Pharmacovigilance (PV or PhV), also known as drug safety, is

the pharmacological science relating to the collection, detection, assessment, monitoring, and
prevention of adverse effects with pharmaceutical products.[1] The etymological roots for the word
"pharmacovigilance" are: pharmakon (Greek for drug) and vigilare(Latin for to keep watch). As such,
pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any
response to a drug which is noxious and unintended, including lack of efficacy (the condition that this
definition only applies with the doses normally used for the prophylaxis, diagnosis or therapy of
disease, or for the modification of physiological disorder function was excluded with the latest
amendment of the applicable legislation).[2] Medication errors such as overdose, and misuse and
abuse of a drug as well as drug exposure during pregnancy and breastfeeding, are also of interest,
even without an adverse event, because they may result in an adverse drug reaction.[3]
Information received from patients and healthcare providers via pharmacovigilance agreements
(PVAs), as well as other sources such as the medical literature, plays a critical role in providing the
data necessary for pharmacovigilance to take place. In fact, in order to market or to test a
pharmaceutical product in most countries, adverse event data received by the license holder (usually
a pharmaceutical company) must be submitted to the local drug regulatory authority. (See Adverse
event reporting below.)
Ultimately, pharmacovigilance is concerned with identifying the hazards associated with
pharmaceutical products and with minimizing the risk of any harm that may come to patients.
Companies must conduct a comprehensive drug safety and pharmacovigilance audit to assess their
compliance with worldwide laws, regulations, and guidance.[4]
Pharmacovigilance has its own unique terminology that is important to
understand. Most of the following terms are used within this article and are
peculiar to drug safety, although some are used by other disciplines within the
pharmaceutical sciences as well.

 Adverse drug reaction is a side effect (non intended reaction to the drug)
occurring with a drug where a positive (direct) causal relationship between the
event and the drug is thought, or has been proven, to exist.
 Adverse event (AE) is a side effect occurring with a drug. By definition, the
causal relationship between the AE and the drug is unknown.
 Benefits are commonly expressed as the proven therapeutic good of a
product but should also include the patient's subjective assessment of its
effects.
 Causal relationship is said to exist when a drug is thought to have caused or
contributed to the occurrence of an adverse drug reaction.
 Clinical trial (or study) refers to an organised program to determine the safety
and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will
depend on the drug and the phase of its development.
 Control group is a group (or cohort) of individual patients that is used as a
standard of comparison within a clinical trial. The control group may be taking
a placebo (where no active drug is given) or where a different active drug is
given as a comparator.
 Dechallenge and rechallenge refer to a drug being stopped and restarted in a
patient, respectively. A positive dechallenge has occurred, for example, when
 an adverse event abates or resolves completely following the drug's
discontinuation. A positive rechallenge has occurred when the adverse event
re-occurs after the drug is restarted. Dechallenge and rechallenge play an
important role in determining whether a causal relationship between an event
and a drug exists.
 Effectiveness is the extent to which a drug works under real world
circumstances, i.e., clinical practice.
 Efficacy is the extent to which a drug works under ideal circumstances, i.e., in
clinical trials.
 Event refers to an adverse event (AE).
 Harm is the nature and extent of the actual damage that could be or has been
caused.
 Implied causality refers to spontaneously reported AE cases where the
causality is always presumed to be positive unless the reporter states
otherwise.
 Individual Case Safety Report (ICSR) is an adverse event report for an
individual patient.
 Life-threatening refers to an adverse event that places a patient at
the immediate risk of death.
 Phase refers to the four phases of clinical research and development: I –
small safety trials early on in a drug's development; II – medium-sized trials
for both safety and efficacy; III – large trials, which includes key (or so-called
"pivotal") trials; IV – large, post-marketing trials, typically for safety reasons.
There are also intermediate phases designated by an "a" or "b", e.g. Phase
IIb.
 Risk is the probability of harm being caused, usually expressed as a percent
or ratio of the treated population.
 Risk factor is an attribute of a patient that may predispose, or increase the
risk, of that patient developing an event that may or may not be drug-related.
For instance, obesity is considered a risk factor for a number of different
diseases and, potentially, ADRs. Others would be high blood pressure,
diabetes, possessing a specific mutated gene, for example, mutations in
the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.
 Signal is a new safety finding within safety data that requires further
investigation. There are three categories of signals: confirmed signals where
the data indicate that there is a causal relationship between the drug and the
AE; refuted (or false) signals where after investigation the data indicate that
no causal relationship exists; and unconfirmed signals which require further
investigation (more data) such as the conducting of a post-marketing trial to
study the issue.
 Temporal relationship is said to exist when an adverse event occurs when a
patient is taking a given drug. Although a temporal relationship is absolutely
 necessary in order to establish a causal relationship between the drug and
the AE, a temporal relationship does not necessarily in and of itself prove that
the event was caused by the drug.
 Triage refers to the process of placing a potential adverse event report into
one of three categories: 1) non-serious case; 2) serious case; or 3) no case
(minimum criteria for an AE case are not fulfilled).

