Upload
ikhwanyudakusuma
View
274
Download
6
Embed Size (px)
Citation preview
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
1/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
2/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
3/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
4/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
5/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
6/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
7/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
8/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
9/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
10/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
11/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
12/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
13/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
14/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
15/27
Company A
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
16/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
17/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
18/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
19/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
20/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
21/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
22/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
23/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
24/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
25/27
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
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
26/27
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.
7/26/2019 ISPE JH Pharmacovigilance (1).pdf
27/27
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)