Pharmacovigilance

Presented By :

Vanita Tohan

Pharmacology

(M.Pharm,Ist year)

Introduction

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"Dying from a disease is sometimes unavoidable. But, dying from an adverse drug reaction is unacceptable“

Pharmacovigilance is the science and activities related to;

o Detection, o Assessment, o Understandingo Prevention of

Adverse effects or

Any other possible drug related problem.

Contd.

o The etymological roots are: pharmakon (Greek), “drug;” and vigilare (Latin), “to keep awake or alert, to keep watch.”

o Pharmacovigilance is used to describe the processes for monitoring and evaluating ADRs

o Recently, its concerns have been widened to include herbals, traditional and complementary medicines, blood products, biologicals, medical devices and vaccines“

(WHO, 2002)

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Why Pharmacovigilance?

Therapeutic

Effect

• Pre-Clinical Testing

• Clinical Trials

Side-effects

• Post Marketing Studies

• Pharmacovigilance

ADR

Historical examples

1880: Chloroform: Cardiac depression1922: Arsenical: Hepatic necrosis1923: Cinchofen: Hepatotoxicity1933: Aminopurine:Agranulocytosis1938: Sulfanilamide:Acute renal insufficiency 1950: Chloramphenicol: Gray baby Syndrome 1953: Phenacetin: Nephrotoxicity1961: Thalidomide: Phocomelia1972: Diethylstilbestrol: Vaginal adenocarcinoma 2004: Rofecoxib: Thrombophilia

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ADVERSE DRUG REACTION

o Adverse Drug Reaction: A response to a drug which is noxious and unintended at the therapeutic level i.e. occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.

o Adverse Event: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with the treatment.

o Side Effect :Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug.

Severity of ADR:

o Minor: No need of therapy, antidote,

or hospitalizationo Moderate: Requires drug change , specific

treatment, hospitalizationo Severe: Potentially life threatening,

permanent damage, and

prolonged hospitalization. o Lethal: Directly or indirectly leads

to death.

MODERATE

SEVERE

LETHALLETHAL

PREDISPOSING FACTORS FOR ADRs

o The main clinical factors which increase the chance that patients will experience an adverse reaction are listed below:

o Age - the elderly and neonates are at greatest risk

o Gender - women are generally at greater risk

o Race - ethnic origin may affect drug metabolism

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Contd.

o Impaired excretory mechanisms - reduced hepatic and/or renal function

o Polypharmacy - drug interactions

o Any previous history of an adverse drug reaction

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What is Pharmacovigilance?

Pharmacovigilance

Adverse effects

Adverse effects

Adverse effects

Adverse effectsAdverse effects

FUNCTIONS OF PHARMACOVIGILANCE

Collects reports , data, ADR’s etc.

Analyses and assesses the reports.

Promotes the safe use of drugs.

Creates appropriate structures and means of communication needed to

perform its tasks.

Identifying new information about hazards associated with medicines.

Preventing harm to the patients.

PHARMACOVIGILANCE - A SHARED RESPONSIBILITY

Company - legally and morally responsible for monitoring their product. Regulatory authorities – are responsible for the safety of the newly licensed drugs. Doctors – responsible for prescription of safe drugs to patients. Pharmacist & nurse – responsible for monitoring of drug therapy given to patients and identification and reporting of ADRs.

AIM OF PHARMACOVIGILANCE

o To improve public health and safety in relation to medicines, cosmetics, herbal products etc.

o Early detection of unknown adverse reactions and interactions

o  Identification of risk factors and possible mechanisms underlying adverse reaction.

o  Estimation of quantitative aspects of benefit/risk analysis of information needed to improve drug prescribing and regulation.

o To promote understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public. 14

Pharmacovigilance Process Flow

Pharmacovigilance Work Flow

PHARMACOVIGILANCE - DATA SOURCES

Spontaneous Reporting Systems

• National PV Centre / Drug Authority

Drug Bulletins

Adverse Reaction Case Reports by the MA (Master Agreement)

Periodic Safety Update Report (PSUR) provided by MA holder

Current paradigm of drug discovery & developments

Current paradigm of drug discovery & developments : Limitations

ADR Detection Methods

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• Passive surveillanceSpontaneous reporting system (SRS)Case series

• Stimulated reporting• Active surveillance

Sentinel sitesDrug event monitoringRegistries

• Comparatives observational studiesCross sectional studyCase control studyCohort study

• Targeted clinical investigations Descriptive studies

Natural history of diseaseDrug utilization study

SPONTANEOUS REPORTS

A communication by consumers or health care professionals to a company or Regulatory Authority that describes one or more ADR in a patient who was given the drug.

