Clinical Research and Regulatory Affairs最新文献_第2页

Linezolid in South Africa: The regulatory authority’s role in supporting access to improved treatment regimens for drug-resistant tuberculosis 南非的利奈唑胺:监管机构在支持获得改进的耐药结核病治疗方案方面的作用

Clinical Research and Regulatory Affairs

Pub Date : 2015-09-18 DOI: 10.3109/10601333.2015.1079216

Julia Hill

Abstract The rising incidence of drug-resistant tuberculosis (DR-TB) in South Africa is cause for concern, with doctors having limited treatment options to offer patients who face excruciating side-effects from existing medications, and poor odds of treatment success. With several newer drugs showing efficacy against DR-TB, increased possibilities exist to stem the tide of the epidemic, shorten treatment duration, and improve outcomes. To take advantage of this potential TB treatment revolution, countries must rapidly facilitate access to existing and future drugs. This requires co-ordinated action from governments, and particularly regulatory authorities, in promoting early access to new treatments, tackling intellectual property and price barriers, expediting regulatory approval, adopting and implementing up-to-date TB management policies, and engaging with research and development processes for new regimens. Doctors Without Borders expended great effort to obtain a less expensive version of the drug, linezolid, for its DR-TB pilot program in Khayelitsha, South Africa. This piece describes that experience, and subsequently offers recommendations for policy reforms which could help South Africa more rapidly access other new TB drugs in the future. The South African experience may be of relevance to other countries seeking advice on how to facilitate access to new treatments and tackle their TB epidemics.

南非耐药结核病(DR-TB)发病率的上升引起了人们的关注，因为医生为患者提供的治疗选择有限，而这些患者面临着现有药物的严重副作用，而且治疗成功的几率很低。随着几种新药显示出对耐药结核病的疗效，遏制这一流行病的趋势、缩短治疗时间和改善结果的可能性增加。为了利用这一潜在的结核病治疗革命，各国必须迅速促进获得现有和未来的药物。这需要各国政府，特别是监管机构采取协调行动，促进早期获得新疗法，解决知识产权和价格障碍，加快监管审批，采用和实施最新的结核病管理政策，并参与新疗法的研发过程。无国界医生组织花费了巨大的努力，为其在南非Khayelitsha的耐药结核病试点项目获得了一种更便宜的药物利奈唑胺。这篇文章描述了这一经验，并随后提出了政策改革建议，这些建议可以帮助南非在未来更快地获得其他新的结核病药物。南非的经验可能对其他就如何促进获得新的治疗方法和应对结核病流行寻求建议的国家具有借鉴意义。

{"title":"Linezolid in South Africa: The regulatory authority’s role in supporting access to improved treatment regimens for drug-resistant tuberculosis","authors":"Julia Hill","doi":"10.3109/10601333.2015.1079216","DOIUrl":"https://doi.org/10.3109/10601333.2015.1079216","url":null,"abstract":"Abstract The rising incidence of drug-resistant tuberculosis (DR-TB) in South Africa is cause for concern, with doctors having limited treatment options to offer patients who face excruciating side-effects from existing medications, and poor odds of treatment success. With several newer drugs showing efficacy against DR-TB, increased possibilities exist to stem the tide of the epidemic, shorten treatment duration, and improve outcomes. To take advantage of this potential TB treatment revolution, countries must rapidly facilitate access to existing and future drugs. This requires co-ordinated action from governments, and particularly regulatory authorities, in promoting early access to new treatments, tackling intellectual property and price barriers, expediting regulatory approval, adopting and implementing up-to-date TB management policies, and engaging with research and development processes for new regimens. Doctors Without Borders expended great effort to obtain a less expensive version of the drug, linezolid, for its DR-TB pilot program in Khayelitsha, South Africa. This piece describes that experience, and subsequently offers recommendations for policy reforms which could help South Africa more rapidly access other new TB drugs in the future. The South African experience may be of relevance to other countries seeking advice on how to facilitate access to new treatments and tackle their TB epidemics.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"21 1","pages":"113 - 118"},"PeriodicalIF":0.0,"publicationDate":"2015-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85172003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The regulation of fecal microbiota for transplantation: An international perspective for policy and public health 粪便微生物群对移植的调节:政策和公共卫生的国际视角

