1. PMAD 385: Critical Analysis of Pharmaceutical Marketing Historic Examples of Unsafe or Misleading Pharmaceutical Marketing Bruce Lambert, Ph.D. Pharmacy Administration, UIC For the FLIP Team

2. PMAD 385: Critical Analysis of Pharmaceutical Marketing Lecture Objectives Define “false and misleading” in the context of claims about the safety and efficacy of prescription drugs. Explain the federal laws and FDA rules that govern prescription drug advertising and promotional labeling. Explain the structure and function of the Division of Drug Marketing, Advertising and Communications within the FDA. Identify at least three examples of unsafe or misleading advertising or promotion. List at least three tactics that manufacturers use when they engage in false or misleading advertising and promotion.

3. PMAD 385: Critical Analysis of Pharmaceutical Marketing Direct-to-Consumer Advertising (see JAMA, 293, 16, pp. 2030-2033) Illegal for the most part until FDA revised rules in 1997 Now > $3 billion per year spent on DTC ads DTCA drives sales of newer, expensive drugs for symptomatic chronic diseases or huge market conditions (e.g., erectile dysfunction, arthritis, allergies Educational quality of ads is poor, as is evidence to support many claims

4. PMAD 385: Critical Analysis of Pharmaceutical Marketing Direct-to-Consumer Ads (see JAMA, 293, 16, pp. 2030-2033) Supposed Risks/Disadvantages/Criticisms –Increases demand for unneeded or inappropriate care –Encourages use of new drugs whose safety is unknown –Increases overall societal expenditure on drugs, without necessarily increasing health benefits –Promotes consumerism over shared decision- making

5. PMAD 385: Critical Analysis of Pharmaceutical Marketing Direct-to-Consumer Ads (see JAMA, 293, 16, pp. 2030-2033) Supposed Benefits/Advantages –Educates consumers about their conditions and possible treatment choices –Increases adherence –Is protected commercial free speech

6. PMAD 385: Critical Analysis of Pharmaceutical Marketing Direct-to-Consumer Ads (see JAMA, 293, 16, pp. 2030-2033) Evidence is somewhat equivocal When is it beneficial? –Evidence for drug benefit is strong –Little risk of adverse effects –Drug is underused or disease is legitimately under diagnosed (e.g., perhaps depression) When is it harmful? –When non-drug therapy or older, cheaper safer drugs are better –When risks are unknown or known and serious –When “condition” has dubious medical credibility

7. PMAD 385: Critical Analysis of Pharmaceutical Marketing “False and Misleading” (3) Scope of information to be included; applicability to the entire advertisement. (i) The requirement of a true statement of information relating to side effects, contraindications, and effectiveness applies to the entire advertisement. Untrue or misleading information in any part of the advertisement will not be corrected by the inclusion in another distinct part of the advertisement of a brief statement containing true information relating to side effects, contraindications, and effectiveness of the drug. If any part or theme of the advertisement would make the advertisement false or misleading by reason of the omission of appropriate qualification or pertinent information, that part or theme shall include the appropriate qualification or pertinent information, which may be concise if it is supplemented by a prominent reference on each page to the presence and location elsewhere in the advertisement of a more complete discussion of such qualification or information. CFR Title 21, Chapter 1, Part 202, Section 202.1

8. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Must address each and every side effect and contraindication from approved label. Must present “true statements” Statements not true if: –It is false or misleading –It fails to present a “fair balance” between risks and benefits –It fails to reveal material facts about consequences that may result from suggested use

9. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –It contains an unapproved statement that the drug is better, safer, or fewer or less severe side effects or contraindications than “substantial evidence and substantial clinical experience” would suggest –It claims (without sufficient evidence) that it’s safer or more effective than another drug –It contains favorable claims or references or quotations that are not supported by evidence and experience

10. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –It selectively presents evidence that makes the drug appear to be safer than “substantial evidence and substantial clinical experience” would suggest –It exaggerates size or generalizability of study data –Cites studies that fail to disclose impact of placebo effect or concurrent therapy on study outcomes

11. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –Uses data from pre-clinical trials to support claims of clinical safety/effectiveness –Uses favorable quotes from experts without using current or more recent unfavorable quotes from same expert –Uses quotations out of context to convey false impression –Uses citations or quotes to suggest support for an advertised claim when in fact those sources do not support the claim in question

12. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –Uses literature, quotes or citations to suggest an unapproved indication –Offers combination of drugs to patients whose disease could be treated by only one drug in the combination –Uses data from studies of normal (i.e., healthy) people to promote use for sick people

13. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –It pools results from many unrelated or statistically insignificant studies to suggest significant results in a large study –Misleadingly uses result of non-significant difference to claim equivalence or deny real clinical difference –Makes favorable claims based on studies using doses other than those in the approved labeling (or compares to drugs using other than approved doses)

14. PMAD 385: Critical Analysis of Pharmaceutical Marketing False and Misleading: Side Effects and Contraindications Statements not true if: –It uses misleading headlines, graphics or pictures –It claims that approved safe and effective doses for one indication are also safe and effective for another indication (without evidence) –Refers to side effects in general categorical terms rather than specifically (e.g., “blood dyscrasias” instead of “leukopenia, agranulocytosis, neutropenia”)

