U.S. Regulation of Prescription Drug Marketing and Promotion October 21, 2004 Bill Ross

U.S. Regulation of Prescription Drug Marketing and Promotion

October 21, 2004

Bill Ross

10/21/2004 U.S. Regulation of Prescription Drug Marketing and Promotion

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Objectives

Review key U.S. federal regulations on prescription drug marketing and promotion

Examine general requirements for drug advertising and promotion

Understand policies and guidelines for scientific and medical education programs


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U.S. federal regulations on prescription drug marketing and

promotion


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History of Drug Regulation

• Vaccine Act of 1813– First federal government program designed to

improve the health and well-being of the general populace

– Statute enacted to ensure adequate amounts of vaccine was available

– Repealed when small pox vaccine was attributed with spreading smallpox


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• Drug Importation Act of 1848– Ban on importation of “adulterated and

spurious” drugs– Law required all drugs entering the U.S.

through its six major ports to be analyzed for "quality, purity, and fitness for medical purposes"


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• Biologics Control Act of 1902– Statute enacted after tetanus-infected diptheria antitoxin

was distributed

– The production of biologics requires a licensing process

– Licensed establishments were inspected by scientists and medical officers from the National Hygienic Laboratory, the forerunner of the present National Institutes of Health (NIH).


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• ‘The Great American Fraud’ Articles of 1905 by Samuel Hopkins Adams – Exposes the fraud of the patent medicine

business– Hard-hitting full scale exposure of medical

quackery– Congress enacts the first of several pure food

and drug laws in 1906


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• Federal Food & Drugs Act of 1906– USDA, Bureau of Chemistry– Law prohibiting interstate commerce in adulterated and

misbranded drugs• Criminal penalties• Seizure of offending products

– Purity standards established by U.S. Pharmacopoeia and National Formulary

– Required narcotics be disclosed on product’s labeling– Forbid imitations


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• Sherley Amendments of 1912– Statute prohibiting labeling medicines with

false therapeutic claims intended to defraud the purchaser

– Difficult to prove


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• Harrison Act of 1914– All opium and coca products require strict

accounting– Upper limits on the amount of opium, opium-

derived products, and cocaine allowed in products available to the public

– Taxation


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• Food and Drug Administration formed in 1931


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• Federal Food, Drug and Cosmetic Act of 1938– Elixir sulfanilamide disaster of 1937 (107 dead)– Penalties for adulteration and misbranding without proof of fraud

(eliminating need for Sherley act)– Authorized NDAs

• Required new drugs to be shown safe before marketing

– Dangerous drugs must be administered under the direction of a qualified expert

• Established prescription only (non-narcotic) drugs• Permitted manufacturers to determine if their drug was a prescription• FDA could sue the manufacturer if it disagreed with the decision


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• Federal Trade Commission Act Amendments of 1938– Gave FTC authority to regulate drug

advertising


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• Kefauver Amendments to Food, Drug and Cosmetics Act (1962)– Response to thalidomide tragedy– Drug manufacturers are required to provide to FDA

“substantial evidence” of efficacy and safety of their products before marketing them

– FDA gains authority to regulate Rx promotion and clinical testing

– Manufacturers must demonstrate the efficacy of products approved prior to 1962


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• FDA requires the first patient package insert: oral contraceptives must contain information for the patient about specific risks and benefits (1972)

• Orphan Drug Act passed, enabling FDA to promote research and marketing of drugs needed for treating rare diseases (1983)

• Prescription Drug Marketing Act of 1987– Bans the diversion of prescription drugs from legitimate

commercial channels– Prohibited reimportation of drugs by anyone other than the

manufacturer– Bans sale, trade or purchase of drug samples


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History of Drug Regulation• FDAMA: Food and Drug Modernization Act of

1997– PDUFA--Prescription Drug User Fee Act – Pediatric studies– Healthcare economics information– Restricted dissemination of “off-label” uses*– “FDA approved”– Established a registry of clinical trials for both federally

and privately funded trials of experimental treatments for serious or life-threatening diseases

