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Food & Drug

June 24, 2009

SUMMARY OF DDMAC AND APLB ENFORCEMENT CORRESPONDENCE MAY 2009

In May 2009, FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) posted three warning letters and one untitled letter on its website.1 The letters addressed the issues below. This summary describes only DDMAC's allegations. It does not reflect the recipient's response or analysis by Covington & Burling.

OMISSION/MINIMIZATION OF RISK

Two sales aids for Spectracef® (cefditoren pivoxil) Tablets presented prominent efficacy claims, including "Spectracef® Changes the Way You WIPE OUT BUGS" and "Stable -lactamase profile." They also included a number of positive claims about the tolerability of the drug, such as "Impressive tolerability" and "3% discontinuation rate in clinical trials due to adverse events." But the main promotional spreads of each sales aid failed to present any of the risks associated with the drug. Instead, these risks were presented in the brief summary appearing inside each sales aid, which was insufficient to provide appropriate qualification or pertinent information for claims made in the main spread. The letter explained: "For pieces to be non-misleading, they must contain risk information in each part as necessary to qualify effectiveness claims made in that part. Cf. 21 CFR 202.1(e)(3)(i)." Additionally, the claim "Low potential for drug/drug interactions" was misleading because it minimized the risk of drug interactions with Spectracef therapy. The sales aids accurately stated that Spectracef does not inhibit the cytochrome P450 system, but they failed to mention that other drug interactions are important to Spectracef therapy. (Cornerstone Therapeutics, Inc., May 4, 2009) A consumer webcast video titled "Making Sure Your Relationships Aren't Pained When You're In Chronic Pain" for ULTRAM® ER (tramadol HCl) ExtendedRelease Tablets failed to convey any risks specific to Ultram ER during the testimonial portion of the video, which encompassed the first six minutes of the video's seven-minute running time. While the testimonial portion prominently presented efficacy claims about Ultram ER, the only specific risk information presented was relegated to the end of the video and was presented in a telescript format, with rapidly scrolling text in small font and no accompanying audio presentation. Furthermore, this disclosure of risk information failed to convey that Ultram ER is contraindicated in any situation where opioids are contraindicated and that it should be used with caution in patients with increased intracranial pressure or head injury. The telescript presentation also minimized some of the serious risks associated with Ultram ER. Finally, the telescript stated, "Taking more than the recommended dose of

1 The Advertising and Promotional Labeling Branch (APLB) in FDA's Center for Biologics Evaluation and Research (CBER) did not post any letters in May. The Taxotere DDMAC letter was posted May 13, 2009.

ULTRAM® ER, alone or in combination with alcohol or medications such as tranquilizers, hypnotics or other opioids, can cause respiratory depression, seizures, overdose and possibly death." But it did not communicate that these risks exist with Ultram ER at all dosage levels, not only when taken at a greater-than-recommended dose but also when taken by patients also taking alcohol, anesthetic agents, narcotics, or phenothiazines. (Johnson & Johnson, May 12, 2009) A professional journal advertisement for PerioChip® (chlorhexidine gluconate) 2.5 mg made numerous safety and efficacy claims for PerioChip, including: "Safe for repeated use" (emphasis in original) and "Patients can eat, drink and brush normally following PerioChip placement." However, the body of the journal ad entirely omitted risk information for PerioChip, including the contraindication, precautions, and most frequently reported adverse events from the package insert (PI). A brief summary was included on the second page of the advertisement, but this presentation was insufficient to provide appropriate qualification or pertinent information for the claims made in the body of the piece. The letter explained: "Promotional materials must contain risk information in each part as necessary to qualify any safety or effectiveness claims made (21 CFR 202.1(e)(3)(i))." (Dexcel Pharma Technologies, Ltd. May 14, 2009)

