ispe jh pharmacovigilance (1).pdf

7/26/2019 ISPE JH Pharmacovigilance (1).pdf

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An Introduction to

PHARMACOVIGILANCE

dr. J.W.S. Hajadi

Survival

Cure

Quality of Life

Conmfort

Prevention

Side Effect

Toxicity

Drug Interaction

Zero risk doesnt exist !

BENEFIT

RISK

DRUG


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Drug Effect

Patient

Illness

Drug

Environment

Pharmacovigilance - WHO

Defini tion :

Is the pharmacological science relating to the

detection, assessment, understanding and

prevention of adverse effects, particularly long-

term and short-term side effects of medicines.

Etymological roots :

pharmacon (Greek) = drugvigilare (Latin) = to keep awake or alert, to keep

watch

Importance of PV,WHO - 2002


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Definition of Pharmacovigi lance - MHRA

Pharmacoviglance is the process of :

Monitoring medicines including traditional herbal medicinesas used in everyday practice to identify previouslyunrecognised risks or changes in the patterns or frequencyof their adverse effects.Assessing the risks and benefits of medicines in order todetermine what action, if any, is necessary to improve theirsafe use. Providing information to users to optimise safe andeffective use of traditional medicine.

Monitoring the impact of any action taken.

Medicine and Healthcare products Regulatory Agency

What is Pharmacovigilance ?

Generally speaking, PV is the science of :

- collecting,

- monitoring,

- researching,

- assessing , and

- evaluating

information from healthcare providers and patients on the

adverse effects of medication, biological products, herbalism

and traditional medicines with a view to :

Identifying new information about hazards associated withmedicines,

preventing harm to patients.


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Safety of Medicines

WHO / Geneve 2002 - Guide to detecting andreporting adverse drug reactions :

The objective of the Guide are to raise awareness of the

magnitude of the drug safety problem and to convince

health professionals that reporting of adverse drug

rections is their moral and professional obligation.The ultimate goal of the Guide is to reduce drug morbidity

and drug mortality by early detection of drug safety problems

in patients and improving selection and rational use of drugs

by health professionals.

Marketing Authorisation

Is granted by the Regulatory Authority

after rigorous evaluation of data on :

SAFETY

EFFICACY

QUALITY


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Main steps of Pharmaceutical R&D

Research (2-10 years)

Preclinical testing (3-4 years)Laboratory and animal testing

Phase I (1 year)20-80 Healthy volunteers used todetermine safety and dosage

Phase II (2 years)100-800 Patient volunteers used to look forefficacy and side effects

Phase III (3 years)1000-8000 Patient volunteers used to

monitor adverse reactions to long-term use

0 2 4 6 8 10 12 14 16Years

5050--70%70%

20%20%

10%10%

5%5%

< 5%< 5%

RelativeRelative

CostCost

10000001000000

100100

1010

66

22

Agencies Review/

Approval

Drug Safety Evaluation along thevalue chain

Clinical PhasesPreclinical Phases

Phase I(safety)

Phase II(safety/efficacy)

Phase III(safety/efficacy)

Phase IVPharmacovigilance

SD ExplTox

Teratology

carcinogenicity

Genetic ToxScreening

Genetic Toxicity

2-week Expl Tox

1 month Tox

Acu te Tox ici ty

Female Fertility

3/6 month Tox

Male fertility

Chronic Tox

Pre-Post NatalItyFirst Dose in HumanGLP

Mechanistic Toxicology

Pharmacovigilance

SafetyPharmacology

Exploratory Safety Pharmacology

PMS


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Safety Data : CT vs Post-marketing

Clinical Studies Marketed drugs Limited number of exposed patients

Blinded or open studies

Well-defined daily dose

Limited number of prescribers

(investigators)

Well-defined indication

Well-defined inclusion and non-inclusion

criteria to be enrolled in the study

Controlled co-medications

Strict clinical and/or biological monitoring

Large number of exposed patients

Uncontrolled co-medications (self

medication)

Variable compliance

Off label use

Limited monitoring

Difficult evaluation of the number ofexposed patients

Specific regulations, Internal interfaces:

Clinical development, projects, toxicology,

regulatory affairs

Specific regulations, Internal interfaces:

Regulatory affairs, Business units,

Current Drug Safety issues

Recent reports in the media on new, unexpected

and severe ADRs with new or existing products

leading to widespread publicity has become part of

our daily life.