15. PMAD 385: Critical Analysis of Pharmaceutical Marketing Ad is False, Lacking in Fair Balance or Misleading If: Claims come from poorly designed studies Uses statistical significance to support claim of clinical significance Uses retrospective analyses to “cherry pick” or “data dredge” for favorable results Uses tables and graphs to distort real relationships and trends Bases claims on statistical methods not generally accepted as valid

16. PMAD 385: Critical Analysis of Pharmaceutical Marketing Ad is False, Lacking in Fair Balance or Misleading If: Makes unsupported claims about site or mechanism of action (without disclosing that those claims are unsupported) Fails to equally emphasize risk and benefit claims –Via font size, layout, contrast, headlines, paragraphing, white space Attempts to disguise that two pages are part of same ad when one page discusses risks and one benefits

17. PMAD 385: Critical Analysis of Pharmaceutical Marketing Ad is False, Lacking in Fair Balance or Misleading If: In ads for special populations, fails to emphasize risks and dosage issues specific to those populations Fails to present risk information on all pages of multi-page ad if risk info is on any page Misrepresents opinions or reports as authoritative or authentic when they’re not

18. PMAD 385: Critical Analysis of Pharmaceutical Marketing FDA Oversight (?): DDMAC DDMAC: Division of Drug Marketing, Advertising and Communication (39 people)DDMAC: Division of Drug Marketing, Advertising and Communication Review Process Mission –To protect the public health by assuring prescription drug information is truthful, balanced and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers

19. PMAD 385: Critical Analysis of Pharmaceutical Marketing FDA Oversight: DDMAC Review ads and labeling to ensure it’s not false or misleading –Provide written comments to sponsors on promotional material to ensure clear communication of laws and regulations –Review complaints about promotional violations –Initiate enforcement action –Compare ads and labels of closely related products to ensure fair application of law –Travel to meetings to monitor promotional activity –Confer with other federal agencies

20. PMAD 385: Critical Analysis of Pharmaceutical Marketing Recent FDA Warning Letters Dyrenium (triamterene)Dyrenium –MisbrandingMisbranding Overstatement of efficacy; unsubstantiated superiority claim; omission of important risks MD-Gastroview (diatrizoate meglumine and diatrizoate sodium solution)MD-Gastroview –MisbrandingMisbranding Omission of important risks

21. PMAD 385: Critical Analysis of Pharmaceutical Marketing Recent FDA Warning Letters Nevenac (nepafenac ophthalmic suspension)Nevenac –False and misleading Broadens indication beyond what is approved Presents unsubstantiated superiority claims Overstates efficacy Omits risk information Presents misleading safety claims See letter (third warning to Alcon in 18 month period)See letter

22. PMAD 385: Critical Analysis of Pharmaceutical Marketing Critique of FDA Oversight Fewer and fewer FDA enforcement actions over time; trend continues into present (GAO report, House Government Affairs Committee Report) Warning letter volume on the decline Often long delays between FDA recognition of false/misleading ad and any enforcement action – In 2003, average delay from first appearance of ad until enforcement action: 177 days

23. PMAD 385: Critical Analysis of Pharmaceutical Marketing Critique of FDA Oversight FDA actions have little deterrent effect –Mostly letters –Power to fine, sue, or seize product rarely used –Loophole in “help seeking” ads where no risk information need be provided Possible relief in PDUFA 2007 –Additional $$ to DDMAC for more reviewers –Companies are increasingly turning to DDMAC for opinions on ad materials. That's a goCompanies are increasingly turning to DDMAC for opinions on ad materials. That's a go

24. PMAD 385: Critical Analysis of Pharmaceutical Marketing

26. Maxair Violations? Omission of material facts –Oops! Fails to present any risk information. –Fails to mention approved indication Unsubstantiated superiority claims –“helps patients breathe easier” –Cites study and displays image that shows increased deposition of particles to the lung –Small print says “Clinical significance of the lung deposition data is unknown”

27. PMAD 385: Critical Analysis of Pharmaceutical Marketing Maxair Violations? Unsubstantiated superiority claim –Implies greater lung deposition leads to easier breathing –Actual studies (cited!) show no differences in asthma control between this dosage form and standard albuterol inhaler –Other reference did not even test Maxair Autohaler –Disclaimer not enough to mitigate deception

28. PMAD 385: Critical Analysis of Pharmaceutical Marketing Maxair Violations? Unsubstantiated superiority claims –“easier to teach…easier to use” –No cited studies assessed ease of use or ease of teaching –One cited study assessed direct and indirect costs, not ease of use!

29. PMAD 385: Critical Analysis of Pharmaceutical Marketing Seroquel Handout Look at Seroquel handouts Read Seroquel prescribing information –Concentrate on warnings and precautions, especially bolded warnings This ad is false and misleading. You have to figure out why. Break into small groups At the end, we’ll read the FDA warning letter