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 >>$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

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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