1. FDA REGULATION: EFFECT ON PAIN MANAGEMENT IN THE ED RICHARD R. ABOOD, R.Ph., J.D. Professor Pharmacy Practice University of the Pacific RICHARD R. ABOOD, R.Ph., J.D. Professor Pharmacy Practice University of the Pacific

2. ROLE OF THE FDA The FDA must approve a drug as safe and effective for the conditions indicated in the labeling prior to marketing. All labeling content must be approved by the FDA The FDA must approve a drug as safe and effective for the conditions indicated in the labeling prior to marketing. All labeling content must be approved by the FDA

3. LABELING REQUIREMENTS Prescription drug labeling must be directed to the health care professional (not the patient) and include warnings describing serious adverse reactions and potential safety hazards. (21 CFR 201.56 & 201.57) Prescription drug labeling must be directed to the health care professional (not the patient) and include warnings describing serious adverse reactions and potential safety hazards. (21 CFR 201.56 & 201.57)

4. “BOXED WARNINGS” “Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box.” (§201.57(e) Warnings) “Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box.” (§201.57(e) Warnings)

5. “BOXED WARNINGS” FDA Commissioner has stated that the Agency reserves boxed warnings only for the most serious warnings and is a “dramatic” step taken only if a new safety issue alters the risk-benefit ratio.

6. FDA GUIDANCE CRITERIA FOR BOXED WARNINGS None exist. FDA has never issued a guidance document relevant to when or how it requires a boxed warning.

7. SOURCE OF EVIDENCE RELIED UPON BY THE FDA Post-market reporting Clinical studies during the NDA Clinical studies after marketing Epidemiological surveys Post-market reporting Clinical studies during the NDA Clinical studies after marketing Epidemiological surveys

8. CRITICISMS OF BOXED WARNINGS Why one drug and not others? Are dose differences considered? How many deaths per patient use are required? Is there consideration of alternative treatments (safety, efficacy, cost)? Why isn’t public comment requested? Why no established criteria? Why one drug and not others? Are dose differences considered? How many deaths per patient use are required? Is there consideration of alternative treatments (safety, efficacy, cost)? Why isn’t public comment requested? Why no established criteria?

9. FREQUENCY OF BOXED WARNINGS One study found that 206 drugs in the PDR in 1995 had boxed warnings, many with more than one warning. (Beach et al, 53 FDLJ 4/03 (1998). One study found that 206 drugs in the PDR in 1995 had boxed warnings, many with more than one warning. (Beach et al, 53 FDLJ 4/03 (1998).

10. FREQUENCY OF BOXED WARNINGS Another study: Of 548 drugs approved between 1975 and 1999, 56 (10.2%) either acquired a black box warning after marketing or were withdrawn. (Lasser et. al, 287 JAMA. 2215 (May, 1 2002) Another study: Of 548 drugs approved between 1975 and 1999, 56 (10.2%) either acquired a black box warning after marketing or were withdrawn. (Lasser et. al, 287 JAMA. 2215 (May, 1 2002)

11. PAIN MANAGEMENT DRUGS WITH BOXED WARNINGS Clonidine Fentanyl transmucosal (Actiq) Fentanyl Oralet Methadone OxyContin Propoxyphene Toradol Clonidine Fentanyl transmucosal (Actiq) Fentanyl Oralet Methadone OxyContin Propoxyphene Toradol

12. NEW DRUG QUESTIONS Are drugs approved too rapidly? Should newly approved drugs be used first line if established drugs are available? Are drugs approved too rapidly? Should newly approved drugs be used first line if established drugs are available?

13. EFFECT ON FORMULARIES Do black box warnings affect formularies?

14. EFFECT ON HEALTH CARE PROFESSIONALS Do they know of the warnings? Do they believe the warnings? Do the warnings affect prescribing behavior? Do they know of the warnings? Do they believe the warnings? Do the warnings affect prescribing behavior?

15. FDA’S POSITION FDA believes that the traditional risk communication tools (e.g. current package insert format, boxed warnings, dear health care professional letters, patient information from the pharmacy) are ineffective.

16. EXAMPLES SUPPORTING FDA’S POSITION NSAIDs withdrawn from market: (Duract, Zomax, Oraflex, Suprol) Other Examples: (Hisminal, Propulsid, Seldane, Posicor, phenylpropanolamine, Rezulin) NSAIDs withdrawn from market: (Duract, Zomax, Oraflex, Suprol) Other Examples: (Hisminal, Propulsid, Seldane, Posicor, phenylpropanolamine, Rezulin)

17. FDA’S POSITION IS IT CORRECT?

18. PATIENTS Do they receive the warnings? Should they receive the warnings? Do they receive the warnings? Should they receive the warnings?

19. WHAT WOULD BE EFFECTIVE RISK MANAGEMENT TOOLS FOR PATIENTS? Revised package insert? Mandatory written patient information? Written informed consent of patients prior to prescribing? Improved reporting of adverse events? Restricted drug distribution? Restricted drug marketing? Others? Revised package insert? Mandatory written patient information? Written informed consent of patients prior to prescribing? Improved reporting of adverse events? Restricted drug distribution? Restricted drug marketing? Others?

20. CONCLUSION