Monitoring the outcome of
risk minimisation activities
iPhVWP Polish Presidency, Warsaw October 6th 2011
Almath Spooner
Irish Medicines Board
Benefit-Risk Management
New EU legislation on
Pharmacovigilance:
Promote and protect
public health by
reducing burden of
adverse drug reactions
through effective
risk minimisation and
optimising use of
medicines.
13/04/2015
Slide 2
Regulation EU 1235/2010 - Legal basis for
Risk Management System
• Risk Management System:
‘ a set of pharmacovigilance activities and
interventions designed to identify,
characterise, prevent or minimise risks
relating to a medicinal product, including
the assessment of the effectiveness of
those activities and interventions’.
• Risk Management Plan:
‘ a detailed description of the risk
management system. ‘
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Slide 3
Waller P and Evans S. A model for the future conduct of Pharmacovigilance.
Pharmacoepidemiology and Drug Safety, 2003; 12: 17–29
Best Evidence
Culture of
Scientific
Development
Robust scientific
Decision Making
Outcome
measures and
audit
Tools for protecting
public health
Measurable performance in terms of
public health benefit
Risk Minimisation Activities
• Public health interventions intended to prevent
the occurrence of an adverse reaction
associated with the exposure to a medicine or to
reduce its severity should it occur.
• Routine – Summary of Product Characteristics,
Package leaflet, use of product labelling
• Additional – targeted risk communication
through healthcare professional or patient
education or control of the use of the medicine.
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Evaluating the need for Risk Minimisation
For each important safety issue, we
consider:
- Are risk minimisation actions needed?
- Is the product information sufficient for
this purpose? How do we establish
this?
- If no, then additional risk minimization
required?
- Potential for medication error/misuse is
considered.
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Additional risk minimisation
Educational materials
- Need for critical evaluation of their
objective and clear measures of success.
- However, potential to be a useful tool.
- Should these be considered in the context
of the broader risk minimisation strategy
rather than as a separate entity?
- Can they complement rather than
compete with the SmPC?
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Slide 7
Current EU Guidance
provision of
information
and education
control the use
New legal basis for monitoring the
effectiveness of risk minimisation
• Regulation (EU) No 1235/2010 (Article
28a) and Directive 2010/84/EU (Article
107h(a))
• New legal requirement.
• MSs/EMA shall: ‘monitor the outcome of
risk minimisation measures contained in
risk management plans and of the
conditions’ of Marketing Authorisation.
13/04/2015
Slide 10
Reflection paper on effectiveness of risk
minimisation – some principles
• Direct measures of the risk being
minimised should be employed whenever
feasible;
• Indirect measures of the risk being
minimised should be limited to those
instances when direct measurement of
the effectiveness is not feasible;
• Surveys and drug utilisation studies using
electronic databases are suggested as
examples of indirect measures.
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What are we evaluating?
• Effectiveness of risk minimisation?
• Outcome of risk minimisation – intended and
unintended?
• Compliance with recommendations?
• Scientific validity of the recommendations?
Understanding of preventability.
- Do we need to provide for a spectrum of approaches to evaluating
public health impact?
- Could each be valid depending on the circumstances?
-
How could we accommodate flexibility but ensure underpinned by
scientific rigor?
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Risk Minimisation Activities
Risk Minimisation Activities = Public Health
Interventions….therefore...
- Complex?* (No of elements)
- Programmatic? (Implementation is
important)
- Context dependent?
L Rychetnik, M Frommer, P Hawe, A Shiell
*Interplay of factors impacting on outcomes.
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Challenges for the evaluation of RMAs
• Need to distinguish between the fidelity of the
evaluation process in detecting the success or
failure of an intervention, and the success or failure
of the intervention itself -- scientific
rigor/methodology - GVP should address.
• If an intervention is unsuccessful, the evidence
should help to determine whether the intervention
was inherently faulty or just badly delivered  GVP
• Descriptive information on the intervention and its
context is required to assess transferability/
generalisability - GVP could provide principles?
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Questions for evaluative research
1. Is the research good enough to conclude
on whether the intervention was
successful?
2. What are the research outcomes?
3. Are the results transferable? Database
study in UK/NL/IT etc…results
transferable to IE?
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Slide 15
1. Is the research good enough?
• ‘Good enough’ = helps us to understand why an
•
-
-
intervention appears to be effective or not.
Contribution of observational studies:
Need to discriminate between observational study
designs
Improve our understanding of bias
Consider the importance of the study design
relative to other dimensions of quality in
evaluation research.
How can the GVP module support the conduct of
studies that are ‘good enough’?
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Slide 16
2. What are the intervention outcomes?
1. Identify the outcome information needed by
regulatory authorities and our stakeholders.
2. Consider both anticipated and unanticipated
effects – ‘outcome’ as well as ‘effectiveness’ of
RMMs.
3. Implementation successes/failures
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3. Are the results transferrable?
To determine this require descriptive
information:
1. Information on the intervention and its
delivery
2. Information on the context
3. Interaction between the intervention and
the context
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Slide 18
Monitoring the effectiveness of risk
minimisation
• Effectiveness is a measure of the extent
to which a specific intervention fulfils its
objectives when deployed in routine
clinical practice.
• The assessment of effectiveness of risk
minimisation is central to the benefit risk
management cycle.
• Assessment of evidence should
differentiate between implementation of
an additional risk minimisation activity and
achievement of its final objective.
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Slide 19
Performance Measure: Survey
Need for guidance and better understanding
of bias?
Common considerations:
• When to survey?
• Whom to survey?
• How to survey?
• Is the sample representative?
• What will the results tell us?
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Slide 20
Drug Utilization Studies in Risk Management
• What is their value?
• Do they provide a valid option for evaluating the
•
•
•
•
performance of risk minimization measures?
Strengths e.g. less biased than survey
Limitations e.g. information available on
databases
Challenges e.g. transferability?
Opportunities for developing methodological
guidance? Should this be part of a GVP module
on this topic?
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Slide 21
Points to consider
What should be the driver for formal evaluation of the
effectiveness of risk minimisation?
1. Nature of the safety issue (adverse reaction burden,
potential impact on the benefit-risk profile etc) ?
2. Uncertainties regarding the evidence base for the risk
minimisation strategy?
3. Concerns regarding how the medicine is used in real life
medical practice and implications for benefit-risk.
4. Classification of the risk minimisation activity as routine or
additional – how would the contribution of the additional
risk minimisation alone be scientifically evaluated?
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Slide 22
Conclusion
Effective risk management requires:
• Measurable objectives - defined measures of success
• Evaluation of the risk minimisation strategy for a product in terms of its
outcomes and not just its evaluation of its individual elements i.e. scope
includes routine and additional risk minimisation measures.
• If risk minimisation is not working, need to analyse where it is failing –
implementation or conceptual failure
• Drug utilisation studies have an important role.
• GVP module will need to include methodological guidance
• Standalone module but needs to be integrated into pharmacovigilance
planning, reporting in PSURs etc.
• Proposals need to be feasible, realistic and underpinned by science.
• Work to be done on terminology.
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Slide 23