1. FDA - INTRODUCTION TO DRUG REGULATION Edward P. Richards Director, Program in Law, Science, and Public Health Louisiana State University Law Center http://biotech.law.lsu.edu

2. 2 Basic Mission Safety Efficacy Drugs Medical Devices Truthful Labeling Adulteration Misbranding

3. 3 FDA's Structure and Organization The Commissioner President Appoints, Senate Confirms 4th Tier in HHS Not an Independent Agency Insulation From Politics (Old Days) Few Political Appointees Scientific Basis of Its Decisions Visibility Protects It From Presidential Pressure

4. 4 Does Congress Defer to the FDA? No, Congress Constantly Reviews the Agency in Committee Meetings Why? Lots of Money Lots of Powerful Interests Drugs, Food Labeling Food and Drug Cranks

5. 5 Political Control - Food Supplements Did Regulate Food Supplements and “Health Foods” Began to Crack Down on Unproven Claims and Raise Questions about Safety Congress was Lobbied (Oren Hatch) Pulled the FDA Authority to Regulate Food Supplements Can Only Act on Evidence of Post-Marketing Harm No Pre-Market Approval

6. 6 What Does the FDA Regulate? Food (with Agriculture Department) Drugs Biologics Medical Devices Cosmetics Anything That Produces Dangerous Radiation 25% of the Consumer Dollar

7. 7 What Is a Drug? 201(g) (A) Articles Recognized in the Official United States Pharmacopoeia, Official Homeopathic Pharmacopoeia of the United States, or Official National Formulary, or Any Supplement to Any of Them Does the FDA Really Treat Every Thing in These As Drugs?

8. 8 What Is a Drug? 201(g) (B) Articles Intended for Use in the Diagnosis, Cure, Mitigation, Treatment, or Prevention of Disease in Man or Other Animals How Do You Judge This? Manufacturer or Seller's Representations Are These Limited to Labels and Advertising? No, Sec Info Is an Example Can Consider Consumer Expectations in Exceptional Circumstances

9. 9 What Is a Drug? 201(g) (C) Articles (Other Than Food) Intended to Affect the Structure or Any Function of the Body of Man or Other Animals Do They Really Mean This? (Guns, Bullets) (D) Articles Intended for Use As a Component of Any Article Specified in Clauses (A), (B), or (C) of This Paragraph.

10. 10 Prescription Drug Regulation Good Old Days In the Early 1900s You Could Get Anything You Wanted No Concern for People Poisoning Themselves Few Effective Drugs Limited Rationale for Physician Supervision Harrison Narcotics Act Heroin Was the Hero Drug Because It Saved People From Morphine

11. 11 Getting a Drug Approved Isolate or Synthesize the Agent Many are Biologicals Cyclosporin Tamoxifen Structure Activity Design Genetic Engineering Do Animal or in Vitro Studies to Determine Activity Apply for an Investigational New Drug (Ind) Permit

12. 12 Requirements for Approval for Sale in Interstate Commerce Safe As compared to what? How is this relative to the underlying condition being treated? Effective How effective? Compared to placebo? Compared to other drugs?

13. 13 Submit for FDA Approval Clinical Trials Can Take Years Very Expensive >>$200,000,000 Most Drugs are Not Approved Labeling is Key to Approval Narrow Use allows More Dangerous Drugs Broader Use Means More Money

14. 14 Clinical Trials Phase I What are the side effects? Is it safe enough to test? Phase II Does it work at all? What is the dosage range? Phase III Is it better than placebo? Is it better than other treatments? What are the side-effects

15. 15 Conflicts in Clinical Trials Life Saving Drugs Patients want a cure Drugs probably do not work What if the drug is available outside the trial? Do you quit a drug that works to get on the trial? What if the patient Lies? Non-Life Saving Drugs Pay the subjects? Docs get paid by the patient Companies want positive results

16. 16 The Drug Lag What Is the Drug Lag? What Are the Conflicts? FDA Risk Aversion? Freedom of Choice? What Are the Conflicting Expectations That the FDA Faces?

