The Impact of IMMPACT Bob A. Rappaport, M.D.

DirectorDivision of Anesthesia, Analgesia and Rheumatology Products

Center for Drug Evaluation and ResearchFood and Drug Administration

American Society for Experimental Neurotherapeutics

Workshop on Disease Specific Clinical Trial Think Tanks

March 9, 2007Washington, D.C.

FDA 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

IMMPACT

• 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)

FDA 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)

IMMPACT 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!

IMMPACT 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

IMMPACT 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

IMMPACT III: Metrics

• Children are not little adults– No validated scales for neonates– Even less validity of available metrics for other

domains

IMMPACT III: Metrics

• Objective data?…not likely – Need to validate PROs!– PRO Guidance

Document: http://www.fda.gov/cder/guidance/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

IMMPACT 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

CPRA for Lyrica

IMMPACT V: Multiple Endpoints and Multiple Comparisons

• Defined acceptable statistical analysis methodologies

• Compared and contrasted the problems associated with multiplicity

• Outcomes?

IMMPACT 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

washout

baseline

titration Painacea™

Placebo

Week 2*

* Taper off drug complete

Week 12**

** Endpoint for analysis

A Successful New Trial Design

Peds 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)

Planned IMMPACT VII

• Acute Pain issues– Domains and outcome measures– Length of trials– Appropriate clinical “models”

• What we won’t ask– How many trials for a specific indication?– What are the correct indications?

The 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

OMERACT

• “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

OMERACT

• 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

Other 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!