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320 Cobert’s Manual of Drug Safety and Pharmacovigilance
not a real awareness or level of suspicion by the patient
that a particular problem could be due to one or more
drugs. Many patients believe that if the government
agency has approved the drug for marketing it is “safe
and effective”. This is an unfortunate phrase since it
implies absolutes — totally safe and always effective
— when in fact its meaning is rather more like: this
product has benefits that outweigh the risks (sometimes
not by much) when used by the approved patient group, at
the approved dosage and route of administration, for the
approved length of time for the approved indication(s).
Safety is not absolute or guaranteed and is not (ever)
fully known, and some patients may have totally unex-
pected (idiosyncratic) bad side effects. This concept is
hard to convey. And sometimes it is challenging to dis-
tinguish an adverse reaction from the progression of the
patient’s underlying disease.
It is often presumed (sometimes incorrectly) that a
drug cannot produce an adverse reaction if it has been
taken safely for months or even years by an individ-
ual. Drug–drug, drug–food, and drug–alcohol interac-
tions, manufacturing issues, and so on are almost never
thought of by patients as explanations of their problem.
Patients often do not think of over-the-counter (OTC)
products, “health foods”, “nutraceuticals”, or “herbals”
(which may contain drugs or interact with drugs), cos-
metics, and illicit drugs as culprits in adverse reactions.
Physicians too often forget to ask about them when tak-
ing the medical history and investigating medical prob-
lems. Many patients who are receiving multiple drugs,
particularly the elderly, who are often “polypharmacy”
patients, cannot recall the drugs or the doses they take.
Moreover, when patients take multiple drugs, it is hard
to know or predict drug interactions.
In some societies or cultures, there has been a per-
ception that AEs are the fault of the patient and repre-
sent a weakness or a shameful act on the patient’s part
and that they need to “tough it out”. This attitude is
changing as the dissemination of information occurs
but is still seen in some older patients.
Healthcare practitioners prescribe, dispense, and
administer drugs. When AEs or reactions occur, it may
not be the same prescriber, dispenser, or administrator
who has to deal with the drug’s medical consequences.
Emergency rooms may not be able to get immediate
access to the patient’s medical records or drug history,
for example, though it is hoped this will change as elec-
tronic medical records become widespread and stan-
dardized — though privacy laws and regulations may
ultimately limit accessibility even if the technology per-
mits it.
Pharmaceutical
(Biopharmaceutical)
Companies
Pharmaceutical companies play a major role in the
world of safety. In the United States, most AEs on mar-
keted drugs are reported to the manufacturers — the
pharma companies. In other countries, most AEs may
be reported to the health agency or other institutions
(e.g., medical centers, pharmacies, national or regional
pharmacovigilance (PV) centers, etc.) The companies,
through trade organizations, e.g., PhRMA, JPMA, and
the EFPIA (see below) and the International Council for
Harmonization (ICH), have worked with the US Food
and Drug Administration (FDA), the European Medi-
cines Agency (EMA), Japanese regulators, and WHO (as
well as many other organizations that have joined this
effort more recently) to harmonize the safety reporting
procedures, requirements, formats, documents, and
expectations. This effort has been largely successful
because the requirements for reporting certain serious
AEs from clinical trials and post-marketing situations
are clear, consistent, and quite rigorous (7 or 15 cal-
endar days). Major efforts are under way, with varying
degrees of harmonization and cooperation between
the industry, government, vendors, and Standards
Development Organizations in the areas of electronic
transmission and standards (e.g., digital formats for
transmission of healthcare documents, laboratory tests,
cardiograms), risk management and minimization, clin-
ical trial standardization, machine learning, and more.
This operational aspect is, in a sense, the low hang-
ing fruit and, with sophisticated IT resources, many of
these operational aspects of data collection and storage
run very well. The higher hanging fruit which is harder
to reach is the analysis of these data and the detection
of “safety signals” and their analysis. The ultimate goal,
we should not forget, is to get new, clinically important
and trustworthy safety data to prescribers and patients
The Many Players in the World of Pharmacovigilance 321
as rapidly as possible. And these data should be pre-
sented in meaningful language that is appropriate for
the target audience.
