Yellow Card Scheme and
Adverse Drug Reactions:
Current Research and Future Developments
Munir Pirmohamed
Director YCC North West
David Weatherall Chair of Medicine
University of Liverpool
Yellow Card Scheme
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Early warning of previously unrecognized ADRs
(signal generation)
Identification of predisposing factors
Comparing ADR profiles of drugs in the same
therapeutic class
Continual safety monitoring of a drug
throughout its marketed life
An important dataset used in making decisions
on drug safety for regulatory purposes
Burden of ADRs
Study
Setting
Number of patients
studied
Frequency of ADRs
ADULTS
Pirmohamed et al1
Hospital
admission
18,820
6.5%
Davies et al2
In-patients
3,695
14.7%
Hospital
admission
8,345
2.9%
CHILDREN
Gallagher et al3
ADRs are under-reported:
Thiesen et al
In-patients
16,601
17.7%
• 4% of ADRs are reported
• 10% of serious ADRs
Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital:
prospective analysis of 18 820 patients. BMJ 2004; 329: 15-9.
• EC,Our
suggests
1%M.are
Davies
Green CF,work
Taylor S, Williamson
PR, Mottram only
DR, Pirmohamed
Adverse reported.
drug reactions in hospital
4
1
2
in-patients: A prospective analysis of 3695 patient episodes. PLoS One 2009; 4:e4439.
3
Gallagher RM, Mason JR, Bird KA, et al. Adverse drug reactions causing admission to a paediatric hospital.
PLoS One 2012; 7:e50127.
4
Thiesen S, Conroy EJ, Bellis JR, et al. Incidence, characteristics and risk factors of adverse drug reactions in
hospitalized children - a prospective observational cohort study of 6,601 admissions. BMC medicine 2013;
11:237.
Yellow Card
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th
50
Anniversary
Yellow Card Roadmap
Important aspect of future strategy
Local Initiatives
MRC Centre for Drug
Safety Science
Yellow
Card
Centre
North
West
Wolfson
Centre for
Personalised
Medicine
Liverpool Health
Partners
Social Media
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80% of users look for
health-related
information online
6000 tweets per second
Can you use social
media to identify signals
of ADRs?
Genetic Contribution to ADRs
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Many factors predispose to
adverse drug reactions
Genetic factors are also
important
The genetic effect will vary
according to drug and
reaction
In order to investigate this,
patients need to be
recruited
Difficult to identify for rare
adverse reactions
Yellow cards as a source of
patients for genetic studies
Technology-Based Reduction in the Burden of
ADRs: The Case of Abacavir Hypersensitivity
Clinical genotype
Association with
HLA-B*5701
Clinical phenotype
Incidence before and after testing for HLA-B*5701
Country
Pre testing
Post testing
Reference
Australia
7%
<1%
Rauch et al, 2006
France
12%
0%
Zucman et al, 2007
UK (London)
7.8%
2%
Waters et al, 2007
Investigator
approaches MHRA
for access to yellow
cards
Investigator defines
phenotype for
investigation
MHRA Searches yellow card
database and identifies
appropriate cases
Anonymised list of cases
sent to investigator
Approval also gained from
Independent Scientific
Advisory Committee
RECRUITMENT
OF CASES VIA
THE YELLOW
CARD SYSTEM
Investigator identifies cases
to recruit and send list back
to MHRA
MHRA contacts reporters
(letter, PIL and consent
form)
Reporter contacts patient
with letter, PIL and consent
form
Patient Interested
Patient send back reply slip
to investigator
Patient send back reply slip to
investigator
Patient Consents
Patient
recruited
Process for
Recruiting
• Ethical
approval
• Utilised for
drug-induced
liver injury
• Further areas
being explored
• Return rate is
1 in 10
Yellow Card Biobank
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Prospective collection of cases: soon as possible after report
received
Focus on serious adverse drug reactions – to be decided by a
working group
We rely heavily on pharmacoepidemiology in making
regulatory decisions. Such decisions would be strengthened
by more information on biological plausibility.
