Unit 4 pharmacovigilance (6hrs) march 13 2021

Unit 4. Pharmacovigilance (6hrs)
Berhanemeskel Weldegerima
Department of Pharmaceutics
School of Pharmacy
College of Medicine and Health Sciences
University of Gondar
aberhaneth@gmail.com
Tel: +251912024213
Fundamentals of Pharmacoepidemiology
(Phar 7041)

Presentation Outline
4.1. Background
4.2. What is pharmacovigilance?
4.3. What is adverse drug reactions?
4.4. Pharmacovigilance methods
4.5. Case-causality assessment
4.6. Data assessment in pharmacovigilance
4.7. Pharmacovigilance case studies

4.1. Background
• The thalidomide tragedy in the mid twentieth century triggered a chain of
activities that were part of a global effort to avert a recurrence.
• Australia, Canada, several European countries, New Zealand and the USA
established monitoring schemes based on reporting of suspected adverse
drug reactions (ADRs).
• This culminated in the setting up of the WHO Programme for
International Drug Monitoring.
• In the past fifty years, there has been a steady growth in the science now
known as pharmacovigilance with an exponential turn in recent years.
• In the course of this growth, various terminologies and parameters
have been introduced to enable communication and exchanges among
workers in the field.

4.1. Background
• The need for communication on drug safety has been further
endorsed in the Erice declaration.
• However, little attention has been paid to the development of indices
• which will provide a baseline and allow for an assessment or
quantification of the growth and performance of
pharmacovigilance,
• which will enable comparison within and between countries,
regions and facilities.
• Pharmacovigilance has attained the maturity and stature of a
discipline that has a significant impact on patient care and public
health.
• An effective pharmacovigilance system ensures
• the monitoring of medicines,
• their availability, and
• safe use.
• There is a need for reliable indices for
• the measurement, monitoring and assessment of the
effectiveness of pharmacovigilance systems,
• including an estimation of their impact in society.

Objectives of Pharmacovigilance
• 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
4.1. Background

Definition and Scope of pharmacovigilance
Definition
• Pharmacovigilance is defined by WHO as “the science and
activities related to the detection, assessment,
understanding and prevention of adverse drug effects or any
other possible drug-related problems”.
Scope of pharmacovigilance
• The scope of pharmacovigilance has grown remarkably in recent
times and is now considered to include the following domains:
• ADRs or events
• Medication errors
• counterfeit or substandard medicines
• lack of efficacy of medicines
• misuse and/or abuse of medicine
• interaction between medicines.

Figure: Scope of Pharmacovigilance

Products covered by pharmacovigilance
• The products under consideration go beyond conventional medicines
• It is important to have in mind the entire scope of pharmacovigilance and
spectrum of products considered during the development and use of any set
of indicators to serve as tools for their monitoring and evaluation.
Figure: Products covered by pharmacovigilance

Importance of pharmacovigilance
1. Complete safety data (especially for unexpected and
serious adverse events) can only be captured through
PV
• It cannot be captured through clinical trials which are
conducted in an “artificial environment.”
• In clinical trials
• patients are not taking any other medications
• do not have concomitant diseases
• are taking the drug short-term (during the duration
of the trials only) and
• are not part of vulnerable groups (e.g., children,
pregnant women, elderly, etc.)

2. Cannot extrapolate data from developed countries:
3. Accelerating use of new drugs in new environments, which are mostly
devoid of pharmacovigilance activities
4. Faster scale up of public health programs
• due to availability of new funding from major donors such as the
Global Fund, World Bank, PEPFAR, PMI, etc
5. New drugs are reaching developing countries in greater numbers
and more quickly
• because of new funding from several donors, including the Bill and
Melinda Gates Foundation
Importance of Pharmacovigilance
• Type of drug use is different
• Do not use the co-formulated ARVs
• Minimally use anti-TB, anti-malarial and anti-diarrhoeal drugs
• Patient genotype, phenotype, social and economic conditions are markedly
distinct
• Large number of malnourished patients
• Patients with concomitant diseases
• High rates of illiteracy and poverty, increases likelihood of inappropriate use
by pregnant women, breast feeding mothers, young children, elderly
• Large number of patients using herbal and other traditional medicines

4.2. What is Adverse Drug Reactions?
Objectives
• Definition of terms associated with Adverse
Drug Reactions (ADRs)
• Classification of ADRs

Definition of terms associated with Adverse Drug
Reactions (ADRs)
• Adverse Event (AE): 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.
• Adverse Drug Reaction (ADR): Any noxious change which is suspected to be
due to a drug, occurs at doses normally used in man, requires treatment or
decrease in dose or indicates caution in future use of the same drug.
• Therefore, an adverse drug reaction is an adverse event with a causal link to a
drug.

Drug administered
Pt. develops a new condition/symptom
ADE
Drug suspected?
Yes
Check literature
Documented ?
(for the product
Or
similar class of products)
Yes
Highly suggestive of ADR

Not documented in literature
Drug continued Drug discontinued
Worsening of symptoms Symptoms improve
(+ve dechallenge)
Drug restarted
Symptoms recur
(+ve rechallenge)
Any other possible causes?
• Concomitant therapy
• Underlying conditions

• Adverse: Untoward, unintended, possibly causing
harm (noxious)
• AE: Adverse Event, Effect or Experience
• ADE (Adverse Drug Event): An AE which happens
in a patient taking a drug
• ADR (Adverse Drug Reaction): An ADE in which a
causal association is suspected between the drug
and the event

Adverse drug events
(ADEs)
Adverse Drug
Reactions
(ADRs)
No need to have
a causal relationship
Causal relationship
is suspected/established
ADEs Vs ADRs

Classification of ADRs
Depending on….
• Onset of event: Acute (<60 minutes), Sub-acute (1-
24 hrs) and Latent (>2 days)
• Type of reaction: Type A (Augmented), B (Bizarre), C
(Chemical),D (Delayed), E (Exit), F (Familial), G (Genotoxicity),
H (Hypersensitivity), U (Un classified)
• Severity: Minor, Moderate, Severe, Lethal ADRs
• Others: Side effects, Secondary effects, Toxic effects,
Intolerance, Idiosyncrasy, Drug allergy, Photosensitivity, Drug
Dependence, Drug Withdrawal Reactions, Teratogenicity,
Mutagenicity, Carcinogenicity, Drug induced disease
(Iatrogenic)

Classification of ADRs....
Wills and brown
• Type A (Augmented)
• Type B (Bizarre)
• Type C (Chemical)
• Type D (Delayed)
• Type E (Exit/End of treatment)
• Type F (Familial)
• Type G (Genotoxicity)
• Type H (Hypersensitivity)
• Type U (Un classified)

Type A (Augmented) reactions
• Reactions which can be predicted from the known pharmacology of the
drug
• Dose dependent,
• Can be alleviated by a dose reduction
E.g.
• Anticoagulants Bleeding,
• Beta blockers Bradycardia,
• Nitrates Headache,
• Prazosin Postural hypotension.
Type B (Bizarre) reactions
• Cannot be predicted from the pharmacology of the drug
• Not dose dependent,
• Host dependent factors important in predisposition
E.g.
• Penicillin Anaphylaxis,
• Anticonvulsant Hypersensitivity

Type C (Chemical) reactions
• Biological characteristics can be predicted from the
chemical structure of the drug/metabolite
E.g.
• Paracetamol Hepatotoxicity
Type D (Delayed) reactions
• Occur after many years of treatment.
• Can be due to accumulation.
E.g.
• Chemotherapy Secondary tumours
• Phenytoin during pregnancy Teratogenic effects
• Antipsychotics Tardive dyskinesia
• Analgesics Nephropathy

Type E (End of treatment) reactions
• Occur on withdrawal especially when drug is
stopped abruptly
E.g.
• Phenytoin withdrawal Seizures,
• Steroid withdrawal Adrenocortical
insufficiency.

Classification of ADRs….
Depending on Severity
• Minor ADRs: No therapy, antidote or prolongation of
hospitalization is required.
• Moderate ADRs: Requires change in drug therapy,
specific treatment or prolongs hospital stay by at least 1
day.
• Severe ADRs: Potentially life threatening, causes
permanent damage or requires intensive medical
treatment.
• Lethal: Directly or indirectly contributes to death of the
patient.

Side effects
• Unwanted but often unavoidable, pharmacodynamic
effects that occur at therapeutic doses
• Predicted from the pharmacological profile of a drug
• Known to occur in a given percentage of drug
recipients
• E.g.
• Side effect based on therapeutic effect:
Atropine (preanaesthetic) dryness of mouth
Acetazolamide (diuretic-bicarbonate excretion)
Acidosis
• Side effect based on a different action: Promethazine
(anti-allergic) sedation
Estrogen (Anti ovulatory) Nausea

4.3. Pharmacovigilance Methods
1. Passive surveillance
• Spontaneous Reports
• Case series
2. Stimulated Reporting
3. Active surveillance
• Sentinel sites
• Drug event monitoring
• Registries
4. Comparative observational studies
• Cross-sectional study (survey)
• Case-control study
• Cohort study
5. Targeted Clinical Investigations
6. Descriptive studies
• Natural history of disease
• Drug utilization study

Spontaneous Reports
 A communication by consumers or health care professionals to
a company or Regulatory Authority that describes one or more
ADR in a patient who was given the drug.
 Plays a major role in the identification of safety signals once
the drug is marketed
 Gives alerts on rare AEs that were not detected in earlier
clinical trials or pre marketing studies.
 Provides important information on at risk groups, risk factors
and clinical features of known serious ADRs.

Case Series
• Series of case reports can provide evidence of an association of a drug and
AE.
• generally more useful for generating hypotheses than for verifying an
association between drug exposure and outcome
• certain distinct adverse events occur more frequently with drug therapy,
such as anaphylaxis, aplastic anemia, toxic epidermal necrolysis and
Stevens- Johnson Syndrome events such as these are spontaneously
reported for detailed and rapid follow- up.
Stimulated Reporting
• A method used to encourage and facilitate reporting by health
professionals for new products, or for limited time period.
• Methods – On line reporting of AE, systematic stimulation of reporting of AE.
• Drawbacks:
• Data are often incomplete.
• Not useful to generate accurate incidence rates.

Active Surveillance
• To ascertain completely the number of AE via a continuous pre-organised
process.
• Eg: Follow up of patients treated with a particular drug.
• More feasible to get comprehensive data on individual AE reports.
Sentinel Sites
• Active surveillance carried out at Institutions, Nursing homes, hospitals etc.
• Provide information such as data from specific patient subgroups, drug abuse
etc.
Weakness:
• Selection bias,
• Small number of patients Increased costs

Drug Event Monitoring
• Patients are identified by electronic prescription data or automated health
insurance claims.
• A follow up questionnaire can be sent to each physician or patient at
specified intervals.
• Information on patient demographics, indication for treatment, duration of
therapy (including start dates), dosage, clinical events, and reasons for
discontinuation can be included in the questionnaire.
Limitations:
• poor physician and patient response rates and unfocused nature of data
collection can obscure important signals.
• A modification of Drug Event Monitoring is Cohort Event Monitoring (CEM), an
active pharmacovigilance method promoted by the World Health Organization
and other agencies.

Registries
 A registry is a list of patients presenting with same characteristics.
• eg: Disease registry, drug registry or pregnancy registry.
 Differ from each other depending on type of patient
 Information can be obtained by using standard questionnaire
Comparative Observational Studies
 Traditional epidemiologic methods are a key component in the
evaluation of adverse events.
 Observational study designs are useful in validating signals from
spontaneous reports or case series.
 Types of designs
1. cross-sectional studies
2. case-control studies
3. cohort studies (both retrospective and prospective)

Cross-sectional study (survey)
• Data collected from a population of patients at a single point in
time (or interval of time) regardless of exposure or disease
status.
• primarily used to gather data for surveys or for ecological
analyses
Major drawback:
• relationship between exposure and outcome cannot be directly
addressed.
Adv:
• best used to examine the prevalence of a disease at one time
point or to examine trends over time, when data for serial time
points can be captured.

Case-control study
• cases of disease (or events) are identified.
• Controls, or patients without the disease or event of interest,
are then selected from the source population
• The controls should be selected : the prevalence of exposure
among the controls represents the prevalence of exposure in
the source population.
• exposure status of the two groups is then compared using the
odds ratio.

Cohort study
• a population-at-risk for the disease (or event) is followed over
time for the occurrence of the disease (or event)
• Information on exposure status is known throughout the follow-
up and hence incidence rates can be calculated.
• comparison cohorts of interest are selected on the basis of drug
use and followed over time
• Multiple adverse events can also be investigated using the same
data source in a cohort study
Targeted Clinical Investigations
• When significant risks are identified from pre- approval clinical
trials, further clinical studies might be called for to evaluate the
mechanism of action for ADRs.
• Pharmacodynamic and pharmacokinetic studies might be
conducted
• Specific studies to investigate potential drug-drug interactions
and food-drug interactions might be called for

Descriptive Studies
 Primarily used to obtain the background rate of outcome
events and/or establish the prevalence of the use of drugs in
specified populations.
1. Natural history of disease: focused on the natural history of
disease, including the characteristics of diseased patients and
the distribution of disease in selected populations, as well as
estimating the incidence and prevalence of potential outcomes
of interest
2. Drug utilization study: These studies provide data on specific
populations, such as the elderly, children, or patients with
hepatic or renal dysfunction, often stratified by age, gender,
concomitant medication, and other characteristics.

4.4. Case-Causality Assessment
 Many researchers developed various methods of
causality assessment of ADRs by using different criteria
like
• chronological relationship between the administration
of the drug and the occurrence of the ADR,
• screening for non drug related causes,
• confirmation of the reaction by in vivo or in vitro tests,
and
• previous information on similar events attributed to
the suspect drug or to its therapeutic class, etc.

Three broad categories of various methods of
causality assessment:
1. Expert judgment/global introspection
 Expert judgments are individual assessments based on previous
knowledge and experience in the field using no standardized tool
to arrive at conclusions regarding causality.
2. Algorithms
 Algorithms are sets of specific questions with associated scores
for calculating the likelihood of a cause-effect relationship
3. Probabilistic methods (Bayesian approaches)
 Bayesian approaches use specific findings in a case to transform
the prior estimate of probability into a posterior estimate of
probability of drug causation.
 The prior probability is calculated from epidemiological
information and the posterior probability combines this
background information with the evidence in the individual case
to come up with an estimate of causation.

Expert judgment/global introspection
• Swedish method by Wilholm
• Evaluates the causal relationship by considering seven
different factors:
(i) the temporal sequence
(ii) previous information on the drug
(iii) dose relationship
(iv) response pattern to drug
(v) rechallenge
(vi) alternative etiological candidates and
(vii) concomitant drugs
• Events are classified as probable or possible and non-
assessable or unlikely.
• A limitation of this method
• is the small number of categories into which causality can be
placed, as there may be an overlap and ADRs could be wrongly
evaluated.

World Health Organization (WHO) – Uppsala
Monitoring Centre (UMC) causality assessment
criteria
• The WHO–UMC causality assessment method includes
the following four criteria :
a. Time relationships between the drug use and the
adverse event.
b. Absence of other competing causes (medications,
disease process itself).
c. Response to drug withdrawal or dose reduction
(dechallenge).
d. Response to drug re-administration (rechallenge).

Example

 ADR can also be categorised into
• Unclassified/Conditional or
• Unassessable/Unclassifiable in WHO-UMC causality
assessment.
 The term Unclassified/Conditional is applied when more
data is needed and such data is being sought or is
already under examination.
 Finally when the information in a report is incomplete or
contradictory and cannot be complemented or verified,
the verdict is Unassessable.

Algorithms
 An algorithm is a problem-specific flow chart with step by-step
instruction on how to arrive at an answer.
 It is a clinical instrument in the form of a questionnaire that gives
detailed operational criteria for ranking the probability of causation
when an ADR is suspected.
 Algorithms give structured and standardized methods of
assessment in a systematic approach to identifying ADRs based on
parameters such as time to onset of the ADR or temporal
sequence, previous drug/adverse reaction history and dechallenge
and rechallenge.
 Individual cases are approached systematically, resulting in a high
degree of consistency and reproducibility.
 Clinical judgment is, however, required at various stages to arrive
at a conclusion.
 Currently, there are many algorithmic methods of causality
assessment but no single algorithm is accepted as the gold
standard, because of the shortcomings and disagreements that
exist between them

Few important algorithmic methods
1. Dangaumou’s French method
• Scores are grouped into likely, possible and
dubious.
• The advantage of this method is that it allows
certain drugs taken at the same time with the
suspect drug to be excluded, because each
drug is imputed separately.
• However, this method requires more time
than most other algorithms.

• The method uses seven criteria (three chronological and
four semiological).
The chronological criteria are
(i) drug challenge
(ii) dechallenge and
(iii) rechallenge, with an overall score of four possible categories
The semiological criteria are
(i) semiology (clinical signs) per se (suggestive or other)
(ii) favoring factor
(iii) alternative non-drug-related explanation (none or possible) and
(iv) specific laboratory test with three possible outcomes (positive,
negative or no test forthe event-drug pair).

2.Kramer et al. method
• This algorithm applies to a single clinical manifestation
occurring after administration of a single suspect drug.
In cases where multiple drugs are involved, each is
assessed separately.
• One of the advantages of this algorithm is its
transparency.
• However, certain levels of expertise, experience and
time are required to use this method effectively.

3. Naranjo et al. method (Naranjo scale)

4. Balanced assessment method (Lagier et al)
• It evaluates case reports on a series of visual analogue scales
(VAS), according to the likelihood that each criterion is fulfilled.
• Its advantage is that it considers the possibility of an alternative to
causation for each of the factors and not just as a separate factor.
• Although each case is assessed by two independent assessors, the
evaluation still depends, to a large extent, on the level of assessor’s
knowledge. An evaluator needs to be an expert in the particular
area to make reliable evaluations.
5. Ciba geigy method (Venulet et al)
• This method was updated and replaced with a checklist of 23
questions, split into three sections:
(i) history of present adverse reaction,
(ii) patients past adverse-reaction history and
(iii) monitoring-physician’s experience.

6. Loupi et al method
• It is developed to assess the teratogenic potential of drug.
• The first sections of the algorithm (chrono-semiological axis) allow for the
drug to be excluded if not implicated in the origin of the abnormality.
• The second section (bibliographical axis) weights the bibliographical data.
• The three questions consider alternative etiological candidates other than
the drug; chronology of the suspect drug and other bibliographical data, to
arrive at a conclusion on causality.
7. Roussel Uclaf causality assessment method (RUCAM)
• This method is designed for predetermined disease states such as liver
and dermatological injuries.
• Although this method seems quite easy to use, it is organ specific
8. Maria and Victorino (M and V) scale
• Maria and Victorino developed this scale for diagnosing drug induced liver
injury (DILI).
• Probability was expressed as a score between 6 and 20, divided into five
causality degrees (score of > 17, definite; 14 - 17, probable; 10 - 13,
possible; 6 – 9, unlikely; < 6)

Probabilistic methods (Bayesian approaches)
1. Australian method
• It is one of the first probabilistic methods used.
• Conclusions are drawn from internal evidence, such as timing, and laboratory
information from case reports.
• Previous knowledge on the suspect-drug profile is deliberately excluded in the
assessment.
2. Bayesian Adverse Reactions Diagnostic Instrument (BARDI):
• Developed to overcome the numerous limitations associated with expert
judgments and algorithms.
• This BARDI is used to calculate the odds in favor of a particular drug
causing an adverse event compared with an alternative cause. These odds
are referred to as the posterior odds.
• The posterior odds factor is calculated by considering six assessment
subsets: one deals with background epidemiologic or clinical trials
information (the prior odds) and the other five deal with case specific
information (the likelihood ratios).

The five likelihood ratios (LRs):
• Patient history (Hi)
• Timing of the adverse event with respect to drug administration (Ti)
• Characteristics of the adverse event (Ch)
• Drug dechallenge (De), which refers to any signs, symptoms, or
occurrences after drug withdrawal
• Drug rechallenge or readministration (Re) of the suspected causal
drug(s).
The product of these factors is the posterior odds (PsO)
PsO = PrO × LR(Hi) × LR(Ti) × LR(Ch) × LR(De) × LR(Re)
• The Bayesian approach can be implemented as a spreadsheet
programme on either paper or computer.
• It calculates and provides instant numerical and graphical feedback
as soon as new pieces of evidence of the suspected ADR are
evaluated

4.5. Data Assessment in Pharmacovigilance
1. Individual case report assessment
2. Aggregated assessment and interpretation
• Signal detection
• Interactions and risk factors
• Serial (clinic-pathological) study
• Frequency estimation

Individual case report assessment
• Relevance of observation
• Coding
• Quality of documentation
• Case follow-up
• Case causality assessment
Components of a case report
• Patient
• Adverse event
• Drug exposure (suspected and other)
• Source

Patient
• Age
• Sex
• Medical history
• Case identification (confidential)
Adverse event
• Description: aspect, place, severity, diagnosis
• Outcome, course, time relationship (‘challenge,
dechallenge, rechallenge’)
• Laboratory data
Suspected drug
• Name (product, generic, ingredients, batch no.)
• Dose, route, dates (interval, duration)
• Indication

Coding of adverse events
• Drug
– WHO Drug Dictionary
• Adverse event
– WHOART
– MedDRA
– Snomed?
Coding of adverse events ‘Reporting adverse drug reactions.
Definitions of terms and criteria for their use.’
Council for International Organizations of Medical Sciences
CIOMS. C/o World Health Organization, Avenue Appia, 1211
Geneva 27, 1999.

Case follow-up
• Missing data
• Laboratory data, pathology
• Outcome data (if not yet recovered)
• Underlying disease
• Verification of findings
Standardized causality assessment
• WHO system
• French system
Relevance of observation
• Unknown, unexpected, unlabeled
• Serious
• New or important drug
• Regulatory
• Scientific
• Educational

2. Aggregated assessment and interpretation
• Signal detection
• Interactions and risk factors
• Serial (clinicopathological) study
• Frequency estimation
WHO-UMC definition of a 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.
Edwards IR, Biriell C. Drug Safety 1994;10:93-102

A signal consists of
• Hypothesis
• Data
• Arguments, in favor or against
Data of a signal
• Qualitative (clinical)
• Quantitative (epidemiological)
• ‘Experimental’
• Develops over time

1. Signal detection
• Selection of a possibly relevant association (hypothesis
generation)
• Preliminary assessment of the available evidence (signal
strengthening)
2. Signal follow-up

4.5. Pharmacovigilance - Data Sources
1. Spontaneous Reporting Systems
• National PV Centre / Drug Authority
• from the published scientific literature.
2. Drug Bulletins
3. Adverse Reaction Case Reports by the MA (master
agreement) holder (e.g. collected by sales representatives)
4. Periodic Safety Update Report (PSUR) provided by MA
holder

4.6. Pharmacovigilance Case Studies

Unit 4 pharmacovigilance (6hrs) march 13 2021

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Unit 4 pharmacovigilance (6hrs) march 13 2021

Similar to Unit 4 pharmacovigilance (6hrs) march 13 2021 (20)

More from University of Gondar

More from University of Gondar (17)

Recently uploaded

Recently uploaded (20)

Unit 4 pharmacovigilance (6hrs) march 13 2021