Responsibilities of Clinical Trial Investigators

Abstract

Never has compliance with Title 18 of the Code of Federal Regulations (CFR) Part 312, and with good clinical practices (GCPs) been of greater importance and under more public scrutiny than today. The current regulatory environment at the Food and Drug Administration (FDA) has fueled a keener awareness not only of how clinical investigators are conducting their research under Investigational New Drug (IND) regulations, but also how they are documenting the research activity. Further, the present climate at the Agency is geared to enforcement of the regulations and to application of sanctions when indicated.

This article describes the responsibilities that a clinical investigator legally assumes upon signing the Statement of Investigator, Form FDA 482, an interpretation of some of the regulations pertinent to IND research, and how to abide by the applicable regulations: what to do, how to do it, and what not to do.     

Nonhuman primates as models for the discovery and development of radiation countermeasures

Introduction: Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.

Area covered: The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.

Expert opinion: The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes for NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.     

Erlotinib and pemetrexed as maintenance therapy for advanced non-small-cell lung cancer: a systematic review and indirect comparison

Abstract

Background:

Two new agents have recently been licensed as maintenance therapy for advanced non-small-cell lung cancer (NSCLC) by the US Food and Drug Administration. This paper aims to systematically review the evidence from all available clinical trials of erlotinib and pemetrexed as maintenance therapy for advanced NSCLC.     

美国FDA鼻用制剂监管科学研究进展及启示

目的 介绍美国食品药品监督管理局（Food and Drug Administration，FDA）鼻用制剂监管科学进展，为中国鼻用制剂开发、生产、质量控制、监管提供参考和借鉴。方法 通过对法规和文献进行翻译、整理与研究，介绍FDA关于鼻用制剂的监管科学研究项目和最新进展，并分析目前鼻用制剂发展中遇到的难点和未来的发展方向。结果 FDA鼻用制剂监管科学主要方向为评价潜在的生物等效性方法作为比较临床终点生物等效性研究的替代方案，运用数字技术建立计算机模型研究鼻部吸收影响因素、药动学和药效学特征，以及儿童用药研究、鼻脑递送等，旨在开发新工具、新方法、新标准，为优化监管策略、提高监管效率提供科学依据。结论 本文总结了FDA鼻用制剂监管科学最新研究成果，为监管机构管理人员提供参考，为提升中国药品监管质量和效率、实现国际接轨提供新思路与新方法。     

The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations

In March 2011 ——— (2011), Code of Federal Regulations Title 21 Food and Drugs Chapter I Food and Drug Administration Department of Health and Human Services Subchapter D Drugs for Human Use Part 312 Investigational New Drug Application. [Google Scholar], a Final Rule for expedited reporting of serious adverse events took effect in the United States for studies conducted under an Investigational New Drug (IND) application. In December 2012, the U.S. Food and Drug Administration (FDA) promulgated a final Guidance describing the operationalization of this Final Rule. The Rule and Guidance clarified that a clinical trial sponsor should have evidence suggesting causality before defining an unexpected serious adverse event as a suspected adverse reaction that would require expedited reporting to the FDA. The Rule's emphasis on the need for evidence suggestive of a causal relation should lead to fewer events being reported but, among those reported, a higher percentage actually being caused by the product being tested. This article reviews the practices that were common before the Final Rule was issued and the approach the New Rule specifies. It then discusses methods for operationalizing the Final Rule with particular focus on relevant statistical considerations. It concludes with a set of recommendations addressed to Sponsors and to the FDA in implementing the Final Rule.     

Compounding botanicals: a legal perspective.

OBJECTIVE: To describe the effects of the new law, section 503A, "Pharmacy Compounding," of the Federal Food, Drug, and Cosmetic Act on the compounding of drugs, dietary supplements, and cosmetics. DATA SOURCES: The Food and Drug Administration (FDA) Modernization Act of 1997; Federal, Food, Drug, and Cosmetic Act; Code of Federal Regulations; Federal Register; Food and Drug Administration Guidances. DATA SYNTHESIS: Pharmacy compounding, which traditionally is considered part of pharmacy practice and is regulated by the states, has been confused with drug manufacturing, an activity regulated by FDA. Section 503A, "Pharmacy Compounding," was enacted as part of the Food and Drug Administration Modernization Act of 1997 to distinguish compounding from manufacturing. This law addresses the compounding of drug products, but not necessarily the compounding of botanicals, which may be considered dietary supplements, cosmetics, or drugs. CONCLUSION: Section 503A applies to the compounding of products intended for a drug use, but does not apply to compounded products that are intended for dietary supplement or cosmetic use. Compounded dietary supplements and cosmetics must instead adhere to relevant federal requirements, including those for good manufacturing practices and labeling.     

Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape

ABSTRACT

Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.     

Current Bioavailability and Bioequivalence Requirements and Regulations

Abstract

The 1977 Bioavailability/Bioequivalence Regulations formalized the position and thinking of the Food and Drug Administration with regard to bioavailability of drug products marketed in the United States. The regulations defined the terminology involved, set forth criteria for waiver of in vivo bioavailability studies and listed the drugs that would require bioavailability/bioequivalence studies. The regulations also delineated the general approaches for determining bioavailability, laid down guidelines for conducting in vivo bioavailability studies for conventional dosage forms, combination drug products, and controlled release drug products; set forth criteria and evidence to establish a bioequivalence requirement and described the types of bioequivalence requirements. Over the last few years, a number of presentations have been made by the officials of the Agency to describe and explain the regulations at various forums. I am sure that most of you are quite familiar with the various aspects of these regulations.     

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.     

Drug Repurposing for Ebola Virus Disease: Principles of Consideration and the Animal Rule

There are no approved drugs or biologics to treat Ebola virus disease (EVD). Literature reviews identified a list of 141 drugs with reports of preliminary in vitro potency and in vivo effectiveness in animals or with reports of clinical use/trials in EVD patients. The majority of these drugs have been individually approved by the U.S. Food and Drug Administration for treating various non-EVD diseases. The anti-Ebola potency data of these drugs were curated from literature and publicly accessible databases, along with their individual biopharmaceutical and pharmacokinetic characteristics. To facilitate the development of antiviral drugs including anti-EVD drugs, highlights include optimization of the exposure-response relationship, design of a safe and effective clinical dosing regimen to achieve an adequate high ratio of clinical C_min to a plasma protein binding-adjusted EC₉₅, and the pharmacokinetic studies needed in animal models (healthy and affected) and in healthy volunteers. The exposure/response relationship for human dose selection is summarized, as described in the U.S. Food and Drug Administration “Animal Rule’’ guidance when human efficacy studies are not ethical or feasible.     

Pharmacoeconomics and Quality of Life: Evaluating the Economic and Social Impact of Pharmaceuticals

Abstract

This presentation reviews briefly the history of antibiotic drug certification program mandated by Section 507 of the Federal Food, Drug, and Cosmetic Act, as amended. Since batch-by-batch testing and certification of antibiotic products was terminated by Food and Drug Administration on October 1, 1982, the number of new manufacturers entering the antibiotic market for the first time has in creased. The current requirements for gaining approval from the FDA to market antibiotic drug products in the U.S.A. are now set forth in the 21 CFR 314.50 and 314.55, as published in the Federal Register on February 22, 1985.     

论《药品管理法》修订背景下的药品犯罪立法完善

目的： 结合《药品管理法》相关条款的修订，分析其对刑法药品犯罪罪名适用的影响，并确立药品犯罪条款的立法完善思路。方法： 检索新修订《药品管理法》与药品犯罪相关的条文，分析其修订目的，对照刑法和药品犯罪相关司法解释，分析新修订《药品管理法》对药品犯罪的司法适用造成的冲击与影响，并提出相应的立法完善性思路。结果与结论： 新修订《药品管理法》重新界定了假药和劣药，导致生产、销售假药罪和生产、销售劣药罪适用范围的限缩，但是不能简单化理解为将进口国内未上市的药品行为除罪化，同时在二元化立法模式下，《药品管理法》部分处罚条款的适用范围会非常狭窄，而假药、劣药证据标准的提高会给刑事司法造成直接的冲击。应结合新修订《药品管理法》，对刑法相关条文和刑法司法解释进行修改和更新。     

