Pharmacovigilance

Definition:
Pharmacovigilance (abbreviated 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. The word "pharmacovigilance" derived
from : pharmakon (Greek for drug) and vigilare (Latin for to keep watch).
Terms commonly used in drug safety
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 (ADR) is a side effect occurring with a drug where a positive
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 Rechallengerefer 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 an adverse event.
• Harm is the nature and extent of the actual damage that could be 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 Study 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 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 2b.
• 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.
• 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 postmarketing 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
DOTS classification
Adverse Event Reporting
• The activity that is most commonly associated with Pharmacovigilance, 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 postmarketing 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:
• The "4 Elements" of an AE case One of the fundamental principles of adverse event
reporting is the determination of what constitutes an adverse event case. During
the triage phase of a potential adverse event report, the triager must determine if
the "four elements" of an AE case are present.
1. an identifiable patient
2. an identifiable reporter
3. a suspect drug
4. an adverse event
Seriousness Determination
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;
2. is life-threatening;
3. requires inpatient hospitalization or prolongation of existing hospitalization (out-patient
treatment would not necessarily be serious);
4. results in persistent or significant disability or incapacity;
5. results in a congenital anomaly (birth defect); or is
6. "medically significant" - does not meet any of the preceding criteria, but is considered
serious because treatment or intervention would be required to prevent one of the
preceding criteria.

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.
Expedited Reporting
This refers to ICSRs that involve a serious and unlabelled 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 timeframe for reporting expedited cases from the time a drug company receives
notification (referred to as "Day 0") of such a case is 15 calendar days. Within clinical trials such a
cases 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, unlabelled event may be subject to non-expedited or periodic reporting.

Clinical Trial Reporting

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
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. 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.
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 recognised as a possible
side effect of a particular drug. In addition, medical personnel may not feel compelled to report events
that are viewed as expected. This is why reports from patients themselves may be of value, although the
confirmation of these events by a healthcare professional is typically considered to increase the value of
these reports.
Aggregate Reporting
Aggregate, or 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). 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

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.
Risk Management
Risk Management is the discipline within Pharmacovigilance that is responsible for
signal detection and the monitoring of the risk-benefit profile of drugs. Other key
activities within the area of Risk Management are that of the compilation of Risk
Management Plans (RMPs) and aggregate reports such as the Periodic Safety Update
Report (PSUR), Periodic Benefit Risk Evaluation Report (PBRER), and the Development
Safety Update Report (DSUR).

Causality Assessment
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 usually
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.