 Adverse event reporting

The activity that is most commonly associated with pharmacovigilance (PV), and
which consumes a significant amount of resources for drug regulatory authorities
(or similar government agencies) and drug safety departments in pharmaceutical
companies, is that of adverse event reporting. Adverse event (AE) reporting
involves the receipt, triage, data entering, assessment, distribution, reporting (if
appropriate), and archiving of AE data and documentation. The source of AE
reports may include: spontaneous reports from healthcare professionals or
patients (or other intermediaries); solicited reports from patient support programs;
reports from clinical or post-marketing studies; reports from literature sources;
reports from the media (including social media and websites); and reports
reported to drug regulatory authorities themselves. For pharmaceutical
companies, AE reporting is a regulatory requirement in most countries. AE
reporting also provides data to these companies and drug regulatory authorities
that play a key role in assessing the risk-benefit profile of a given drug. The
following are several facets of AE reporting:
Individual Case Safety Report (ICSR)[edit]
One of the fundamental principles of adverse event reporting is the determination
of what constitutes an Individual Case Safety Report (ICSR). During the triage
phase of a potential adverse event report, it is important to determine if the "four
elements" of a valid ICSR are present: (1) an identifiable patient, (2) an
identifiable reporter, (3) a suspect drug, and (4) an adverse event.
If one or more of these four elements is missing, the case is not a valid ICSR.
Although there are no exceptions to this rule there may be circumstances that
may require a judgment call. For example, the term "identifiable" may not always
be clear-cut. If a physician reports that he/she has a patient X taking drug Y who
experienced Z (an AE), but refuses to provide any specifics about patient X, the
report is still a valid case even though the patient is not specifically identified.
This is because the reporter has first-hand information about the patient and
is identifiable (i.e. a real person) to the physician. Identifiability is important so as
not only to prevent duplicate reporting of the same case, but also to permit
follow-up for additional information.
The concept of identifiability also applies to the other three elements. Although
uncommon, it is not unheard of for fictitious adverse event "cases" to be reported
to a company by an anonymous individual (or on behalf of an anonymous
patient, disgruntled employee, or former employee) trying to damage the
company's reputation or a company's product. In these and all other situations,
the source of the report should be ascertained (if possible). But anonymous
reporting is also important, as whistle blower protection is not granted in all
countries. In general, the drug must also be specifically named. Note that in
different countries and regions of the world, drugs are sold under various
tradenames. In addition, there are a large number of generics which may be
mistaken for the trade product. Finally, there is the problem of counterfeit drugs
producing adverse events. If at all possible, it is best to try to obtain the sample
which induced the adverse event, and send it to either the EMA, FDA or other
government agency responsible for investigating AE reports.
If a reporter can't recall the name of the drug they were taking when they
experienced an adverse event, this would not be a valid case. This concept also
applies to adverse events. If a patient states that they experienced "symptoms",
but cannot be more specific, such a report might technically be considered valid,
but will be of very limited value to the pharmacovigilance department of the
company or to drug regulatory authorities.[5]
Coding of adverse events[edit]
Adverse event coding is the process by which information from an AE reporter,
called the "verbatim", is coded using standardized terminology from a medical
coding dictionary, such as MedDRA (the most commonly used medical coding
dictionary). The purpose of medical coding is to convert adverse event
information into terminology that can be readily identified and analyzed. For
instance, Patient 1 may report that they had experienced "a very bad headache
that felt like their head was being hit by a hammer" [Verbatim 1] when taking
Drug X. Or, Patient 2 may report that they had experienced a "slight, throbbing
headache that occurred daily at about two in the afternoon" [Verbatim 2] while
taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the
MedDRA coding dictionary. However, both quotes describe different
manifestations of a headache. As a result, in this example both quotes would be
coded as PT Headache (PT = Preferred Term in MedDRA).
Seriousness determination[edit]
Although somewhat intuitive, there are a set of criteria within pharmacovigilance
that are used to distinguish a serious adverse event from a non-serious one. An
adverse event is considered serious if it meets one or more of the following
criteria:
 1. results in death, or is life-threatening;
2. requires inpatient hospitalization or prolongation of existing hospitalization;
3. results in persistent or significant disability or incapacity;
4. results in a congenital anomaly (birth defect); or
5. is otherwise "medically significant" (i.e., that it does not meet preceding
criteria, but is considered serious because treatment/intervention would be
required to prevent one of the preceding criteria.)[5]
Aside from death, each of these categories is subject to some interpretation. Life-
threatening, as it used in the drug safety world, specifically refers to an adverse
event that places the patient at an immediate risk of death, such as cardiac or
respiratory arrest. By this definition, events such as myocardial infarction, which
would be hypothetically life-threatening, would not be considered life-threatening
unless the patient went into cardiac arrest following the MI. Defining what
constitutes hospitalization can be problematic as well. Although typically
straightforward, it's possible for a hospitalization to occur even if the events being
treated are not serious. By the same token, serious events may be treated
without hospitalization, such as the treatment of anaphylaxis may be successfully
performed with epinephrine. Significant disability and incapacity, as a concept, is
also subject to debate. While permanent disability following a stroke would no
doubt be serious, would "complete blindness for 30 seconds" be considered
"significant disability"? For birth defects, the seriousness of the event is usually
not in dispute so much as the attribution of the event to the drug. Finally,
"medically significant events" is a category that includes events that may be
always serious, or sometimes serious, but will not fulfill any of the other criteria.
Events such as cancer might always be considered serious, whereas liver
disease, depending on its CTCAE (Common Terminology Criteria for Adverse
Events) grade—Grades 1 or 2 are generally considered non-serious and Grades