Plays a major role in the identification of safety signals once the drug is marketed.

Gives alerts on rare AEs that were not detected in earlier clinical

trials or pre marketing studies.

Provides important information on at risk groups, risk factors and clinical features of known serious ADRs.

CASE SERIES

Series of case reports can provide evidence of an association of a

drug and AE.

Generally more useful for generating hypothesis than for

verifying an association between drug exposure and outcome.

Certain distinct adverse events occur more frequently with drug

therapy, such as anaphylaxis, aplastic anaemia, toxic epidermal

necrosis and Stevens- Johnson Syndrome.

STIMULATED REPORTING

A method used to encourage and facilitate reporting by health

professionals for new products.

On line reporting of AE; Systematic stimulation of reporting of AE.

Limitations Data are often incomplete. Not useful to generate accurate

incidence rates. ACTIVE SURVEILLANCE More feasible to get comprehensive data on individual AE reports.To ascertain completely the number of AE via a continuous pre- organised process. E g : Follow up of patients treated with a particular drugs.

 SENTINEL SITES

Active surveillance carried out at Institutions, Nursing homes,

hospitals

etc.

Provide information such as data from specific patient subgroups,

drug

abuse etc.

LIMITATIONS

Selection biasness, Small number of patients and Increased costs.

DRUG EVENT MONITORING

Patients are identified by electronic prescription data or automated health insurance claims.

A follow up questionnaire can be sent to each physician or patient at

specified intervals. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events, and reasons for discontinuation can be included in the questionnaire.

Limitations: Poor physician and patient response rates and unfocused nature of

data collection can obscure important signals.

REGISTRIES

A registry is a list of patients presenting with same characteristics.eg:

Disease registry, drug registry or pregnancy registry.

Differ from each other depending on type of patient.

Information can be obtained by using standard questionnaire.

Comparative Observational Studies

Traditional epidemiologic methods are a key component in the

evaluation of adverse events.

Observational study designs are useful in validating signals from

spontaneous reports or case series.

Types of designs

Cross sectional study.Case control study.Cohort study.

Cross-sectional study (survey)

Data collected from a population of patients at a single point in time

(or interval of time) regardless of exposure or disease status.

Primarily used to gather data for surveys or for ecological analyses

Major drawback:Relationship between exposure and outcome cannot be directly addressed.

Case-control study

Cases of disease (or events) are identified.

Controls, or patients without the disease or event of interest, are then

selected from the source population.

The controls should be selected : the prevalence of exposure among

the controls represents the prevalence of exposure in the source

population.

Exposure status of the two groups is then compared.

Cohort study

A population-at-risk for the disease (or event) is followed over time for

the occurrence of the disease (or event).

Information on exposure status is known throughout the follow-up

and hence incidence rates can be calculated.

Comparison cohorts of interest are selected on the basis of drug use

and followed over time.

Multiple adverse events can also be investigated using the same data

source in a cohort study.

Descriptive studies

Primarily used to obtain the background rate of outcome events and/or establish the prevalence of the use of drugs in specified populations.

Natural history of disease: Focused on the natural history of disease, including the characteristics of diseased patients and the distribution of disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest.

Drug utilization study: These studies provide data on specific populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics.

Scope of Pharmacovigilance

Improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions.

Improve public health and safety in relation to the use of medicines.

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

Encouraging their safe, rational and more effective (including cost-effective) use, and

Promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public .

To monitor Adverse Drug Reactions (ADRs) in population.

