Presented by Lee S. Simon, MD Division Director Analgesic, Anti-inflammatory and Ophthalmology Drug Products ODEV, CDER,

1. Presented by Lee S. Simon, MD Division Director Analgesic, Anti-inflammatory and Ophthalmology Drug Products ODEV, CDER, FDA at the Arthritis Advisory Committee meeting on 07/30/02

2. Pain • We reviewed acute and chronic pain • Clinical approach • Mechanistic approach

3. Pain • Temporal descriptions (acute vs chronic) or Intensity differences such as mild, moderate or severe are not enough • Need clinical trials to further the definition of mechanisms • Unknown whether there can be global analgesics for what we now know are quite different mechanisms driving the sensation of pain

4. Chronic Pain • There was clear concern that : • The agency needs to design claims and consider proposed trial designs which will foster new drug development for pain • The chronic pain proposal has merit: • The chronic pain indication proposal: three models, three co-primary outcomes of pain, function, and pt global • Replicate trials in three models: disparate etiopathogenesis • Are three trials in replicate necessary when you are doing studies in models with similar mechanisms general consensus: • Three co-primary outcomes? • Yes to pain • Yes to patient global (used as a measure of clinical relevance of the response) • Qualified yes to function: really applicable to patients with cancer? Need to be design by design

5. Chronic Pain • How many different models are required to gain any type of specific claim for chronic pain? Are three different models/diseases/mechanisms really required? • Dr. Verburg: suggested 4 models with 1 trial in each, 550 is suggesting 3 models with 2 replicate trials in each • Dr Ferrar suggested 2 neuropathic and 2 somatic pain models

6. Chronic Pain • Should we lump or split? • Global chronic pain vs • Pain of musculoskeletal disease or • Osteoarthritis • In fact the latter two indications are splitting and are available to any sponsor and to pursue iteratively the broader indications by accruing more data post approval for the more narrow indication

7. Pain Acute Pain: is not dissimilar to thinking about the drugs that would treat it: thus short term analgesics Chronic pain: is not dissimilar to thinking about drugs which would be used chronically These issues inform the safety issues, durability issues

8. Chronic Pain • Chronic low back pain is a heterogeneous syndrome consisting of many different processes but which can be delineated • If can select a specific population which has some similar natural history (sans radiculopathy or neuropathy) • Nonetheless the general thoughts were this could be a labeled indication and can be studied • Subtract those patients with neuropathic component and systemic disease

9. Pain • Elderly are an important population many of whom need to be treated chronically for pain, and little info has been developed about this issue • Often polypharmacy is typical • For a safety purpose these two issues need to be addressed • Pediatric studies need to be fostered

10. Pain • Today’s design: • Flare design pre-selects patients who both tolerate (toxicity) and respond to the analgesics • Suggestion for future • Run in phase followed by withdrawal phase • Problems • Pre-selects patients who can tolerate and who respond to the drug (the run in phase eliminates those patients who cannot tolerate the drug) • How do you insure in the withdrawal phase the patients are not unblinded?

11. Pain • Is opioid sparing an indication that should be sought • Might be a good response to measure, both demonstrating that the study drug works and decreases the needs for opioids, and has less side effects • Study drug might enhance the effects of concomitant opioid therapy: might decrease the use of opioid • Study drug might enhance the toxic effects of the opioids: might decrease the use of opioids • How much decrease of an opioid is good, desirable and clinically important ( 3 mgs vs 30 mgs) • There may be a change in the PK of the opioid due to induction of metabolism

12. The ABC’s of Acute Pain

13. Acute Pain • Want to improve info in label by turning from inference as evidenced by PK modeling to data derived from clinical trials (multidose assessments) Informed by “B” of “ABC’s” • Want to improve safety analysis of short term use by analyzing long term exposures for even drugs approved for ONLY short term use (may not need replicate long term trials if only acute pain to be pursued) • Informed by “C” of “ABC’s”

14. Acute Pain • Clearly, cannot generalize to post op pain from dysmenorhea or dental pain trials from the single dose studies (thus the suggestion of both outpatient and inpatient study requirements) • Additional info on dosing interval is needed (“B” of the “ABC’s”) • More optimizing of dosing schedule • Responder and non responder inclusion

15. Acute Pain • Issues of “dose creep” in real world use demonstrates that patients vote with their feet and real world use is a better reflection thus we need to design trials which will help to determine real world use • Issues of longer time of use requires chronic studies

16. Acute Pain: Discussion • Metrics • Clinical trials should inform us about real world usage • Time to rescue should include non-responders (ITT design) • Must consider new designs with pre-emtive analgesia: new indication? • Short term studies: pain relief, patient global • In terms of level of response for how long and when is the onset not when it separates from placebo • Drugs not with onset within an hour but are very good analgesics: inform about acute to sub acute

17. Acute Pain: Discussion • Dose descriptions: • Minimum time to the next dose informed by the time to onset and needs to be also limited by total dose • Dose ranges may be better described by quartiles of response

18. Pain • Likely a tiered responder analysis will inform patients and clinicians much more so than the present analyses for pain • In acute pain to define level of pain relief and duration of effect • In chronic pain would develop an information data base which would include efficacy (pain and suffering relief), durability of response (time to treatment failure), function and HRQOL measures and safety