These efforts regarding “mechanics and operations”
go beyond the pharmaceutical industry as the FDA and
the Department of Health and Human Services and many
other governmental and private entities standardize the
transmission of healthcare data among all stakeholders
(hospitals, doctors, pharmacies, laboratories, insurance
companies, NGOs, etc.) and produce significant addi-
tional benefits for the public. Most dealings between
scientific personnel in the industry and the FDA, EMA,
and other agencies are cordial and correct, with the goal
of protecting the public health and helping each do his
or her job more efficiently and more rapidly, given lim-
ited resources. Complicating this effort are privacy and
safety protections introduced in many countries includ-
ing the US and EU. In addition, hackers and cybercrime
also complicate matters. The data and analytical tools
must be safe, secure, and fit-for-purpose with access
limited to only those who should have access. This is
a major issue now and laws and regulations have only
started to address it.
The reverse of this coin, however, is represented
by controversies about specific medical products and
safety issues. Some people (consumer groups in partic-
ular) believe there is too much cordiality and warmth
between the regulators and the regulated, allowing the
companies to “get away” with many things to increase
profit at the expense of public health. However, there
is little evidence for this, even though people move
from the government to industry (as in other regulated
industries) and vice versa. They claim that this may
compromise the safety of the public because regulators
will be hesitant to cross or oppose a company they may
shortly wish to work for. There are clearly professional
and medical differences between and within the com-
panies and the industry. Many of these “battles” occur
behind closed doors or through written (e-mail) or
telephonic communications. Most of these communica-
tions are privileged to protect intellectual property and
not available to the public.
This came to the fore during the Covid crisis of 2020
and beyond. The flow and trustworthiness of informa-
tion from FDA, CDC, the White House, academia, EU
health agencies, WHO and many others were chaotic,
often confusing and even contradictory. The public did
not know what to believe in regard to taking the various
Covid vaccinations, masking, lockdowns, and proposed
therapeutics.
In addition, there has been some bad behavior on
the part of the pharmaceutical companies in the Oxy-
contin/opioid crises, epinephrine pen pricing and the
rapid jump in Daraprim pricing from $13.50 to $750
per tablet. Pharmaceutical companies play a major role
by promoting their products to healthcare professionals
and the public (direct-to-consumer advertising in the
United States in particular). Sometimes the promotion
is not balanced in the eyes of the FDA, and Warning
Letters are sent to companies by the FDA’s Office of
Prescription Drug Promotion (OPDP). See the Warn-
ing Letter section of the FDA’s website. FDA and other
health agencies are now struggling with social media in
which drugs are publicized, criticized, and commented
upon by users, providers, and companies on blogs,
tweets, and Facebook, Twitter, Instagram and elsewhere
without fair balance and often without attribution.
Much of the “information” is not curated. It is often
hard to know what data are real and what data represent
“fake news”.
Physicians and other healthcare workers are also
“detailed” by pharmaceutical representatives on prod-
ucts for their patients. The detail (the “sales pitch”)
should contain balanced information and include the
ADR profile. The approved prescribing information
should also be supplied.
Governments
In each country or region, there is, of course, the gov-
ernmental agency or agencies that regulate medicines
(the FDA, the EMA, the Medicines and Healthcare
Products Regulatory Agency (MHRA), the Agence
Nationale de Sécurité du Médicament et des Produits
de Santé (ANSM), etc.) In addition to the agency, its
parent organization may exert significant control and
pressure (in the United States the Department of Health
and Human Services; in other countries the Ministry of
Health or Parliament/National Assembly/Congress), and
so forth. In the United States, Congress and other fed-
eral departments and agencies also provide healthcare
322 Cobert’s Manual of Drug Safety and Pharmacovigilance
and medications (e.g., Veterans Affairs, the Department
of Defense (DOD) for the Armed Forces, the Centers
for Disease Control and Prevention (CDC), Medicare,
Medicaid and others), as do state/provincial and local
health departments, including boards of health.