* See Washington Legal Foundation (WLF) vs. FDA 1994

General requirements for drug advertising and promotion


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Labeling

• All written matter accompanying a drug

• FDA determines whether the labeling of drugs is false or misleading

• Must be accompanied by full prescribing information


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Labeling• PI

– Prescribing information– Package insert– Product information– Detailed prescribing information

• PPI– Patient package insert– Patient product information

• Brief Summary– Brief summary of prescribing information


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Content and Format of PI

• Description

• Clinical pharmacology

• Indications and usage

• Contraindications

• Warnings

• Precautions

• Adverse reactions

• Overdosage

• Dosage and administration

• How supplied

• References


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Content and Format of Patient Information

• How to pronounce it• What is it?• How does it work?• How should I take it?• Who should not take it?• What other medical conditions should I discuss with my doctor?• What are the possible side effects?• Can it be take with other medications?• What should I know about the disease?• How should I store it?• General information (e.g., keep away from children, overdose, etc.)


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Advertising and Promotion[Code of Federal Regulations][Title 21, Volume 4][Revised as of April 1, 2001]From the U.S. Government Printing Office via GPO Access[CITE: 21CFR202.1]

[Page 72-81] TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICESPART 202--PRESCRIPTION DRUG ADVERTISING--Table of Contents Sec. 202.1 Prescription-drug advertisements:

(a)(1) The ingredient information required by section 502(n) of the Federal Food, Drug, and Cosmetic Act shall appear together, without any Intervening written, printed, or graphic matter, except the proprietary names of ingredients, which may be included with the listing of established names. (2) The order of listing of ingredients in the advertisement shall be the same as the order of listing of ingredients on the label of the product, and the information presented in the advertisement concerning the quantity of each such ingredient shall be the same as the corresponding information on the label of the product.(3) The advertisement shall not employ a fanciful proprietary name for the drug or any ingredient in such a manner as to imply that the drug or ingredient has some unique effectiveness or composition, when, in fact, the drug or ingredient is a common substance, the limitations of which are readily recognized when the drug or ingredient is listed by its established name.(4) The advertisement shall not feature inert or inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation.

Office of Medical PolicyDivision of Drug Marketing,

Advertising, and Communications

Laws, Regulations, Guidances, and Enforcement Actions


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Advertising and Promotion

• Musts– Accompanied by a brief summary adjacent to ad– Can’t be false or misleading– Provide adequate directions for use– Contain true statement of safety and effectiveness– Include fair balance– Include all material facts– Consistent not contrary to labeling

• Must not– Be False, Misleading, or Lacking in Fair Balance 21 C.F.R. 202.1– Failure to do all of the above Musts is in violation of this statute


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Advertising and Promotion• Unsubstantiated claims include:

– Statements suggesting the drug is better than it in fact is• Failure to disclose clinical claims which may be due to concomitant

therapy or placebo effect

– Claims not studied in a population• Claims based on data from healthy subjects

– Clinical statements that are not current – Clinical statements that are not representative of the study

population– Claims based on retrospective analysis– Use of information from an inadequate study– Mechanism of action claims not established


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Advertising and Promotion

• False, Misleading or Lacking Fair Balance– Uses tables or graphs to distort or misrepresent the

relationships, trends, differences, or changes among the variables or products

– Failure to include balance (talking about a drugs efficacy w/o discussing SE’s, contraindications, etc.) on each spread “with a prominence and readability reasonably comparable with the presentation of information relating to effectiveness of the drug…”


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Enforcement Issues

• Broad Issues– Omission/minimization of risks– Promotion of unapproved uses– Unsubstantiated claims

• Efficacy– Outcomes– Survival

• Safety• Comparative


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Enforcement Scope

• Journal Ads• Sales aids/detailers• Giveaways• Sales representatives• Commercial exhibit halls• DTC broadcast ads• DTC print ads• Websites


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Warning Letters

• Lack of important risk information• Minimization of important safety information• Misleading comparative claims• Overbroadening of the indication• Omission from body of ad

– crucial facts related to potential risks– potential for abuse– limitations on appropriate indicated use

