E-ALERT Food & Drug SUMMARY OF FDA ADVERTISING AND PROMOTION ENFORCEMENT ACTIVITIES FEBRUARY April 5, 2010

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1 E-ALERT Food & Drug April 5, 2010 SUMMARY OF FDA ADVERTISING AND PROMOTION ENFORCEMENT ACTIVITIES FEBRUARY 2010 This e-alert is part of a monthly series of e-alerts summarizing publicly-available FDA enforcement letters (i.e., warning letters and untitled letters) relating to the advertising and promotion of drugs, biologics, and medical devices. In February 2010, FDA s Division of Drug Marketing, Advertising, and Communications (DDMAC) posted the following five enforcement letters (all untitled) on its website: 1 OraVerse (phentolamine mesylate) Injection, Novalar Pharmaceuticals, Inc. (Jan. 22, 2010) 2 BenzaClin (clindamycin 1% - benzoyl peroxide 5%) gel, sanofi-aventis U.S. LLC (Jan. 22, 2010) ASTELIN (azelastine hydrochloride) Nasal Spray, Meda Pharmaceuticals, Inc. (Jan. 26, 2010) Adcirca (tadalafil) Tablets, Lilly Corporate Center (Jan. 27, 2010) Aricept (donepezil hydrochloride) Tablets, Eisai Medical Research, Inc. (Feb. 3, 2010) The letters address the following issues: Omission/Minimization of Risk Information; Overstatement of Efficacy; Broadening of Indication; False/Misleading Claim; and Failure to Submit Form FDA DDMAC s letters conclude that the cited advertising/promotional issues render the subject product misbranded. This alert merely summarizes the allegations contained in DDMAC s letters. It does not contain any analysis, opinions, characterizations, or conclusions by or of Covington & Burling LLP. As a result, the information presented herein does not necessarily reflect the views of Covington & Burling LLP or any of its clients. 1 Only enforcement letters posted to FDA s website during February 2010 are included herein. Letters issued in February but not posted to the website by February 28, 2010 will be summarized in our alerts for the months in which those letters are posted. As of the date of publication of this alert, the following additional letters, issued in February, have been posted on the DDMAC website: Durezol (difluprednate ophthalmic emulsion) 0.05%, Sirion Therapeutics, Inc. (issued Feb. 18, 2010, posted Mar. 16, 2010) (Warning); and Kadian (morphine extended-release) Capsules, CII, Actavis US (issued Feb. 18, 2010, posted Mar. 16, 2010) (Warning)). Neither the Advertising and Promotional Labeling Branch (APLB) in FDA s Center for Biologics Evaluation and Research nor the Center for Devices and Radiological Health (CDRH) posted any applicable letters on its website in February. 2 Dates referenced for the letters are issue dates. BEIJING BRUSSELS LONDON NEW YORK SAN DIEGO SAN FRANCISCO SILICON VALLEY WASHINGTON

2 Omission/Minimization of Risk Information FDA s letters contain several allegations under the Omission/Minimization of Risk Information subheading. These include: DDMAC untitled letter to Novalar Pharmaceuticals, Inc. (Jan. 22, 2010) ( Novalar untitled letter ): A direct-to-consumer patient brochure for OraVerse (phentolamine mesylate) Injection omitted information about material risks associated with treatment. In particular, although the Important Safety Information presentation in the brochure disclosed that tachycardia, bradycardia, and cardiac arrhythmias may occur, it failed to disclose other risk information, including other common adverse reactions experienced with OraVerse treatment. Additionally, the patient brochure failed to present risk information with a prominence and readability reasonably comparable to the efficacy presentation. Finally, although the brochure presented efficacy claims in language that would be easily understandable to consumers, it presented risk information using complex medical terminology that was not likely to be comprehended by the same audience. DDMAC untitled letter to sanofi-aventis U.S. LLC (Jan. 22, 2010) ( sanofi-aventis untitled letter ): A direct-to-consumer patient brochure for BenzaClin (clindamycin 1% - benzoyl peroxide 5%) gel minimized the risk of the product by failing to convey material information from the bolded WARNINGS section of the package insert (PI). Although the brochure indicated that the product may cause diarrhea and that patients who experience severe diarrhea should stop using the drug and call their doctor immediately, it failed to reveal that severe abdominal cramps are another symptom of severe colitis. Additionally, the patient brochure failed to convey other pertinent information from the PRECAUTIONS/Information for Patients section of the PI. The patient brochure also failed to present risk information with a prominence and readability reasonably comparable to the efficacy presentation. For instance, the patient brochure presented numerous efficacy claims for BenzaClin throughout the 12 pages of the piece, but it failed to present any risk information until the back cover (page 12). DDMAC untitled letter to Meda Pharmaceuticals, Inc. (Jan. 26, 2010) ( Meda untitled letter ): A waiting room sign for ASTELIN (azelastine hydrochloride) Nasal Spray failed to present risk information with a prominence and readability reasonably comparable to the efficacy presentation. For instance, in contrast to the large, colorful font and graphic in the efficacy presentation, the only risk information contained on the sign a disclosure of common adverse events was presented at the bottom, after the indication for the drug, in extremely small font size, and in a single-spaced format that made it very difficult to read. Furthermore, although the efficacy claims were written in consumer friendly language, some of the risk information (e.g., somnolence and rhinitis ) was presented in medical terminology that was not likely to be understood by consumers. The presentation also failed to disclose certain material risks associated with Astelin, such as items from the Precautions section of the package insert (PI) related to the risk of somnolence and certain of the most common adverse events. Finally, inclusion of the statement, Please see accompanying full Prescribing Information in small type did not mitigate the overall effect of the presentation, which undermine[d] the communication of important risk information. DDMAC untitled letter to Lilly Corporate Center (Jan. 27, 2010) ( Lilly untitled letter ): A web page for Adcirca (tadalafil) Tablets presented the most common side effects associated with Adcirca, but failed to include any of the Contraindications or Warnings and Precautions information from the package insert (PI). Furthermore, the web page failed to indicate where a viewer may get more risk information about the drug. 2

