看似听似药品管理问题探讨和建议

目的：探讨看似听似（look-alike and sound-alike，LASA）药品管理中存在的问题，以期保证患者用药安全。方法：采用文献资料法，对LASA药品分类及产生原因进行比较分析。结果：LASA药品包括"看似"药品与"听似"药品两类。其中"看似"药品又包括名称与包装"看似"药品，"听似"药品又包括通用名"听似"、商品名"听似"的药品。"看似"药品的产生主要是由于语言体系内字符相似。此外，药厂为了固化品牌形象，有意按特定模式设计了不同产品的包装，导致大量外包装相似的药品的产生。住院及急诊工作人员人为将药品进行分装时，也会人为形成"看似"药品。不同药品通用名"听似"的主要原因是药品结构性之比较相似，药品商品名"听似"则多是药品公司出于商业考虑，进行品牌延伸所导致的。结论：建议通过管理审批中的药品名称及包装，补充LASA药品使用的管理规定；采用技术性方法区分、储存已上市的LASA药品；加强对LASA药品人工调配的规范化管理；推进分级诊疗，改善门诊用药环境及增强患者教育，构建用药安全文化来减少LASA药品导致的用药差错事件。     

A modified large sample approach in the assessment of population bioequivalence

The U.S. Food and Drug Administration (FDA) requires pharmaceutical companies to show bioequivalence between different formulations or generic companies to show bioequivalence between generic drugs and brand drugs before approval. In a recent FDA guidance on bioequivalence, new criteria were proposed for assessment of population and individual bioequivalence. In this article, computer simulation is used to compare a modified large sample (MLS) upper bound for the population bioequivalence ratio with the bootstrap upper bound recommended by the FDA. The comparison criteria are the ability to maintain the stated confidence level and the estimated power of tests based on these bounds.     

Bioequivalence studies for levothyroxine

The Food and Drug Administration (FDA) Guidance for Bioavailability and Bioequivalence Studies for Levothyroxine has been challenged by companies that manufacture brand-name products. Their contention is that the current guidance does not adequately address the endogenous background levels of the drug, and that the ratios of the PK parameters, a basis for approval of equivalence, are not assessed correctly. In particular, they conclude that products that have a potency differing by 12.5% cannot be differentiated using the present guideline and criteria for acceptance of bioequivalence. They claim that such a difference can be a public health hazard because of the perception among practitioners that levothyroxine is a narrow therapeutic index drug. This article describes the procedure recommended in the current Guidance for Levothyroxine and demonstrates that the methods recommended are adequate and will accept products that are therapeutically equivalent. To date, no generic product accepted as equivalent using FDA Guidances has been shown to result in a safety and efficacy profile different from its brand counterpart.     

Key issues in the pharmaceutical industry: consequences on R&D

Drug discovery is hard, and is becoming progressively harder, with the passage of time! No other field has to handle such an interplay of scientific, fiscal and political factors. The rewards are, nonetheless, worth it: people now live healthier and longer lives than at any point of time in the past. Times are, however, hard for pharmaceutical companies: research and development (R&D) costs are spiralling out of control. New drug approvals, on the other hand, have hit a record low; and the situation is expected to worsen, now that the FDA seems to be exhibiting stricter drug approval standards. Other issues also exacerbate circumstances: huge numbers of blockbuster medicines, which drugmakers rely on to generate their incomes, are coming off patent, and generic competition is intensifying. Both public and investor confidence in the industry have fallen drastically owing to rising drug prices, product safety concerns and late-stage clinical trial failures. This article discusses the key issues that pharmaceutical companies face and in particular the implications they have for the R&D process. I finish by suggesting how drugmakers should change their R&D strategies to succeed.     

The Kennedy version of the Drug Regulation Reform Act.

Provisions of Senator Edward Kennedy's version of the Drug Regulation Reform Act of 1979 (S.1075) are discussed. Included in the discussions are pre- and postmarketing approval controls on drug products, product equivalency, drug promotion and information, penalties, and the National Center for Drug Sciences. Provisions of the act are compared with the Carter Administration's 1978 (S.2775, H.R.11611 and H.R.12980) and 1979 (S.1045 and H.R. 4258) drug reform bills. The Kennedy bill does not depart radically from the existing drug approval process but would open it to the public and give FDA more flexibility to impose conditions, such as limited distribution and postmarketing surveillance, to product approval. It establishes drug compendia that would meet federal standards but that preferably would be published by the private sector. Hospitals and other health care institutions are exempted from the bill's patients package insert requirements, except as otherwise regulated by FDA.     

