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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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 >>$200,000,000 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 FD&C 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