3 Overstatement of Efficacy FDA s letters contain several allegations under the Overstatement of Efficacy subheading. These include: Novalar untitled letter: The direct-to-consumer patient brochure for OraVerse Injection (discussed above) contained claims that misleadingly implied that treatment with OraVerse would provide comfort for dental patients. FDA is not aware of substantial evidence to support this. Moreover, these claims minimized risks associated with OraVerse that may prevent a patient from feeling comfortable. According to the package insert (PI), the most common adverse reaction with OraVerse that was greater than the control group was injection site pain. The brochure also contained claims such as From numb to normal it s about time, OraVerse brings you back, and Your return to normal (emphasis in original). Such claims were misleading because they implied that the drug has a broad impact on a patient s daily living activities. FDA is not aware of substantial evidence to support these claims. The brochure also contained the claim, And for parents, there is added peace of mind in knowing that children will regain normal feeling more quickly with OraVerse. This claim overstates the treatment benefit of OraVerse by implying that it will give parents peace of mind regarding the effects of reversal of soft-tissue anesthesia or other aspects related to treatment with OraVerse, when this has not been demonstrated by substantial evidence. Furthermore, this claim misleadingly suggests a safety benefit associated with the reversal of the local anesthetic when no such benefit has been evaluated or observed in clinical studies for the drug. The claim is particularly troubling given the misleading claim in the brochure (discussed [infra]) that OraVerse has been shown to be safe and effective for children as young as 4 years of age. sanofi-aventis untitled letter: The direct-to-consumer patient brochure for BenzaClin gel (discussed above) contained claims suggesting that patients could begin to see clearer skin in two weeks and could see up to 50% of inflammatory acne gone in one month. These claims misleadingly implied a substantial effect of BenzaClin at two weeks and at one month when this has not been demonstrated by substantial evidence or substantial clinical experience. According to the CLINICAL STUDIES section in the package insert (PI), the primary efficacy measures were lesion counts and the investigator s global assessment evaluated at week 10. (emphasis added by DDMAC). Although patients were also evaluated during clinical visits at weeks 2, 4, 6, and 8, these earlier time points were not pre-specified endpoints in the clinical study and the data collected in these earlier weeks were analyzed only on a retrospective basis. The patient brochure also included images of people with completely clear, acne-free skin, implying that treatment with BenzaClin will result in complete clearing of acne when this has not been demonstrated by substantial evidence or substantial clinical experience. As stated in the CLINICAL STUDIES section of the PI, the mean percent reductions in total lesion counts after treatment for 10 weeks in the two pivotal studies were 36% and 58% for patients receiving BenzaClin versus 0.2% and 39% for placebo in study 1 and study 2, respectively. Meda untitled letter: The waiting room sign for ASTELIN Nasal Spray (discussed above) presented the claim, Time to toss the tissues with Astelin, along with the image of a box of tissues being tossed into a waste basket. This presentation misleadingly implied that treatment with Astelin would result in complete resolution of symptoms. According to the package insert (PI), treatment with Astelin demonstrated improvement, but not complete resolution, in symptom scores. Lilly untitled letter: Two patient videos for Adcirca Tablets (discussed above) presented statements by Adcirca users implying that patients treated with the drug will greatly increase their walking time and distance. These statements significantly exaggerate[d] what was demonstrated in the clinical trials for Adcirca. The statements also misleadingly implied that patients treated 3