Some countries separate drug safety from drug
approval, and some countries, particularly in the Euro-
pean Union, have an overlay at the European level in
addition to national- and local-level agencies involved
in drug registration, pricing and safety.
Government entities involved directly or indirectly
in drug safety are complex. In the United States, at the
federal level, the executive cabinet-level (ministry-level)
Department of Health and Human Services controls the
FDA and other health-related agencies and entities.
The US Congress controls the budget for the FDA and
has legislative oversight of FDA and other health mat-
ters. Other federal-level groups with major interests in
healthcare and pharmaceuticals include the Veterans
Administration, which maintains hospitals, clinics, and
pharmacies; the US armed forces, which also main-
tain hospitals clinics and pharmacies; and the National
Institutes of Health, the National Cancer Institute, and
the Centers for Disease Control and Prevention. Similar
complexities may be seen in many countries around the
world, depending on their level of centralization and
federalism. Some countries (France in particular) have
tight arrangements with academic medical centers in
the world of drug safety.
At the state and local level in the United States, there
are state and local health departments, Medicaid offices
(the program that supplies healthcare to the indigent
and certain others at the state level), and state budget
and formulation offices. One of the recent controversies
has been the push by state and local governments to aid
consumers in importing prescription drugs from out-
side the United States.
Views on drug safety by all of the players may some-
times be simplistic and polarized, especially if they are
conveyed in short sound bites. One may hear that the
health authority should approve safe drugs only after
careful and thorough study. Side effects, if any, should
be mild, reversible, and of limited duration. Some sup-
posedly neutral observers refuse to admit a drug to a for-
mulary for cost reasons rather than for medical reasons
and justify this with either lack of efficacy or increased
safety concerns. Others believe that there should be
no more than two or three products in any particular
class of drugs because the me-too drugs add no value
to the public health. Others feel that the FDA, the EMA
and other agencies have been too slow and too strict
in approving new drugs for dying patients or diseases
with no adequate treatment currently. Some want drugs
approved (or given interim approval) based on early
phase II trials which are positive (“right to try”). This
is starting to happen. The safety profile will be further
explored in the post-marketing setting. Each of these
positions has its positives and negatives and there is no
consensus yet.
Consumers often believe that, if any really bad side
effects occur, someone (somewhere) should be made to
pay. At the extreme end, some groups assume malev-
olence and ill will on the part of the drug companies,
whose goal (they say) is only to make money, and help-
ing the ill is a “side effect” of making profit. There are
periodic reports of bribery or various illegal actions
to get drugs sold, studied, or put on formularies. The
FDA encourages whistle-blowers to come forth with
information on bad behavior with the inducement of
substantial monetary rewards. As rhetoric heats up, the
science and clarity disappear.
The controversy and politics tend to cloud some of
the very real areas of controversy and concern:
How much secrecy should be permitted in the com-
petitive area of drug development and drug safety?
How much transparency should there be? What
happens in emergencies and pandemics?
What is the role of the industry in patient and
healthcare professional education?
Is direct-to-consumer advertising a good or bad
thing for the public and how does it play regarding
drug safety?
Is a single-payer system for drugs a good or bad
thing for drug safety, and is it too expensive?
Are the current drug safety systems in the United
States, the European Union, and elsewhere adequate?
Should the universities be more heavily involved?
Should there be a single national formulary?
Should me-too drugs be limited? Is the WHO
Model List of Essential Drugs (http://www.who.
The Many Players in the World of Pharmacovigilance 323
int/medicines/publications/essentialmedicines/en/) a
good way to handle pharmaceuticals?
Should drug safety be separated from the drug
agency that approves drugs, as the approvers would
be hesitant to “admit” they might have approved a
drug with safety issues that appear after marketing?
As healthcare is finite and demand infinite, how
should rationing of care, treatment, medications,
etc., be done?
Should some level of drug imports by consumers
from abroad be tolerated or even encouraged to
save money? And how will quality be ensured?
How should OTC drug safety be handled? Are con-
sumer reports without any healthcare professional
confirmation worth collecting and how much effort
should be expended in their analysis?
