Pharmacovigilance

Moderator: Dr. Mohammad Tariq Salman

Presented by : Dr. Fariha Fatima

Junior Resident 1

Pharmacovigilance

What is Pharmacovigilance

???

“The science and activities relating to the detection,

evaluation, understanding and prevention of adverse

drug reactions or any other drug-related problems.”

Pharmakon (Pharmacon) = Drug

+

Vigilare = to watch; alert watchfulness;

- watchfulness in respect of danger;

- process of paying close and continuous attention.

• So Pharmacovigilance generally refers to continuous

monitoring for unwanted effects and other safety – related

aspects of marketed drugs.

Why pharmacovigilance is needed ??? Tests in animals are insufficiently predictive of human safety.

In clinical trials patients are selected and limited in number—may miss rare ADRs

Conditions of use in trials differ from those in clinical practice—may miss drug interactions; Off-label uses.

Duration of trials is limited—may miss ADRs that develop after years.

Special groups (such as children, the elderly or pregnant women)—not involved in clinical trials.

Illegal sale of medicines and drugs of abuse.

Increasing self-medication practices OTC drugs.

Widespread manufacture and sale of counterfeit and substandard

medicines.

Increasing use of traditional medicines and herbal medicines with

other medicine with potential for adverse interactions.

Additional factors which enhance the need of Pharmaco-Vigilance:

The ultimate goal of Pharmacovigilance is to ensure the safe and

rational use of medicines, thereby, improving patient care and

public health.

To prevent unnecessary suffering by patients and to decrease the

financial loss sustained by the patient due to the inappropriate or

unsafe use of medicines.

What are the major Aims of PV ??? According to WHO….

Early detection of unknown safety problems

Detection of increases in frequency

Identification of risk factors

Quantifying risks

Preventing patients from being affected unnecessarily

Rational and Safe use of Medicines

Some of the drugs are mandatorily banned by Drugs

Controller General of India (DCGI) but are still available in

the market (e.g. human placental extract).

Adverse Drug Reaction (ADR)?

The Drug Regulatory Authority defines an Adverse Drug

Reactions (ADR) or adverse reaction as a response to a

medicine used in humans or animals, which is noxious and

unintended, including lack of efficacy, and which occurs at

any dosage and can also result from overdose, misuse or

abuse of a medicine.

Type of

Reaction

Mnemonic Features Examples Mx

A: Dose

related

Augmented Common,

Related to ph.

Action,

Predictable,

Low mortality

Digoxin toxicity,

SSRI serotonin syn.

S/E

TCA- anti-Ach

Reduce dose or

with hold

B: Non-dose

related

Bizarre Uncommon,

Not related to

ph. Action,

Unpredictable,

High mortality

Idiosyncratic

reaction,

Acute porphyria,

Malig.

Hyperthermia,

Withhold and

avoid in future

C: Dose

related and

time related

Chronic Uncommon,

Related the

cumulative dose

Steroid- decrease

HPA axis

Reduce doses or

withhold

withdrawal

- slowly

- prolonged

Type of

Reaction

Mnemonic Features Examples Mx

D: Time

related

Delayed Uncommon,

Dose related,

Teratogenesis ,

Carcinogenesis,

Tardive

dyskinesia

Often

intractable

E: Withdrawal End of

use

Uncommon,

After

withdrawal

Opioid withdrawal

MI- β blocker

withdrawal

Reintroduce

and withdraw

slowly

F: Failure of

therapy

Failure Common,

Dose related,

Caused by

drug

interaction

Contraceptive

failure

Increase dose,

Consider effect

of concomitant

therapy

ADRs are common and constitute major health problem.

World statistics show that 5 -10% of the hospital admissions are attributed to adverse drug reactions, and 0.3% of adverse reactions are fatal in nature.

Several studies in Europe, Israel, and USA have estimated 5-10% of all admittance to emergency medical ward are due to ADRs.

As many as 98,000 death in USA per year due to medical error.

Severity of ADR: it has been graded as:

Minor: no therapy , antidote or prolongation of

hospitalization is required.

Moderate: requires change in drug therapy, specific

treatment or prolongs hospital stay by atleast one day.

Severe: potentially life threatening, causes permanent

damage or requires intensive medical treatment.

Lethal: directly or indirectly contributes to the death of the

patient.

Side effects:

These are unwanted but often unavoidable

Pharmacodynamic effects that occur at therapeutic doses.

They can be predicted from the pharmacological profile of a

drug and are known to occur in a given percentage of drug

recipients.

Reduction in dose generally ameliorates the symptoms.

Toxic effects:

These are the results of excessive pharmacological action of

drug due to overdosage or prolonged use.