Affecting : patients,

their doctor,

pharma company,

regulatory agencies,

legal system.


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Need for Postmarketing Surveillance and

ADR reporting The information collected during the pre-marketing phase of

drug development is inevitably incomplete with regard topossible ADRs. This is mainly because :Animal tests are insufficient to predict human safety; Patients used in clinical trials are selected and limited in number,the conditions of use differ from those in clinical practice and theduration of trials is limited; By the time of licensing, exposure of less than 5000 humansubjects allows only the more common ADRS to be detected;At least 30.000 people need to be treated with a drug to be surethat you do not miss at least one patient with an ADR which has anincident of 1 in 10,000 exposed individuals; Information about rare but serious adverse reaction, chronic

toxicity, use in special groups (i.e. children, elderly, pregnancy) ordrug interactions is often incomplete or not available.

Thus, post-marketing surveillance is important to permitdetection of less common but sometimes very serious ADRs.

Current PV issues

First World August 14, 2007FDA : Stronger warning to be added to some type 2 diabetesdrugsThe FDA announced that a stronger warning on the risk of heartfailure will be added to the thiazolidinedione class of type 2diabetes drugs (rosiglitazone and pioglitazone).

First World October 18, 2007EU regulator confirms benefit-risk profile for rosiglitazone andpioglitazoneThe EMEA concluded that the benefits pf rosiglitazone and

pioglitazone outweigh the risk in approved indications. The agencystated that it conducted a review of thiazolidinediones because ofnew information on potential side effects including bone fracturesin women and ischemic heart disease


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Current PV issues

First World September 17, 2007New York City, State suing Merck&Co. over VioxxThe city and state of New York filed a lawsuit against Merck&Co.over allegations that the drug maker misrepresented the risks ofVioxx. The suit is seeking tens of millions of dollars in damages andcivil penalties as restitution for money spent on prescriptions for theCOX-2 inhibitor therapy through healthcare program.

First World November 09, 2007Merck&Co. to settle Vioxx lawsuits, shares riseTo pay 4.85 billion to settle state and federal claims related to Vioxxin the US (as of October 9 : 27,000 lawsuits 47,000 plaintiff

groups as well as 264 class-action suits).

Current PV issues

Buletin BERITA MESO, Vol 25 No 2,November 2007 Pembatalan ijin edar dan penarikan produk yangmengandung Clobutinol HCl dari peredaran.....karena adanya informasi potensi efek samping KV.Walaupun belum ada laporan efek samping tersebut olehPusat MESO Nasional, namun keputusan ini merupakanbagian dari keputusan global......... Rosiglitazone terkait efek samping pada KV Metoklopramide terkait peningkatan laporan gejala ekstra-piramidal


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Magnitude of the Problem

Estimated that ADRs are the 4th 6th largest

cause for mortality in the USA

Percentage of hospital admissions due to ADRs in

some countries is about or more than 10% :

Norway 11.5% France 13.0% UK 16.0%

A high financial burden on health care for drug

related problems. Medicine related problems

include drug abuse, misuse, poisoning,

therapeutic failure and medication errors.

Lazarou J. et al, 1998. Incidence of ADR in hospitalized patients : a meta-

analysis of prospective studies.JAMA, 1998,279 (15) 1000-5.

Why PV is needed in every country

There are differences among countries (and even

regions within countries) in the occurence of ADRs

and other drug-related problems. This may be due

to differences in eg : diseases and prescribing practices;

genetics, diet, traditions of people;

drug manufacturing processes used which influence

pharmaceutical quality and composition;

drug distribution and use, including indication, dose andavailability;

the use of traditional and complementary drugs (e.g. herbal

remedies) which may pose specific toxicological problems,

when used alone or in combnation with other drugs.


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How voluntary reporting on ADRs can prevent new medicine

tragedies from developing

It took many decades before the deleterious effects of aspirin on the G-I

tract became apparent or that the protracted abuse of phenacetin could

produce renal papillary necrosis. 35 five years elapsed before it became

clear that amydopyrine could cause agranulocytosis; and several years

before the association of phocomelia and thalidomide became obvious.

