Posted by FDA:  1/2010

Joanne Robinett, Director
U.S.  Regulatory Affairs Marketed Products
sanofi-aventis U.S. LLC 55
Corporate Drive, P.O. Box 5925
Bridgewater, NJ 08807

RE:   NDA # 50-756
        BenzaClin® (clindamycin 1% - benzoyl peroxide 5%) gel
        MACMIS #18206

Dear Ms. Robinett:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a Direct-to-Consumer (DTC) patient brochure (US.CLI.09.06.015) for BenzaClin® (clindamycin 1% - benzoyl peroxide 5%) gel (BenzaClin) submitted by sanofi-aventis U.S.  LLC (sanofi-aventis) under cover of Form FDA 2253.  This patient brochure is false or misleading because it overstates the efficacy of BenzaClin, omits material facts and important risk information associated with the use of the product, and makes a false or misleading claim about the product.  Therefore, this piece misbrands BenzaClin in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii). 

Background

According to the INDICATIONS AND USAGE section of its FDA-approved product labeling (PI), BenzaClin is indicated for “the topical treatment of acne vulgaris.”

The WARNINGS section of the PI states (in pertinent part):

ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEEN ASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENT DEATH.  USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTS IN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE.  DIARRHEA, BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUS COLITIS) HAVE BEEN REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC CLINDAMYCIN.  STUDIES INDICATE A TOXIN(S) PRODUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF ANTIBIOTIC-ASSOCIATED COLITIS.  THE COLITIS IS USUALLY CHARACTERIZED BY SEVERE PERSISTENT DIARRHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE ASSOCIATED WITH THE PASSAGE OF BLOOD AND MUCUS.  ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDOMEMBRANOUS COLITIS.  STOOL CULTURE FOR Clostridium Difficile AND STOOL ASSAY FOR C.  difficile TOXIN MAY BE HELPFUL DIAGNOSTICALLY.  WHEN SIGNIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE DISCONTINUED.  LARGE BOWEL ENDOSCOPY SHOULD BE CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS IN CASES OF SEVERE DIARRHEA.  ANTIPERISTALTIC AGENTS SUCH AS OPIATES AND DIPHENOXYLATE WITH ATROPINE MAY PROLONG AND/OR WORSEN THE CONDITION.  DIARRHEA, COLITIS, AND PSEUDOMEMBRANOUS COLITIS HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL WEEKS FOLLOWING CESSATION OF ORAL AND PARENTERAL THERAPY WITH CLINDAMYCIN. 

The PRECAUTIONS section of the PI states (in pertinent part):

General: For dermatological use only; not for ophthalmic use.  Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents…. 

Information for Patients:

….Avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as this product may be irritating. 

….Patients should not use any other topical acne preparation unless otherwise directed by physician. 

Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using BenzaClin Topical Gel.  To minimize exposure to sunlight, a wide-brimmed hat or other protective clothing should be worn, and a sunscreen with SPF 15 rating or higher should be used. 

Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue BenzaClin Topical Gel and contact their physician immediately. 

BenzaClin Topical Gel may bleach hair or colored fabric…. 

The CLINICAL STUDIES section of the PI states (in pertinent part):

Overstatement of Efficacy

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.  The patient brochure makes the following claims (emphasis added):

•  “Begin to see clearer skin in 2 weeks*”
•  See up to 50% of inflammatory acne gone in 1 month*”

These claims misleadingly imply a substantial effect of BenzaClin at 2 weeks and at 1 month, respectively, when this has not been demonstrated by substantial evidence or substantial clinical experience.  The CLINICAL STUDIES section of the PI states that “the primary efficacy measures were the lesion counts and the investigator's global assessment evaluated at week 10” (emphasis added).  While 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 studies and the data collected in these earlier weeks were only analyzed on a retrospective basis; thus, the clinical studies for BenzaClin do not provide substantial evidence to support the above claims.  If you have substantial evidence or substantial clinical experience to support these claims, please submit it to FDA for review.  We note that the above claims have an asterisk that leads to the disclaimer “Individual results may vary.” However, this disclaimer does not mitigate the misleading impression that BenzaClin will have a substantial effect at week 2 or 4 (1 month). 

The patient brochure also includes images of people with completely clear, acne-free skin.  The overwhelming impression conveyed by these images is 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 reduction 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. 

Omission and Minimization of Risk

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials.  The patient brochure minimizes the risk of BenzaClin by failing to convey material information from the bolded WARNINGS section of the PI.  While the brochure indicates that the drug “may cause diarrhea” and that patients who experience severe diarrhea should stop using the drug and call their doctor immediately, it fails to reveal that severe abdominal cramps are another symptom of severe colitis. 

Additionally, the patient brochure fails to convey pertinent information from the PRECAUTIONS/Information for Patients section of the PI, including that:

•  Patients should avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as the product may be irritating. 
•  Patients should not use any other topical acne preparation unless otherwise directed by physician. 
•  Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using BenzaClin. 
•  Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue BenzaClin and contact their physician immediately. 
•  BenzaClin may bleach hair or colored fabric.  The omission of these important risks misleadingly suggests that BenzaClin is safer than has been demonstrated. 

Furthermore, the patient brochure is misleading because it fails to present risk information for BenzaClin with a prominence and readability reasonably comparable with the claims of effectiveness related to the drug.  Specifically, while the patient brochure presents numerous effectiveness claims for BenzaClin throughout the 12 pages of the piece, it fails to present any risk information until the back cover (page 12) of the patient brochure.  Furthermore, the first two sentences of this “Important Safety Information” section on the back cover fail to convey any risk information, but rather discuss the population the drug was studied in and that it is an acne product that can be obtained with a doctor’s prescription.  This presentation of risk information is not comparably prominent to the presentation of effectiveness information in the piece, and serves to further minimize the risks associated with the drug. 

False/Misleading Claim

The patient brochure claims “BenzaClin® was studied in mild to moderate acne patients” (emphasis added).  This claim is inaccurate; according to the CLINICAL STUDIES section of the PI, BenzaClin was studied in patients that had moderate or moderately severe acne.  Specifically, patients had acne designated as Grade II or III on the Pillsbury classification scale.  Moreover, the clinical studies excluded patients with Grade I acne, patients with fewer than 10 inflammatory lesions, and patients with fewer than 10 comedones.  This claim misleadingly suggests that the drug has demonstrated effectiveness in treating mild acne in clinical trials when this is not the case. 

Conclusion and Requested Action

For the reasons discussed above, the patient brochure misbrands BenzaClin in violation of the Act, 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1 (e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii). 

DDMAC requests that sanofi-aventis immediately cease the dissemination of violative promotional materials for BenzaClin such as those described above.  Please submit a written response to this letter on or before February 5, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for BenzaClin that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials.  Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS # 18206 in addition to the NDA number.  We remind you that only written communications are considered official. 

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for BenzaClin comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Sheetal Patel, PharmD
Regulatory Review Officer
Division of Drug Marketing,
  Advertising, and Communications