Pharmacovigilance Overview

Sivasankaran V
Clinical Research Professional
Bangalore

What is Pharmacovigilance?
 "The science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects or any other drug-
related problem."

Why it is essential?
 It is an essential component of patient care and
rational use of medicines.
 It is also variously referred to as adverse drug
reaction monitoring, drug safety surveillance,
side effect monitoring, spontaneous reporting,
post-marketing surveillance or variations of these.
 Pharmacovigilance involves the safety monitoring of
all medicines including herbal and complementary
remedies, vaccines and biological substances.

Harm related to use of medicines
 The information obtained during clinical trials of new drugs is by design
insufficient to provide a comprehensive overview of its safety and effectiveness
in routine clinical practice (limitations of pre-licensure clinical studies include
short duration, small numbers of patients, exclusion of patients with other
diseases, exclusion of pregnant women, infants and the elderly).The long-term
safety of a medicine is thus only known when the drug is being used widely in a
population and its safety is being monitoring by organized local, national and
international efforts.
 Many adverse drug reactions (ADRs) are preventable and a good knowledge of
pharmacology, good prescribing practices and the provision of simple tools and
facilities would reduce drug-related morbidity and mortality in humans.
However, there are some ADRs which are unknown, unpredictable and not
preventable though an understanding of the characteristics of patients likely to
suffer such ADRs may help in reducing their occurrence. The ultimate safety
decisions on medicines may need considerations of comparative benefit/risk
evaluations between products for similar indications, so the complexity is great


Pharmacovigilance Methods
 Several methods can be used to collect safety
information.
1. Spontaneous reporting forms the bedrock of
all national pharmacovigilance systems.
 It is relatively inexpensive and provides a life-time
monitoring of all medicines in all patients in any
healthcare system.
2. Active patient follow-up
e.g. Cohort Event Monitoring (CEM) that maybe
useful when addressing specific research or
pharmacovigilance queries.

Pharmacovigilance methods are given below (adapted
from the ICH E2E Guidelines):
 Passive surveillance
 Spontaneous Reporting
 Case series
 Active Surveillance
 Sentinel sites
 Drug Event Monitoring
 Registries
 Stimulated Reporting

Pharmacovigilance methods
 Comparative Observational Studies
 The Non-experimental traditional epidemiologic methods are
a key component in the evaluation of adverse events. A
number of observational study designs are useful in
validating signals from spontaneous reports or case series.
Major types of these designs are:
1. Cross sectional study
2. Case control study
3. Cohort study (both retrospective and
prospective)
 Others
 Targeted Clinical Investigation
 Descriptive studies

E2A - E2F Pharmacovigilance
CodeDocument TitlePreviously codedE2E Pharmacovigilance Planning , Finalised Guideline: November 2004
• E2E Concept Paper
 Description:
 The tripartite harmonised ICH Guideline was finalised under Step 4 in November 2004. This Guideline is
intended to aid in planning pharmacovigilance activities, especially in preparation for the early
postmarketing period of a new drug (in this Guideline, the term "drug" denotes chemical entities,
biotechnology-derived products, and vaccines). The main focus of this Guideline is on a Safety
Specification and Pharmacovigilance Plan that might be submitted at the time of licence application.
 Implementation:Step 5
 EC, Europe - Adopted by CHMP, 1 December 2004, issued as CPMP/ICH/5716/03.Coming into
operation in June 2005
 MHLW/PMDA, Japan - Adopted 16 September 2005, PFSB/ELD Notification No. 0916001 & PFSB/SD
Notification No. 0916001
 FDA, United States - Published in the Federal Register, 1 April 2005, Vol. 70, No. 62, p. 16827-16828
 Health Canada, Canada - Implemented 16 February 2009, File #: 09-103644-626
 Swissmedic, Switzerland - Refer to the press release on Swissmedic, Switzerland's website

What are the functions of a National
Pharmacovigilance System?
 The minimum functions of a national pharmacovigilance (PV) system have been defined to include the following:
 1. To promote PV in the country, collect and manage adverse drug reaction (ADR) reports as
well as reports of medication errors and suspected counterfeit/substandard drugs
 2. To collaborate and harmonize with other ADR collection activities within the country
(e.g. national disease control programmes, poison control centres, etc.) as well as international
monitoring of ADRs in cohorts of defined patients
 3. To identify signals of drug safety, i.e. unknown or poorly characterized adverse events in
relation to a drug or drug combination and/or its use
 4. To undertake assessment of risk and options for risk management
 5. To identify if there are quality problems in medicines resulting in ADRs; and more
generally, support the identification of medicine quality issues

What are the functions of a
National Pharmacovigilance
System?
 6. To provide effective communication on aspects related to drug
safety, including dispelling unfounded rumors of toxicity attributed to
medicines and/or vaccines
 7. To apply information from pharmacovigilance for the
benefit of public health programmes, individual patients and
national medicines policies and treatment guidelines
 8. To develop and maintain drug utilization information
 9. To identify issues associated with unregulated prescribing and
dispensing of medicines.