Overdosage may be :

Absolute(accidental,homicidal,suicidal)

Relative (i.e., usual dose of gentamicin in presence of renal

impairment)

Who should report Adverse Drug Reactions?

All health care workers, including doctors, dentists, pharmacists,

nurses and other health professionals are requested to report all

suspected adverse reactions to drugs (including vaccines, X-ray

contrast media, traditional and herbal remedies),

especially when the reaction is unusual, potentially serious or

clinically significant.

Firstly, find out whether a patient taking Suspected drug or not

Obtain complete details of Event ,Suspected drug & other Relevant information

Event:-

•Time of onset

•Duration

•Nature & Severity

•Previous history

Suspected drug:-

•Name (Trade name if possible)

•Dose (frequency & duration)

•Time & Route of administration

•Previous report of reaction

Other relevant information:-

•Patient’s demographic data

•Presenting complaints

•Past medication history

•Current drug therapy details

•OTC medications

•Treatment with any other system of medicine

•Risk factors

Causality assessment

Patient’s interview Reviewing prescriptions

How do we detect ???

Causality assessment :

To determine likelihood of a causal relationship b/w

drug exposure and adverse events.

Causality Classification:

The WHO has provided a list of causality assessment

criteria for deciding on the contribution of the medicine

towards the adverse event.

WHO Definitions for Causality Assessment:

Certain:

Clinical event, lab test abnormality with plausible time

relationship to drug intake.

Cannot be explained by concurrent disease or other drugs

/chemicals.

Response to dechallenge- plausible.

Event must be definitive pharmacologically /

immunologically.

Positive rechallenges (if performed).

Probable/ Likely:

Unlikely to be to concurrent disease, drugs / chemicals.

Clinically reasonable response to withdrawal (dechallenge).

Rechallenge not required.

Clinical event, lab test abnormality with reasonable time


Possible:

Clinical event lab test abnormality with reasonable time


Could also be explained by concurrent disease or other

drugs or chemical.

Information on drug withdrawal may be lacking or unclear.

Unlikely:

Clinical event , lab test with improbable time relationship to

drug intake.

Other drugs , chemicals or underlying disease provide

plausible explanations.

Inaccessible /unclassifiable:

Insufficient /contradictory evidence which cannot be

supplemented or verified.

Conditional / unclassified:

More data is essential for proper assessment or additional data

are under examination.

Periodic Safety Update Reports

(PSURs)

Provides an update of world-wide safety experience at 6

months for 2 years, annually for two years, and then 5-yearly

or immediately on request

Description of the reaction

Detail about the Contents

Overall safety evaluation

Approval of the product, new drugs should be closely monitored for their

clinical safety once they are marketed. The applicants shall furnish

Periodic Safety Update Reports (PSURs) in order to-

a) Report all the relevant new information from appropriate sources;

b) Relate these data to patient exposure;

c) Summarize the market authorization status in different countries

and any significant variations related to safety; and

d) Indicate whether changes should be made to produce information in

order to optimize the use of the product.

Schedule Y :

Structure of PSUR:

A title page stating: Periodic safety update report for the product,

applicant’s name, period covered by the report, date of approval of

new drug, date of marketing of new drug and date of reporting;

Introduction,

Current worldwide market authorization status,

Update of actions taken for safety reasons,

Changes to reference safety information,

Estimated patient exposure,

Presentation of individual case histories,

Studies,

Other information,

Overall safety evaluation,

Conclusions,

Appendix providing material relating to indications, dosing,

pharmacology and other related information.

The Licensing Authority reserves the right to reject

any data or any document(s) if such data or contents of

such documents are found to be of doubtful integrity.

The Drug Regulatory Authority and the Department of

Health’s Essential Drug Programme are committed to

improving drug safety through adverse drug reaction

monitoring .

Through the Drug Regulatory Authority’s national

pharmacovigilance programme, adverse reactions should be

reported on a daily basis.

In general, the prime activity of the Pharmacovigilance

Program of India (PvPI) is to collect, collate and analyze

data on adverse drug reactions to arrive at an inference to

recommend regulatory interventions, besides communicating

associated risks to healthcare professionals.

In June 2010, Central Drugs Standard Control Organization

(CDSCO), Directorate General of Health Services under the

aegis of Ministry of Health & Family Welfare, Government

of India in collaboration with Indian Pharmacopeia

Commission, Ghaziabad initiated a nation-wide

Pharmacovigilance programme for protecting the health of

the patients by assuring drug safety with well defined goal

with predestined road map to ensure its future growth and

progress.

Objectives of the PvPI:To monitor Adverse Drug Reactions in Indian population.

To create awareness amongst healthcare professionals about

the importance of ADR reporting in India.

To monitor benefit-risk profile of medicines.

Generate independent, evidence based recommendations on

the safety of medicines.

