3. Pharmacovigilance
Pharmacovigilance (PV) is defined as the
science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects or any other
drug-related problem.(WHO)
It is the pharmacological science relating
to the collection, detection, assessment,
monitoring, and prevention of adverse
effects with pharmaceutical products.
4. What is an ICSR?
Individual case safety report (ICSR) in Pharmacovigilance, Individual Case Safety Report is an adverse
event report for an individual patient and is source of data in pharmacovigilance.
It is the format and content for the reporting of one or several suspected ADR’s from a medicinal
product that occurs in a single patient at a specific point of time.
Individual Case Safety Report (ICSR) captures information necessary to support reporting of suspected
adverse reaction(s) due to use of a medicinal product by a patient at a specific point of time.
ICSR content and format requirements for drug and biologics reporting to various regulatory
authorities is based upon the International Conference on Harmonization ICH E2B(R2), ICH E2B(M), and
ICH E2B(R3) specifications.
The Guideline on Good Pharmacovigilance practices (GVP) Module VI for direct database-to-database
transmission of information using standardized data elements.
5. ICSR reporting is one of the key activities performed by drug safety departments and
encompasses the receipt, triage, data entry, quality, and medical review, distribution,
reporting, and archiving of adverse event (AE) data which is necessary for assessing the
risk-benefit profile of a given medicinal product.
Adverse event coding is the process by which adverse event information received from a
reporter/patient, called the “verbatim,” is coded using standardized terminology from a
medical coding dictionary, such as Medical Dictionary for Regulatory Activities (MedDRA).
MedDRA is a clinically validated international medical terminology dictionary used to
convert adverse event information into terminology that can be readily identified,
retrieved, and analysed.
6. Validity
criteria
ICSR is considered to be valid for reporting to a
regulatory authority if it has at least :-
(1) one single identifiable patient,
(2) one identifiable reporter,
(3) one or more suspect adverse drug reaction,
(4) one or more suspect identifiable product
7. Seriousness
criteria
Although somewhat intuitive, there are a set of
criteria within pharmacovigilance that are used to
distinguish a serious adverse event from a non-serious
one. An adverse event is considered serious if it meets
one or more of the following criteria:
Death
Life-threatening
Requires in-patients hospitalization or prolongation
of existing hospitalization
Results in persistent or significant disability or
incapacity
Congenital anomaly/birth defect
Or is otherwise medically significant
8. PROCESS OF ICSR
Case Received In Mail Box
(Case received from Different Sources)
Case validation
(Validity assessment is done on the
basis of 4 minimum data elements
required)
Duplicate check
(check within the different
demographics and numbers to avoid
misleading information)
Step 1
Step 1
Step 2
Step 3
CASE TRIAGE
9. Case Registration
(case is registered in the safety
database with unique case number)
Data Entry
(All relevant data to be entered via
MeDdra, WHO-ART, WHO-drug
dictionary )
Narrative Writing
(summary or synopsis in chronological
order)
Step 4
Step 5
Step 6
Process of
determining the
validity
categorization and
priority of case
10. Quality Review
(To ensure regulatory, scientific and
medical standards are met )
Medical Review
(Medical assessment of the case will
done by physicians)
Report Submission
(If the case qualifies the reportability
criteria then it will be reported to
relevant regulatory authority )
Step 7
Step 8
Step 9
11. Source of
ICSR
Unsolicited
sources
solicited
sources
Post-approval
Named Patient Use
Programs
Regulatory Authority
Sources
Clinical Trials and surveys of
patient or healthcare
providers
Other Patient Support
And Disease
Management Programs
Contractual Agreements
Spontaneous Reports Licensing partners
Literature Reports
Registries
Internet or digital
media
Step 1:Case Received In Mail Box
Health Authority
12. Step 2:Case
validation
ICSR is considered to be valid for reporting
to a regulatory authority if it has at least :-
(1) one single identifiable patient,
(2) one identifiable reporter,
(3) one or more suspect adverse drug
reaction,
(4) one or more suspect identifiable
product
13. Step 3 :Duplicate check
• Due to greater awareness, stringent regulations and multiple reporting source duplicate report is a
common phenomenon.
