罕见药研发热引发新竞争 常见病用药研发疲软 制药公司偏爱罕见药

近日,美国FDA在药品评价和研究中心（CDER）设置了一个新的职位,以帮助罕见病治疗药物顺利的通过审评上市。此外,FDA和EMEA还就罕见病用药的审评达成合作协议,允许申办人就同一罕见病用药申请提交完全相同的年度报告,以尽量简化此类药物的审评程序,减少企业的研发投入,尽快满足临床上未被满足的需求。两大监管机构在罕见药审评政策上的倾斜,的确激发了制药行业开发罕见药的热情。     

2012年度中国药品审评报告

2012年,经过药品审评中心的审评,提出建议批准以下多个重要治疗领域的药品,为患者获得最新治疗手段提供了可能性,为患者用药可及性及可支付性提供了重要保证。1抗艾滋病药物(HIV)领域针对HIV耐药以及增加治疗的顺应性方面,今年提供了以下与全球同步的、最新的治疗手段。1.1利匹韦林片(批准文号:H20120561),是一种二苯胺嘧啶衍生物,属于新型的非核苷类逆转录酶抑制剂(NNRTl),具有很强的抗野生型HIV-1和耐药突变株活性。对耐药的HIV患者具有治疗作用。FDA批准时间2011年5月。2012年我国批准该药品上市,使     

刍议FDA米多君片审评审批历程及对我国药品监管的启示

美国食品药品管理局（FDA）在聚焦临床需求的监管理念和策略的实践中,不断调整修正监管在法规和措施上不适应,对我国完善药品监管制度有借鉴价值。采用文献研究法,通过查找相关文献以及FDA网站发布的一些信息和数据以及专家访谈,研究分析产品的临床治疗特点和审评审批历程,并就其存在的现象进行思考,旨在分析心血管疾病治疗药物盐酸米多君片在美国获得加快审评审批、上市、撤市、再次批准上市等全过程,探讨FDA聚焦临床需求的风险-获益平衡的药品监管理念及相关策略和措施,以期对我国药品审评审批的理念调整和监管制度的完善提供借鉴。     

美国FDA药品生产质量监管体系

美国食品药品监督管理局(Food and Drug Administration,FDA)作为全球药品监管机构的领先者,具备先进的科学和完善的法规体系及合理的机构设置和有效的运行机制。本文针对药品生产质量监管,剖析FDA注册审评、现场检查及合规审评三方面职能,讨论其部门设置和职能划分、运行机制,及资源配置和技术支持,为药监部门加强科学监管提供借鉴,也为企业了解美国FDA药品生产质量监管体系并与其有效沟通提供参考。     

从利司扑兰浅谈我国罕见病药物的审评审批

利司扑兰是基于我国罕见病监管政策快速获批的脊髓性肌萎缩症(SMA)治疗药物,其注册上市有效解决了我国患者未满足的临床需求和药物可获得性问题。本文结合SMA的疾病特征和未满足临床需求,简要回顾了利司扑兰的研发过程,以及申请人在早期临床研究期间与国家药品监督管理局药品审评中心(CDE)之间的沟通交流,进而阐述了CDE对利司扑兰关键性临床研究的评估,着重介绍了有关地区间差异问题的数据分析和审评考量。这个案例不仅展现了我国监管机构从患者的临床需求出发、积极解决罕见病药物可及性的价值导向,和对罕见病人群的人文关怀,另一方面也彰显了以数据为基础、以科学为依据的审评原则。     