关于直接接触药品的包装材料和容器标准化管理的探讨和改进

简要回顾我国药包材管理的发展历程,分析药包材标准的管理现状和执行过程中出现的不足.依据国家局13号令《直接接触药品的包装材料和容器管理办法》对药包材标准的名称、标准编号、企业标准以及注册管理中有待进一步规范之处进行了初略讨论,提出合理的改进建议,以强化药包材的管理,为药品质量提供有力的保障.     

Nonclinical safety testing of imaging agents,contrast agents and radiopharmaceuticals

Drug development includes imaging agents, contrast agents and radiopharmaceuticals; these materials differ from therapeutic drugs in that they are largely used to diagnose and/or monitor diseases and not treat them. Consequently, nonclinical safety testing needs are different. An examination of testing packages supporting clinical entry and/or marketing of these materials has shown a common approach to some study types (eg, imaging, biodistribution and toxicity testing). Recent regulatory guidelines to support development are the United States Food and Drug Administration (FDA)’s “Guidance for Industry Microdose Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations” and the European Medicines Agency (EMA)’s “Guideline on the Non‐Clinical Requirements for Radiopharmaceuticals” (currently draft). It is hoped that these documents will allow developers to only perform nonclinical studies that are necessary to support functionality, follow distribution of the material and examine general safety/toxicity. However, as they are mainly focused on radiopharmaceuticals, companies are likely to apply knowledge of established testing packages to other new imaging agents and/or follow principles given in older regulatory guidelines, namely FDA’s “Guidance for Industry Developing Medical Imaging Drug and Biological Products Part I Conducting Safety Assessments”. Thus, in some cases, the need for regulatory agency interaction is still vital to avoid development surprises and delays due to an incomplete or badly performed testing package.     

美国孤儿药资格认定及批准上市情况分析

目的： 系统了解美国孤儿药批准情况,分析资格认定和审批趋势。方法：以美国食品药品监督管理局(FDA)数据库Drugs@ FDA和孤儿药资格认定和批准在线数据库为主要数据来源,系统收集美国FDA自1983至2020年认定和批准的孤儿药信息,从审批数量、审批时间、治疗领域等方面进行统计分析。结果：1983-2020年FDA共认定孤儿药资格5757个,批准孤儿药适应症943个。从孤儿药认定身份到获批上市平均所需的时间为5.14年。批准的孤儿药适应症中抗肿瘤和免疫机能调节相关适应症最多,为 408个,占比为43.27%。结论：自1983年《孤儿药法案》实施以来,FDA授予的孤儿药资格数量和批准的孤儿药适应症数量呈现明显的增长趋势。     

处方药说明书[用法用量]项的撰写要点和案例分析

介绍我国国家食品药品监督管理总局(CFDA)、欧洲药品管理局(EMA)和美国食品药品管理局(FDA)对处方药说明书[用法用量]项撰写要点的要求,分析在我国注册报送的说明书样稿典型案例,包括进口药和跨国公司在华药厂的药品说明书样稿,揭示不符合上述要求和违背有效而安全用药基本原则的表现,期待对说明书撰写和监管有益。     

美国与欧盟孤儿药研发上市管理制度及对我国的启示

目的通过对美国与欧盟对孤儿药研发上市相关管理政策的分析,为我国孤儿药研发上市管理提供借鉴。方法分析美国和欧盟药政管理部门公开的法规文献和数据库检索数据,总结其对孤儿药的激励政策,分析获得孤儿药资格认定和批准上市的药物特点。结果美国和欧盟对孤儿药研发均颁布实施了诸如市场独占期、政府资助、审评专家对研究方案的指导等相应的激励政策。研发机构应采取及早申请孤儿药认定、多途径发现孤儿药及孤儿药的再开发等研发策略。结论美国和欧盟对孤儿药的研发与上市激励政策,刺激了制药企业对罕见病治疗药物的研发热情,有效缓解了罕见病无药可治的现状,对我国制定相关孤儿药政策提供了有益的借鉴。国内创新型制药企业应尽早布局孤儿药的研发,应重点关注国内已经被大众接受的罕见病和治疗,以及超说明书使用的问题;重点关注生物仿制药如单克隆抗体的研发动态;重点关注国际孤儿药专业公司的研发动态,使孤儿药在国内相关法律法规建立健全后,立即有所响应,尽早抢占孤儿药研发的领先地位和市场地位。     

Adverse effects in women: implications for drug development and regulatory policies

The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.     