• After triaging the case must be evaluated to confirm duplication of report, if the case is not a duplicate
report then it will be considered as a initial report.
• Certain characteristics of case (sex, age or date of birth, date of drug exposure, clinical trial code,
country etc ) may be used to identify duplicate reporting.
For example- 1.An event/reaction occurrence being reported by the original reporter to both the MAH
and the National pharmacovigilance centers or National Competent Authority (NCA).
2.Multiple health care professionals treating the same patient reporting the same event/reaction
occurrence.
3.A consumer and health care professional reporting the same event/reaction occurrence.
• The duplicate could actually be follow up information that could alter the seriousness and hence
reporting timeline of the case, missed out duplicates could send misleading information to signal
detection system.
14. Step 4: Case
registration
Case is registered in the safety database with unique
case number, Once the case processor has completed
duplicate search for a case in database, there are two
ways of processing a case. They are as follows:
1.Upon positive duplicate search, i.e., when the
processor finds a case in the database, the processor
can add a follow-up to the existing case and process
the information.
2.Upon negative duplicate search, i.e., when the
processor does not find any case in the database, the
case processor will create a new case to process the
information.
15. Step 5:Data Entry
• Once the case has been triaged, the case processor will perform the complete data entry.
• The case processor will enter all the details from the source documents into the
database, which include reporter information, patient information, patient medical
history, laboratory details, family and surgical history, clinical course, and treatment
details of the patient.
• This step involves coding of the adverse events in the Medical Dictionary for Regulatory
Activities (MedDRA), World health organisation drug dictionary (WHO Drug), World
health organisation adverse reaction terminology (WHO-ART) .
• MedDRA is a single standardized international medical dictionary which can be used for
regulatory communication and evaluation of data pertaining to medicinal products for
human use.
16. STEP 6: NARRATIVE WRITING
o A narrative can be defined as a summary or synopsis of the event that has occurred to a subject participating in
the clinical trial.
o A CIOMS report can be cited as an example of a narrative which provides valuable information about the
occurrence of the event.
# General style of narratives
Narratives should be summary of relevant information, information should be presented in a logical time
sequence.
Narratives should be written in third person using past tense.
Time to onset should generally be given in most appropriate units (eg: hours, days, weeks) but actual dates can be
given.
Abbreviations and acronyms should not be used with exception of laboratory assays and units which should be
quoted in S.I units.
If information comes from more than one source , all sources should be acknowledged.
If supplementary reports are important then they should be cited eg: post mortum .
If conflicting information are from different sources then it should be documented and query should be raised .
17. Chronological order of Narrative Format
1. Source Of Report And Patient Demo Graphs.
2. Medical And Drug History .
3. Suspect Drugs, Timings And Conditions
Surrounding The Onset Of Reactions
4. Progression Of Event And Its Outcome In The
Patient
5. Dechallenge/Rechallenge Information.
6. If Outcome Is Fatal, Relevant Details.
7. Original Reporter’s Clinical Assessment.
8. Narrative Preparers Medical Evaluation And
Comment.
18. Step 7: Quality Review
• Quality reviewer (Quality control)
reviews the data entry against the
source documents.
• Any addition or change in a case is
made at this level.
• QC reviewers is responsible to check
every stage of case documentation
such as data collection, transfer of data,
coding, case validation and follow up
reports.
