1. Fibromyalgia: Creating a Claim James Witter MD, PhD Arthritis Advisory Committee June 23, 2003

2. 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. estimates of 4.4 - 10.0 million in U.S. Better understand how fibromyalgia represents a “model” of chronic pain

3. 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

4. Fibromyalgia (FM): What is it? Arthritis Foundation: 2003 Arthritis-related condition characterized by: Generalized muscular pain and fatigue Generalized muscular pain and fatigue Condition referred to as a “syndrome” because it is a set of signs and symptoms that occur together Confusing…often misunderstood Common symptoms with no specific labs

5. FM: Classification American College of Rheumatology: 1990 History ( > 3 months) of widespread pain Left and right sided Left and right sided Above and below waist Above and below waist Axial skeletal pain must be present 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

6. 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) Antidepressants (tricyclics, SSRIs) Benzodiazepines Benzodiazepines Other… Other…

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

8. NIH-FDA Analgesic Drug Development Workshop: Translating Scientific Advances into Improved Pain Relief Clinical Journal Pain, 2003 May-June 19(3) 139-147

9. Chronic Pain: Unmet needs NIH-FDA 2002 Need new models to better: Understand important clinical aspects of chronic pain Understand important clinical aspects of chronic pain Understand chronic pain mechanisms which may serve as treatment targets Understand chronic pain mechanisms which may serve as treatment targets Design better clinical trials Design better clinical trials Ultimately improve treatment of chronic pain Ultimately improve treatment of chronic pain

10. “Models” of Chronic Pain? NIH-FDA 2002 Osteoarthritis Lower back pain Diabetic neuropathy Cancer pain FibromyalgiaAIDSTMD

11. Chronic Pain: Outcomes NIH-FDA 2002 Pain Patient global Health-related quality of life Physical function/disease specific Rescue meds Economics Adverse events

12. July 2002 AAC: Pain July 2002 AAC: Pain Analgesic claims described as: Clinical acute acute chronic chronicMechanistic Minimal clinically-important difference in pain relief Responder approach in analgesia Need to revise analgesic guidance

13. Chronic Pain: Labels July 2002, AAC General claim (treats all chronic pain) Replicates of three different pain models Replicates of three different pain models OA, fibromyalgia, cancer pain OA, fibromyalgia, cancer pain Clinical Claim (treats musculoskeletal pain) OA, fibromyalgia, chronic lower back pain) OA, fibromyalgia, chronic lower back pain) Disease claim (treats specific cause) Osteoarthritis Osteoarthritis Fibromyalgia Fibromyalgia Chronic lower back pain Chronic lower back pain

14. 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

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

16. pain fatigue sleep disturbance dysfunction FM: Disease Approach? diminished QOL depression cognitive difficulties

17. Fibromyalgia/Chronic Pain: What is Important to the patient? Patient Reported Outcomes (PRO) are: Patient report of a health condition or treatment Patient report of a health condition or treatment Scientific patient-centered measures that can evaluate change in health outcomes Scientific patient-centered measures that can evaluate change in health outcomes Handled like other endpoints for both drug approval and promotion Handled like other endpoints for both drug approval and promotion Selection, development and validation issues same as other clinical measures Selection, development and validation issues same as other clinical measures

18. Ideal Metric-Pain Understandable to patients and clinicians in clinical trials in clinical trials in product label in product label Applicable across studies to allow cross trial comparison to allow cross trial comparison Detects a clinically meaningful result Responsive to differences in analgesia Valid

19. WOMAC pain index Western 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

20. Osteoarthritis: treatment of signs and symptoms claim Co-Primary efficacy endpoints : Pain Function Patient global Trial length: 3 months

21. 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

22. 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%)

23. ACR 20 responder index > 20% improvement in swollen and tender joint count…….plus... > 20 % improvement in 3 of following 5: patient global physician global patient pain (VAS) modified HAQ acute phase reactant (CRP or ESR)

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

25. Selecting Core Outcome Domains in Chronic Pain Clinical Trials: IMMPACT recommendations: 2003 Pain Physical functioning Emotional functioning Patient Global Negative Health States Patient Disposition

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

28. Assess the patient… …not just the pain …not just the pain IMMPACT II