of Clinical Investigators.","authors":"Xin Wang, Shuang Zhao, Han Yang, Miao Miao, Siwei An, Wenbing Yao","doi":"10.1007/s43441-024-00688-5","DOIUrl":"10.1007/s43441-024-00688-5","url":null,"abstract":"<p><strong>Background: </strong>To construct a competency model for clinical investigators involved in the process of new drug development, providing a reference for the training, selection and assessment of clinical investigators.</p><p><strong>Methods: </strong>The Behavioral Event Interview (BEI) method was used to interview 12 excellent clinical investigators and 8 clinical investigators of average performance. Each competency characteristic was extracted from the interview text by semantic coding. Total frequency, total score, average score and highest score were calculated for each competency element. Category agreement coefficient, coefficient of reliability and Spearman correlation coefficient were used to assess the consistency of two coders for coding and classification. Independent-samples Mann-Whitney U test was applied to compare the differences in competency elements between the group of excellent clinical investigators and the group of average investigators.</p><p><strong>Results: </strong>The average coefficient of category agreement was 0.671, and the average coefficient of reliability was 0.803. No significant differences were observed between the two groups in the aspect of interview time (P = 0.190) and the interview words (P = 0.184), indicating comparability between the two groups. However, there was a clear performance difference between the excellent and average groups. In addition, we found that the competency model for clinical investigators contained 24 prominent competence elements and 8 benchmark competency elements.</p><p><strong>Conclusions: </strong>Clinical investigator is a medical professional who is involved in a highly research-intensive and practical job, where prominent competency element largely reflects clinical practice skills, innovation and awareness of Good Clinic Practice (GCP). Our results provide a reference for assessing clinical investigators' competencies, encouraging and guiding them to modify their behaviors according to the competency model, and also cultivating clinical investigators so as to improve the competence level of clinical investigators.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"45-53"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751669","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":"Paediatric Drug Development in Japan: Current Status and Future Challenges.","authors":"Rieko Inagaki, Mamoru Narukawa","doi":"10.1007/s43441-024-00700-y","DOIUrl":"10.1007/s43441-024-00700-y","url":null,"abstract":"<p><strong>Introduction: </strong>Until around 2000, the number of medicinal products labelled for paediatric use was limited worldwide. Regulatory measures to promote paediatric drug development in the US and Europe and the establishment of an international guideline (ICH-E11) have led to an increase in the number of paediatric labels. In Japan, efforts have been made to promote the development of paediatric drugs. This study was aimed to examine whether these supportive efforts are successful in Japan.</p><p><strong>Methods: </strong>This study examined the number of new drugs approved for paediatric indications in Japan from 2006 to 2023, as well as the clinical data package, that is, characteristics of the approved paediatric drugs and paediatric clinical trials, and the percentage of extrapolation of adult data, in the most recent 9-year period.</p><p><strong>Results: </strong>The number of paediatric drug approvals showed an increasing trend between 2006 and 2023 with some fluctuations. The proportion of drugs indicated for paediatric patients to the total number of approved drugs was about 30% until 2022, but increased to 48% in 2023. During the period from 2015 to 2023, simultaneous development in adults and children accounted for 59% (159/269) of paediatric development, but the complete extrapolation of adult data to paediatric populations has not been widely utilized (11.2%, 30/269).</p><p><strong>Conclusions: </strong>The number of paediatric drug approvals has shown an upward trend, suggesting that measures to promote the development of paediatric drugs may have been exerting a favourable effect in Japan. However, there is still a limited number of drugs that have additional indications for paediatric use. Appropriate development strategies, such as the extrapolation of adult data to paediatric populations, should be considered if scientifically justified.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"54-62"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354378","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":"Provision of Drug Information Using Database Surveys-Enhancing Clinical Information for Patients with Specific Backgrounds.","authors":"Kiyohito Nakai, Mie Ikeda, Yumiko Nomura","doi":"10.1007/s43441-024-00715-5","DOIUrl":"10.1007/s43441-024-00715-5","url":null,"abstract":"","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"150-152"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508549","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":"Turning the Page on Hardcopy Risk Management Plan Educational Materials: Digitalization Made Possible.","authors":"Anabel Ng, Ayn Nova Celo, Beliz Fernandes","doi":"10.1007/s43441-024-00717-3","DOIUrl":"10.1007/s43441-024-00717-3","url":null,"abstract":"<p><p>'Risk Management Plan Educational Materials' (RMP EMs) are additional risk minimization measures (aRMMs) intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient. While the healthcare sector is embracing various digital tools and platforms for educational and/or awareness building purposes, paper-based materials have remained the mainstay approach for implementation of aRMMs by pharmaceutical companies. Novartis in Singapore conducted a pilot on the feasibility of distributing electronic copies of RMP EMs (e-RMP). Post-pilot, e-RMP was officially implemented in Novartis Singapore. A year following the launch of e-RMP, a survey was performed with healthcare professionals (HCPs) to understand end-users' experience. The survey responses revealed a general preference by both HCPs and patients towards e-RMP. Digital methods of delivering educational aRMMs offer great benefits over traditional paper-based programs. e-RMP significantly reduces the time needed for updated RMP EMs to reach HCPs and their patients/caregivers. This is important to ensure that HCPs and patients/caregivers are made aware of any updates in key safety messages of the products in a timely manner to ultimately ensure patient safety. The successful transition to digital solutions requires purposeful collaborations between key stakeholders of the healthcare ecosystem including regulatory authorities, pharmaceutical companies, HCPs, patients and caregivers. This article aims to provide insights on the digitalization journey of e-RMP, a case study in Singapore, outlining the value but also some of the challenges faced during this transformation.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"164-172"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717154","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":"Experimental Study of the Promotional Implications of Proprietary Prescription Drug Names.","authors":"Susana Peinado, Amie C O'Donoghue, Kevin R Betts, Ryan S Paquin, Kristen Giombi, Jennifer E Arnold, Bridget J Kelly, Christine Davis","doi":"10.1007/s43441-024-00704-8","DOIUrl":"10.1007/s43441-024-00704-8","url":null,"abstract":"<p><strong>Background: </strong>The meaning and characteristics embedded in proprietary drug names have the potential to affect name recall, perceptions of drug benefits and risks, and attitudes toward a drug. In this study, we examined: (1) whether names that reference the drug's medical indication affect consumers' and primary care physicians' (PCPs') perceptions of the drug and (2) whether names that overstate the drug's efficacy affect consumers' and PCPs' perceptions of the drug.</p><p><strong>Methods: </strong>We conducted an online experiment with 455 PCPs and 450 consumers to test the effects of fictitious proprietary prescription drug names. Participants were randomized to view one neutral drug name, one name that overstated the drug's efficacy, and five names that referenced the drug's medical indication.</p><p><strong>Results: </strong>Names that referenced the drug's medical indication and names that overstated the drug's benefit both influenced perceptions of efficacy and risk compared to neutral names. For several outcomes, names evoking medical indications had similar effects to those designed to overstate the drug's efficacy. The patterns of effects were similar for PCPs and consumers.</p><p><strong>Conclusion: </strong>Findings suggest drug names alone can be sufficient to produce attitudes and risk and benefit perceptions about drugs, even in the absence of any information beyond the drug's medical indication.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"80-88"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354377","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}