Scientific drug safety information for patients' consent

One of the important roles of pharmacists is to continue their contributions to new drug discovery and development. However, it seems to be very difficult to obtain patient satisfaction with new drugs. Because new medicines have both benefit and risk, there should be many systems to maximize the safety and efficacy of the drugs. In clinical trials, the rights, safety and welfare of human subjects under the investigator's care must be protected. Good Clinical Practice is a harmonized ICH-guideline, and the safety information of an investigational product is explained to patients who voluntarily enter the clinical trials. Since safety information about investigational products is still limited, subjects are informed about the results of animal experiments and those of finished clinical trials. The sponsor of clinical trials should be responsible for the on-going safety evaluation of the investigational products. When additional safety information is collected in the clinical trials, the written informed consent form should be appropriately revised. During the review process, quality, safety and efficacy of new drugs are evaluated and judged based on the scientific risk-benefit balance. The safety information collected in clinical trials is reflected in the decision-making process written in the review reports. All-case investigation should be also performed until data from a certain number of patients has been accumulated in order to collect early safety and efficacy data. Important messages written in review reports for drug safety and patient consent are explained. Risk communication will improve the application of patients' consent for new drugs.     

Analysis of information submitted by clinical trial sponsors regarding the safety of investigational drugs

During performance of clinical trials in medical institutions, information regarding the safety of investigational drugs is submitted by trial sponsors according to guidelines for good clinical practice. In the present study, reports of clinical trials conducted at the University of Tokyo Hospital were examined, focusing on the safety information provided to the Institutional Review Board (IRB). Two hundred two reports (52 protocols) of safety information were submitted to the IRB by clinical trial sponsors between April 2000 and March 2001, of which 185 contained a total of 3021 cases of adverse events. Of those, 194 reports were judged by clinical investigators/physicians not to be associated with any significant problems and the trials were continued. For 157 of those 194 reports, it was considered unnecessary to inform the test subjects of the report contents, including the adverse events. The decision of whether or not the test subjects should be informed of such contents tended to depend on the causal relationship between the adverse events and drug intake, as well as the predictability of the adverse events. For 8 of those 194 reports, the IRB recommended that the clinical investigators/ physicians provide information to the test subjects and/or submit detailed information on the status of these subjects to the IRB. From these results, we suggest that establishment of a system to unify and evaluate drug safety information is necessary to provide safe and efficient clinical trials.     

Investigational drug tracking: phases I-III and NDA submissions--Part II

The author catalogs over 800 investigational drugs/biologicals currently in Phase I, II or III clinical trials or drugs/biologicals submitted to the FDA as new drug applications. Part I of this article appeared in the September issue of Hospital Pharmacy. The list assists in predicting when new drugs will be marketed. The entries include generic/chemical name, investigational drug number, synonyms, trade names, manufacturers, clinical trial status, predicted approval year, indications or drug class, whether the drug has been developed through biotechnology, and references. Entries were gleaned from medical journals, stock market analysis publications, and the Pharmaceutical Manufacturers Association's Medicines in Development Series. The list is alphabetized by the generic/chemical name or investigational drug number and cross-indexed by the trade name and synonyms. The list reflects those drugs which were not FDA approved as of April 15, 1994. Part I concludes with the remaining alphabetical listing by generic/chemical name or investigational drug number.     

Procedures for emergency or treatment use of investigational drugs

The procedures for obtaining and dispensing investigational drugs for single-patient compassionate use are described, and roles for pharmacists in this process at a university medical center are identified. To obtain an investigational drug, a physician must contact a pharmaceutical-company study monitor to discuss the details of the case. Other responsibilities of the physician include obtaining institutional review board approval; completing FDA form 1572 or 1573, or both; and securing written informed consent from the patient. The responsibilities of the pharmacist are to ensure that informed consent has been obtained; inform nursing, pharmacy, and medical staffs about the use, admixture requirements, and administration of the investigational agent; provide a therapeutic drug monitoring plan; and store, handle, and prepare the medication. The pharmacist also keeps inventory of all shipped drugs and returns all unused drugs to the manufacturer. Pharmacists should be knowledgeable about the proper procedure for obtaining and dispensing investigational drugs on an emergency or treatment basis.     

Clinical research: regulatory issues.

