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Lessons about risk-benefit assessment from OMERACT. Jasvinder Singh, MBBS, MPH Associate Professor of Medicine, UAB School of Medicine & VA Medical Center, Birmingham, Alabama Mayo Clinic School of Medicine, Rochester, MN. IMMPACT-XIV, Arlington, VA June 16-17, 2011. Acknowledgement. - PowerPoint PPT Presentation
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Jasvinder Singh, MBBS, MPHAssociate Professor of Medicine, UAB School of Medicine & VA
Medical Center, Birmingham, AlabamaMayo Clinic School of Medicine, Rochester, MN
IMMPACT-XIV, Arlington, VA June 16-17, 2011
Entire OMERACT Executive: Developed OMERACT 3 X 3
Slides: Dr. Maarten Boers
Comments: Drs. Maarten Boers & Lee Simon
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
Risk: ◦ Oxford: “a situation involving exposure to danger”◦ Merriam-Webster: “possibility of loss or injury”◦ Medical context: an effect that is harmful to the
patient’s or public’s health and which can relate to safety, efficacy or quality of a product.
Benefit: ◦ Oxford: “an advantage or profit gained from
something”◦ Merriam-Webster: “something that promotes well-
being “
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
Assigning causality:◦ Bradford-Hill criteria + biological plausibility +
Bayesian methods◦ No agreement on magnitude of frequency, i.e.,
when does something become a “signal” Utility of large trials to define risk
◦ Large, simple trials such as prospective randomized open blinded endpoint (PROBE)
◦ Randomization to two effective treatments◦ Alternative: observational studies with
confounding by indication and channeling bias
Utility of metanalyses of RCTs◦Multiple small RCTs ?statistically
equivalent to a large single trials with same denominator
◦200-300 events needed for credible estimates
◦Role for indirect comparisons- unclear◦Observational studies: may be included; Selection and confounding bias issues Outcome definition and measurement
and follow-up
Postmarketing Surveillance◦ Essential for drug safety evaluation◦ All drugs in a class should be analyzed identically
and concurrently◦ Desired components:
More than one defined population Full protocol with outcomes assessed at regular
intervals Concurrent control subjects Outcomes- patient-recoded + documented in electronic
records Pre-defined hypothesis Oversight by FDA and data management council
Utilities of Drug registries◦ Advantages: real world experience, long-term FU◦ Disadvantages: lack of comparator group, data
quality, patients not obligated to follow protocol, loss to follow-up
Pharmacoepidemiologic studies◦ Cohort studies generally better than case-control
studies in providing risk estimates◦ Issues need to addressed
Misclassification bias Validation of outcomes Guidelines for confounding bias and methods for
adjustment
Simple versus complex metric◦Simple: OMERACT 3 x 3 Benefit and risk categorized into 3 levels
each- none, substantial, (near) remission or death
◦Complex: multicriteria decision analysis• Complex Frameworks: Quantitative methods◦Decision analysis method◦Conjoint analysis◦Incremental net-benefit◦BRAT approach
GRADE approach◦ Classifies evidence into 4 levels: high, moderate, low
and very low based on Study design, weaknesses, special strengths (large
effect, dose response)◦ 2 recommendations: strong and weak◦ RCTs always starting at high and non-RCTs starting
at low? Other models of Risk: Nontreatment
◦ Risk and value of available treatment versus nontreatment options
◦ Type, intensity and severity of adverse event◦ Acute, subacute or chronic; manageable, treatable
or not
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
Create three categories of harm and benefit
Benefit: none/minimal, major, (near) remission
Harm: none/minimal, major, (near) death
Key components of this approach:◦Harms versus benefits
measurement of benefit is measurement of benefit is specific and evolved, but specific and evolved, but measurement of risk (or harm) is measurement of risk (or harm) is generic and more primitivegeneric and more primitive
Benefit and harm not placed on Benefit and harm not placed on a single scale a single scale
single scale benefit-harm 14
placing value judgments on scientific factsplacing value judgments on scientific facts◦ values will vary depending on
the perspective of the assessor comparing benefit and risk involves: comparing benefit and risk involves:
◦ comparing apples and pears◦ trading off (and discounting)
long-term against short-term effects◦ assessing multiple benefits and risks
assessment mostly driven assessment mostly driven by the need to make decisions, by the need to make decisions, whereas most research is ‘truth-driven’whereas most research is ‘truth-driven’
single scale benefit-harm 15
...placing value judgments on scientific facts
Requires qualitative research
...multiple comparisons and trade-offsDifficult scienceRequires decision analysis
...mostly driven by decision-makersLow speed of developmentsLiterature difficult to access
single scale benefit-harm 16
single scale benefit-harm 17
COBRA trialCOBRA trial VIGOR trialVIGOR trial
single scale benefit-harm 18
RCT comparing combination therapy RCT comparing combination therapy (COBRA) (COBRA) including step-down high-dose prednisolone including step-down high-dose prednisolone with single drug therapy (sulfasalazine, with single drug therapy (sulfasalazine, SSZ) SSZ) in early rheumatoid arthritisin early rheumatoid arthritis
Main result showed COBRA to be more Main result showed COBRA to be more effective and result in less side effects than effective and result in less side effects than SSZSSZ
single scale benefit-harm 19
20
Major benefit = Disease activity score <=3.7(near) Remission = Disease activity score <=2.4Severe Harm = treatment discontinuation due to serious harm, loss of efficacy or both(near) death = death or severe inacapacitation
single scale benefit-harm 21
ARR: Unqualified success: 80-54% = 26%; NNT = 4ARR: Unmitigated failure: 5-14% = –9%; NNH = ?