3-5 serious—may be considered non-serious.[6]
Expedited reporting[edit]
This refers to ICSRs (individual case safety reports) that involve a serious and
unlisted event (an event not described in the drug's labeling) that is considered
related to the use of the drug. (Spontaneous reports are typically considered to
have a positive causality, whereas a clinical trial case will typically be assessed
for causality by the clinical trial investigator and/or the license holder.) In most
countries, the time frame for reporting expedited cases is 7/15 calendar days
from the time a drug company receives notification (referred to as "Day 0") of
such a case. Within clinical trials such a case is referred to as a SUSAR (a
Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an
event that is life-threatening or fatal, it may be subject to a 7-day "clock". Cases
that do not involve a serious, unlisted event may be subject to non-expedited or
periodic reporting.
Clinical trial reporting[edit]
Also known as SAE (serious adverse event) reporting from clinical trials, safety
information from clinical studies is used to establish a drug's safety profile in
humans and is a key component that drug regulatory authorities consider in the
decision-making as to whether to grant or deny market authorization (market
approval) for a drug. SAE reporting occurs as a result of study patients (subjects)
who experience serious adverse events during the conducting of clinical trials.
(Non-serious adverse events are also captured separately.) SAE information,
which may also include relevant information from the patient's medical
background, are reviewed and assessed for causality by the study investigator.
This information is forwarded to a sponsoring entity (typically a pharmaceutical
company) that is responsible for the reporting of this information, as appropriate,
to drug regulatory authorities.
Spontaneous reporting[edit]
Spontaneous reports are termed spontaneous as they take place during the
clinician's normal diagnostic appraisal of a patient, when the clinician is drawing
the conclusion that the drug may be implicated in the causality of the event.
Spontaneous reporting system relies on vigilant physicians and other healthcare
professionals who not only generate a suspicion of an ADR, but also report it. It
is an important source of regulatory actions such as taking a drug off the market
or a label change due to safety problems. Spontaneous reporting is the core
data-generating system of international pharmacovigilance, relying on healthcare
professionals (and in some countries consumers) to identify and report any
adverse events to their national pharmacovigilance center, health authority (such
as EMA or FDA), or to the drug manufacturer itself.[7] Spontaneous reports are,
by definition, submitted voluntarily although under certain circumstances these
reports may be encouraged, or "stimulated", by media reports or articles
published in medical or scientific publications, or by product lawsuits. In many
parts of the world adverse event reports are submitted electronically using a
defined message standard.[8][9]
One of the major weaknesses of spontaneous reporting is that of under-
reporting, where, unlike in clinical trials, less than 100% of those adverse events
occurring are reported. Further complicating the assessment of adverse events,
AE reporting behavior varies greatly between countries and in relation to the
seriousness of the events, but in general probably less than 10% (some studies
suggest less than 5%) of all adverse events that occur are actually reported. The
rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported
and 10 being the most likely to be reported, an uncomplicated non-serious event
such as a mild headache will be closer to a "0" on this scale, whereas a life-
threatening or fatal event will be closer to a "10" in terms of its likelihood of being
reported. In view of this, medical personnel may not always see AE reporting as
a priority, especially if the symptoms are not serious. And even if the symptoms
are serious, the symptoms may not be recognized as a possible side effect of a
particular drug or combination thereof. In addition, medical personnel may not
feel compelled to report events that are viewed as expected. This is why reports
from patients themselves are of high value. The confirmation of these events by
a healthcare professional is typically considered to increase the value of these
reports. Hence it is important not only for the patient to report the AE to his health
care provider (who may neglect to report the AE), but also report the AE to both
the biopharmaceutical company and the FDA, EMA, ... This is especially
important when one has obtained one's pharmaceutical from a compounding
pharmacy.
As such, spontaneous reports are a crucial element in the worldwide enterprise
of pharmacovigilance and form the core of the World Health
Organization Database, which includes around 4.6 million reports (January
2009),[10] growing annually by about 250,000.[11]
Aggregate reporting[edit]
Aggregate reporting, also known as periodic reporting, plays a key role in the
safety assessment of drugs. Aggregate reporting involves the compilation of
safety data for a drug over a prolonged period of time (months or years), as
opposed to single-case reporting which, by definition, involves only individual AE
reports. The advantage of aggregate reporting is that it provides a broader view
of the safety profile of a drug. Worldwide, the most important aggregate report is
the Periodic Safety Update Report (PSUR) and Development Safety Update
Report (DSUR). This is a document that is submitted to drug regulatory agencies
in Europe, the US and Japan (ICH countries), as well as other countries around
the world. The PSUR was updated in 2012 and is now referred to in many
countries as the Periodic Benefit Risk Evaluation report (PBRER). As the title
suggests, the PBRER's focus is on the benefit-risk profile of the drug, which
includes a review of relevant safety data compiled for a drug product since its
development.
Other reporting methods[edit]
Some countries legally oblige spontaneous reporting by physicians. In most
countries, manufacturers are required to submit, through its Qualified Person for
Pharmacovigilance (QPPV), all of the reports they receive from healthcare
providers to the national authority. Others have intensive, focused programmes
concentrating on new drugs, or on controversial drugs, or on the prescribing
habits of groups of doctors, or involving pharmacists in reporting. All of these
generate potentially useful information. Such intensive schemes, however, tend
to be the exception. A number of countries have reporting requirements or
reporting systems specific to vaccine-related events.[12]
Causality assessment[edit]
One of the most important, and challenging, problems in pharmacovigilance is
that of the determination of causality. Causality refers to the relationship of a
given adverse event to a specific drug. Causality determination (or assessment)
