An introduction to pharmacovigilance, basic types like active pharmacovigilance and passive pharmacovigilance, purpose, adverse event reporting, data processing, causality, assessement, signal detection, risk management plans and analysis

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An Overview
on
Pharmacovigilance

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3. Definition: The pharmacological science relating to the detection, assessment,
understanding and prevention of adverse effects with pharmaceutical
products. Focuses on drug Safety, adverse reactions and patient care
Types: Passive Pharmacovigilance
 No active measures are taken to look for adverse effects to report safety concern
 Most common
 Spontaneous or voluntary reporting
Active Pharmacovigilance
 Active measures are taken to look for adverse effects to report safety
 The events may be detected by asking patients directly or screening patient
records
 Cohort Event Monitoring (CEM)
eg: Intensive Medicines Monitoring Programme (IMMP) in Newzealand &
Prescription Event Monitoring (PEM) in England
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 Aggregate Reporting
 Sources of AER
 Unsolicited Reports  Solicited Reports
 Spontaneous Reporting
 Patient support Programs
 Literature Sources
 Clinical or Post Marketing Studies
 Media (Social & Websites)
 DRA (Drug Regulatory Authority)
 Pharmaceutical Companies
 Expedited Reporting

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Definition: Unsolicited report is not expressly requested by a person and is produced
for them without their permission. Unsolicited is something proposed to
a client/customer and they did not ask for it
1. Spontaneous reports
2. Literature reports-Marketing authorization holders (MAH) are therefore
expected to maintain awareness of possible publications through a systematic
literature review of widely used reference databases (e.g. Medline, Excerpta Medica
or Embase) no less frequently than once a week
3. The internet or digital media
A spontaneous report is an unsolicited communication by a healthcare professional, or consumer to a competent authority,
marketing authorization holder or other organization (e.g. Regional Pharmacovigilance Centre, Poison Control Centre) that
describes one or more suspected 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 systems where adverse events reporting is actively sought

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Definition: Derived from organized data collection systems (which include clinical trials,
post-approval named patient use programs, other patient support and disease management
programs, surveys of patients or healthcare providers, or information gathering on efficacy or
patient compliance)
.
Note: Adverse event reports obtained from any of those should NOT be considered spontaneous
 Solicited reporting involved healthcare workers completing an AE form when
requesting for a change in regimen due to an adverse event
 For the purposes of safety reporting, solicited reports should be handled as if
they were study reports, and therefore should have an appropriate causality
assessment

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 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
 For marketed medicines through the CIOMS-1 and CIOMS-2 Working Groups on
expedited (alert) reports and periodic safety update reporting, respectively, are
important precedents and models
 What Should be Reported?
Single Cases of Serious, Unexpected ADRs:
All ADRs that are both serious and unexpected are subject to expedited reporting
 Expedited reporting is also inappropriate for serious events from clinical
investigations that are considered not related to study product, whether the event is
expected or not. Similarly, non-serious adverse reactions, whether expected or not,
will ordinarily not be subject to expedited reporting

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 The CIOMS-I form has been a widely accepted standard
 Certain basic information/data elements, when available, be included either
in a tabular or narrative presentation
 Sent to regulators or other official parties requiring them
 The sponsor of an interventional clinical trial is responsible for the expedited
reporting of Suspected Unexpected Serious Adverse Reaction (SUSAR)
related to Investigational Medicinal Products (IMPs) to the MEB & CCMO
(As from March 1, 2006 )
 Not later than 15 days after the sponsor obtained first knowledge of the
adverse reactions
 For fatal or life threatening cases the maximal term is 7 days
 For a preliminary report with another 8 days for completion of the reports
 How to Report
As from 1 January 2010 all adverse events/reactions (SUSAR’s and SAE's) from investigator initiated
trials should be submitted via the CCMO web portal Toetsing Online
Medicines Evaluation Board (MEB) & Central Committee for Research Involving Human Subjects (CCMO)

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Definition: 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
 Key role in the safety assessment of drugs & provides a broader view of the safety
profile of a drug
 Periodic Safety Update Report (PSUR) (Worldwide, the most important aggregate report )
 This is a document that is submitted to drug regulatory agencies (in Europe, the US and
Japan (ICH countries), as well as other countries around the world)
 It is now referred to as the Periodic Benefit Risk Evaluation report (PBRER)
 PBRER's focus is on the benefit-risk profile of the drug
The PSUR was updated in 2012

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Only valid ICSRs qualify for reporting. All reports of suspected adverse reactions
should therefore be validated before reporting them to the competent authorities to
make sure that the minimum criteria for reporting are included in the reports (ICH-
E2D guideline)
Validation of Reports
Patient
Details
Initials, Other relevant identifier (patient number, for example) Gender, Age, age category (e.g.,
adolescent, adult, elderly) or date of birth, Concomitant conditions, Medical history & Relevant family
history
 For any reporting following elements are
needed

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Brand name as reported, International Non-Proprietary Name (INN), Batch number, Indication(s) for
which suspect medicinal product was prescribed or tested, Dosage form and strength, Daily dose (specify
units - e.g., mg, ml, mg/kg) and regimen, Route of administration, Starting date and time, Stopping date
and time, or duration of treatment
Concomitant medicinal products (including non-prescription, over-the-counter medicinal products,
herbal remedies, dietary supplements, complementary and alternative therapies, etc.) & Relevant
medical devices
Full description of reaction(s), including body site and severity, The criterion (or criteria) for regarding
the report as serious, Description of the reported signs and symptoms, Specific diagnosis for the
reaction, Onset date (and time) of reaction, Stop date (and time) or duration of reaction, Dechallenge
and rechallenge information, Relevant diagnostic test results and laboratory data, Setting (e.g., hospital,
out-patient clinic, home, nursing home), Outcome (recovery and any sequelae), For a fatal outcome,
stated cause of death, Any autopsy or other post-mortem findings (including a coroner's report)
Name, Mailing address, Electronic mail address, Telephone and/or facsimile number,
Reporter type (consumer, healthcare professional, etc.), Profession (specialty)
Source of report (spontaneous, epidemiological study, patient survey, literature, etc.), Date the
event report was first received by manufacturer/company, Country in which the event occurred
Type (initial or follow-up) and sequence (first, second, etc.) of case information reported to
authorities, Name and address of MAH, Name, address, electronic mail address, telephone
number, and facsimile number of contact person of MAH, Identifying regulatory code or number
for marketing authorization dossier, Company/manufacturer's identification number for the case
(this number must be the same for the initial and follow-up reports on the same case)
Administrative and
MAH Details
Details on Reporter
of an ADR
Details (all available)
of Adverse Drug
Reaction(s)
Other Treatment(s)
Suspected Medicinal
Product

13. After getting the report from various sources, the information from an AE
reporter is coded using Standardized Terminology from Medical Coding
Dictionary known as MedDRA. Through which the information is readily
identified and analyzed
AE is classified by triage. For serious, the event should meet one or more of the
following criteria,
 Results in death
 Life threatening
 Requires inpatient hospitalization or prolongation of existing hospitalization
 Results in persistent or significantly disability or incapacity
 Results in Congenital anomaly (Birth defects)
Triage- Process placing a potential AE report into one of the three categories, Serious, Non serious or No case
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 Coding of Adverse Event (AE)
 Determination of Seriousness

14.  Data entry - data must be accurate
 Standard Formats (SF) [Other than predetermined terms will be rejected]
 Field Controls (FC) [Certain values can only be entered]
 Drop-Down Lists (DDL) [For Standard choices]
 Quality Control
 Use SF, FC and Codes (ICD-10 & ATC)
 Coding of Medicines and Diseases
ATC – Medicines & ICD-10 – Diseases (for this, coding sheet is used, these codes are
 Collating and summarizing the events
 The events are sorted out by print codes in the dictionary
 This events collation should incorporate the following fields
ATC – Anatomic Therapeutic Classification; ICD-10 – International Statistical
Classification of Diseases and related health Problems 10th Version (2010) 14
Event , sex , age , dose , duration to onset in days, hours or minutes, relationship, coded as follows:
1 (certain), 2 (probable), 3 (possible), 4 (unlikely), 5 (unclassified), 6 (unclassifiable) , report
number , death & withdrawal
accessible in vigiFlow)

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16.  Definition: When a drug is thought to have caused or contributed to the occurrence of
an AE or the relationship of a given AE to a specific drug
 Factors to be considered when assessing the relationship
 Did the event begin before the patient commenced the medicine?
 Did the event occur after the commencement of some other medicine?
 Did the event occur after the onset of some new illness?
 Is there any other possible cause for the event?
 Is the duration to onset of the event plausible?
 What is the response to the withdrawal of medicine (dechallenge)?
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17.  Specific Categories of Causality
 Certain
 Probable
 Possible
 Unlikely
 Unclassified
 Unclassifiable
 Process for Establishing the Relationship
 Result of dechallenge and rechallenge with same medicine by itself
 Outcome of the event
 Clinical details
 Observational Studies
Observational Studies- Incident of the event in a patient population taking the drug is compared to control groups.
If the event is statistically significantly higher than the active group Vs placebo group, relationship may exist
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18.  Logic Check
 If there is no rechallenge or outcome of rechallenge is unknown- it is not Certain
 No dechallenge or unknown dechallenge-
 Outcome of event is unknown-
 Other possible causes of event-
not Probable
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19.  Signal Detection
 Definition: Reported information on a possible causal relationship between an AE
and a drug, the relationship being unknown or incompletely documented
Previously or new safety finding within the safety data
 For strongest signal, several reports of ‘Certain’ or ‘Probable’
 At least one ‘Certain’ or three ‘Probable’ (Index cases), ‘Possible’ will provide
Supporting evidence
 ‘Unclassified ‘and ‘Unassessable’ should not be considered in the investigation of
signal
 Unlikely reports may produce unexpected reactions
 Types: Confirmed Signals- Causal relationship exists between drug & AE
Refuted (False) Signals- Causal relationship does not exist
Unconfirmed Signals- Requires further investigation
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20.  Selection Criteria for Events to Investigate
 Good data
 Event is clinically significant
 Several reports (Certain or Probable)
 Requires Regulatory action & advice to prescribers
 Be of Scientific importance
 Methods of Signal Identification
Clinical Assessment of Individual Event- First check the adverse reaction reference
sources, if, no, proceed with its investigation
Clinical Review of Collated Events- By sorting on the events dictionary print codes.
There is a dictionary code for each of terms. WHO-ART adapted for coding and
additional terms can be added for the event monitoring
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21.  Record Linkage & Automated Signal Detection
Bayesian Confidence Propagation Neural Network (BCPNN)-
1. Provides IC values for drug-event combinations
2. These can be plotted as graphs over time to examine
3. A +ve signal will have significant
Proportional Reporting Ratio (PRR)-
1. Measure the proportion of reports
2. With a particular drug-event combination and compares this proportion with that
3. For the same event, for all other drug combinations
4. It is significantly high and may represents a signal
IC- Information Component; both BCPNN & RPR requires clinical evaluation
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22.  Strengthening the Signal
 Search the literature for the similar reports using searching tools
Pub med, Martindale (Complete Drug Reference), Micromedex
(Online Drug Reference), Physicians Desk Reference
 Ask the P’ceutical Companies if they have received the similar reports?
 Were similar reports identified in clinical trials and in pre-clinical studies?
 Investigative epidemiological studies, if the event seems important
Cohort Studies & Case-Control Studies
 Communication- the following stakeholders can provide invaluable advice
Expert Safety Review Panel (ESRP), Regulatory Authority, Health Practitioner,
The UMC, P’ceutical Company, Letter or Report to a Medical Journal
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23.  Characteristic associated with an increased probability of occurrence of an event
Patient is more likely to develop adverse reaction
 Provides a means of avoiding or minimizing the adverse reactions
 To assure a positive risk –benefit profile once the drug is marketed
Types: Identified Risks, Potential Risks and Unknown Risks
 Factors Associated with Risk
 Patient
 Medicine
 Environment
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24.  Identification
 Pharmacology- P’dynamics & P’Kinetics
 Clinical Trials
 Clinical Experience
 Spontaneous reporting- very less, because rates will be low
 Cohort event Monitoring (CEM)-Measure relative risk (RR) and confidence interval
Should be calculated to assess the statistical significance of any difference found &
rates will be high
 Risk Evaluation and Mitigation Strategies (REMS)
Rates can be calculated by Defined Daily Dose (DDD)-Comparing similar medicines given under similar conditions
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25.  Using statistical softwares eg: MedCalc
 Data Manipulation-Tabular and Graphics
 Statistical Methods- RR with Confidence interval,
t- test for the comparison of means and
Multiple Logistic regression (Biostatistician)
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26.  Legal Authorization
 Data collection should be authorized or required by law for Spontaneous Reporting (SR)
and CEM programmes
 All medicines are subject to SR, but selected new medicines that have public importance
and wide use should be subject to CEM
 Conditional Registration
 Full registration is granted after doing CEM
 It is offered until the outcome of a CEM is known
 Regulation of Professional Standards
Standards of health professional are maintained and improved by Compulsory
Continuing Medical Education (CME)
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27.  Prerequisite to collecting data-to declare publicly what data are being collected
 Training of staff
 Security Issues
 Use of Data & Confidentiality
 Centre Staff-Clinical Supervisor (in charge of CEM activities), Data Manager &
Data Processor
 Peripheral Staff- Field Coordinator & sentinel Site (SS ) or
National Pharmacovigilance Centre (NPvC)
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pv

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Drop-down lists
Causality