Pub Date : 2024-05-01Epub Date: 2024-02-10DOI: 10.1007/s43441-024-00616-7
Colleen Davenport, Patricia Gravel, Yamei Wang, Setareh A Williams, Alethea Wieland, Bruce Mitlak
Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.
真实世界证据(RWE)在历史上一直被用于支持批准后的安全性研究,最近在新药申请中作为支持性证据或作为孤儿药和/或需求未得到满足的疾病领域的新临床证据得到了认可。在此,我们将介绍一个案例,说明在欧盟(EU)批准阿巴帕肽(商品名为 Eladynos)时使用 RWE 的情况。除了来自关键性 3 期研究的数据外,上市许可申请(MAA)还包括来自其他介入性和观察性研究的临床数据,以及自 2017 年食品药品管理局(FDA)批准阿巴拉帕肽以来从美国市场获得的上市后数据。新的介入性研究并非旨在评估骨折疗效和心血管安全性,而这正是人用医药产品委员会(CHMP)在审查2015年提交的初始MAA时提出的关注主题。然而,这些研究与 RWE 一起构成了新 MAA 的基础。在计划向欧盟重新提交之前,就拟议的临床计划征求了国家科学建议(SA),特别是关于从观察性研究中获得的真实世界数据(RWD)的相关性,以支持和补充前瞻性随机临床试验中已有的疗效和安全性数据。本案例研究表明,RWE 的成功应用解决了 CHMP 在审查早期 MAA 时提出的差距问题,从而使 Eladynos 在欧盟获批用于治疗骨质疏松症。
{"title":"Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe.","authors":"Colleen Davenport, Patricia Gravel, Yamei Wang, Setareh A Williams, Alethea Wieland, Bruce Mitlak","doi":"10.1007/s43441-024-00616-7","DOIUrl":"10.1007/s43441-024-00616-7","url":null,"abstract":"<p><p>Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"505-518"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716430","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}
Pub Date : 2024-05-01Epub Date: 2024-01-29DOI: 10.1007/s43441-023-00604-3
Armel Zemsi, Lorraine Jinette Guedem Nekame, Nuredin Mohammed, Elizabeth Stanley Batchilly, Edgard Dabira, Sheikh Omar Sillah, Gibbi Sey, Daisy H Williams, Bai-Lamin Dondeh, Carla Cerami, Ed Clarke, Umberto D'Alessandro
A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant's rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.
临床试验是指任何涉及研究用医药产品或器械的人体研究。研究用医药产品包括未经许可的药物或在产品许可证之外使用的药物(如用于新适应症)(ICH-GCP)。根据国际公认的 ICH-GCP 指南,临床试验应严格按照批准的方案进行。然而,在试验的生命周期内,可能会出现方案偏离的情况。根据 ICH 疗效指南,方案偏差分为非重要(次要)和重要(主要)两种,后者可能会危及参与者的权利、安全或研究产生的数据质量。现有的方案偏差管理指南并没有详细说明或规范对参与者、研究产品、数据或样本所采取的行动,作为重要方案偏差整体管理的一部分。在此,我们提出指导方针,以解决目前的文献空白,并促进处理临床试验中重要方案偏差的行动标准化。建议的行动应与当地机构审查委员会和国家监管机构的现有要求相辅相成。
{"title":"Practical Guidelines for Standardised Resolution of Important Protocol Deviations in Clinical Trials Conducted in Sub-Saharan Africa.","authors":"Armel Zemsi, Lorraine Jinette Guedem Nekame, Nuredin Mohammed, Elizabeth Stanley Batchilly, Edgard Dabira, Sheikh Omar Sillah, Gibbi Sey, Daisy H Williams, Bai-Lamin Dondeh, Carla Cerami, Ed Clarke, Umberto D'Alessandro","doi":"10.1007/s43441-023-00604-3","DOIUrl":"10.1007/s43441-023-00604-3","url":null,"abstract":"<p><p>A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant's rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"395-403"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139571508","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}
Pub Date : 2024-05-01Epub Date: 2024-02-06DOI: 10.1007/s43441-023-00609-y
Bernadette Johnson-Williams, Kellie Reynolds, Joga Gobburu, Albert Rundio
Introduction: Competency-based education has been commonly used to enhance the healthcare workforce for some time. A translational discipline that is integral to drug development and impactful on healthcare and public health is clinical pharmacology. With such contribution, it is essential that the clinical pharmacology workforce is adequately equipped to address the demands of emerging trends of drug development.