美国食品和药物管理局对临床试验申办者现场核查情况分析

目的为加强和促进对我国药物临床试验申办者的监管提供借鉴。方法收集美国食品和药物管理局(FDA)网站上公布的生物研究监查(BIMO)项目2007—2014财政年度工作情况报告、科学调查办公室(OSI)工作情况更新报告及FDA 2010—2016财政年度预算报告中相关数据,分析FDA对临床试验申办者现场核查的比例、结果分级及FDA对药物临床试验核查的情况等。结果 2007—2011财政年度,FDA对临床试验申办者的现场核查比例逐年上升,自2012年降至中间水平后呈现平稳波动,同时自2009年起FDA对此类核查中发现的问题采取官方行动的比例明显下降。FDA药品审评和研究中心(CDER)组织实施的药物临床试验核查数量超过BIMO项目各中心GCP核查总数的一半,其未对所有新药申请和生物制品许可申请的申办者进行现场核查,受委托承担部分申办者职责的合同研究组织(CRO)亦是此类核查的重要内容。结论针对申办者的现场核查是药物临床试验监管的重要组成部分,借鉴国外成熟的监管经验建立符合我国国情的药物临床试验申办者和CRO的监管制度并开展相关的现场核查势在必行。     

国外药品审评专家咨询制度在药品审评体系中的作用及思考

目的：进一步促进我国药品审评专家咨询制度发挥其在药品注册申请审评体系中的作用。方法： 通过介绍美国食品药品监督管理局(FDA)、欧洲药品管理局(EMA)及日本药品和医疗器械管理局 (PDMA)对于药品审评专家咨询委员会(简称“专家咨询委员会”)的管理、定位及日常工作程序设定,分析欧美日监管体系下专家咨询委员会在药品审评审批体系中发挥的作用,进一步探索我国药品审评专家咨询制度的发展方向。结果和结论：FDA、EMA和PMDA均具有完善的专家咨询委员会工作制度。其中,FDA的咨询委员会中包含消费者代表、行业代表和病人代表,涵盖面广,充分考虑到各方利益;EMA的科学咨询小组和PMDA的科学委员会则要求成员不能为监管部门成员。这些举措对提高专家咨询会公正性和工作透明度均具有借鉴意义。我国药品监管部门可以进一步完善药品审评专家咨询委员会工作制度,充分发挥专家咨询制度在专业审评阶段与综合审评阶段的咨询作用,在保护申请人商业秘密前提下,提高专家咨询会工作透明度,加强网络建设,将更有利于发挥药品专家委员会在药品审评体系中的作用。     

治疗痤疮的非专利药Benzamycin获FDA批准

Atrix公司治疗痤疮的Benzamycin(3%红霉素/5%过氧化苯甲酰)非专利药获美国FDA批准,该药作为简化程序的新药申请(ANDA)时由于对非炎症损伤与原创药的生物等效性未被证实而于2003年8月被FDA驳回。但由于该申请的数据是来自400例患者的临床试验而非仅仅是药代动力学数据而与其他ANDA药品不同,同时原创药的标签也标     

世界新药之窗

抗感染药物研发最新动态FDA批准Reyataz更新药品标签用于治疗感染人免疫缺陷病毒(HIV)的孕妇FDA已经批准百时美-施贵宝公司Reyataz(atazanavirsulfate)最新药品标签,其中新增了针对感染HIV的孕妇的推荐剂量。该项更新基于一项多中心、开放性、前瞻性、单组药代动力学临床研究的数据(Study 182;临床编号:     

Janssen公司提交了新作用方式的抗结核病药物的新药申请

Janssen Research&Development向美国FDA提交了在研药物bedaquiline(TMC-207)的新药申请(NDA),以寻求加速批准其口服用于联合治疗成人多重耐药肺结核。如果获得FDA批准,本品将成为40多年以来首个具有新作用机制的结核病治疗药物,并且成为惟一一个特别适用于多重耐药肺结核     

Timing of carcinogenicity studies and predictability of genotoxicity for tumorigenicity in anti-HIV drug development

The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment. We also examine the correlation of genotoxicity data with carcinogenicity data for the varied subclasses of anti-HIV drugs. We suggest that this regulatory policy regarding the timing of carcinogenicity testing does not compromise the safety standards of FDA's drug evaluation and the approval process. The policy does facilitate availability of these agents to meet the medical needs of the target population. Our analysis on the profile of carcinogenicity findings of anti-HIV drugs shows trends of class effects. Additionally, both carcinogenicity and genotoxicity data show significant correlations, which provide useful insights into issues involving these 2 important areas of toxicological investigations.     

Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008

Pharmacometric analyses have become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submissions to the US FDA to support drug approval, labelling and trial design decisions. Pharmacometrics is defined as a science that quantifies drug, disease and trial information to aid drug development, therapeutic decisions and/or regulatory decisions. In this report, we present the results of a survey evaluating the impact of pharmacometric analyses on regulatory decisions for 198 submissions during the period from 2000 to 2008. Pharmacometric review of NDAs included independent, quantitative analyses by FDA pharmacometricians, even when such analysis was not conducted by the sponsor, as well as evaluation of the sponsor's report. During 2000-2008, the number of reviews with pharmacometric analyses increased dramatically and the number of reviews with an impact on approval and labelling also increased in a similar fashion. We also present the impact of pharmacometric analyses on selection of paediatric dosing regimens, approval of regimens that had not been directly studied in clinical trials and provision of evidence of effectiveness to support a single pivotal trial. Case studies are presented to better illustrate the role of pharmacometric analyses in regulatory decision making.     

Statistical considerations for rare diseases drug development

ABSTRACT

One of the most challenges for rare disease clinical trials is probably the availability of a small patient population. It is then a great concern on how to conduct clinical trials with a small number of subjects available for obtaining substantial evidence regarding safety and effectiveness for approval of the rare disease drug product under investigation. FDA, however, does not have the intention to create a statutory standard for approval of orphan drugs that are different from the standard for approval of drugs in common conditions. Thus, it is suggested that innovative trial designs such as a complete n-of-1 trial design or an adaptive design should be used for an accurate and reliable assessment of rare disease drug products under investigation. In this article, basic considerations, innovative trial designs, and statistical methods for data analysis are discussed. In addition, some innovative thinking for the evaluation of rare disease drug products is proposed.     

Regulatory Decision‐Making in the United States Based on a Single Pivotal Clinical Study: Principles and Precedents

The concept of regulatory approval in the United States based on substantial evidence from a single adequate and well‐controlled clinical study is not a new or radical concept. Appropriate discussions and developmental milestone meetings between sponsors and U.S. Food and Drug Administration (FDA) have provided a means to reach a shared understanding of specific situations where a single adequate and well‐controlled study may yield substantial evidence to enable a regulatory approval in the United States. FDA's issuance of its final guidance document on evidence of clinical effectiveness brought additional attention to this topic. The basis in US law, regulations, and guidance for regulatory decision making based on a single adequate and well‐controlled trial is reviewed. Further, to illustrate practical implementation of these provisions, this paper summarizes a number of examples of situations in which a single clinical study was the basis for approval by FDA. These examples were grouped into categories for the purpose of illuminating the patterns of established regulatory precedents. Sufficient examples were available to show logical groupings of experiences to demonstrate circumstances in drug development where there are reasonable precedents for use of a single adequate and well‐controlled trial for regulatory decision making. Regulatory decision‐making based on a single adequate and well‐controlled trial appears to be a well‐accepted approach to attaining approval for 1) use of a product for a new indication where patients attain a significant reduction in morbidity or mortality (or both) with treatment with a drug that was previously approved for a related indication, 2) a new dosage regimen for a previously approved product, and 3) a Supplemental Application seeking traditional approval of a product based on confirmatory evidence of clinical efficacy for a product subject to accelerated approval. Not surprisingly, reliance on a single adequate and well‐controlled trial as the basis for approval of an original NDA or BLA for a new chemical entity or new biologic has been infrequent and typically limited to special situations where patients are refractory to other available therapies or where no alternative therapy exists. The examples presented here illustrate a range of practical experiences where a single adequate and well‐controlled trial has successfully provided the primary basis for regulatory approval in the United States. This information should assist developers of drugs and biologics in their consideration of alternative approaches to development and registration of new products and new indications.     