single scale benefit-harm 22
Unqualified success
Unmitigated failure
large industry-sponsored trial to compare high-dose rofecoxib with naproxen in RAobject was GI safety, not efficacyrofecoxib proved safer for GI, but less safe for cardiovascular eventsMerck withdrew the drug voluntarily amidst much controversy
no access to individual patient datasafety and efficacy assumed independent
single scale benefit-harm 23
single scale benefit-harm 24
Data from original report and from Strand V. Lancet 2007;370:2138-51.Major harm is defined as cardiovascular event; gastrointestinal event; death.
single scale benefit-harm 25
Unqualified success
Unmitigated failure
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
Specifying the therapeutic context◦ Explicit definition of product, indication, target
population, formulation, dosage and contraindications
Specifying the comparator◦ Standard of care, best in class, watchful waiting,
placebo and nonpharmacological intervention Defining the time horizon
◦ Duration of exposure and time period over which benefit-risk events are measured
Specifying the stakeholder perspective◦ Sponsor, regulators, patients, physicians
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
Identifying pool of candidate outcomes for the assessment
Deciding which outcomes to include or exclude from the framework
Documenting all critical assumptions for these inclusion and exclusion decisions
Value tree is a visual hierarchical presentation of key ideas, values or concepts
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
Information may come from multiple data sources
A repository of all data, called data source table is kept
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
Customization done based on data quality and limitations
Study end-points are organized in value tree at 2 levels◦ Body system category of the benefit or risk◦ The end-point measured in studies
Approaches to capturing level of severity of outcomes identified and the value tree is enhanced
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
Assess relative weights◦ Stated choice methods◦ QALYs◦ Utilities◦ Value functions
Application of weighted approach in analysis◦ Net clinical benefit◦ Number needed to harm (NNH)◦ Multicriteria decision analysis
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
Key risk benefit table◦ Flexible table summarizing the key information
needed to quantify outcomes in the value trees
Additional items to enhance key table◦ Heat map color coding◦ Embedded graphs
1Coplan PM Clin Pharma Therap 2011; 89:2: 312-15
1Levitan Clin Pharma Therap 2011; 89:2: 217-234
1Levitan Clin Pharma Therap 2011; 89:2: 217-234
1Levitan Clin Pharma Therap 2011; 89:2: 217-234
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
How to come up with method (s) for risk-benefit assessment that is/are◦ Easily understood by regulators, patients and physicians◦ Take into account non-treatment or alternative
treatments◦ Allow sensitivity analyses?
How to mandate and conduct efficient postmarketing surveillance studies?◦ Requirement by FDA and EMEA etc.◦ Funding◦ Preventing bias◦ Design and follow-up methodology
Can efficacy trials be better designed to allow better short-term risk-benefit analysis?
What steps must be taken to use large databases to conduct postmarketing studies?◦ Standardization of methods for reduction of bias◦ Data integrity and privacy issues
How to achieve an agreement on methods by major regulators (FDA, EMEA)?
Definitions Summary and Discussions at 2008
OMERACT Drug Safety Summit OMERACT approach Benefit Risk Action Team (BRAT) approach
◦ Pharmaceutical Research and Manufacturers of America
Questions and potential solutions The Future
Collaborative networks of academia, regulatory agencies, patients and pharma
Use of preferences, values, cost and delay in drug approval (risks of alternatives) in risk-benefit analysis
Universally applicable methods Ability to vary values, weights and perform
sensitivity analyses Utilize non-randomized studies Design and conduct useful large simple
comparative effectiveness trials