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100 Cobert’s Manual of Drug Safety and Pharmacovigilance
should be made to populations likely to be
exposed during the intended or expected use
of the product in medical practice;
b. The worldwide experience should be briefly
discussed, including the extent of the world-
wide exposure, any new or different safety
issues identified, any regulatory actions
related to safety, and populations not studied
in the pre-approval phase (for example, chil-
dren, elderly, pregnant or lactating women,
patients with relevant co-morbidity, such
as hepatic or renal disorders, patients with
disease severity different from that studied
in clinical trials, subpopulations carrying
known and relevant genetic polymorphism,
patients of different racial or ethnic origins);
c. AEs/ADRs: This section should list the import-
ant identified and potential risks that require
further characterization or evaluation. Discus-
sion of risk factors and potential mechanisms
should draw on information from the Com-
mon Technical Document and other relevant
information, such as other drug labels, scien-
tific literature, and post-marketing experience;
d. Important identified risks that require further
evaluation:
More detailed information should be
included on the most important iden-
tified AEs/ADRs, which would include
those that are serious or frequent and that
also might have an impact on the balance
of benefits and risks of the product. This
information should include evidence
bearing on a causal relationship, severity,
seriousness, frequency, reversibility, and
at-risk groups, if available. Risk factors
and potential mechanisms should be dis-
cussed. These AEs/ADRs should usually
call for further evaluation as part of the
pharmacovigilance plan (e.g., frequency
in normal conditions of use, severity,
outcome, at-risk groups).
e. Important potential risks that require further
evaluation:
Important potential risks should be
described and the evidence that led to
the conclusion that there was a potential
risk should be presented. It is anticipated
that for any important potential risk, there
should be further evaluation to character-
ize the association;
Identified and potential interac-
tions, including food–drug and drug–drug
interactions, should be discussed with
consideration of the evidence, and poten-
tial health risks posed for the different
indications and in the different popula-
tions should be discussed.
f. Epidemiology
The epidemiology of the indication should
be discussed, including incidence, preva-
lence, mortality, and relevant comorbidity,
and should take into account whenever
possible stratification by age, sex, and
racial or ethnic origin. Differences in the
epidemiology in different regions should
be discussed (because the epidemiology of
the indication(s) may vary across regions),
if this information is available;
For important AEs that may require fur-
ther investigation, it is useful to review
the incidence rates of these events among
patients in whom the drug is indicated
(i.e., the background incidence rates).
g. Pharmacologic class effects
The safety specification should identify
risks believed to be common to the phar-
macologic class;
Summary: This should include the import-
ant identified risks, important potential
risks, and important missing information
on an issue-by-issue basis.
Pharmacovigilance Plan
The pharmacovigilance plan should be based on the
safety specification and developed by the sponsor. It
can be discussed with regulators during product devel-
opment, before approval of a new product (i.e., when
the marketing application is submitted or in advance
of submission), or when a safety concern arises post-
marketing. It can be a stand-alone document (in the
U.S., this document is the Package Insert).
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 101
For products for which no special concerns have
arisen, routine pharmacovigilance should be suffi-
cient for post-approval safety monitoring, without
the need for additional actions (e.g., safety studies).
However, for products with important identified risks,
important potential risks, or important missing infor-
mation, additional actions designed to address these
concerns should be considered. It should be updated as
important information on safety becomes available and
milestones are reached.
The format and content should include the
following:
1. Summary of ongoing safety issues, including the
important identified risks, important potential
risks, and important missing information;
2. Routine pharmacovigilance practice should be
conducted for all medicinal products, regardless
of whether additional actions are appropriate as
part of a pharmacovigilance plan. This routine
pharmacovigilance should include the following:
3. Systems and processes that ensure that informa-
tion about all suspected adverse reactions that
are reported to the personnel of the company are
collected and collated in an accessible manner;
4. The preparation of reports for regulatory author-
ities, including expedited ADR reports and peri-
odic aggregate reports;
5. Continuous monitoring of the safety profile,
including signal detection and management, issue
evaluation, updating of labeling, and liaison with
regulatory authorities;
6. Other requirements, as defined by local regulations.
7. Action plan for safety issues:
a. The plan for each important safety issue
should be presented and justified according
to the safety issue, objective of the proposed
action, non-routine action proposed, rationale
for proposed action, monitoring by the spon-
sor for the identified safety issue and proposed
action, and milestones for evaluation and
reporting. Any protocols for specific studies
may also be provided.