Should cosmetics, “health foods”, supplements, etc.
be more heavily regulated?
What role should automation and Artificial Intelli-
gence (AI) play in safety?
One positive outcome of the controversies of the
last several years in drug safety is more availability and
transparency of safety information by companies and
governments in some areas of drug safety. This has been
accelerated and enhanced by the expanding domains
of digital data, data standards, and analytical abilities.
Detailed information on most clinical trials is now avail-
able online at governmental websites, such as Clintrials.
gov in the US (www.clinicaltrials.gov) and the Clinical
Trials Information System (CTIS) in the EEA, as well as
pharmaceutical companies’ individual clinical trial sites.
Post-marketing AEs are now appearing online or
are available as files of variable user-friendliness. The
FDA now has a fairly user-friendly system to search
the post-marketing safety database known as FAERS.
The EEA repository for AEs (pre- and post-marketing)
is EudraVigilance. See the Database chapter in this
Manual for further information.
Anonymized line listings and individual Med-
Watch reports are available from the FDA for nominal
fees or from private companies (for higher costs but
with anonymity of the requester). The data can also be
downloaded from the FAERS website. Other countries
(France, Canada, the UK, etc.) also have websites with
similar search pages.
Much of the older and some of the current clinical
trial data are largely proprietary and unavailable to the
public or medical profession beyond what is in a drug’s
labeling, monograph, or presented in summary form at
clintrials.gov. The European Union puts summaries of
some approvals (“European Public Assessment Reports”
or EPARs) online, and the FDA has some Summary
Bases of Approval (SBOAs) also available online. Data
from many clinical trials are published as peer-reviewed
articles. However, the emphasis is usually on efficacy/
effectiveness and detailed safety data are often limited.
The EMA, via the Pharmacovigilance Risk Assess-
ment Committee (PRAC) is posting monthly meeting
minutes on the website; this highlights transparency on
their processes and decisions.
Many countries (United States, United Kingdom,
Japan) have Freedom of Information laws that allow
anyone to obtain non-classified and non-proprietary
data for minimal cost. However, often one must know
exactly what one is looking for. “Fishing expeditions”
can be hard or not permitted.
The United Kingdom MHRA also has a Freedom of
Information act and some safety information is avail-
able. Interestingly, unlike the US government’s pub-
lished information, which is not subject to copyright,
there is strict copyright control of information released
by the UK government:
“All material created by the Medicines and
Healthcare products Regulatory Agency
(MHRA) is subject to Crown copyright pro-
tection. We control the copyright to our work
(which includes all information, database
rights, logos and visual images), under a del-
egation of authority from the Controller of His
Majesty’s Stationery Office (HMSO).”
“The MHRA authorizes you to make one free
copy, by downloading to printer or to elec-
tronic, magnetic or optical storage media, of
any items featured on this website (exclud-
ing Agency logos) for the purposes of private
research, study and reference. Any other copy
or use of Crown copyright materials featured on
this site, in any form or medium is subject to
the prior approval of the MHRA.”
324 Cobert’s Manual of Drug Safety and Pharmacovigilance
Further information on the “Crown Copyright” can
be found online. One public venue where differences
are aired, often with full media coverage, is represented
by public meetings of the FDA advisory committees and
similar groups in other countries. See the FDA’s web-
site Regarding advisory committees, in particular the
Drug Safety and Risk Management Advisory Commit-
tee. These are standing committees called by the FDA to
discuss and recommend courses of action in controver-
sial or unclear areas in which the agency wishes exter-
nal advice. Members include the FDA and academia, a
patient advocate and, sometimes, non-voting industry
members. They receive, in advance, data from the FDA
and the industry and then meet in public (usually) to
discuss the issues involved. The companies are usually
well represented in the audience and industry scientists
often make presentations. The discussions are usually
scientific and technical but can become adversarial and
even quite heated. Some sessions may be held behind
closed doors and are not open to the public when pro-
prietary information is discussed. Recent FDA practice
has been to broadcast the public portions of meetings
in real time. Transcripts and presentations of the pub-
lic sessions are often available shortly afterward on
the FDA website. These sessions are often attended
by media and Wall Street/Venture Capital types when
public companies’ products are involved. Comments
by the committees often influence stock prices of both
the company whose drug is discussed, and competitors’
drugs whose sales might be threatened by a new drug.
