Pv

1. Introduction to
Pharmacovigilance
Rana EL-Bakry
Lecturer of Clinical Pharmacy & Pharmacy Practice
B.Sc., M.Sc., Ph.D., MBA, IMCert.
Special Thanks to Prof.Dr. Mahmoud Khattab for his kind assist in preparation of the material

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WHO Definition of
Pharmacovigilance (PV)
’’The science and activities relating
to the detection, assessment,
understanding and prevention of
adverse effects or any other drug-
related problems”

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Ethical Face & Importance of PVG
 It may be reasonable that disease-induced
mortality/morbidity is sometimes UNAVOIDABLE with
continuous improvement of therapeutic modalities
(610,000 die of heart disease/year in USA, CDC)
 It is unreasonable to accept medicines-induced
harm/mortality that is PREVENTABLE
40,393 drug-induced deaths occurred in the USA (1999-2010)(http://www.cdc.gov/mmwr/preview/mmwrhtml/su6203a27.htm)

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PVG and Economic Impact
 Preventable Adverse Drug Reactions account for a
high percentage of hospital admission and LOS
(Primohamed et al., BMJ 2004)
 The cost of drug-related morbidity and mortality
exceeded $177.4 billion in 2000 in the USA (Ernst &
Grizzle, J Am Pharm Ass 2001)

7. Adverse Event
An unanticipated, undesirable, or potentially dangerous occurrence in a health care
organization.
First Dose ResponseF-PHY-010-89 First dose response 2.pdf
Causality Causality Assessment of Suspected ADRs -F-PHY-010-78.pdf
Medication Error medication error categoery.pdf

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Sources of Adverse Drug
Reactions for PV
 Preclinical Animal Studies
o Safety Pharmacology
o Toxicity Data
 Clinical Trials especially Phase II & III
 Post-marketing ADRs monitoring (Phase IV):
o Rare but severe ADRs
o Risk Factors
o Interactions

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Preclinical
Development
Discovery
Clinical
Development
Phases I, II, III
Approval
Marketing
Post-
marketing
Surveillance
Investigational
New
Drug
IND
Proof of
Molecular
Target
Safety &
Efficacy
Dose Ranging
Drug Delivery
Pivotal Proof
of Safety &
Efficacy
Human PK
Dose Selection
Post-marketing
Surveillance for
Safety and
Efficacy
Drug Development Process

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Emergence of Pharmacovigilance
Thalidomide Disaster
 Late 1950s, Thalidomide was marketed with
unjustified claims as of safety in pregnancy
outside USA as a sedative in absence of any
regulatory activity
 The drug turned out to be a teratogen,
producing a variety of birth defects but
particularly limb defects known as phocomelia
 It is only quite recently, in the early 1990s,
where that the term pharmacovigilance has
become widely accepted
Child affected by thalidomide-induced phocomeli

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Timeline of the historical evolution of Pharmacovigilance
Fornasier, G., Francescon, S., Leone, R. et al. An historical overview over Pharmacovigilance. Int J Clin Pharm 40, 744–747 (2018).
https://doi.org/10.1007/s11096-018-0657-1

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Lessons From Thalidomide
• The need for adequate pre-marketing testing of medicines under
regulatory governmental authority
• Systems that can identify the adverse effects of medicines are essential for
their prevention
• Controlled use of medicines in pregnancy
• Some risks can be successfully minimised

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Risk Management and Risk/Benefit Balance
• Risk Management: the risk of fetal malformation could be successfully
managed by avoidance of the drug during pregnancy
• Risk/Benefit Balance: Thalidomide benefits in refractory multiple myeloma
outweigh the risk of fetal malformation together with an effective pregnancy
prevention scheme
• Special Population: Pregnant or women who are planning childbearing, are
at highest risk, but not all women

