The 505(b)(2) Application for Marketing Approval in the USA

Worldwide expenditure on R&D by the pharmaceutical industry is continually increasing. Most of the financial investment in the production of a new drug is allocated to clinical trials. Given the financial risk involved, it is crucially important that clinical trials be designed and set up efficiently to obtain adequate and accurate data in compliance with regulatory requirements. This module aims to provide effective strategies for the preparation and conduct of a clinical trial, while adhering to regulatory safety standards. Management of data for submission is also covered.

This course provides an understanding of how clinical trials fit into the drug development process. It outlines the key historical events leading to the development of controlled clinical trials. It specifies the purpose of trials, outlines their features, and identifies codes and regulations that apply to them. Finally, it describes the environment of cost control in which the modern pharmaceutical industry operates.

Drug safety monitoring and risk management are vitally important for medicinal product developers, licence holders and clinical investigators. In addition to their duty to protect public health increasingly tight regulation and potentially massive payments to litigants provide strong incentives for pharmaceutical and biotechnology companies to ensure that they maintain efficient systems for drug safety / pharmacovigilance and that all staff are aware of the basic requirements. This course will provide them with an overview of the most important aspects of this discipline both before and after marketing of products especially as they apply in Europe and the USA.

Everyone who works in a processing, quality control, packaging, or warehouse environment for a pharmaceutical or biotechnology company, or one of their contractors, must understand why Good Manufacturing Practice (GMP) is important, how it applies to them, and how to comply with it. This module provides an ideal induction and refresher course in the basics of GMP. We begin by explaining what GMP is and why it is necessary. We then set out its main principles. Finally, we focus on two aspects of GMP that apply to everyone in the manufacturing environment, hygiene, cleaning, and sanitation, and documentation.

Pharmacokinetic (PK) and pharmacodynamic (PD) studies provide a bridge between science and medicine in the development of a drug. In this module we describe the role of in-vivo PK and PD studies in a drug development programme, set out the uses to which the findings can be put, and discuss their implications for clinical development and application for marketing approval.

This course introduces the basics of the regulation of medical devices, especially the requirements that manufacturers must meet in order to market devices in Europe and the USA. The module explains what medical devices are and gives examples of the various types. It outlines the principles of their regulation and the criteria for placing them on the market, and it identifies major players in regulation worldwide. It then outlines prominent characteristics of the regulation of medical devices in the USA and in Europe.

Pharmaceutical, biotechnology and medical device companies and clinical researchers need to assure regulatory authorities of the reliability of the data that they generate during product development and testing – that is, to demonstrate data integrity. Practices that provide assurance of data integrity in clinical research are required by law and/or established as expectations in regulatory guidance. The data are reviewed in regulatory applications or during inspections of clinical trial sponsor and investigational sites. This course explains the requirements and describes principles and practices that should be followed by trial sponsors, investigators and other clinical research personnel to assure data integrity.

Pharmaceutical and biotechnology companies and researchers need to assure regulatory authorities of the reliability of the data that they generate or acquire during product development and manufacturing – that is, to demonstrate data integrity. Data integrity is assessed during regulatory inspections of manufacturing and research sites. Inadequacies of data integrity are frequently reported by inspectors and result in regulatory actions against the companies or individuals concerned. This course explains the requirements and describes principles and practices that should be followed to assure regulators and contractual partners of data integrity in the manufacture of medicinal products.

The sponsor of a clinical trial needs to reach agreement with clinical investigators to conduct the trial. The suitability of investigators and their institutional sites, typically hospitals, has to be evaluated, and the trial has to be set up at each site. This module describes the processes involved, focusing particularly on the role of a Clinical Research Associate (CRA) employed or contracted by the sponsor to monitor the trial. We set out the criteria, procedures and documentation for evaluating a site and setting up a trial there.

The sponsor of a clinical trial must arrange for it to be monitored throughout its duration to ensure that the rights and wellbeing of subjects are protected, the trial data are accurate, complete and verified from source documents, and the conduct of the trial complies with the study protocol, Good Clinical Practice and regulatory requirements. In this module we describe how a Clinical Research Associate (CRA) monitors an ongoing trial to its conclusion.

This course sets out the legal and regulatory requirements for safety reporting in clinical trials of medicinal products under the jurisdictions of the European Union and the USA. It builds on the foundation laid by our companion course CT13, Safety Reporting in Clinical Trials, and provides greater detail of specific requirements in those jurisdictions.