Objectives: The primary objective of this study was to determine the most significant competencies needed for a clinical pharmacologist in the regulatory environment.
Methods: A two round modified Delphi technique was administered to 29 clinical pharmacologists within the Office of Clinical Pharmacology (OCP) between November 2021-January 2022. A questionnaire consisting of core and technical competencies was administered electronically using SurveyMonkey ® to gain consensus about essential clinical pharmacology competencies. Participants used a Likert scale to rank importance of competencies from strongly agree (1), agree (2), neutral (3), disagree (4), strongly disagree (5). Participants also suggested topics to be included in the next round. Consensus was set at 60%. The competencies receiving the most consensus at 60% in round one and the new topics proceeded to the second round. In the second and final round, participants ranked the suggested competencies. Descriptive statistics and a McNemar change test were utilized to analyze data. Only data from the participants who completed both rounds was used in the study.
Results: In round one participants ranked all fifty-six core and technical competencies as essential with consensus of at least 60%. In round two, participants ranked sixty-two competencies as essential with consensus of at least 60%. A McNemar change test demonstrated stability of ranking between rounds.
Conclusion: Essential core and technical competencies can build education programs to sustain the emerging clinical pharmacology workforce in the Office of Clinical Pharmacology. The Delphi technique is a suitable approach to determine essential competencies because it cultivates consensus and gains insight from experts in the forefront of drug development.
{"title":"A Modified Delphi Study to Establish Essential Clinical Pharmacology Competencies.","authors":"Bernadette Johnson-Williams, Kellie Reynolds, Joga Gobburu, Albert Rundio","doi":"10.1007/s43441-023-00609-y","DOIUrl":"10.1007/s43441-023-00609-y","url":null,"abstract":"<p><strong>Introduction: </strong>Competency-based education has been commonly used to enhance the healthcare workforce for some time. A translational discipline that is integral to drug development and impactful on healthcare and public health is clinical pharmacology. With such contribution, it is essential that the clinical pharmacology workforce is adequately equipped to address the demands of emerging trends of drug development.</p><p><strong>Objectives: </strong>The primary objective of this study was to determine the most significant competencies needed for a clinical pharmacologist in the regulatory environment.</p><p><strong>Methods: </strong>A two round modified Delphi technique was administered to 29 clinical pharmacologists within the Office of Clinical Pharmacology (OCP) between November 2021-January 2022. A questionnaire consisting of core and technical competencies was administered electronically using SurveyMonkey ® to gain consensus about essential clinical pharmacology competencies. Participants used a Likert scale to rank importance of competencies from strongly agree (1), agree (2), neutral (3), disagree (4), strongly disagree (5). Participants also suggested topics to be included in the next round. Consensus was set at 60%. The competencies receiving the most consensus at 60% in round one and the new topics proceeded to the second round. In the second and final round, participants ranked the suggested competencies. Descriptive statistics and a McNemar change test were utilized to analyze data. Only data from the participants who completed both rounds was used in the study.</p><p><strong>Results: </strong>In round one participants ranked all fifty-six core and technical competencies as essential with consensus of at least 60%. In round two, participants ranked sixty-two competencies as essential with consensus of at least 60%. A McNemar change test demonstrated stability of ranking between rounds.</p><p><strong>Conclusion: </strong>Essential core and technical competencies can build education programs to sustain the emerging clinical pharmacology workforce in the Office of Clinical Pharmacology. The Delphi technique is a suitable approach to determine essential competencies because it cultivates consensus and gains insight from experts in the forefront of drug development.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"473-482"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693036","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}
Background: Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products.
Methods: We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter.
Results: A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA.
Conclusion: Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .
{"title":"Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.","authors":"Sai Dharmarajan, Zhong Yuan, Yeh-Fong Chen, Leila Lackey, Saurabh Mukhopadhyay, Pritibha Singh, Ram Tiwari","doi":"10.1007/s43441-023-00611-4","DOIUrl":"10.1007/s43441-023-00611-4","url":null,"abstract":"<p><strong>Background: </strong>Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products.</p><p><strong>Methods: </strong>We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter.</p><p><strong>Results: </strong>A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA.</p><p><strong>Conclusion: </strong>Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"415-422"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543108","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}
Pub Date : 2024-05-01Epub Date: 2024-03-25DOI: 10.1007/s43441-024-00628-3
Karen Zhou, Ginny Gattinger
Artificial intelligence (AI)-enabled technologies in the MedTech sector hold the promise to transform healthcare delivery by improving access, quality, and outcomes. As the regulatory contours of these technologies are being defined, there is a notable lack of literature on the key stakeholders such as the organizations and interest groups that have a significant input in shaping the regulatory framework. This article explores the perspectives and contributions of these stakeholders in shaping the regulatory paradigm of AI-enabled medical technologies. The formation of an AI regulatory framework requires the convergence of ethical, regulatory, technical, societal, and practical considerations. These multiple perspectives contribute to the various dimensions of an evolving regulatory paradigm. From the global governance guidelines set by the World Health Organization (WHO) to national regulations, the article sheds light not just on these multiple perspectives but also on their interconnectedness in shaping the regulatory landscape of AI.
{"title":"The Evolving Regulatory Paradigm of AI in MedTech: A Review of Perspectives and Where We Are Today.","authors":"Karen Zhou, Ginny Gattinger","doi":"10.1007/s43441-024-00628-3","DOIUrl":"10.1007/s43441-024-00628-3","url":null,"abstract":"<p><p>Artificial intelligence (AI)-enabled technologies in the MedTech sector hold the promise to transform healthcare delivery by improving access, quality, and outcomes. As the regulatory contours of these technologies are being defined, there is a notable lack of literature on the key stakeholders such as the organizations and interest groups that have a significant input in shaping the regulatory framework. This article explores the perspectives and contributions of these stakeholders in shaping the regulatory paradigm of AI-enabled medical technologies. The formation of an AI regulatory framework requires the convergence of ethical, regulatory, technical, societal, and practical considerations. These multiple perspectives contribute to the various dimensions of an evolving regulatory paradigm. From the global governance guidelines set by the World Health Organization (WHO) to national regulations, the article sheds light not just on these multiple perspectives but also on their interconnectedness in shaping the regulatory landscape of AI.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"456-464"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140289044","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}
Pub Date : 2024-05-01Epub Date: 2024-03-15DOI: 10.1007/s43441-024-00626-5
Nicholette Conway, Orin Chisholm
Introduction: Integration of precision medicine (PM) competencies across the Medical Technology and Pharmaceutical industry is critical to enable industry professionals to understand and develop the skills needed to navigate the opportunities arising from rapid scientific and technological innovation in PM. Our objective was to identify the key competency domains required by industry professionals to enable them to upskill themselves in PM-related aspects of their roles.
Methods: A desktop research review of current literature, curriculum, and healthcare trends identified a core set of domains and subdomains related to PM competencies that were consistent across multiple disciplines and competency frameworks. A survey was used to confirm the applicability of these domains to the cross-functional and multi-disciplinary work practices of industry professionals. Companies were requested to trial the domains to determine their relevance in practice and feedback was obtained.
Results: Four PM-relevant domains were identified from the literature review: medical science and technology; translational and clinical application; governance and regulation and professional practice. Survey results refined these domains, and case studies within companies confirmed the potential for this framework to be used as an adjunct to current role specific competency frameworks to provide a specific focus on needed PM capabilities.
Conclusion: The framework was well accepted by local industry as a supplement to role specific competency frameworks to provide a structure on how to integrate new and evolving technologies into their current workforce development planning and build a continuous learning and cross-disciplinary mindset.
