Post-Authorization Safety Studies of Medicinal Products

The PASS Book

Ayad K. Ali, Abraham G. Hartzema

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128092170
• eBook ISBN: 9780128092088
• Topic: Médecine
• Subtopic: Théorie, pratique et référence de la médecine

Post-Authorization Safety Studies of Medicinal Products: The PASS Book bridges the gap in the literature by providing a complete look at post-authorization safety studies and important pharmacoepidemiology and pharmacovigilance aspects. It covers various types and limitations of active surveillance programs, including the use of large databases and disparate data sources for rapid signal detection, as well as novel and advanced design and analysis approaches for causal interference from observational data. This book serves as an important reference for pharmacovigilance scientists and pharmacoepidemiologists who are searching for the appropriate study design to answer safety research questions.Readers will be able to effectively and efficiently design and interpret findings from post-authorization safety studies with the goal of improving the benefit-risk balance of a drug in order to optimize patient safety.- Discusses all types of observational studies in post-marketing drug safety assessment, from spontaneous reporting systems, to pragmatic trials, with examples from real-world settings- Presents various types of post-authorization safety studies- Offers solutions to the common challenges in the design and conduct of these studies- Highlights active surveillance programs, including common data models for rapid signal detection of drug safety issues

Chapter 1

Introduction

Ayad K. Ali¹, and Abraham G. Hartzema^{2 1}Eli Lilly and Company, Indianapolis, IN, United States ²University of Florida, Gainesville, FL, United States

Contents

1. Risk Management and Benefit–Risk Evaluation
2. Transparency
3. About This Book
4. References

On submission of the marketing authorization application (MAA), regulatory agencies review the submitted evidence with the aim to learn as much as possible about the efficacy and safety of the medicinal product during the preauthorization phase, which assists in making marketing authorization decision to allow patients to have timely access to efficacious and safe medicinal products. However, studies conducted in the preauthorization phase of product development have inherent limitations that prevent characterization of all adverse events (Table 1.1 lists the main limitations of typical preauthorization clinical trials). The full safety profile of medicinal products can be determined after exposure by relatively large number of patients of diverse demographics and medical histories, and by those who are treated for extended periods. Preauthorization studies are sufficient to elucidate and characterize adverse events that are more frequently occurring and those that are detected in short follow-ups. Thus, other uncommon, rare, and serious adverse events are increasingly gone undetected during the preauthorization phase of product development.

Post-authorization studies (PAS)—including post-authorization safety studies (PASS) and post-authorization effectiveness studies (PAES)—are intended to fill the knowledge gap about the safety and effectiveness of medicinal products in the postmarket setting; they are more commonly used to better delineate the benefit–risk profile of medicinal products during their life cycle. These studies are optimal for the detection and evaluation of adverse events that are uncommon, rare, and serious; those that occur after prolonged exposure; and those that increase in frequency and severity with time. Table 1.2 describes the categories of adverse events according to frequency of occurrence (CIOMS, 1999).

Using real-world data, PASS are studies conducted to evaluate the benefit–risk profile of medicinal products after marketing, which also provide support to regulatory decision-making. From regulatory standpoint, any study with safety objectives are considered PASS, which include those that aim to identify (i.e., signal detection), characterize (i.e., signal clarification), or quantify product-related risks (e.g., establish the likelihood of risk occurrence and investigate missing information); confirm the safety profile of medicinal products (i.e., signal evaluation); or measure the effectiveness of risk minimization activities (EMA, 2018). Additionally, PASS can speed up the marketing authorization process by being added as a conditional requirement for approval in the new MAA or can be required when the medicinal product is marketed and new questions about its safety arise. The main purpose of PASS is to establish the safety profile of medicinal products as early as possible in their life cycle.

Table 1.1

Common Limitations of Preauthorization Studies

Component	Description
Objectives	Investigate the efficacy and characterize the most common adverse events of the medicinal product. Usually do not have safety objectives.
Size	Not of sufficient size to detect uncommon and rare adverse events of the medicinal product.
Target	Results are not generalizable to patients who will use the medicinal product in the usual health-care setting.
Setting	Highly controlled environment that may not reflect the real-world setting. Protocol-mandated treatment and testing, and scheduled patient visit with high patient adherence.
Duration	Short treatment duration that prevents the detection of adverse events with long latency periods.
Analyses	Focus on efficacy endpoints rather than safety.

Table 1.2

Frequency Categories of Adverse Events

Category	Frequency of Occurrence (%)
Very rare^a	<0.01
Rare^a	0.01 to <0.1
Uncommon (infrequent)^a	0.1 to <1
Common (frequent)	1 to <10
Very common	≥10

^a Possible to be detected by post-authorization safety studies.

