Pharmacovigilance and the WHO

Collaborating Centre for International

Drug Monitoring in Uppsala

Technical Briefing Seminar in Essential

Medicines Policies, Geneva, October 2007

Ronald Meyboom, MD, PhD

The Uppsala Monitoring Centre
www.who-umc.org
16% of hospital admissions are drug-
related (medical ward). Nelson KM, Talbert
RL. Pharmacotherapy 1996;16:701-7.

Adverse drug reactions are the 5th

leading cause of death in a hospital.
Lazarou J. Pomeranz BH, Corey PN. JAMA
1998;279:1200-5.

Avoidable in ca. 50 %
 Definition of Pharmacovigilance:
(WHO, 2002, ISBN 9241590157)

• The science and activities relating to the

detection, assessment, understanding
and prevention of adverse effects or any
other drug-related problems
• Treatment evaluation science
 Why pharmacovigilance?

• Clinical trials focus on demonstrating

efficacy and tolerability (selected ‘healthy’
patients, limited in number and duration)
• Incomplete knowledge, e.g. effectiveness,
rare but serious adverse reactions,
interactions, ‘real-live’ patients, sub-
populations
• Do not produce all the information needed
for the balance of benefit and harm
 How pharmacovigilance?

• Spontaneous Reporting
• Intensive monitoring (hospital)
• Prescription Event Monitoring
• Case Control Surveillance
• Comprehensive population databases,
data-mining
• Patient series
• Observational studies
 Formal studies Vigilance

• Defined aim (identified • Open question:

problem) looking for the
• Hypothesis testing unexpected
(problem solving) • Hypothesis generation
(‘problem raising’)
• Established methods
• Exploratory,
(clinical trial, case controversial (SR,
control, cohort) PEM, CCS)
• Comparison • No comparison
• Limited in time, drugs, • Continuous, all drugs,
population, place total population
 Emphasis on

• Early warning
• Generation of knowledge
• Dissemination of information
• Rational and safe use of medicines
– Benefit and harm together
Three categories of adverse drug reactions
Need different methods for detection
An ABC of drug-related problems. Drug Saf 2000;22:415-23

Type A Clinical trial

(pharmacological)
Type B Spontaneous reporting
(hypersensitivity)
Type C Pharmacoepidemiology
(more frequent in challenge
exposed than in
unexposed)
 Spontaneous Reporting

• A country-wide system for the reporting

of suspected adverse reactions to drugs
• A case report is a notification from a
health care professional, describing the
history of a patient with a disorder that is
suspected to be drug-induced
• Limitations because of privacy protection
and medical secrecy
 Spontaneous Reporting

• When different doctors independently

report the same unknown and unexpected
adverse experience with a drug, this may
be a valid early signal
• Quantitative: more frequently reported
than expected from the background
Advantages of Spontaneous Reporting
• Effective
• ‘All’ patients; ‘all’ drugs; many ADRs
• Continuous
• Rapid
• Cheap
• Not much health care infrastructure
needed
Limitations of Spontaneous Reporting
• Suspicions, incomplete, uncertain
• Underreporting is vast but unknown
and variable
• Exposure data available?
• No frequency measurement
• Comparison of drugs difficult
• Insensitive to type C adverse effects
• Further study for signal testing and
explanation
Data assessment in pharmacovigilance

1. Individual case report assessment

• Interest, relevance (new, serious?)
• Medical, pharmacological; coding
• Follow-up
• Causality assessment
2. Aggregated study and interpretation
• Signal detection
• Risk factors, interactions
• Serial (clinicopathological) study
• Frequency estimation
General design of systems for
causality assessment
Drug Safety 1997;17:374-389

• Basic questions
– Sub-questions
• Scores
• Overall score
• Causality category,
e.g. possible, probable, etc
None of the available systems has been
validated (i.e. shown to consistently and
reproducibly gives a reasonable
approximation of the truth)

• Validation = ‘proving that a procedure

actually leads to the expected results’
• No gold standard
• Causality category definitions
• What causality • What causality assessment
assessment can do cannot do
– Decrease disagree- – Give accurate quantitative
ment between measurement of relationship
likelihood
assessors
– Distinguish valid from invalid
– Classify relationship
cases
likelihood (semi-
– Prove the connection
quantitative) between drug and event
– Mark individual case – Quantify the contribution of
reports a drug to the development of
– Education / improve- an adverse event
ment of scientific – Change uncertainty into
assessment certainty
 Underreporting

