FDA, Labeling, and Marketing David W Feigal, Jr MD MPH Adjunct Professor, O’Connor College of Law, ASU January 16, 2016 Workshop: Pharmaceutical Pricing and Marketing: Markets versus Regulation

“When I use a word” Humpty Dumpty said in a rather scornful tone, “it means just what I chose it to mean – neither more nor less.” Lewis Carroll

What’s in a word (to FDA) ? Label Container and packaging labels “Accompanying Materials” Brochures, pamphlets, books… Labeling Exchange of Scientific Information

Why is labeling important to FDA? The Pure Food and Drug Act 1906

Labeling (Speech) determines if an article is a Drug In the FDCA, the term "drug“ means — articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and articles (other than food) intended to affect the structure or any function of the body. The same compound could be a drug or not – depending on the intended use. Intent is determined by labeling (speech) ,i.e., the packaging

The Courts and Labeling: False Claims United States v. Johnson 1911 “This is an indictment for delivering for shipment from Missouri to Washington, D.C., packages and bottles of medicine bearing labels that stated or implied that the contents were effective in curing cancer, the defendant well knowing that such representations were false. ” “…a word as to what Congress was likely to attempt. It was much more likely to regulate commerce in food and drugs with reference to plain matter of fact, so that food and drugs should be what they professed to be …” In other words, the Supreme Court interpreted that false and misleading applied only to the contents of a drug packaging, not the health claims

The Shirley Amendment 1912 Misbranding: IN CASE OF DRUGS: Note: “If its package or label shall bear or contain any statement, design, or device regarding the curative or therapeutic effect of such article or any of the ingredients or substances contained therein, which is false and fraudulent.” 37 Stat. 416 (1912) Note: Now a stricter standard than false and misleading for claims Removed from the FDCA in 1938 Moot after 1979 when the drug approval process included strict labeling requirements before marketing – labeling which cannot be changed without FDA approval

Label and Labeling Court Decisions 1906 - 1938 1911 – Supreme Court: false and misleading does not apply to medical claims 1912 – Shirley Amendment – Fraudulent medical claims prohibited 1916 -Supreme Court agrees that labeling definition includes “accompanying materials” Court cases for the next three decades define “accompanying” and the boundaries of “interstate commerce” 1922 – Supreme Court: false claims constitute unfair competition False drug claims become the majority of the FTC case load

The “Elixer of Sulfanilamide” FDA Takes Misbranding Action The labeling described the product as an “Elixir of Sulfanilamide” For drug products an elixir contains alcohol As there was no alcohol in the product FDA could seize and destroy the product Only the Misbranding (Speech) allowed FDA to take action to seize and destroy the product

What’s in a word (to FDA) ? Label Labeling Prescribing Information (Package Insert) Instructions for Use (Medical Devices) Medication Guide (Safety information for patients) Consumer Labeling (e.g., Food label, OTC label) Promotion Advertising Exchange of Scientific Information

1938 Food Drug & Cosmetic Act Established basic structure of today’s law Gave FDA authority to require New Drug Applications FDA could block new drugs if it concluded that additional safety testing needed Prohibition of false therapeutic claims (not just fraud) FDA now needed to define “New Drugs” Misbranding is the authority that FDA uses to control unapproved drugs

Definitions: “New” Drug The term "new drug“ means: Any drug, the composition of which is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof.

Adequate Directions for Use

OTC v RX “Adequate Directions for Use” “Adequate Directions for Use” only applies to products sold directly to consumers An OTC product that cannot provide adequate directions for use is a prescription product (Rx) Until 1945 Rx drugs could not mention intended uses An prescription (Rx) product is exempt from “adequate directions for use” if it follows the prescription labeling and promotion regulations

Label and Labeling 1938 - 1962 1948 – Supreme Court: Labeling is defined “functionally” 1956 – Court of Appeals: Sales force materials are labeling 1960 – Congressional Hearings on biased materials supplied to physicians by manufacturers 1960 – FDA asks medical textbook author to warn of unsafe (off-label) uses 1962 – Kefauver Amendments return Rx advertising to FDA (from FTC)

Off label use v. Off label promotion Use in the practice of medicine of a product for indication not included in FDA prescribing labeling Not prohibited Often standard of care Often reimbursed Off label promotion Proactive communications about an indication not included in FDA prescribing information

What is “Off-Label” promotion? Not a term found in the Food Drug and Cosmetic Act, nor the Regulations, and not very often in FDA Guidance documents The FDA Term is “Misbranded” (but not every type of misbranding is off-label…) FDA uses violations of the “New Drug” requirements to prohibit off-label use

Label and Labeling 1962 to 1997 1968 – Congressional hearings on off-label use of methotrexate for psoriasis 1971 – FDA ‘educational approach’ through journal articles …Congress not impressed 1972 – FDA proposed rule to take action when physician off-label use created public health threat Vigorous push back from medical groups FDA shifts emphasis to manufacturers 1984 Direct to Consumer advertising of Rx drugs begins 1991 FDA prohibit distribution of text books by manufacturers if they contain off-label uses FDA takes actions against manufacturers for distribution of medical literature

What is in a word (to FDA) ? Label Labeling Exchange of Scientific Information Response to requests for information about an labeled or unlabeled indication Most companies differentiate between their sales force (detailers) and have a separate group to respond to requests (often called Medical or Scientific Affairs Distribution of journal articles, professional society recommendations, white papers, company safety experience

FDA Review of Labeling Organization of Prescription Drug Labeling Reviews New Drug Divisions Prescribing Information, Medguides, some patient materials - Approves labeling changes Division of Drug Marketing, Advertising and Communication (old Name) Office of Prescription Drug Promotion Advertisements, sales force materials, web-sites - Issues ‘notice of violation’ and ‘warning’ letters

Off Label Promotion vs. Scientific Exchange Proactive Marketing v. Reactive Information Requests 1995 FDA refers off-label promotion cases to DOJ 1996 and 1997 FDA guidances to create safe harbors Enjoined after WLF suit 1997 FDAMA Compromise that no one liked Off label use could be proactively marketed if a company was pursing an Efficacy Supplement to their NDA to add that application WLF decision / Appeal decision based on “safe harbor” Law sunsets 2006 Subsequent 2009 Guidance by FDA on Scientific Exchange

Labeling and Social Media

Is Off Label Promotion Illegal? “Promoting an approved drug for off-label uses is not itself a prohibited act under the FDCA, nor is it an element of any prohibited act.”  Brief of United States, United States v. Caronia, Nos. 09-5006, 10-0750, 2010 WL 6351497, at *51 (2d Cir., filed Oct. 8, 2010).† However Is it evidence of intent to defraud, infringe patents, misbrand a product? † as discussed in http://druganddevicelaw.blogspot.com/ January 15, 2016

Off-Label Promotion: Why does it Matter? Enforcement actions by FDA for misbranding Whistle-blower suits for defrauding the government health care purchasers Violations of anti-kick back laws Exposure to ‘failure to warn’ product liability actions (Wyeth v. Levine) Pre-empted for generic drugs which do not control their own labeling (Pliva v. Mensing)

Off-Label and the 1st Amendment Commercial Free Speech ? Is off-label promotion entitled to 1st amendment protection ? Does the government have an interest in restricting dissemination of truthful information ? Who vettes “truthful” ? Are there alternatives to categorical prohibition

FDA’s Dilemmas Categorical prohibition of Off-Label information While only applying to manufacturers – manufacturers often possess more information about their use than any other source FDA acknowledges the public health importance of off-label use How is the public health served by off-label use without off-label information? Is the patient held hostage to FDA’s goal of encouraging NDA applications?