OVERSTATEMENT OF EFFICACY

Two sales aids for Spectracef® (cefditoren pivoxil) Tablets presented graphics of either diseased lungs or legs being wiped completely clean of disease and organisms by a prescription for Spectracef. The images appeared underneath the claim "Spectracef® Changes the Way You WIPE OUT BUGS." These presentations suggested that the drug will completely eradicate lung and skin pathogens and symptoms of infection in patients. In fact, not all patients in the clinical trials were cured by Spectracef, and even among patients who were assessed as clinical cures, the drug did not necessarily eliminate all symptoms of infection. The pictures thus suggested that Spectracef is more effective than has been demonstrated by substantial evidence or substantial clinical experience. One of the sales aids also included a number of claims that suggested that Spectracef is more effective for the treatment of uncomplicated skin and skin-structure infections (uSSSI). But the cure rates and skin pathogen eradication rate presented in the sales aid were generated using criteria for clinical cure that are inconsistent with the FDA-defined criteria for clinical cure for these trials. Specifically, the percentages of patients reported as experiencing "clinical cure" in the sales aid included patients who continued to have multiple (i.e., more than two) remaining symptoms following antibiotic treatment, but the approval of Spectracef for uSSSI was based on clinical cure defined as patients having two or fewer remaining symptoms after treatment. FDA's analysis of the data from these clinical trials demonstrates that the overall cure rates were lower than those given in the sales aid. Finally, the sales aid was misleading because it presented in vitro susceptibility data for S. aureus but failed to reveal that the study cited in support of the data was performed using only methicillin-susceptible isolates. The presentation thus suggested that the susceptibility data presented is representative of Spectracef's activity against all S. aureus, including methicillin-resistant S. aureus. In fact, as indicated in the Clinical Pharmacology section of the package insert (PI), "Cefditoren is inactive against methicillinresistant Staphylococcus aureus." (Cornerstone Therapeutics, Inc., May 4, 2009) A consumer webcast video titled "Making Sure Your Relationships Aren't Pained When You're In Chronic Pain" for ULTRAM® ER (tramadol HCl) Extended-Release Tablets presented statements by a physician about the consequences of chronic pain and the impact of treatment with Ultram ER, including the following: "[I]f you are one of the estimated fifty million Americans suffering from persistent chronic pain, stress caused by persistent chronic pain may be affecting your relationships more than you think." The 2

webcast also included statements by Olympic gold medalist Nikki Stone, including: The thought of being in severe chronic pain the rest of my life, let alone experiencing the pain itself, made me feel a sense of hopelessness. The hopelessness grew into a feeling of depression and as a result, my relationships with my parents, my friends, and my boyfriend became strained. I was not interested in group outings and ended up losing some friends . . . I just wasn't my same happy self and no one seemed to understand. These presentations implied that an outcome of treatment with Ultram ER is a positive effect on patients' overall mood (including the alleviation of depression) and interpersonal relationships, but FDA is not aware of any evidence to support such effects of Ultram ER treatment. In addition, the webcast misleadingly implied that patients treated with the drug will experience an improvement in their sleep quality, but it did not cite any references in support of these claims. Nor is FDA aware of substantial evidence or substantial clinical experience to support this effect. (Johnson & Johnson, May 12, 2009) A professional journal advertisement for PerioChip® (chlorhexidine gluconate) 2.5 mg included the following claim: "The use of PerioChip® + SRP resulted in a clinically meaningful improvement compared to SRP alone . . . 5x the number of pockets were reduced from 7-8 mm to 24 mm" (emphasis in original). This claim misleadingly overstated the effectiveness of PerioChip by suggesting that PerioChip will reduce pocket depth by 3-6 mm in five times the number pockets compared to scaling and root planning (SRP) alone. But the reference cited to support this claim did not constitute substantial evidence because the information presented was derived from a post-hoc subgroup analysis. As a general matter, when looking for differences between treatment groups, a study must be designed to look for these differences prospectively. The five-fold efficacy claim is also inconsistent with the efficacy results demonstrated in the pivotal clinical trials for PerioChip and reflected in its package insert (PI). In addition, the journal ad included the following claim: "PerioChip . . . Suppresses pocket flora up to 11 weeks post treatment" (emphasis in original). The reference cited to support this claim did not constitute substantial evidence or substance clinical experience because the dosing regimen for the study described in this article is inconsistent with the approved dosing regimen reflected in PerioChip's PI. Furthermore, the article does not refer to the product used in the study as "PerioChip" and does not describe the product's composition in any detail. It is therefore not clear that the product tested in the article is identical to the currently marketed PerioChip, particularly considering that the article was published in 1986 and PerioChip was not approved until 1998. Finally, the advertisement included the following claim: "PerioChip allows for PRECISION PLACEMENT which can be accomplished in less than 1 minute" (emphasis in original). Three pictures were tiled horizontally underneath the claim, and a one-minute clock icon appeared above each picture. The first picture showed tooth scaling, with the clock at approximately 20 seconds; the second and third pictures showed placement of PerioChip, with the clocks at 30 seconds and approximately 50 seconds, respectively. This presentation misleadingly suggested that both tooth scaling and the placement of PerioChip can be accomplished within one minute. While it is possible for a dentist to accomplish placement of PerioChip within one minute, it is not possible for the dentist to accomplish both the scaling and placement of a PerioChip within one minute. (Dexcel Pharma Technologies, Ltd. May 14, 2009)