This is a good example of transparency in the world of
pharmaceuticals.
Broadly speaking, professionals working in the
drug safety area of government and industry tend to
be more aligned and better able and motivated to share
ideas with each other than are professionals in other
areas of the industry (research, marketing, legal, etc.),
because they are less constrained by legal restrictions
and by competitive issues (e.g., anti-trust concerns).
Sharing ideas about “what works” operationally in drug
safety, PV, and risk management is common and is seen
particularly with operational issues (e.g., drug coding,
conventions for the Medical Dictionary for Regulatory
Activities (MedDRA) coding of AEs, and, for oncology
products, the Common Terminology for Adverse Events
(CTCAE)). Proprietary drug-specific safety informa-
tion is not shared. Such alignment and cooperation is
now international and facilitated by the web. Data are
now being shared on Facebook, LinkedIn and other
social media. Shared databases of anonymized clinical
trial data are being assembled by trusted third parties
for research purposes. Key regulators, e.g., FDA, EMA,
Health Canada, and others, have confidentiality agree-
ments under which they hold virtual meetings on a reg-
ular basis to share perspectives.
It is in everyone’s interest for AEs to be sent to the
FDA and other health authorities in a timely, complete,
and correct manner. Companies do, in fact, want their
competitors to have well-run and efficient safety depart-
ments so that the competition’s AEs are sent to the
health agencies in a timely and complete manner too!
Media
The media, including social media, the Internet (blogs,
websites, RSS feeds, wikis, customer engagement pro-
grams, etc.), and old media (television, radio, news-
papers), play active roles from all perspectives of the
political and medical scene. This field is evolving, with
the health agencies struggling to understand how to
use the media themselves as well as how to regulate
use by industry. The newest addition to this scene is
AI which does indeed promise to be yet another “game
changer”. The agencies use Facebook and many other
social media sites and apps and many other modalities
on the internet. They are also adapting the old paper-
based reporting systems to the Internet (MedWatch,
Yellow Cards, Blue Cards, etc.). Nonetheless, agencies
must be careful what they put on the Internet and how
they use these sites. There is much controversy over
Tweets by senior political or medical leaders! The Covid
wars of 2020-2022 are a prime example of this. Issues of
privacy and hacking are also arising. Data security and
privacy are major topics of the big Internet players now.
It is likely that data sharing will become more restrictive
in the future.
The Many Players in the World of Pharmacovigilance 325
Other aspects of the Internet are now “fake news”
and information overload with far too much informa-
tion available — not all of which is reliable.
NGOs and Lobbies
Non-governmental organizations (NGOs) play major
roles in healthcare throughout the world, including
the World Health Organization (WHO) in drug poli-
cies and its affiliate, the Uppsala Monitoring Centre in
Sweden (See Chapter 11), in drug safety, pandemics and
other public health areas; various foundations that fund
healthcare initiatives (e.g., the Gates Foundation); the
Drug Safety Research Unit in the United Kingdom; and
others.
Lobbies or professional organizations, NGOs from
many domains (e.g., Pharmaceutical Research Manu-
facturers of America [PhRMA], European Federation of
Pharmaceutical Industries and Associations (EFPIA),
International Society of Pharmacoepidemiology, the
Centers for Education and Research on Therapeutics,
the American Association of Retired Persons), OTC drug
manufacturers, generic manufacturers, hospital groups,
vaccine manufacturers, device manufacturers, physi-
cian groups, nursing groups, pharmacy groups, con-
sumer groups, disease groups, and advocacy groups,
such as Public Citizen (https://www.citizen.org/), also
play roles in drug safety. The list is growing.
These groups, which often espouse special interests,
petition or file position papers to influence legislation,
regulatory decisions, and perceptions at the local, state/
provincial, and national levels as well as in litigation
and in the media. The groups work from all parts of the
spectrum, including some who strive to increase prof-
its, speed up or slow down drug approval, and increase
or decrease governmental oversight and regulation.