Minimum requirements for a
functional PV System
 Pharmacovigilance activities may be undertaken by several organisations, individuals and agencies. In most countries,
the national system is organized and coordinated by the Ministry of Health or one of its agencies, typically the
National Medicines Regulatory Authority. In some countries, it is undertaken by academic institutions, by hospitals or
by independent legally-recognised organisations. The core minimum requirements that should be present in any
funtional national pharmacovigilance system as follows:
01. A national PV center
 A national pharmacovigilance center with designated staff (at least one full-
time), stable basic funding, clear mandates, well defined structures and roles
and collaborating with the WHO Programme for International Drug
Monitoring
02. A national spontaneous reporting system
 The existence of a national spontaneous reporting system with a national
individual case safety report (ICSB) form i.e. an adverse drug reaction (ADR)
reporting form
03. A national database
 A national database or system for collating and managing ADR reports

Minimum requirements for a
functional PV System
04. PV Advisory Commitee
 A national ADR or pharmacovigilance advisory commitee able to provide
technical assistance on causality assessment, risk assessment, risk
management, case investigation and, where neccessary, crisis management
including crisis communication
05. Communications strategy
 A clear strategy for routine and crisis communications

Reporting of Adverse Drug
Reactions (ADRs)
Spontaneous reporting is currently the most common method of reporting ADRs.
A case report in pharmacovigilance can be defined as:
“A notification relating to a patient with an adverse medical event (or laboratory test
abnormality) suspected to be induced by a medicine”
A case report should (as a minimum) contain information on:
1.The patient: age, sex and brief medical history (when relevant). In some countries ethnic origin may
need to be specified.
2. Adverse event: description (nature, localization, severity, characteristics), results of investigations
and tests, start date, course and outcome.
3. Suspected drug(s): name (brand or ingredient name + manufacturer), dose, route, start/stop dates,
indication for use (with particular drugs, e.g. vaccines, a batch number is important).
4. All other drugs used (including self-medication): names, doses, routes, start/stop dates.
5. Risk factors (e.g. impaired renal function, previous exposure to suspected drug, previous allergies,
and social drug use).
6. Name and address of reporter (to be considered confidential and to be used only for data
verification, completion and case follow-up).
 Special free-post or business reply reporting forms, containing questions 1-6 mentioned above, can be
distributed to healthcare professionals at regular intervals (for example, four times a year). Reply-paid
reporting forms may be included in the national formulary, drug bulletin or professional journals.
Also telephone, fax and electronic mail or internet may be easy means of reporting where reliable

SAMPLE SPONTANEOUS REPORTING FORM
SAMPLE REPORTING FORM FOR ADVERSE EVENTS (AE): □ADR □AEFI □Other
1.PATIENT IDENTIFICATION
Last name /Initials:
Record patient N°:
Sex: □ Male □ Female
Trimester:_______(if pregnant)
Breast-feeding: □Yes □ No
Date of Birth: _ _ /_ _ /_ _ _ _ OR Age at onset: _ _ Years _ _ Months _ _ _Days
Weight (kg) ___ Height (cm) ___
2. ADR(s)/AEFI(s) details Describe the reaction(s) symptoms
Outcome
Recovering □
Recovered □
Recovered □
with sequelae
Not recovered □
Death □
Date of death:
_ _ /_ _ /_ _ _ _
Date and time of treatment/vaccination:
_ _ /_ _ /_ _ _ _ _ _ □ am □ pm
Date and time AE(s) started:
_ _ /_ _ /_ _ _ _ _ _ □ am □ pm Date AE(s) stopped: _ _ /_ _ /_ _ _ _
Autopsy: □Yes □ No
Do you consider the reaction(s) to be serious? □ Yes □ No
If yes, please indicate why the reaction is considered to be serious (tick all that apply and describe if necessary)
□ Life threatening □ Involved or prolonged hospitalization □ Involved persistent or significant disability
□ Disability □ Congenital anomaly □ Other important medical event: ……………………………….
Describe here:
3. ACTION TAKEN and TREATMENT GIVEN
Action taken:
□ Drug withdrawn □ Dose reduced □ Dose increased □ Dose not changed □ Unknown □ Not applicable
Further Action Taken:
□ Frequency reduced □ Infusion rate reduced □ Medical record documented □ Patient counselled
□ Therapy changed □ Therapy not changed □ No treatment required for the AE □ Prescriber notified
□ Supportive treatment necessitated (if yes, describe below)
Treatment given:
4. SUSPECTED PRODUCT(s) DETAILS: □ Medicine □ Vaccine □ Other:
Product Name Batch/Lot
number
Diluent
Batch/Lot
number
Route Dosage/Unit Dose
(1st
,
2nd
…)
Date
treatment
started
Date
treatment
stopped
Indication
_ _ /_ _ /_ _ _ _ _ _ /_ _ /_ _ _ _
_ _ /_ _ /_ _ _ _ _ _ /_ _ /_ _ _ _
_ _ /_ _ /_ _ _ _ _ _ /_ _ /_ _ _ _
5. CONCOMITANT PRODUCT(s) and MEDICAL HISTORY:
Did the patient take any other Medicine/Vaccine/Other remedies (including traditional medicines, cosmetics etc.) in the last 3 months
prior to reaction? □ Yes □ No
If yes, provide additional relevant information (Name, prescribed for, batch, dosage, treatment dates, etc.)
6. FIRST DECISION MAKING (For Healthcare Professionals)
Investigation needed: □Yes
□ No
If yes, please describe investigation planned:
7. REPORTER’S INFORMATION (Who is reporting?) □ Patient □ Health Care Professional □ Other:
Reporter’s Name: Date reported: _ _ /_ _ /_ _ _ _ Institution:
Address: Profession:
E-mail address: Telephone:
8. NATIONAL PHARMACOVIGILANCE CENTRE (to complete):
Date report received at National level: _ _ /_ _ /_ _ _ _ Worldwide unique ID:
Received by: Comments:

Spontaneous ADR reporting
methods
 Different countries have different ways of collecting
spontaneous reporting forms; ultimately it depends on
the available resources. Some of these methods
include;
 Online reporting into a national database
 Smartphone apps
 Visiting regulatory centres to file reports
 Telephone calls
 Scanning/faxing of ADRs

Data
 Data
 It is possible to receive millions of adverse drug reaction reports. This represents a huge chunk of data,
which can be analyzed to find both new and already existing relationships. It is also important, as a
pharmacovigilance centre to constantly do research.
 Pharmacovigilance is an interesting and ever changing field; new topics are being discussed and
innovative methods are frequently introduced into the field. This is why constantly updated data should
be an essential part of any pharmacovigilance centre’s activities.
Data sources
 HERE YOU CAN FIND A USEFUL LIST OF
 “data sources for your pharmacovigilance activities“
 DOWNLOAD
Data Analyses
Individual case assessment
 The establishment of relationship between medicine intake and occurrence of adverse events is an
important activity in pharmacovigilance. Different national pharmacovigilance centres have different
procedures for carrying out case causality assessment, driven sometimes by differing philosophies on
the need for and importance of case causality assessment. The material below is reproduced from the
WHO Manual “A practical handbook on the pharmacovigilance of antiretroviral medicines” authored
by Dr. David Coulter, formerly Director of the Intensive Medicines Monitoring Programme in New
Zealand (WHO, 2009).
Background
 Establishing causality or a relationship between a drug and an adverse event involves two basic
questions. These questions need to be addressed separately:
 Is there a convincing relationship between the drug and the event?
 Did the drug actually cause the event?
 READ MORE

Data Analyses Data Analyses
Individual case assessment
 The establishment of relationship between medicine intake and occurrence of adverse events is an important activity in pharmacovigilance.
Different national pharmacovigilance centres have different procedures for carrying out case causality assessment, driven sometimes by
differing philosophies on the need for and importance of case causality assessment. The material below is reproduced from the WHO Manual
“A practical handbook on the pharmacovigilance of antiretroviral medicines” authored by Dr. David Coulter, formerly Director of the Intensive
Medicines Monitoring Programme in New Zealand (WHO, 2009).
Background
 Establishing causality or a relationship between a drug and an adverse event involves two basic questions. These questions need to be
addressed separately:
 Is there a convincing relationship between the drug and the event?
 Did the drug actually cause the event?
 Objective and subjective assessments

The objective phase
 This takes into account actual observations and establishes the relationship.
 The subjective phase
 This is the process of making an attempt to establish a firm opinion about causality in those events for which a close relationship has
been established. It takes into account the plausibility of the drug being the cause of the event, after having considered the (known)
pharmacology, other experience with the medicine or related medicines, and inferences made from epidemiological observations and
statistical evaluations.
 General understanding of causality/relationship assessment
 Establishing causality is a process which begins by examining the relationship between the drug and the event. The relationship in a
single case-report can be established by checking the way in which the diagnosis has been reached with positive reasons supporting the
diagnosis with the drug as a cause, and the exclusion of other possible causes. It may not be possible to establish a firm opinion on
causality until a collection of such reports is assessed or new knowledge is gained. The ultimate goal of assessment of each event, or a
cluster of events being treated as a signal, is an answer to the question:
 Did the drug cause the event(s)? Yes or no?
 Causality for individual reports, even those with a close relationship, can seldom be established beyond doubt and our assessments are
based on individual case probability, the increasing support of a case series and then controlled observational or even interventional
studies.
 A causality assessment should be seen as provisional and subject to change in the light of further information on the case, or new
knowledge coming from other sources.

Data Analyses
 General understanding of causality/relationship assessment
 Did the event begin before the patient commenced the medicine? This may seem
an obvious consideration, but reports are received in which this has not been
taken into account, and a careful check has then revealed that the event preceded
the use of the suspect medicine and therefore there was no relationship.
 Is there any other possible cause for the event?
 Could the event be due to the illness being treated?
 Could it be due to some other co-existent disease?
 Could it be due to some other medicine being used concurrently?
 Is the duration to onset of the event plausible?
 Is the event likely to have occurred in the time frame in question?
 Did it occur too quickly to be related to the particular medicine, taking into
account its pharmacological action?
 Did the patient take the medicine for a long time without any problems? (Delayed
reactions after long-term exposure does occur, but most reactions will occur soon
after the patient starts to take the medicine.)
 The nature of the event should be considered when assessing the significance of
the period of exposure, for example:
 some events take a long time to develop (e.g. cancer);
 some develop quickly (e.g. nausea and headache);
 allergic reactions to first-time exposure to a drug generally take around 10 days to
appear. On repeat exposure they may occur immediately.
 did the event occur after the commencement of some other medicine?

