Therapeutic innovation & regulatory science最新文献

{"title":"Overdosage Section in US and EU Labeling.","authors":"Sarah Condon, Thomas G Cantu, Antony Constantinou, Erin C Degnan, Monica Lungu, Marcella G Paglione, Shreya J Parikh, Joanna Szewczyk","doi":"10.1007/s43441-024-00673-y","DOIUrl":"10.1007/s43441-024-00673-y","url":null,"abstract":"<p><p>The Prescribing Information (PI) in the United States (US) and the Summary of Product Characteristics (SmPC) in the European Union (EU) are approved by the US Food & Drug Administration (FDA), and the European Medicines Agency (EMA), respectively. The inclusion of overdosage information in these documents is a regulatory requirement in both regions. This research evaluates the content of the overdosage section of US and EU labeling. The overdosage sections of labels for drugs approved in the US in three time periods were analyzed: 2000-2001, 2010-2011, and 2020-2021. EU labels for these same products were also reviewed if registered through the Centralized Procedure. Data collection and analyses were performed using a predefined questionnaire, focusing on adherence to regulatory requirements and identifying areas where additional regulatory guidance may be beneficial. The findings indicate that the content of the overdosage sections largely comply with the regulatory requirements of their respective regions. Fewer than half of the labels included information on supratherapeutic doses observed from clinical studies, risk factors for overdose or population specific data associated with overdose. Inconsistencies were noted concerning the incorporation of animal data when human data were available, in addition to the referencing of Poison Centers. The overall utility of non-specific treatment recommendations, in addition to gastric lavage is discussed. While the content of the overdosage section generally aligns with regulatory expectations, additional regulatory guidance could enhance consistency in how this section of labeling is presented and clarify expectations to improve its usefulness for health care professionals (HCPs).</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421104","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":"Patient and Public Perceptions in Canada About Decentralized and Hybrid Clinical Trials: \"It's About Time we Bring Trials to People\".","authors":"Dawn P Richards, John Queenan, Linnea Aasen-Johnston, Heather Douglas, Terry Hawrysh, Michael Lapenna, Donna Lillie, Emily I McIntosh, Jenna Shea, Maureen Smith, Susan Marlin","doi":"10.1007/s43441-024-00665-y","DOIUrl":"10.1007/s43441-024-00665-y","url":null,"abstract":"<p><strong>Background: </strong>Little is known about patient and the public perspectives on decentralized and hybrid clinical trials in Canada.</p><p><strong>Methods: </strong>We conducted an online survey (English and French) promoted on social media to understand perspectives of people in Canada about decentralized and hybrid clinical trials. The survey had two sections. We co-produced this project entirely with patient, caregiver, and family partners.</p><p><strong>Results: </strong>The survey had 284 (14 French) individuals who started or completed Section 1, and 180 (16 French) individuals who started or completed Section 2. People prefer to have options to participate in clinical trials where aspects are decentralized or hybridized. 79% of respondents preferred to have options related to study visits. There were concerns about handling adverse events or potential complications in decentralized trials, however, communication options such as a dedicated contact person for participants was deemed helpful. Most respondents were amenable to informed consent being done at a satellite site closer to home or via technology and were split on privacy concerns about this. Most preferred travel to a site within an hour, depending on what the trial was for or its impact on quality of life. Due to the response rate, we were unable to explore associations with gender, age, health status, geography, ethnicity, and prior clinical trial participation.</p><p><strong>Conclusion: </strong>Our findings indicate an openness in Canada to participating in trials that decentralize or hybridize some aspects. These trials are perceived to provide benefits to participants and ways to increase equity and accessibility for participants.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432832","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":"Standalone Regulatory Agreements for Product-Development Collaborations in the Medical Products Industry.","authors":"Mary E Wilhelm, Nancy Pire-Smerkanich, Frances J Richmond","doi":"10.1007/s43441-024-00646-1","DOIUrl":"10.1007/s43441-024-00646-1","url":null,"abstract":"<p><strong>Background: </strong>Medical-product companies often outsource research and manufacturing needs to contracting or partnering organizations but then must manage a challenging patchwork of regulatory activities. A standalone regulatory agreement could clarify the relationships and responsibilities between companies working jointly on a single regulated product. This study explored the need for and current use of standalone regulatory agreements.</p><p><strong>Methods: </strong>A survey instrument was developed using an implementation framework and disseminated to mid- to senior-level employees and consultants for sponsor and vendor companies in the medical products sector.