4 with Adcirca will experience an improvement in their symptoms of pulmonary arterial hypertension (e.g., breathlessness) and an improvement in WHO functional class (e.g., walking, exercising more), despite the fact that clinical trials measuring these endpoints failed to show a statistically significant difference versus placebo. Other statements misleadingly implied that Adcirca will reduce the need for an oxygen tank in patients who needed one prior to therapy and that Adcirca has demonstrated long-term benefits (including a potential survival benefit). FDA is not aware of any substantial evidence or substantial clinical experience to support such claims. Although patients from Adcirca's clinical trial entered a long-term extension study, these patients were treated with Adcirca for only six months to one year, and the study lacked a control group. DDMAC untitled letter to Eisai Medical Research, Inc. (Feb. 3, 2010): Two consumer broadcast television ads overstated the efficacy of Aricept (donepezil hydrochloride) Tablets, implying a greater benefit than has been supported by substantial evidence or substantial clinical experience. Both ads presented patients with Alzheimer s disease looking blank, confused, distant, and walking off and apart from their family members. After talking to their doctors about treatment with Aricept, these patients were seen interacting and communicating with their family members, happily and actively involved in activities with them. The presentations implied that, as a result of Aricept treatment, patients cognitive and daily functioning will be restored to normal. The results from the Aricept efficacy trials in patients with mild to moderate and severe Alzheimer s disease do not support such a drastic improvement. (emphasis added by DDMAC). The CLINICAL PHARMACOLOGY section of the package insert (PI) indicates that less than 5% of patients treated with Aricept at either dose were markedly improved or moderately improved. The majority of patients experienced no change or became worse on Aricept treatment. (emphasis added by DDMAC). The inclusion of the superimposed text, Individual results may vary did not mitigate the misleading presentations in these ads. Broadening of Indication FDA s letters contain several allegations under the Broadening of Indication subheading. These include: Novalar untitled letter: The direct-to-consumer patient brochure for OraVerse Injection (discussed above) was misleading because it suggested that OraVerse is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the patient brochure contained the claim, And now the safety and effectiveness of OraVerse have been successfully demonstrated through clinical trials involving pediatric, adolescent and adult patients ages 4 through 92. FDA is not aware of substantial evidence to support efficacy claims in patients under the age of six. Furthermore, according to the Indications and Usage section of the package insert (PI), OraVerse is not recommended for use in patients less than six years of age or weighing less than 15 kg (33 lbs). Furthermore, the Pediatric Use section of the PI states, The safety, but not the efficacy of OraVerse has been evaluated in pediatric patients under the age of 6 years old. (emphasis added by DDMAC). Meda untitled letter: The waiting room sign for ASTELIN Nasal Spray (discussed above) implied that Astelin is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. It prominently presented the headline, Allergic to house cleaning? and suggested that Astelin will treat such allergies. Housecleaning is typically associated with exposure to perennial allergens. Astelin is not approved to treat perennial allergens associated with perennial allergic rhinitis. Rather, according to the package insert (PI), Astelin is indicated for the treatment and symptoms of seasonal allergic rhinitis in adults and children five years and older and for the treatment of the symptoms of vasomotor rhinitis in adults and children 12 years and older. Although household cleaning products can trigger vasomotor 4

5 rhinitis symptoms, the overall message of the sign was that Astelin can treat any allergen associated with house cleaning, such as perennial allergens, when this is not the case. False/Misleading Claim FDA s letters contain one allegation under the False/Misleading Claim subheading: sanofi-aventis untitled letter: The direct-to-consumer patient brochure for BenzaClin gel (discussed above) claimed that the product was studied in mild to moderate acne patients. (emphasis added by DDMAC). This claim was inaccurate. According to the CLINICAL STUDIES section of the package insert (PI), BenzaClin was studied in patients that had moderate or moderately severe acne. (emphasis added by DDMAC). This claim misleadingly suggested that the drug has demonstrated efficacy in treating mild acne in clinical trials when this is not the case. Failure to Submit on Form FDA-2253 FDA s letters contain one allegation under the Failure to Submit on Form FDA-2253 subheading: Lilly untitled letter: The web page and the two patient videos for Adcirca Tablets (discussed above) violated 21 C.F.R (b)(3)(i) because the manufacturer did not submit a copy of the web page and the patient videos to FDA under cover of Form FDA-2253 prior to initial dissemination. * * * If you have any questions concerning the material discussed in this client alert, please contact the following members of our food & drug practice group: Ellen Flannery eflannery@cov.com Richard Kingham rkingham@cov.com Peter Safir psafir@cov.com Michael Labson mlabson@cov.com Erika Lietzan elietzan@cov.com Scott Cunningham scunningham@cov.com Scott Danzis sdanzis@cov.com Elizabeth Jungman ejungman@cov.com Stefanie Doebler sdoebler@cov.com Alissa Jijon ajijon@cov.com The information presented in this alert does not necessarily reflect the views of the firm or any of its clients. This information is not intended as legal advice. Readers should seek specific legal advice before acting with regard to the subjects mentioned herein. Covington & Burling LLP, an international law firm, provides corporate, litigation and regulatory expertise to enable clients to achieve their goals. This communication is intended to bring relevant developments to our clients and other interested colleagues. Please send an to unsubscribe@cov.com if you do not wish to receive future s or electronic alerts Covington & Burling LLP, 1201 Pennsylvania Avenue, NW, Washington, DC All rights reserved. 5