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Goals of PV
• Ultimate Goal of PV is to minimise practically the harmful potential
hazards of medicinal products specially those defined to be serious (Fatal,
Life-threatening, hospitalisation-causing, or associated with long-term
disability)
• All congenital abnormalities are considered serious
• As per medical judgement a reaction may be considered serious, even if
there is not clear evidence that one of the above criteria is met

16. PV and Public Health
• PV may be seen as a public health function in which minimization in the occurrence of
serious harms are achievable through procedures promoting the safest possible use of
drugs
• Preventive specific measures against known hazards
 Pregnancy prevention in users of teratogenic CVS drugs as ACEIs is an example of
preventive measures
 Monitoring white blood cell counts to detect agranulocytosis in the antipsychotic drug
clozapine users is another example
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1970s
Practolol-Induced Oculo-mucocutaneous
Syndrome
• Several thousand individuals were permanently damaged before the association was
recognised
• The monitoring doctors failed to report association between Practolol and oculo-
mucocutaneous syndrome early because:
the unusual nature of the syndrome: dry eyes, skin rash and bowel obstruction
long latency period almost two years
• The association was identified in the medical literature
• Around 3,000 cases were then retrospectively reported to the UK ‘Yellow Card’ system
• Establishing animal model of practolol toxicity failed, making pre-clinical study of no
benefit

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Lessons from Practolol
• Pre-clinical studies cannot predict some ADRs
• Long drug-induced adverse effects and unusual clinical signs may not report
as ADRs by physicians
• Spontaneous ADR reporting alone is not efficient as a measure of studying
post-marketing safety

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Benoxaprofen (Opren)-Associated Death Reports
‘Prescription-Event Monitoring’
• Benoxaprofen (Opren), a NSAID with large number of photosensitivity
reactions spontaneous reports was withdrawn in 1982 because of a published
case series of five deaths related to hepatic and renal failure
• Many of the Opren users who reported serious ADRs were elderly, a
population in which the drug was not studied before marketing
• A reduction in the dosage recommendations for the elderly was implemented
briefly but it was too late to save the drug

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Lessons from Opren
• Importance of causality assessment of effect from individual case reports
• Studying drugs in special populations
• The need for purpose-designed computer systems to handle ADRs more
promptly and effectively
• The need of intensive surveillance of new drugs, achieved in the EU by the
introduction of the Black Triangle scheme ▼
• The need for patients to be informed about possible ADRs (PIL)

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Pharmacoepidemiology
• In the mid-1980s, pharmacoepidemiology was first used to mean the
scientific discipline of the study of drug use and safety at a population level
• During the 1990s with the increasing use of computerised databases
containing records of prescriptions and clinical outcomes for rapid and
efficient study of potential safety hazards

22. Benzodiazepine-Induced
Dependence
• Chlordiazepoxide (Librium) and diazepam (Valium)
that had been introduced in the 1960s
• Recommendations were issued to limit the dose and
duration of such treatments but are widely ignored
• The issue highlighted the problems faced in dealing
with the misuse and abuse of prescription drugs
• This is another example of a serious ADR that escaped
spontaneous ADR reporting
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False Hazard Identification
Bendectin Case
• Bendectin, a combination product containing an antihistamine doxylamine, was
widely used for the treatment of nausea and vomiting of pregnancy in the 1970s
• In the early 1980s, it was withdrawn based on foetal malformations’ concerns
• At the time, the evidence of teratogenicity was very weak, but it was not possible
to ignore a significant risk to the foetus
• In 2013, and then an extended-release version in 2016, the combination vitamin
B6 (pyridoxine) plus doxylamine were approved by the FDA in the US for
treatment of nausea and vomiting of pregnancy in women who do not respond
to dietary and lifestyle changes (evidence for safety and efficacy).
• Why back to use a suspected teratogen?