Support the CDSCO for formulating safety related

regulatory decisions for medicines.

Communicate findings with all key stakeholders.

Create a national centre of excellence at par with global

drug safety monitoring standards.

Program was designed in five phases which included:

initiation phase (2010-2011)

expansion and consolidation phase (2011-2012),

expansion and maintenance phase (2012-2013),

expansion and optimization phase(2013-2014)

Excellence phase (2014-15).

Phase I (Initiation phase), 2010 -2011

Enrol 40 medical colleges.

Start data collection for Adverse event following

immunization.

Development and establishment of training centre.

Training of pharmacovigilance human resource.

Linkage with uppsal monitoring centre, sweden.

Initiate software development for national drug safety data

base.

Publication of drug safety news letter.

Phase II (Expansion and consolidation phase), 2011-2012

Enrol additional 60 medical colleges.


Training in pharmacovigilance software provided by UMC.

Identify gaps and address through appropriate training

Software development and validation.

Zonal workshop for public awareness of drug safety.


Phase III (Expansion and maintenance phase),2012- 2013:

Enroll additional 100 medical college.


Zonal workshop for public awareness of drug safety.


Phase IV (Expansion and optimization phase), 2013- 2014:

Enroll additional 100 medical college.


Interaction with international pharmacovigilance bodies.


Phase V (Excellence phase) 2014-2015

Create centre of excellence for pharmacovigilance in Asia

pacific

To ensure that the PvPI is functioning effectively and

achieving its objectives, there is a provision to monitor and

evaluate the program using indicators viz ;

(i) process (i.e. process number of AMCs participating in the

PvPI, number of AMC personnel trained in a year, funds

budgeted for PvPI and funds spent and AMC personnel

working full-time for PvPI).

(ii) outcome (i.e. software platform established, outcome

number of ADR reports received in a year, number of ADR

reports processed in a year and number of ADR reports

submitted to Vigiflow) and ;

(iii) impact (i.e. number of impact signals generated and

confirmed, number of safety related alerts issued by

CDSCO).

Drug safety suveillance relies heavily on the techniques of

pharmacoepidemiology which includes:

Voluntary Reporting:

doctors, nurses and pharmacists are supplied with cards

on which to record suspected adverse reaction to drugs.in

the UK this is called the ‘yellow card’ system and the

committee on safety of medicines collates the results and

advises the government’s medicines control agency.

It is recommended for :

Newer drugs: all suspected reactions should be noted.

Established drugs: all serious suspected reactions should be

reported, even if the effect is well recognised.

HISTORICAL BACKGROUND

Non systematized form

Thalidomide disaster in early 1960

Yellow card system in UK (now CSM)

Spontaneous reporting system in USA in 1968 by FDA

Benefits of spontaneous reporting are:

Early recognition/actual potential problem

Continuous monitoring system

Compare ADR profile

Iatrogenic syndrome/predisposing factors

What to report ??? 22

For new drugs

All suspected reactions including minor ones.

For established drugs All serious or unexpected ADRs

Any increased frequency of a given reaction

All suspected ADRs associated with drug-drug interactions

ADRs of special population Elderly, Child, Pregnancy &

Lactation

ADRs associated with Drug abuse & Drug withdrawals

ADRs occurring from overdose or medication error

Lack of efficacy

All adverse events should be reported.

Need and Advantage of Spontaneous Reporting

Large population can be covered

All marketed drugs can be monitored

Drug may be monitored throughout their lifetime

Risk factors predisposing to ADR may be identified

Inexpensive and simple ADR system

PEM (Prescription Event Monitoring):

Generating and testing hypothesis about ADRs in defined

population of users.

Active Surveillance: Registries

Hospital-based systems: Intensive Surveillance

Form of observational cohort study.

Medical record linkage:

Allows computer correlation in a population of life and

health events(birth , marriage ,death , hospital admission)

with history of drug use.

The largest medical record linkage is the General

Practitioner Research Data Base at the Medicines Control

Agency.

Population statistics: eg . Birth defect registers and cancer

registers.

These are insensitive unless a drug induced event is highly

remarkable or very frequent.

If suspicions are aroused then case control and

observational cohort studies will be initiated.

Conclusion

If all healthcare professional including physicians, nurses,

pharmacist and others including the patient report all ADRs

then regulatory authority can take action as soon as possible,

and drugs which are banned worldwide may be not available

in India too.

Careful premarketing screening should reduce the problem

but may also reduce the number of potentially useful drugs

available for full development and subsequent licensing.

Better risk management strategies are needed to handle

problems when they arise, by means other than revocation of

licenses.

You can reduce the suffering and save thousands of

patients lives by doing one thing :

Report suspected adverse drug

reactions

Health & Medicine

Pharmacovigilance