Comments on: The Guideline for the Clinical Evaluation of Analgesic Drugs Sharon Hertz, M.D.

1. Arthritis Advisory Committee July 29,2002 Comments on: The Guideline for the Clinical Evaluation of Analgesic Drugs Sharon Hertz, M.D. Division of Anesthetic, Critical Care, and Addiction Drug Products

2. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline for the Clinical Evaluation of Analgesic Drugs has been in use for a decade. Subsequent advances in pain research and pain management call for a new approach.

3. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline places undue emphasis on clinical trials in pain “models”, rather than on studying the painful indication for which the product is most likely to be considered safe, effective and appropriate.

4. The Guideline for the Clinical Evaluation of Analgesic Drugs Focus on “models” of pain rather than target populations and the clinical setting of intended use has led to ambiguous labeling and inadequate exploration of drugs in the context of clinical use.

5. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline lacks emphasis on adequate Phase 2 dose finding.

6. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline does not adequately address duration of clinical trials to study drugs for chronic administration.

7. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline recommends study designs that are no longer considered practical and which have been shown to yield ambiguous results.

8. The Guideline for the Clinical Evaluation of Analgesic Drugs Selection of adequate control groups as described in the ICH guidelines has replaced the older thinking represented in the 1992 Guideline.

9. The Guideline for the Clinical Evaluation of Analgesic Drugs The 1992 Guideline makes a distinction between pain due to inflammatory v. non-inflammatory conditions. It fails to recognize the greater variability in pain etiologies that may impact response to different analgesics.

10. DACCADP Approach to Analgesic Development--Phase 1 Characterize PK profile of the product in single AND multiple dose studies. Provide preliminary safety and tolerability data over a wide range of doses, anticipating dosing for early efficacy trials.

11. DACCADP Approach to Analgesic Development--Phase 2 Begin to explore the test drug in the target population. Pain conditions identified in preclinical trials or experience with drugs of a similar class may help to define the target population.

12. DACCADP Approach to Analgesic Development--Phase 2 Analgesics are rarely only used as single dose agents. Single dose studies should be planned for exploring analgesic properties, NOT as the basis for supporting efficacy in a marketing application.

13. DACCADP Approach to Analgesic Development--Phase 2 Phase 2 studies should explore a wide range of doses (dose ranging studies) to provide information for designing treatment arms for Phase 3 trials.

14. DACCADP Approach to Analgesic Development--Phase 2 Phase 2 provides the opportunity to explore outcome measures and determine what approach is most likely to demonstrate the efficacy of the product.

15. DACCADP Approach to Analgesic Development--Phase 2 Is there a subgroup that responds well, suggesting a responder analysis as a better primary analysis? What are the characteristics of that subgroup? Do most patients exhibit a moderate but important improvement suggesting mean scores are most informative of the product’s efficacy?

16. DACCADP Approach to Analgesic Development--Phase 2 Do approved products provide better analgesia than the study drug, suggesting that although capable of beating placebo, the study population does not reflect an appropriate indication for that product?

17. DACCADP Approach to Analgesic Development--Phase 3 Consider ways to prospectively define a clinically meaningful response for the primary pain variables--using validated measures--and include these in the primary efficacy analysis. Invalidated QOL or global scales are generally not considered useful.

18. DACCADP Approach to Analgesic Development--Phase 3 For a product likely to be used chronically, studies of adequate duration should be planned. Twelve week studies provide an opportunity to assess durability of effect. This is a concept that is used throughout the Agency for drugs intended for chronic administration.

19. DACCADP Approach to Analgesic Development--Phase 3 These 12 week studies offer an opportunity to provide information concerning tolerance if designed accordingly.

20. DACCADP Approach to Analgesic Development--Phase 3 Efficacy should be replicated, not necessarily in an exact duplicate design, but in a similar population. Confirmatory studies provide the basis for the indication and inform the label on how the product is to be used.