8. Summary of actions to be completed, including
milestones:
a. An overall pharmacovigilance plan for the
product, bringing together the actions for all
individual safety issues, should be presented and
organized in terms of the actions to be under-
taken and their milestones;
b. It is recommended that milestones for com-
pleting studies and for submitting safety
results be included in the pharmacovigilance
plan. The milestones should reflect when
exposure to the product will have reached
a level sufficient to allow potential identifi-
cation/characterization of the AEs/ADRs of
concern or resolution of a particular concern
and when the results of ongoing or proposed
safety studies are expected to be available;
c. These milestones might be aligned with regu-
latory milestones (e.g., PSURs, annual reassess-
ment, and license renewals) and used to revise
the pharmacovigilance plan.
d. Pharmacovigilance methods
The best method to address a specific situ-
ation can vary, depending on the product,
the indication, the population treated, and
the issue to be addressed. When choos-
ing a method to address a safety concern,
sponsors should use the most appropriate
design.
e. Design and conduct of observational studies
Carefully designed and conducted phar-
macoepidemiologic studies, specifically
observational (non-interventional, non-
experimental) studies, are important tools
in pharmacovigilance;
A protocol should be finalized and
experts from relevant disciplines (e.g.,
pharmacovigilance experts, pharmacoep-
idemiologists, and biostatisticians, etc.)
should be consulted. It is recommended
that the protocol be discussed with the
regulatory authorities before the study
starts (in many cases this is required).
A study report after completion, and
interim reports, if appropriate, should be
submitted to the authorities according to
the milestones within the pharmacovigi-
lance plan;
The sponsor should follow good epidemio-
logic practice for observational studies and
internationally accepted guidelines, such
102 Cobert’s Manual of Drug Safety and Pharmacovigilance
as the guidelines endorsed by the Interna-
tional Society for Pharmacoepidemiology.
f. Annex
g. A detailed discussion of pharmacovigilance
methods is appended to the document to
which the reader is referred for further details.
E2F: Development Safety
Update Report
This document has been formally adopted in many reg-
ulatory jurisdictions and is accepted in most jurisdic-
tions. The contents of the DSUR in E2F are very similar
to those in the CIOMS DSUR report.
The DSUR is intended to be the common standard
for annual clinical trial safety reporting and would
replace other required pre-market periodic safety
reports. It presents an annual review and evaluation of
pertinent interval safety information: (1) to summarize
the current understanding and management of identi-
fied and potential risks, (2) to describe new safety issues
that could have an impact on the protection of clinical
trial subjects, (3) to examine whether the information
obtained during the reporting period is in accord with
previous safety knowledge, and (4) to provide an update
on the status of the clinical investigation/development
program. This is similar to the CIOMS proposal. Full
details on the contents can be found in the E2G guide-
line on the ICH website.
E19: Optimization of Safety
Data Collection
Work on this topic began in late 2016 and the guideline
was in development as of mid-2018. According to ICH,
when this guideline reaches ICH step 5, it will “provide
harmonised guidance on when it would be appropri-
ate to use a targeted approach to safety data collection
in some late-stage pre-marketing or post-marketing
studies, and how such an approach would be imple-
mented. Recognising that protection of patient welfare
during drug development is critically important, unnec-
essary data collection may be burdensome to patients
and serve as a disincentive to participation in clinical
research. By tailoring safety data collection in some cir-
cumstances, the burden to patients would be reduced,
a larger number of informative clinical studies could be
carried out with greater efficiency, studies could be con-
ducted with greater global participation, and the public
health would be better served.” This reflects applica-
tions of risk-based principles by ICH and a systematic
approach to product development.
M1: MedDRA® Terminology
(Medical Dictionary for
Regulatory Activities)
The development of a regulatory terminology, Medi-
cal Dictionary for Regulatory Activities, was approved
by ICH in 1997 and it was launched in 1999 with
English as the base language. In addition to the ter-
minology, which is available by subscription, ICH
created “Points to Consider” documents that are avail-
able from the sole-source MedDRA provider of the
terminology (see www.meddra.org). As of mid-2018,
MedDRA was available in eleven languages (Chinese,
Czech, Dutch, English, French, German, Hungarian,
Italian, Japanese, Portuguese, and Spanish). Note,
however, that not all terms are translated in each lan-
guage. For example, English word order (“neck red”
vs “red neck”) does not translate to two unique terms
in Japanese.
