FDA Sends Warning Letter to Website to Cease & Desist: It Doesn't

@skypen posted this tweet recently: "Interesting warning letter for flu med for false claims via web, twitter & facebook http://t.co/FWI0y4Ch," which I found in the ePharma Pioneer Club Forum.

What I found interesting about this letter is that it addressed an issue more serious than the typical "false claims" letter that Rx pharma companies sometimes receive. This letter pointed out that a product ("Triple Flu Defense") was being "promoted for conditions that cause the product to be a drug" subject to FDA regulation. "Triple Flu Defense," however, never submitted a new drug application to the FDA for marketing approval. Hence the letter.

FDA pointed out that several unsubstantiated efficacy claims were made, such as:

• “Relieves Flu Symptoms” 
• “Eases Flu Vaccine Side Effects” 
• “…[T]his product is of inestimable value in the prevention and mitigation of influenza.” “Triple Flu Defense can also be used to alleviate side effects from the flu vaccine.”

In addition, said FDA, the website "includes claims in the form of testimonials that establish the intended use of your product as a drug. Examples of these testimonials include the following:

• “It really works. My husband didn’t take the formula and got sick and I didn’t. It has no side effects.” 
• “I have been around people with the flu and haven’t gotten sick since taking Triple Flu Defense.” 
• “I had been sick for a week with the flu and thought I was never going to feel better. I took two doses of Triple Flu Defense and felt a lot better. It works great.” 
• “I'm one of the few people I know who didn't get the flu this past year because of Triple Flu Defense!”  
• “I took Triple Flu Defense during the season. I didn’t get sick all winter.”

Pretty amazing claims!

When I accessed the Triple Flu Defense Web site (here), I expected to see that it had been taken down in response to the FDA's waring. After all, the FDA sent the letter via UPS overnight on December 14, 2011 and demanded action within 15 days. But it's almost a month later and all the claims are still there (see screen shot; click to enlarge and read the claims).

In contrast, when Rx Web sites are cited for violations by the FDA, the offending pages are gone by the time you learn about the letter!

Pharma Walks, Devices Balk When It Comes to FDA User Fees

While brand name drug manufacturers pay about 62% of FDA's $930 million drug review budget, medical device companies only pay about 20% of FDA's $292 million budget allocated to reviewing devices (see "Pharma Pays 62% of FDA's Drug Review Budget").

Are device manufacturers cheap skates?

I don't think so. My guess is that they don't have as many sympathetic people inside FDA as does Big Pharma. Why else would the device industry and its allies have been "especially vocal this year in denouncing what they perceive as the relative length and unpredictability of the FDA's device-approval process"?

Big Pharma on the other hand is suspected to have close ties to DDMAC. Of course, it cannot be proved that FDA plays favorites depending on how much of the bill is paid by the companies it regulates. However, I am keeping tract of two trends:

1. the rise in PDUFA (the 1992 Prescription Drug User Fee Act) fees (ie, user fees) and 
2. the number of warning letters FDA sends each year to pharma companies. 

I get the former data straight from the FDA (here) and the latter from EyeOnFDA blog, which monitors warning letters (here, for example). The following chart shows the trends:

It appears that 2010 saw a slight decrease in user fees received by FDA, but this is an early estimate that is sure to be higher in the next report. In fact, the WSJ article cited above indicates that "the Food and Drug Administration has reached an agreement with the brand-name drug industry on a five-year plan that will increase industry fees paid to the agency by about 6%." I'm pretty sure they are talking about a 6% increase EVERY year for the next 5 years. The average yearly increase over the past 12 years has been 16.7%. Hmmm... I guess the FDA expects to be reviewing fewer new drug applications in the coming years than in the past.

P.S. In 1997, only 36% of FDA's drug review budget was paid for by pharma user fees.

FDA Sucker Punches Sepracor with Warning Letter After the Match Is Over!

On June 9, 2010, Carrie Newcomer, Regulatory Review Officer in FDA's Division of Drug Marketing, Advertising and Communications (DDMAC), sent a "warning" letter to Kathleen Grim, Executive Director, Regulatory Compliance at Sepracor Inc., about a Lunesta TV ad that Newcomer said "presents unsubstantiated claims, including unsubstantiated superiority claims."