• Vast (> 90%)

• Unknown
• Variable
• Biased
• Difficult to adjust for
• No frequency calculation
• Delays signal detection
A signal is a set of data constituting a
hypothesis that is relevant to the
rational and safe use of a medicine
Hypothesis, data, arguments

• Pharmacological
• Clinical/pathological
• Epidemiological
• Quantitative / qualitative
• Dynamic; develops over time

Drug Safety 1997;17:355-65.

 100
//
90
signal assessment
80
Knowledge of adverse effect (%)

70

60

50

40

30

20

10

0
//
signal signal signal Time
generation strengthening follow-up
 The balance of evidence in a signal
• Quantitative strength of the association
– number of case reports
– statistical disproportionality
– drug exposure
• Consistency of the data (pattern)
• Exposure-response relationship
– site, timing, dose, reversibility
• Biological plausibility of hypothesis
– pharmacological, pathological
• Experimental findings
– e.g. dechallenge, rechallenge, blood levels,
metabolites, drugdependent antibodies
• Analogies
• Nature and quality of the data
– objectivity, documentation, causality assessment
• Signal detection is searching for the unknown.
The same data can lead to different
conclusions. Since the truth is unknown it is
uncertain who is right, but nobody is wrong!
• Dilemma: a signal should be early and credible
at the same time
• Signals may consist of only a few cases and
may not be statistically prominent
• A signal is a snapshot and changes over time
• Signal testing and explanation require further
study
• Many signals remain unconfirmed
– scientific limitations
– no funding
 WHO Collaborating Centre for
International Drug Monitoring

The Uppsala Monitoring Centre

Stora Torget 3, 75320 Uppsala, Sweden
www.who-umc.org
 The Uppsala Monitoring Centre

• 1968 - WHO Collaborating Centre for

International Drug Monitoring, Geneva
• 1978 - Moved to Uppsala after agreement
between Sweden and WHO
• Non-profit foundation with international
administrative board
• WHO Headquarters responsible for policy
• Self-financing
• Global pharmacovigilance
 The Uppsala Monitoring Centre

• Director: Prof Ralph Edwards

• Deputy director: Dr Marie Lindquist
• International affairs: Sten Olsson
• Pharmacists
• (Bio)medics
• IT specialists
• Financing (‘Products and Services’)
• Administrative
• Together 45
WHO International Pharmacovigilance
Programme, March 2006
 Aims and activities
• Collaboration with National Centres
• World-wide collection, analysis and
distribution of data
– Signal detection and analysis
– Pooling of data, comparing experiences
• Communication, exchange of information
• Technical support
• Development of methods and tools
• Improvement of pharmacovigilance around
the world
Cumulative number of reports
in ’Vigibase’
World-wide accumulation and assessment
of data
• 80 participating National Pharmaco-
vigilance Centres around the world
• 3.5 million case reports
• Early warning - acceleration of signal
detection
• Early signal strengthening by
comparing countries
Automated quantitative signal detection
• Extremely large numbers of drug -
adverse reaction combinations
• Selects automatically high-interest
combinations, using quantitative
disproportionality
• Manageable subsets of data
• No human time needed
• No investigators bias
• Objective, transparent, reproducible
• Flexible / adjustable
• Explorative
 Signal detection at the
Uppsala Monitoring Centre
Eur J Clin Pharmacol 1998;54:315-321
A combination of
1. Automated quantitative data mining,
using Bayesian statistics and a
neural network architecture
(Information Component – ‘IC value’)
2. ‘Triage’
3. Human assessment
– National Centres
– Review Panel
– UMC staff
Triage filter, combining quantitative and
qualitative criteria; automatic selection of
associations that

• IC025 > 0; two or more countries

• Quarterly IC increase of 2 or more
• New and serious (WHOART Critical
Terms)
• Target reaction terms (e.g. SJS), two or
more reports, irrespective of IC value
 Literature check
 Captopril - Coughing
6

-1
IC
-2
79:1 81:1 83:1 85:1 87:1 89:1 91:1 93:1 95:1
Time(year)
 In fo rm a tio n C o m p o n e n t