我国药品附条件批准程序实施情况及相关思考

目的：对我国药品附条件批准上市相关政策和实施情况进行深入分析和探讨,参考美国与欧盟药品附条件上市政策,对我国附条件批准上市的实施和推进提出建议。方法：通过梳理药品注册管理办法发布后国家药品监督管理局(NMPA)药品附条件批准上市申请审评审批法规政策实施情况,重点围绕当前法规中的准入条件、准入程序、上市后监管要求、撤销情形以及撤销程序进行综述,针对实施过程中发现的问题,借鉴美国食品药品管理局(FDA)药品加速审批(Accelerate Approval)与欧洲药品管理局(EMA)药品附条件批准(Conditional Marketing Authorisation)经验以及对各国附条件政策进行比较分析,探讨我国药品附条件批准上市政策的发展方向。结果与结论：为了加快具有突出价值的临床急需药品上市,缩短新技术临床应用时间,美国与欧盟均设立了相对完备的附条件上市法规政策及程序。我国的附条件批准制度虽然建立时间较短,但有欧美的经验作为参考,结合我国的临床实践和监管需要, 相关法规也在趋于完善。未来,监管部门更多需要考虑的是对程序和技术要求的细化、制度之间的衔接 (如疫苗的紧急使用授权与附条件批准制度),以及加强上市后监管等方面。     

Current Status of Ind/Nda Regulations

Abstract

In order to improve the investigational drug development process, the efficiency of the Agency's drug approval process and the Agency's dealings with applicants while still maintaining the high level of public health protection, the Food and Drug Administration has undertaken the revision of the current regulations and policies for investigational new drug applications and new drug applications. On October 19, 1982, the FDA published in the Federal Register a proposal for revision of the NDA regulations, and on June 9, 1983, the Agency published a proposal for revision of the IND regulations.

The status of the proposed revisions is discussed along with projections of their impact on the American public, pharmaceutical industry, and the FDA. Since the revised regulations will refer to several guidelines, the status and scope of the guidelines are described. In addition, changes that have already been put into effect prior to finalization of the proposed regulations are described.     

The product label: how pharmacokinetics and pharmacodynamics reach the prescriber

The product label, or package insert, is the 'manual' for the safe and effective use of a drug. Important pharmacokinetic and pharmacodynamic properties of a drug product should appear in the label under specific sections, as required in the Code of Federal Regulations (CFR), using a format and language recommended by the Food and Drug Administration (FDA) in various guidances to the industry. The relevant regulations and guidance documents impacting on how this information is conveyed to the healthcare professional are discussed, with special emphasis on how the new proposed rule will impact upon how information is to be conveyed. With the availability of new clinical pharmacology information not available at the time of approval, package inserts for older drugs should be updated to reflect the new data and recommend the proper dosage regimen, enabling prescribers to optimise drug therapy and minimise possible adverse events.     

Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed

Introduction: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry.

Areas covered: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations.

Expert opinion: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments.     

A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug’s safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic.

Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management.

Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.     

Examination of risk evaluation and mitigation strategies and drug safety in the US

BackgroundThe Food and Drug Administration Amendment Act of 2007 (FDAAA 2007) enabled the US Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) for a drug or biologic to ensure that its benefits outweigh the risks.ObjectiveThis study sought to evaluate REMS approved and released by the FDA since the program inception in 2008, to assess the characteristics of REMS approved and to calculate the time lag between FDA drug application approval and REMS approval.MethodsData were derived from Approved Drug Products with Therapeutic Equivalence Evaluations, Approved REMS and Drugs@FDA. Data included generic availability, application type and approval date, therapeutic class and FDA review class, orphan designation, priority review and market status.ResultsThe FDA approved REMS for 259 marketing applications (217 new drug applications -NDAs, 10 abbreviated NDAs, and 32 biologic license applications) in the study period. The FDA granted orphan designation to 11.4% of active ingredients with REMS and priority review to 38.4% of the NDAs with REMS. The largest number of REMS approvals was for nervous system products (31.8% of total approved REMS) and antineoplastic and immunomodulating agents (15.3%).ConclusionsThe FDA approved REMS for one in three biologics and one in thirteen chemical entities available in the market. A pharmaceutical product can be in the market for an average of 14 years before the FDA identifies and evaluates the risk problems that warrant the approval of a REMS.     

Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials

Abstract

Objectives:

Docetaxel and paclitaxel show significant clinical activity in metastatic breast cancer (MBC) and have been approved for MBC by the U.S. Food and Drug Administration, but it is still unclear whether a paclitaxel-based regimen improves outcomes over a docetaxel-based regimen in patients with MBC. We therefore performed a meta-analysis of randomized controlled trials to compare the safety and efficacy of these two regimens in MBC.