Pharmacoepidemiology and Pharmacovigilance

Synergistic Tools to Better Investigate Drug Safety

Sabrina Nour, Gilles Plourde

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128161838
• eBook ISBN: 9780128163818
• Topic: Medicine
• Subtopic: Epidemiology

Pharmacoepidemiology and Pharmacovigilance: Synergistic Tools to Better Investigate Drug Safety examines the role of pharmacoepidemiologic studies in drug development and its use as a prevention tool in pharmacovigilance activities. The book introduces the various epidemiologic tools and study designs commonly used for the surveillance of drug-related adverse effects and reviews the strengths and weaknesses of each. Criticisms surrounding pharmacoepidemiologic research and issues that often interfere or complicate the conduct and interpretation of these studies are also explored. Case studies illustrate the passive and active surveillance of adverse drug reactions in clinical situations, covering important pharmacoepidemiologic concepts like health risk management and safety.The book helps pharmaceutical industry groups engaged in drug safety, clinical investigators, medical evaluators and those seeking regulatory approval enhance the safety of the drug development process for all patient populations.- Describes the main prevention tools for the passive and active surveillance of adverse effects associated with drugs- Provides examples of diseases in various contexts related to clinical studies and the analysis of adverse drug reactions- Offers case studies that illustrate real-life clinical situations- Discusses important concepts related to pharmacoepidemiology and pharmacovigilance

Chapter 1

Introduction

Abstract

This chapter provides a general introduction to the world of epidemiology, and more specifically a unique branch of epidemiology, known as pharmacoepidemiology. Pharmacoepidemiology refers to the study of the use and effects of health products in populations. The second concept explored in this chapter is that of pharmacovigilance. The chapter sets the tone for the remainder of this book, which intends to look at how the tools and concepts of pharmacoepidemiology and pharmacovigilance are used for the management of adverse drug reactions.

Keywords

Epidemiology; Pharmacoepidemiology; Pharmacovigilance

Epidemiology refers to a scientific discipline that uses knowledge from the biological sciences, social sciences, the theory of probabilities, and statistical tools to study and quantify the presence and causes of health problems in humans. ^1–4 Although various definitions have been proposed to describe the word “epidemiology,” the common theme that emerges from almost all of these definitions is that the study of epidemiologic data serves three main objectives:

• (1) Epidemiology is often used for descriptive purposes to describe the distribution and frequency of a health problem in humans or among specific subgroups of the population.
• (2) It is also commonly used for analytic purposes to identify the causes and risk factors of many health problems.
• (3) It is also used for assessment purposes to assess the results of an intervention on a specific health problem in a specific subpopulation. ^2,5–6

For a thorough introduction to the concepts of epidemiology, the reader is invited to consult the following books: Modern Epidemiology (3rd ed.) by Rothman et al. and Epidemiology for the Uninitiated (5th ed.) by Coggon et al. ¹

Notice that the definition of epidemiology is purposefully kept broad since it has a large scope with major applications for the study of a variety of health issues, thus creating smaller but more focused branches. For instance, pharmacoepidemiology is one such branch and will be the focus of this book. A comprehensive definition of pharmacoepidemiology is found in the fifth edition of the book A Dictionary of Epidemiology, and it is defined as: “The study of the distribution and determinants of drug-related events in populations and the application of this study to efficacious treatment. The application of epidemiological knowledge, methods, and reasoning is to describe, explain, control and predict the uses and effects (beneficial and adverse) of drugs, vaccines and related biological products in human populations […]. P``harmacoepidemiology also aids pharmacology, public health, and other health sciences by increasing knowledge about the occurrence and causes of diseases, the distribution of health states and the functioning of the healthcare system.” ²