is often difficult because of the lack of clear-cut or reliable data. While one may
assume that a positive temporal relationship might "prove" a positive causal
relationship, this is not always the case. Indeed, a "bee sting" AE—where the AE
can clearly be attributed to a specific cause—is by far the exception rather than
the rule. This is due to the complexity of human physiology as well as that of
disease and illnesses. By this reckoning, in order to determine causality between
an adverse event and a drug, one must first exclude the possibility that there
were other possible causes or contributing factors. If the patient is on a number
of medications, it may be the combination of these drugs which causes the AE,
and not any one individually. There have been a number of recent high-profile
cases where the AE led to the death of an individual. The individual(s) were not
overdosed with any one of the many medications they were taking, but the
combination there appeared to cause the AE. Hence it is important to include in
your/one's AE report, not only the drug being reported, but also all other drugs
the patient was also taking.
For instance, if a patient were to start Drug X and then three days later were to
develop an AE, one might be tempted to attribute blame Drug X. However,
before that can be done, the patient's medical history would need to be reviewed
to look for possible risk factors for the AE. In other words, did the AE occur with
the drug or because of the drug? This is because a patient on any drug may
develop or be diagnosed with a condition that could not have possibly been
caused by the drug. This is especially true for diseases, such as cancer, which
develop over an extended period of time, being diagnosed in a patient who has
been taken a drug for a relatively short period of time. On the other hand, certain
adverse events, such as blood clots (thrombosis), can occur with certain drugs
with only short-term exposure. Nevertheless, the determination of risk factors is
an important step of confirming or ruling-out a causal relationship between an
event and a drug.
Often the only way to confirm the existence of a causal relationship of an event to
a drug is to conduct an observational study where the incidence of the event in a
patient population taking the drug is compared to a control group. This may be
necessary to determine if the background incidence of an event is less than that
found in a group taking a drug. If the incidence of an event is statistically
significantly higher in the "active" group versus the placebo group (or other
control group), it is possible that a causal relationship may exist to a drug, unless
other confounding factors may exist.
Signal detection[edit]
Signal detection (SD) involves a range of techniques (CIOMS VIII). The WHO
defines a safety signal as: "Reported information on a possible causal
relationship between an adverse event and a drug, the relationship being
unknown or incompletely documented previously". Usually more than a single
report is required to generate a signal, depending upon the event and quality of
the information available.
Data mining pharmacovigilance databases is one approach that has become
increasingly popular with the availability of extensive data sources and
inexpensive computing resources. The data sources (databases) may be owned
by a pharmaceutical company, a drug regulatory authority, or a large healthcare
provider. Individual Case Safety Reports (ICSRs) in these databases are
retrieved and converted into structured format, and statistical methods (usually a
mathematical algorithm) are applied to calculate statistical measures of
association. If the statistical measure crosses an arbitrarily set threshold, a signal
is declared for a given drug associated with a given adverse event. All signals
deemed worthy of investigation, require further analysis using all available data in
an attempt to confirm or refute the signal. If the analysis is inconclusive,
additional data may be needed such as a post-marketing observational trial.
SD is an essential part of drug use and safety surveillance. Ideally, the goal of
SD is to identify ADRs that were previously considered unexpected and to be
able to provide guidance in the product's labeling as to how to minimize the risk
of using the drug in a given patient population.
Risk management plans[edit]
A risk management plan (RMP) is a documented plan that describes the risks
(adverse drug reactions and potential adverse reactions) associated with the use
of a drug and how they are being handled (warning on drug label or on packet
inserts of possible side effects which if observed should cause the patient to
inform/see his physician and/or pharmacist and/or the manufacturer of the drug
and/or the FDA, EMA)). The overall goal of an RMP is to assure a positive risk-
benefit profile once the drug is (has been) marketed. The document is required to
be submitted, in a specified format, with all new market authorization requests
within the European Union(EU). Although not necessarily required, RMPs may
also be submitted in countries outside the EU. The risks described in an RMP fall
into one of three categories: identified risks, potential risks, and unknown risks.
Also described within an RMP are the measures that the Market Authorization
Holder, usually a pharmaceutical company, will undertake to minimize the risks
associated with the use of the drug. These measures are usually focused on the
product's labeling and healthcare professionals. Indeed, the risks that are
documented in a pre-authorization RMP will inevitably become part of the
product's post-marketing labeling. Since a drug, once authorized, may be used in
ways not originally studied in clinical trials, this potential "off-label use", and its
associated risks, is also described within the RMP. RMPs can be very lengthy
documents, running in some cases hundreds of pages and, in rare instances, up
to a thousand pages long.
In the US, under certain circumstances, the FDA may require a company to
submit a document called a Risk Evaluation and Mitigation Strategies (REMS) for
a drug that has a specific risk that FDA believes requires mitigation. While not as
comprehensive as an RMP, a REMS can require a sponsor to perform certain
activities or to follow a protocol, referred to as Elements to Assure Safe Use
(ETASU),[13] to assure that a positive risk-benefit profile for the drug is maintained
for the circumstances under which the product is marketed.
Risk/benefit profile of drugs[edit]
Pharmaceutical companies are required by law in most countries to
perform clinical trials, testing new drugs on people before they are made
generally available. This occurs after a drug has been pre-screened for toxicity,
sometimes using animals for testing. The manufacturers or their agents usually
select a representative sample of patients for whom the drug is designed – at
most a few thousand – along with a comparable control group. The control group
may receive a placebo and/or another drug, often a so-called "gold standard" that
is "best" drug marketed for the disease.
The purpose of clinical trials is to determine:

 if a drug works and how well it works

 if it has any harmful effects, and
 if it does more good than harm, and how much more? If it has a potential for
harm, how probable and how serious is the harm?
Clinical trials do, in general, tell a good deal about how well a drug works. They
provide information that should be reliable for larger populations with the same
characteristics as the trial group – age, gender, state of health, ethnic origin, and
so on though target clinical populations are typically very different from trial
populations with respect to such characteristics[citation needed].
The variables in a clinical trial are specified and controlled, but a clinical trial can
never tell you the whole story of the effects of a drug in all situations. In fact,
nothing could tell you the whole story, but a clinical trial must tell you enough;
"enough" being determined by legislation and by contemporary judgements
about the acceptable balance of benefit and harm. Ultimately, when a drug is
marketed it may be used in patient populations that were not studied during
clinical trials (children, the elderly, pregnant women, patients with co-morbidities
not found in the clinical trial population, etc.) and a different set of warnings,
precautions or contraindications (where the drug should not be used at all) for the
product's labeling may be necessary in order to maintain a positive risk/benefit
profile in all known populations using the drug.
The World Health Organization (WHO)[edit]
The principle of international collaboration in the field of pharmacovigilance is the
basis for the WHO Programme for International Drug Monitoring, through which
over 150 member nations have systems in place that encourage healthcare
personnel to record and report adverse effects of drugs in their patients.[15] These
reports are assessed locally and may lead to action within the country. Since
1978, the programme has been managed by the Uppsala Monitoring Centre to
which member countries send their reports to be processed, evaluated and
entered into an international database called VigiBase. Membership in the WHO
Programme enables a country to know if similar reports are being made
elsewhere.[16] When there are several reports of adverse reactions to a particular
drug, this process may lead to the detection of a signal, and an alert about a
possible hazard communicated to members countries after detailed evaluation
and expert review.[citation needed]
The International Council for Harmonisation (ICH)[edit]
The ICH is a global organization with members from the European Union, the
United States and Japan; its goal is to recommend global standards for drug
companies and drug regulatory authorities around the world, with the ICH
Steering Committee (SC) overseeing harmonization activities. Established in
1990, each of its six co-sponsors—the EU, the European Federation of
Pharmaceutical Industries and Associations (EFPIA), Japan's Ministry of Health,
Labor and Welfare (MHLW), the Japanese Pharmaceutical Manufacturers
Association (JPMA), the U.S. Food and Drug Administration (FDA), and the
Pharmaceutical Research and Manufacturers of America (PhRMA)—have two
seats on the SC. Other parties have a significant interest in ICH and have been
invited to nominate Observers to the SC; three current observers[when?] are the
WHO, Health Canada, and the European Free Trade Association (EFTA), with
the International Federation of Pharmaceutical Manufacturers Association
(IFPMA) participating as a non-voting member of the SC.[17][18]
The Council for International Organizations of Medical Science
(CIOMS)[edit]
The CIOMS, a part of the WHO, is a globally oriented think tank that provides
guidance on drug safety related topics through its Working Groups.[citation needed] The
CIOMS prepares reports that are used as a reference for developing future drug
regulatory policy and procedures, and over the years, many of CIOMS' proposed
policies have been adopted.[citation needed] Examples of topics these reports have
covered include: Current Challenges in Pharmacovigilance: Pragmatic
Approaches (CIOMS V); Management of Safety Information from Clinical Trials
(CIOMS VI); the Development Safety Update Report (DSUR): Harmonizing the
Format and Content for Periodic Safety Reporting During Clinical Trials (CIOMS
VII); and Practical Aspects of Signal Detection in Pharmacovigilance: Report of
CIOMS Working Group (CIOMS VIII).[citation needed]
The International Society of Pharmacovigilance (ISoP)[edit]
The ISoP is an international non-profit scientific organization, which aims to
foster pharmacovigilance both scientifically and educationally, and enhance all
aspects of the safe and proper use of medicines, in all countries.[19] It was
established in 1992 as the European Society of Pharmacovigilance.[20]
Society of Pharmacovigilance, India, also established in 1992, is partner member
of ISoP. Local societies include the Boston Society of Pharmacovigilance
Physicians.[21]

Regulatory authorities
Drug regulatory authorities play a key role in national or regional oversight of
pharmacovigilance. Some of the agencies involved are listed below (in order of
2011 spending on pharmaceuticals, from the IMS Institute for Healthcare
Informatics).[22]
United States[edit]
See also: Regulation of therapeutic goods in the United States

In the U.S., with about a third of all global 2011 pharmaceutical

expenditures,[22] the drug industry is regulated by the FDA, the largest national
drug regulatory authority in the world.[citation needed] FDA authority is exercised
through enforcement of regulations derived from legislation, as published in the
U.S. Code of Federal Regulations(CFR); the principal drug safety regulations are
found in 21 CFR Part 312 (IND regulations) and 21 CFR Part 314 (NDA
regulations).[citation needed] While those regulatory efforts address pre-marketing
concerns, pharmaceutical manufacturers and academic/non-profit organizations
such as RADAR and Public Citizen do play a role in pharmacovigilance in the
US.[citation needed] The post-legislative rule-making process of the U.S. federal
government provides for significant input from both the legislative and executive
branches, which also play specific, distinct roles in determining FDA policy.[citation
needed]

Emerging economies (including Latin America)[edit]

The "pharmerging", or emerging pharmaceutical market economies, which
include Brazil, India, Russia, Argentina, Egypt, Indonesia, Mexico, Pakistan,
Poland, Romania, South Africa, Thailand, Turkey, Ukraine and Vietnam, accrued
one fifth of global 2011 pharmaceutical expenditures; in future, aggregated data
for this set will include China as well.[22]
China's economy is anticipated to pass Japan to become second in the ranking
of individual countries' in pharmaceutical purchases by 2015, and so its PV
regulation will become increasing important; China's regulation of PV is through
its National Center for Adverse Drug Reaction (ADR) Monitoring, under China's
Ministry of Health.[23]
As JE Sackman notes, as of April 2013 "there is no Latin American equivalent of
the European Medicines Agency—no common body with the power to facilitate
greater consistency across countries".[24] For simplicity, and per sources, 17
smaller economies are discussed alongside the 4 pharmemerging large
economies of Argentina, Brazil, Mexico and Venzuala—Bolivia, Chile, Colombia,
Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Haiti,
Honduras, Nicaragua, Panama, Paraguay, Peru, Suriname, and Uruguay.[25] As
of June 2012, 16 of this total of 21 countries have systems for immediate
reporting and 9 have systems for periodic reporting of adverse events for on-
market agents, while 10 and 8, respectively, have systems for immediate and
periodic reporting of adverse events during clinical trials; most of these have PV
requirements that rank as "high or medium...in line with international standards"
(ibid.). The WHO's Pan American Network for Drug Regulatory
Harmonization[26] seeks to assist Latin American countries in develop harmonized
PV regulations.[25]
Some further PV regulatory examples from the pharmerging nations are as
follows. In India, the PV regulatory authority is the Indian Pharmacopoeia
Commission, with a National Coordination Centre under the Pharmacovigilance
Program of India, in the Ministry of Health and Family Welfare.[27][28] Scientists
working on pharmacovigilance share their experiences, findings, innovative ideas
and researches during the annual meeting of Society of Pharmacovigilance,
India.[citation needed]In Egypt, PV is regulated by the Egyptian Pharmacovigilance
Center of the Egyptian Ministry of Health.[citation needed]
European Union[edit]
The EU5 (France, Germany, Italy, Spain, United Kingdom) accrued ~17% of
global 2011 pharmaceutical expenditures.[22] PV efforts in the EU are coordinated
by the European Medicines Agency (EMA) and are conducted by the national
competent authorities (NCAs).[citation needed] The main responsibility of the EMA is to
maintain and develop the pharmacovigilance database consisting of all
suspected serious adverse reactions to medicines observed in the European
Community; the data processing network and management system is
called EudraVigilance and contains separate but similar databases of human and
veterinary reactions.[29] The EMA requires the individual marketing authorization
holders to submit all received adverse reactions in electronic form, except in
exceptional circumstances; the reporting obligations of the various stakeholders
are defined by EEC legislation, namely Regulation (EC) No 726/2004, and for
human medicines, European Union Directive 2001/83/EC as amended
and Directive 2001/20/EC.[citation needed] In 2002, Heads of Medicines
Agencies[30] agreed on a mandate for an ad hoc Working Group on establishing a
European risk management strategy; the Working Group considered the conduct
of a high level survey of EU pharmacovigilance resources to promote the
utilization of expertise and encourage collaborative working.[citation needed]
In conjunction with this oversight, individual countries maintain their distinct
regulatory agencies with PV responsibility.[31] For instance, in Spain, PV is
regulated by the Agencia Española de Medicamentos y Productos
Sanitarios (AEMPS), a legal entity that retains the right to suspend or withdraw
the authorization of pharmaceuticals already on-market if the evidence shows
that safety (or quality or efficacy) of an agent are unsatisfactory.[32]
Rest of Europe, including non-EU[edit]
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expansion. You can help
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The remaining EU and non-EU countries outside the EU5 accrued ~7% of global
2011 pharmaceutical expenditures.[22] Regulation of those outside the EU being
managed by specific governmental agencies. For instance, in Switzerland, PV
"inspections" for clinical trials of medicinal products are conducted by the Swiss
Agency for Therapeutic Products.[33]
Japan[edit]
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In Japan, with ~12% of all global 2011 pharmaceutical expenditures,[22] PV

