https://ebookmass.com/product/coberts-manual-of-drug-safety-
Instant digital products (PDF, ePub, MOBI) ready for you
Download now and discover formats that fit your needs...
Cobertu2019s Manual of Drug Safety and Pharmacovigilance 3rd Edition, (Ebook PDF)
https://ebookmass.com/product/coberts-manual-of-drug-safety-andpharmacovigilance-3rd-edition-ebook-pdf/
ebookmass.com
Drug Safety Evaluation, 4th Edition Shayne Cox Gad
https://ebookmass.com/product/drug-safety-evaluation-4th-editionshayne-cox-gad/
ebookmass.com
The Organic Chemistry of Drug Design and Drug Action 3rd Edition, (Ebook PDF)
https://ebookmass.com/product/the-organic-chemistry-of-drug-designand-drug-action-3rd-edition-ebook-pdf/
ebookmass.com
Understanding Pathophysiology u2013 E-Book
https://ebookmass.com/product/understanding-pathophysiology-e-book/
ebookmass.com
The Hijaz: The First Islamic State Malik Dahlan
https://ebookmass.com/product/the-hijaz-the-first-islamic-state-malikdahlan/
ebookmass.com
eTextbook 978-0134319056 Excellence in Business Communication
https://ebookmass.com/product/etextbook-978-0134319056-excellence-inbusiness-communication/
ebookmass.com
Heart on My Sleeve: Knit With Care Shannon Cook
https://ebookmass.com/product/heart-on-my-sleeve-knit-with-careshannon-cook/
ebookmass.com
Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation Guangming Ye
https://ebookmass.com/product/clinical-characteristics-of-severeacute-respiratory-syndrome-coronavirus-2-reactivation-guangming-ye/
ebookmass.com
Clinical Handbook for Brunner & Suddarthu2019s Textbook of Medical Surgical Nursing 14th Edition, (Ebook PDF)
https://ebookmass.com/product/clinical-handbook-for-brunner-suddarthstextbook-of-medical-surgical-nursing-14th-edition-ebook-pdf/
ebookmass.com
(Heaven Hill Shorts Book 9) Laramie Briscoe
https://ebookmass.com/product/dalton-heaven-hill-shortsbook-9-laramie-briscoe-briscoe/
ebookmass.com
CIOMS III (1995 and 1998/1999): Guidelines for Preparing Core Clinical Safety Information on Drugs (1995), Including New Proposals for Investigator’s Brochures (1998/1999)
CIOMS IV (1998): Benefit–Risk Balance for Marketed Drugs: Evaluating Safety Signals
VI (2005): Management of Safety Information from Clinical Trials
Reporting and Communications of Safety Information from
VII (2006): Development Safety Update Report (DSUR)
CIOMS VIII (2010): Signal Detection (Points to Consider in Application of Signal Detection in Pharmacovigilance)
CIOMS/WHO Working Group on Vaccine Pharmacovigilance (2012): Definitions and Applications of Terms for Vaccine Pharmacovigilance.
CIOMS IX (2014): Practical Approaches to Risk Minimization for Medicinal Products
CIOMS X (2016): Evidence Synthesis and Meta-analysis
CIOMS SMQs (2016): Development and Rational Use of Standardized MedDRA Queries: Retrieving Adverse Drug Reactions with MedDRA — Second Edition
Other Sources of Reports
Follow-Up
Notes on United States Requirements for Post-marketing NDA Reporting of SAEs
in Play in Regard to Drug Safety and Academic and Non-academic
in Play in Regard to Drug Safety and Consumer Groups, Disease Groups, and the Internet (Blogs, Websites, Social Media, etc.)
Chapter 38 The Safety Department’s Role in Clinical Research, CROs, Marketing and Sales, Labeling, Regulatory, Quality, Due Diligence, Legal Issues,
E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
E2B: Clinical Safety Data Management: Data Elements for Transmission of Individual Case
E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER)
E2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting
Abbreviations
Introductions
Introduction to the First Edition
This manual is a practical instruction book on drug safety. It is aimed at newcomers, old-timers, and outsiders to the field who would like a demystification and explanation of what adverse events are and how drug safety departments work. Hopefully, readers, especially those not in the field, will understand that drug safety, like all other areas of medicine, is as much an art as it is a science.
For newcomers, this is a “Drug Safety 101” course giving a broad overview of how adverse events are handled from start to finish. For old-timers, this book will fill in gaps in knowledge on drug safety. For outsiders not working directly in this field, this book will explain how “side effects” are handled by the industry and by health authorities.
This book is not meant to be an encyclopedia. There are other such books already available. Rather, it is my
hope that this will be an approachable book that will give a global overview of the field.
It is expected that, after carefully reading and absorbing the contents, the reader will be able to begin work in a drug safety department, or, if an outsider, understand what happens in such a department and where listings or adverse events come from.