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Oral Contraceptives (OCs) and the Risk of Venous
Thromboembolism (VTE)
• In the late 1960s, when it was discovered through spontaneous ADR reporting
and confirmed in formal studies that combined OCs increased the risk of VTE
• A reduction in the dose of ethinyl-estradiol to 20–30 μg lowered the VTE risk
without compromising efficacy
• When OCs were stopped abruptly by young active women without immediate
use of an effective alternative, unwanted pregnancies occurred, and abortion
rates increased
• The same occurred upon wrong perception of a possible association of OCs
use with myocardial infarction and a small increase in the risk of breast cancer

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Oral Contraceptives (OCs) and the Risk of Venous
Thromboembolism (VTE)
• In 1995 a WHO study of OCs unexpectedly found a two-fold increase in the
risk of VTE when use of so-called ‘third-generation’ OCs was compared to
‘second-generation’ OCs
• According to several trials, there was consensus that the absolute level of
VTE risk is quite rare in healthy young women, even if they take the pill
• This issue resulted in urgent need to develop and improve safety PV
Communications (1997)
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-possible-increased-risk-blood-clots-birth-control

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Lessons from OCs Risk of VTE
• Need to develop more effective safety communication tools
• Drugs are sometimes marketed at the wrong dose
• Harm may result from safety warnings
• Uncertainty and debate about risks may induce public concern
• The power of the media to influence users is much greater than the
authorities
• The need for greater international co-operation (harmonization) in
pharmacovigilance

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Lessons from OCs Risk of VTE
Type of Evidence
• The data on which they were based, did not come from spontaneous ADR
reporting
• The causation was debatable because the studies were not randomised
trials but ‘observational’
• VTE is a sufficiently rare outcome in young women that it would be extremely
difficult to conduct a large enough clinical trial to detect a doubling of risk

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Probable Drug-Induced and Disease-
Associated Risk
• Suicidal ideations and actions are of the criteria of depression
• In 1990, an American psychiatrist published a case series suggesting that
fluoxetine (Prozac) might be responsible for the observed increased suicidal
thoughts
• Clinical data showed the possible risk among other agents
• Children and adolescents were shown to be at high-risk
• Completed and attempted suicides are rare in clinical trials as are suicidal
ideation

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Probable Drug-Induced Disease-Associated
Risk
• Trials of paroxetine in children produced worrying findings that for some time
were known only to the manufacturer
• When the regulatory authorities eventually received the data, they issued
warnings against the use of this drug in children
• Prosecution was considered against the company
• To ensure clinical data transparency, considerable effort have been taken
towards making data publicly available through mechanisms other than
publication in the literature

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Coxibs and CVS Risk
• Coxibs-related CVS risk was first reported in basic research
• The first related clinical trial VIGOR was published in 2000, at a time rofecoxib
and celecoxib were authorized
• The VIGOR was a RCT comparing rofecoxib versus and naproxen to examine
the difference in the rates of serious gastrointestinal adverse effects of these
two drugs
• Rofecoxib was clearly preferrable, and the trial results led to rapid uptake of
coxibs on the basis that they were supposedly safer

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Coxibs and CVS Risk
• CVS events including MI were five-fold more common in patients taking
rofecoxib, compared to naproxen
• Data was presented in publication as a five-fold reduction with naproxen
rather than an increase with rofecoxib
• One FALSE finding from VIGOR study was that naproxen is ‘cardioprotective’
whereas rofecoxib is not
• Read the following article in the link below and write your comment: (N
Engl J Med 2005; 352:2576-2578
DOI: 10.1056/NEJMp058136)
https://www.nejm.org/doi/full/10.1056/nejmp058136

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Coxibs and CVS Risk
• A large clinical trial comparing rofecoxib with placebo to establish was the
link to increased CVS events as an adverse effect of rofecoxib or a lack of
benefit
• The findings of that study led to the drug being withdrawn from the market
in late 2004
• A question was raised why such a trial had not been done earlier before the
exposure of millions of people to the deleterious effects of the drug