matters are regulated by the Pharmaceuticals and Medical Devices
Agency (PMDA) and the Ministry of Health, Labour, and Welfare MHLW.[citation needed]
Canada[edit]
This section needs
expansion. You can help
by adding to it. (March 2014)
In Canada, with ~2% of all global 2006 and 2011 pharmaceutical
expenditures,[22] PV is regulated by the Marketed Health Products Directorate of
the Health Products and Food Branch(MHPD).[34] Canada was second, following
the United States, in holding the highest total prescription drug expenditures per
capita in 2011 at around 750 US dollars per person. Canada also pays such a
large amount for pharmaceuticals that it was second, next to Switzerland, for the
amount of money spent for a certain amount of prescription drugs (around 130
US dollars). It was also accessed that Canada was one of the top countries that
increased its yearly average per capita growth on pharmaceutical expenditures
the most from 2000-2010 with 4 percent a year (with taking inflation into
account) [35] The MHPD mainly collects adverse drug reaction reports through a
network of reporting centers to analyze and issue possible warnings to the public,
and currently utilizes newsletters, advisories, adverse reaction centers, as well as
electronic mailing lists. However, it does not currently maintain a database or list
of drugs removed from Canada as a result of safety concerns.[36]
In August 2017, there was a government controversy in which a bill, known as
“Vanessa’s Law”, to protect patients from potentially dangerous prescription
drugs was not being fully realized by hospitals; Health Canada only required
hospitals to report “unexpected” negative reactions to prescription drugs, rather
than any and all adverse reactions, with the justification of managing
“administrative overload”.[25][37]
South Korea[edit]
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expansion. You can help
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The Republic of Korea, with ~1% of all global 2011 pharmaceutical

expenditures,[22] PV matters are regulated in South Korea by the Ministry Of Food
And Drug Safety (MFDS)[citation needed]
Africa[edit]
Kenya[edit]
In Kenya, PV is regulated by the Pharmacy and Poisons Board.The Pharmacy
and Poisons Board provides a Pharmacovigilance Electronic Reporting System
which allows for the online reporting of suspected adverse drug reactions as well
as suspected poor quality of medicinal products.[38] The Pharmacovigilance
activities in Kenya are supported by the School of Pharmacy, University of
Nairobi through its Master of Pharmacy in Pharmacoepidemiology &
Pharmacovigilance program offered by the Department of Pharmacology and
Pharmacognosy.[39]
In Uganda, PV is regulated by the National Drug Authority.[citation needed]
Rest of world (ROW)[edit]
This section needs
expansion. You can help
by adding to it. (March 2014)

ROW accrued ~7% of global 2011 pharmaceutical expenditures.[22] Some

examples of PV regulatory agencies in ROW are as follows. In Iraq, PV is
regulated by the Iraqi Pharmacovigilance Center of the Iraqi Ministry of
Health.[citation needed]

Pharmacoenvironmentology; (Ecopharmacovigilance
[EPV])[edit]
Despite attention from the FDA and regulatory agencies of the European Union,
procedures for monitoring drug concentrations and adverse effects in the
environment are lacking.[citation needed] Pharmaceuticals, their metabolites, and related
substances may enter the environment after patient excretion, after direct release
to waste streams during manufacturing or administration, or via terrestrial
deposits (e.g., from waste sludges or leachates).[40] A concept combining
pharmacovigilance and environmental pharmacology, intended to focus attention
on this area, was introduced first as pharmacoenvironmentology in 2006 by Syed
Ziaur Rahman and later as ecopharmacology with further concurrent and later
terms for the same concept (ecopharmacovigilance [EPV], environmental
pharmacology, ecopharmacostewardship).[40][41][42][43]
The first of these routes to the environment, elimination through living organisms
subsequent to pharmacotherapy, is suggested as the principal source of
environmental contamination (apart from cases where norms for treatment of
manufacturing and other wastes are violated), and EPV is intended to deal
specifically with this impact of pharmacological agents on the environment.[40][44]
Activities of EPV have been suggested to include:

 Increasing, generally, the availability of environmental data on medicinal

products;
 Tracking emerging data on environmental exposure, effects and risks after
product launch;
 Using Environmental Risk Management Plans (ERMPs) to manage risk
throughout a drug's life cycle;
 Following risk identification, promoting further research and environmental
monitoring, and
 In general, promoting a global perspective on EPV issues.[40]
Related to medical devices[edit]
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A medical device is an instrument, apparatus, implant, in vitro reagent, or similar

or related article that is used to diagnose, prevent, or treat disease or other
conditions, and does not achieve its purposes through chemical action within or
on the body (which would make it a drug). Whereas medicinal products (also
called pharmaceuticals) achieve their principal action by pharmacological,
metabolic or immunological means, medical devices act by physical, mechanical,
or thermal means. Medical devices vary greatly in complexity and application.
Examples range from simple devices such as tongue depressors,
medical thermometers, and disposable gloves to advanced devices such
as medical robots, cardiac pacemakers, and neuroprosthetics. This modern
concept of monitoring and safety of medical devices which is known
materiovigilance was quite documented in Unani System of medicine.[45]
Given the inherent difference between medicinal products and medical products,
the vigilance of medical devices is also different from that of medicinal products.
To reflect this difference, a classification system has been adopted in some
countries to stratify the risk of failure with the different classes of devices. The
classes of devices typically run on a 1-3 or 1-4 scale, with Class 1 being the least
likely to cause significant harm with device failure versus Classes 3 or 4 being
the most likely to cause significant harm with device failure. An example of a
device in the "low risk" category would be contact lenses. An example of a device
in the "high risk" category would be cardiac pacemakers.
Medical device reporting (MDR), which is the reporting of adverse events with
medical devices, is similar to that with medicinal products, although there are
differences. For instance, in the US user-facilities such as hospitals and nursing
homes are legally required to report suspected medical device-related deaths to
both FDA and the manufacturer, if known, and serious injuries to the
manufacturer or to FDA, if the manufacturer is unknown.[46] This is in contrast to
the voluntary reporting of AEs with medicinal products.

For herbal medicines[edit]

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rather than vague statements. You can help by adding to it. (March 2014)

The safety of herbal medicines has become a major concern to both national
health authorities and the general public.[47][full citation needed] The use of herbs
as traditional medicines continues to expand rapidly[vague] across the world; many
people[vague] now take herbal medicines or herbal products for their health care in
different national health-care settings.[vague][citation needed] However, mass media
reports[which?] of adverse events with herbal medicines can be incomplete and
therefore misleading.[citation needed] Moreover, it can be difficult to identify the causes
of herbal medicine-associated adverse events since the amount of data on each
event is generally less than for pharmaceuticals formally regulated as drugs
(since the requirements for adverse event reporting are either non-existent or are
less stringent for herbal supplements and medications).[48]

Industry associations[edit]
Boston Society of Pharmacovigilance Physicians.[49]
Being a member of the
WHO Programme for
International Drug
Monitoring
The combined resources of member countries and UMC
give members of the WHO Programme access to
expertise, information, and tools to support the
operation of their pharmacovigilance systems and the
vision of the safer use of medicines.

What does it mean to be a member?

In each participating country, the ministry of health establishes a
pharmacovigilance centre with responsibility for the safety of medicines and
for contact with WHO in this specific field. Members have access to the
resources of UMC to support their work. They enjoy many benefits from
being part of the global pharmacovigilance community; there are obligations,
too, such as regularly making their crucial contributions of data to VigiBase,
the WHO global database of individual case safety reports (ICSRs). Members
also disseminate decisions about the causes of harm that their patients have
suffered and share support, advice and experience. Some countries take part
 in regional consultations and training; all countries have the opportunity of
attending the annual WHO Programme meeting.

Resources and benefits of membership of the WHO Programme include:

 unrestricted access to VigiBase

 early information about potential safety hazards shared informally amongst
members or from the UMC Signal detection team
 VigiFlow and VigiLyze – tools for reporting, storing, structuring, searching,
and analysing ICSRs
 first call on support, training, guidelines and resources, such as courses and
publications, from UMC and others
 engagement in the relationships and activities of the international network
 a voice in the shaping of international pharmacovigilance policy.

Membership obligations: to ensure that the international data is as up-to-

date as possible, member countries are asked to send ICSRs to UMC at least
every quarter, preferably more frequently. The reports must be submitted in
E2B compatible format, with attention to both the quality and completeness
of the data. The data is stored in VigiBase, in a structured, hierarchical form
to allow easy and flexible retrieval and analysis. VigiBase is the largest and
most comprehensive source of data about the adverse effects of medicines
in the world. It is maintained and developed by UMC on behalf of WHO.
Why pharmacovigilance
is needed
All of us, from children to parents, friends and partners,
will take medicines at some point in their lives. The aim
of pharmacovigilance is the safer and more effective use
of medicines for everyone. It involves all activities that
relate to noticing, assessing, understanding, managing
and preventing adverse effects of medicines for
individuals and populations.

Medicines do cause harm

Medicines have brought enormous benefits, but no medicine is 100% safe
for all people in all situations. While some medicines can seriously injure or
even kill, most have predominantly beneficial effects for most people - even
while they may cause occasional minor harm (such as headache, rash or
tiredness).

Every time a treatment decision is made, the prescriber and patient must
decide if the benefits are sufficient to accept the possibility of discomfort or
harm, which may already be known and recorded on the patient leaflet.
Sometimes there is unexpected minor or serious harm. This is why watching
and reporting are so important: the more we know about what patients have
experienced, the more all of us can be accurately informed, and harm can be
prevented in the future. The risks of vaccines causing harm are much lower
than those of

medicines, but monitoring is still necessary.

