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xxii Cobert’s Manual of Drug Safety and Pharmacovigilance
Data Safety Management Boards and Ethics Committees/Institutional
Review Boards
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Safety Assessment Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
Dynamics in Play Regarding Drug Safety and Health Agencies . . . . . . . . . . . . . . . . . . . . 457
Dynamics in Play in Regard to Drug Safety and Academic and Non-academic
Healthcare Facilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Dynamics in Play Regarding Drug Safety and Consumer Groups, Disease
Groups, and the Internet (Blogs, Websites, Social Media, etc.)
. . . . . . . . . . . . . . . . . . . . . 460
Dynamics in Play Regarding Drug Safety and Lawyers/Litigation . . . . . . . . . . . . . . . 460
Codes of Conduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .461
Comments and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .461
Chapter 45 Universities and Academic Medical Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
The Bayh–Dole Act in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Clinical Research Units/Academic Study Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Translational Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Drug Safety Training in Academia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .466
Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .466
Academic Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
A google search on “universities partnering with pharmaceutical
companies” will reveal many instances of these arrangements. Bad
Behavior
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
The Sunshine Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Chapter 46 Vaccinovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .471
Differences between Vaccinovigilance and Pharmacovigilance . . . . . . . . . . . . . . . . . . .471
Causality versus Attribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .472
Temporal Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .472
Drugs are Metabolized; Vaccines are Processed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .472
Incidence and Prevalence of Adverse Event Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . .473
Vaccine Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .474
United States Initiative: The Vaccine Adverse Events Reporting System . . . . . . . . 474
GACVS and the European Commission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Vaccine Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
European Union System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Sources of Additional Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Chapter 47 Real-World Issues: Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Ongoing Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Fialuridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Fen–Phen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
Nomifensine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
TGN-1412/TAB08 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Contents xxiii
Chapter 48 Medical Marijuana and Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
US Federal Regulatory Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Bottom Line . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Abbreviations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
xxv
Manual 4 Introductions
This is now the fourth edition of the Manual.
Edition 1 was published in 2007 which now seems
like it was a century ago. This was when the internet
was in its “infancy” and the use of information technol-
ogy was largely unknown in pharmacovigilance which
was also younger — perhaps a toddler. Edition 2 was
published in 2012 and edition 3 in 2019. Things were
clearly changing between 2007 and 2019. We had antic-
ipated another 5 to 7 years for the fourth edition but
clearly the changes that have occurred since 2019 were
major. Similarly in the four years since edition 3 major
changes have occurred in the pharmaceutical world not
the least of which has been Covid. There were many
causes for these changes. Perhaps the biggest was the
rapidly evolving field of information technology, arti-
ficial intelligence, new and powerful databases, social
media and fake news, instantaneous communication as
well as new duties and functions in the FDA, EMA and
other health agencies, Brexit (with the MHRA moving
from London to Amsterdam), multi-polar global phar-
macovigilance rather than dominance by the US, the
EU and Japan (the original ICH partners), changes in
the pharmaceutical industry, more generics, pharmaco-
epidemiology, signaling, marijuana “approval”, opioid
abuses and many others you could name. The first two
editions were single author books. At that time, this
was reasonable and possible. Now the field has become
so large and complicated that expertise is needed from
multiple authors. We have still tried to keep this Man-
ual simple and readable. We’ve tried to minimize jargon
and long compound and complex sentences.
We are delighted that Catherine Baldridge has
joined the team! She has provided wonderful insight
into what is happening in the world of drug safety as
well as functioning as Chief Operating Officer of this
endeavor! Thank you, Catherine.
The numerous reasons mentioned above pushed us
to update this Manual somewhat sooner than we had
anticipated. By necessity, we have made some changes
to the contents compared to previous editions. There
is more on signaling and pharmacoepidemiology but
those fields now seem to merit a manual or textbook
of their own. We have cut back on looking at global
xxvi Cobert’s Manual of Drug Safety and Pharmacovigilance
PV as there are now far too many countries involved in
PV with rapidly changing rules, laws, regulations and
procedures. Practically speaking, because of language
issues and local “unwritten” practices keeping up with
PV in over 100 countries is nearly impossible.
Finally, any thought that we might get some breath-
ing room after this edition is probably not going to hap-
pen. The next changes on the horizon will be in the
field of AI (artificial intelligence). AI will make major
changes in the way the whole world works, commu-
nicates and analyzes data. There may also be some sig-
nificant changes in drug approval by regulators. This
has been spurred on by the “waivers”, shorter review
times and other exceptions to the usual rules to allow
drugs and vaccines to be used against Covid. We expect
new pathways to emerge to get products to the patients
faster but with less data. To put it another way, if efficacy
can be shown quickly the product can get provisional
approval with the proviso that more efficacy and safety
data will be collected. This means that we will collect
more and more safety data after marketing. This is now
being seen with Covid medications and marijuana.
