FDA“简化新药申请的透皮和局部给药系统黏附性评估的供企业用指导原则草案”介绍

美国食品药品管理局（FDA）于2023年4月发布了“简化新药申请的透皮和局部给药系统（TDS）黏附性评估的供企业用指导原则草案”,修订了2018年公布的同名指导原则草案。该修订的指导原则草案包括前言、背景、黏附性的评价、黏附性和生物等效性的综合评价以及数据提交格式5部分。重点讨论了仿制TDS黏附性的临床评价,包括其研究设计和实施以及统计分析。中国目前还没有类似的指导原则,详细介绍FDA的该指导原则草案,期望对我国仿制的TDS的黏附性评估的临床研究和药品监管部门的审评有帮助。     

Progress report on the guidance for industry for statistical aspects of the design, analysis, and interpretation of chronic rodent carcinogenicity studies of pharmaceuticals

The U.S. Food and Drug Administration (FDA) is in the process of preparing a draft Guidance for Industry document on the statistical aspects of carcinogenicity studies of pharmaceuticals for public comment. The purpose of the document is to provide statistical guidance for the design of carcinogenicity experiments, methods of statistical analysis of study data, interpretation of study results, presentation of data and results in reports, and submission of electronic study data. This article covers the genesis of the guidance document and some statistical methods in study design, data analysis, and interpretation of results included in the draft FDA guidance document.     

Regulatory Administrative Databases in FDA's Center for Biologics Evaluation and Research: Convergence Toward a Unified Database

Regulatory administrative database systems within the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) are essential to supporting its core mission, as a regulatory agency. Such systems are used within FDA to manage information and processes surrounding the processing, review, and tracking of investigational and marketed product submissions. This is an area of increasing interest in the pharmaceutical industry and has been a topic at trade association conferences (Buckley 2012). Such databases in CBER are complex, not for the type or relevance of the data to any particular scientific discipline but because of the variety of regulatory submission types and processes the systems support using the data. Commonalities among different data domains of CBER's regulatory administrative databases are discussed. These commonalities have evolved enough to constitute real database convergence and provide a valuable asset for business process intelligence. Balancing review workload across staff, exploring areas of risk in review capacity, process improvement, and presenting a clear and comprehensive landscape of review obligations are just some of the opportunities of such intelligence. This convergence has been occurring in the presence of usual forces that tend to drive information technology (IT) systems development toward separate stovepipes and data silos. CBER has achieved a significant level of convergence through a gradual process, using a clear goal, agreed upon development practices, and transparency of database objects, rather than through a single, discrete project or IT vendor solution. This approach offers a path forward for FDA systems toward a unified database.     

Improper Selection of a Pre-specified Primary Dose–Response Analysis Delays Regulatory Drug Approval

Dose–response analysis is one of the accepted efficacy endpoints to establish effectiveness. The purpose of this research was to inform selection of an appropriate pre-specified primary dose–response analysis to demonstrate drug efficacy in a registration trial. The power and the type I error rate of the placebo-corrected (i.e., simply adjusting the observed treatment value by subtracting the placebo mean) and the placebo-anchored (i.e., including the placebo data as dose 0 in the regression) slope analyses were assessed based on regulatory submission data for two antihypertensive drugs and simulated data from hypothetical clinical trials. In the simulated hypothetical trials, the impact of different dosing strategies (i.e., the fixed dose versus the weight-based per kilogram dose), sample size, and scenarios governing the drug exposure–response relationship (e.g., E _max, ED ₅₀ , and SD) was also evaluated. For each scenario, a total 300 replications were simulated. The placebo-anchored slope analysis is always more powerful to demonstrate effectiveness in all plausible scenarios. The difference between the placebo-anchored and the placebo-corrected analyses was maximum when the studied doses were too high. However, the dose–response analysis is not sensitive to the dosing strategies. Furthermore, the type I error rate of these two methods was also found to be comparable. The design of dose–response studies should carefully consider these results to justify the inclusion of placebo and the analysis method. The pharmaceutical industry and the regulatory agencies are equally responsible for using the appropriate methods of primary analysis and providing justification in the protocol.     