</p><p><strong>Results: </strong>Of 294 respondents, about half, primarily from companies with more than 200 employees, were familiar with standalone regulatory agreements, and half of this subgroup had moved forward to implement them. Such agreements were considered beneficial to clarify regulatory roles and responsibilities, standardize regulatory expectations between the companies, and stimulate earlier discussion about joint regulatory strategies. However, the development of regulatory agreements appears challenged by the fact that such agreements are not required by regulatory agencies overseeing medical products and have no standardized templates, agency or industry guidance. Respondents whose organizations do not now use regulatory agreements either had not considered or did not see a need for a standalone agreement.</p><p><strong>Conclusions: </strong>Standalone regulatory agreements are becoming more common but are not yet implemented fully by most companies. Their usefulness and content appeared to depend upon the type of partner, the complexity of the relationship and the availability of internal expertise and support.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184639","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":"Good Statistical Monitoring: A Flexible Open-Source Tool to Detect Risks in Clinical Trials.","authors":"George Wu, Spencer Childress, Zhongkai Wang, Matt Roumaya, Colleen McLaughlin Stern, Chelsea Dickens, Jeremy Wildfire","doi":"10.1007/s43441-024-00651-4","DOIUrl":"10.1007/s43441-024-00651-4","url":null,"abstract":"<p><strong>Background: </strong>Risk-based quality management is a regulatory-recommended approach to manage risk in a clinical trial. A key element of this strategy is to conduct risk-based monitoring to detect potential risks to critical data and processes earlier. However, there are limited publicly available tools to perform the analytics required for this purpose. Good Statistical Monitoring is a new open-source solution developed to help address this need.</p><p><strong>Methods: </strong>A team of statisticians, data scientists, clinicians, data managers, clinical operations, regulatory, and quality compliance staff collaborated to design Good Statistical Monitoring, an R package, to flexibly and efficiently implement end-to-end analyses of key risks. The package currently supports the mapping of clinical trial data from a variety of formats, evaluation of 12 key risk indicators, interactive visualization of analysis results, and creation of standardized reports.</p><p><strong>Results: </strong>The Good Statistical Monitoring package is freely available on GitHub and empowers clinical study teams to proactively monitor key risks. It employs a modular workflow to perform risk assessments that can be customized by replacing any workflow component with a study-specific alternative. Results can be exported to other clinical systems or can be viewed as an interactive report to facilitate follow-up risk mitigation. Rigorous testing and qualification are performed as part of each release to ensure package quality.</p><p><strong>Conclusions: </strong>Good Statistical Monitoring is an open-source solution designed to enable clinical study teams to implement statistical monitoring of critical risks, as part of a comprehensive risk-based quality management strategy.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899593","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":"Regulatory Framework for Drug-Device Combination Products in the United States, Europe, and Korea.","authors":"Joo Hee Kim, Sera Kwon, Ju Eun Seol, Mi Hye Kim, Su Dong Kim","doi":"10.1007/s43441-024-00661-2","DOIUrl":"10.1007/s43441-024-00661-2","url":null,"abstract":"<p><p>Combination products (CPs) combine two or more product types such as drugs, devices, and/or biological products for increased safety and clinical effectiveness. The emergence of innovative CPs poses new challenges for regulatory agencies in assigning jurisdiction for premarket review and oversight. In US, the 1990 Safe Medical Devices Act defines and provides classification criteria for CPs, and the US government has developed a regulatory process through multiple acts, including the 21st Century Cures Act of 2016. Meanwhile, regulators in the European Union (EU) and the Republic of Korea have recently recognized the importance of premarket pathways for CPs. The European Medicines Agency (EMA) has issued guidelines and explanations on compliance issues related to drug-device CPs under MDR. EMA doesn't have the definitions of CPs, but uses the term drug-device combination products (drug-device CPs). CPs are categorized as drugs or medical devices, which follow their relevant regulatory framework. The Ministry of Food and Drug Safety (MFDS) in Korea has legal definitions of CPs under the Notice of the MFDS. CPs are designated as drugs or medical devices according to their primary mode of actions (PMOA) and follow regulatory processes through the framework of drugs or medical devices. This study aims to comprehensively summarize the regulatory oversight of CPs by analyzing the regulatory policies and legal frameworks in the US, the EU, and Korea. The regulatory challenges encountered when developing CPs are also discussed. With specific emphasis on the combination of drugs and devices, this study provides in-depth insights into the regulatory landscape, shedding light on the unique challenges associated with the development of CPs for this particular intersection of drugs and devices.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877429","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":"New Estimates on the Cost of a Delay Day in Drug Development.","authors":"Zachary P Smith, Joseph A DiMasi, Kenneth A Getz","doi":"10.1007/s43441-024-00667-w","DOIUrl":"10.1007/s43441-024-00667-w","url":null,"abstract":"<p><p>Two frequently cited figures by clinical research insiders and observers - the cost of missing a day to generate prescription drug sales and the cost of a day to conduct a clinical trial - are outdated and based on anecdotal evidence. In late 2023, the Tufts Center for the Study of Drug Development conducted empirical research to gather more accurate and granular estimates and to test whether average sales per day have changed over time. 645 drugs launched since 2000, and 409 clinical trial budgets were drawn from commercially available and proprietary data sets and analyzed. The results indicate that a single day equals approximately $500,000 in lost prescription drug or biologic sales, with daily prescription sales for infectious, hematologic, cardiovascular, and gastrointestinal diseases among the highest. The results also show that each year, the average sales per day of prescription drugs and biologics has decreased by approximately $80,000-$100,000. The estimated direct daily cost to conduct a clinical trial is approximately $40,000 per day for phase II and III clinical trials, with those in respiratory, rheumatology, and dermatology having the highest relative daily direct costs.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076749","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":"EU's Medical Device Expert Panels: Analysis of Membership and Published Clinical Evaluation Consultation Procedure (CECP) Results.","authors":"Colleen Watson, Frances J Richmond","doi":"10.1007/s43441-024-00632-7","DOIUrl":"10.1007/s43441-024-00632-7","url":null,"abstract":"<p><strong>Background: </strong>The new EU Medical Device Regulation (MDR) places greater importance on the role of clinical evidence to establish safety and performance. Article 54 of the MDR calls for expert committees to independently review the scientific, technical, and clinical evidence supporting the market authorization of certain novel devices independently from the established process of Notified Body reviews. These experts provide a review and opinion that ultimately is taken into consideration alongside the information reviewed by the Notified Body during the review process. Four expert committees (General and Plastic Surgery and Dentistry; Orthopaedics, Traumatology, Rehabilitation, Rheumatology; Circulatory System; and Neurology) have published at least one Scientific Opinion (SO) under the Clinical Evaluation Consultation Procedure (CECP) in 2021-2022.</p><p><strong>Methods: </strong>The four expert committees with published CECP opinions were reviewed to assess the academic backgrounds and professional expertise of each member with respect to clinical, technical, and biological domains on a 0-2 scale for each domain. A content review was conducted on the 10 CECP opinions published by these committees to assess their consistency with the goals and outcome expectations set by the MDR. The extent of content related to each of the clinical, technical, and biological domains was also assessed on a 0-2 scale.</p><p><strong>Results: </strong>All committees were composed primarily by members with strong clinical expertise, but only a few had strong technical and biological expertise. Across committees, the average scores of members related to academic background and professional expertise both ranged from 1.64 to 2.00 in the clinical domain, but only 0-0.15 and 0.15-0.69, respectively, in the biological domain, and 0.12-0.55 and 0.23-0.73, respectively, in the technical domain. A content review for the 10 SOs showed that all opinions focused exclusively or primarily on the clinical evidence. Three contained a modest amount of additional text directed at technical/engineering issues and five at biological issues.</p><p><strong>Conclusion: </strong>Expert committees are composed predominantly of expert clinical reviewers but have many fewer members with significant technical or biological expertise. This may limit the ability of the committees to evaluate the significant technical and biological risks that are often best understood by preclinical testing. Broadening the expertise across the committees may improve the depth of their benefit/risk critiques.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296741","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":"International Comparison of Qualification Process for Medical Product Development Tools.","authors":"Daichi Uchijima, Shingo Kano","doi":"10.1007/s43441-024-00630-9","DOIUrl":"10.1007/s43441-024-00630-9","url":null,"abstract":"<p><strong>Introduction: </strong>Qualification of medical product evaluation tools is underway in the United States, Europe, and Japan to reflect the advancements in the basic science of medical products. In Europe and the U.S., Guidance of Guidances (GoG) policies that clarify regulators'processes, tasks, and methods of sponsor involvement are adopted to issue tool guidance. However, in Japan, a non-GoG type policy focusing on supporting the research and development for tools without defining a tool guidance-making process has been adopted.