In any case, some of the observations from the
introductions in previous editions still apply and are
worth looking at:
We now have four 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.
Given the extraordinary changes in IT and data col-
lection, it is now presumed by the health agencies
that global data can and will be accurately and com-
pletely collected and processed both in clinical tri-
als 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. The
potential to mine safety data from electronic health
records is promising and could supplement and, per-
haps, reduce some duplication of pharmacovigilan-
ties’ efforts. 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, particularly as technol-
ogy has evolved.
ISO has entered the picture and many more coun-
tries and outside organizations are now involved in
the pharmaceutical world. Hopefully these are good
things.
On the disheartening side, we see corporatization,
digitalization, depersonalization, politicization, com-
moditization, 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, govern-
ment, universities, and nongovernmental organiza-
tions. 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 fragmenta-
tion and duplication of efforts, and little upside.
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 demystifica-
tion and explanation of what adverse events are and
how drug safety departments work. Hopefully, read-
ers, 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.
It is expected that, after carefully reading and absorb-
ing 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.
We have attempted to avoid excess jargon (“This
spontaneous SAE is expeditable since it is unlisted”)
and make the book approachable for those with lim-
ited or no knowledge of medicine or pharmacology.
There it is. We hope you find the book useful, accu-
rate, and easy to read and absorb. Best of luck. You’ll
need it.
xxvii
Authors
The original text, and “founding father” of
this textbook series, Dr. Barton Cobert, has
worked tirelessly over the years to share his
knowledge, experience and insight in this sci-
entific field. His contributions to the industry
are well known and he was one of the first
to set forth and publish a text regarding the
basic principles and theory of drug safety and
pharmacovigilance. Throughout his illustri-
ous career, he has forged relationships with
other key opinion leaders and graciously
invited others to contribute their knowledge
to the text Each contributor has provided a
summary of their background to showcase
their experience and for the readers to have a
better understanding of who has contributed
to the text. Collectively, we as contributing
authors are grateful to have been included in
this endeavor and hope that our readers will
find just as much value in our advice as we
have had in providing it.
— Catherine Baldridge
Barton Cobert, MD, FACP, FACG
United States
Dr. Cobert is an expert on Drug
Safety and medication side
effects, and author of several
textbooks and multiple journal
articles on these topics. He has
extensive experience in Drug
Safety, Clinical Drug Research,
Regulatory Affairs, Risk Manage-
ment, and Computer Informat-
ics in pharmaceuticals. He was previously in practice
doing gastroenterology before entering the pharma-
ceutical world as Global Head of Drug Safety at Sch-
ering Plough and Novartis OTC. He has worked for
several pharmaceutical companies and consulted to
FDA and other regulatory agencies. He created his
own consulting group BLCMD Associates in 2008.
Dr Cobert is a 1974 graduate of the New York Univer-
sity School of Medicine where he also did his train-
ing in Internal Medicine and Gastroenterology. He
xxviii Cobert’s Manual of Drug Safety and Pharmacovigilance
also did a post-doctoral fellowship in liver disease in
France. He is board certified in Internal Medicine and
Gastroenterology.
Dr. Jean-Loup Thomas, MD
France
Dr. Jean-Loup Thomas is M.D.
graduate of the Paris (France)
Medical School (La Pitié
Salpétrière), specialized in clin-
ical Pharmaco-Toxicology. He
started his medical career at
the Paris Poison Control and
Pharmacovigilance Center. He
then moved to the pharmaceu-
tical industry within Pharmacovigilance for several
companies (Lilly, Novartis, Merck-Serono, Sanofi-
Pasteur, Sanofi Pharma), at both affiliate and corpo-
rate levels. He is an expert in Clinical Pharmacology,
Clinical Safety/Pharmacovigilance, Safety Signals and
Risk Management, Drug Safety Crisis, Data Monitoring
Committees/Data Safety Monitoring Boards, Labelling/
Product Information and Clinical Development. He has
been EU QPPV within the Sanofi group and also led the
Sanofi Global Labelling team. He is now Senior Consul-
tant for the clinical pharmaco-toxicology department at
the Hospices Civils de Lyon (France).
