FDA - INTRODUCTION TO DRUG REGULATION

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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

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Basic Mission

• Safety
• Efficacy
• Drugs
• Medical Devices
• Truthful Labeling
• Adulteration
• Misbranding

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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

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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

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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

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What Does the FDA Regulate?

• Food (with Agriculture Department)
• Drugs
• Biologics
• Medical Devices
• Cosmetics
• Anything That Produces Dangerous Radiation
• 25 of the Consumer Dollar

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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?

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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

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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.

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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

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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

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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?

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Submit for FDA Approval

• Clinical Trials Can Take Years
• Very Expensive gtgt200,000,000
• Most Drugs are Not Approved
• Labeling is Key to Approval
• Narrow Use allows More Dangerous Drugs
• Broader Use Means More Money

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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

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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

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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?

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Sources of Law on Drug Labels

• Federal Trade Commission
• FDA
• State Deceptive Trade Practices Laws
• State Tort Laws
• No FDA preemption of state requirments

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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!

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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

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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)

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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 FDC Act."

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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

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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

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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?

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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

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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

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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

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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

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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?

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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?

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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?

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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

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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?

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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

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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?

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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Warranty Theories

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

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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?

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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

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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

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Shift to Strict Liability

• Hard to Prove Negligence for Products
• Generic Goods - No Specific Information
• Defendants 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