Clinical Research and Regulatory Affairs

Pub Date : 2015-07-03 DOI: 10.3109/10601333.2015.1046602

Carolyn Edelstein, Z. Kassam, J. Daw, Mark B. Smith, C. Kelly

Abstract Clostridium difficile is the most common hospital-acquired pathogen in the US, and recurrent C. difficile infection (CDI) is a major public health issue. Twenty per cent of CDI patients experience recurrence, and their risk of recurrence rises with each failure to achieve clinical resolution. Fecal microbiota transplantation (FMT) is a remarkably efficacious treatment for recurrent CDI. However, national health agencies are grappling with the appropriate regulatory paradigm to apply to this innovative treatment. Current FMT regulations in the US, Canada, Western Europe, Australia, and China are in varying degrees of flux, although many regulators are choosing to apply the drug and biologic framework. FMT regulations should allow recurrent CDI patients safe access to this treatment as research continues. Regulating FMT like a drug or biologic, although most convenient from a legal perspective, overly restricts access while under-regulating the methods by which the stool is screened, processed, stored, and used. Human tissue and tissue-based products regulations could achieve the desired level and kind of oversight, but fecal microbiota for transplantation fail to meet applicable statutory definitions. A custom regulatory solution would be more appropriate, but many pathways that regulators may take to achieve this goal require time and resources for health agencies to develop.

艰难梭菌(Clostridium difficile)是美国最常见的医院获得性病原体，复发性艰难梭菌感染(CDI)是一个重大的公共卫生问题。20%的CDI患者会经历复发，并且随着每次临床治疗失败，他们的复发风险会增加。粪便微生物群移植(FMT)是治疗复发性CDI非常有效的方法。然而，国家卫生机构正在努力寻找适用于这种创新治疗的适当监管范例。目前美国、加拿大、西欧、澳大利亚和中国的FMT法规处于不同程度的变化中，尽管许多监管机构选择应用药物和生物框架。随着研究的继续，FMT法规应允许复发性CDI患者安全获得这种治疗。虽然从法律角度来看，将FMT作为一种药物或生物制剂进行监管是最方便的，但它过度限制了获取，而对粪便筛选、处理、储存和使用的方法监管不足。人体组织和基于组织的产品法规可以达到所需的水平和监督类型，但用于移植的粪便微生物群未能满足适用的法定定义。定制监管解决方案更为合适，但监管机构为实现这一目标可能采取的许多途径需要卫生机构开发时间和资源。

{"title":"The regulation of fecal microbiota for transplantation: An international perspective for policy and public health","authors":"Carolyn Edelstein, Z. Kassam, J. Daw, Mark B. Smith, C. Kelly","doi":"10.3109/10601333.2015.1046602","DOIUrl":"https://doi.org/10.3109/10601333.2015.1046602","url":null,"abstract":"Abstract Clostridium difficile is the most common hospital-acquired pathogen in the US, and recurrent C. difficile infection (CDI) is a major public health issue. Twenty per cent of CDI patients experience recurrence, and their risk of recurrence rises with each failure to achieve clinical resolution. Fecal microbiota transplantation (FMT) is a remarkably efficacious treatment for recurrent CDI. However, national health agencies are grappling with the appropriate regulatory paradigm to apply to this innovative treatment. Current FMT regulations in the US, Canada, Western Europe, Australia, and China are in varying degrees of flux, although many regulators are choosing to apply the drug and biologic framework. FMT regulations should allow recurrent CDI patients safe access to this treatment as research continues. Regulating FMT like a drug or biologic, although most convenient from a legal perspective, overly restricts access while under-regulating the methods by which the stool is screened, processed, stored, and used. Human tissue and tissue-based products regulations could achieve the desired level and kind of oversight, but fecal microbiota for transplantation fail to meet applicable statutory definitions. A custom regulatory solution would be more appropriate, but many pathways that regulators may take to achieve this goal require time and resources for health agencies to develop.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"15 1","pages":"107 - 99"},"PeriodicalIF":0.0,"publicationDate":"2015-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87888578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

Inter-ethnic differences in drug response: Implications for drug development and complying with drug regulation 药物反应的种族间差异:对药物开发和遵守药物监管的影响

Clinical Research and Regulatory Affairs

Pub Date : 2015-07-03 DOI: 10.3109/10601333.2015.1064131

R. Shah

Abstract The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.