Endpoints and Analyses to Discern Disease-Modifying Drug Effects in Early Parkinson’s Disease

Parkinson’s disease is an age-related degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech, as well as other functions. Symptoms can include tremor, stiffness, slowness of movement, and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60. Presently, there is no precedent for approving any drug as having a modifying effect (i.e., slowing or delaying) for disease progression of Parkinson’s disease. Clinical trial designs such as delayed start and withdrawal are being proposed to discern symptomatic and protective effects. The current work focused on understanding the features of delayed start design using prior knowledge from published and data submitted to US Food and Drug Administration (US FDA) as part of drug approval or protocol evaluation. Clinical trial simulations were conducted to evaluate the false-positive rate, power under a new statistical analysis methodology, and various scenarios leading to patient discontinuations from clinical trials. The outcome of this work is part of the ongoing discussion between the US FDA and the pharmaceutical industry on the standards required for demonstrating disease-modifying effect using delayed start design.     

中药基原鉴定的科学内涵

中药是中国人千百年使用的药品,中药基原鉴定是对中药临床应用的传承性鉴定.药品基原和药材基原具有本质区别.不同版本<中药鉴定学>教材中的中药米源鉴定应该修正为基原鉴定,对其概念、方法和内容应定位在药品上.探讨了中药基原鉴定的定义与范围,分别论述了中药材、中药饮片以及中药复方基原鉴定的内容、方法与基本原理.认为中药的基原具...     

Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.     

Quantification of PFS Effect for Accelerated Approval of Oncology Drugs

By the accelerated approval (AA) mechanism (Code of Federal Regulations 1992), the FDA may grant approval of drugs or biologic products that are intended to treat serious or life-threatening diseases using a surrogate endpoint that is reasonably likely to predict clinical benefit. In oncology, progression-free-survival (PFS) is increasingly used as such a surrogate of overall survival (OS) in Phase III confirmatory trials. Improved understanding on how to deal with the PFS endpoint in trial conduct and data analysis has mitigated some regulatory concerns about this endpoint. However, a glaring gap still exists as how to determine whether the outcome from a registration trial with PFS as the primary endpoint at the time of analysis is reasonably likely to predict a clinical benefit as normally reflected through an effect on OS. Since there is no guidance on this, regulatory agencies tend to look for a compelling PFS effect coupled with an OS effect in the right direction without specification of the effect sizes and significance levels. To address this issue, we propose a synthesized approach that combines the observed OS effect and the estimated OS effect from the PFS data to explicitly test the implicit OS hypothesis at the time of primary analysis. The proposed approach is applied to hypothetical Phase III trials in metastatic colorectal cancer and adjuvant colon cancer settings using the relationships between OS effect size and PFS effect size established from historical data. Prior information on such a historical relationship is frequently cited by relevant decision makers during regulatory reviews for drug approval. However, the information is rarely fully accounted for in the actual (mostly qualitative) decision-making process. Our approach provides a simple analytic tool for deriving a more quantitative decision. It is clear that the design based on our approach may have a larger sample size than a conventional trial with PFS as the primary endpoint, but directly address the elusive OS question that a conventional PFS trial cannot, no matter how good a surrogate endpoint PFS is.     

A Note on Breast Cancer Trials With pCR-Based Accelerated Approval

Accelerated approval by the Food and Drug Administration (FDA), under the agency’s Fast Track review designation, allows early approval of drugs to treat serious diseases and fill an unmet medical need based on a surrogate endpoint. In May 2012, FDA issued a draft Guidance for Industry on the accelerated approval of breast cancer drugs based on the surrogate endpoint “pathologic complete response” (pCR). The research reported in this article investigates potential issues in designing clinical studies for pCR-based accelerated approval. The correlation between pCR and long-term survival was investigated. Two sample comparisons based on a conditional survival model under different assumptions were performed and are discussed along with simulation results. The findings from this research may shed some light on the implementation of the FDA draft guidance.