The regulatory issues faced by institutions performing clinical research are described. Many institutions do not have on staff an expert who understands the regulatory issues involved in managing investigational new drug research and who knows the institution's obligations under the federal rules. Because pharmacists understand the FDA regulations that apply to the management of drugs in clinical research, institutions are asking pharmacists to expand their role and manage clinical research offices. Many authorities govern various aspects of investigational drug research. FDA has published regulations for good clinical practice (GCP), and the International Conference on Harmonisation is developing an international standard for the proper management of clinical trials. The guidelines published by the Joint Commission on Accreditation of Healthcare Organizations aim to protect patients who are in the institution to receive health care and also participate in clinical trials. The Social Security Administration Acts specifically state that only items and services that are reasonable and necessary for the diagnosis and treatment of injury or disease can be billed to the government; research-related billings are excluded from coverage. Proper management of drug research is crucial to the success of a research program that is integrated with patient care.     

A Conputerized System for Monitoring and Accounting of Investigational Drug Supplies in a Multi-Center Clinical Trial

Abstract

In any clinical trial involving investigational drugs, federal regulations require accurate and adequate drug accounting. In addition, it is advantageous to monitor individual patient compliance for its relationship to response to therapy, adverse reactions, etc. Accomplishing these objectives can be very time consuming, especially when there are multiple participating centers.

A computer system has been designed to meet these needs and was tested on a investigational drug supplies used in a multicenter clinical trials. The computer generated reports, which can be easily developed by a supporting statistical and data processing center are helpful in monitoring drug supplies at field stations and in achieving compliance with federal regulations. Sponsors of clinical trials, especially physicians, could use CDAS to assist in assuming the drug accountability responsibilities of a multicenter clinical trial.

To develop a CDAS similar to the one just described which can be used to monitor and verify the usage of all drug supplies used in a clinical trial, the sponsor must:

1) Identify each dispensible unit with a number (i.e. bottle number)

2) Package all drug supplies in patient kits.

3) Collect the appropriate drug accountability data on clinic visit forms

4) Supplement the study master file with appropriate drug shipping data, lot numbers and expiration dates.

The goal of any CDAS should be to monitor and account for all investigational drug supplies. Otherwise many of the problems identified by the FDA, such as lost drugs or laxity in drug accountability, may go undetected.     

Investigational drug tracking: Phases I-III and NDA submissions--Part I

The author catalogs over 800 investigational drugs/biologicals currently in Phase I, II or III clinical trials or drugs/biologicals submitted to the FDA as new drug applications. The list assists in predicting when new drugs will be marketed. The entries include generic/chemical name, investigational drug number, synonyms, trade names, manufacturers, clinical trial status, predicted approval year, indications or drug class, whether the drug has been developed through biotechnology, and references. Entries were gleaned from medical journals, stock market analysis publications, and the Pharmaceutical Manufacturers Association's Medicines in Development Series. The list is alphabetized by the generic/chemical name or investigational drug number and cross-indexed by the trade name and synonyms. The list reflects those drugs which were not FDA approved as of April 15, 1994. Part I includes the trade name and synonym cross-indexes and the beginning of the main alphabetical listing by generic/chemical name or investigational drug number.     

FDA与EMA关于化学药申请Ⅰ期临床试验相关药学质量文件要求简介

FDA与EMA先后颁布了关于临床试验申请申报资料技术要求的指导原则,本文主要介绍其中关于新药Ⅰ期临床试验申请药学研究技术要求的相关内容,期望能对相关工作提供参考和借鉴,以加速我国创新药进入临床试验的时间.     

Reporting of deaths during pre-approval clinical trials for advanced HIV-infected populations.