To create awareness amongst health care 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.

Create a national centre of excellence at par with global drug safety monitoring standards

ORGANIZATIONS INVOLVED

WHO – collaborating center for international drug monitoring is Uppsala monitoring centre provides activities and events in PV.

CIOMS – council for international organizations of medical sciences-safety information communication between regulators and industries. ICH – international conference on harmonization discusses scientific and technical aspects of product registration.

WHO-ART – WHO adverse reaction terminology for coding clinical information to drug therapy.

India's Central Drugs Standard Control Organization (CDSCO)

o Headquartered in New Delhi, the CDSCO is India's main regulatory body for pharmaceuticals and medical devices.

o The Drug Controller General of India (DCGI) is responsible for the regulation of pharmaceuticals and medical devices.

o The DCGI is advised by the Drug Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC).

o The CDSCO establishes safety, efficacy, and quality standards for pharmaceuticals and medical devices.

o It publishes and updates the Indian Pharmacopoeia, a list of regulated pharmaceuticals and devices. 34

The Yellow Card

Product recall due to toxicityr.

A product recall is a request to return to the maker a batch or an entire production run of a product, usually due to the discovery of safety issues.

The recall is an effort to limit liability for corporate negligence (which can cause costly legal penalties) and to improve or avoid damage to publicity.

Recalls are costly to a company because they often entail replacing there called product or paying for damage caused by use, although possibly less costly than consequential costs caused by damage to brand name and reduced trust in the manufacturer.

Withdrawal of drug from market

Drug name Withdrawn Remarks

Thalidomide 1950s–1960s

Withdrawn because of risk of teratogenicity; returned to market for use in leprosy and multiple myeloma under FDA orphan drug rules.

Lysergic acid diethylamide (LSD) 1950s–1960s

Marketed as a psychiatric drug; withdrawn after it became widely used recreationally.

Diethylstilbestrol 1970s Withdrawn because of risk of teratogenicity.

Phenformin and Buformin 1978 Withdrawn because of risk of lactic acidosis.

Ticrynafen 1982 Withdrawn because of risk of hepatitis.

Phenacetin 1983 An ingredient in "A.P.C." tablet; withdrawn because of risk of cancer and kidney disease.

Methaqualone 1984 Withdrawn because of risk of addiction and overdose.

Zimelidine 1983 Withdrawn worldwide because of risk of Guillain-Barré syndrome.

Nomifensine (Merital) 1986 Withdrawn because of risk of haemolytic anaemia.

Triazolam 1991

Withdrawn in the United Kingdom because of risk of psychiatric adverse drug reactions. This drug continues to be available in the U.S.

Terodiline (Micturin) 1991 Prolonged QT interval.

Temafloxacin 1992Withdrawn in the United States because of allergic reactions and cases of haemolytic anemia, leading to three patient deaths.

Tolrestat (Alredase) 1997 Withdrawn because of risk of severe hepatotoxicity

Terfenadine (Seldane, Triludan) 1998Withdrawn because of risk of cardiac arrhythmias; superseded by fexofenadine

Mibefradil (Posicor) 1998 Withdrawn because of dangerous interactions with other drugs

Etretinate 1990s Risk of birth defects; narrow therapeutic index

Tolcapone (Tasmar) 1998 Hepatotoxicity

Temazepam (Restoril, Euhypnos, Normison, Remestan, Tenox, Norkotral)

1999

Withdrawn in Sweden and Norway because of diversion, abuse, and a relatively high rate of overdose deaths in comparison to other drugs of its group. This drug continues to be available in most of the world including the U.S., but under strict controls.

Astemizole (Hismanal) 1999 Arrhythmias because of interactions with other drugs

Conclusion Current progress in pharmacovigilance is marked by increasing use of databases and by attempts to make the process more proactive and organized.

Attempts are being made to augment the spontaneous, random nature of the generation of pharmacovigilance data and to make the process more systematic and structured.

There has been a coming together of academic, regulatory and industrial interests across many countries to produce the guidance documents for the conduct of pharmacoepidemiology studies.

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