The Points to Consider documents are updated
on a regular basis, as relevant for each new version of
MedDRA. Both documents are maintained in English
and Japanese; summaries are provided in the other lan-
guages that are otherwise available in MedDRA.
CHAPTER
103
8
The Uppsala
Monitoring Centre
T
he Uppsala Monitoring Cen-
tre (UMC) is a non-profit foun-
dation that operates the WHO
Programme for International Drug
Monitoring and maintains both a
drug dictionary, WHODrug Global,
and a post-marketing safety database,
VigiBase. An obsolete third UMC tool
was WHO-ART, an adverse reaction
terminology database that is currently
only available to regulators who spe-
cifically request access from the UMC.
The UMC also provides many research
publications and services related to
pharmacovigilance. These activities
have been essential in expanding the
concepts and principles of pharma-
covigilance beyond the traditional
ICH regions and have paved the way
for ICH expansion. The UMC has a
variety of services related to research
including signal detection, general
education and training, tools for man-
aging pharmacovigilance communica-
tions, a pharmacovigilance reference
library and glossary of terms for ref-
erence. They also play a crucial role in
global efforts to standardize the way
products and substances are identi-
fied by helping implement the Identi-
fication of Medicinal Products (IDMP)
standards which “aim to increase clar-
ity and efficiency in communications
about medicines and provide greater
certainty to patients no matter where
they are”.
104 Cobert’s Manual of Drug Safety and Pharmacovigilance
UMC and the WHO Program
for International Drug
Monitoring
Ten founding government safety organizations (Aus-
tralia, Canada, Czechoslovakia, Federal Republic of
Germany, Ireland, Netherlands, New Zealand, Sweden,
United Kingdon, USA) created the WHO Programme
for International Drug Monitoring in 1968 following
the thalidomide birth defect tragedy. To prevent recur-
rence of another such tragedy, the concept was to sys-
tematically collect spontaneously reported drug safety
information from around the world regarding the harm
caused by medicines.
Since 1978, the programme has been managed from
Uppsala, Sweden, by the UMC and today over 170 gov-
ernment drug safety organizations participate in the
network (as full or associate members), along with the
WHO in Geneva, and the UMC.
The reach of the WHO Programme for Interna-
tional Drug Monitoring is extensive and Individual
Case Safety Reports in VigiBase originate from across
the globe. Countries have started to contribute cases in
a staggered manner. It is worth noting that the pharma-
covigilance capacity of some countries is more robust
than in others. Nevertheless, these data are a key part of
the global pharmacovigilance system.
UMC is one of the five WHO collaborating centers
in the network. Member countries submit domestic sus-
pected serious and non-serious adverse reactions elec-
tronically to VigiBase at UMC. Suspected reactions are
pre=coded with either MedDRA
®
or legacy WHO-ART
(A UMC coding terminology that is now largely out of
date and is no longer maintained). However, enhanced
capabilities for VigiFlow, the interface for electronic
reporting to VigiBase, were introduced in 2017 and
require MedDRA-coded adverse reactions. Fortunately,
a one-way “cross-walk” is available for conversion of
WHO-ART terms to MedDRA. Consistent with legisla-
tion, the interface also accommodates direct reporting
from healthcare professionals, public health programs,
patients, and the pharmaceutical industry.
As of 2023, VigiBase contained more than 30 mil-
lion reports of suspected adverse reactions for marketed
medicines, including vaccines. VigiBase is continuously
updated with new reports on a periodic basis. Impor-
tantly, UMC has developed vigiMatch, an automatic
algorithm in VigiLyze that has been available since early
2017 for detection of suspected duplicates in VigiBase.
vigiMatch uses a statistical model that scores pairs of
reports, taking into account the amount of matching
and mismatching information. This is a complex system
and much more information is available from the UMC.
