Fibromyalgia: Fibromyalgia: Creating a ClaimCreating a Claim

James Witter MD, PhDJames Witter MD, PhDArthritis Advisory CommitteeArthritis Advisory Committee

June 23, 2003June 23, 2003

Goals of MeetingGoals of Meeting

Gather input regarding development and Gather input regarding development and approval for drugs that treat fibromyalgiaapproval for drugs that treat fibromyalgia

Enrich analgesic guidance documentEnrich analgesic guidance document

Address an important public health issueAddress an important public health issue estimates of 4.4 - 10.0 million in U.S. estimates of 4.4 - 10.0 million in U.S.

Better understand how fibromyalgia Better understand how fibromyalgia represents a “model” of chronic pain represents a “model” of chronic pain

Claims and LabelsClaims and Labels

Although Although label claimslabel claims have legal and have legal and regulatory uses, their central purpose is to regulatory uses, their central purpose is to inform health care providers and patients inform health care providers and patients about the about the documented documented benefits and risks benefits and risks associated with a productassociated with a product

Claims describe clinical benefitsClaims describe clinical benefits

Accurate product labels allow for effective Accurate product labels allow for effective risk managementrisk management

Fibromyalgia (FM): What is it?Fibromyalgia (FM): What is it?Arthritis FoundationArthritis Foundation: 2003: 2003

Arthritis-related condition characterized by:Arthritis-related condition characterized by: Generalized muscular pain and fatigueGeneralized muscular pain and fatigue

Condition referred to as a “syndrome” Condition referred to as a “syndrome” because it is a set of signs and symptoms because it is a set of signs and symptoms that occur togetherthat occur together

Confusing…often misunderstoodConfusing…often misunderstood

Common symptoms with no specific labsCommon symptoms with no specific labs

FM: ClassificationFM: ClassificationAmerican College of RheumatologyAmerican College of Rheumatology: 1990: 1990

History (History ( > 3 months) > 3 months) of widespread painof widespread pain Left and right sidedLeft and right sided Above and below waistAbove and below waist Axial skeletal pain must be presentAxial skeletal pain must be present

Pain (not tenderness) on digital (4 kg) Pain (not tenderness) on digital (4 kg) palpation in 11 of 18 tender pointspalpation in 11 of 18 tender points

Both criteria must be satisfiedBoth criteria must be satisfied

FM: How is it treated?FM: How is it treated? Arthritis FoundationArthritis Foundation: 2003: 2003

Education Education (understand and manage) (understand and manage)

Relaxation Relaxation (ease tension and anxiety)(ease tension and anxiety)

Exercise Exercise (flexibility and CV fitness)(flexibility and CV fitness)

Drugs Drugs (decrease pain and improve sleep) (decrease pain and improve sleep) Antidepressants (tricyclics, SSRIs)Antidepressants (tricyclics, SSRIs) BenzodiazepinesBenzodiazepines Other…Other…

FM: History of ClaimFM: History of Claim

NIH-FDA workshop (March, 2002)NIH-FDA workshop (March, 2002) Chronic pain is unmet medical needChronic pain is unmet medical need Fibromyalgia, example of chronic painFibromyalgia, example of chronic pain

Arthritis Advisory: Pain (July, 2002)Arthritis Advisory: Pain (July, 2002) Claims for marketing for analgesicsClaims for marketing for analgesics www.fda.gov/cderwww.fda.gov/cder

NIH-FDA Analgesic Drug NIH-FDA Analgesic Drug Development Workshop: Development Workshop:

Translating Translating Scientific Advances into Scientific Advances into

Improved Pain ReliefImproved Pain Relief

Clinical Journal Pain, 2003Clinical Journal Pain, 2003May-June 19(3) 139-147May-June 19(3) 139-147

Chronic Pain: Unmet needsChronic Pain: Unmet needsNIH-FDA 2002NIH-FDA 2002

Need new models to better:Need new models to better: Understand important clinical aspects of Understand important clinical aspects of

chronic painchronic pain Understand chronic pain mechanisms which Understand chronic pain mechanisms which

may serve as treatment targetsmay serve as treatment targets Design better clinical trialsDesign better clinical trials Ultimately improve treatment of chronic pain Ultimately improve treatment of chronic pain

““Models” of Chronic Pain? Models” of Chronic Pain? NIH-FDA 2002NIH-FDA 2002

OsteoarthritisOsteoarthritis

Lower back painLower back pain

Diabetic neuropathyDiabetic neuropathy

Cancer painCancer pain

FibromyalgiaFibromyalgia

AIDSAIDS

TMDTMD

Chronic Pain: OutcomesChronic Pain: OutcomesNIH-FDA 2002NIH-FDA 2002

PainPainPatient globalPatient globalHealth-related quality of lifeHealth-related quality of lifePhysical function/disease specificPhysical function/disease specificRescue medsRescue medsEconomicsEconomicsAdverse eventsAdverse events

July 2002 AAC: PainJuly 2002 AAC: Pain

Analgesic claims described as:Analgesic claims described as:ClinicalClinical

acute acute chronicchronic

MechanisticMechanistic

Minimal clinically-important difference in Minimal clinically-important difference in pain relief pain relief

Responder approach in analgesiaResponder approach in analgesia

Need to revise analgesic guidance Need to revise analgesic guidance

Chronic Pain: Labels Chronic Pain: Labels July 2002, AACJuly 2002, AAC

General claim (treats all chronic pain)General claim (treats all chronic pain) Replicates of three different pain models Replicates of three different pain models

OA, OA, fibromyalgiafibromyalgia, cancer pain, cancer pain

Clinical Claim (treats musculoskeletal pain)Clinical Claim (treats musculoskeletal pain) OA, OA, fibromyalgiafibromyalgia, chronic lower back pain), chronic lower back pain)

Disease claim (treats specific cause)Disease claim (treats specific cause) OsteoarthritisOsteoarthritis

FibromyalgiaFibromyalgia

Chronic lower back painChronic lower back pain

Fibromyalgia:Fibromyalgia: How to Structure the Claim?How to Structure the Claim?