Data Analyses
 If the event began shortly after commencing another medicine, then two possibilities should be
considered: The new medicine may have caused the event or there may have been an interaction
between the two drugs and the interaction caused the event.
 Did the event occur after the onset of some new illness? If so, the event may be due to the new illness.
 What is the response to withdrawal of the medicine (dechallenge)?
 Did the patient recover?
 Did the patient improve?
 Was there no change?
 Did the patient get worse?
 Is the response to dechallenge unknown? If this is the case, then it should always be recorded as
unknown.
 If more than one medicine has been withdrawn, and if rechallenge is considered appropriate, it
should be performed with only one medicine at a time.
 What is the response to rechallenge?
 Conditions for a positive rechallenge are:
 the patient recovered on initial withdrawal;
 the patient developed the same problem again when re-exposed to the same medicine alone, although it
may be of different severity;
 the patient recovered when the medicine was withdrawn once again;
 It should be noted that it is not always safe to subject the patient to a rechallenge; if the response to
rechallenge is unknown, this should be recorded.
 Categories of relationship:
 The WHO International Drug Monitoring Programme uses six standard categories of relationship or
causality between a drug and an adverse reaction or event. These are:

Methods of Signal Detection
 The identification of signals in the national pharmacovigilance (PV) centre’s database, or
another database, of adverse events or suspected adverse reactions requires careful
review of individual reports and events.
 Careful, informed, routine, systematic and standardized clinical review of the Centre’s
reports with the recording and appropriate collation of good data provides the quickest
and most satisfying way of identifying previously unsuspected adverse reactions.
Following through the whole process from relationship assessment, to signal
identification, to signal strengthening, to communicating the findings is essential.
 It is important to stress that new pharmacovigilance systems may have very few reports
and may not be able to detect signals using statistical methods, but may be able to do
case by case signal detection. PV centres should follow closely what is going on in other
centres and also rely on the WHO Pharmaceuticals Newsletter and the signal document
prepared by the WHO Collaborating Centre for International Drug Monitoring, UMC to
keep abreast of signals that may be of importance to them. International collaboration is
key to both signal identification and signal strengthening, and should be encouraged.
 What is a Signal
 A signal is defined as “Reported information on a possible causal relationship between an
adverse event and a drug, the relation..
 READ MORE
 Methods of Signal Identification
 Careful, routine, standardized clinical assessment of individual reports with alertness to
the possibility of a signal, offers..
 READ MORE
 Data-mining of large databases
 Data Mining has been described as “any computational method used to automatically and
continuously extract...

Methods of Signal Detection
What is a signal
 In 1991, the WHO defined a signal as “Reported
information on a possible causal relationship between an
adverse event and a drug, the relationship being unknown
or incompletely documented previously”. Other definitions
have since emerged from other scholars and publications.
The Council for International Organizations of Medical
Sciences (2010) defines a signal as “Information that arises
 from one or multiple sources (including observations or
experiments), which suggests a new, potentially causal
association, or a new aspect of a known association
between an intervention [e.g., administration of a
medicine] and an event or set of related events, either
adverse or beneficial, that is judged to be of sufficient
likelihood to justify verificatory action” Ultimately, a signal
is a hypothesis.

Methods of Signal Identification
Methods of Signal Identification
There are essentially 2 methods by which signals can detected;
 1. Case by case (qualitative signal detection) for individual reports
 2. Statistical methods (Quantitative) for large databases
 3. Clinical assessment of individual events
 Careful, routine, standardized clinical assessment of individual reports
with alertness to the possibility of a signal, offers the quickest method
of identifying signals. This approach should be taken during routine
review of incoming reports. During routine assessment of reports, if an
assessor identifies an event and thinks that it could be a new type of
adverse reaction, a search should be undertaken for records of other
similar events to confirm the opinion. First, the national or WHO
global database for Individual Case Safety Report (ICSR) should be
checked for other similar reports or clinically related terms. Then the
adverse reaction should be checked in appropriate reference sources. If
there is no reference to the occurrence of the event as an adverse
reaction, then the PV Centre should proceed with its investigation.
 4.Clinical review of collated events

4.Clinical review of collated events
 4. Clinical review of collated events
01. Regular review
All the events in the database for the drug(s) of interest (or
class of drugs) should be reviewed at regular intervals e.g.
each month.
02. Clinical presentation
This is facilitated by collating (sorting) the events by
means of a computer programme into a clinically
orientated structure so that the overall clinical picture of
events occurring with the drug or regimen can be viewed.
This is accomplished by sorting the event terms by the
events dictionary codes.