Withdrawals from the market as a result of spontaneous reportingINN Reason for Year of Year of

(brand name) withdrawal marketing withdrawal

bromfenac (Duract) serious hepatotoxic effect 1997 1998

encainide (Enkaid) excessive mortality 1987 1991

flosequinan (Manoplax) excessive mortality 1992 1993

temafloxacin (Omnifox) haemolytic anemia 1992 1992

benoxaprofen (Oraflex) liver necrosis 1982 1982

mibefradil (Posicor) multiple drug interaction 1997 1998

terfenadine (Seldane) fatal cardiac arrhytmias 1985 1998

How voluntary reporting on ADRs caninfluence labelling

Cyclophosphamide has been on the market for several years inmany countries. In January 2001 there were some new reactionsincluded in the labels : Steven-Johnson syndome and toxicepidermal necrolysis; they were not included in the PDR 1995.

For example : EPIDERMAL NECROLYSISERYTHEMA MULTIFORMESTEVEN-JOHNSON SYNDROME

Losartan was marketed in the USA since 1995. Some of the newreactions that have been discovered after launch and included inthe PDR are :

VASCULITISPURPURA ALLERGIC (incl. Henoch-Schoenlein purpura)

ANAPHYLACTIC SHOCKANAPHYLACTOID REACTION

Levofloxacin was launched in the USA in 1997. In February 2000the label

TORSADES DES POINTES

was included.


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How to recognize ADRs (1)

1. Ensure that the medicine ordered is the medicine received

and actually taken by the patient at the dose advised;

2. Verify that the onset of the suspected ADR was after the

drug was taken, not before and discuss carefully the

observation made by the patient;

3. Determine the time interval between the beginning of drug

treatment and the onset of event;

4. Evaluate the suspected ADR after discontinuing the drugs

or reducing the dose and monitor the patients status. If

appropriate, re-start the drug treatment and monitor

recurrence of any adverse events.5. Analyse the alternative causes (other than drug) that could

on their own have caused the reaction;

How to recognize ADRs (2)

6. Use the relevant up-to-date literatures and personal

experience as a health professional on drugs and their

ADRs and verify if there are previous conclusive reports

on this reaction. The manufacturer of the drug can also be

a resource to consult;

7. Report any suspected ADR to the person nominated for

ADR reporting in the hospital or directly to the National

ADR Center.


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What should be reported ? For new drugs report all suspected reactions, including minor

ones (In many countries drugs are still considered new up to 5years after marketing authorization);

For established or well-known drugs report all serious orunexpected (unusual) suspected ADRs;

Report if an increased frequency of a given reaction is observed;

Report all suspected ADRs associated with drug-drug, drug-food ordrug-food supplement (including herbal and complementaryproducts) interactions;

Report ADRs in special field of interest such as drug abuse, druguse in pregnancy and during lactation;

Report when suspected ADRs are associated with drugwithdrawals;

Report ADRs occuring from overdose or medication error;

Report when there is a lack of efficacy or when suspectedpharmaceutical defetcs are observed.

Thus, report all suspected adverse reaction that you consider

clinically important as soon as possible !

How to report ADRs ?

There are different Case Report Forms used in

different countries. Basically all of them have at

least 4 sections which should be completed :

1. Patient Information

2. Adverse Event or product problem

3. Suspected Medication(s)

4. Reporter


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1. Patient Information

Patient identifier

Age at time of event or date of birth

Gender

Weight

2. Adverse event or product problem

Description of event or problem

Date of event

Date of this report

Relevant tests/laboratory data (if available)

Other relevant patients information/history

Outcomes attributed to adverse event


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3. Suspected medication(s)

Name (INN and brand name)

Dose, frequency & route of administration

Therapy date

Diagnosis for use

Event abated after use stopped or dose reduced

Batch number

Expiration date

Event reappeared after reintroduction of the

treatment

Concomitant medical products and therapy dates

4. Reporter

Name, address and telephone number

Speciality and occupation


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Company A


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Where to send ADR reports

National Drug Regulatory Authority (in

Indonesia : Badan POM, Jl. Percetakan

Negara No. 23, Jakarta Pusat).

The manufacturer of the suspected

product.


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Systems for PMS of drug-associated

events Voluntary reporting

Intensified adverse drug reaction reporting

Special regiestries of drug-associated disorders

Intensive hospital monitoring

Multiple case control surveillance

Disease-based case control surveillance

Medical record linkage

Prescription event monitoring

Computers in physicians office

Terminology in PV

Adverse events

Adverse drug reactions

Side effects

Seriousness

Causality

Expectedness


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Terminology

Adverse events (experience)Any untoward medical occurence in a patient

treated with a pharmaceutical product wich is not

necessarily suspected as being due to the drug.

