EMA对儿科治疗细菌性感染药物评价的特殊临床数据要求

欧洲药品管理局（EMA）于2022年5月发布了“治疗细菌性感染药物评价指导原则”及其对儿科特殊临床数据要求的补编，旨在指导治疗儿科感染性疾病的抗菌药的临床开发方案的设计。该补编阐明了对儿科治疗细菌性感染药物临床研究的特殊要求，说明了为达到全身效应的全身给药和为达到局部效应的局部或口服给药的设计要点和在少数需要单独儿科人群疗效研究的具体疾病的研究设计要点，特别说明了对药动学研究和疗效研究患者选择的要求。还详细说明了可在年龄亚群间外推和不能外推疗效的感染性疾病。另外还说明了其安全性研究应考虑的问题。而我国还没有类似的指导文件。详细介绍该补编主要内容，希望对中国儿童用抗菌药的临床研发有直接帮助，并对目前促进儿童用药研发创新的举措有益。     

Characteristics of orphan drug applications that fail to achieve marketing approval in the USA

The US Orphan Drug Act has fostered the development of drugs for patients with rare diseases by granting 'orphan designations', although several orphan drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.     

治疗类风湿关节炎中药新药的临床评价核心问题

类风湿关节炎(RA)是最常见的风湿性疾病之一,治疗RA的中药已经成为新药研发的热点,但是其临床评价中还存在很多需要注意的核心问题。参考国内外相关法规与文献,并结合作者多年来从事中药新药临床研究的实践经验,对治疗RA中药新药的临床评价中在研发目标、设计类型、诊断标准与目标人群、基础治疗、试验周期、有效性评价、安全性评价及试验结束后医疗措施等方面存在的核心问题进行分析与探讨,并提出了解决办法。     

对EMA草药质量标准指南（第3修订版草案）的思考

草药及其产品的质量标准具有区别于化学药品或生物制品的特殊性，因此欧洲药品管理局（EMA）于2018年发布了“质量标准指南：草药物质、草药制剂和草药产品或传统草药产品的检验程序和可接受标准（第3修订版草案）”。EMA的草药及其产品的情况与我国中药有相似之处，从起始物料到成品多为活性成分未知的复杂混合物。目前我国尚未制定关于中药或中药材（饮片）质量标准相关指导原则。介绍该指南文件的主要内容，并结合中药质量监管情况进行分析，以期EMA相关质量标准制定的指导思路为制定中药质量标准提供参考。     

FDA的《长效局部麻醉药开发供企业用指导原则草案》介绍

美国食品药品监督管理局（FDA）于2023年3月发布了《长效局部麻醉药开发的供企业用的指导原则草案》。该指导原则针对长效局部麻醉药新药申请的不同适应证和说明书的声明,尤其是术后镇痛,提出了对这类药物开发和试验设计的详细而具体的许多建议,包括一般临床药理学、人因工程学评价、试验设计、临床有效性评价、临床安全性评价和说明书的声明等诸方面。而我国目前尚没有类似的指导原则,详细介绍FDA该指导原则的主要内容,期望对我国这类药物的开发研究及其监管有所帮助。     

EMA关于固定复方药物临床开发指导原则介绍

欧洲药品管理局（EMA）于2017年3月发布了关于固定复方药物临床开发的指导原则,该指导原则讨论了固定复方药物临床开发过程中的考虑要点和基本技术要求。我国目前尚无类似文件,通过对该指导原则的介绍,希望对我国固定复方药物的研发和审评工作提供参考。     

Advances in the treatment of rheumatoid arthritis: old versus new therapies

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.     

Advances in the treatment of rheumatoid arthritis: old versus new therapies

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.     