-4.Clinical review of collated
events
03. Collating the events
 After assessment, individual events should each have a term applied to
it that is selected from the events dictionary. Most dictionary terms
e.g. MedDRA, are coded in such a way that clinically related events can
be sorted to appear together. The events can then be printed out or seen
on the computer monitor in a systematic clinical structure.
 Groups of related events are then seen clearly. For instance, for the
investigation of cardiac failure as a possible signal, all possibly related
events and conditions that might be associated with heart failure
should be considered together. These would include cardiac failure
aggravated, cardiac failure right, congestive heart failure, cardiac failure
left, dyspnoea (assessed as of cardiac origin), peripheral oedema,
jugular venous pressure increased, cardiomegaly, cardiomyopathy and
heart valve disorders. The whole group of events should then be taken
into consideration.

Data Mining of Large Databases
 Data Mining has been described as “any computational method used
to automatically and continuously extract useful information from
large amounts of data”. It is an important aspect of the knowledge
discovery from data (KDD) process. Many use the expression “finding a
needle in a haystack” to describe this activity. In pharmacovigilance,
data mining is very significant in detecting Adverse Drug Events. Many
established drug regulatory agencies use data mining techniques to
detect ADEs. Case by case becomes difficult when you have large data,
as you cannot assess thousands of cases every day; hence statistical
methods have been developed to identify ADR-drug pairs that occur
more frequently that you would expect Examples of include:
- Association of pericarditis with practolol and not other β-blockers
 Association of captopril and other angiotensin converting enzymes
with cough
 Association of terfenadine with heart rate and rhythm disorders.

01. Useful Databases for Data Mining
 It is important to note that choosing a database is highly dependent on
the PV centre and its specific resources. New PV centres may not
necessarily have a large repository of data to choose from, but ideally, a
dataset size is dependent on the data quality, the background
frequency of the event and the strength of the association of the event
with the drug. Some useful databases include:
02. Spontaneous reporting databases:
 WHO global database for ICSRs ,Vigibase is the largest database of its
kind in the world, and to date (October 2018), it holds over 18 million
reports of suspected adverse effects of medicines, submitted, since
1968, by the over 150 member countries of the WHO Programme for
International Drug Monitoring.
03. Other sources of data:
 Electronic medical records
 Prescription event monitoring and Claim database

-Data-mining techniques
Data-mining techniques
 Some examples of data mining techniques include Clustering or database
segmentation, predictive modelling, deviation detection etc. Currently in
pharmacovigilance, “disproportionality analysis” is the common technique
used by most centres with large databases of at least 100,000 reports.
 Disproportionality uses all reports in the database as a background to predict
how frequently you would expect an ADR-Drug combination. The
disproportionality measure expresses the extent to which the reported ADR is
associated with the suspected drug compared with all other drugs (or a
subgroup of drugs) in the database. Under measures of disproportionality, two
methods are used; these include the common Frequentist/classical measures
and the more complex Bayesian statistics.
 The Frequentist approach involve the calculation of relative reporting ratio
(RRR), proportional reporting ratio (PRR) and reporting odds ratio (ROR)
together with certain hypothesis tests of independence to determine
association.
 The Bayesian approach uses more complex algorithms such as the Bayesian
Confidence Propagation Neural Network (BCPNN), Gamma-Poisson shrinker
(GPS), Multi-item gamma-Poisson shrinker (MGPS) and Empirical Bayesian
geometric means (EBGMs).

-Data-mining techniques
BCPNN
 The WHO Collaborating Centre for International Drug Monitoring regularly scans the WHO
global database for potential signals using its automated data mining program, the Bayesian
Confidence Propagation Neural Network (BCPNN). It uses neural network architecture to scan
incoming reports and identify unexpectedly strong dependencies between drugs and adverse
reactions. This produces the disproportionality measure known as the Information Component
(IC) value for drug–event combinations. A positive signal will have IC values that become more
significant over time as more cases are included. If the IC value is positive IC>0 for a Drug-ADR
combination, the combination is reported more frequently than expected IC values for drug-ADR
combinations using data from the WHO global database of ICSRs is available for WHO PIDM
members via the Vigilyze tool.
Proportional reporting ratios (PRR)
 This is a method that uses software to measure the proportion of reports in the database with a
particular drug–event combination and compares this proportion with that for the same event in
the reports for all other drugs combined. If the PRR for a particular drug–event combination is
significantly high, and it is not a recognized reaction, it may represent a signal.
 These automated methods can strengthen a signal identified by clinical evaluation. They may
identify signals that were missed during assessment of the reports and later review.
 Data Mining can be a complicated process that requires a high level of expertise and huge amount
of data, but it is a scientifically proven tool to detect signals at a faster and more accurate pace than
others.
 If you are interested in reading more about data mining, please look at the reference list for more
details

References for Signal detection
Edwards, R., Lindquist, M., Bate, A. and Noren, N. (2006). Data Mining in
Pharmacovigilance: A View from the Uppsala Monitoring Centre. p.Chapter 21.
 Han, J., Kamber, M. and Pei, J. (2012). Data mining. Amsterdam: Morgan
Kaufmann.
 Liu, M., Matheny, M., Hu, Y. and Xu, H. (2012). Data mining methodologies for
pharmacovigilance. ACM SIGKDD Explorations Newsletter, 14(1), p.35.
 Poluzzi, E., Raschi, E., Piccinni, C. and De Ponti, F. (2012). Data Mining
Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA
Adverse Event Reporting System (AERS). [online] Intech OpenScience.
Available at: https://www.intechopen.com/books/data-mining-applications-
in-engineering-and-medicine/data-mining-techniques-in-pharmacovigilance-
analysis-of-the-publicly-accessible-fda-adverse-event-re [Accessed 8 Oct.
2018].
 Wilson, A., Thabane, L. and Holbrook, A. (2003). Application of data mining
techniques in pharmacovigilance. British Journal of Clinical Pharmacology,
[online] 57(2), pp.127-134. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14748811 [Accessed 26 Sep. 2018].
 Witten, I. and Frank, E. (n.d.). Data mining. San Francisco, Calif.: Morgan
Kaufmann.