药物剂量-浓度(药代动力学)和/或浓度-反应(药效学)关系的药理学两个关键组成部分经常受到遗传变异的影响。这些因素解释了剂量反应或药物反应的很大一部分差异，不仅在个体之间，而且在不同的种族群体之间。“BiDil”被批准用于治疗自我认定为黑人的心力衰竭患者，这是一个引人注目的例子，说明了药物反应和研究人群种族监管意识的种族间差异。药物开发项目越来越多地在全球范围内进行，以降低成本，缩短时间框架，并解决有关全球处方的问题。监管当局对这种药物开发的全球化作出了回应，颁布了指导方针，建议新药的赞助商探索基因变异的作用，以及不同种族人群之间药物反应的潜在差异。他们可能会拒绝接受申请，或者要求衔接学习，当这些差异是预期的，但没有充分解决。这些桥接研究可能包括(i)药代动力学研究，(ii)药效学研究，(iii)剂量反应研究，和/或(iv)在极端情况下，关键的iii期研究，以推断从一个人群到另一个人群的疗效和/或安全性数据。

{"title":"Inter-ethnic differences in drug response: Implications for drug development and complying with drug regulation","authors":"R. Shah","doi":"10.3109/10601333.2015.1064131","DOIUrl":"https://doi.org/10.3109/10601333.2015.1064131","url":null,"abstract":"Abstract The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"38 1","pages":"88 - 98"},"PeriodicalIF":0.0,"publicationDate":"2015-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85379053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Evaluating the impacts of the FDA’s guidance for patient-reported outcomes (PROs) measures on clinical trial-based approved drug product labeling claims, 2006–2014 评估2006-2014年FDA关于基于临床试验的批准药品标签声明的患者报告结果(PROs)措施指南的影响

Clinical Research and Regulatory Affairs

Pub Date : 2015-07-03 DOI: 10.3109/10601333.2015.1064441

A. Palsgrove

Abstract The FDA’s Guidance for Industry, Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (i.e. “PRO Guidance”; 2009) outlines the agency’s perspectives on how PRO measures, used to support efficacy end-points in therapeutics clinical trial programs, may be evaluated by the FDA. Prior reviews have attempted to identify PRO-based statements in product labels in order to evaluate the potential impacts of the PRO guidance on the rate of approvals of PRO-based claims, but none have been enacted after 2010. An in-depth search identified drug product labels approved by the FDA from January 2006 through to December 2014, with efficacy statements supported by PRO measures. Drug product labels were sorted by chemical type and year of approval, and the differences between time periods before and after the finalization of the PRO Guidance were reviewed with statistical tests. Results showed a reduction in the overall approvals of label-based efficacy statements supported by PRO measures after 2009, which may indicate that fewer phase 3 clinical trial programs have met agency benchmarks for the inclusion of subjective assessments as primary or secondary end-points in support of therapeutic efficacy.

FDA的行业指南，患者报告的结果(PRO)措施:用于医疗产品开发以支持标签声明(即“PRO指南”);2009年)概述了FDA如何评估用于支持治疗学临床试验项目疗效终点的PRO测量方法的观点。之前的审查试图在产品标签中识别基于PRO的声明，以评估PRO指南对基于PRO的声明批准率的潜在影响，但在2010年之后没有颁布。深入搜索了2006年1月至2014年12月期间FDA批准的药品标签，其功效声明得到了PRO措施的支持。按化学药品类型和批准年份对药品标签进行分类，并对PRO指南定稿前后时间段的差异进行统计检验。结果显示，2009年之后，由PRO措施支持的基于标签的疗效声明的总体批准数量有所减少，这可能表明，更少的3期临床试验项目达到了将主观评估作为支持治疗疗效的主要或次要终点的机构基准。