"Telling your doctor or pharmacist about

adverse effects will help make drug use safer for
everyone."
How do medicines cause harm?
You may ask why it is that medicines cause harm at all. Medicines are a
powerful, usually chemical or biological invasion of the body; that is why
they can cure diseases but also why they sometimes cause damage.

We get to know about many of the benefits and harms that any medicine
can cause when it is tested in clinical trials. These involve only a few hundred
or thousand carefully selected people, so they do not represent the whole
population of patients (maybe millions) who will eventually use the drug. It is
only after it has been used by large numbers of patients over a longer period
of time that more of its effects become clear, especially effects that are rare.
Reporting of rare effects is particularly important in building up a full picture
of a drug’s character and safety profile.

It’s also the case that different people react differently to

medicines, because everyone has different risk factors – relating to genetics,
other diseases and medication, allergies, social conditions, psychology and so
on. We need to know what it is that makes every patient vulnerable to harm;
when harm occurs, it needs to be added to the body of knowledge that will
influence how medicines are used in the future.

In this video clip Rebecca Chandler, UMC's medical doctor, talks about
benefit–risk assessment of medicines.

How do we reduce the risk of harm from medicines?

Wise therapeutic decisions, which give patients the greatest benefits with
the least risk, must be made jointly by health professionals and patients.
Asking a number of essential questions and having satisfactory answers for
them is the starting point.

The heart of pharmacovigilance: questions to ask

A patient must understand, anticipate and recognise the known negative

side effects of a drug; there must be a plan for when they first appear, and
agreed action taken. The first essential step is likely to be returning to report
the problem to the prescriber.

Taking the drug as prescribed, finishing the course, avoiding interactions

with other foods or drugs – in other words adherence to the prescribing
guidelines – all help to reduce the possibility of harm.

Nevertheless, we cannot eliminate the risk of harm completely. We must

be prepared for occasional mild adverse side effects and be alert if there is
any indication at all of potentially more serious ones. In that case, urgent
action may be necessary.
Watching for safer medicines
Understanding patients’ experiences of treatment, and especially the harm
that they may suffer, is an important aspect of patient care and public health.
Recognising, recording and reporting adverse effects – as well as lack of
effect and even unexpected benefits – will help us improve treatment and
prevent harm for other patients in the future.

As patients, we can all report the effects of treatment to our doctor or

pharmacist, especially harmful effects (such as a medicine causing diarrhoea
or not working at all). When we tell them about a problem, they should
discuss it with us, diagnose the cause of the problem and agree with us what
needs to be done. Action could include changing the dose or stopping the
drug and trying an alternative.

Medicines may have effects in many aspects of a patient’s life, not only in
relation to their specific impact on disease. Adverse effects, even mild ones,
may negatively impact a patient’s work or lifestyle (by making them drowsy
and unable to drive, for example). Patients may assess benefit and harm in
ways very different from professionals. Information about these aspects of
therapy is critical to a full understanding of patients’ experiences, but they are
beyond the bounds of most current medical record keeping or reporting.

What happens to reports of problem with medicines?

What happens to reports
of problems with
medicines?
After a patient has shared information about an adverse effect with their
doctor or other health provider, it should be reported to the local or national
pharmacovigilance centre (the great majority are not reported, which is a big
problem). Here the likelihood of the medicine having caused the problem is
further investigated. All possible causes are reviewed and the strength of the
evidence is assessed, including other reports and material from reference
works and journals.

Depending on the outcome, action may be taken - such as changing the

way the drug is used, or even withdrawing it from the market. If the problem
seems to be caused by sub-standard or counterfeit drugs, or there has been an
interaction with another drug or substance, or the diagnosis or choice of drug
was doubtful, other solutions are needed.

Reports of suspected adverse effects from member countries of the WHO

Programme for International Drug Monitoring are sent to VigiBase, the
WHO international database, managed by the UMC. There they are reviewed
and analysed and the bigger picture of worldwide evidence begins to emerge.
 Being part of the bigger picture

The path taken by information about a patient’s problem with a

medicine
Patient suffers adverse effects, apparently from a medicine
Patient reports problem to doctor or pharmacist or nurse OR patient reports
directly to the local or national pharmacovigilance centre
(UMC’s Take&Tellmay help)
The problem is discussed with the health professional; possible causes are
examined:
• Possibility of misdiagnosis
• Interactions with other medicines or foods or substances
• Non-adherence to advice for taking the medicine (missing doses, doubling
up doses, wrong time of day, before or after food)
• Source and quality of medicine (is it genuine, counterfeit, sub-standard?)
Decision is made about what to do for the patient (maybe change dose or
frequency or medicine)
Doctor, pharmacist or nurse reports problem to the local or national
pharmacovigilance centre (spontaneous reporting)
The centre reviews the problem and any other reports about the drug (may
also look at international data in WHO’s VigiBase)
The centre advises the national regulatory authority if the evidence
suggests there is a problem
The regulatory authority may decide to take action*
The centre, in countries that are members of the WHO Programme for
International Drug Monitoring, notifies WHO through UMC
UMC reviews the international data about the drug; if there seems to be a
plausible link between the medicine and the adverse effect, UMC
communicates its assessment of the problem as a signal to member countries
and WHO.
Regulatory authorities around the world decide if action* should be taken.
If action is taken, information is published and made available to health
professionals and patients.

The processes in the cycle may involve consultations among local, national
or international colleagues and experts, manufacturers and members of the
WHO Programme.

*Possible action: changing published information about the benefit-harm

profile or other aspects of the medicine; restricting or amending the way it is
used; withdrawing it from the market (very rare). Sometimes further research
may be commissioned. Other causes of adverse effects (e.g. counterfeit
medicines) may result in communications to patients or health professionals,
public warnings, alerts, prosecutions or other measures.