PASS have gained much interest over the last decade, especially after the enactment of the European Pharmacovigilance Legislation in 2010 and subsequent implementation in 2012 (EMA, 2012a), which was described as the biggest change in the regulation of medicinal products in the European Union (EU) since early 1990s, as it added legal requirements for the planning and conduct of pharmacovigilance activities—including PASS by marketing authorization holders (MAH) (Engel et al., 2017). Regulatory guidelines have been developed to guide the design, implementation, and reporting of PASS in the EU, including the guideline on good pharmacovigilance practices (GVP) (EMA, 2012b), which includes a specific module on PASS (Module VIII) that highlights regulatory classifications, and format and content of study protocols and final study reports (EMA, 2012c, 2013; 2017).

The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) use different nomenclatures to refer to safety studies that are voluntarily or mandatorily conducted by MAH in the postmarket setting. For the FDA, the Food and Drug Administration Amendments Act of 2007 may require MAH to conduct postmarketing studies to assess known serious risks or signals of serious risks related to the use of medicinal products or identify an unexpected serious risk when available data indicate that a potential for such risks exits (FDA, 2011). The FDA makes a distinction between postmarketing commitments (PMC) and postmarketing requirements (PMR). PMC are voluntary agreements between the FDA and the MAH to conduct studies; on the other hand, PMR are studies that are obligatory to be conducted by the MAH. Although all PASS in the pharmacovigilance plan are considered legally enforceable, the EU regulators classify them in three categories based on the expected impact of their results on the post-authorization benefit–risk evaluation (EMA, 2018). For imposed PASS (Category 1 and 2), noninterventional PASS have specific legislative requirements for the protocol submission and final results assessment, under the supervision of the EMA's Pharmacovigilance Risk Assessment Committee (PRAC). Although the protocol submission to the competent authority is not mandatory for required PASS (Category 3), unless specifically requested, the final study results are required to be submitted within the agreed due dates as variations to the marketing authorization. Furthermore, the EMA uses the term MAH or license holders for those companies responsible for the marketing of the medicinal product; the FDA uses the term sponsors and may use the term applicants for those responsible for conducting the PMR or PMC. Similarly, as the EMA uses the term post-authorization phase, the FDA uses the term postapproval to indicate the postmarketing phase in the life cycle of the product. In this book, we adopt terms that are used by the EU regulators.

Plans for PASS may be submitted with the original MAA or subsequently as a stand-alone submission. They can be part of the new application dossier and proposed by the MAH in support of the new application, may be required by the regulatory authority at the time of authorization of the product, or by post-authorization as new safety questions emerge. These can be related to any medicinal products intended for human use, including pharmaceuticals, biologics, vaccines, devices, and combination products.

Risk Management and Benefit–Risk Evaluation

Risk identification and assessment is key for successful planning of PASS. Data from multiple sources are evaluated to provide a list of safety concerns for the particular medicinal product. The safety concerns may be important identified risks, important potential risks, or areas of missing information that could impact patient treatment. These safety concerns form the basis for subsequent planning of PASS.

At the time of authorization, many risks of the medicinal products would have been identified as part of the assessment of the MAA. The ones deemed important for the benefit–risk balance of the products might require further characterization to confirm if they are real or not, or to establish their severity, frequency, and risk factors. Often such research takes form of PASS. In addition, PASS might also be able to identify new safety concerns, investigate missing information, or measure the effectiveness of risk minimization activities established for the products.

Risk management is an iterative process that involves the identification, characterization, evaluation, and minimization of risks associated with medicinal products. It also includes assessing the effectiveness of risk minimization activities. Some of these components have existed for many years—even if not being formally recognized as risk management—but the Pharmacovigilance Planning E2E guideline of the International Conference on Harmonization (ICH) provided a framework for pharmacovigilance planning, which encompassed the first three components (ICH, 2004). Risk minimization was not included in the ICH E2E guideline but is an essential part of maximizing benefit–risk balance of medicinal products both for the individual patient and for the target population as a whole.

In the context of the life cycle approach to risk management, risk minimization is aimed to prevent or reduce the probability of the occurrence of adverse events with the exposure to medicinal products or to reduce their severity should they occur. For all medicinal products, an EU risk management plan includes routine risk...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Chapter 1. Introduction
• Chapter 2. Risk Management Process
• Chapter 3. Data Sources for Post-Authorization Safety Studies
• Chapter 4. Study Designs for Post-Authorization Safety Studies
• Chapter 5. Analytical Approaches for Post-Authorization Safety Studies
• Chapter 6. Benefit–Risk Evaluation
• Chapter 7. Post-Authorization Safety Studies for Specialty Products
• Chapter 8. The European Union Post-Authorization Study Register
• Index