PHARMACOVIGILANCE

- An Overview

What is Pharmacovigilance?

Pharmakon = drug Vigilare = to keep watch

Development of science and regulation in drug safety.

Safety of drugs under the practical conditions of clinical use

Identifying new information about hazards associated with medicines, preventing harm to patients

Pharmacovigilance: science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions

WHO

History Thalidomide tragedy (1961-62): The

greatest of all drug disasters.

Thalidomide: introduced and welcomed as a safe and effective drug for the treatment of nausea and vomiting in early pregnancy.

Tragically the drug proved to be a potent human teratogen that caused major birth defects in an estimated 10,000 children

Phocomelia was a characteristic feature

Aim of PV

improve patient care and safety

improve public health and safety

contribute to the assessment of benefit, harm, effectiveness and risk of medicines

promote understanding, education and clinical training

Need of PV

Insufficient evidence of safety from clinical trials Animal experiments Phase 1 – 3 studies prior to marketing

authorization

Medicines are supposed to save lives!

Phase IVPost-approval studies to

determine specific safety issues

Clinical development of medicines

Animal experiments for acute toxicity, organ

damage, dose dependence, metabolism, kinetics,

carcinogenicity, mutagenicity/teratogenicity

PreclinicalAnimal Experiments

Phase I Phase II

Development Post Registration

Phase III Phase IVPost-approval

SpontaneousReporting

Phase I

20 – 50 healthy volunteers to gather preliminary data

Phase II150 – 350 subjects with disease - to determine

safety and dosage recommendations

Phase III250 – 4000 more varied

patient groups – to determine short-term safety

and efficacy

Drug Development

Standard conditions

limited group of selected patients

narrow population: age and sex specific

narrow indications: only the specific disease studied

short duration: often no longer than a few weeks

Clinical trials Phase 1-3 limitations

Adverse Events vs Adverse Drug Reactions

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

ADR: A noxious and unintended response to a drug at normal doses for prophylaxis, diagnosis or therapy of disease

ADEs

ADRs

Diseases

Genetics

Other Drugs

Environment

Diet

Other factors

Types of ADRs

Type A Effects (“Augmented”): common, dose dependent & predictable

Type B Effects (“Bizzare”): rare, dose independent & unpredictable

Type C Effects (“Chronic”): after long term therapy, no time relationship

Type D Effects (“Delayed”): may be presented years after Type E Effects (“End of treatment”): Absence of drug after

withdrawal

Serious Adverse Drug Reactions

ADRs that is either:• life-threatening, • fatal, • cause of prolong hospital admission, • cause persistent disability

Unexpected Adverse Drug Reactions

ADR, the nature or severity of which is not consistent with market authorization, or expected from the characteristics of the drug.

Causality Assessment

Association in timeLikelihood of a causal relationship between drug exposure and adverse events

It is necessary to evaluate Temporal relationship between drug use and event Dechallenge and rechallenge information Pharmacology (including current knowledge of nature and

frequency of adverse reactions) Medical or pharmacological plausibility (signs and

symptoms, tests, pathological findings, mechanism)

Few assessment scales for causality evaluation include: WHO probability scale Naranjo scale Karch and Lasagna scale Jones scale

Causality Assessment

WHO probability scale:Certain: positve dechallenge & positve rechallenge Probable: positve dechallenge & negative rechallenge Possible: temporal relationshipUnlikely: disease or drug provide plausible explanationsUnclassified: more data needed (under assessment)Unclassifiable: data cannot be verified

NA RANJO'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 specif icantagonist was administered?

+1 0 0

Did the AR reappear when drug was readministered? +2 -1 0

Are there alternate causes [other than the drug] that could solely havecaused the reaction? -1 +2 0

Did the reaction reappear when a placebo was given? -1 +1 0

Was the drug detected in the blood [or other f luids] in a concentrationknow n to be toxic? +1 0 0

Was the reaction more severe when the dose was increased, or lesssevere when the dose was decreased? +1 0 0

Did the patient have a similar reaction to the same or similar drugs in anyprevious exposure?

+1 0 0

Was the adverse event confirmed by objective evidence? +1 0 0

> 9 = definite ADR5-8 = probable ADR1-4 = possible ADR0 = doubtful ADR

Signal: reported information on a possible relationship between an adverse event and a drug, unknown or incompletely documented previously

Usually more than a single report is required to generate a signal

Data mining pharmacovigilance databases - become increasingly popular with the availability of extensive data sources and inexpensive computing resources

Signal Detection

New drug: Any drug product that has not been marketed for more than five years

PSUR: A report containing information collected by marketing authorisation holders through pharmacovigilance activities. It is usually required by regulatory authorities for drugs that have not been marketed for more than five years

Periodic Safety Update Report (PSUR)

ADR Reporting

Spontaneous reporting: healthcare professionals (and in some countries consumers)

Aggregate Reporting: compilation of safety data of drug over a prolonged period of time - PSUR

Expedited Reporting: serious and unlabelled event Within clinical trials such a cases is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction)

Clinical Trial Reporting: safety information from clinical studies

Working of PV

Patient-HW

Suspicion of ADR

PV Unit/Coordinator

hand

delivery

Reporting ADR

NDA

PV Unit/MoH

HQ

fax - mail

courier

Analyze ADR& submit to WHO/UMCdatabase

Analyze globalADRs

Web

upload

Sharing the findings

• India – Central Drugs Standard Control Organization (CDSCO)• UK – Medicines and Healthcare Products Regulatory Agency

(MHRA) • USA – Food and Drug Administration (US FDA)• Europe - The European Medicines Agency (EMEA)• Japan - Ministry of Health, Labor and Welfare (MHLW)• Australia – Therapeutic Goods Administration• Canada – Heath Canada• Switzerland - Swiss Agency for Therapeutic Products

Regulation of PV

EudraVigilence – data processing network for reporting and evaluating suspected ADRs in European Economic Area

WHO- Uppsala Monitoring Centre (WHO-UMC) in Sweden– Established in 1978– Coordination of the WHO programme for International

Drug Monitoring– Collection, processing of data, Education, Research

International cooperation in Drug Safety

Increased awareness and interest amongst doctors and pharmacists to report ADRs

More hospitals and companies using on-line reporting system – less hassle than submitting hard copy reports

Increasing involvement by hospital pharmacists in pharmacovigilance – during clinical ward rounds and when counseling patients

Current Scenario of PV

Current Scenario of PV

Increasing number of clinical trials being conducted especially in Singapore, Thailand and Malaysia

GCP training for investigators served to increase awareness of SAE and ADR reporting amongst health care professionals and the industry

New PV challenges! Generic Substitution Increased self medication Increased use of herbal medicines outside

traditional culture of use Biosimilars Widespread Counterfeiting Illegal sale on internet