Therapeutic innovation & regulatory science最新文献

{"title":"Paediatric Drug Development in Japan: Current Status and Future Challenges.","authors":"Rieko Inagaki, Mamoru Narukawa","doi":"10.1007/s43441-024-00700-y","DOIUrl":"https://doi.org/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":""},"PeriodicalIF":2.0,"publicationDate":"2024-09-27","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":"A Framework for the Use and Likelihood of Regulatory Acceptance of Single-Arm Trials","authors":"Disha Subramaniam, Colin Anderson-Smits, Rebecca Rubinstein, Sydney T. Thai, Rose Purcell, Cynthia Girman","doi":"10.1007/s43441-024-00693-8","DOIUrl":"https://doi.org/10.1007/s43441-024-00693-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":"10 1","pages":""},"PeriodicalIF":1.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247786","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":"Latest Developments in “Adaptive Enrichment” Clinical Trial Designs in Oncology","authors":"Yue Tu, Lindsay A. Renfro","doi":"10.1007/s43441-024-00698-3","DOIUrl":"https://doi.org/10.1007/s43441-024-00698-3","url":null,"abstract":"<p>As cancer has become better understood on the molecular level with the evolution of gene sequencing techniques, considerations for individualized therapy using predictive biomarkers (those associated with a treatment’s effect) have shifted to a new level. In the last decade or so, randomized “adaptive enrichment” clinical trials have become increasingly utilized to strike a balance between enrolling all patients with a given tumor type, versus enrolling only a subpopulation whose tumors are defined by a potential predictive biomarker related to the mechanism of action of the experimental therapy. In this review article, we review recent innovative design extensions and adaptations to adaptive enrichment designs proposed during the last few years in the clinical trial methodology literature, both from Bayesian and frequentist perspectives.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":"23 1","pages":""},"PeriodicalIF":1.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247788","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":"Advanced Regenerative Medicines for Rare Diseases: A Review of Industry Sponsors Investment Motivations","authors":"Ubaka Ogbogu, Anja Nel","doi":"10.1007/s43441-024-00690-x","DOIUrl":"https://doi.org/10.1007/s43441-024-00690-x","url":null,"abstract":"<p>Despite regulatory changes designed to stimulate investment in therapies for rare diseases, many of these conditions lack government-approved treatments. Advanced regenerative medicines, which are therapies and clinical interventions aimed at healing or replacing damaged or defective human cells, tissues, and organs, offer great promise for addressing many rare diseases. A major challenge facing advanced regenerative medicines for rare diseases is securing financial support to assist in bringing a therapy to market. This paper describes the factors cited by pharmaceutical industry players globally for sponsoring the development of advanced regenerative medicines for rare diseases. The paper examines the motivations of 53 sponsors that meet the latter criteria. The motivations behind investments were broadly similar amongst sponsors and map closely onto regulatory requirements for clinical development and marketing authorization of advanced therapeutic products, including the presence of accelerated or attenuated pathways for regulatory approval, use for indications with high unmet medical needs, and/or that have advantages over existing therapies, and robust preclinical data. Other factors include availability of investment incentives and opportunities for off-label use in the post-approval stages.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":"15 1","pages":""},"PeriodicalIF":1.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206237","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":"Preventive Effects of Bioabsorbable Anti-Adhesion Barriers on Bowel Obstruction After Colectomy in Colon Cancer Patients: A Retrospective Cohort Study Using an Insurance Claims Database.","authors":"Risa Iwata, Shuichi Mochizuki, Tomoaki Hasegawa, Kensuke Ishii, Naoki Matsumaru, Katsura Tsukamoto","doi":"10.1007/s43441-024-00660-3","DOIUrl":"10.1007/s43441-024-00660-3","url":null,"abstract":"<p><strong>Purpose: </strong>Postoperative adhesions can be prevented by the use of bioabsorbable anti-adhesion barriers. Although the occurrence of postoperative bowel obstruction is an important concern for patients, at the time of approval of anti-adhesion barriers, its effectiveness in preventing postoperative bowel obstruction had not been evaluated. We aimed to retrospectively evaluate the incidence of bowel obstruction after colectomy in patients with colon cancer using an insurance claims database.