FDA加快新药审批程序及突破性治疗药物分析

FDA注重加快审批治疗人类严重疾病的新药,尤其是可填补空白或优于现有治疗的药物。为加快这类药物的审批,FDA已经建立了3种不同但很成功的方法,即快速通道指定、优先审评途径、加速批准指定。2012年7月9日,《FDA安全与创新法案》正式实施,法案中制定了一个新的加快药物开发审批的方式,即突破性治疗药物指定。突破性治疗药物指定自实施以来得到多方面的认可,截止到2014年5月5日,FDA共收到186项突破性治疗药物指定申请,其中授予48项,拒绝96项,另外42处正在审核过程中。这些药物涵盖小分子化学药、抗体、蛋白类、反义寡核苷酸类等。它们治疗多种疾病,尤其是癌症、丙型肝炎和囊性纤维化。授予突破性治疗药物指定资格后获得FDA批准上市的有5项。综述FDA的4种加快重要药物审批的程序以及突破性治疗药物指定的情况,以期为我国完善药物审批方式提供一定的参考。     

药包材变更管理的分析与探讨

目的：通过汇总分析美国对药包材变更的管理法规和管理方式,为我国实施关联审评审批后对药包材变更管理提供借鉴,从而保证药品在整个生命周期内的安全、有效和质量可控。方法：从法规和技术层面分析美国FDA对制药企业以及药包材企业的变更监管,探讨其优势和存在的问题,对比中国与美国行业的特点。结果：中国与美国在监管理念和法规上日渐趋同,但是国内药包材企业与美国在规模和管理上还存在较大差异。结论：药包材变更是药品生命周期维护的组成部分,行业监管机构需要出具相应的变更技术指导原则以及相应的法规路径作为研发人员对变更评估的重要参考依据。     

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.     

Pharmacotherapy of neuropsychiatric syndromes in neurologic disorders: definitional and regulatory aspects

Background: Neuropsychiatric symptoms are common in many neurologic diseases. Psychosis, depression, agitation, anxiety, irritability, and apathy occur in degenerative, traumatic, vascular, and demyelinating brain diseases. Design: Regulatory policies regarding approval of psychotropic agents for treatment of neuropsychiatric symptoms in neurologic disorders are reviewed. Results: Psychotropic agents previously received broad labeling such as treatment for psychosis or depression. Food and Drug Administration (FDA) policy now requires that labeling be limited to the population included in clinical trials providing the basis for the application. When applying for approval for use of psychotropic agents in neurologic disorders, pharmaceutical companies will be required to demonstrate efficacy in the neurologic disease of interest. Definitions of specific neuropsychiatric symptoms in neurologic diseases are required for study design. Approval will depend on demonstrating efficacy in two independent, randomized, controlled trials with symptom-focused and global outcome measures. Labeling for treatment of a nonspecific symptom (eg, agitation) can be approved if efficacy is demonstrated across several neurologic diseases. Conclusion: Patients with neurologic diseases may have dosage ranges, side effects, or response profiles of psychotropic agents that differ from those of patients with idiopathic psychiatric disorders. FDA policy now requires demonstration of efficacy, safety, and tolerability of psychotropic agents within neurologic disorders, allowing clinicians to make more rational choices regarding treatment options.     

Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders

Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification. To this end, the pharmaceutical industry is pursuing many novel drug targets. Although this view is probably not justified, the recent tribulations of rimonabant have created a perception that the regulatory bar for the approval of antiobesity drugs has been raised. Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end-point, it is improvements in cardiovascular risk factors that the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) require to grant approval. Safety aspects are also critical in this indication. Many companies are now switching development of their antiobesity drug candidates into other metabolic disorders. Type 2 diabetes is accepted by the industry and FDA, but not EMEA, as the most appropriate alternative. On the other hand, improvements in plasma lipids produced by antiobesity drugs are moderate compared with established therapies, suggesting dyslipidaemia is not a viable development option. Metabolic Syndrome is not accepted by FDA or EMEA as a discrete disease and the agencies will not licence antiobesity drugs for its treatment. The regulatory environment for antiobesity drugs and the spectrum of indications for which they can be approved could change dramatically if positive data for sibutramine emerge from the SCOUT outcome trial.