Introduction
 Benefit risk assessment is a vital part of the activities of any
pharmacovigilance entity. Every drug or medicinal product is bound to have
positive and negative effects, some of which may not be detected until they
have been released into the market.
 How we define “Benefits” or “Risks” varies immensely and is highly
contextual. Generally, we expect “Benefits” to contribute to an individual’s
wellbeing, whiles risk poses harm. Once ADRs are detected, it is important
that a regulatory authority makes a decision based on scientific evaluation of
the benefits and/or harms. It is a truly complex activity which requires
evaluation of a large amount of data to ensure that the benefits outweigh the
risks, upon this premise a drug can authorised for marketing or not. Ideally,
greater risk can be acceptable if the disease is fatal and there is a chance of
cure by using the treatment. However, we can only accept little risk if the
disease has a good outcome without the treatment, or if these are essential
medicines given to healthy people such as vaccines and oral contraceptives.
 The decision on making the right balance between effectiveness and risk is
not straightforward. Indeed many authorities use different methods to
regulate the system. According to the Council for International
Organizations of Medical Sciences (CIOMS), “it is a frustrating aspect of
benefit risk evaluation that there is no defined and tested algorithm or
summary metric that combines benefit and risk data and that might permit
straightforward quantitative comparisons of different treatment options,
which in turn might aid in decision making”.

balance
Models used for benefit risk balance
 In trying to shed more light on the issue, the European
Medicines Agency Committee for Medicinal Products for Human
Use (CHMP) provided a report on the various benefit-risk
assessment models and methods. The report described 2 types of
models; mainly for individual clinical trials, and general models.
Number Needed to Treat to Number Needed to Harm
 For individual clinical trials, it is possible to use the ratio
of Number Needed to Treat to Number Needed to Harm
(NNT/NNH) which is also mostly used in HTA assessments.
NNT: Number of patients who need to be treated to prevent one
additional adverse outcome
NNH: Number of patients to be treated before one experience of an
adverse treatment related outcome.

Other general models include
Principle of Threes
“The Principle of Threes” proposed by Edwards et al., in 1996 is a method which explores the
paradigms of Seriousness, Duration and Incidence with respect to the
 Disease
 Improvement produced by the drug
 Adverse effects of the drug
These various paradigms can be described using the terms below:
Other General Models
These other models use quantitative and graphical approaches and complex algorithms to
conduct benefit risk assessment. They include
 Multi criteria decision analysis (MCDA)
 The TURBO (“Transparent Uniform Risk Benefit Overview”) model
Ultimately none of these methods are cut in stone, and for any regulatory body, it is
important to ask the essential questions, obtain the necessary data and evaluate a safety
concern using the appropriate benefit risk assessment method. Benefit Risk Assessment
is highly dependent on the environment. If your country has a solid pharmacovigilance
system in place, it is possible to explore the methods discussed above.
 SHOW REFERENCES


 You can read more about all these models in the CIOMS
Working Group IV Report on Benefit-Risk Balance for Marketed Drugs: Evaluating Safety Signals

References

Caster, O. (n.d.). Benefit-Harm Assessment. [online] Pdfs.semanticscholar.org. Available
at:
https://pdfs.semanticscholar.org/presentation/3541/2a92e22c75153eb893a61b13a7e5d91f8
990.pdf [Accessed 25 Sep. 2018].
 Coulter, D. (2003). [online] Who.int. Available at:
http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/ben
efit_harm.pdf [Accessed 25 Sep. 2018].
 Edwards IR, Wilholm B-E, Martinez C. Concepts in Risk-Benefit Assessment. Drug
Safety, 1996; 15(1): 1-7
 Ema.europa.eu. (2007). Report Of the CHMP Working Group On Benefit-Risk
Assessment Models And Methods. [online] Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural
_guideline/2010/01/WC500069668.pdf [Accessed 25 Sep. 2018]
 Working CIOMS Group IV. Benefit-Risk Balance for Marketed Drugs: Evaluating safety
signals. CIOMS: Geneva, 1998.


 Every day, somewhere in the world, there are crises in
healthcare: serious or fatal unexpected adverse effects
of drugs; allegations about damage from vaccines;
outbreaks of infections in hospitals; the emergence of
resistant strains of bacteria; the discovery of sub-
standard drugs; evidence of failure to prevent harm to
patients, and hundreds more.
 No system of regulation, no hospital, public health
programme, clinic, pharmaceutical company, Ministry,
department or official is immune to the risk; crises will
happen and usually when you least expect them.