Dr. William W. Gregory
United States
Dr. Gregory received formal
training in infectious diseases
and molecular mechanisms of
pathogenesis at Davidson Col-
lege, the University of St Andrews
(Dundee), and the Univer-
sity of North Carolina Medical
School (Chapel Hill) followed
by postgraduate fellowships
at The University of Chicago Hospitals and Clinics
and the University of Rochester Medical Center. He
has practical experience in diagnostic methodology/
techniques, product in/out licensing due diligence,
pharmacovigilance, benefit-risk assessment, drug
safety operations, clinical trial design, pre- and post-
registration protocol development and execution,
regulatory phases I-IV of medicinals and large molecule
development for successful product registration. He
also held positions at the US Army Institute for Infec-
tious Diseases (Fort Detrick), the Veterans Administra-
tion (consultant in laboratory medicine), the US Army
Combat Engineers (Captain), the University of Virginia
Medical School (pathology professor), the University of
Virginia Hospitals and Clinics, the Blue Ridge Hospital,
and a 40-year career at Pfizer Inc. in positions of increas-
ing responsibility and influence in R & D, including
Team Leader for several commercially-successful prod-
ucts launched around the world. He was awarded the
prestigious Excellence in Research and Development
Award by Pfizer for innovation in clinical research and
efficiencies in global product development and registra-
tion. He has served on many consensus panels, includ-
ing ICH, CIOMS, ISO, Eu2P, DIA, NCCLS, and HL7 as
well as trade groups. He is an accomplished jazz trom-
bonist, dog breeder, and is credited with more than 50
scientific publications as an author or co-author.
Mrs. Catherine Baldridge, MS
United States
Mrs. Catherine Baldridge is a rec-
ognized leader in product safety
& pharmacovigilance operations.
She is a graduate of Hollins Uni-
versity with a degree in Psychol-
ogy, with a concentration in both
neuro and clinical psychology,
and later received her Masters of
Science degree from the Univer-
sity of Virginia in Clinical Investigations and Patient
Oriented Research. Mrs. Baldridge has worked for sev-
eral CROs and Pharmaceutical and biotech companies,
and has held positions as an Adjunct Faculty at Temple
University, teaching several courses in Clinical Trial
Safety and Good Pharmacovigilance Operations. She
has been a leader within the DIA organization, serving
as the Chair of the Clinical Safety and Pharmacovigi-
lance community as well as leading several discussions
in the field and providing expert peer review of pub-
lished articles in therapeutic journals. Mrs. Baldridge
has also served as an industry consultant, helping
many companies develop safety operations and reme-
diate inspection findings and outcomes.
xxix
Chapter Contributions
“You don’t know what you don’t know”
To acknowledge when you are not the expert, when
are still educating yourself, and to realize the power of
seeking guidance and advice from others, is really one
of the only ways to grow and succeed in life as well
as in this industry. We understand our limitations as
professionals in the medical and scientific field of drug
safety and pharmacovigilance and have sought thought-
ful insights and educational wisdom from several other
experts within the field, who are listed below.
The authors would like to acknowledge and thank
our contributors, without whom some of these chapters
could not be realized.
We thank them for their time, dedication, and
expert advice and opinion towards the industry and
their contribution to this text.
Lisa Beth Ferstenberg, MD
United States
Lisa Beth has worked in the pharmaceutical industry
for over 40 years during which she has assisted in the
development of multiple biopharmaceutical, monoclo-
nal antibody, cell therapy and vaccine products. Her
experience spans four epidemics, the evolution of bio-
technology, the remarkable advances in organ and cel-
lular transplantation and the use of gene therapies for
rare diseases.
Her global engagement has given her experience in
the most sophisticated research centers and the most
basic community care outposts. She has had the oppor-
tunity to learn the impact of cultural beliefs, econom-
ics, social requirements and political influences on the
availability and delivery of healthcare.
xxx Cobert’s Manual of Drug Safety and Pharmacovigilance
Currently, Lisa Beth is Executive Director of Phar-
macovigilance for the Biopharmaceutical Division of
AstraZeneca where she recently oversaw safety manage-
ment for the deployment of the COVID vaccine.
Chapter Contributions: Author of Chapter 41,
Vaccinovigilance
Gretchen S. Dieck, MPhil, PhD
Epidemiologist and safety & risk management consultant
United States
Gretchen Dieck, PhD, is currently an epidemiology,
safety, and risk management consultant to the pharma-
ceutical industry. Previously, she was Vice President,
Safety, Epidemiology, and Risk Management at UBC
where she was responsible for a group that develops,
validates, and supports automated tools for safety, risk
management, and cost and utilization. Before working
at UBC, Dr. Dieck was 23 years at Pfizer where she was
Senior Vice President, Safety and Risk Management.