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BROADENING OF INDICATION

Two sales aids for Spectracef® (cefditoren pivoxil) Tablets were misleading because they failed to reveal limitations to Spectracef's indications in the main promotional spreads of the pieces and therefore suggested that Spectracef is effective for a broader range of conditions than has been demonstrated by substantial evidence or substantial clinical experience. Labeling for Spectracef identifies the "designated microorganisms" to which the drug's various approved indications apply, but the sales aids omitted the specific organism for which the drug is indicated. For example, one of the sales aids contained the headline that Spectracef "is a highly potent cephalosporin for the pathogens commonly associated with uncomplicated skin and skin structure infections [uSSSI]" followed by comparative graphs of Spectracef's in vitro activity against clinical isolates of S. aureus and S. pyogenes. This presentation failed to reveal that these are the only organisms encompassed by the drug's uSSSI indication; instead these and other claims misleadingly suggested that Spectracef is effective against a wider range of pathogens than has been demonstrated by substantial evidence. In addition, the tagline, "Spectrum. Activity. Efficacy." contributed to the misleading impression that the range of organisms covered by Spectracef is wide, that the drug is active in vitro against this wide spectrum, and that it is effective clinically for the treatment of infections caused by this wide range of organisms. The fact that both sales aids contained a distinct brief summary on their center pages, consisting of excerpted information from the package insert (PI) and a reprinting of the drug's full indications from the PI, was insufficient to provide appropriate qualification or pertinent information for claims made in the main promotional parts of the sales aids. (Cornerstone Therapeutics, Inc., May 4, 2009)

MISLEADING/UNSUBSTANTIATED SUPERIORITY CLAIMS

A professional reprint carrier for Taxotere® (docetaxel) Injection Concentrate, Intravenous Infusion presented a number of claims that compared the efficacy of Taxotere to paclitexel. For example, the piece stated: "Phase III trial demonstrates improved survival for Taxotere vs paclitaxel in metastatic breast cancer." These claims misleadingly suggested that Taxotere is superior to paclitaxel in the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy and overstated the efficacy of Taxotere. The reference cited in support of these claims did not constitute substantial evidence or substantial clinical experience because, among other factors, the study failed to demonstrate statistical significance on the primary endpoint of objective response rate in the intent-to-treat population and has not been replicated. In the absence of a finding of statistical significance for the primary endpoint, any further analyses conducted on this study, including secondary endpoints and subpopulations, are considered exploratory and do not generally constitute substantial evidence. In addition, a claim of superiority generally must be supported by two well-designed, head-to-head clinical trials comparing appropriate doses and dose regimens of the drug and the comparator drug. (sanofi aventis, April 16, 2009) Two sales aids for Spectracef® (cefditoren pivoxil) Tablets used in vitro data to suggest that Spectracef is clinically superior to other antibiotics for respiratory infections and uncomplicated skin and skin structure infections (uSSSI), which has not been demonstrated by substantial evidence or substantial clinical experience. For example, the front cover of each sales aid contained a prominent header that claimed "Spectracef® Changes the Way You WIPE OUT BUGS." The back covers presented graphs comparing the MIC90 of Spectracef versus other antibiotics against pathogens commonly associated with respiratory diseases or uSSSI. The MIC90 represents the minimum concentration of antibiotic necessary to inhibit 90% of a particular pathogen in vitro. Each graph showed Spectracef with the lowest MIC90 against each pathogen. The totality of these 4

