FUNDAMENTALS OF

PHARMACOVIGILANCE
Pharmacovigilance

• The process of monitoring, evaluating and improving the safety of

medicines. It is carried out by pharmaceutical companies on their
products and by government agencies on all medicinal products.
Also, the science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other drug-
related problems (WHO).
 Adverse Drug Reaction (ADR)

• A response to a medicinal product which is noxious and unintended

and which occurs at doses normally used in man for the prophylaxis,
diagnosis or therapy of disease or for the restoration, correction or
modification of physiological function. A causal relationship
between the medicinal product and an AE should at least be a
reasonable possibility. An ADR in post-marketing situations
normally refers to ADRs occurring at therapeutic doses, but for the
purposes of reporting any dosage should be considered.
Adverse Event (AE)
• Any untoward medical occurrence in a patient or clinical
investigation subject administered the pharmaceutical product
that does not necessarily have to have a causal relationship with
the treatment for which the product is used. An AE can therefore
be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom or disease temporally associated
with the use of the medicinal (investigational) product, whether or
not considered related to the medicinal (investigational) product.
A pre-existing condition which, worsened in severity after
administration of the product would also be considered as an
adverse event.

• For clinical studies, the definition of an Adverse Event includes any

untoward events occurring at any time after the subject’s formal
entry into the study (being after receipt of the signed informed
consent) until the follow-up period as defined in the respective
study protocol.
Annual Safety Report (ASR)

• An aggregate Safety Report in the context of clinical trials, taking

into account all newly available safety information produced during
a defined reporting period. Where several clinical trials are
conducted with the same Investigational Medicinal Product (IMP)
the reporter should include a concise global analysis of the actual
safety profile of the tested IMP based on the experience for all the
clinical trials.
Company Core Data Sheet (CCDS)
• This document is prepared by the Marketing Authorization Holder and
contains, in addition to safety information, material relating to
indications, dosing, pharmacology and other aspects of the product

• Company Core Safety Information (CCSI):

► All relevant safety information contained in the Company Core Data

Sheet prepared by the Marketing Authorization Holder and which the
Marketing Authorization Holder requires to be listed in all countries where
the company markets the product, except when the local authority
specifically requires a modification.

► It is the reference safety information (RSI) by which listed and unlisted

are determined for the purpose of periodic reporting for marketed
products, but not by which expected and unexpected are determined for
expedited reporting
 Expedited Reporting
• Notification (submission) of an ICSR in a designated format to the
appropriate Regulatory Authorities in compliance with the
parameters and timelines specified by legislation and local
regulatory guidelines. An expedited report would be an ICSR
meeting the criteria for rapid transmission to a Competent
Authority.

• Summary of Product Characteristics (SPC):

Basis of information for health professionals on how to use the
medicinal product safely and effectively
Healthcare Professional

• For the purposes of reporting suspected adverse reactions,

healthcare professionals are defined as medically qualified persons,
such as physicians, dentists, pharmacists, nurses and coroners.

• International Birth Date (IBD):

The date of the first marketing authorization for a medicinal product
granted to the Marketing Authorization Holder in any country of the
world.
• Development international birth date (DIBD):
Date of first approval (or authorization) for conducting an
interventional clinical trial in any country.
• Individual Case Safety Report (ICSR)
A report received by a company or agency which describes an adverse
event.
►A document providing the most complete information related to an
individual case at a certain point of time.
►An individual case is the information provided by a primary source to
describe suspected adverse reaction(s) related to the administration of
one or more medicinal products to an individual patient at a particular
point of time.

• Investigator Brochure (IB)

A compilation of the clinical and non-clinical data on the
Investigational Medicinal Product relevant to the study of the product
in humans.

• Data Lock Point (DLP):

The date designated as the cut-off date for data to be included in a
aggregate Report.
• Consumer
A person who is not a healthcare professional such as a patient,
lawyer, friend or relative/ parents/ children of a patient.

• Investigational Medicinal Product (IMP)

A pharmaceutical form of an active substance or placebo being tested
or used as a reference in a clinical trial, including products already
with a marketing authorization but used or assembled in a different
way from the authorized form, or when used for an unauthorized
indication, or when used to gain further information about the
authorized form.

• Periodic Safety Update Report (PSUR):

Periodic summary of safety information for regulators, including any
changes in the risk-benefit relationship for an approved drug,
prepared by the Marketing Authorization Holder
• Marketing Authorization (MA)
The approval granted by the Regulatory Authority to market a
specific product in a particular country

• Marketing Authorization Holder (MAH)

The company named on the Marketing Authorization for a specific
product in a particular country.

