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PHARMACOVIGILANCE OVERVIEW
• What is pharmacovigilance• Pharmacovigilance center in India• History of Pharmacovigilance• Who reports• What to report• How it is categorized• Reporting methods• Reporting timings• Flow of data• Methods to assessment( scales/ algorithms)• Data mining/ software used• MedDRA• Discussion• conclusion
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem
a
Humanitarian concerns
• Hippocrates’ admonition.• “First, do no harm”
Check if drugs on the market fulfill their intended role in society i.e. if resources spent on drugs produce optimal results in terms of benefits
Economical concerns
Why pharmacovigilance?
World Health Organisation
Drugs withdrawn from Market due to severe ADR
Drug ADR Company Year
Rofecoxib Myocardial infarction Merck 2004
Cerivastatin Rhabdomyolysis Bayer 2001
Cisapride Cardiac arrythmia J&J 2000
Astemizole Cardiac arrythmia J&J 1999
Bromfenac Liver toxicity Wyeth 1998
WHO ALL ARE INVOLVED
The problem of ADRsAccount for 5% of all hospital admissions.
Occur in 10-20% of hospital inpatients.
Cause death in 0.1% of medical and 0.01% of surgical inpatients.
Adversely effect patients quality of life.
Cause patients to lose confidence in their doctors.
Increase costs of patients care.
What to report: ADVERSE EVENT-1
Any unfavorable, unintended sign, symptom, illness or experience (untoward medical occurrence) that develops or worsens in a subject during the period of observation (defined by protocol) « Adverse event » does not imply causal relationship with the study medication
• Abnormal results of diagnostic procedures, including laboratory findings considered by investigator to be of clinical relevance, are considered to be adverse events
ADVERSE DRUG REACTION
“A noxious and unintended response at doses normally used for
prophylaxis, diagnosis, or therapy of diseases, or for the modification of physiological function.”
All ADRs are AEs…….
but all AEs are NOT ADRs
SAEresults in death
is life threatening
requires inpatient hospitalisation or prolongation of existing hospitalisation
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is important medical event
WHAT IS NOT AN AE/SAE?
Surgical Procedures
They are therapeutic measures of a condition requiring surgery
They are not AEs/SAEs per se;
The condition for which the surgery is performed, may be an AE/SAE which has to be reported
Surgical procedures planned prior to randomization and conditions leading to these measures are not adverse events (medical history)
An Unexpected ADR • the Investigator’s Brochure • the Package Insert or Product Monograph of a marketed drug
An ADR whose nature, intensity or incidence falls outside the information provided in
Adverse Event
Intensity Seriousness Expectedness
• Mild• Moderate• Severe
• Serious• Non serious
• Expected• Unexpecte
d
• Related• Un-related
Relatedness
DIMENSIONS OF AN ADVERSE EVENT
OUTCOME OF AN AE & FOLLOW UPS
Complete
recovery
Ongoing
Recovered
with sequel
ae
Unknown
Death
Follow Ups are necessary
• to know outcome (ongoing)
• get critical missing information (concomitant med.)
• hospital / lab reports (autopsy report)
• causal assessment (revision / delayed)
CAUSAL ASSESSMENT – WHO ALGORITHM • Certain• Probable• Possible• Unlikely• Unclassifiable
REPORTING METHOD & SYSTEM
Medwatch
Yellow Card
ADR form
THE MINIMUM CRITERIA FOR A VALID ADR REPORT*
Identifiable patient
A suspect drug
An adverse event
Identifiable Reporter
ICH / CIOMS (Centre for international organization of Medical Science) group
V working recommend
ADR FORM
I. Reaction Information
II. Suspect Drug
III. Concomitant
Drugs & History
IV. Manufacture’s Information
LAWS, REGULATIONS AND GUIDELINES
Schedule Y requirements
ICH guidelines
International regulations (US FDA)
04/22/2023 17
Adv.Event
DCGI
Sponsorwithin 14 calendar days
SeriousNon -Serious
Record in CRF
Record in CRFSUSAR / U.SAE
Report EXPEDITEDLY
Global TeamHQ
PIs / ECs
DSMB
EC
immediately /within 24 hours/
within 7 calendar days
SafetyReview
Safety Profile Update
CURRENT US FDA REGULATIONS Safety reporting requirements are specified in
Title 21, Code of Federal Regulations:
Part 310.305 Old Drugs (marketed pre-1938)
Part 312.302 Safety reporting from INDsPart 314.80 Marketed drugsPart 314.98 Generic drugsPart 600.80 Therapeutic Biologic products
ICH-GCP GUIDELINES - III
E2A Expedited clinical safety reportingE2B Safety reporting data elements spec’sE2B(M) Data Elements for Electronic submissionE2C & E2C Addendum – PSURsE2D Post-marketing expedited reporting standard
E2E Pharmacovigilance planning
The post marketing surveillance may comprise of one of the following;
Phase IV Clinical Trials
PMS Studies
Observational Studies Registries
Prescription Event
MonitoringSpontaneous reporting
AIMS OF POST MARKETING SURVEILLANCE Expose more patients to confirm and better
understand safety of new molecule (delayed effects, prolonged use
effects. Evaluation in unexposed
population (children, pregnant women, nursing mothers, elderly, immuno-
suppressed) Identification of risk
groups
Occurrence of rare and serious ADRs
Assessment of costs of ADRs to various sectors
of the society
SPONTANEOUS REPORT“An unsolicited communication to a company, regulatory authority or other organization that describes an adverse drug reaction in a patient given one or more medicinal products and which does not derive from a study or any organized data collection scheme is called “Spontaneous Report”.
Strengths
Cornerstone of ‘PV’
Cheap & Easy
Encompass all clinical settings
Life-time span
Detection of rare ADRs
Weaknesses
Underreporting
Quality of reporting
No denominator
Subject to bias
Delayed effects go undetected
Its a formal, structured update of the worldwide safety experience for a registered medicinal product (per ICH E2C standards), prepared for submission to regulatory authorities at defined times post-authorization
PSUR- PERIODIC SAFETY UPDATE REPORTS
PERIODIC SAFETY UPDATE REPORTS
• New safety information from appropriate sources.
1 • Data to patient exposure.
• Summarizes the market authorization status in different countries.
• Create periodically the opportunity for an overall safety re-evaluation.
• Indicate whether changes should be made to product information.
REPORTING TIMINGS Schedule Y (Indian) EU Requirements US Requirements
o Only ‘New Drug’
o Six Monthly – first 2 years
o Annual – subsequent 2 years
o To be submitted within 30 calendar days
o Even if not marketed
o Six Monthly – first 2 years
o Annual – subsequent 2 years
o At the first renewal, and then
o 5-yearly at renewal thereafter
o One PSUR for each active substance
o To be submitted within 60 days of last data lock
o Pre-Approval PSUR – 4 months after application
o Post Approval for each approved NDA/ANDA/BLA
o Quarterly– for first 3 years
o Then annual interval / on request
o Within 30 days of the close of quarter
o Annual reports within 60 days
THE FLOW
DataEvaluation Database
Signal Detection & Evaluation
R / BEvaluation
DecisionMaking Communication
DataCollection
PV SOFTWARES & DATABASE
1. Intranet / Internet based2. Restricted Access3. Level privileges4. MedDRA / WHO integrated5. Company Product Library6. Time bound process7. QBS8. Signal generation9. Report generation10.Electronic submissions
1. ArgusAERS (US FDA)2. Eudravigilance
(EMEA) 3. ARIS global4. Clint race5. Oracle
MedDRA
MedDRA is a clinically-validated international medical terminology
used by regulatory authorities and the regulated
biopharmaceutical industry.
The terminology is used through the entire regulatory process,
from pre-marketing to post-marketing, and for data entry,
retrieval, evaluation, and presentation.”
Med DRA: medical Dictionary for Regulatory Activities
MedDRA
Adverse event
Medical history
Procedures
Medication
Indication
MedDRA - Structure
SOC – System Organ class
HLGT – High Level Group Term
HLT – High Level Term
PT – Preferred Term
The Gains from PV Database
• Patient’s safety & care
• Dissemination of information to all concerned
• Regulatory compliance
• Detection of new safety issues
• Changes in design / documents
• Ongoing safety review
• Regulatory actions
ADR detection
Subjective report Objective report
patient complaint
Direct observation of event
abnormal findings
physical exam Laboratory test Diagnostic procedure
NARANJO's ALGORITHM Question Yes No Don't
know
Are there previous conclusion reports on this reaction? +1 0 0
Did the adverse event appear after the suspect drug was administered?
+2 -1 0
Did the AR improve when the drug was discontinued or a specific antagonist was administered?
+1 0 0
Did the AR reappear when drug was re administered? +2 -1 0
Are there alternate causes [other than the drug] that could solely have caused the reaction?
-1 +2 0
Did the reaction reappear when a placebo was given? -1 +1 0
NARANJO's ALGORITHM
Question Yes No Don’t know
Was the drug detected in the blood [or other fluids] in a concentration known to be toxic?
+1 0 0
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?
+1 0 0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
+1 0 0
Was the adverse event confirmed by objective evidence? +1 0 0
NARANJO's ALGORITHM
> 9 = definite ADR
5-8 = probable ADR
1-4 = possible ADR
0 = doubtful ADR
SCORING FOR
NARANJO's ALGORITHM
Other methods
Irey’s method
Karch and Lasanga’s Method
Blanc et al’s method
Kramer et al’s method
FDA(Jones Method)
Emmanuel and Sacchetti’s method
The French Method
Stephen’s personal scoring method
Venulet et al’s method
Methods of assessment
Expert judgment/global introspection
Probabilistic methods (Bayesian approaches)
Three broad categories
Methods of assessment
Expert judgments(global introspection): They are individual assessments based on previous knowledge
and experience in the field.
Algorithms : Are sets of specific questions with associated scores for calculating the likelihood of a cause-effect
relationship.
Bayesian approaches: use specific findings in a case to transform the prior estimate of probability into a posterior
estimate of probability of drug causation
Desirable Attributes
Reproducibility
simplicity
Drawbacks
Different causality categories are adopted in each method, and the categories are assessed using different criteria.
Not entirely devoid of individual judgments, so inter-rater reliability can be low.
Which method to use?
Naranjo WHO
Widely used
WHO v/s Naranjo
A disagreement in causality assessment
was found in 31% cases
Mean time taken: • WHO 5.3±0.37
minutes vs. Naranjo 13.26±1.33 minutes
WHO: simple and less time consuming