{"title":"Building a Competency Framework to Integrate Inter-disciplinary Precision Medicine Capabilities into the Medical Technology and Pharmaceutical Industry.","authors":"Nicholette Conway, Orin Chisholm","doi":"10.1007/s43441-024-00626-5","DOIUrl":"10.1007/s43441-024-00626-5","url":null,"abstract":"<p><strong>Introduction: </strong>Integration of precision medicine (PM) competencies across the Medical Technology and Pharmaceutical industry is critical to enable industry professionals to understand and develop the skills needed to navigate the opportunities arising from rapid scientific and technological innovation in PM. Our objective was to identify the key competency domains required by industry professionals to enable them to upskill themselves in PM-related aspects of their roles.</p><p><strong>Methods: </strong>A desktop research review of current literature, curriculum, and healthcare trends identified a core set of domains and subdomains related to PM competencies that were consistent across multiple disciplines and competency frameworks. A survey was used to confirm the applicability of these domains to the cross-functional and multi-disciplinary work practices of industry professionals. Companies were requested to trial the domains to determine their relevance in practice and feedback was obtained.</p><p><strong>Results: </strong>Four PM-relevant domains were identified from the literature review: medical science and technology; translational and clinical application; governance and regulation and professional practice. Survey results refined these domains, and case studies within companies confirmed the potential for this framework to be used as an adjunct to current role specific competency frameworks to provide a specific focus on needed PM capabilities.</p><p><strong>Conclusion: </strong>The framework was well accepted by local industry as a supplement to role specific competency frameworks to provide a structure on how to integrate new and evolving technologies into their current workforce development planning and build a continuous learning and cross-disciplinary mindset.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"567-577"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140779","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}
Pub Date : 2024-05-01Epub Date: 2024-02-18DOI: 10.1007/s43441-024-00614-9
Anders Vinther, Emma Ramnarine, Thierry Gastineau, Laura O'Brien, Oliver Brehm, David Fryrear
The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.
{"title":"Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.","authors":"Anders Vinther, Emma Ramnarine, Thierry Gastineau, Laura O'Brien, Oliver Brehm, David Fryrear","doi":"10.1007/s43441-024-00614-9","DOIUrl":"10.1007/s43441-024-00614-9","url":null,"abstract":"<p><p>The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"433-442"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900431","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}
Pub Date : 2024-05-01Epub Date: 2024-02-20DOI: 10.1007/s43441-024-00620-x
Wan Lee Chow, Nur Afiqah Mohd Salleh, Tse Siang Kang
Background: Drug approval lag is the time difference for new medicine to obtain marketing authorization approval in the study country compared to the first global approval. Drug approval lag delays the availability of innovative medicine to patients. This may lead to delay in treatment and severe public health implications. The study aimed to determine drug approval lag in Malaysia, the factors associated with drug approval lag (drug characteristics, regulatory factors and applicant type) and the association of the submission lag and review time with the regulation change.
Methods: All new pharmaceutical products approved between January 2015 and March 2021 were examined (n = 136) using publicly available information. Factors associated with drug approval lag were determined using multiple linear regression.
Results: The median drug approval lag was 855 days. Drug approval lag was associated with drug characteristics and regulatory factors. Median submission lag and median review time for products which fulfilled the requirement for the new regulations (Conditional Registration/ Facilitated Registration Pathway) were shorter compared to products which did not fulfil the requirement.
Conclusion: Drug approval lag may delay the access of innovative medicine to patients, and this may lead to an increase in morbidity, mortality and healthcare costs. Good Regulatory Practices ensure efficient and transparent regulatory system which support the public health policy objectives in the most efficient way. The new regulations in Malaysia reduced the median submission lag and review time. The findings may be useful for regulators to consider for future policy development for medication access.