FDA复杂仿制药的监管现状研究

本文从两方面对FDA复杂仿制药(非生物复杂药物)的现状进行分析:复杂仿制药的药物等效性、生物等效性技术评价的可行性及FDA面对复杂仿制药质疑和挑战的应对策略。总结了FDA面对复杂仿制药的科学挑战,运用监管科学大力推动科学研究,推动的方式包括制定科学研究计划、确定研究的重点领域、设立课题、总结年度科学研究成果、加强与业界的沟通交流。FDA定义的复杂仿制药包含天然来源的复杂活性成分,其复杂仿制药的研究思路有可能为中药同名同方药技术评价提供参考。     

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 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.     

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.     

Bioanalytical approaches,bioavailability assessment,and bioequivalence study for waiver drugs: In vivo and in vitro perspective

Evidence of differences in bioavailability from different oral formulations of the same therapeutic agents had become obvious by the early 1960s. The consequent 40 years have produced the body of scientific belief, debate, and policy on the subject of bioequivalence. The motivating force behind many of these events has been the continued interest of the food and drug administration (FDA) to improve the manner in which these studies are conducted, the quality of the data generated from such studies, and the methods by which they are evaluated. Bioanalytical data used to support regulatory submission needs to be accurate and reproducible. In order to have confidence in the reliability of the data, it is important that the analytical method used to generate it is well characterized and fully validated. However, bioavailability assessment (BA) and bioequivalence (BE) studies are necessary in filing of the data towards the drug approval. This review article describes the methods for assessing bioavailability and bioequivalence; and bioanalytical approaches of pharmaceuticals in vivo and in vitro and also a waiver of BA/BE studies based on the biopharmaceutical classification (BCS) system.     

The impact of FDA guidance on pharmacogenomic data submissions on drug development

After a long wait, the US Food and Drug Administration (FDA) finally released the much anticipated 'Guidance on Pharmacogenomic Data Submissions on Drug Development' in March 2005, but what impact will this have on the drug industry as a whole? It is becoming increasingly apparent that the field of pharmacogenomics can add value to both clinical trial design and the drug development process, but uptake by the pharmaceutical industry has so far been variable between companies. The opinion of the FDA is that the use of pharmacogenomics in drug development is a 'good thing' and one that it wishes to promote, hence, this new guidance is designed to assist drug companies to adopt pharmacogenomic technology in clinical development, and covers both targeted and exploratory aspects. While targeted pharmacogenomics must be included as part of any regulatory submission, exploratory approaches may be submitted voluntarily with assurances from the FDA that any such submissions will not be used to make regulatory decisions. With this regulatory framework now in place it is only a matter of time before it is known how the industry reacts and the impact it will have on drug development.     

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.     

The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered ～ 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the ‘thorough QT/QTc study’ recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes – one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.     

GL-701 Genelabs

Genelabs is developing GL-701 (prasterone), oral dehydroepiandrosterone (DHEA), for the potential treatment of systemic lupus erythematosus (SLE) [154020]. In September 2000, the company completed submission of its rolling NDA, begun in May 2000 [340361], [355642], [361381], [380239], [383545]. In October 2000, the FDA granted the company's NDA Priority Review designation [387020]. Genelabs began its NDA submission for GL-701 in May 2000, by submitting the complete clinical, statistical and human pharmacokinetic sections to the FDA. This includes all the human efficacy and safety data for the NDA [368932]. In March 1999, Genelabs received Fast Track designation for GL-701 from the US FDA, allowing the development and review of an NDA to be expedited [319963]. Genelabs met with the US FDA in November 1999 to present the data from the two phase III trials in women and was advised by the FDA that its NDA proposal appeared adequatefor submission [348192], [361381]. Because of the public domain nature of DHEA, Genelabs was not certain that it would obtain patent protection. In the US it received Orphan Drug designation, providing seven years of exclusive marketing rights, and in October 1996, Genelabs received US-05567696, covering the use of GL-701 in lupus patients to reduce their dosage of concomitant corticosteroids [222741], [329646]. The US FDA has also granted Subpart E designation to GL-701, which permits expedited development [169754], [222741]. Genelabs licensed the product exclusively worldwide from Stanford University, which performed the early-stage clinical studies. The Asian marketing rights have been licensed to Genelabs Biotechnology Ltd (GBL), a joint investment with the government of Taiwan [229812]. In January 2001, analysts at UBS Warburg predicted that GL-701 would be launched in 2001, and reach sales of US $ 90 million by 2004 [398731].     