17. 17 Sources of Law on Drug Labels Federal Trade Commission FDA State Deceptive Trade Practices Laws State Tort Laws No FDA preemption of state requirments

18. 18 Why Is Labeling So Important? All Drugs Pose Risks Inherent Risks Risks Due To Interactions With Other Drugs Risks Due To Disease States Risk Of Over and Under Dosage NO RISKS ARE OBVIOUS!

19. 19 Manufacturers Have The Most Information Clinical Trials Under The IND Proprietary Information Controlled By The Manufacturer Should Be Reported To The FDA Post-Market Information Manufacturer Gets Primary Reports Should Pass Information To The FDA

20. 20 What is a Label - I "Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio or visual matter descriptive of a drug and references published (for example, the Physician's Desk Reference)

21. 21 What is a Label - II for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labeling as defined in section 201(m) of the FD&C Act."

22. 22 Rx Drugs Physician Information Package Insert Information Sheets For Physicians Depends on Expertise of Physician What about non-physician prescribers? Rarely, Patient Package Insert When Patients Have Significant Control Over Choice of Drugs Birth Control Pills

23. 23 OTC On The Box Insert In The Box Must Allow Safe Use By Consumer Labeling Issues Often Determine Whether A Drug Is OTC or Rx

24. 24 Labels Can Make The Drug Apple Cider Vinegar Alone is not a Drug Apple Cider Vinegar with a Label that Says It Will Cure Cancer is a Drug, Subject to FDA Regulation Also Subject to FTC Regulation Does a Book Saying it Treats Cancer Make it a Drug? Is the Author Guilty of Misrepresentation?

25. 25 FDA Standards for Labels A Drug is Misbranded If: [Its] "labeling is false or misleading in any particular" or the labeling does not bear "adequate directions for use." Drugs are Misbranded if the Manufacturer Does Not Use the FDA Approved Label Information Misbranded Products Cannot Be Sold

26. 26 Federal Trade Commission Standards for Labels Misleading Or Deceptive FTC Looks At All Advertising And Promotional Materials Penalties Civil Fines Criminal Prosecution Usually Secondary To The FDA For Drugs Governs Medical Products That Are Not Under the FDCA

27. 27 Tort Law Standards for Labels Must Provide Full Prescribing Information Must Provide All Side-effects and Contraindications Must Anticipate Misuse and Warn Against it Must Quickly Add Any New Information about the Drug

28. 28 What the Label Cannot Have Unapproved Uses Only Uses From Approved NDAs Hence "Off-Label" Uses Disputes with the FDA No Over-Warning CYA in Tort Cases Interferes with Rational Prescribing

29. 29 Patient Package Inserts Legal Authority To Require? Regulatory History Why Did Physicians Oppose Them? What Drugs Must Have Them Now? Why Is The FDA Interested In Them Again?

30. 30 Promotional Materials Real Issues Off Label Uses Inappropriate Use FDA Authority Over Promotional Materials Can The FDA Control What Detailmen Say? How Have Companies Gotten In Trouble?

31. 31 Providing Information On Unapproved Uses The Manufacturer Cannot Advertise Unapproved Uses The Manufacturer Can Send Out Medical Journal Reprints On Unapproved Uses Must Log and Notify FDA May Have to Retract if the Science Changes Must A Manufacturer Warn Against Known Unapproved Uses?

32. 32 Requirements for Direct to Consumer Ads All the contraindications All the warnings All the major precautions All other frequently occurring side effects that are likely to be drug-related Include Contact Phone and URL

33. 33 Internet Information WWW Pages are Subject To FDA Regulation Non-Manufacturer Sites Can Pharmacies Tout Unapproved Uses? What about Access to Rx Drugs without an Rx? Can Manufacturers Link To Non-Manufacturer Sites?