-6
-4
-2
0
2
4
6
" 1 9 8 8 :1 "
" 1 9 8 9 :1 "
" 1 9 9 0 :1 "
" 1 9 9 1 :1 "
" 1 9 9 2 :1 "
" 1 9 9 3 :1 "
" 1 9 9 4 :1 "
" 1 9 9 5 :1 "
" 1 9 9 6 :1 "
" 1 9 9 7 :1 "
All SSRI

" 1 9 9 8 :1 "
withdrawal syndrome

" 1 9 9 9 :1 "
" 2 0 0 0 :1 "
" 2 0 0 1 :1 "
" 2 0 0 2 :1 "
SSRI Neonatal convulsions or neonatal

" 2 0 0 3 :1 "
Example of results in one Quarter (2004)

Total number of combinations: 60000

No. of associations IC025 > 0: 2300
Triage selection: 560
No. of signals for SIGNAL: 28
 Signal Review Panel

• 40 Experts around the world

• Evaluate signals, together with UMC
staff and National Centres
• Select associations for follow-up
• Write signals in the SIGNAL document
• Preference for System Organ Class or
drug group (ATC)
 The SIGNAL document

• Sent to all National

Centres (national
distribution)
• Individualized
section available to
industry
• All recipients
encouraged to
comment on topics
presented
 Presentations at ISOP annual meeting 2006
• HMG-CoA inhibitors and pulmonary fibrosis
• β-2-Adrenoceptor agonists and nocturnal
enuresis
• Systemic effects of intranasal cortico-
steroids (neuropsychiatric reactions,
spontaneous abortion)
• Taxoids (paclitaxel and docetaxel) and
myocardial infarction
• Hypersensitivity reactions to Umckaloabo
(Pelargonium sidoides and P. reniforme)
• Potentiation of warfarin by glucosamine
 Examples of articles
• Clark DW, Strandell J. Myopathy including
polymyositis: a likely class adverse effect
of proton pump inhibitors? Eur J Clin
Pharmacol 2006;62:473-9.
• Sanz E, et al. Selective serotonin reuptake
inhibitors in pregnant women and neonatal
withdrawal syndrome. Lancet 2005;365:
482-7.
• Coulter D, et al. Antipsychotic drugs and
heart muscle disorders in international
pharmacovigilance: data mining study.
BMJ 2001;322:1207-9.
 Support to National Centres

• Methodology
• Terminologies, guidelines
• Software (VIGIFLOW)
• Harmonisation, standardisation
• VIGIMED email discussion group
• Annual meetings
• Training
• Books and brochures
 Terminologies, guidelines
Links with WHO Geneva, CIOMS, ICH
• WHOART
• Drug Dictionary
• Guidelines for setting up and running of
a Pharmacovigilance Centre
www.who-umc.org/DynPage.aspx?id=13136&m
n=1512#8
• Herbal ATC
• Accepted scientific names of therapeutic
plants. 2005, ISBN 91 974750 3 3.
• WHO guidelines on safety monitoring of
herbal medicines
 Harmonisation, standardisation

• Definitions (Biriell C, Edwards IR. Drug

Safety 1994;23:95-9)
• WHO causality categories
• Reporting adverse drug reactions.
Definitions of terms and criteria for
their use (CIOMS Council for International
Organizations of Medical Sciences. WHO,
1999, Geneva. ISBN 92 9036 071 2.)
 Herbal and traditional medicines

• UMC Herbals database (Dr Mohamed

Farah)
• Herbal reviewers panel
• Collaboration with
– Uppsala University, Sweden
– WHO Collaborating Centre, Cape Town,
South Africa
– Royal Botanical Garden, Kew, UK
– University of Exeter, UK
– Harvard, US
 New development areas
• Integrate Chinese ADR database
• Patient safety focus including medication errors
– World Alliance for Patient Safety
• Improved reporting and analysis of vaccine
reactions (AEFI)
– Flu pandemic planning
• Safety surveillance for other Public Health
Programmes
• Involvement in active surveillance
– Cohort Event Monitoring
• Data mining analysis of longitudinal patient
records
 Thank you for your attention

info@who-umc.org
www.who-umc.org