The ad in question is the so-called "Boxing Bed" ad, which shows a sleepless woman tossing and turning in a bed that is also a boxing ring. Here's a panel from the storyboard that was submitted to the FDA on November 19, 2009, about the time the ad first ran on TV:

This ad was voted one of "The 10 Worst TV Ads of 2009" (see here).

In other words, the ad appeared way back in 2009 and the FDA is just now sending Sepracor a warning letter after having the storyboard in its possession for 7 months! Of course, the ad has run its course and Sepracor and Lunesta have long left the ring. But the FDA still went after them with this sucker punch.

What is FDA demanding? "DDMAC requests that Sepracor immediately cease the dissemination of violative promotional materials for Lunesta such as those described above. Please submit a written response to this letter on or before June 23, 2010, stating whether you intend to comply with this request..."

I imagine a grin on Ms. Grim's face as she sits in her office somewhere in Malborough, MA reading Newcomer's letter. "Yes," says Grim, "we'll cease airing that commercial three months ago and I will write this 'newcomer' a response as soon as I return from my vacation on the Cape. Meanwhile, I'll have my staff frame this letter to add to the collection hanging behind my desk."

BTW, while searching Google for this ad, I found an interesting Lunesta paid search ad as seen here:

This is the first time I have ever seen a drug ad that talks ONLY about side effects! I assure you that the ad linked to the official Lunesta Web site and NOT a lawyer's class action Web site. Perhaps Sepracor is trying to atone for running those infamous "badWords," which violated FDA regulations (see Lunesta, Google, and "bAdWords").

Voltaren "Adherence Email" Gets FDA Warning Letter: Is It Justified?

As of April 15, 2010, FDA's Division of Drug Marketing, Advertising and Communications (DDMAC) sent out 5 "notice of violation" (aka "warning") letters to drug companies regarding various promotional pieces. One letter is of interest because it concerns a direct-to-consumer (DTC) adherence "wave 5 e-mail" ("Adherence Email") for Voltaren, an NSAID topical gel marketed by Novartis. This may be the FIRST FDA warning letter issued for an email promotion. But is it justified?

Among other violations, the letter cites "minimization of risk information." The letter (find it here) states:

"The Adherence Email prominently presents efficacy claims in large bolded font size and in colorful text and graphics surrounded by a significant amount of white space. In contrast, the risk information is relegated to the bottom of the email and is presented below the indication for use in extremely small black font, and in single-spaced paragraph format that makes the information very difficult to read. Furthermore, while the Adherence Email presents efficacy claims for Voltaren Gel in language that is easily understandable to consumers, it presents risk information using complex medical terminology that is not likely to be comprehended by the same audience (e.g., “cardiovascular thrombotic events” and “hematological effects”). The overall effect of this presentation undermines the communication of important risk information, minimizing the risks associated with Voltaren Gel, and misleadingly suggesting that Voltaren Gel is safer than has been demonstrated."

"For me, that is a little out of left field," said Mark Senak over at EyeOnFDA Blog. "To my knowledge," said Senak, "FDA/DDMAC has not issued any standards on how to do this [present risk information] aptly." I disagree with Senak. The FDA has issued "standards" about presenting risk information.

In my previous analysis of DDMAC warning letters (see "An Analysis of DDMAC Warning Letters Regarding Risk Information in Broadcast Drug Ads"), I noted that the FDA Amendments Act (FDAAA), which was signed into law in 2007, requires that the FDA issue new regulations regarding the presentation of risk information in broadcast (TV and radio, specifically) drug ads directed to consumers (DTC ads). On March 29, 2010, the FDA published the proposed regulations in the Federal Register (see here).