Some NGOs are now actually functioning as phar-
maceutical companies setting up clinical trials in areas
of need (particularly in resource-constrained settings)
where the pharmaceutical industry does not venture
(for many reasons). One example is TB Alliance, a
non-profit, which has several new and old drugs under
clinical trial for the treatment of tuberculosis.
Industry Organizations
The industry organization for pharmaceutical compa-
nies in the United States is PhRMA (www.phrma.org),
and in Europe it is the European Federation of Phar-
maceutical Industries and Associations (EFPIA) (www.
efpia.eu). In Japan it is the Japanese Pharmaceutical
Manufacturers Association (JPMA). Not all companies
are members, especially the smaller companies and
those that do not do research. PhRMA, which is based
in Washington, DC, has 13 offices, including in China,
Japan, and the United Arab Emirates. PhRMA supports
multiple functions including lobbying for the industry’s
position on public issues and legislation, outreach to
the public, assisting with patient assistance programs,
and representing US industry in the ICH. Its goal is
to “encourage discovery of important new medicines
for patients by pharmaceutical/biotechnology research
companies.” This is a highly political and controversial
area.
The EFPIA is based in Brussels, with an office in
Japan. The EFPIA is an association of associations and
includes national industry associations in Europe as well
as biopharma companies. Similar organizations exist in
other countries and industry associations also exist for
vaccines, OTCs, biologics, generics, and cosmetics.
In Canada, the industry association is known as
Innovative Medicines (http://innovativemedicines.ca/).
There are multiple other organizations representing
OTC manufacturers, generic manufacturers, parenteral
drugs, vaccine companies, biologics, device manufac-
turers, and cosmetics that interact, as well as groups
representing physicians (American Medical Associa-
tion in the United States), hospitals (American Hospi-
tal Association in the United States), nurses, insurance
companies, and so forth. The permutations and combi-
nations of interactions are many, complex, and grow-
ing, as groups sometimes work with one another and
326 Cobert’s Manual of Drug Safety and Pharmacovigilance
sometimes against one another. As attributed to Benja-
min Disraeli, “There are no permanent allies, no perma-
nent friends, only permanent interests.”
Litigation, Lawyers, and
Legalities
Litigation plays a major role in safety decisions made
regarding drugs in some countries, particularly the
United States. Any significant episode of AEs produces
a flurry of lawsuits, often numbering in the thousands.
They may take years to resolve, and costs run into the
billions of dollars. The issues usually revolve around
who in the company and sometimes in the government
knew about the drug’s toxicity, when it was known,
whether it was adequately publicized and labeled, and
whether remedial actions were taken in a timely fash-
ion. In the United States (and other countries such as
Canada, Italy and France) the phenomenon of “class
action lawsuits” often plays a significant role in drug
safety litigation. In these lawsuits, a group of people
(sometimes a very large group) will sue a company or
several companies if their problems are similar. This
groups many hundreds or thousands of people into one
lawsuit.
To a large degree, litigation and the fear of litigation
influence behavior in the drug safety world. Some com-
panies are hesitant to admit in a report sent to the health
authorities that their drug might have caused a particu-
larly serious AE. Such reports can be used in court cases
against the company or against the reporting physician,
nurse, pharmacist, and hospital, even if the report only
notes the possibility of a causal relationship with the
drug (e.g., “a causal relationship cannot be excluded”,
“possibly related”, “probably related”). The United
States is the major country where such issues occur, but
hesitancy in commenting on causality may be seen in
reports to health authorities outside the United States
because these reports may be obtained and used in
US courts, especially if the reports are easily available
in English (e.g., from the United Kingdom, Canada,
Australia, New Zealand, Uppsala Monitoring Centre).