{"title":"Access to Innovative Medicines: Regulation Change and Factors Associated with Drug Approval Lag in Malaysia.","authors":"Wan Lee Chow, Nur Afiqah Mohd Salleh, Tse Siang Kang","doi":"10.1007/s43441-024-00620-x","DOIUrl":"10.1007/s43441-024-00620-x","url":null,"abstract":"<p><strong>Background: </strong>Drug approval lag is the time difference for new medicine to obtain marketing authorization approval in the study country compared to the first global approval. Drug approval lag delays the availability of innovative medicine to patients. This may lead to delay in treatment and severe public health implications. The study aimed to determine drug approval lag in Malaysia, the factors associated with drug approval lag (drug characteristics, regulatory factors and applicant type) and the association of the submission lag and review time with the regulation change.</p><p><strong>Methods: </strong>All new pharmaceutical products approved between January 2015 and March 2021 were examined (n = 136) using publicly available information. Factors associated with drug approval lag were determined using multiple linear regression.</p><p><strong>Results: </strong>The median drug approval lag was 855 days. Drug approval lag was associated with drug characteristics and regulatory factors. Median submission lag and median review time for products which fulfilled the requirement for the new regulations (Conditional Registration/ Facilitated Registration Pathway) were shorter compared to products which did not fulfil the requirement.</p><p><strong>Conclusion: </strong>Drug approval lag may delay the access of innovative medicine to patients, and this may lead to an increase in morbidity, mortality and healthcare costs. Good Regulatory Practices ensure efficient and transparent regulatory system which support the public health policy objectives in the most efficient way. The new regulations in Malaysia reduced the median submission lag and review time. The findings may be useful for regulators to consider for future policy development for medication access.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"528-538"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139906514","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}
Pub Date : 2024-05-01Epub Date: 2024-02-05DOI: 10.1007/s43441-024-00615-8
Rima Izem, Emmanuel Zuber, Nadia Daizadeh, Frank Bretz, Oleksandr Sverdlov, Pascal Edrich, Janice Branson, Evgeny Degtyarev, Nikolaos Sfikas, Robert Hemmings
While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.
尽管业界和监管机构对分散临床试验(DCT)的兴趣由来已久,但 Covid-19 大流行加速并扩大了这些试验的应用和经验。分散临床试验的关键理念是使临床试验设计(通常是现场设计)更贴近患者的体验(现场或非现场)。因此,分散临床试验的潜在益处包括减轻参与试验的负担、扩大更多不同人群的参与范围或使用场外收集的创新终点。本文将帮助研究人员仔细评估 DCT 的附加值及其实施操作之外的影响。建议采用的方法是使用 ICH E9(R1) 估计指标框架来指导围绕每个权力下放组成部分的战略决策。此外,该框架还能指导临床试验人员依次系统地考虑权力下放对估算指标每个属性的影响。我们通过一个完全 DCT 的案例研究来说明这种方法的使用,并表明所建议的系统流程可以发现与试验设计中可能使用的分散化组件相关的科学机遇、假设和潜在风险。这一过程还能突出以细粒度的方式指定估计值属性的好处。因此,我们证明,在设计中引入分散成分不仅会影响估算者和估算,还能解决更细化的问题,从而发现新的目标估算值。
{"title":"Decentralized Clinical Trials: Scientific Considerations Through the Lens of the Estimand Framework.","authors":"Rima Izem, Emmanuel Zuber, Nadia Daizadeh, Frank Bretz, Oleksandr Sverdlov, Pascal Edrich, Janice Branson, Evgeny Degtyarev, Nikolaos Sfikas, Robert Hemmings","doi":"10.1007/s43441-024-00615-8","DOIUrl":"10.1007/s43441-024-00615-8","url":null,"abstract":"<p><p>While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"495-504"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693037","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}
Pub Date : 2024-05-01Epub Date: 2024-03-04DOI: 10.1007/s43441-024-00622-9
Kenneth Getz, Zachary Smith, Emily Botto, Elisabeth Murphy, Arnaud Dauchy
The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I-IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments-77%-were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.
{"title":"New Benchmarks on Protocol Amendment Practices, Trends and their Impact on Clinical Trial Performance.","authors":"Kenneth Getz, Zachary Smith, Emily Botto, Elisabeth Murphy, Arnaud Dauchy","doi":"10.1007/s43441-024-00622-9","DOIUrl":"10.1007/s43441-024-00622-9","url":null,"abstract":"<p><p>The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I-IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments-77%-were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"539-548"},"PeriodicalIF":1.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029070","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}