I have attempted to avoid excess jargon (“This spontaneous SAE is expeditable since it is unlisted”) and make the book approachable for those with limited or no knowledge of medicine or pharmacology.
Housekeeping: In this age of high technology, the references in the text are primarily websites rather than published citations. After much discussion, it was felt that putting URLs directly in the text would be distracting and of little use. Thus, they are noted in an appendix at the back of the book. In addition, accompanying this text is a CD-ROM with the entire contents of the book. This allows for rapid and easy searching for any topics the reader wishes. The URLs are “active” so that with a click or two the reader will be able to jump to
that website when using the CD-ROM. All of the links were active and correct when this book was prepared but they cannot be guaranteed to be so in the future. Also, copying and pasting links into your browser may solve errors that you encounter.
I wish you well in the world of drug safety.
Introduction to the Second Edition
The first edition of this book was written several years ago and since that time, much has changed in the world of drug safety. The use of technology, which exploded in other areas of medicine over the past 30 or 40 years, has now hit drug safety (EDC, E2B, CDISC, HL-7, DSUR, PPR, ICSR—if you don’t know what these mean, read the rest of this book). This is and will be a “game changer.” It is likely that our current systems will look prehistoric or at best medieval in 10, 20, or 30 years, as everyone’s medical life (if not entire life) is digitalized and readily available for review, study, analysis, correlation, tweeting, social media, and so on. Whether one likes this or not, it is necessary to keep up to date to remain employable and to conduct quality drug safety work. This book attempts to help the reader wade through the theory and methodology of drug safety and pharmacovigilance to high quality work.
Many changes in the field are heartening, but many are disheartening. On the heartening side, we are starting to understand pharmacology better. We are starting to develop methodology that will allow us to hopefully predict potential and likely drug toxicity in an individual. Perhaps genomics will allow us to truly tailor drug therapy to the individual. But we are not there yet, and genomics is barely mentioned in this book. With luck, we will see significant contributions to public health as our medical knowledge increases. The paradigms (sorry for the use of that word, but it fits) are changing: it is now “benefit–risk,” “quality management systems,” and “risk aversion.” These words and concepts were hardly used in medicine 50 years ago. Next, drug safety has gone global. It is quaint to think that the International Conference on Harmonization, which began in 1989, included all the major players in the field: the United States, Europe (actually just three or four major
western European countries), and Japan, with a few silent observers. Drug safety is now global, in large part because of the Uppsala Monitoring Centre, with new and vibrant ideas coming from all over the world.
On the disheartening side, we see corporatization, digitalization, depersonalization, politicization, commoditization, and other “-izations” in drug safety and medicine in general. Medicine is now a mass-market commodity, and drug safety is following that path too. We see laxity and bad behavior on the part of industry, healthcare practitioners, patients, consumers, government, universities, and nongovernmental organizations. We see politics and money continue to play a big role in the world of pharmacology. We also see the downside of globalization, with enormous fragmentation and duplication of efforts, and little upside. Add to this the “human condition” of wanting a magic pill to allow us to eat, drink, smoke, and do other things to our heart’s content without damage to our health.
A suggestion: There are two major uses for this manual. The first is as a textbook for those who wish to learn the field or review their knowledge of drug safety. Those folks may wish to read the book cover to cover (on their own or as part of a course) or the parts they need to brush up on. The second is as a reference. For this, I would highly suggest loading the manual onto your PC, Mac, iPhone, iPad, Android, or other techno-marvel and using a PDF search tool (e.g., in Adobe) for the key word or concept you are looking for. Although I have attempted to keep concepts in their dedicated chapters, many ideas (e.g., causality determinations) must be discussed in multiple chapters. Using a PDF search will quickly get you to the right place in the text.
There it is. I hope you find the book useful, accurate, and easy to read and absorb. Best of luck. You’ll need it.
Introduction to the Third Edition
This is now the third edition of this manual. You will notice several things.
First, we now have three authors not just one. The field has become so complex, diverse, global and messy that it is impossible for one person to be fully versed in the field to do a single author textbook.
Second, we have eliminated some country specific chapters and removed other chapters or details which are now out of date (e.g. the three 2005 FDA guidances on risk). Obviously, no slight is intended to those countries which are not discussed in this edition. Rather we have chosen to focus on the US and the European Union where the bulk (we believe) of our readers have been found and which, realistically, play pivotal roles in pharmacovigilance and drug safety.
The field is changing so rapidly that it is hard to even keep up with the changes in the US, EU and EU member states let alone the many other nations now doing drug safety.
The special and extraordinary case of the United Kingdom’s leaving the EU (Brexit) has put us in a quandary. This manual was written in the midst of the negotiations between the UK and the EU. Things have been and will clearly continue to change for the UK and the EU/member states as the EMA moves out of the UK to the Netherlands. We made a practical decision to leave out much of the UK/MHRA information fully realizing this is a major loss. We felt that whatever we said when the material was written would surely change by the time you read this.