{"title":"Evaluating the impacts of the FDA’s guidance for patient-reported outcomes (PROs) measures on clinical trial-based approved drug product labeling claims, 2006–2014","authors":"A. Palsgrove","doi":"10.3109/10601333.2015.1064441","DOIUrl":"https://doi.org/10.3109/10601333.2015.1064441","url":null,"abstract":"Abstract The FDA’s Guidance for Industry, Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (i.e. “PRO Guidance”; 2009) outlines the agency’s perspectives on how PRO measures, used to support efficacy end-points in therapeutics clinical trial programs, may be evaluated by the FDA. Prior reviews have attempted to identify PRO-based statements in product labels in order to evaluate the potential impacts of the PRO guidance on the rate of approvals of PRO-based claims, but none have been enacted after 2010. An in-depth search identified drug product labels approved by the FDA from January 2006 through to December 2014, with efficacy statements supported by PRO measures. Drug product labels were sorted by chemical type and year of approval, and the differences between time periods before and after the finalization of the PRO Guidance were reviewed with statistical tests. Results showed a reduction in the overall approvals of label-based efficacy statements supported by PRO measures after 2009, which may indicate that fewer phase 3 clinical trial programs have met agency benchmarks for the inclusion of subjective assessments as primary or secondary end-points in support of therapeutic efficacy.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"13 1","pages":"75 - 82"},"PeriodicalIF":0.0,"publicationDate":"2015-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81901120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Challenges of risk-based monitoring of clinical trials 基于风险的临床试验监测的挑战

Clinical Research and Regulatory Affairs

Pub Date : 2015-07-03 DOI: 10.3109/10601333.2015.1046990

M. Simović, N. Nikolić

Abstract The oversight of monitoring activities in clinical trials generally comes from the ICH GCP Guidelines and covers a wide range of responsibilities: trial progress oversight, adherence to the Study Protocol, Standard Operating Procedures, Good Clinical Practice, applicable regulatory requirement(s) and Source Data verification vs accuracy and completeness of the Case Report Form entries. Risk-based monitoring was developed and adopted by Sponsors, Investors, and CROs to decrease the costs of clinical trials and make study management more effective. Both the EMA and the FDA support such an approach with their papers. Interestingly, the review of the EMA “Annual report of the GCP Inspectors working group in 2012” has consistently shown persistence of a significant number of findings in fields/areas of monitoring that cannot be fully or partially captured with a centralized or targeted monitoring approach and cannot be identified, such as essential documents, presence and adherence to SOPs, trainings, and the quality of source documentation. Such results open up new challenges for Sponsors, CROs, and other stakeholders. As long as all current ICH GCP Guidelines are a cornerstone of clinical research, monitoring plans and risk assessments will include overseeing a significant pool of additional aspects, apart from the SDV.

临床试验中监测活动的监督通常来自ICH GCP指南，涵盖了广泛的责任:试验进度监督，对研究方案的遵守，标准操作程序，良好临床实践，适用的监管要求以及源数据验证与病例报告表条目的准确性和完整性。基于风险的监测是由发起人、投资者和cro开发和采用的，以降低临床试验的成本，使研究管理更有效。EMA和FDA都在他们的论文中支持这种方法。有趣的是，EMA对“2012年GCP检查员工作组年度报告”的审查一致显示，在监测领域/领域中存在大量持续存在的发现，这些发现无法通过集中或有针对性的监测方法全部或部分捕获，也无法识别，例如基本文件、对sop的存在和遵守、培训和源文件的质量。这样的结果给发起人、cro和其他利益相关者带来了新的挑战。只要所有现行的ICH GCP指南都是临床研究的基石，监测计划和风险评估将包括监督除SDV之外的大量其他方面。