FDA had issued guidance relating to presentation of risk information previously and most experts agree that the proposed regulations pretty closely resemble that guidance (see "Draft Guidance on Presenting Risk Information in Prescription Drug and Medical Device Promotion"; pdf file). Specifically, the regulations focus on determining whether a drug ad's "major statement" (ie, disclosure of the major side effects and contraindications of the drug) is presented in a "clear, conspicuous, and neutral manner" as required by FDAAA. FDA says that a major statement would be considered to be presented in this manner if:

1. Information is presented in language that is readily understandable by consumers;
2. Audio information is understandable in terms of the volume, articulation, and pacing used;
3. Textual information is placed appropriately and is presented against a contrasting background for sufficient duration and in a size and style of font that allows the information to be read easily; and
4. The advertisement does not include distracting representations (including statements, text, images, or sounds or any combination thereof) that detract from the communication of the major statement.

The Voltaren Adherence Email (find it here) seems to violate "rules" #1 and #3 above. That is, it would violate those rules IF it were in the category of "broadcast" DTC. FDAAA requires FDA to enforce "clear and conspicuous" risk information in TV and radio ads that are broadcast to a mass audience. The Voltaren Adherence Email does not seem to fit in that category of ad because it was not a TV or radio ad and it was likely sent to a select group of consumers, not a mass audience.

However, in the draft guidance mentioned above, FDA states: "Unless otherwise specified in this draft guidance, the principles set forth below apply to all promotional pieces, regardless of the medium used or the target audience."

So I am a bit confused as to whether or not, in the case of the Voltaren letter, the FDA has overstepped the authority given it by Congress to regulate risk information in non-broadcast media. What do you think?

An Analysis of DDMAC Warning Letters Regarding Risk Information in Broadcast Drug Ads

The FDA Amendments Act (FDAAA), which was signed into law in 2007, requires that the FDA issue new regulations regarding the presentation of risk information in broadcast (TV and radio) drug ads directed to consumers (DTC ads). On March 29, 2010, the FDA published the proposed regulations in the Federal Register (see here). FDA had issued guidance relating to presentation of risk information previously and most experts agree that the proposed regulations pretty closely resemble that guidance (see "Draft Guidance on Presenting Risk Information in Prescription Drug and Medical Device Promotion"; pdf file).

Specifically, the regulations focus on determining whether a drug ad's "major statement" (ie, disclosure of the major side effects and contraindications of the drug) is presented in a "clear, conspicuous, and neutral manner" as required by FDAAA. FDA says that a major statement would be considered to be presented in this manner if:

1. Information is presented in language that is readily understandable by consumers;
2. Audio information is understandable in terms of the volume, articulation, and pacing used;
3. Textual information is placed appropriately and is presented against a contrasting background for sufficient duration and in a size and style of font that allows the information to be read easily; and
4. The advertisement does not include distracting representations (including statements, text, images, or sounds or any combination thereof) that detract from the communication of the major statement.

FDA's Kristin Davis, deputy to Tom Abrams, head of FDA's Division of Drug Marketing, Advertising and Communication (DDMAC), reminded attendees of a recent industry conference that the FDA is "using the principles of the draft guidance virtually every day in both pre-reviews and Warning Letters," according to John Kamp, Executive Director, Coalition for Healthcare Communication.

I was curious to learn if recent Notice of Violation (NOV) letters (aka "warning letters") issued by DDMAC actually cited violations of one or more of the 4 rules for the presentation of the major statement in DTC ads. I looked at all of the 16 NOV letters that DDMAC issued in the first quarter of 2010. Of these, only 10 included violation warnings related to consumer promotional pieces/ads.

Many NOV letters include warnings about several different types of violations, including

• Broadening of Indication
• Failure to State Full Indication
• Failure to Submit Under Form FDA-2253
• Minimization of Risk Information
• Omission of Material Facts
• Omission of Risk Information
• Overstatement of Efficacy
• Promotion of an Unapproved Drug
• Unsubstantiated Claims
• Unsubstantiated Comparative Claims
• Unsubstantiated Effectiveness Claims

I counted a total of 22 such violations concerning promotional pieces intended for consumers and/or patients in the ten letters.  These promotional pieces included print and TV ads, web sites, videos, patient brochures, waiting room signs, and co-pay brochures. That is, not all of these were "broadcast" print and TV ads, which is the focus of the draft guidance and proposed regulations. In fact, ONLY 4 letters included violations relating to broadcast DTC ads!