The Division of Antiviral Drug Products of the US FDA has regulatory authority over the investigational new drugs under development by various sponsors to treat HIV-infected populations. The FDA and the sponsors of investigational new drugs use the Code of Federal Regulations to guide the entire drug development process, in order to ensure that safe and efficacious drugs are brought to market. To achieve this goal, diligent monitoring for safety during the pre-approval phase of new drug development is particularly crucial. When deciding what adverse experiences on clinical trials should be expeditiously reported, the Division recommends a conservative interpretation of the Code of Federal Regulations, where an adverse experience in a clinical trial of advanced HIV-infected patients is considered to be 'associated with the use of the drug' when the relationship cannot be ruled out with objective evidence. Fatal adverse experiences for subjects on clinical trials should be especially scrutinised. Safety reporting should be expedited when death occurs during clinical trials of advanced HIV-infected populations. The three components of an expedited reportable death occurrence, namely 'serious', 'unexpected' and 'associated with the drug use' as they relate to advanced HIV-infected populations, are discussed in this article. An occurrence of death is by definition serious. Unexpected experiences are unlisted adverse experiences, but need to be put into the context of specificity and severity. 'Associated with the drug use' has been clarified as 'relationship to the drug cannot be ruled out'. Because death in the advanced HIV-infected/AIDS population is usually a complex event, the possible contribution of the study drug is difficult to rule out. Thus, if the three components of the reporting requirement are met or insufficient information is available to make a firm determination of causality by the seventh day of the reporting period, the Division of Antiviral Drug Products expects expedited death reports on subjects participating in investigational new drug clinical studies.     

Obtaining drugs from foreign markets.

Guidelines are presented for pharmacist coordination of the importation for use by institutionalized patients of drugs not currently approved by the FDA. A prerequisite for importation of foreign drugs is that traditional therapies have failed or are not an option. Steps that are required for drug importation and administration include completing an investigational new-drug application, obtaining institutional review board approval, obtaining informed consent, contacting a customs broker or the local FDA district import program manager, arranging for drug shipment, and documenting receipt and administration of the drug. Conditions are described under which portions of this process may be waived. By helping to ensure compliance with FDA requirements, pharmacists can expedite drug importation for institutionalized patients.     

FDA's conduct, review, and evaluation of inspections of clinical investigators.

This review of the Food and Drug Administration's Bioresearch Monitoring Program focuses on the inspection of clinical investigators who study investigational drugs. The differences between routine, "for-cause," and bioequivalency/bioavailability inspections are examined, with emphasis on the responsibilities of the clinical investigator, reasons for conducting the inspections, and problems found. Important aspects of the inspection report, such as protocol adherence, records maintenance, informed consent, institutional review board approval, and drug accountability, are outlined. The disqualification and consent agreement processes for investigators with serious problems are explained. FDA policies on third-party notification and remote data entry are noted.     

抗辐射药Ex-RAD的研究进展

摘 要Ex-RAD（ON01210）是近几年由美军联合昂克诺瓦制药公司研发的新型高效、低毒抗辐射药物。由于其显著的生存率和低毒性,已于2008年被美国FDA批准进行Ⅰ期临床试验。本文结合近年文献,对Ex-RAD的结构、合成路线、检测方法及药理作用等进行综述,探讨Ex-RAD的应用前景。     

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.     

美国食品药品监督管理局接受不确定性:治疗多重耐药的人类免疫缺陷病毒感染的单克隆抗体加速获批

未满足的临床需求影响着临床试验的科学设计和药品审批的监管决策。美国食品药品监督管理局(FDA)于2018年批准了全球首个抗艾滋病的单克隆抗体艾巴利珠单抗(ibalizumab)用于治疗多重耐药的人类免疫缺陷病毒(HIV)感染。该药物的上市批准主要基于1项纳入40例患者的Ⅲ期单臂的简化临床试验。这体现了面对抗HIV多重耐药的未满足的医疗需求,FDA所做的风险和获益的权衡,以及采取的科学、灵活的审评态度。本文以此药为例,讨论了简化临床试验设计和FDA在审评中的监管考量,以期对我国药品审评的制度改革有所裨益。     

FDA对研究者在新药和医疗器械临床研究期间安全性报告的要求

上市前药物和医疗器械安全性信息主要来自临床试验,而观察受试者对试验药物和器械反应的是研究者,因此,研究者的不良事件报告至关重要。为帮助研究者确认临床研究期间非预期的安全性信息并遵守安全性报告要求,美国食品药品管理局（FDA）于2021年9月发布了“研究者职责-研究性药物和器械的安全性报告”指导原则（草案）,详细说明了对研究者在IND和IDE研究中向申请人和伦理委员会报告的要求。我国目前还没有类似的指导原则,详细介绍FDA的该指导原则,以期对我国新药和新医疗器械研究者在临床研究期间识别非预期的安全信息并按要求及时报告有帮助并对该方面的监管有所启示。     