34. 34 Direct to Patient Marketing and OTC Switch Are the Vast Majority of People Prepared for Self- medication? What Is the Products Liability Problem? Labels for Idiots Social Policy for Communicable Diseases? Defeats the Reporting System Improper Antibiotics Use Leads to Drug- resistant Infections

35. 35 Tort Implications of Direct Advertising Undermines Learned Intermediary Defense Can Trigger a Duty to Warn the Patients Directly Makes Rx Drugs More Like OTC Must the FDA Approve a Voluntary PPI?

36. 36 Future Issue Commercial Speech Restrictions On FDA Authority Blurring of OTC And RX Labeling Because Of Internet Sales Shifting Of Warning Duties To Pharmicists Changing Labeling Standards As States License Non-Physician Prescribers

37. 37 Controlled Substances Drug Enforcement Administration (DEA) What Are the 5 Schedules? I High Potential for Abuse and No Currently Accepted Medical Use (in the Us) - Heroin II High Potential for Abuse but a Medical Use III Moderate Potential for Abuse IV Low Potential for Abuse V Lowest Potential for Abuse Constitutional Right to Do Dope?

38. 38 Post-Market Surveillance - The Vioxx Question Clinical Trials Are Limited in Time and Scope Many Serious Side-effects Cannot be Detected in Trials Dangerous to Include Pregnant Women, so no tetragons are detected Docs are Supposed to Report Side-effects Not always very effective Large Scale Trials Should Continue Who will fund them? Drug Companies do not want to undermine their products

39. 39 History of Drug Liability FDA History is the History of Drug Injuries FDA Regulation Tries to Prevent Future Injuries Tort Litigation Compensates for Past Injuries

40. 40 Multiple Sovereigns Tort Law for Drugs is State Law Basic Theories are the Same Significant Variation on Details Federal Courts Apply State Law Individual Judges Have Great Discretion Many Case Depend on Whether the Judge Admits the Plaintiff's Evidence Forum Shopping

41. 41 Negligence Traditional Cases Were Usually Based in Negligence Had to Show Legal Relationship – Privity No Relationship Between Patient and Drug Company Ended with Pharmacist Made Sense when Pharmacists Compounded all the Drugs

42. 42 Fall of Privity Courts Found Privity Out of Date with the Industrial Revolution Thomas v. Winchester (1852) Supplier Provided Belladonna rather than Dandelion Privity would have Blocked the Claim Court Limited Privity for Dangerous Activities

43. 43 Early Strict Liability Many States Imposed Strict Liability for Ultrahazardous Activities Blasting Impounding Water Plaintiff did not need to Show Negligence, only Injury Due to the Activity Very Limited Application – not generally extended to Drugs

44. 44 Limits of Negligence Must Show Breach of Standard of Care What a Reasonable Manufacturer Would Do? Only Evidence is Other Manufacturers Must Show What Happened to the Specific Batch

45. 45 Warranty Theories Predate Strict Liability Related to UCC Warranties Cannot Disclaim for Personal Injuries Based on Promises Special Problem for Promoting Off-Label Uses

46. 46 Express Warranty Manufacturer Is Held to Specific Promises Shatterproof Windshield Case Claimed It Was Just “Puffing” Court Said It Was a Clear Promise Did Not Matter If It Was Impossible Can Be Written or Verbal Can Physicians Give Binding Warranties About Products?

47. 47 Implied Warranties Implied From the Context of the Sale A Product Is Safe for What It Is Sold for FDA Approved Drugs Have Only the Stated Risks Implied Warranty of Fitness for a Specific Purpose Manufacturer or Seller Says the Product Is Good for Something Other Than Its Usual Purpose Use of Drugs For Unapproved Purposes

48. 48 Jeep Case Jeep Sold for off the Road Use Rolled and Killed and Injured Passengers Made Like a Sardine Can Manufacturer Claimed Improper Use How Do You Prove? Advertising Representations by Sales Persons

49. 49 Shift to Strict Liability Hard to Prove Negligence for Products Generic Goods - No Specific Information Defendant’s Have Lots of Resources Defects Affect Lots of People Strict Liability Encourages Safety Cannot Escape Liability by Just Doing What Others Do Safer Products = Lower Costs