19. Step 8: Medical Review
THE CHRONOLOGY OR
ASSOCIATION IN TIME
(OR PLACE) BETWEEN
DRUG
ADMINISTRATION
AND THE EVENT
CURRENT
KNOWLEDGE OF
NATURE AND
FREQUENCY OF
ADVERSE REACTIONS
DUE TO THE SUSPECT
MOLECULE, OR THE
PHARMACOLOGY OF
THE DRUG
MEDICAL OR
CONFOUNDERS BASED
ON SIGNS AND
SYMPTOMS,
LABORATORY TESTS,
PATHOLOGICAL
FINDINGS AND
MECHANISM OF
ACTION
LIKELIHOOD OR
EXCLUSION OF OTHER
CAUSES FOR THE
SAME ADVERSE
EVENTS, OFTEN THE
DISEASE CONDITION
OR CONCOMITANT
MEDICATION.
20. Medical review
• This group is almost composed of physicians with expertise
in drug safety and case review.
• They generally review the assessment, the AE coding and
the medical content of the narrative.
• Prepare and Review of signals aggregate reports.
• Assessment of causality, seriousness and expectedness of
adverse drug reactions/adverse event reports.
• Medical review of narratives and CIOMS/MedWatch and
similar reports in safety database.
• Review of MedDRA coding in safety database.
• Preparation and medical review of medical parts of Risk
Management Plans.
• On-going evaluation of benefit/risk ratio, both pre-
authorisation or post-authorisation
• Participation in signal management.
21. Step 9: Report submission
If the case qualifies the
reportability criteria then it will be
reported to relevant regulatory
authority.
All ICSR should be reported
electronically by the marketing
authorization holder (MAH).
Reporting of ICSR is by CIOMS
forms accepted worldwide for
foreign reports .
USFDA(USA), MHRA(UK), TGA(Australia),
CDSCO(India), HEALTH CANADA(CANADA),
MCC(South Africa),ANVISA (Brazil) , EMEA
(European Union), SFDA
(China),NAFDAC(Nigeria),
MEDSAFE(Newzeland), MHLW(Japan),
MCAZ(Zimbabwe),
SWISSMEDIC(Switzerland), KFDA(Korea),
MoH (Sri Lanka) are the few
regulatory agencies and organizations
established in respective countries.
22. Regulatory timelines
SERIAL NO TYPE REPORTING TIME FOLLOW UP
1 Serious 15 days
2 Non-serious 90 days
3 SUSAR 7 calendar days 8 additional days
4 Fatal or life-
threatening
7 days 24 hrs
SERIAL NO TYPE REPORTING TIME FOLLOW UP
1 Serious 15 days
2 Non-serious 90 days
3 SUSAR 7 days
4 Fatal or life-
threatening
7 calendar days 8 additional days
Clinical
trials
Post-
marketing
23. Summary
• All ICSRs should be reported electronically by the marketing
authorisation holder (MAH).
• ICSR content and format requirements for drug and biologics
reporting to various regulatory authorities is based upon the
International Conference on Harmonization ICH E2B(R2), ICH
E2B(M), and ICH E2B(R3) specifications and the Guideline on
Good Pharmacovigilance practices (GVP) Module VI for
direct database-to-database transmission of information
using standardized data elements
• Reporting of ICSR: CIOMS 1 Form designed by CIOMS group,
CIOMS 1 Form accepted worldwide for foreign reports.
• Day zero is the date when the minimum information for an
ICSR to be valid is available.
24. References
• https://www.who-umc.org/global-pharmacovigilance/global
pharmacovigilance/glossary/. Accessed 8 August 2018.
• https://eudravigilance.ema.europa.eu/human/index.asp Accessed 15
August 2018.
• http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/
07/WC500230934.pdf.Accessed 15 August 2018.
• http://www.transceleratebiopharmainc.com/initiatives/intelligent-
automationopportunities-pharmacovigilance/Accessed 16 August 2018.
• Alexion Pharmaceuticals, Inc. Why Are We Still Creating Individual Case
Safety Reports?/Mariette Boerstoel Streefland, MD, MBA, MS(epi)
• ICH Harmonized Tripartite Guideline. Maintenance of the ICH Guideline
on Clinical Safety DataManagement: Data Elements for Transmission of
Individual Case Safety Reports E2B (R2), February2001.