Third, the field of DS and PV has continued to evolve. There is now a much greater emphasis on analysis of risk and toxicities in drug safety rather than an emphasis on collection of data (“filling in all the boxes”). Health agencies and “pharmacovigilantes” (a humorous term referring to people working in the field of drug safety) emphasize more and more that risk analysis and the minimization of toxicity and risk are the major goals of PV. Given the extraordinary changes in IT and data collection, it is now presumed by the health agencies that global data can and will be accurately and completely collected and processed both in clinical trials and in the post-marketing setting. With changes in approval procedures for marketing we are now seeing drugs reach the market with fewer patients studied and less known about the safety profile. We are also seeing more post-marketing requirements. This may or may not be a good thing.
Other major changes include the divergences in many areas that were more or less harmonized by ICH. Harmonization seems to have peaked in the early 2000s. We now see divergences in the US and EU and in many other areas. ISO has entered the picture and many more countries and
outside organizations are now involved in the pharmaceutical world. Hopefully these are good things.
The downside of the manual seems to be largely unchanged from the notes in the introduction to the second edition:
“On the disheartening side, we see corporatization, digitalization, depersonalization, politicization, commoditization, and other “-izations” in drug safety and medicine in general. Medicine is now a mass-market commodity, and drug safety is following that path too. We see laxity and bad behavior on the part of industry, healthcare practitioners, patients, consumers, government, universities, and nongovernmental organizations. We see politics and money continue to play a big role in the world of pharmacology. We also see the downside of globalization, with enormous fragmentation and duplication of efforts, and little upside.”
Several housekeeping comments:
We have eliminated most of the URLs which were much more extensive in the earlier two editions. We found that they changed rapidly and became useless very shortly after publication. You should google the desired sites or documents for the latest URL.
Although there is a good index in this Manual, you’re best bet to find something is to use the electronic version and use the pdf search tool to find what you are looking for.
So, to conclude, with all the changes underway in the world both in general and in the pharmaceutical PV arenas, we need to keep in mind that the goal of DS and PV remains rather simple and straightforward: protect the patients and minimize toxicity and risk from medications.
Whether we are making progress in this area is hard to know.
The last sentence from the second edition introduction also remains valid:
“There it is. We hope you find the book useful, accurate, and easy to read and absorb. Best of luck. You’ll need it.”
This page intentionally left blank
Contributors
Lisa Beth Ferstenberg, MD
Chief Medical Officer, Praxis Scientific, Washington DC
(Author of Chapter 41 Vaccinovigilance)
Germano Ferreira, PharmD, PhD
Consultant, Epidemiologist and Senior Real World Data Scientist.
(Reviewer of Chapters 5 (Mathematics of AE) and 6 (Pharmacoepidemiology)
This page intentionally left blank
Notice
This book is not meant to be used in the practice of medicine or for the prescription of medicines, drugs, biologics, over-the-counter medications, health foods, supplements, and so forth. The medications described do not necessarily have specific approval by the U.S. Food and Drug Administration, European Medicines Agency, Health Canada, or any other regulatory or health agency for use in the diseases, patients, or dosages discussed. The approved labeling in the United States and other countries and regions must be consulted for that jurisdiction before any product is used or prescribed. Because standards for usage change, it is advisable to keep abreast of revised recommendations, precautions, safety warnings, and adverse events, particularly those concerning new products.
This book is not intended to express opinions about the value of specific products or their comparative value within a drug class, even when a specific product is used to provide examples of adverse reactions. The content of this book is not meant to be used in choosing therapies in medical practice by healthcare practitioners or consumers. As with all medications and therapies, the official approved product labeling should be consulted before prescribing or using.
And finally, this manual is not meant to be a comprehensive drug development guide. We have given our opinions on many areas of safety in drug development and marketing but things change daily. Check many sources. Trust but verify. Good luck!
This page intentionally left blank
What is an adverse event (AE)? A serious AE (SAE)? An adverse drug reaction (ADR)? A suspected, unexpected, serious adverse reaction (SUSAR)? A suspected, expected, serious adverse reaction? What do expected, unexpected, listed and unlisted mean?
Note: Unless otherwise noted, the words “drug” or “drug product” or “medicinal product” should be taken in this book to include “biologics” and “vaccines”, too.
The Theory
There have been many variants on the terms and definitions used to talk about safety issues over the years.
The Theory and Definitions of Drug Safety — Pharmacovigilance
Pharmacovigilance terminology and related initialisms are somewhat confusing; commonly used terms are explained below. Table 1 contains a list of associated initialisms. For a more extensive listing of initialisms used in pharmacovigilance, see the Acronyms section of this manual.
The “official” and accepted definitions in most countries are based on the International Conference on Harmonization (ICH) E2A Guideline and are given in the following sections. Note that the ICH changed its name to International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use in 2015. They still refer to it as ICH.
Adverse Event (AE) — ICH
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment (ICH E2A).
Any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom,