{"title":"Challenges of risk-based monitoring of clinical trials","authors":"M. Simović, N. Nikolić","doi":"10.3109/10601333.2015.1046990","DOIUrl":"https://doi.org/10.3109/10601333.2015.1046990","url":null,"abstract":"Abstract The oversight of monitoring activities in clinical trials generally comes from the ICH GCP Guidelines and covers a wide range of responsibilities: trial progress oversight, adherence to the Study Protocol, Standard Operating Procedures, Good Clinical Practice, applicable regulatory requirement(s) and Source Data verification vs accuracy and completeness of the Case Report Form entries. Risk-based monitoring was developed and adopted by Sponsors, Investors, and CROs to decrease the costs of clinical trials and make study management more effective. Both the EMA and the FDA support such an approach with their papers. Interestingly, the review of the EMA “Annual report of the GCP Inspectors working group in 2012” has consistently shown persistence of a significant number of findings in fields/areas of monitoring that cannot be fully or partially captured with a centralized or targeted monitoring approach and cannot be identified, such as essential documents, presence and adherence to SOPs, trainings, and the quality of source documentation. Such results open up new challenges for Sponsors, CROs, and other stakeholders. As long as all current ICH GCP Guidelines are a cornerstone of clinical research, monitoring plans and risk assessments will include overseeing a significant pool of additional aspects, apart from the SDV.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"9 1","pages":"83 - 87"},"PeriodicalIF":0.0,"publicationDate":"2015-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80553614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Opportunities to improve clinical trial design in urothelial bladder cancer 改善尿路上皮性膀胱癌临床试验设计的机会

Clinical Research and Regulatory Affairs

Pub Date : 2015-04-03 DOI: 10.3109/10601333.2015.1022282

J. Chiu, S. Sridhar

Abstract Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.

摘要:在过去的三十年中，尿路上皮癌(UC)的治疗进展有限。随着新药物的出现，需要对UC范围内的试验设计进行批判性的审视。早期UC试验的目标应该是根据风险水平对患者进行分层，通过分子特征来定义，以减少异质性并改善对试验结果的解释。对于肌肉侵袭性UC，应鼓励新辅助化疗的实践，特别是完全病理反应可以用作试验的替代终点测量，并且有可能获得加速的药物批准。新辅助设置也提供了一个独特的机会，评估生物标志物和靶向治疗给予肿瘤组织的可用性。对于晚期疾病，更应重视对不符合顺铂治疗条件或表现较差的患者的研究，这代表了许多UC患者。保膀胱治疗，结合靶向HER2或PI3K/AKT/mTOR通路的药物，或免疫治疗是UC潜在的新方向。生活质量作为UC临床试验终点的重要性也不应被忽视。最终，多学科的大规模合作将是推动这一领域向前发展的关键。

{"title":"Opportunities to improve clinical trial design in urothelial bladder cancer","authors":"J. Chiu, S. Sridhar","doi":"10.3109/10601333.2015.1022282","DOIUrl":"https://doi.org/10.3109/10601333.2015.1022282","url":null,"abstract":"Abstract Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"5 1","pages":"61 - 69"},"PeriodicalIF":0.0,"publicationDate":"2015-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73612859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EU regulatory guidelines for the clinical evaluation of adjuvants 辅助剂临床评价的欧盟法规指南

Clinical Research and Regulatory Affairs

Pub Date : 2015-04-03 DOI: 10.3109/10601333.2015.1001899

B. Klug, P. Celis, Robin Ruepp, J. Robertson

Abstract Adjuvants have been incorporated into vaccines for decades to improve the immune response to vaccine antigens. In developing new vaccines or simply improving existing vaccines, interest in adjuvants has been growing rapidly, with various types of adjuvant (some novel; some already incorporated into specific vaccines) used in clinical research or under development. The development of adjuvants is generally closely linked to the development of a specific vaccine. With the adjuvant being an integral constituent of the final medicinal product, current legislation does not foresee authorization being granted for an adjuvant as a stand-alone product. A dedicated EU guideline addresses the quality non-clinical and clinical development of vaccine adjuvants, and this guidance needs to be considered alongside the specific guidelines for medicinal products in general. This paper provides an overview of the requirements for developing or modifying an adjuvanted vaccine. The authors also address the experience gained for the adjuvanted 2009 H1N1 pandemic influenza vaccine and its implications.