This course on US Regulation 21CFR11 explains what needs to be done to ensure that computer systems in environments regulated by the Food and Drug Administration (FDA) comply with the regulation. It clarifies the complicated picture of regulatory requirements and enforcement discretion applying to computer systems operated by companies that market or intend to apply for approval to market drugs or medical devices in the USA and by suppliers to those companies.

This module extends the learner’s understanding of pharmacokinetic and pharmacodynamic studies from the basics described in our companion module PKPD01, An Introduction to Pharmacokinetics and Pharmacodynamics in Drug Development and Registration. It provides detail on a variety of aspects of such studies, design, sampling, data analysis, research in special populations, and bioequivalence testing.

Unlike most other countries, the advertising of prescription drugs directly to consumers is permitted in the USA. Spending by drug companies on direct-to-consumer (DTC) advertising of prescription drugs has increased more than four-fold over two decades, with a dramatic increase in the number of TV ads. In addition, the Internet and social media platforms have increasingly enabled companies to engage more actively with the public. In addition to those that apply to all advertising and promotion, specific regulatory requirements and industry and regulatory guidance's apply to DTC advertising and promotion, including online promotion, and we discuss these in this course.

A company’s Corrective and Preventive Action (CAPA) system establishes how personnel should deal with manufacturing problems that have occurred or that may occur if not prevented. This module explains the principles of corrective and preventive action and describes typical CAPA procedure. It goes on to introduce root cause analysis and outline the role of progress tracking, escalating, and trending of CAPA procedures.

The eCTD specification has been developed to facilitate the global electronic submission, review and lifecycle management of medicinal product dossiers for regulatory applications. Use of the eCTD is mandatory for all applications for marketing approval and all subsequent related submissions in the European Economic Area, the USA and Canada. This module outlines the eCTD specification, discusses the approach to regional differences in dossiers, and provides guidance on creation of an eCTD submission. The module provides a training and reference tool that will be of particular value to those new to the use of the format.

This foundation-level module is the ideal introduction for new entrants to the field of pharmaceutical regulatory affairs and compliance. It describes the principal requirements that must be satisfied to gain and maintain approval to market medicinal products in the USA and Europe. The legal framework and the roles of major players in regulation are presented. The life-cycle of a drug is outlined. The various procedures available for assessment and approval of products are described and their requirements outlined. Obligations to be fulfilled after marketing approval are discussed.

Monoclonal antibodies (mAbs for short) are the leading products of biotechnology. Drugs based on mAbs dominate the list of top-selling medicines worldwide. In addition, mAbs have many uses in medical diagnosis, in laboratory analysis, and in the biotechnology industry itself. This module provides an introduction to monoclonal antibodies, explaining how they work, how they are made, and the many uses to which they are put.

The work of analytical laboratories in examining biological samples is crucial in the diagnosis and treatment of patients, in public health screening, and in clinical research. Various published guidelines and consensus standards set out criteria that laboratories should meet to provide assurance of the quality of the data and reports that they generate. This course, focusing on the work of laboratories that examine samples collected from subjects in the course of clinical trials, compiles relevant quality criteria under the title of Good Clinical Laboratory Practice (GCLP). Compliance with GCLP supports assurance of the reliability of a laboratory’s findings.

Good Clinical Practice (GCP) inspections and audits are carried out to provide assurance that, the rights, safety and welfare of clinical trial subjects are protected, the data that constitute the results of the trials are accurate and reliable, and the trials are carried out in compliance with relevant legal requirements. This module describes what investigational medicinal product sponsors, contract research organisations and clinical investigators can expect when they undergo inspection or audit. It focuses in particular on inspection by European and US regulators.

Good Manufacturing Practice (GMP) for medicinal products relies on documentation. Good Documentation Practice (GDocP) is that part of GMP that applies to the creation, maintenance, use, and retention of documents to provide assurance of the quality of products. In this module, we emphasise the crucial importance of GDocP and we identify principles that underpin it. We explain the functions of the types of documents that are used and discuss how they should be created and controlled. Finally, we specify requirements for record keeping – how data are to be entered into records, corrected if necessary, and how records must be retained.

