1. 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

2. “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

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

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

5. 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

6. 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

7. 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

8. Label and Labeling Court Decisions
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

9. 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

10. 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

11. 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

12. 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.

13. Adequate Directions for Use

14. 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

15. Label and Labeling
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)

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Labeling and Social Media

23. 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 , , 2010 WL , at *51 (2d Cir., filed Oct. 8, 2010).†
However
Is it evidence of intent to defraud, infringe patents, misbrand a product?
† as discussed in January 15, 2016

24. 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)

25. 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

26. 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?