 What is a crisis
 Any event that comes to public notice and threatens the
health or safety of individuals or groups, or the
reputation or stability of
 READ MORE
 The purposes of crisis management
 Every system and organization has actual or potential
weaknesses and vulnerabilities arising from internal and
external sources.
 READ MORE

What is a crisis
What is a crisis
 Any event that comes to public notice and threatens the health or
safety of individuals or groups, or the reputation or stability of an
organization. Crises usually erupt suddenly and dramatically; they
require rapid and effective response and communications.
 Management of a crisis requires not only resolution of the crisis
event, but also very skilled management of the often intense
emotions and outrage that the public may feel.
Unexpected or not?
 Crises are generally regarded as sudden and unexpected, but many
arise from conditions where there has been a history of neglect,
carelessness or poor safety management; where warning signs and
vulnerabilities have been ignored. Many crises were long in the
making and were waiting to happen; many of these could have been
prevented or the damage they caused reduced through early
awareness, planning and action.

The purposes of crisis management
1. To prevent crises happening
2. To manage crises that happen rapidly and effectively,
minimizing damage to all parties, resolving problems
and recovering stability and credibility.

Prevention
 Every system and organization has actual or potential weaknesses and vulnerabilities
arising from internal and external sources. Every aspect of management and safety
systems, communications, data collection; staff motivation, knowledge and
commitment; quality control, supplier management, and so on, needs to be examined
for any potential failures, weaknesses or problems: what could possibly go wrong and
how can it be anticipated and prevented?
 The second aspect of prevention is being in a high state of alert for early, maybe weak
signals of problems: a handful of ADR reports; a newspaper report of patient injury;
new safety concerns emerging in another country; unexplained failure of treatment;
anything that could escalate over time into a major crisis. Bureaucracies tend to stifle
dissent and minor signs of possible trouble, sometimes leading to explosive problems
later on: when, as so often, there were early signs of problems, how can an organization
hold up its head and convincingly explain its neglect of them?
 The third element of crisis prevention is reputation. An organization that has open
communications with its audiences, conscientiously explains what it is doing at all
times, is known and trusted, will suffer far less in crisis than one that is regarded as
remote and secretive. A regulator that has thoroughly and openly communicated about
the risks of medicines and its activities will be subject to much less criticism than one
that has been defensive and distant; indeed some crises arise simply because patients,
or the media, or healthcare professionals have been kept in the dark about what is
going on and are angry and hostile when the facts eventually emerge. All organizations
need to be actively communicating with their audiences at all times; when crises
emerge, a familiar voice is more likely to be trusted, even forgiven.

A sudden batch of unexpected and serious ADRs
 This is one of the commonest causes of crisis in
pharmacovigilance for which every PV centre should plan.
The issues and relationships and communications are more
complex than in the case of fires, but the basic crisis
management process is exactly the same:
 Identify the risk: unexpected injury to patients and public
outrage
 Assess the risk: probable and serious
 Initiate preventive measures: a constant state of high alert
and attention for any evidence or allegation, however
seemingly weak, from any source, of unexpected injury or
death or other problems
 Establish procedures for rapid investigation, review,
analysis and decision-making about problems, and for
communication with all stakeholders (this may require, for
example, immediate access to pre-designated technical
experts to be sent out into the field)
 Review and rehearse procedures prior to crisis erupting.

 The following definitions are used in the WHO Programme for
International Drug Monitoring and member countries are encouraged
to utilize them. Most of these definitions have been incorporated into
guidelines issued by the ICH, EMEA and other competent national
authorities. Full details, comments and explanatory notes for these are
available in the Glossary of Terms from the Uppsala Monitoring
Centre (WHO-UMC – Public Services – Pharmacovigilance –
Definitions – Glossary of Terms in Pharmacovigilance).
 In spite of the above it is important to understand that there is a rapid
change in the scope of pharmacovigilance and its practice. The move
towards a greater patient safety focus, changes in legislation largely in
the USA and the EU, and changes in databases and technology has
caused some re-thinking of definitions. Some of this thinking is
incorporated in the article Adverse drug reactions: definitions,
diagnosis, and management[1]. Even this will be updated soon. Of
course, definitions are important so that we can converse and write
about pharmacovigilance with greater clarity each of us knowing what
the jargon means. Change upsets this so that below in italics newer
definitions are accompanied by the reasons for changes.

Pharmacovigilance
“The science and activities relating to the detection,
assessment, understanding and prevention of adverse
effects or any other drug-related problems[2].”
In line with this general definition, underlying objectives of
pharmacovigilance in accordance with the applicable EU
legislation for are:
 preventing harm from adverse reactions in humans arising
from the use of authorized medicinal products within or
outside the terms of marketing authorization or from
occupational exposure; and
 promoting the safe and effective use of medicinal products, in
particular through providing timely information about the
safety of medicinal products to patients, healthcare
professionals and the public.
 Pharmacovigilance is therefore an activity contributing to the
protection of patients’ and public health.[3]

Adverse reaction
“A response to a drug 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 modification of physiological
function.[4]“
A more recent definition is:
Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction, Adverse
effect, Undesirable effect
 “An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a
medicinal product, which predicts hazard from future administration and warrants prevention or
specific treatment, or alteration of the dosage regimen, or withdrawal of the product.[5]”
 Adverse reactions may arise from use of the product within or outside the terms of the marketing
authorization or from occupational exposure. Conditions of use outside the marketing authorization
include off-label use, overdose, misuse, abuse and medication errors.
 This definition can include medication error which is a major cause of adverse effects due to drugs, it
includes harm from counterfeit drugs, it includes accidental overdose, it includes all medicinal
products (so it includes delivery systems such as inhalers), it includes quality problems and
excipients. This definition therefore includes adverse effects from a much broader range of causes. On
the other hand the latter part of the definition focuses on the value of knowing about adverse effects:
we want to know about those we can do something about in terms of prevention, diagnosis or
treatment.
 ‘Adverse reaction’ and ‘adverse effect’ are interchangeable but adverse effect is more patient-centred,
and adverse reaction is more drug-centred.

Unexpected adverse reaction
 An adverse reaction, the nature or severity of which is
not consistent with domestic labeling or market
authorization, or expected from characteristics of the
drug.

Adverse event (AE); synonym:
Adverse experience
 Any untoward medical occurrence that may present
during treatment with a pharmaceutical product but
which does not necessarily have a causal relationship
with this treatment.
 An adverse event can therefore be any unfavourable
and unintended sign (e.g. an abnormal laboratory
finding), symptom, or disease temporally associated
with the use of a medicinal product, whether or not
considered related to the medicinal product.

Side effect
 Any unintended effect of a pharmaceutical product
occurring at doses normally used in man which is
related to the pharmacological properties of the drug.

Signal
 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 seriousness of the event and the quality
of the information.
 This is considerably outmoded as a general definition. It retains some value in
respect of signals from ‘spontaneous reports’, but it fails to include signals from
published series or from examination of health care records, laboratory
experiments, or from clinical trials or epidemiological studies. ‘Incompletely
documented previously’ is also a statement which requires interpretation. A
single definition of a Signal is very challenging, because of the different types
of information that might constitute a signal in different contexts. A basic
difficulty is: what is new? And to whom? Aronson and Hauben[6] considered
all definitions they could find and then produced a new one:
 “Information that arises from one or multiple sources (including observations
and experiments), which suggests a new potentially causal association, or a
new aspect of a known association, between an intervention and an event or set
of related events, either adverse or beneficial, which would command
regulatory, societal or clinical attention, and is judged to be of sufficient
likelihood to justify verifiable and, when necessary, remedial actions.”
 Edwards and Lindquist in, ‘First catch your signal’[7] , took a different
approach giving a more descriptive view of what a signal means and some
practical advice on an approach to signal management.
 The latest CIOMS monograph – CIOMS VIII – recently published gives a good
deal of information about current thinking on signal management. It is a
lengthy document, but it has an authoritative section on data mining in the

Serious adverse event or reaction
A serious adverse reaction is any untoward medical occurrence that at any dose:
 results in death or
 is life-threatening or
 requires in-patient hospitalization or prolongation of existing hospitalization or
 results in persistent or significant disability or incapacity or
 results in a congenital anomaly/birth defect
 To ensure no confusion or misunderstanding of the difference between the terms “serious” and
“severe”, the following note of clarification is provided:
 The term “severe” is not synonymous with serious. In the English language, “severe” is used to
describe the intensity (severity) of a specific event (as in mild, moderate or severe); the event itself,
however, may be of relatively minor medical significance (such as severe headache). Seriousness (not
severity) which is based on patient/event outcome or action criteria serves as guide for defining
regulatory reporting obligation.
 Life-threatening in this context refers to a reaction in which the patient was at risk of death at the
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if
more severe.
 Medical and scientific judgement should be exercised in deciding whether other situations should be
considered serious reactions, such as important medical events that might not be immediately life
threatening or result in death or hospitalization but might jeopardize the patient or might require
intervention to prevent one of the other outcomes listed above. Examples of such events are intensive
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization or development of dependency or abuse
 Any suspected transmission via a medicinal product of an infectious agent is also considered a serious
adverse reaction.

Spontaneous report, synonym:
Spontaneous notification An unsolicited communication by a healthcare professional or
consumer to a company, regulatory authority or other
organization (e.g. the World Health Organization, a regional
centre, a poison control centre) that describes one or more
adverse reactions in a patient who was given one or more
medicinal products and that does not derive from a study or any
organized data collection scheme.
 In this context, an adverse reaction refers to a suspected adverse
reaction.
 Stimulated reporting can occur in certain situations, such as after
a direct healthcare professional communication (DHPC), a
publication in the press or questioning of healthcare
professionals by company representatives, and adverse reaction
reports arising from these situations are considered spontaneous
reports provided the report meets the definition above.
Reporting can also be stimulated by invitation from patients’ or
consumers’ organizations to their members. Reporting made in
the context of early post-marketing phase vigilance (EPPV), e.g.
in Japan, is also considered stimulated reporting.

Pharmacovigilance Overview

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