The purpose of Good Laboratory Practice (GLP) is to provide assurance of the quality and reliability of nonclinical study data. GLP covers the planning, performance, monitoring, recording and reporting of studies. Regulatory authorities typically require GLP rules to be followed for nonclinical studies intended to support an application for approval of clinical research or marketing of a product containing the test item. This course outlines the history of GLP and explains why it is important, identifies the penalties that may be incurred for noncompliance, and sets out requirements that need to be met.

This module explains the requirements of Good Manufacturing Practice (GMP) for the warehouse, and how to comply with them. We describe how goods may be stored in a typical layout. We identify methods of segregating stock, and we set out goals of GMP for the warehouse. We discuss how inward goods are checked, recorded and labelled, quarantined, sampled and tested, and released for use or rejected. We describe good practice for storage, inventory control, and transfer of materials and products to and from production. We discuss dispatch of finished products, and procedures for dealing with returns and recalls.

Cleaning and sanitation of premises and equipment are essential to efforts to prevent contamination of product, and they need to be done in compliance with Good Manufacturing Practice (GMP) regulatory requirements. This module shows why it is so important to do a good job, what to consider before and during each job, and how best to go about the work. We explain what can be done to prevent contamination, we set out good practices to keep the factory clean and sanitary, and we describe how to prepare for and carry out cleaning and sanitation of premises and equipment.

Packaging operations constitute the last manufacturing step before release of a product to the market. They convert bulk product to the final product. Packaging for medicinal products is subject to Good Manufacturing Practice rules similar to those for the products themselves. In this module we describe the functions that packaging must fulfil and the quality controls that are applied to packaging materials and operations. We set out the requirements for control of printed materials. We describe preparation, in-process control, and completion of a packaging run. Finally, we explain how to carry out reconciliation of packaging materials.

Operations in the dispensary and on processing lines are at the heart of medicinal product manufacturing. This module describes how to carry out such operations in compliance with the requirements of Good Manufacturing Practice. We discuss how to, dispense starting materials, set up, control, and record formulation processes, evaluate product yield and calculate materials reconciliation. We set out the Good Manufacturing Practice (GMP) requirements that must be met in carrying out these tasks.

Pharmacoepidemiology is the study of the use and effects of drugs in large numbers of people. It provides a bridge between clinical pharmacology and epidemiology. The increasing demand for real-world evidence of the safety, efficacy and utility of medicinal products has focused greater attention on pharmacoepidemiological research. This module will help those who plan and conduct such research and analyse and report the findings to follow good practice.

This short entry-level module introduces the learner to good practices (GxP) in drug development and manufacturing. It outlines how the industry operates and how it is regulated. It identifies regulatory authorities and other important sources of guidance on Good Manufacturing Practice (GMP), Good Clinical Practice (GCP), and Good Laboratory Practice (GLP).

The medicinal products industry is heavily regulated by governments. Within the industry’s Good Manufacturing Practice (GMP) framework, analytical laboratories engaged in quality control (QC) of starting materials, intermediates, bulk products, finished products, and packaging need to comply with relevant GMP standards. We refer to these as Good Quality Control Laboratory Practice, or GQCLP. Regulatory authorities inspect laboratories to confirm that they meet the standards. This course explains how to comply with GQCLP, and it provides advice on laboratory work in general.

This course describes the requirements that must be met by, and options available to, the sponsor during the conduct of a clinical trial authorised under the European Union Clinical Trials Regulation. It identifies the various interactions with concerned member states that occur via the Clinical Trials Information System, and it summarises and links to the extensive guidance available from the European Commission and the European Medicines Agency.

To conduct a clinical trial in the European Economic Area under the Clinical Trials Directive the sponsor must apply for authorisation from the national competent authority (medicines regulator), and favourable opinion must be obtained from a research ethics committee, in each member state in which the trial is to take place. This module sets out the requirements for successful compilation, submission and maintenance of the applications. During the first year of transition to the Clinical Trials Regulation, sponsors have the option of applying for approval under the Directive, and they can continue trials under that regime until 31 January 2025.

This module outlines the legislative and regulatory context for the development of generic drugs and describes the essential role of the Abbreviated New Drug Application (ANDA) in gaining marketing approval. The use of information in the ‘Orange Book’ is explained, as is the role of patent certification in the application. The importance of establishing bioequivalence between a generic and its reference product is emphasised. The module specifies the content and format requirements for an ANDA submission and describes the FDA’s review and approval process. An outline is given of the Generic Drug User Fee Amendments (GDUFA) and the law’s effects.