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Decision making and
communication in
the face of
uncertainty: the
challenge of
pharmacovigilance.
I Ralph Edwards
WHO Foundation Collaborating
Centre for International Drug
Monitoring
A critique of pharmacovigilance
 Current tools and resources are not used maximally to
deliver useful outputs for patient care
• Current decision–making processes do not result in
public confidence
• Current practice underplays several areas of safety
importance
• Current gaze of regulation is on the control of drugs,
not the safety of patients
What issues I will cover
• Decision making in drug safety
• Delays in action (examples)
– Outcome research?
• Prevention in drug safety
– Effectiveness and risk
• Comparison between medicines
– Risk assessment
• Communication and miscommunication
– Communication of uncertainty
• Patient involvement
– Patient, and not drug, safety
• An international Programme
Decision making in drug safety
Items in red are key issues to be tackled
Managing a signal ?
Public
Information
1
Public
Information
2
Increasing information and knowledge
(also misinformation)
A
first
signal
SCARE
Media coverage
Five broad activities essential
to pharmacovigilance:
• Suspected ADR signal generation and formation of
hypotheses
Decisions
• Analysis of all issues around the signal, particularly
confirmation (or refutation) of hypothesis, estimation of the
size of the risk and whether susceptible patients exist
Decisions
• Consideration of possible effectiveness-to-risk issues in
therapy (comparative)
– How to do it?
– Economics
Decisions
• Communication of information to health professionals and
patients in a useful way. And possible regulatory action.
• Consequence evaluation.
Decisions
Do we really use our tools?
• Studies tell us about populations and not
individuals
– Most ADRs are rare (< 1/1000)
• Large numbers of patients and controls needed
• Case reports can tell us a huge amount about
what concerns individual
doctors/h.p’s/consumers
– We could get much more information on what
happens to people, medication error, interactions,
patients at risk, how to diagnose ADRs, etc.
Frequently repeated myths?:
• Case reports
– Cannot prove causality
– Under-reporting is a big problem
– Bias is unavoidable
• Epidemiological studies
– Prove/disprove causality
– Only, should be used for regulatory
action and information
• Databases
– What actually happens (effectiveness
and risk)?
Delays in action (examples)
Consequences - Outcomes research needed
Example of a decision problem to
be solved [1] ...
Cisapride - heart rhythm disorders
• 1986: double blind study “cisapride
produced tachycardia”
• 1992 WHO Signal published in Br
Med J on serious arrhythmia
letters to Br Med J “no epidemiological
support”
• 1995 case report published, Lancet
“QT prolongation and tachycardia”
Dear Doctor letter in USA by manufacturer
Example of a decision problem to
be solved [2] ...
• Piroxicam is the most GI toxic of the
NSAIDS in several comparative studies
– GI toxicity is a major cause of morbidity
• Why is it still available?
Example of a decision problem to
be solved ?? [3] ...
• . At the WHO Meeting,Tunis ( Oct,
2000) the Netherlands Monitoring
Centre (Lareb) presented the first
signal of cardiovascular disorders
relating to rofecoxib, for 8
cardiovascular ADRs (of 62 total
reports) with 4 fatalities and which
occurred early in treatment. (ROR 12.4
(4.5-35), all drugs: 12.0 (3.8-38.2),
NSAIDS
Consequences
• Newspaper article
showing extensive
scars on the legs of a
young woman following
venous thrombectomy
• Cause for thromboses
given as Diane
(cyprotereone acetate :
ethinyloestradiol) used
for acne
Consequences
• Patient given wide media coverage
• Many patients reported to stop taking
Diane
• Dermatologist rings National Monitoring
Centre
– ' Many patients taking Diane are also taking
Roaccutane. The logic is to provide both
contraception and an additional (anti-androgenic)
therapy for their acne'.
– 'They are at risk for malformed fetus, if they
stop contraception'
Consequences
• Since all prescriptions of Roaccutane
must be prescribed by a dermatologist
– And patients must give informed consent
• Notify all dermatologists
• Call in patients on Roaccutane
• Advise about contraception and relative
risks of Diane
• Also make a media announcement on the
above
Consequences
• No unwanted pregnancies reported!
• By luck and rapid, complete and
appropriate action a disaster was
anticipated and avoided
• But this was a special case!
Consequences
• Letter:
– The 'Dear Doctor' letter on cerivastatin, interaction and
rhabdomyolysis
• ....do not co-prescribe with ....
• Intention:
– To change prescribing, to reduce rhabdomyolysis particularly
linked with interaction with gemfibrosil
• Result:
– After 3 letters and 2 years only a 2% reduction in coprescription, BUT more reports sent to the authority
• Lesson:
– Check response; modify approach; give guidance as well as
warning
This is only part of the story!
•
•
•
•
•
•
Vigilance
Signal
Hypothesis
Analysis
Probability
Frequency
•
•
•
•
•
•
•
Epidemiology
Signal
Hypothesis
Analysis
Confirmation
Probability
Frequency
Prevention in drug safety
Effectiveness and risk
Need for comparison between medicines
Risk assessment
The true balanced concepts
• Efficacy (hard data)
• Effectiveness
• Benefit
feels)
NO!
• Hazard
• Risk
Yes!