She has over 35 years of experience in the pharmaceuti-
cal industry. She was a Founding Board Member of the
International Society for Pharmacoepidemiology and
is the past Chair of the Pharmacovigilance and Epide-
miology Technical Group of PhRMA. She represented
PhRMA during PDUFA III and PDUFA IV discussions
and co-led the PostMarket Safety Group. Dr. Dieck
received an AB in Biological Sciences from Smith Col-
lege and has obtained M. Phil. and Ph.D. in epidemiol-
ogy and also completed a Postdoctoral Fellowship in
cardiovascular disease epidemiology at Yale University.
Chapter Contributions: Chapter 5, Mathematics of
AEs; Chapter 6, Pharmacoepidemiology
Aurore GOURAUD PharmD
Pharmacovigilance Specialist, Clinical Pharmaco
Toxicology Department, Lyon, France
Aurore Gouraud, PharmD, is currently a hospital prac-
titioner in the pharmaco-toxicology department of the
Hospices Civils de Lyon, where she works as a tox-
icologist at the poison control center. Formerly, she
was Deputy Director of the Lyon Pharmacovigilance
Center, where she managed all post-marketing phar-
macovigilance activities; her interest is focused on
benefit-risk assessment and drug exposure for preg-
nant and breast-feeding women. She is responsible for
the Dynamic Meta-analysis Unit, which deals with the
evaluation of the benefits and risks of medicines (http://
metaevidence.org/). She has been an expert in pharma-
covigilance for the French national agency (ANSM) for
over 10 years. She holds a doctorate in pharmacy and
a Master of Science in medical engineering, and led a
Pharmacovigilance Certificate over ten years (Univer-
sity of Lyon).
Chapter Contributions: Chapter 16: Vulnera-
ble populations, Chapter 17: Pregnancy & Lactation,
Chapter 18: Acute & chronic AEs, Chapter 19: Drug-
Drug Interactions
Isabelle BRUYERE, PharmD
Therapeutic Area Head — Pneumo, Meninge and
Endemic vaccines, Patient Safety & Pharmacovigilance
Department, Sanofi-Pasteur
Dr. Isabelle Bruyère is Therapeutic Area Head (TAH) at
Sanofi Patient Safety & Pharmacovigilance, dedicated
to meninge, pneumo and traveler vaccines. In this role,
Isabelle is responsible for a wide range of functions
including, management of Global Safety Officers (GSO),
providing strategic guidance to ensure best in class eval-
uation and communication of safety signals, benefit risk
assessment and answers to Health Authorities, interac-
tions with external committees and partners.
Isabelle obtained her PharmD with honors, Mas-
ter of Biological and Medical Sciences and an Inter-
University Diploma in Toxicology and Drug Safety from
Claude Bernard University, Lyon France. She has also
further training in signal substantiation and quantifica-
tion from the Erasmus University in Rotterdam/Euro-
pean program for Pharmacovigilance and Pharmaco-
epidemiology. She is involved as a lecturer in various
training programs on pharmacovigilance, notably the
Master of Vaccinology in Siena, Italy, the Inter-Univer-
sity Diploma curriculum from the Regional PV center
and the Eudipharm master from the University in Lyon,
France.
She started her career in Pharmacovigilance more
than 15 years ago at the Public Regional PV center of
Lyon in 2006 in the framework of her Pharmacy Intern-
ship. After working in the hospital setting supporting
clinical trials, Isabelle joined the industry and served as
a Global Safety Officer at Sanofi for 11 years. During this
period, she developed expertise in signal management,
benefit-risk assessment, and risk management planning.
Chapter Contributions xxxi
Chapter Contributions:
Chapter 10: EU Qualified Person for Pharmacovigi-
lance; Chapter 30: Pharma Companies; Chapter 36:
Pharmacovigilance System Master File
Magnus Ysander, MD
Executive Director, EU QPPV
Chapter Contributions: Co-author Chapter 41,
Vaccinovigilance
xxxiii
Notice
This manual is meant to be a guide to those new to,
or those who already have experience with, the history,
theory, and basic principles of drug safety and pharma-
covigilance. We acknowledge the ever-changing regu-
latory, legal and “medical culture” environment with
regards to the principles and topics outlined within,
which makes it an ongoing challenge to keep this text
up to date. However, we hope that our insights will help
further the understanding of these topics in order to
promote best practice when it comes to product devel-
opment in regard to safety and pharmacovigilance.
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 dis-
cussed. 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 ther-
apies 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 com-
prehensive drug development guide.
We have given our opinions on many areas of safety
in drug development and marketing, but things change
daily. Therefore, we urge you to investigate further
what we have written as reference and realize that
this is a science that is ever developing. Check many
sources. Trust but verify.