Workers in the field of PV should familiarize them-
selves with the rules (both written and “unwritten”)
about how much and what sort of statements and con-
clusions can be made in reports submitted to govern-
ments, kept in computers, or on file, and which are
“discoverable” (that is, may be obtained by lawyers for
use in court cases). If a drug safety case from a company
has entered the legal system via a lawyer or lawsuit, the
drug safety group will often have to work through the
company’s legal department to obtain follow-up infor-
mation and to do its normal drug safety follow-up and
due diligence. Some companies also have a legal review
of all reports submitted to health authorities (e.g., expe-
dited reports, PSURs).
Finally, drug safety personnel may be called on to
testify in court and to give long and complex deposi-
tions either in individual cases that are on trial (e.g.,
malpractice, unexpected SAEs, or deaths) or in large
lawsuits (such as class action suits in the United States),
particularly those following major drug withdrawals
(Baycol
®
, Vioxx
®
, etc.)
Other Groups
Consumer groups, insurance companies, employers
paying health insurance, health maintenance organi-
zations, retired persons groups, and others also play
roles, sometimes direct and sometimes indirect, in drug
safety. Broadly speaking, many or all of these groups
favor, to some degree or another, lower-cost (or even
“free”) drugs, limited formularies (“no need for me-too
drugs”), generics, OTC status for many more drugs,
and lessening the influence of pharmaceutical com-
panies and increasing the role of regulators, without
giving much thought to what this might do (both pos-
itively and negatively) to drug safety, or result in other
unintended consequences. In the United States, many
of these groups have strong lobbies in Washington, DC,
and at the state levels. Many similar groups exist out-
side the United States, but their activities and influence
on the political systems do not appear to be as strong as
in the United States.
The Many Players in the World of Pharmacovigilance 327
Organizations for Drug
Safety Personnel
There are several organizations that personnel working
in the field of drug safety often join as follows:
DIA (formerly the Drug Information Asso-
ciation): The big international organization covers
all areas of the drug world, with academia, industry,
government, and others joining. They have annual
meetings each year in the United States, Canada,
Europe, and Asia. They run training programs,
publish a journal, Therapeutic Innovation and Reg-
ulatory Science, and have an extensive (though
hard-to-navigate) website. Annual membership
costs are fairly low, and if one is joining only one
organization, this is usually it.
International Society for Pharmacoepi-
demiology (ISPE): The main organization for
pharmacoepidemiology, including PV and risk man-
agement. Members are from industry, academia,
government agencies, and non-profit and for-profit
private organizations. Members have degrees in a
number of fields, including epidemiology, biostatis-
tics, medicine, nursing, pharmacology, pharmacy,
law, health economics, and journalism. They hold
multiple meetings each year and publish the journal
Pharmacoepidemiology and Drug Safety.
International Society of Pharmacovigi-
lance (IsoP), originally formed as the European
Society of Pharmacovigilance — An international
non-profit scientific organization to foster PV both
scientifically and educationally and to enhance all
aspects of the safe and proper use of medicines in
all countries.
Regulatory Affairs Professionals Society
(RAPS): A global organization of regulatory profes-
sionals. A bit peripheral to drug safety, as they cover
the full range of drug regulatory matters. They offer
training and hold meetings and have publications of
interest to drug safety personnel.
Academy of Physicians in Clinical
Research (APCR): A non-profit membership
organization representing physicians (MD, DO,
MBBS or equivalent) engaged in or preparing to
engage in clinical research within Clinical Practice,
Academic Institutions, Specialized Medical Clinics,
and Pharmaceutical Industry Researchers.
European Programme in Pharmacovigi-
lance and Pharmacoepidemiology (Eu2P):
An organization that is a European private and
academic partnership offering training in PV and
pharmacoepidemiology for specialists and non-
specialists. They work with universities in Spain,
Italy, UK, The Netherlands, and Italy.
Institute for Safe Medical Practices (ISMP):
A US non-profit organization devoted entirely to
medication error prevention and safe medication
use (www.ismp.org).
Many PV groups have been created on social net-
works; as of today, they are not replacing the large,
official and well-established organizations. This could
change in the next years, mainly for rapid information
exchanges.