• Medicinal Product
A substance or combination of substances presented as having
properties for treating or preventing disease in human beings; or a
substance or combination which may be used in or administered to
human beings either with a view to restoring, correcting or
modifying physiological functions by exerting a pharmacological,
immunological or metabolic action, or to making a medical
diagnosis
• Non-interventional Trial
A study where the medicinal product is prescribed in the usual
manner in accordance with the terms of the marketing
authorization. The assignment of the patient to a particular
therapeutic strategy is not decided in advance by a trial protocol
but falls within the current practice and the prescription of the
medicine is clearly separated from the decision to include the
patient in the study. No additional diagnostic or monitoring
procedures shall be applied to the patients and epidemiological
methods should be used for the analysis of the collected data.

• Post-authorization Study
A clinical study conducted within the conditions of the approved
Summary of Product Characteristics or under normal conditions of
use. A post-authorization study may also be a Post-authorization
safety study (PASS).
• Spontaneous Report
An unsolicited communication by a regulatory authority,
healthcare professional, consumer or other person that describes
an ADR/AE in a patient administered the Product and which does
not derive from a study or any organized data collection scheme.

• Unexpected Adverse Reaction:

An ADR whose nature, severity, specificity, or outcome is not
consistent with the Summary of Product Characteristics (SPC).

• Unlisted Adverse Reaction:

An ADR that is not specifically included as a suspected adverse
effect in the Company Core Safety Information (CCSI). This includes
an adverse reaction whose nature, severity, specificity, or outcome
is not consistent with the CCSI.
 Main aims of Pharmacovigilance
• To identify the unknown ADRs and calculate their incidence;

• To have more and better information on known ADRs, and to

calculate the incidence of serious and non serious ones;

• To evaluate the risk-benefit balance of a drug in comparison with

other drugs, for the same indication or for other kinds of treatment;

• To communicate adequately the risk and to improve the clinical

practice
 Product Registration
A marketing authorization for a medicinal product in more than one
Member State in the EU must be sought via one of three procedures.

1. Centralized Procedure

2. Mutual Recognition Procedure

3. Decentralized Procedure
 Centralized Procedure

• Administered by the EMEA.

• Consists of one application which, if approved, grants marketing
authorization for all countries within the European Union (and the
European Economic Area, i.e. the EU countries plus Iceland, Norway
and Liechtenstein).
• To all new, or innovative pharmaceuticals, and is obligatory for
biotechnology medicines.
• For products containing new substances for which the therapeutic
indication is the treatment of serious disease.
 Mutual Recognition Procedure

• The marketing authorization in one Member State, the ‘Reference

Member State’, is “mutually recognized” by other ‘Concerned
Member States.’

• There is a 90 day assessment period after which Member States

grant a marketing authorization with an identical summary of
product characteristics to that in the Reference Member State,
provided that they accept the assessment of the product
 Decentralized Procedure

• This applies where an authorization does not yet exist in any of the
Member States.

• Identical dossiers are submitted in all Member States where a

marketing authorization is sought.

• A Reference Member State, selected by the applicant, prepares a

preliminary assessment report within 120 days and sends it to the
Concerned Member States
• Good Pharmacovigilance practices (GVP) for the European Union:

A set of guidelines for the conduct of Pharmacovigilance in the EU,

drawn up based on Article 108a of Directive 2001/83/EC, by the
Agency in cooperation with competent authorities in Member States
and interested parties, and applying to marketing authorization
holders in the EU, the Agency and competent authorities in Member
States.

• Important missing information:

Critical gaps in knowledge for specific safety issues or populations

that use the marketed product.
• Identified risk:

An untoward occurrence for which there is adequate evidence of an

association with the medicinal product of interest. Examples include:
• an adverse reaction adequately demonstrated in non-clinical
studies and confirmed by clinical data;
• an adverse reaction observed in well-designed clinical trials or
epidemiological studies for which the magnitude of the difference,
compared with the comparator group on a parameter of interest
suggests a causal relationship;
• an adverse reaction suggested by a number of well-documented
spontaneous reports where causality is strongly supported by
temporal relationship and biological plausibility, such as anaphylactic
reactions or application site reactions (see ICH-E2F Guideline, Volume
10 of the Rules Governing Medicinal Products in the EU).
• Important identified risk and Important potential risk:

An identified risk or potential risk that could have an impact on the

risk-benefit balance of the product or have implications for public
health (see ICH-E2F Guideline, Volume 10 of the Rules Governing
Medicinal Products in the EU).
What constitutes an important risk will depend upon several factors,
including the impact on the individual, the seriousness of the risk,
and the impact on public health. Normally, any risk that is likely to be
included in the contraindications or warnings and precautions
section of the product information should be considered important.