pmad 385: critical analysis of pharmaceutical marketing historic examples of unsafe or misleading...

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


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.


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


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



• Supposed Benefits/Advantages– Educates consumers about their conditions

and possible treatment choices– Increases adherence– Is protected commercial free speech



• 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


“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


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



• 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



• 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



• 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



• 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



• 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)



• 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”)


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



• 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



• 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


FDA Oversight (?): DDMAC

• DDMAC: Division of Drug Marketing, Advertising and Communication (39 people)

• 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

http://www.fda.gov/cder/ddmac/organizationlist.htm

http://www.fda.gov/cder/ddmac/organizationlist.htm

http://www.fda.gov/cder/handbook/ddmacrev.htm


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


Recent FDA Warning Letters

• Dyrenium (triamterene)– Misbranding

• Overstatement of efficacy; unsubstantiated superiority claim; omission of important risks

• MD-Gastroview (diatrizoate meglumine and diatrizoate sodium solution)– Misbranding

• Omission of important risks

http://www.fda.gov/cder/warn/2006/Dyrenium-promo.pdf

http://www.fda.gov/cder/warn/2006/Dyrenium-letter.pdf

http://www.fda.gov/cder/warn/2006/Gatroview-Optimark-promo.pdf

http://www.fda.gov/cder/warn/2006/Gatroview-Optimark-promo.pdf

http://www.fda.gov/cder/warn/2006/Gastroview-wl.pdf


Recent FDA Warning Letters

• Nevenac (nepafenac ophthalmic suspension)– 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)

http://www.fda.gov/cder/warn/2006/nevanac-promo.pdf

http://www.fda.gov/cder/warn/2006/nevanac-wl.pdf


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

http://www.eyeonfda.com/eye_on_fda/pdufa/index.html


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 opi

nions on ad materials. That's a go

http://www.pharmexec.com/pharmexec/article/articleDetail.jsp?id=382534

http://www.pharmexec.com/pharmexec/article/articleDetail.jsp?id=382534


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”


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


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!


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

pmad 385: critical analysis of pharmaceutical marketing historic examples of unsafe or misleading...

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