2. Introduction.
Definitions.
Aim and objectives
Adverse event reporting.
International collaboration in pharmacovigilance.
National and regional drug regulatory authorities.
Pharmacoenvironmentology.
Pharmacovigilance of Medical Devices.
Pharmacovigilance of Herbal Medicines.
4. 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 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.
ADR, is 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 function).
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 adverse event itself),
because they may result in an ADR.
5. 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 organized 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.
6. Dechallenge and Rechallenge refer to a drug being stopped and restarted in a patient,
respectively. A positive de-challenge has occurred, for example, when an adverse event abates
or resolves completely following the drug's discontinuation. A positive re-challenge has
occurred when the adverse event re-occurs after the drug is restarted. De-challenge and re-
challenge 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.
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 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.
7. 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 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.
8. 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).
9. Aim:-
To identifying new information about hazards as associated with
medicines
Objective:-
Improve patient care and safety
Improve public health and safety
Encourage safe, rational and appropriate use of drugs
Promote understanding, education and clinical training in
pharmacovigilance
10. ADVERSE EVENT REPORTING
What information should be reported ?
1) On ADRs occurring
in the course of the use of a drug.
from drug overdose whether accidental or intentional.
from drug abuse / misuse / non-approved use.
from drug withdrawal.
in the infant or a nursing mother.
possibly as a result of exposure of the mother or the fetus during pregnancy.
2) Even if no ADR has been observed
from drug overdose whether accidental or intentional.
from drug abuse / misuse / non-approved use.
from drug administration during pregnancy.
11. SERIOUS ADR (Adverse Drug Reactions).
Any ADR occurring at any dose which fulfills one of the following criteria:
1. Results in death.
2. Is life threatening.
3. Requires inpatient hospitalization or prolongation of existing hospitalization.
4. Results in persistent or significant disability/incapacity.
5. Is a congenital anomaly or birth defect.
6. Is an important medical event.
12. 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.
Identifiable”
Patient/reporter does not need to be identified at time of report but is identifiable
if some effort is taken.
13. If one or more of these four elements is missing, the case is not a valid AE report. 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.
14. 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 trade names.
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.
15. Coding of Adverse Events
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.
16. 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). Within clinical trials such a cases is referred to as a
SUSAR (a Suspected Unexpected Serious Adverse Reaction).
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.
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.
17. 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.
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
programs 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
18. 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.
Signal Detection
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.
19. Risk Management Plans
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.
20. PHARMACOENVIRONMENTOLOGY
Despite receiving attention and necessary action by regulatory agencies like FDA and the European
Union, there is a lack of substantial procedures regarding impending monitoring of drug
concentrations in the environment and the palpable adverse effects.
In 2006 a new concept of pharmacovigilance in environmental pharmacology, entitled as
'Pharmacoenvironmentology' was suggested by Syed Ziaur Rahman.
It is a form of pharmacovigilance which deals specifically with those pharmacological agents that
have impact on the environment via elimination through living organisms subsequent to
pharmacotherapy.
21. PHARMACOVIGILANCE OF MEDICAL DEVICES
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.
Given the inherent difference between medicinal products and medical products, the pharmacovigilance
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.
22. PHARMACOVIGILANCE OF HERBAL MEDICINES
The safety of herbal medicines has become a major concern to both national health authorities and the
general public.
The use of herbs in Traditional medicines continues to expand rapidly across the world. Many people
now take herbal medicines or herbal products for their health care in different national health-care
settings.
However, mass media reports of adverse events with herbal medicines can be incomplete and, therefore,
misleading regarding the use of herbal medicines.
Nevertheless, it can be difficult to identify the causes of adverse events since the amount of data is
generally less than with more traditional medicines since the requirements for adverse event reporting is
far less stringent with herbal medications than it is with more traditional medicines