佐剂已被纳入疫苗几十年，以提高免疫应答疫苗抗原。在开发新疫苗或仅仅改进现有疫苗的过程中，对佐剂的兴趣迅速增长，有各种类型的佐剂(一些是新型的;有些已被纳入临床研究或正在开发的特定疫苗中。佐剂的开发通常与特定疫苗的开发密切相关。由于佐剂是最终药品的组成部分，目前的立法没有预见到将佐剂作为独立产品授予授权。专门的欧盟指南涉及疫苗佐剂的非临床和临床开发的质量，该指南需要与一般药品的具体指南一起考虑。本文概述了开发或修改佐剂疫苗的要求。作者还讨论了2009年H1N1大流行性流感佐剂疫苗获得的经验及其影响。

引用次数: 2

Clinical trial design methodologies for advanced sarcoma therapy 晚期肉瘤治疗的临床试验设计方法

Clinical Research and Regulatory Affairs

Pub Date : 2015-04-03 DOI: 10.3109/10601333.2015.1012209

B. Petek, S. Pollack, A. Constantinidou, Robin L. Jones

Abstract Sarcomas are rare and heterogeneous mesenchymal tumors affecting connective tissue. For many years, doxorubicin-based chemotherapy has been the main systemic therapy option for patients with metastatic soft tissue sarcoma. This ‘one size fits all’ approach has led to marginal benefit, but the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumors has shown that sub-type-specific, molecularly targeted therapy can lead to significant advances. Next generation sequencing has led to the discovery of the biologic nature of many histological sub-types of sarcomas, and now an emphasis has been placed on assessment of novel therapies for each sub-group. However, the transition into the clinic is both challenging and protracted due to the rarity and heterogeneity of these tumors. The high failure rate of phase III trials in oncology has shown that clinical trials can be difficult to run, especially in rare forms of cancer like sarcomas. In this review, the authors provide an evaluation of the potential approaches toward better clinical trial design in sarcoma studies.

肉瘤是影响结缔组织的罕见异质性间充质肿瘤。多年来，以阿霉素为基础的化疗一直是转移性软组织肉瘤患者的主要全身治疗选择。这种“一刀切”的方法带来了边际效益，但在胃肠道间质肿瘤中引入酪氨酸激酶抑制剂已经表明，亚型特异性、分子靶向治疗可以带来重大进展。下一代测序已经发现了许多肉瘤组织学亚型的生物学性质，现在的重点是评估每个亚组的新疗法。然而，由于这些肿瘤的罕见性和异质性，向临床的过渡既具有挑战性又旷日持久。肿瘤学三期试验的高失败率表明，临床试验可能很难进行，尤其是在像肉瘤这样的罕见癌症中。在这篇综述中，作者对肉瘤研究中更好的临床试验设计的潜在方法进行了评估。

引用次数: 0

Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel. 经颅直流电刺激（tDCS）临床和研究使用的监管考虑因素：专家小组的审查和建议。

Clinical Research and Regulatory Affairs

Pub Date : 2015-03-01 DOI: 10.3109/10601333.2015.980944

F Fregni, M A Nitsche, C K Loo, A R Brunoni, P Marangolo, J Leite, S Carvalho, N Bolognini, W Caumo, N J Paik, M Simis, K Ueda, H Ekhitari, P Luu, D M Tucker, W J Tyler, J Brunelin, A Datta, C H Juan, G Venkatasubramanian, P S Boggio, M Bikson

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.

在过去 15 年中，经颅电刺激（tES）领域取得了长足的发展。其中，经颅直流电刺激（tDCS）是最受关注的经颅电刺激技术之一。大量研究工作致力于确定经颅直流电刺激在人体中的临床潜力。尽管 tDCS 在基础和临床神经科学领域取得了令人鼓舞的成果，但由于国际监管途径不明确，阻碍了进一步的进展。因此，我们召集了一组有关 tDCS 的研究和临床专家，对 tDCS 的研究和临床应用进行审查。在本报告中，我们回顾了 tDCS 的监管现状，并根据以下国家的 tDCS 研究、标示外使用和同情使用情况对结果进行了总结：澳大利亚、巴西、法国、德国、印度、伊朗、意大利、葡萄牙、韩国、台湾和美国。本研究审查的大多数国家都采用了 tDCS 的研究使用、标签外治疗和同情使用。至关重要的是，应在全球或地方范围内做出努力，以充分的随机对照治疗试验为基础，寻求明确的证据来批准和规范或限制 tDCS 在临床实践中的使用。