The development of a biobank would be in keeping with the
emerging area of regulatory science
A YC biobank would in most cases not have enough samples
on one drug/ADR combination, but is likely to bear fruit if
combined with samples from other sources including CPRD, GP
practices, specialist clinics etc.
MRC Centre for Drug Safety
Science: Mission
To use the critical mass and knowledge in drug safety
science that we have now accrued within the Centre:
 to undertake leading edge science, and train the next
generation of drug safety scientists
 to understand the fundamental mechanisms of clinically
important, and currently relevant, adverse drug
reactions
 to develop strategies to improve the benefit-risk ratio of
current and new medicines, for the benefit of patients,
industry and regulators.
ADRIC: Adverse Drug Reactions
in Children
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Funded by a NIHR Programme Grant
Many different workstreams
Two most important have been:
• ADRs causing hospital admission
• ADRs occurring in hospital
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17.7% of whom experienced at least one ADR.
Opiate analgesics and drugs used in general anesthesia (GA) accounted for
more than 50% of all drugs implicated
Risk factors
• GA: HR 6.40; 95% confidence interval (CI) 5.30 to 7.70).
• Increasing age (HR 1.06 for each year; 95% CI 1.04 to 1.07)
• Increasing number of drugs (HR 1.25 for each additional drug; 95% CI 1.22 to
1.28)
• oncological treatment (HR 1.90; 95% CI 1.40 to 2.60).
Quantitative Risk-Benefit
Analysis
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Evaluation of benefits and risks is important to
all stakeholders (patients, clinicians, industry,
regulators etc)
Decision making in relation to risk and benefit is
complex, and often subjective
While expert opinion and experience will always
be important, can more objectivity be
introduced into complex decision making?
Follow on from ADRIC aims to focus on this area
The Burden of Adverse Drug Reactions in Adults
Admission
(6.5%)
In patients
(14.7%)
Emergency
Room
(2.5%)
Primary Care
(25%)
Quantify
Evaluate
Intervene
Top 3 ADRs Causing Hospital
Admission
1.
2.
3.
Peptic ulceration and GI bleeding from
NSAIDs and low dose aspirin
Renal impairment caused by diuretics
Warfarin related adverse events
(bleeding, high INR)
Top 3 ADRs Causing Hospital
Admission
1.
Peptic ulceration and GI bleeding from
NSAIDs and low dose aspirin
• New mechanisms identified with a future
view to better prevention
2.
Renal impairment caused by diuretics
• Personalised renal function monitoring
(CLAHRC)
3.
Warfarin related adverse events
(bleeding, high INR)
Warfarin
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Number of users UK:
600,000
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Dose (mg) range per day:
0.5-20
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Fold variability in dose:
40
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Major bleeding rate per 100person years:
2.6
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Ranking in ADR list:
3
Approved for human use in 1954
Determinants of Anticoagulation Control
McLeod and Jonas, 2009
Most replicated genotype-phenotype association
Pharmacogenetic-Based Dosing: Warfarin
Randomised Controlled Trial
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FP7 sponsored EU trials
454 patients
 226 in genotype arm
 228 in standard care arm
Point of Care test for
genotyping
European Union Pharmacogenetics
of AntiCoagulant Therapy
Genotyped arm
%TTR
Standard dosing
(control) arm
%TTR
Adjusted
Difference
P value
ITT ANALYSIS (n= 211 vs 216)
67.4%
60.3%
7%
P<0.001
PER-PROTOCOL (n=166 vs 184)
68.9%
62.3%
6.6%
P=0.001
PRIMARY OUTCOME MEASURE: Percent time within therapeutic INR range 2.03.0 (TTR) during 12 weeks following the initiation of warfarin therapy
Differences Between GenotypedGuided Group and Control Group
No difference between genotyped
and control arms
Algorithmic strategy
 Ethnic heterogeneity
 Control arms
 Clinical relevance
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“Genotype added
information
Beyond clinical risk
scoring”
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YC system is going to evolve
over the next 50 years
Electronic reporting is likely to
become the norm
Novel ways of identifying and
using YC data to improve the
benefit-harm ratio of drugs
A great deal of local expertise
which is quantifying, evaluating
and preventing ADRs
Please interact with us at the
YCC North West