Figure 1.1 Product life cycle. 1, The OCDE Good Laboratory Practices (GLP): The OCDE GLP is the study of the molecule, its effect on cells of animals, target organs and other aspects related to the management of preclinical studies including data analyzing, archiving, planning, publication, and other aspects related to laboratory activities. This first point also includes GLP inspection to ensure quality, reproducibility, and the integrity of the results regarding the efficacy and safety of chemical or biological substances. It also includes best practices from Health Canada's Good Manufacturing Practice (GMP) and GMP inspection to ensure the quality of the material chosen for the production and to ensure that the techniques of packaging, labeling, analysis, distribution, import, and sales meet the established standards. (For more information the reader is invited to consult these Guidelines at the Resources for Readers section). 2, Additional tools: these tools are the ICH M3 (R2) and S6 (R1) Guidelines on preclinical safety evaluation for pharmaceutical and biotechnology products, respectively. There are various other ICH guidelines discussing preclinical safety studies (pharmacology, target organ toxicity, reproductive toxicity, genotoxicity, carcinogenicity, maximum tolerated dose, without toxic effects, and others) http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html (this information is used to estimate an initial safe dose for clinical trials in humans and to identify parameters for medical follow-up of potential adverse effects). 3, Good Clinical Practice of Division 5 of the Food and Drug Regulations, the ICH E6 on Good Clinical Practice Guidelines and Inspection Guidelines: These measures are meant to ensure and verify the validity of the data presented on the clinical, pharmacological, pharmacokinetic, or pharmacodynamic effects of drugs for human use to detect and require the report of adverse reactions and to study the absorption, distribution, metabolism, efficacy, and efficiency. This also contains the recommendations of the ICH E2A Guidelines on the mandatory reporting to Health Canada of all serious and unexplained adverse reactions observed in clinical trials. The goal is to ensure the safety of clinical trials participants. 4, Division 8 of the Food and Drug Regulations and the Management of Health Canada Drug Submission Guidelines: These tools are used to determine what must be submitted and evaluated to confirm the quality, efficacy, and safety (favorable benefit/risk ratio) of a health product for marketing authorization purposes and includes (1) basic scientific information about the health product; (2) the aspects related to the quality of the product; (3) preclinical studies; (4) clinical efficacy and safety of a health product; (5) an analysis of the benefit/risk ratio; (6) a product monograph labeling and patient’s information leaflet; (7) a risk management plan, including the pharmacovigilance plan, if necessary. After approval the manufacturer must take the necessary measures to ensure that the benefit/risk ratio remains favorable and the risks can be mitigated, managed, and warned throughout the product life cycle by a passive and active surveillance of the adverse drug reactions, by the reporting of safety report synthesis annually or on request (risk management plan, periodic benefit–risk evaluation report, and development safety update report) and by providing additional studies on specific populations including post–market phase IV studies, registries, and others (discussed below). 5, Good pharmacovigilance practice and Inspections: These tools are used to monitor the safety, efficacy, and quality of drugs after the marketing approval. This activity consists in monitoring, prevention, and reassessment of adverse drug reactions and must conform to the Food and Drug Regulations (see sections C.01.016 to C.01.020) that require the manufacturers to report adverse reactions to Health Canada and any product failure in a timely manner according to their severity and novelty as well as all changes in the benefit/risk ratio of a health product. As a result of this monitoring activity terms of use can be changed and modified, suspended, or even authorization revoked by the Minister. The goal is to ensure the safety of patients during real-world use.

As mentioned, pharmacoepidemiology includes the study of the use and effects of health products in populations. As it will be discussed in this book, the designs used in pharmacoepidemiologic studies are not much different from those used in other areas of clinical epidemiology. However, there are three key differences between both statistical sciences and this will be discussed below:

• (1) Because pharmacoepidemiologic studies are usually performed after a health product has been approved for marketing, and because around 500–3000 patients are generally studied during the premarket phase (before approval), pharmacoepidemiologic studies usually must include substantially larger numbers of patients (depending on the indication) that must be followed for a longer duration to add new useful information;
• (2) Because at least one randomized control trial (RCT) (or a pivotal trial) was already performed prior to drug marketing, pharmacoepidemiologic studies are less likely to use RCT study designs because many of the same limitations, which the premarketing RCTs were subject to, would apply as well as to any postmarketing RCT and therefore would not contribute adding new useful information. For example, because RCTs are not an efficient means of studying uncommon adverse effects, the drug effects in patients are commonly excluded from such trials;
• (3) Because, pharmacoepidemiologic questions often arise from regulatory and public health concerns, answers must often be obtained very quickly. This need for rapidly performed studies of massive sample size has led to a series of special approaches that have characterized the field of pharmacoepidemiology.

The second partner involved in the management of adverse drug reactions is pharmacovigilance. This component is defined as being the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other safety problem related to health products on the market (intolerance to drugs, unauthorized use or misuse, therapeutic error, drug dependence, drug resistance, drug abuse, and others). Please consult the glossary of pharmacovigilance terms at the end of Chapter 2 to have a more in-depth understanding of terms related to pharmacovigilance.

To reduce adverse drug reactions, regulatory authorities such as Health Canada, FDA, EMA, and others regulatory authorities have developed pharmacovigilance programs for the evaluation, control, and monitoring of these adverse drug reactions, including the monitoring programs in postapproval phase. Again, the information included in the glossary at the end of Annex 1 would be relevant to consolidate the information discussed about pharmacovigilance.

It is well known that many adverse drug reactions remain unknown for years following marketing of a health product. Therefore, it is essential to learn more about their use in the long term and in specific population groups. Usually, people who are at high risk because of their age (such as young children and the elderly), a special situation (pregnant or breast-feeding women or persons of different racial or ethnic origin), a particular condition (the carriers of genetic polymorphisms), or their health status (complex pathology, polypharmacy) are generally excluded from clinical trial protocols. However, all these patients may receive the drug when it becomes available on the market, hence the importance of setting up an effective pharmacovigilance program for them. It is therefore essential that new health products are subject to a control of efficacy and safety in real conditions of use, i.e., after their authorizatio...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Biography
• Foreword
• Chapter 1. Introduction
• Chapter 2. Pharmacovigilance
• Chapter 3. Pharmacoepidemiology in the Prevention of Adverse Drug Reactions
• Chapter 4. Case Studies
• Chapter 5. Conclusion
• Annex 1. Glossary of Pharmacovigilance Terms
• Annex 2. Glossary of Pharmacoepidemiology Terms
• Annex 3. Food and Drug Act and Regulations
• Annex 4. Resources for Readers
• Index