Fibromyalgia: Creating a Claim

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Fibromyalgia Creating a Claim

• James Witter MD, PhD
• Arthritis Advisory Committee
• June 23, 2003

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Goals of Meeting

• Gather input regarding development and approval
  for drugs that treat fibromyalgia
• Enrich analgesic guidance document
• Address an important public health issue
• estimates of 4.4 - 10.0 million in U.S.
• Better understand how fibromyalgia represents a
  model of chronic pain

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Claims and Labels

• Although label claims have legal and regulatory
  uses, their central purpose is to inform health
  care providers and patients about the documented
  benefits and risks associated with a product
• Claims describe clinical benefits
• Accurate product labels allow for effective risk
  management

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Fibromyalgia (FM) What is it?Arthritis
Foundation 2003

• Arthritis-related condition characterized by
• Generalized muscular pain and fatigue
• Condition referred to as a syndrome because it
  is a set of signs and symptoms that occur
  together
• Confusingoften misunderstood
• Common symptoms with no specific labs

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FM ClassificationAmerican College of
Rheumatology 1990

• History ( gt 3 months) of widespread pain
• Left and right sided
• Above and below waist
• Axial skeletal pain must be present
• Pain (not tenderness) on digital (4 kg) palpation
  in 11 of 18 tender points
• Both criteria must be satisfied

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FM How is it treated? Arthritis Foundation 2003

• Education (understand and manage)
• Relaxation (ease tension and anxiety)
• Exercise (flexibility and CV fitness)
• Drugs (decrease pain and improve sleep)
• Antidepressants (tricyclics, SSRIs)
• Benzodiazepines
• Other

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FM History of Claim

• NIH-FDA workshop (March, 2002)
• Chronic pain is unmet medical need
• Fibromyalgia, example of chronic pain
• Arthritis Advisory Pain (July, 2002)
• Claims for marketing for analgesics
• www.fda.gov/cder

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NIH-FDA Analgesic Drug Development Workshop
Translating Scientific Advances into Improved
Pain ReliefClinical Journal Pain, 2003May-June
19(3) 139-147
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Chronic Pain Unmet needsNIH-FDA 2002

• Need new models to better
• Understand important clinical aspects of chronic
  pain
• Understand chronic pain mechanisms which may
  serve as treatment targets
• Design better clinical trials
• Ultimately improve treatment of chronic pain

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Models of Chronic Pain? NIH-FDA 2002

• Osteoarthritis
• Lower back pain
• Diabetic neuropathy
• Cancer pain
• Fibromyalgia
• AIDS
• TMD

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Chronic Pain OutcomesNIH-FDA 2002

• Pain
• Patient global
• Health-related quality of life
• Physical function/disease specific
• Rescue meds
• Economics
• Adverse events

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July 2002 AAC Pain

• Analgesic claims described as
• Clinical
• acute
• chronic
• Mechanistic
• Minimal clinically-important difference in pain
  relief
• Responder approach in analgesia
• Need to revise analgesic guidance

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Chronic Pain Labels July
2002, AAC

• General claim (treats all chronic pain)
• Replicates of three different pain models
• OA, fibromyalgia, cancer pain
• Clinical Claim (treats musculoskeletal pain)
• OA, fibromyalgia, chronic lower back pain)
• Disease claim (treats specific cause)
• Osteoarthritis
• Fibromyalgia
• Chronic lower back pain

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Fibromyalgia How to Structure the Claim?

• Treat fibromyalgia as a symptom, or cluster of
  symptoms
• Treat fibromyalgia as a complex disease state
  with varying clinical presentations

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FM Symptom Approach

• Pain outcome
• Obvious and necessary
• Patient global outcome
• Physical function or HRQOL outcome
• Adversely impacted by pain
• Analgesics need to improve, not worsen
• Combination allows improved assessment of the
  patients experience with analgesic

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FM Disease Approach?
dysfunction
fatigue
pain
cognitive difficulties
depression
diminished QOL
sleep disturbance
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Fibromyalgia/Chronic PainWhat is Important to
the patient?

• Patient Reported Outcomes (PRO) are
• Patient report of a health condition or treatment
• Scientific patient-centered measures that can
  evaluate change in health outcomes
• Handled like other endpoints for both drug
  approval and promotion
• Selection, development and validation issues same
  as other clinical measures

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Ideal Metric-Pain

• Understandable to patients and clinicians
• in clinical trials
• in product label
• Applicable across studies
• to allow cross trial comparison
• Detects a clinically meaningful result
• Responsive to differences in analgesia
• Valid

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WOMAC pain indexWestern Ontario and McMaster
Universities
1. Walking on flat surface 2. Going up or
down stairs 3. At night while in bed 4. Sitting
or lying 5. Standing upright
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Osteoarthritis treatment of signs and symptoms
claim

• Co-Primary efficacy endpoints
• Pain
• Function
• Patient global
• Trial length
• 3 months

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FM Outcome Considerations

• Single or composite question
• Statistically/clinically meaningful results
• Inclusion and exclusion criteria
• Landmark vs. time-weighted approach
• Daily pain vs. weekly assessment
• Length of clinical trial
• Superiority to placebo

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FM Responder approach

• Outcomes of interest in same patient
• May lessen or eliminate data imputation
• Allows flexibility in design to capture different
  aspects of condition
• Widely utilized in RA (ACR 20)

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ACR 20 responder index

• gt 20 improvement in swollen and tender joint
  count.plus...
• gt 20 improvement in 3 of following 5
• patient global
• physician global
• patient pain (VAS)
• modified HAQ
• acute phase reactant (CRP or ESR)

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FM Responder endpoints?

• Required Outcome
• Pain
• Other Important Outcomes
• Quality of life (general or specific)
• Dysfunction
• Sleep disturbance
• Fatigue
• Cognitive impairment
• Patient Global
• Responder is four of six plus pain?
• Percent of improvement like ACR 20?

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Selecting Core Outcome Domains in Chronic Pain
Clinical TrialsIMMPACT recommendations 2003

• Pain
• Physical functioning
• Emotional functioning
• Patient Global
• Negative Health States
• Patient Disposition

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Fibromyalgia The Label

• End result of randomized, controlled trials
• What should it mean to the health care provider?
• Who should take it
• What type of risk management is involved
• What should it mean to the patient?
• Relief of pain
• Relief of associated symptoms
• Duration and degree of relief

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Assess the patient not
just the pain
IMMPACT II