{"title":"Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel.","authors":"F Fregni, M A Nitsche, C K Loo, A R Brunoni, P Marangolo, J Leite, S Carvalho, N Bolognini, W Caumo, N J Paik, M Simis, K Ueda, H Ekhitari, P Luu, D M Tucker, W J Tyler, J Brunelin, A Datta, C H Juan, G Venkatasubramanian, P S Boggio, M Bikson","doi":"10.3109/10601333.2015.980944","DOIUrl":"10.3109/10601333.2015.980944","url":null,"abstract":"<p><p>The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.</p>","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"32 1","pages":"22-35"},"PeriodicalIF":0.0,"publicationDate":"2015-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431691/pdf/nihms-646440.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33310564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Adaptive designs for comparative effectiveness research trials 比较有效性研究试验的适应性设计

Clinical Research and Regulatory Affairs

Pub Date : 2015-01-02 DOI: 10.3109/10601333.2014.977490

John Kairalla, C. Coffey, Mitchell A. Thomann, R. Shorr, K. Muller

Abstract Medical and health policy decision-makers require improved design and analysis methods for comparative effectiveness research (CER) trials. In CER trials, there may be limited information to guide initial design choices. In general settings, adaptive designs (ADs) have effectively overcome limits on initial information. However, CER trials have fundamental differences from standard clinical trials including population heterogeneity and a vaguer concept of a “minimum clinically meaningful difference”. The objective of this article is to explore the use of a particular form of ADs for comparing treatments within the CER trial context. To achieve this, the authors review the current state of clinical CER. They also identify areas of CER as particularly strong candidates for application of novel AD and illustrate the potential usefulness of the designs and methods for two group comparisons. The authors found that ADs can stabilize power. Furthermore, the designs ensure adequate power for true effects are at least at clinically significant pre-planned effect size, or when variability is larger than expected. The designs allow for sample size savings when the true effect is larger or when variability is smaller than planned. The authors conclude that ADs in CER have great potential to allow trials to successfully and efficiently make important comparisons.

医疗卫生政策决策者需要改进比较有效性研究(CER)试验的设计和分析方法。在CER试验中，指导初始设计选择的信息可能有限。在一般情况下，自适应设计(ADs)有效地克服了初始信息的限制。然而，CER试验与标准临床试验存在根本差异，包括人群异质性和“最小临床意义差异”的模糊概念。本文的目的是探讨在CER试验背景下使用一种特殊形式的ad来比较治疗。为了达到这个目的，作者回顾了临床CER的现状。他们还确定了CER领域作为新型AD应用的特别强有力的候选者，并说明了两组比较的设计和方法的潜在有用性。作者发现ADs可以稳定电力。此外，设计确保足够的功率，以达到真正的效果，至少在临床显著的预先计划的效应大小，或当变异性大于预期。当真实效果较大或变异性小于计划时，设计允许节省样本量。作者得出结论，CER中的ad具有很大的潜力，可以使试验成功和有效地进行重要的比较。

{"title":"Adaptive designs for comparative effectiveness research trials","authors":"John Kairalla, C. Coffey, Mitchell A. Thomann, R. Shorr, K. Muller","doi":"10.3109/10601333.2014.977490","DOIUrl":"https://doi.org/10.3109/10601333.2014.977490","url":null,"abstract":"Abstract Medical and health policy decision-makers require improved design and analysis methods for comparative effectiveness research (CER) trials. In CER trials, there may be limited information to guide initial design choices. In general settings, adaptive designs (ADs) have effectively overcome limits on initial information. However, CER trials have fundamental differences from standard clinical trials including population heterogeneity and a vaguer concept of a “minimum clinically meaningful difference”. The objective of this article is to explore the use of a particular form of ADs for comparing treatments within the CER trial context. To achieve this, the authors review the current state of clinical CER. They also identify areas of CER as particularly strong candidates for application of novel AD and illustrate the potential usefulness of the designs and methods for two group comparisons. The authors found that ADs can stabilize power. Furthermore, the designs ensure adequate power for true effects are at least at clinically significant pre-planned effect size, or when variability is larger than expected. The designs allow for sample size savings when the true effect is larger or when variability is smaller than planned. The authors conclude that ADs in CER have great potential to allow trials to successfully and efficiently make important comparisons.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"32 1","pages":"36 - 44"},"PeriodicalIF":0.0,"publicationDate":"2015-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91273927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0