(what the patient
• Harm
(soft data)
Size and severity of the ADR problem
Meta-analysis
• 39 prospective studies from US
hospitals
• Overall incidence of serious ADRs =
6.7%
• Overall incidence of fatal ADRs =
0.32%
(106 000 individuals)
• 4th - 6th leading cause of death
Lazarou et al JAMA 1998;279: 1200 - 1205
6.7% of hospital patients have serious adverse
drug reactions (medication error excluded)
Lazarou J. Pomeranz BH, Corey PN. JAMA 1998;279:1200-5
16.2% of hospital admissions are drug-related
Therapeutic failure
54.8%
Adverse reactions
32.9%
Overdose
12.3%
Avoidable
49.3%
Nelson KM, Talbert RL. Pharmacotherapy 1996;16:701-7
Pirmohamed M JS, Meakin S, Green C, Scott AK,
Walley TJ, Farrar K, Park BK, Breckenridge AM.
Adverse drug reactions as cause of admission to
hospital: prospective analysis of 18 820 patients.
BMJ 2004;329(7456):15-19.
• ….identifies the main drug culprits in a large
hospital based study. They are old drug
groups (low dose aspirin, diuretics, warfarin,
and non-steroidal anti-inflammatory drugs
other than aspirin: the most common reaction
being gastrointestinal bleeding) on which we
have much information……
Proposed risk assessment
Eliminating risk (not possible!)
• Risk specification
• Risk plan
– Milestones
• Risk minimisation
• Start early and continue
• High potency, high risk
products
– Tripartite involvement:
• Prescriber
• Dispenser
• Patient
How do the new compare with the old?
Some new challenges
• Medication error
• ADR diagnosis
• Therapy adherence
– ‘Intelligent non-compliance’
• Lack of effect
– Sub-standard and counterfeit drugs
• Interactions
• Herbals
• Public health programmes
– incl. Vaccines
• Comparisons of therapies
– UK NICE
– Data mining
Communication and
miscommunication
Communication of uncertainty
Effectiveness/risk
communication
•
•
•
•
The correct message
To the right audience
By the right medium
Consequences
–
–
–
–
Message received?
Message understood?
Followed up?
Acted upon appropriately?
Warning and communication of risk
-now
• SPC
– Use of PSUR
– Legal v. Communication
– Which section of SPC
• Contra indication,
warning
– When changed?
– Design ?
• ‘Dear Health Professional‘
communication
– Web
– Design
– Repeated
• Media
• Bulletins
Warning and communication of risk
• Players may have competing interests
in communication even if public health
is a common aim
• Media
– Dramatic news a priority
– Internet
• No control
• Wide range of issues possible
– Difficult to predict response
– Prepare for rapid and intense
communication
Warning and communication of risk
– the future
• Outcomes
– Follow up?
• Questionnaires
– General
– Specific
– Need more information on outcomes
– Better public education
– Less paternalism
• Better view of us!
• Openness
– Constructive law & media interaction
The Erice Declaration on Communicating
Drug Safety Information
•
The following declaration was drawn
up at the International Conference on
Developing Effective Communications in
Pharmacovigilance, Erice, Sicily, 24-27
September 1997. It was attended by health
professionals, researchers, academics, media
writers, representatives of the
pharmaceutical industry, drug regulators,
patients, lawyers, consumers and international
health organisations.
The Erice Declaration
•
1. Drug safety information must
serve the health of the public. Such
information should be ethically and
effectively communicated in terms of
both content and method. Facts,
hypotheses and conclusions should be
distinguished, uncertainty
acknowledged, and information provided
in ways that meet both general and
individual needs.
The Erice Declaration
• 2. Education in the appropriate use of
drugs, including interpretation of safety
information, is essential for the public
at large, as well as for patients and
health-care providers. Such education
requires special commitment and
resources. Drug information directed
to the public in whatever form should be
balanced with respect to risks and
benefits.
The Erice Declaration
• 3. All the evidence needed to assess and
understand risks and benefits must be
openly available. Constraints, on
communication participants, which
hinder their ability to meet this goal
must be recognised and overcome.
Managing a signal: the future
Public
Information
2
Public
Information
1
A first
signal
Pre-marketing risk
management
Increasing information
and knowledge
(also misinformation)
Media coverage
Patient involvement
Patient, and not drug, safety
Patient involvement
• Patients need more general information
about drugs and their effectiveness and
risk
• VERY IMPORTANT
– We need much more information about
what risks patients are prepared to take
for what benefit to them. Until we know
this we will continue to ‘second-guess’
about what is acceptable or not
Measuring true effectiveness and
risk
• Needs knowledge
finding in patient
care databases
– E.g Data mining in
IMS Health database
of 2 million patients
• Can show
comparative
effectiveness and
risk
– Data quality
Fluoxetine
Amitrityline
(One
Year)
Suicidality
An international Programme
WHO Programme for International
Drug Monitoring
plus Global Alliance for Patient
Safety
Functions
• Collection and processing of international ADR data
– > 3.5 million concerns about drugs from HPs and
patients since 1968
• Signal detection and analysis
– Available free
• Tools
– WHO DD and terminologies are world standards
• Research
– Data mining of patient care databases
• Information and feedback
• Education and support
• Harmonisation
Conclusions
• Think less about drug safety: more about patient
safety
• Think less about regulating and automating data
input: more about useful information output
• Think more about impact and consequences of
decisions and non-decisions
• Think more about global cooperation: not
competition