某机构药物临床试验数据核查发现问题及改进措施

目的：对某机构药物临床试验项目数据核查发现的问题进行系统分析,剖析项目开展过程中发现的问题的原因,提出意见和建议,以提高临床试验质量,为同行提出参考。方法：收集某机构16个项目数据核查发现的问题,对照"药物临床试验数据现场核查要点"进行分类,对16个项目数据核查发现的问题进行分析。结果：11个项目存在违反数据核查要点的问题53项,其中在受试者的筛选/入组相关数据链的完整性方面存在问题7项（占13.21%）;在知情同意书的签署与试验过程的真实完整性方面存在问题2项（占3.77%）;在临床试验过程记录及临床检查、化验等数据的溯源方面存在问题29项（占54.72%）;在CRF中违背方案和严重不良事件例数等关键数据方面存在问题2项（占3.77%）;在试验用药品管理过程与记录方面存在问题9项（占16.98%）;在临床试验的生物样本采集、保存、运送与交接记录方面存在问题1项（占1.89%）;在原始数据、统计分析和总结报告与锁定的数据库一致性方面存在问题3项（占5.66%）。结论：本次分析显示,某机构在临床试验过程记录及临床检查、化验等数据的溯源方面、受试者的筛选/入组相关数据链的完整性方面和药品管理方面存在问题较多,加强对临床试验的质量控制,确保临床试验质量,保护受试者的权益。     

Expert opinion on existing and developing drugs to treat female sexual dysfunction

ABSTRACT

Introduction: Female sexual dysfunction (FSD) is a highly prevalent, yet commonly underdiagnosed and undertreated condition. This paper reviews the diagnostic terminology for FSD, and basic sexual physiology in women. The Food and Drug Administration (FDA) approved drugs for FSD are discussed, followed by investigational drugs for FSD currently in phase 2 or 3 clinical trials, reasons for failure of drug development, and potential future drug targets.

Areas covered: A literature review was conducted for available treatments for FSD: flibanserin, estrogen, ospemifene and prasterone. Potential treatments are assessed, as was the Pharmaprojects database which includes clinical trial information. Testosterone, bremelanotide, bupropion-trazodone, PDE-5 inhibitors, prostaglandins, tibolone and combination therapies, and the theoretical basis of potential drug targets are discussed.

Expert opinion: The lack of established endpoints for phase 3 studies of FSD has impeded approval of new treatments, and required additional studies for validation, resulting in proposed changes to the FDA draft guidance for FSD clinical trials in October 2016. Current DSM-5 diagnostic nosology also fails to capture the full range of symptomology. Several promising compounds have shown no movement for several years limiting women’s options. Overcoming socio-cultural bias against women’s sexual and reproductive health will be critical in the approval of new treatments for FSD.     

临床试验的伦理审查:知情同意

知情同意是人体生物医学研究的主要伦理要求之一。知情同意的伦理审查一般要考虑以下要点 :信息的充分性 ,语言表达 ,知情同意过程 ,知情同意的文件 ,知情同意的例外 ,隐瞒信息和欺骗 ,随机化、双盲和安慰剂对照临床试验 ,重新获取知情同意     

PD-1抑制剂信迪利单抗的临床研究进展

信迪利单抗（商品名：达伯舒^®）是一种全人源化IgG4单克隆抗体,可与程序性细胞死亡受体-1（PD-1）结合,从而阻断PD-1与其配体（PD-L1和PL-L2）相互作用,从而有助于恢复内源性抗肿瘤T细胞反应。信迪利单抗由信达生物制药和礼来制药共同合作研发,已在我国批准用于至少经过二线系统化疗的复发或难治性经典型霍奇金淋巴瘤的治疗。目前正在我国进行多项Ⅰ期、Ⅱ期和Ⅲ期临床试验,开发用于多种实体肿瘤的治疗,包括非小细胞肺癌和食道癌。该药用于治疗实体瘤的Ⅰ/Ⅱ期临床试验也正在美国进行,美国FDA已于2018年1月接受信迪利单抗的研究性新药申请。本文对该药的作用机制、药动学和临床研究等进行总结,为更好地指导临床应用提供建议。