presentations implied that Spectracef is the most effective agent for treating respiratory and skin infections, respectively, but none of the references cited in support of these presentations presented a head-to-head clinical comparison of Spectracef to the other antibiotics. Instead, they presented comparisons of in vitro data only, which do not necessarily predict clinical efficacy. In addition, one of the sales aids implied that Spectracef is clinically superior to cefuroxime and cefadroxil in the treatment of uSSSI, which has not been demonstrated by substantial evidence or substantial clinical experience. The sales aid contained claims that misleadingly presented clinical cure and pathogen eradication rates that show Spectracef as superior in most cases to comparator antibiotics for selected skin infections. But these data were generated using criteria for clinical cure for both the Spectracef and comparator treatment groups that are inconsistent with the FDA-defined criteria for clinical cure for these trials. In fact, FDA's analysis of the data from the trials demonstrated that the efficacy of Spectracef is similar to cefuroxime and cefadroxil. (Cornerstone Therapeutics, Inc., May 4, 2009)

MISLEADING DOSING

A sales aids for Spectracef® (cefditoren pivoxil) Tablets included on its front cover a graphic depicting severely diseased lungs being wiped clean of organisms and disease by a prescription pad presenting a Spectracef dosing regimen of 400 mg twice daily for 10 days. Beneath the graphic, Spectracef's four approved indications were partially presented. But Spectracef is indicated for use at this dose and duration only for the treatment of one of the four indications (acute bacterial exacerbation of chronic bronchitis). A second sales aid included a graphic depicting diseased legs being wiped clear of organisms and the resultant infection by a prescription for Spectracef 200 mg twice daily for 10 days. The graphic, combined with the partial presentation of Spectracef's four approved indications at the bottom of the page, suggested that the dosing regimen is safe and effective for all of the approved indications for Spectracef, including the respiratory infections, which is not the case. While the approved dosing regimens for all the infections were presented on the back cover of each sales aid, the location of this information was insufficient to mitigate the misleading impression created by the graphic and indication claims on the front covers. (Cornerstone Therapeutics, Inc., May 4, 2009)

OMISSION OF MATERIAL FACT

A professional journal advertisement for PerioChip® (chlorhexidine gluconate) 2.5 mg omitted the material fact that PerioChip is recommended for use in periodontal pockets with a pocket depth greater than or equal to 5 mm. As a result of this omission, the journal ad misleadingly suggested that this product has been demonstrated to be effective for use in periodontal pockets of any depth. Additionally, the advertisement included the claim "Slow release of Chlorhexidine for 7-10 days" (emphasis in original). However, as reflected in the Pharmacokinetics section of the package insert (PI), PerioChip releases chlorhexidine in vitro in two distinct phases, "initially releasing approximately 40% of the chlorhexidine within the first 24 hours and then releasing the remaining chlorhexidine in an almost linear fashion for 7-10 days." By omitting this material information regarding the initial release characteristics of chlorhexidine, this claim misleadingly suggested that the product releases chlorhexidine at a constant slow rate over 7 to 10 days, which is not the case. Moreover, this claim was misleading because it failed to reveal that the release profile is based on an in vitro analysis and thus incorrectly suggested that this information is derived from clinical observations. (Dexcel Pharma Technologies, Ltd. May 14, 2009)

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If you have any questions concerning the material discussed in this client alert, please contact the following members of our food & drug practice group: Richard Kingham Peter Safir Michael Labson Erika Lietzan Stefanie Doebler 202.662.5268 202.662.5162 202.662.5220 202.662.5165 202.662.5271 [email protected] [email protected] [email protected] [email protected] [email protected]

This information is not intended as legal advice, which may often turn on specific facts. Readers should seek specific legal advice before acting with regard to the subjects mentioned herein. Covington & Burling LLP is one of the world's preeminent law firms known for handling sensitive and important client matters. This promotional communication is intended to bring relevant developments to our clients and other interested colleagues. Please send an email to [email protected] if you do not wish to receive future emails or electronic alerts. Covington & Burling LLP is located at 1201 Pennsylvania Avenue, NW, Washington DC, 20004-2401. © 2009 Covington & Burling LLP. All rights reserved.

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