Pharmacogenetics of therapies in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory, aggressive arthritis causing irreversible joint destruction and damage when left untreated. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment for RA and ameliorate not only the clinical signs and symptoms but also joint damage associated with the disease. In recent years, biological therapies have been introduced for the treatment of RA, and the effectiveness of these agents in slowing the clinical and radiographic progression in RA has been established beyond question. However, there is significant variability in the response of patients with RA to these therapies. Moreover, the biological therapies are expensive, totaling several thousand dollars in yearly patient costs. Pharmacogenomics, the study of genetic variations in drug-metabolizing enzymes and their translation to differential responses to drugs, is a nascent but rapidly evolving field. The application of pharmacogenomics to therapies used in RA, particularly the new expensive biological agents, holds great promise for tailoring therapy with these agents based on a patient's genetics. Published literature on the pharmacogenetics of commonly used DMARDs and the emerging body of literature on the pharmacogenetics of the new biological therapies in RA are the focus of this review. As evident from the contents of this review, pharmacogenomics is an exciting field which is progressing productively and rapidly. Pharmacogenomic approaches offer powerful tools to optimize drug therapy in individual patients.     

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.     

FDA“慢性鼻-鼻窦炎伴鼻息肉：开发治疗药物供企业用的指导原则草案”介绍

美国食品药品管理局（FDA）于2021年12月发布了"慢性鼻-鼻窦炎伴鼻息肉：开发治疗药物供企业用的指导原则草案"，对慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）治疗药物临床研究的试验人群、设计、有效性、安全性和统计分析提出了许多建议，内容具体、详细，而且便于实际操作。中国目前没有类似的指导原则，详细介绍FDA该指导原则，期待对我国这类药物的临床研究及其监管有直接的参考价值，对制定类似的临床研究指导原则有所启迪。     

Combination therapy for early rheumatoid arthritis

Around 1% of adults in the U.K. have rheumatoid arthritis (RA). U.K. national guidelines recommend that such people should receive disease-modifying anti-rheumatic drugs (DMARDs) as soon as possible after diagnosis, as earlier treatment is more effective in reducing disease progression. Also, it has been proposed that combination DMARD therapy may reduce joint damage more than single drugs. In the light of several recently published trials on combination therapy in early RA, here we update our recommendations on such treatment.     

FDA“供企业用社区获得性细菌性肺炎：治疗药物开发指导原则”介绍

美国食品药品监督管理局（FDA）于2020年6月发布了“供企业用社区获得性细菌性肺炎：治疗药物开发指导原则”。该指导原则阐述了FDA目前对支持治疗社区获得性细菌性肺炎适应症药物的总体开发方案和临床试验设计的看法。详细介绍该指导原则,期望对中国“社区获得性细菌性肺炎抗菌药物研发临床试验技术指导原则（征求意见稿）”的修订以及这类药物的临床研究和监管有帮助。     

Targeting angiogenesis for the treatment of prostate cancer

INTRODUCTION: While multiple therapies exist that prolong the lives of men with advanced prostate cancer, none are curative. This had led to a search to uncover novel targets for prostate cancer therapy, distinct from those of traditional hormonal approaches, chemotherapies, immunotherapies and bone-targeting approaches. The process of tumor angiogenesis is one target that is being exploited for therapeutic gain. AREAS COVERED: The most promising anti-angiogenic approaches for treatment of prostate cancer, focusing on clinical development of selected agents. These include VEGF-directed therapies, tyrosine kinase inhibitors, tumor-vascular disrupting agents, immunomodulatory drugs and miscellaneous anti-angiogenic agents. While none of these drugs have yet entered the market for the treatment of prostate cancer, several are now being tested in Phase III registrational trials. EXPERT OPINION: The development of anti-angiogenic agents for prostate cancer has met with several challenges. This includes discordance between traditional prostate-specific antigen responses and clinical responses, which have clouded clinical trial design and interpretation, potential inadequate exposure to anti-angiogenic therapies with premature discontinuation of study drugs and the development of resistance to anti-angiogenic monotherapies. These barriers will hopefully be overcome with the advent of more potent agents, the use of dual angiogenesis inhibition and the design of more informative clinical trials.     