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Current Methods in Pharmacovigilance
• PV, a branch of pharmacoepidemiology, is restricted to the study of ADE/ADR
on a population scale
• Studies are intended to be either ‘hypothesis-generating’ or ‘hypothesis-
testing’
• Hypothesis-generating studies for a newly marketed drug, aim to detect
unexpected ADRs
• Hypothesis-testing studies aim to prove whether any suspected ADEs (signals)
that may have been raised are justified

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Hypothesis-Generating Methods
Spontaneous ADR Reporting
• Health Care Professionals (HCP) are provided with forms to notify a central
authority of any suspected ADRs that they detect
• In the United Kingdom, the ‘yellow card’ has been used for this purpose since
1964
• Similar forms are provided in the FP10 prescriptions pads, the British National
Formulary

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Safety Issues Identified by the Yellow Card
Scheme
Serious haemorrhages from
dabigatran (Pradaxa) and the need
to closely monitor kidney function
 Interaction between grapefruit juice
and a particular brand of Amlodipine
 Seizures with the anti-smoking
medicine Zyban when taken with
other medicines
 Alopecia in women taking the
Yasmin contraceptive pill

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Information in a Yellow Card Report
• Suspected drug: For any given ADR it is important to include the route of administration,
daily dosing schedule, dates of administration, and the brand and batch number
• Suspected reaction: It is helpful to include when the reaction occurred in their treatment,
the seriousness of the reaction, any treatment given and the outcome of the reaction
• Patient details: It is important to know the patient’s age at the time of reaction, gender and,
if possible, the weight
The Yellow Card database is designed to be anonymous so full name and date-of-birth are
not required, but it may be useful to provide initials and a local identification number to
identify the patient in any future correspondence
• Reporter details: MHRA does contact reporters from time to time for further information, so
it is important for full details of the reporter (name and address) to be provided

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MedWatch ADRs Reporting Program
• In the United States, the MedWatch form is used and is made broadly available to health professionals
to encourage reporting
• Forms for Reporting to FDA at www.fda.gov found at
https://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm
• Form FDA 3500 - Voluntary Reporting
chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/76299/download
 For use by healthcare professionals, consumers, and patients. Submit the completed form using built-in
postage-paid mailer, or fax
• Form FDA 3500B - Voluntary Reporting for Consumers
• Form FDA 3500A - Mandatory Reporting
 For use by IND reporters, manufacturers, distributors, importers, user facilities personnel

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Introduction to FDA's MedWatch Adverse Event Reporting Program, by Brenda J. Rose
www.fda.gov

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Spontaneous Reporting
• The advantage of spontaneous reporting is that it includes the whole of
lifetime of drugs
• It is the only affordable method of detecting rare ADRs
• It provides the opinion of health professional attending a real-life patient-
drug exposure and outcome

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Spontaneous Reporting
• The main disadvantage is that there is huge under-reporting
• The data provide a ‘numerator’ (the number of reports of each suspected
reaction) only
• It is an essential method by which health professionals can reporting their
suspicions about patient-drug related events

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Spontaneous Reporting
• Spontaneous reporting has resulted in the identification and verification of
many unexpected and serious ADRs
• These findings have resulted in many marketed drugs being withdrawn or
additional information being provided to guide safer use of the product

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Prescription Event Monitoring (PEM)
• PEM, conducted in the UK and New Zealand, represents a blend of aspects of formal
epidemiological surveillance and spontaneous reporting
• In UK, within National Health Service (NHS), prescriptions written by general
practitioners are sent, to a central Prescription Pricing Authority (PPA)
• The PPA provides confidential copies of certain prescriptions for newly introduced
drugs that are being monitored to the Drug Safety Research Unit (DSRU) at
Southampton responding Six or twelve months thereafter
• The prescriptions provide the patient-drug ‘exposure data’ and the DSRU green
forms provide the ‘outcome data’ showing any events noted during the monitoring
period