</p><p><strong>Methods: </strong>This retrospective cohort study analyzed the data of colon cancer patients (between 2005 and 2017 from a national insurance claims database) who underwent colectomies to compare the proportion of individuals with postoperative bowel obstruction between the barrier and no barrier groups.</p><p><strong>Results: </strong>Of the 587 patients who met the inclusion criteria, 308 and 279 patients were identified as the barrier and no barrier groups, respectively. The incidence of postoperative bowel obstruction was significantly lower in the barrier group (log-rank test, P = 0.0483). The cumulative incidence of postoperative bowel obstruction 37 months after the initial colectomy was 6.1% and 10.9% in the barrier and no barrier groups, respectively. Moreover, consistent results were obtained in the matched cohort.</p><p><strong>Conclusion: </strong>In colectomies for patients with colon cancer, the use of anti-adhesion barriers could significantly reduce the incidence of postoperative bowel obstruction. Evaluations using insurance claims databases could provide important information on outcomes following implementation of medical devices.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"831-837"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140852170","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":"The Impact of Serialisation on Operational Efficiency and Productivity in Irish Pharmaceutical Sites.","authors":"Daniel O' Mahony, Alan Lynch, Olivia McDermott","doi":"10.1007/s43441-024-00662-1","DOIUrl":"10.1007/s43441-024-00662-1","url":null,"abstract":"<p><p>Technology enabling drug serialisation technology was introduced by regulators to enhance security in pharmaceutical supply chain and protect drugs from infiltration by falsified and substandard medicines. The introduction of systems for serialisation required huge financial outlays manufacturers of pharmaceuticals. This study investigated the impact of serialisation on the operational efficiency and productivity in Irish pharmaceutical sites. A qualitative study was conducted with 11 manufacturing sites in Ireland. The participating companies operated a total of 114 pack-lines, representing approximately 65% of the automated packing lines in the country. The study found that serialisation had a negative effect on packaging production line OEE and line availability and on the individuals cost per unit of packaged pharmaceuticals. The research results estimated that the capital costs of serialisation were four times greater than those estimated by the regulators. There was a 4.1 cents average cost per pack for serialisation with high volume sites reporting an annual cost of serialisation of up to €4.5 m per annum and a 2.7% increase in the average cost of goods sold. A pattern whereby where many pharmaceutical manufacturers are transitioning from smaller batch production and moving toward larger batch production sizes in order to increases efficiencies was identified. The research also proposed the use of a serialisation depreciation factor as a method to determine the impact of serialisation on the cost of goods sold. This is the first study of its kind into the cost of serialisation from a manufacturer's viewpoint and studying the effects of serialisation on productivity, line availability and operational efficiency.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"883-896"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176410","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":"A Method to Redesign and Simplify Schedules of Assessment and Quantify the Impacts. Applications to Merck Protocols.","authors":"Steven R Cummings, Scott Chetham, Andy Lee","doi":"10.1007/s43441-024-00666-x","DOIUrl":"10.1007/s43441-024-00666-x","url":null,"abstract":"<p><p>The growing complexity of biopharmaceutical sponsored trials has adverse impacts on increased burdens on participants, clinical sites, and sponsors, including greater difficulty recruiting and retaining participants, difficulty engaging sites to participate in trials, excessive cost of trials, and increased cycle times. The schedule of assessments (SoAs) is the origin of and blueprint for complexity that is often generated by copying and pasting from previous SoAs. We developed an approach, termed Lean Design, for redesigning the assessments in SoAs that generate data, the 'Data SoA.' It starts with a simple \"ground zero\" SoA. Any addition is challenged using several principles of trial design. We employed a system, the Faro Trial Designer Tool, to quantify the impacts of changes in an SoA to provide real-time feedback to the team and sponsor. We applied the approach in workshops with teams for six clinical trials in various stages of design and implementation. The approach resulted in recommendation for substantial potential savings in participant and site staff time, costs, and complexity of the trials. Application of this approach to very early stages of protocol design has the potential to reduce the complexity of biopharmaceutical sponsored trials and its consequences.