Treat fibromyalgia as a Treat fibromyalgia as a symptomsymptom, or , or cluster of symptomscluster of symptoms

Treat fibromyalgia as a complex Treat fibromyalgia as a complex diseasedisease state with varying clinical presentationsstate with varying clinical presentations

FM: Symptom ApproachFM: Symptom Approach

Pain outcomePain outcome Obvious and necessary Obvious and necessary

Patient global outcomePatient global outcome

Physical function or HRQOL outcomePhysical function or HRQOL outcome Adversely impacted by painAdversely impacted by pain Analgesics need to improve, not worsen Analgesics need to improve, not worsen

Combination allows improved assessment Combination allows improved assessment of the patients’ experience with analgesic of the patients’ experience with analgesic

pain

fatigue

sleep disturbance

dysfunction

FM: Disease Approach?FM: Disease Approach?

diminished QOL

depressioncognitivedifficulties

Fibromyalgia/Chronic Pain:Fibromyalgia/Chronic Pain:What is Important to the patient?What is Important to the patient?

Patient Reported Outcomes (PRO) are:Patient Reported Outcomes (PRO) are: Patient report of a health condition or treatmentPatient report of a health condition or treatment Scientific patient-centered measures that can evaluate change in Scientific patient-centered measures that can evaluate change in

health outcomes health outcomes Handled like other endpoints for both drug approval and Handled like other endpoints for both drug approval and

promotion promotion Selection, development and validation issues same as other Selection, development and validation issues same as other

clinical measuresclinical measures

Ideal Metric-Pain Ideal Metric-Pain

Understandable to patients and cliniciansUnderstandable to patients and clinicians in clinical trialsin clinical trials in product labelin product label

Applicable across studiesApplicable across studies to allow cross trial comparisonto allow cross trial comparison

Detects a clinically meaningful resultDetects a clinically meaningful result

Responsive to differences in analgesia Responsive to differences in analgesia

Valid Valid

WOMAC pain indexWOMAC pain indexWestern Ontario and McMaster UniversitiesWestern Ontario and McMaster Universities

1. Walking on flat surface2. Going up or down stairs3. At night while in bed4. Sitting or lying5. Standing upright

Osteoarthritis: treatment of signs and symptoms claim

Co-Primary efficacy endpoints: Pain Function Patient global

Trial length: 3 months

FM Outcome: ConsiderationsFM Outcome: Considerations

Single or composite questionSingle or composite question

Statistically/clinically meaningful resultsStatistically/clinically meaningful results

Inclusion and exclusion criteriaInclusion and exclusion criteria

Landmark vs. time-weighted approachLandmark vs. time-weighted approach

Daily pain vs. weekly assessmentDaily pain vs. weekly assessment

Length of clinical trialLength of clinical trial

Superiority to placeboSuperiority to placebo

FM: Responder approachFM: Responder approach

Outcomes of interest in same patientOutcomes of interest in same patient

May lessen or eliminate data imputationMay lessen or eliminate data imputation

Allows flexibility in design to capture Allows flexibility in design to capture different aspects of conditiondifferent aspects of condition

Widely utilized in RA (ACR 20%) Widely utilized in RA (ACR 20%)

ACR 20 responder indexACR 20 responder index

> > 20% improvement in swollen and tender 20% improvement in swollen and tender joint count…….plus...joint count…….plus...

>> 20 % improvement in 3 of following 5: 20 % improvement in 3 of following 5:patient globalpatient global

physician globalphysician global

patient pain (VAS)patient pain (VAS)

modified HAQmodified HAQ

acute phase reactant (CRP or ESR)acute phase reactant (CRP or ESR)

FM: Responder endpoints?FM: Responder endpoints?Required OutcomeRequired Outcome PainPain

Other Important OutcomesOther Important Outcomes Quality of life (general or specific)Quality of life (general or specific) Dysfunction Dysfunction Sleep disturbanceSleep disturbance FatigueFatigue Cognitive impairmentCognitive impairment Patient GlobalPatient Global

Responder is four of six plus pain?Responder is four of six plus pain?

Percent of improvement like ACR 20?Percent of improvement like ACR 20?

Selecting Core Outcome Domains in Selecting Core Outcome Domains in Chronic Pain Clinical Trials:Chronic Pain Clinical Trials:

IMMPACT recommendations: 2003IMMPACT recommendations: 2003

PainPain

Physical functioningPhysical functioning

Emotional functioningEmotional functioning

Patient GlobalPatient Global

Negative Health StatesNegative Health States

Patient DispositionPatient Disposition

Fibromyalgia: The LabelFibromyalgia: The Label

End result of randomized, controlled trialsEnd result of randomized, controlled trialsWhat should it mean to the health care What should it mean to the health care provider?provider? Who should take itWho should take it What type of risk management is involvedWhat type of risk management is involved

What should it mean to the patient?What should it mean to the patient? Relief of painRelief of pain Relief of associated symptomsRelief of associated symptoms Duration and degree of reliefDuration and degree of relief

Assess the patient…Assess the patient… … …not just the painnot just the pain

IMMPACT II