Title: The Impact of IMMPACT Bob A. Rappaport, M.D. Director Division of Anesthesia, Analgesia and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration American Society for Experimental Neurotherapeutics Workshop on
1The Impact of IMMPACT Bob A. Rappaport,
M.D.DirectorDivision of Anesthesia, Analgesia
and Rheumatology ProductsCenter for Drug
Evaluation and ResearchFood and Drug
Administration American Society for
Experimental NeurotherapeuticsWorkshop on
Disease Specific Clinical Trial Think
TanksMarch 9, 2007Washington, D.C.
2FDA and IMMPACT
- In the beginning
- A brief history of analgesics at FDA
- Neuropharmacology
- Pilot Drugs
- Anesthesia vs Analgesia 96
- White Oak Reorganization 05
- The new DAARP
3IMMPACT
- Initiative on Methods, Measurements and Pain
Assessments in Clinical Trials - http//www.immpact.org/
- Co-Chairs Dennis Turk, Ph.D. (University of
Washington) and Robert Dworkin, Ph.D. (University
of Rochester)
4FDA and IMMPACT
- Reps at every meeting (DAARP SEALD team)
- Our role
- Provide regulatory insight
- Provide insight as to what we need
- Trial design
- Drug development
- Comment on proposals
- We do not approve any decisions or
recommendations - Although we do put our names on the publications
(with a disclaimer)
5IMMPACT I and II Core Outcome Domains
- Clear agreement Pain is 1
- Much debate about what level of importance for
each of the others - E.g., function should it be a required outcome?
- How did we resolve this?
- Each domain should be included in a study unless
a justification is provided as to why it was not
necessary in this case - Not a regulatory requirement!
6IMMPACT I II Core Outcome Domains
- Of course, pain has always been 1 for us
- We request that sponsors include the other
domains (as appropriate) - As secondary outcome measure
- Must trend in the right direction, but
statistical significance not required - Examples of how this has influenced us
- Stopped requiring multiple primaries for pain of
RA, OA, etc. - Evaluation of clinical significance based on
secondary outcomes
7IMMPACT III Metrics
- Process
- VAS most commonly used (except for rheum
endpoints WOMAC) - Not the most reliable for particular populations
- NRSs more reliable and equally sensitive/specific
- We allow either for most studies as populations
of concern less prominent in pivotal efficacy
studies for approval - Children are not little adults
- Faces Scale Wong-Baker vs. the Modified Faces
Scale
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10IMMPACT III Metrics
- Children are not little adults
- No validated scales for neonates
- Even less validity of available metrics for other
domains
11IMMPACT III Metrics
- Objective data?not likely Need to validate
PROs! - PRO Guidance Document http//www.fda.gov/cder/gui
dance/index.htm - E.g., a new scale has been studied and validated
after collaborative efforts
- Standard treatment results in unpleasant,
potentially harmful side effect - Novel product to reduce that side effect
- But, for the most part, the effect and
counter-effect are PROs - Studies designed to validate the outcome measures
- Approved by Agency
- Validation successful!
- Efficacy studies ongoing
12IMMPACT IV Clinically Meaningful Differences
- What were we thinking?
- What we learned
- Not really possible to define MIDs for measures
of central tendency - The impact
- No further minimal clinical difference
requirement on measures of central tendency - Although secondaries must be supportive
- Request Cumulative Proportion of Responders
Analysis for all chronic pain trials - CPRAs in labels, even though not primary
13CPRA for Lyrica
14IMMPACT V Multiple Endpoints and Multiple
Comparisons
- Defined acceptable statistical analysis
methodologies - Compared and contrasted the problems associated
with multiplicity - Outcomes?
15IMMPACT VI Clinical Trial Designs
- Placebo-Controlled Designs and Their
Alternatives - Our major impact No non-inferiority trials!
- Missing data in some (opioid) chronic pain trials
complicates design - Randomized withdrawal (incorporating features to
account for opioid withdrawal) - Enriched enrollment
- The Totally Titratable Trial
16A Successful New Trial Design
Week 12
titration
Painacea
washout
baseline
Placebo
Week 2
Endpoint for analysis
Taper off drug complete
17Peds IMMPACT
- Reviewed most of the topics previously discussed,
but from a pediatric perspective - Came to the same conclusions in most cases
- Assessed the information that is still missing
(e.g., the scales for neonates)
18Planned IMMPACT VII
- Acute Pain issues
- Domains and outcome measures
- Length of trials
- Appropriate clinical models
- What we wont ask
- How many trials for a specific indication?
- What are the correct indications?
19The Impact of IMMPACT
- An essential collaborative effort
- Open door? No, but?Transparency
- Exploration followed by Validation
- The (draft) Analgesic Drug Development Guidance
Document - A wealth of opportunity for communication, and
- Advancing the science, approving new analgesic
drug products
20OMERACT
- Outcome Measures in Rheumatology (originally,
Outcome Measures in Rheumatoid Arthritis
Clinical Trials) - Developed ACR20 for RA clinical trials
- Expert opinion on paper patients
- Delphi technique
- Other methodologies
21OMERACT
- Developed standards for metrics in SLE
- Recommended validated instruments for domains
- Developed disease activity measures
- Recently, involvement of patient reps
- Developed the Pediatric ACR30, the current
standard metric for JRA outcomes
22Other Collaborative Efforts in Rheumatology
- ACR consensus group developed highly sensitive
metric for improvement in RA - Consensus group on outcome measures in AS
- GRAPPA consensus group on outcome measures in
PA - EULAR requested our participation in consensus
group on conduct of clinical trials in RA - Thanks, Jeff Siegel!