</p><p><strong>Methods: </strong>In this study, an analytical framework for the lifecycle of development tools was constructed, including pre- and post-tool qualification processes, to compare the two above-mentioned approaches. For this study, Japanese cases were selected as experimental cases, whereas Western cases served as controls. The progress of tool qualification and composition of deliverables were analyzed.</p><p><strong>Results and conclusions: </strong>It was indicated that in the GoG type policy, in which processes are defined, and involvement methods are clarified, tool qualification can progress more smoothly than in a non-GoG type policy. This policy indicates that deliverables may have a consistent composition. Contrastingly, GoG-type policies alone present challenges in connecting upstream tools for R&D support.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140307019","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":"An Open-Source R Package for Detection of Adverse Events Under-Reporting in Clinical Trials: Implementation and Validation by the IMPALA (Inter coMPany quALity Analytics) Consortium.","authors":"Björn Koneswarakantha, Ronojit Adyanthaya, Jennifer Emerson, Frederik Collin, Annett Keller, Michaela Mattheus, Ioannis Spyroglou, Sandra Donevska, Timothé Ménard","doi":"10.1007/s43441-024-00631-8","DOIUrl":"10.1007/s43441-024-00631-8","url":null,"abstract":"<p><p>Accurate and timely reporting of adverse events (AEs) in clinical trials is crucial to ensuring data integrity and patient safety. However, AE under-reporting remains a challenge, often highlighted in Good Clinical Practice (GCP) audits and inspections. Traditional detection methods, such as on-site investigator audits via manual source data verification (SDV), have limitations. Addressing this, the open-source R package {simaerep} was developed to facilitate rapid, comprehensive, and near-real-time detection of AE under-reporting at each clinical trial site. This package leverages patient-level AE and visit data for its analyses. To validate its efficacy, three member companies from the Inter coMPany quALity Analytics (IMPALA) consortium independently assessed the package. Results showed that {simaerep} consistently and effectively identified AE under-reporting across all three companies, particularly when there were significant differences in AE rates between compliant and non-compliant sites. Furthermore, {simaerep}'s detection rates surpassed heuristic methods, and it identified 50% of all detectable sites as early as 25% into the designated study duration. The open-source package can be embedded into audits to enable fast, holistic, and repeatable quality oversight of clinical trials.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336953","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":"New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials.","authors":"Emily Botto, Zachary Smith, Kenneth Getz","doi":"10.1007/s43441-024-00629-2","DOIUrl":"10.1007/s43441-024-00629-2","url":null,"abstract":"<p><strong>Background: </strong>The drug development industry's focus on cancer-related treatments continues to rise, with narrow patient populations and complex procedures increasing the complexity of oncology protocols at an accelerated rate compared to non-oncology drugs. Tufts Center for the Study of Drug Development utilized data from a study investigating the impact of protocol amendments to compare how oncology clinical trials differ from non-oncology and identify opportunities to optimize performance in oncology clinical trials.</p><p><strong>Methods: </strong>Sixteen drug development industry companies contributed data from 950 protocols and 2,188 amendments to a study conducted in 2022 investigating protocol amendments. Analysis compared differences in amendment impact and causes between 249 oncology and 701 non-oncology protocols.</p><p><strong>Results: </strong>Compared to non-oncology, oncology protocols had a significantly higher prevalence (72.1% and 91.1%, respectively) and number (3.0 and 4.0, respectively) of protocol amendments. Oncology protocols with amendments had significantly lower participant completion rates compared to oncology protocols without amendments, while no significant differences were found among non-oncology. During the COVID-19 pandemic, the study found an increased number of substantial amendments, lower completion rates, and higher dropout rates among oncology protocols compared to before the pandemic.</p><p><strong>Conclusions: </strong>Efforts to prevent avoidable protocol amendments in the industry have not been effective in oncology, where increasingly complex designs are reflected in difficult to predict cycle times, barriers to recruitment and retention and an increase in protocol amendments.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140294600","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}