These 4 letters included 6 such violations, only 33.3% (2) of which were about risk communication. One concerned Cymbalta, a drug promoted by Eli Lilly. The FDA letter stated:

"We note that the Print Ad contains the statement, 'See left page for Important Safety Information, including Boxed Warning.'  at the bottom of the page and that risk information is presented on an adjacent page, but this is not sufficient to provide appropriate qualification or pertinent information for the claims made in the body of the ad or to mitigate the overall misleading presentation. This risk information is placed in a single column in a single-spaced paragraph on a page with unrelated advertisements or magazine content. It appears unconnected to the main body of the Print Ad and is not likely to draw readers’ attention."

This seems to violate "rule" number 3 above (ie, "Textual information [should be] placed appropriately and is presented against a contrasting background for sufficient duration and in a size and style of font that allows the information to be read easily").

The second broadcast DTC risk-related violation concerned Truvada, a drug marketed by Gilead Sciences, Inc. The FDA letter stated:

"The Print Ad is false or misleading because it fails to present the risks associated with Truvada with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of the drug. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis. In the Print Ad, claims pertaining to efficacy and benefits of Truvada are conveyed through headlines, colorful text, illustrations, bullets, and eye-catching graphics and images. In contrast, the risk information is presented in several long, single-spaced paragraphs in small font/text type in a single column along one side of the Print Ad."

Again, a violation of "rule" number 3.

At least one letter cited language in an OraVerse patient brochure that "presents efficacy claims for OraVerse in language that is easily understandable to consumers, it presents risk information using complex medical terminology that is not likely to be comprehended by the same audience." This would violate "rule" number 1 above, except that patient brochures are not "broadcast" media and hence are NOT covered by the newly proposed rules.

Even when you look at ALL the 52 violations cited in ALL 16 letters, only 34.6% (18) are concerned with risk information. So, FDA may not be overly focused on risk. It is, however, focusing on much more than broadcast TV and print ads in its warning letters. Increasingly, FDA is focusing on Web-based promotions, for which there is no guidance and no proposed rules.

FDA Blasts Lilly's PAH eCommunity Videos!

In a Notice of Violation letter to Lilly (see here), FDA cited two videos supposedly submitted by patients who take ADCIRCA, Lilly's drug approved for the treatment of Pulmonary Arterial Hypertension (PAH).

The patient videos present statements made by Adcirca users, “Traci” and “Carolyn" who make the following claims among others:

• “I can walk, and stairs don’t bother me [after Adcirca treatment] . . . . Bending over used to make me breathless, picking up my cat used to make me breathless and it doesn’t affect me anymore.”
• “Exercising and stairs and heat used to bother me and it didn’t bother me anymore [after Adcirca treatment].”
• "Promotional materials are misleading if they represent or suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience," said the FDA letter.
• “I could walk a block without stopping and having to take a deep breath [after taking Adcirca]. I don’t have to drag my oxygen tank with me as many places as I used to.”
• “I am exercising again . . . and I couldn’t exercise [before Adcirca], now I am walking on the treadmill. You know and I am walking along the beach, slowly I am beginning to do a lot more of the exercising that I used to be able to do”

FDA said:

First, “Traci’s” and “Carolyn’s” statements misleadingly imply that patients treated with Adcirca will greatly increase their walking time and distance (e.g., “from . . . five minutes . . . to one hour,” “spending all night at the mall”, “now I am walking on the treadmill,” and “walking along the beach”). These statements significantly exaggerate what was demonstrated in the clinical trials for Adcirca. As stated above, the placebo-adjusted mean change increase in 6-MWD was 33 meters. Thus, there is only data to support that study subjects can increase their walking distance by 33 meters in six minutes.

Does the FDA really believe that Traci and Carolyn are real patients? I don't think so -- FDA is careful to put their names in parantheses, ie, "Traci" and "Carolyn." Maybe if Lilly and other drug companies used actual patient video testimonials, there would not be so many misleading statements.

When you try to access the videos of the Adcirca Web site, this is what you get: