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Drugs withdrawn from Market due to severe ADR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