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"789-795"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899591","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":"Harmonizing Quality Improvement Metrics Across Global Trial Networks to Advance Paediatric Clinical Trials Delivery.","authors":"Sabah Attar, Angie Price, Collin Hovinga, Breanne Stewart, Thierry Lacaze-Masmonteil, Fedele Bonifazi, Mark A Turner, Ricardo M Fernandes","doi":"10.1007/s43441-024-00663-0","DOIUrl":"10.1007/s43441-024-00663-0","url":null,"abstract":"<p><strong>Background: </strong>Despite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct.</p><p><strong>Methods: </strong>Three paediatric networks, Institute for Advanced Clinical Trials for Children, the Maternal Infant Child and Youth Research Network and conect4children, have each developed metrics to address delays and create efficiencies. We identified the methodology by which each network identified metrics, described the metrics of each network, and mapped consistency to come to consensus about core metrics that networks could share.</p><p><strong>Results: </strong>Metric selection was driven by site quality improvement in one network (11 metrics), by network performance in one network (13 metrics), and by both in one network (five metrics). The domains of metrics were research capacity/capability, site identification/feasibility, trial start-up, and recruitment/enrolment. The network driven by site quality improvement did not have indicators for capacity/capability or identification/feasibility. Fifteen metrics for trial start up and conduct were identified. Metrics related to site approvals were found in all three networks. The themes for metrics can inform the development of 'shared' metrics.</p><p><strong>Conclusion: </strong>We found disparity in drivers, methodology and metrics. Tackling this disparity will result in a unified approach to addressing delays in paediatric drug approvals. Collaborative work to define inter-operable metrics globally is outlined.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"953-964"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432831","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":"Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.","authors":"Daniel Li, Zhenzhen Xu, Shihua Wen, Revathi Ananthakrishnan, Yeonhee Kim, Khadija Rerhou Rantell, Patricia Anderson, James Whitmore, Alan Chiang","doi":"10.1007/s43441-024-00652-3","DOIUrl":"10.1007/s43441-024-00652-3","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"817-830"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857894","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":"Role of Neutrophils as Therapeutic Targets in Intracerebral Hemorrhage.","authors":"Alper Fatih Ardic, Nurittin Ardic","doi":"10.1007/s43441-024-00668-9","DOIUrl":"10.1007/s43441-024-00668-9","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a major health problem. It is one of the most common types of stroke and results in mortality in approximately half of patients. More than half of the fatalities occur in the first 2 days. In addition to the mass effect after ICH hemorrhage, complex pathophysiological mechanisms such as intracranial vessel vasospasm, microthrombosis, and inflammatory immune reaction also increase brain damage. Both resident (including microglia and astrocytes) and circulating immune cells (including neutrophils, macrophages, and lymphocytes) involved in the inflammatory process. The inflammatory response is especially harmful in the acute phase due to harmful substances secreted by infiltrating immune cells. The inflammatory response also has beneficial effects, especially in the later stages. Their role in pathophysiology makes immune cells important therapeutic targets. General immunosuppressive approaches and depleting cell groups such as neutrophils or keeping them away from the lesion site may not be sufficient to prevent poor outcomes after ICH. This is most likely because they suppress anti-inflammatory activities and pro-inflammatory effects. Instead, directing immune cells to the beneficial subpopulation seems like a more rational solution. The pro-inflammatory N1 subpopulation of neutrophils damages the tissue surrounding ICH. In contrast, the N2 subpopulation is associated with anti-inflammatory reactions and tissue repair. Studies show that when neutrophils are polarized toward the N2 subpopulation, clinical outcomes improve and the volume of the infarct decreases. However, more research is still needed. This study aims to evaluate the role of neutrophils as immunotherapeutic targets in ICH in light of current knowledge.</p>","PeriodicalId":23084,"journal":{"name":"Therapeutic innovation & regulatory science","volume":" ","pages":"807-816"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945940","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}