Key Functions of UMC
Maintenance and operation of an international
safety database, VigiBase, which contains spon-
taneous reports submitted by Member State reg-
ulators (or local equivalent) and interaction with
contributing Member States.
Identification and analysis of aggregate data by
scientific staff to detect new safety signals from
VigiBase, primarily via a data mining tool, VigiLyze.
Information exchange between WHO and national
pharmacovigilance centers, mainly through
“VigiMed,” a restricted Internet forum set up in
1997 for rapid e-mail information exchange among
government safety agencies on pharmacovigilance
matters. This is not generally available to the public
or industry.
Publication of periodic newsletters (e.g., “Uppsala
Reports”), guidelines, and books on the topics of
pharmacovigilance and risk management. Some are
available on the Internet and in languages other
than English. Some are available at no charge, oth-
ers not so.
Supply of tools for management of clinical informa-
tion, including adverse drug reaction case reports.
The main product is the WHO Drug Dictionary
(- UMC formerly provided and maintained the
WHO Adverse Reaction Terminology (WHO-ART).
This terminology and system is no longer being
maintained, and is obsolete. Most users should now
user MedDRA as their preferred dictionary.
The Uppsala Monitoring Centre 105
Training and consulting support to national centers
and countries for establishing and helping pharma-
covigilance systems mature.
Computer software for case report management,
designed to suit the needs of national centers and
consistent with the enhanced VigiFlow electronic
interface.
Annual meetings for representatives of national
centers, at which scientific and organizational mat-
ters are discussed.
Methodological research for the development of
pharmacovigilance as a science, particularly in
resource-constrained settings, but also customized
research to complement mature pharmacovigilance
systems (at a fee).
Publication of scientific articles in pharmacovigi-
lance. Note that all scientific papers by UMC authors
have been freely available online at no charge since
2015 (www.who-umc.org).
The UMC has played a major role in the develop-
ment and propagation of the concepts and techniques of
pharmacovigilance, particularly pragmatic approaches
in less developed countries. For many years, it was a
lone international voice. It has now been joined by oth-
ers to advance the field of pharmacovigilance. The key
publications on its website are well worth reviewing.
Benefits of the UMC
There are many benefits to familiarizing oneself with the
UMC, its offerings, and its relevance within the indus-
try. Safety and Pharmacovigilance professionals, along
with those in Clinical Development, Drug Manufactur-
ing, Labeling, Regulatory, Data Management, Marketing
and Communications, and many other areas, should
be familiar with what UMC has to offer. Training from
the UMC is offered via self-paced e-learning on You-
Tube channels and can be found by simply visiting their
website and doing a search for relevant offered training,
which currently includes videos and material on gen-
eral Pharmacovigilance, Signal Detection, adverse drug
report (ADR) reporting, and pharmacovigilance com-
munications. Why create your own training when this
is readily available (one might ask)?
Pharmacovigilance
Communications
The UMC “strives to meet a global need for better com-
munication practices in our field”. Their activities focus
on raising awareness of the importance of pharmacovig-
ilance, and the basics of how adverse drug reactions
occur and should be handled. They have also taken on
the mission to strengthen communications capacities
within the global pharmacovigilance community, by
conducting training and lectures, social science-based
research, and by producing and sharing innovative cam-
paign materials and information packages.
Pharmacovigilance professionals as well as those in
marketing and communications, should take advantage
of the efforts of the UMC and consider implementing
the recommendations outlined from the organization
when it comes to communicating risks and how to
effectively communicate those risks to the public.
The UMC also publishes “Uppsala Reports” which
are pharmacovigilance focused and available for free, as
well as a podcast called Drug Safety Matters which hosts
new speakers and focuses on relevant and hot topics
within drug safety and pharmacovigilance.
Why a chapter on the UMC?
We have dedicated a chapter solely to the UMC because
we feel it is important for professionals to understand
its functions, its impact on product development and
research, and its utilization in the ongoing pursuit of
pharmacovigilance.
CHAPTER
107
9
Biopharmaceutical
Companies
T
here are many types of companies
and institutions in the pharma-
ceutical world with responsibil-
ities regarding drug safety. A general
summary of various types of institu-
tions follows, although there is a wide
variety of business approaches that
result in a myriad of hybrid combi-
nations. The creative organizational
structures can (and do) morph over
time. The common feature is a require-
ment to comply with regulations or go
out of business.
Introduction
There are many large drug companies in the world that
sell billions of dollars of products each year. Although
the number of companies has decreased through merg-
ers and acquisitions, there still remain more than 50
publicly traded companies with annual sales of more
than US$1.5 billion per year and roughly another 400
with sales less than $1 billion per year. The largest public
company has sales of more than $100 billion per year in
2022 (including approximately $30 billion attributed to
the COVID 19 pandemic). In addition, there are several
very large and many other small and mid-sized com-
panies that are privately held (not traded on the stock
exchange). As noted throughout this book, companies
are obligated to report animal and human safety data
108 Cobert’s Manual of Drug Safety and Pharmacovigilance
(among other information) to health authorities, ethics
committees, investigational review boards, and so on.
Companies also have a fiduciary duty to timely report
material facts to the investment community.
Big and Somewhat Big
Pharma
Big pharma generally refers to the dozen or so large,
“full-service” companies with global reach and revenues
in the billions to tens of billions of dollars. These com-
panies are multinational, with headquarters primarily
in the United States or Europe, but with some located
in Japan and elsewhere (India, China, or Israel). They
usually have scientists doing drug discovery to come up
with new patentable drugs that will, it is hoped, become
“blockbusters” (drugs with sales of more than a bil-
lion dollars a year by some definitions). Some of these
highly capitalized companies have adopted a strategy
of developing a larger number of products that are not
blockbusters to avoid a “patent cliff”, i.e., when reve-
nues decline as a major product goes off patent.
The big innovative companies have the capacity to
do their own pre-clinical studies (pharmacology and
toxicity) and clinical trials (phase I–IV) though many of
them now out-source parts of these complex processes.
Many now also have generic divisions that develop and
market generics, both of their own branded products
and of other companies’ products that are off patent.
Another active area is switching prescription products
to non-prescription status.
These companies have large marketing and sales
divisions with hundreds to thousands of “represen-
tatives”, “sales reps”, or “detailers”. The big pharma
company does some of its own manufacturing in fac-
tories throughout the world, sometimes with active
pharmaceutical ingredients (APIs) from contractors,
as well as outsourcing full or partial production from
other countries (often India or China). There are large
departments to handle regulatory issues, legal issues,
patents, and other key activities. Since pharmacovigi-
lance touches many different functions, it is essential
to have a well-established communication network to
support coordination of activities amongst the various
functions. Many companies have subsidiaries in the
major markets (50 or more) throughout the world.
Some subsidiaries are only sales organizations, whereas
others are staffed to do clinical research and medical
affairs as well. Some functions may be located outside
the mother country (e.g., home office in the United
States but a phase I clinical research unit in the EU or
Asia, or vice versa). These often-far-flung contributors
to safety are frequently in different time zones and have
different holiday periods when facilities are essentially
closed, and routine pharmacovigilance is handled by a
slimmed down “skeleton” team.
Of course, there is a large drug safety department.
The safety department is often, but not always, located
in the corporate headquarters in the mother country.
This is the major center for drug safety, with receipt
of some or all of the individual case safety reports for
data entry as well as preparation of MedWatch and
CIOMS I forms, electronic submissions (E2B), Com-
mon Technical Documents (eCTDs), Marketing Autho-
rizations, PSURs/PBRERs, NDA periodic reports, IND
annual reports, DSURs, Risk Management Plans/REMS,
signal management, reference safety information, clin-
ical trial reports, and other aggregate reports. There is
usually a large IT department and dedicated IT staff to
support drug safety as much of the work is now elec-
tronic rather than paper based. There is often a large
IT department based in the US if the company is not
headquartered there. Since pharmacovigilance touches
many different functions, it is essential to have a well-
established communications function to coordinate.
This also facilitates workload-sharing across time zones
and geographies. Servers for the safety database and
back-up servers are located at a central location as a rule
as well as data storage in the Cloud, often through third
parties. There are usually drug safety departments (or
at least a person) in most or all subsidiaries to receive
local safety reports (in the local language) and make
submissions (sometimes in English, sometimes in the
local language) if electronic E2B reporting is not done
centrally. If not otherwise required, a local person may
be needed to perform expectedness determinations
based on the local reference safety information.