Adverse drug reaction

Side effect

Terminology

Adverse events

Adverse drug react ionsA response which is due to the drug and

considered noxious and unintended.

WHO : occures at doses normally used in man.

Side effects


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Terminology

Adverse events

Adverse drug reactions

Side effects

broad term to express any untoward event

occuring with the use of a product.(therapeutic effect = an unintended/undesirable

consequence of medical treatment),

(unintended consequence = effect that is unforeseen,

regardless of type / quality).

Severe vs Serious Event

Severe :

Term to describe the intensity (severity) of a

specific event.

Grading : mild moderate severe

Serious :

Term which is based on patient outcome criteria,

serves as a guide for defining regulatory reportingobligations.


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Seriousness Criteria

A serious medical occurence is one that at any dose

results in death

requires in-patient hospitalisation or

prolongation of current hospitalisation,

results in persistent or significant

disability/incapacity ,

is life-threatening,

cancerand congenital anomaly,

any event which suggests a signi ficant hazard

to a patient.

Expectedness

From the perspective of previously observed, an

event could be :

- Expected (= labelled)

The event is consistent with the available data in

the official product information (e.g. Investigators

Brochure, Core Data Sheet, Product

Information/label, etc.).

- Unexpected (= unlabelled)The event has not been recorded previously


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Causality

Certain

Probably / likely

Possible

Unlikely

Unclassified

Causality

CertainImplies a plausible time relationship to drug

administration which cannot be explained by

concurrent disease or other drugs/chemicals.

Response to dechallenge (= drug withdrawal)

should be clinically plausible.

Event must be definitive pharmacologically, using

a satisfactory rechallenge procedure if necessary.


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Causality

Probable / likelyEvent had a reasonable time sequence to

administration of drug which is unlikely to be

attributed to concurrent disease or other

drugs/chemicals.

There must be a reasonable response on drug

withdrawal.

Rechallenge is not required to fulfil this definition.

Causality

PossibleEvent had a reasonable time sequence to

administration of drug, but it could also be

explained by concurrent disease or other drugs /

chemicals.

Information on dechallenge may be lacking or

unclear.


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Causality

Unlikely

Temporal relationship to drug administration

makes a causal relationship improbable, or

Other drugs / chemicals, underlying disease or

other factors provide a more plausible explanation.

Causality

UnclassifiedThere is insufficient information to decide on other

options, or unclassifiable if the required

information in not likely to be forthcoming.


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Category of Report

CRITERIA

Seriousness

Expectedness

Relatedness

SERIOUS NON-SERIOUS

UNEXPECTED EXPECTED

RELATED UNRELATED

X

X

X

Source of Report (unsolicited)

Health Care professionals :

physicians, dentists, nurses, pharmacists, midwife,

etc.

Consumer (patient, lawyer, etc.)

Health Authorities

Literatures (journals, newspapers, etc.)

Internet

Etc.


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Source of Report (solicited)

Clinical trials

Registries

Post-approval programs

Disease management

Etc.

Reporting Procedures

National Drug Safety(BPOM)

Local Industry/Affiliate

Physician

MR

Form MESO

HQ Intl Agencies


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Timeframe for Reporting

In SERIOUS cases :

International Companies have to report to their

HQ within 24 hours.

HQ has the obligation to report to the European

Agency or FDA within 15 days.

Closing notes

Continuous monitoring on the safety aspects of a drug (and

device) is important to secure the safety of patients/

consumers.

Roles of regulatory agencies, physician, consumers and

industry are complementory and important

To ensure more active participation in PV activities (e.g.

reporting), National Center for Drug Safety to conduct

regular training on PV and establish a system to collect

reports on adverse event at least for those meeting SURcriteria.


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Thank You for Attention,

SAFETY FIRST !

Biodata

Name : Wiriadi S. Hajadi (James)

Place & DoB : Jakarta, June 22, 1951

Education : Medical Doctor, ATMA JAYA Catholic University

Jakarta (1980)

Working experience :

1990 2007 : sanofi-aventis Group (Medical & Regulatory

Director, Affiliate Pharmacovigilance Head, Member

of Management Committee)

1985 1990 : WKS / Dokter Puskesmas Jakarta Selatan1979 1985 : Ciba-Geigy Pharma (Associate Medical Director)

1978 1979 : Le Laboratoires Servier (Scientific Coordinator)

ispe jh pharmacovigilance (1).pdf

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