Conclusion and Comments
And, finally, there are the unfortunate patients and
sometimes unfortunate individual doctors, pharma-
cists, and nurses who deal on one-to-one levels and
who must wade through the controversy, politics, and
unclear and equivocal safety information (“the follow-
ing AEs have been reported with this drug but causality
cannot be determined”) to come to good decisions for
individual patients. When it comes to specific numbers,
it is usually prudent to demur because that number
could change tomorrow (or tonight).
The bottom line is: drug safety is a high-stakes,
multi-party, politicized, highly controversial affair with
multiple players involved with multiple agendas and
multiple millions of dollars, euros, yuan, rupees, and
so forth. Data are often soft, incomplete, and skewed in
one direction or another. One should look at multiple
sources for information and keep an open mind on the
328 Cobert’s Manual of Drug Safety and Pharmacovigilance
ultimate outcome of safety issues with drugs. Usually
the “truth will out”, although it may take a long time.
Frequently Asked Question
Q: So then how should the individual in the
doctor’s office, hospital, drug company, health
agency, or elsewhere act? What can the indi-
vidual do to help sort this out?
A: In general, act as a good scientist and citizen, an
honest person, and do not judge until there is a good
amount of evidence examined from multiple sources.
Trust but verify. A good rule of thumb would be whether
you or a loved one would take the product in question.
Company safety personnel should always act with
the public health foremost in their mind and the com-
pany profits secondary. This may be difficult because
there are always pressures to “protect the drug” or
“hold off on this signal until the data are stronger”.
Safety workups and signaling should always be done
with due diligence and an open mind. Sometimes those
terrible-looking serious AEs really do melt away after
all the data are in. When the results are bad for the
drug, these data must be conveyed to management and
to all involved health authorities in a timely and cor-
rect manner. That can be an unpleasant experience, but
“always do the right thing.”
Practitioners, pharmacists, nurses, and patients
should maintain a healthy skepticism regarding data,
whether they are from the company, academia, the
health authority, or the media — especially during the
acute controversy when the “fog of war” is at its height
and angry words, images, and charges are flying. They
should seek out data from all sides and from neutral
authorities (if such exist). Healthcare practitioners
must always act in the best interest of the patient.
As a person rises in the company or governmental
hierarchy in drug safety, the pressures increase as well.
More money, more sales, more lives, more consequences
(intended and unintended) are in play. This can clearly
influence one’s judgment in safety and medical mat-
ters even unintentionally. To quote the dictum of Lord
Acton: “Power corrupts; absolute power corrupts abso-
lutely”. Another useful piece of wisdom is from the late
Senator Daniel Patrick Moynihan: “Everyone is entitled
to his own opinion, but not his own facts”.
Patients should find honest, caring health person-
nel and trust them to act in their best interest. Nonethe-
less, verification (looking at the approved drug labeling,
looking on the Internet at reliable sites, being treated
at major or academic medical centers, etc.) is also well
worth doing. Good luck.
CHAPTER
329
29
Pharmacovigilance
System Master File
C
ompanies applying for or holding
Marketing Authorizations (MAs)
for biopharmaceutical products
in the EEA, must have a critical docu-
ment on file: the Pharmacovigilance
System Master File (PSMF). Likewise,
in India a company must have in place
the PvMF, which is extremely similar
to the EU PSMF in format and purpose.
Indeed, the India-specific document
can be produced from the EU PSMF.
These master files required in the EU,
India, and elsewhere should not be con-
sidered as a static document only but
as a dynamic tool that supports active
governance of the PV System and
undergoes constant revision. It must be
kept up to date and details are described
in the EU Guideline on Good Pharma-
covigilance Practice (GVP) Module II.
The master files are prepared and kept
in good order by the MAH and provided
to the regulator on request (promptly!)
Introduction
This document is legally required at the moment of
submission of a Marketing Authorization Application
(MAA) in the EU. As described in GVP Module II, the
content of the PSMF should reflect global availability of
safety information for medicinal products authorized in
the EU, presenting information on the pharmacovigi-
lance system applied at global, regional, and local levels.
The PSMF will be required for pharmacovigilance (PV)
inspections by European Union Competent Authori-
ties. Several non-EU countries are now following this