Discovery Groups: The Detectives of Cell Biology

Abstract

Both Industry and the FDA benefit when firms submit acceptable, complete Abbreviated New Drug Applications (ANDAs) which can be processed expediently and culminate in approval. An overview of the mechanics of the ANDA submission and review process is presented, and current problem areas in the submission process are identified. The criteria used in evaluating an ANDA submission in terms of acceptability and completeness are set forth. The ANDA Management Information System used in the tracking of submissions under review in the Division of Generic Drugs is described.     

Are literature references sufficient for dose recommendations? An FDA case study of efavirenz and rifampin

One of the numerous regulatory functions of the Food and Drug Administration (FDA) is the evaluation of drug-drug interactions and the determination of appropriate dose adjustments, if necessary, to ensure the safe and effective use of medications. The FDA considers several data sources when determining the significance of drug-drug interactions. The majority of dose adjustment recommendations are based on specific drug-drug interactions studies. The FDA reviews individual patient pharmacokinetic and safety data from drug interaction studies, determines appropriate dose adjustments, and provides recommendations to update the respective product labeling. Sometimes literature references are submitted to the FDA to support dosing recommendations. Determining an appropriate dose adjustment recommendation based on literature reports is a challenge for the FDA due to the lack of individual patient pharmacokinetic or safety data from these studies. Recently, the FDA encountered a challenging regulatory situation when evaluating literature reports to determine the appropriate dose of efavirenz and rifampin. Although numerous studies were found in the literature about this combination, a dosing recommendation cannot be concluded from the reported data. This article reviews the process the FDA used to evaluate literature to support potential dose adjustments for efavirenz when coadministered with rifampin and the challenges encountered during the process.     

RIGScan CR: RIGScan CR49

RIGScan CR49, a 125I-labelled CR monoclonal antibody directed against the tumour-associated antigen TAG-72, is undergoing development with Neoprobe for the intraoperative detection of metastatic colorectal cancer. The Neoprobe's proprietary RIGS (radioimmunoguided surgery) technology combines an injectable radiolabelled cancer-targeting agent and hand-held radiation detection probe that emits an audible tone when located tissue has accumulated a significant amount of the radioactive agent. Neoprobe's RIGS technology also includes a patented surgical method providing surgeons with real-time information to locate tumour deposits that can not be detected by other conventional methods. The RIGS technology has been evaluated in late clinical studies for the detection of adenocarcinomas including primary colorectal, gastrointestinal, breast, ovarian, pancreatic, prostate and neuroendocrine/endocrine. Neoprobe signed an option agreement for its first-generation RIGScan compound, RIGScan CR, with OncoSurg Inc. (formerly NuRigs Ltd). The second-generation humanised RIGScan CR agent was also optionally licensed to OncoSurg Inc. In 1997, Neoprobe filed for approval with the US FDA and the EMEA for RIGScan CR for the intraoperative detection of metastatic colorectal cancer. Both regulatory agencies have requested additional clinical data. On 19 April 2004, Neoprobe announced that it had met with the US FDA to discuss its position on submitting additional clinical information in response to the FDA's questions regarding the Biologic Licence Application (BLA) for RIGScan CR49. The company provided the FDA with new information related to a survival differential for patients whose colorectal cancer was evaluated with RIGScan CR49. The information was not available at the time of the BLA's submission in 1997. The agency indicated that it would consider accepting survival data from one of the two phase III trials, NEO2-14, but not from another trial NEO2-13, as supportive data for a prognostic indication for colorectal cancer. The FDA also clarified that two well controlled studies were required for approval, and indicated that Neoprobe needed to complete an additional confirmatory phase III study for a prognostic indication in colorectal cancer. In its Annual Report 2002, Neoprobe stated that it had been working to secure a partner for further development of its proprietary RIGS technology. The company intends either to find a development partner or sell or licence out their RIGS assets if the partner is not found.