These subsidiaries, depending on size and func-
tion, may have a separate physician, pharmacist or
other health care professional serving as safety officer
Biopharmaceutical Companies 109
or have the medical director (often the only medical
doctor in the local company) also serve as the safety
physician. Many jurisdictions have a legal requirement
for an individual who is “responsible” for pharmacovig-
ilance functions. The subsidiaries often serve as “pass
through” points for AEs to be sent to central or regional
data centers for data entry into the safety database.
Sometimes a subsidiary (or regional center) will have
expanded functions covering multiple countries. For
example, some companies (e.g., whose headquarters
are in the US or Japan) will set up a major center in
the EU to do data entry and to prepare PSURs/PBRERs
and other documents for submission to the EMA and
EEA national health authorities or elsewhere. In some
instances, work is segmented and done on several con-
tinents and then synthesized into an aggregate report,
e.g., PSUR/PBRER. In addition to routine (e.g., peri-
odic) reports, these activities are often required on short
notice when an Urgent Safety Measure is contemplated.
In other situations, where the corporate headquar-
ters are in a smaller country (e.g., Switzerland), one of
the “subsidiaries” may become the dominant center
for drug safety (e.g., in the EU or US). There is a ten-
dency for safety departments to now be located in major
English-speaking countries, such as the US or the UK,
which, coincidentally or not, are the regulatory sites
for the two major world pharmaceutical markets, the
United States and the European Union (Note: The move
of EMA from London to Amsterdam (Brexit) impacted
drug safety centers covering the EU if they were/are
based in the UK).
Things are changing, however, in biggish pharma.
The large companies are getting larger, following merg-
ers and acquisitions (e.g., Merck, Pfizer, Novartis,
Sanofi, Roche, Eli Lilly, etc.). There is now a trend in
the very big companies to have some functions remain
centralized for the entire corporation, such as IT and
the safety database, but for the drug safety functions
to be separate. That is, there may be several relatively
independent drug safety groups (one for prescription
products, another for OTC, another for vaccines, etc.)
doing individual case processing and aggregate report-
ing but sharing common supportive functions, i.e., IT,
epidemiology, risk management, etc. Thus, big com-
panies may function as “holding companies” for mul-
tiple smaller safety subunits. Others remain rigidly
monolithic. There is no single model applicable to all.
The use of outsourcing vendors, for the holistic safety
function overall or a specific activity, such as data entry
or writing case narratives, is also increasing.
There are several trends evident. One is that drug
discovery has been somewhat slow of late in big pharma,
with fewer novel blockbusters and many old blockbust-
ers going off patent (“the patent cliff”). Many firms, both
large and mid-sized, have been “rightsizing” or “down-
sizing” (i.e., firing workers and replacing them, if at all,
with temporary workers and consultants or outsourc-
ing some activities). Thus, they tend to do less research
and more development as “R&D” components are now
becoming distinct. Research is, to a significant degree,
being left to the small biotech companies that do the
early development and then sell the product to the big-
ger pharmas for the late phase II and III development
for submission of the New Drug Application (NDA) or
Marketing Authorization (MA) dossier. Advanced high-
tech therapies have tended to be discovered by smaller
biotech firms with larger pharma companies purchasing
or co-developing the drug (or even the whole biotech
company) in phase II or III and beyond.
Another trend is the use of generics in the developed
world as well as in developing countries. 85% of the
drugs sold in the United States are now generics and this
trend will continue as many older drugs go off patent
(https://www.statista.com/) and payers balk at ever-
increasing reimbursement schedules. Europe is follow-
ing this trend, too; but with lower percentages (around
20% in France and Germany and 55% for Poland). Some
national and multinational companies are devoted only
to generic products and, thus, have little or no drug dis-
covery or clinical research capacity. They may do small,
required studies to show bioequivalence. Occasionally,
if needed, they do formal phase II, III, or IV clinical
trials but these activities are usually outsourced. The
generic companies create safety departments accord-
ing to the functions required, but they tend to be less
involved with critical issues than the companies that
deal with new chemical entities. By the time a drug
is generic, most of the safety issues have already been
addressed. AE reporting and pharmacovigilance tends
to be a “maintenance function”, with few unique data or
new and clinically important signals appearing. Many
of the safety reports are, in fact, literature cases with