• Unsupported outcomes claims


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OxyContin Warning Letter

• Journal advertisements

• Lack of important risk information

• Overbroadening of the indication

• Omission from body of ad– crucial facts related to potentially fatal risk– potential for abuse– limitations on appropriate indicated use


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Claims

• Claim– Often considered an indication

– Non-comparative• “Improvement”

– Scientific evidence of diminution of the signs and symptoms of a condition

• “New”– Only for the first six months of US market introduction

• “Safe”– Prescription drugs are inherently unsafe

– Use tolerability or safety profile


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Comparative Claims

• Comparative claim– Conveys comparability, superiority– May be done to support a change in promotion of a product

• Must be consistent with labeling• Statistically significant

– Misleading use of statistics is misbranding of a drug– Must indicate level of statistical significance with “P value.”– Usually ≤ 0.05

• Clinically significant– True statements without clinical significance can be misleading

• Presented with fair balance


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Comparative Claims

• Cannot be based on:– Partial information– Selected facts of the underlying study– In vitro evidence– Computer modeling– Blood levels or tissue levels– Anecdotal evidence– Label comparisons


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Comparative Claims

• Substantiation– Generally requires two adequate and well-controlled

studies

– Reasons for two studies• Any clinical study may be subject to undetected, systematic

bias

• The inherent variability in biological systems may produce a positive result purely by chance

• Results obtained from a single site may be investigator specific

• Possibility of fraud


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Comparative Claims

• Adequate and well-controlled– Clear statementof objectives

– Valid comparison to a control

– Randomized

– Blinded

– Pre-specified endpoints

• Consistent with and not contrary to approved labeling– Approved for indication studied

– Dosage regimens must be appropriate for comparison

– Dosages must be consistent with approved labeling


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Comparative Claims

• Situations where a single study may suffice– Trial demonstrating meaningful effect on

morbidity, mortality or prevention of a serious disease AND

– Confirmation of the result in a second trial would be unethical AND

– Must be consistent with all available evidence


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Comparative Claims• Types of comparative claims

– Superiority• Indicates that a product is superior to a therapeutic alternative• Must be demonstrated on all relevant factors• Implies product should be administered preferentially in most cases

– Price comparisons– Preference claims– Most “prescribed” claims– “More potent” claims– “Drug of choice” claims– Comparisons to generics: cannot suggest any therapeutic or quality

difference between a branded and generic product– “First line”– Statements about other drugs: can be misleading

Policies and guidelines for scientific and medical education programs


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Medical Education

• CME (Continuing Medical Education)– Educational activities which are not

promotional in nature may be sponsored by industry and not subject to regulation by the FDA

– FDA closely scrutinizes educational programs to insure they are truly independent educational/scientific discourse, and not just “disguised” promotion


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Medical Education• FDA criteria for determining whether MedEd programs are truly educational

– Written agreement between provider of the activity and sponsoring company that the provider is not influenced by the sponsoring company

– Provider has full control over the program content including selection of speakers and moderators

– Any financial relationship between providers, speakers and company sponsor must be disclosed

– Sponsoring company cannot dictate content of program– No ancillary promotional activities are permitted by the company in the same location

area as the program– Data presented must be objective and balanced– There should be disclosure on limitations of data presented– Provider and/or speaker should disclose any unapproved indications– There should be opportunity for debate– Invited guests cannot be targeted by marketing to discuss marketing of the product– The speaker should not focus on one company’s product or show bias– Repeat performances of the same seminars can be deemed promotional`


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Medical Education• A company may pay for meals, travel and lodging for speakers.

However, extravagant gifts beyond the speakers costs are considered promotional.

• AMA guidelines– No gifts if there are reciprocities– Physician gifts should be no more than $100 in value. No cash

payments– Gifts should be medically relevant (related to a physician’s work)– Subsidies to underwrite educational program costs should be made to

provider and not to physicians in attendance– Subsidies cannot be made for travel, lodging or other personal

expenses to physicians attending a MedEd conference unless it is for faculty at the conference. Only hospitality gestures such as a meal can be made by a company to physicians at a conference.


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U.S. Regulation of Prescription Drug Marketing and Promotion October 21, 2004 Bill Ross