New prospects for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Current therapies fail to stop joint damage and reduce long-term disability. Greater understanding of disease pathogenesis has identified many inflammatory mediators as possible therapeutic targets. Novel therapeutic agents, such as monoclonal antibodies (mAbs), cytokine receptor-human immunoglobulin constructs, recombinant human proteins and antisense oligodeoxynucleotides targeting these inflammatory mediators have been tested in rheumatoid arthritis with some success. In particular, inflammation can be effectively suppressed using anticytokine therapies. However, the ideal treatment for RA, one that is immunomodulatory and induces prolonged disease remission after a single course of therapy, still eludes us. Strategies aiming to achieve this include TCR peptide vaccination and anti-CD4 mAbs, currently in clinical trials in RA.     

中药治疗类风湿性关节炎及临床应用的研究进展

类风湿性关节炎是一种全身性的自身免疫性疾病,病变呈持续、反复发作过程,致残率非常高,是临床难治的疾病之一。目前,常用的治疗药物以非甾体类抗炎药、激素类药物、生物制剂等为主,但由于价格昂贵、长期服用毒副作用大,限制了其应用。中药治疗类风湿性关节炎历史悠久,具有疗效好、毒副作用小的优势。因此,有广泛的应用前景。本文就近年来中药治疗类风湿性关节炎及其临床应用的研究进展作一综述。     

FDA “糖尿病足感染：开发治疗药物的供企业用的指导原则草案”介绍

美国食品药品监督管理局（FDA）于2023年11月发布了"糖尿病足感染：开发治疗药物的供企业用的指导原则（草案）"。该指导原则草案提出了糖尿病足感染治疗药物临床开发的建议,包括对这类药物临床试验设计关键要素的许多具体建议,如试验设计、试验人群、疗效评估等方面。而我国目前尚没有类似的指导原则。详细介绍FDA该指导原则草案,期望对我国这类药物开发的临床研究及其评价有所裨益。     

Targeted therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most common inflammatory joint disease in adults leading to pain and disability. New drugs, called biologicals, have opened up new possibilities in the treatment of RA. Objective: Targeting pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) or interleukin-1 (IL-1) is well established in clinical care of RA patients. However, lack or loss of clinical response occurs in up to 25% of the patients. New strategies beyond these targets, namely blocking T cells by abatacept or B cells by rituximab (RTX), have been introduced recently. Methods: All relevant clinical trials published in peer-reviewed journals are discussed in this article. Data from abstracts presented at congresses have not been included. Conclusion: TNF blocking agents have significantly improved therapy of and outcome in RA patients and, therefore, are still the first choice biologicals for the treatment of RA. Alternatively, abatacept or RTX offer new options in case of inefficacy of or contraindications against anti-TNF therapy. Forthcoming drugs, such as tocilizumab, will extend our armamentarium to treat RA effectively.     

Remission, a therapeutic goal in inflammatory arthropathies? Clinical data from adalimumab studies

In recent years, there have been major advances in the management of rheumatoid arthritis (RA), leading to the development of tumour necrosis factor (TNF) antagonists. With these agents, it is possible to arrest joint damage and, by treating early in the disease course, to prevent joint damage. It is also now thought that early treatment can achieve clinical remission in a substantial proportion of patients. With these increased expectations, a change is required in the way clinical improvement and drug efficacy is measured. The existing standard endpoint commonly used in RA clinical trials, the American College of Rheumatology (ACR) 20% response measure, is inadequate for the new goals of therapy that should be based on clinical remission and radiographic assessment.Adalimumab, a fully human anti-TNF monoclonal antibody, has been shown to be effective in achieving remission and preventing radiographic progression of joint damage in patients with RA and other inflammatory arthropathies, including psoriatic arthritis and ankylosing spondylitis. In a placebo-controlled trial in patients with early RA, combination treatment with adalimumab plus methotrexate (MTX) has been shown to be superior to either treatment alone in inducing significant clinical remission while being generally well tolerated. Compared with monotherapy, combination therapy resulted in significantly more patients (49% vs 25%; p < 0.001) remaining in clinical remission after 2 years. Suppression of joint damage assessed by the degree of inhibition of radiographic progression was also significantly higher for patients treated with adalimumab plus MTX (and with adalimumab alone) at 6 months, 1 and 2 years than for those treated with MTX alone. These data support the notion that clinical remission is a realistic therapeutic goal in patients with RA.