1. 1 Pain Arthritis Advisory Committee July 30, 2002 James Witter MD, PhD Division of Analgesics, Anti-Inflammatory & Ophthalmologic Drug Products HFD-550

2. 2 Acute Pain: Some Causes/Therapy Outpatient setting (mostly oral analgesics) –minor injury (sports injury) –dysmenorrhea* –major injury (trauma i.e. MVA) –surgical (voluntary)* Inpatient setting (oral/parenteral analgesics) –surgery (non-elective) –surgery (elective)* * studied in clinical trials for drug approval

3. 3 The Analgesic Box? Relief Onset Effect size Duration Time Pain

4. 4 Acute Pain Relief: Needs Onset of meaningful pain relief Duration of relief Effect size Establish these in circumstances of: –acute outpatient pain –acute inpatient pain

5. 5 ABC’s of Acute Pain Metrics: A (onset of meaningful pain relief) –time needs to be accurately established –onset needs to occur more frequently in drug vs. placebo patients –established in a variety of outpatient and inpatient settings –single-dose studies

6. 6 Time Pain Pain intensity Onset of meaningful pain relief? 2 1

7. 7 Individual Responder Approach: Focus on a single person, not group Allows efficacy assessment to be individualized Eliminates imputation –“forward filling” of diaries –LOCF-type methods in clinical trials

8. 8 Individual Responses: Acute Pain onset/duration (single-dose) Pain intensity measure throughout trial –including at rescue or censoring Pain relief measured to establish onset of meaningful pain relief Allows for 100% of information capture on patient response to analgesic

9. 9 Threshold Complete Response placebo Effect Size ? MCID Analgesic “Effect” Size? drug

10. 10 ABC’s of Acute Pain Metrics: B (duration) –defines dosing interval based on clinical data –established in a variety of outpatient and inpatient settings –multiple-dose, day 1 of pain –need to factor in: rescue (outpatient) background medication (inpatient)

11. 11 ABC’s of Acute Pain Metrics: C (minimally effective dose) –intended to define the lowest effective dose –not intended for chronic use –established in two settings outpatient models inpatient models –multiple-dose over several days –safety and efficacy assessments begin on Day 2

12. 12 Acute Pain: Special Issues Pain not equal in intensity or duration –moderate to severe post dental extraction pain –moderate to severe post CABG pain Pain tends to improve with time PK estimates and clinical results may describe different aspects of pain relief –PK for onset early, and safety later

13. 13 Acute Pain Labels Should be as informative as possible and so should contain information regarding onset, duration and minimally effective dose from two clinical settings –outpatient –inpatient

14. 14 Safety Mechanisms claims? acuteacute chronicchronic To support meaningful labeling for: Chronic claim

15. 15 Approved Drug X Clinical Studies (the entire section) “In single-dose studies of post surgical pain (abdominal, gynecological, orthopedic), 940 patients were studied at doses of one or two tablets. Drug X produced greater efficacy than placebo…No advantage was demonstrated for the two-tablet dose.”

16. 16 Approved Drug X Dosage and Administration “For the short-term (generally less than 10 days) management of acute pain, the recommended dose of Drug X is one tablet every 4 to 6 hours, as necessary. Dosage should not exceed 5 tablets in a 24 hour period.”

17. 17 Ideal Characteristics-Pain Metric Easy and understandable by patients and clinicians –in labeling and in clinical results Applicable across studies –to facilitate IND development, NDA approval Defines a clinically meaningful result –so that it is a useful addition to pain control Valid in a variety of pain conditions Achievable with current meds –tiered to define important differences in drugs

18. 18 Responder Analysis: Pain Has potential to characterize pain at individual level in both acute and chronic situations May be useful to compare relative efficacy (against placebo or standard-of-care) in clinical trials –in acute pain –in chronic pain

19. 19 Responder Analysis: Hypothesis If properly constructed and validated, could be major advance in clinical analgesia Outcomes = domains, not instruments –can agree on outcomes even if instruments not yet available/validated

20. 20 ACR 20 Responder: > 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)

21. 21 Analgesic Domains: Discussed NIH-FDA workshop Pain (types, metrics) Rescue meds Patient global HRQOL (health-related quality of life) Physical function/disease specific measure Economics Organ damage Suffering Adverse events

22. 22 Analgesic domains: Acute Pain? Pain Concomitant meds (rescue meds?) Pt global HRQOL (health-related quality of life) Physical function/disease specific measure Adverse events

23. 23 Acute Pain Responder: Domains?

24. 24 Acute Responder Example: AR 20/12 AR = analgesic relief has been established 20 = % PR over standard-of care/placebo 12 = hours of relief

25. 25 Drug X 100/300 Clinical Trials section Analgesics for acute pain need to establish: –A (onset) –B (dosing interval) –C (lowest effective dose) These analgesic properties are described in the following outpatient and inpatient settings.

26. 26 Drug X (300 mg) Indications section Drug X (300 mg) is indicated for acute pain Drug X is described as AR90/24 –details in Clinical Trials Daily use should not exceed 5 days –details in Clinical Trials

27. 27 Drug X (100 mg) Indications section Drug X (100 mg) is indicated for acute pain Drug X is described as AR20/24 –details in Clinical Trials Daily use should end when the pain has resolved or can be managed in another way –details in Clinical Trials

28. 28 July 30, 2002 Presenters Lawrence Goldkind, M.D. (FDA) Dennis Bashaw, Pharm.D. (FDA) Lourdes Villalba, M.D. (FDA) Vibeke Strand, M.D. (Stanford) Lee Simon, M.D (FDA)