Robert J. Anderson, Esq, General Counsel
Vice President, Regulatory Affairs
Nycomed US Inc.
60 Baylis Road
P.O. Box 2006
Melville, NY 11747

RE: NDA 021005
      Solaraze® (diclofenac sodium) Gel, 3%
      MACMIS 20126

Dear Mr. Anderson:

As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed a flashcard (98NSG1171109) for Solaraze® (diclofenac sodium) Gel, 3% (Solaraze) submitted by Nycomed Laboratories under cover of Form FDA-2253. This flashcard is false and misleading because it overstates the efficacy, minimizes the risks, and contains a misleading patient compliance claim for the drug. Thus, the flashcard misbrands Solaraze in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) Cf. 21 CFR 202.1(e)(5)(i), (e)(6)(i) & (e)(7)(i).

Background

According to the FDA-approved product label (PI), Solaraze is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.

The PI explains that Solaraze is associated with several risks. It states (in pertinent part):

ADVERSE REACTIONS

Of the 211 patients treated with Solaraze®, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated patients.

. . . .

Eighteen percent of Solaraze®-treated patients and 4% of vehicle-treated patients discontinued from clinical trials due to adverse events (whether considered related to treatment or not). These discontinuations were mainly due to skin irritation or related cutaneous adverse reactions.

In addition, the Clinical Studies section of the PI states (in pertinent part):

Clinical trials were conducted involving a total of 427 (213 treated with Solaraze® and 214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any patient. All patients were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lacitic acid /peel, 50% glycolic acid peel) and hyaluronan containing cosmetics. Patients were excluded from participation for reasons of known or suspected hypersensitivity to any Solaraze® ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Patients were instructed to apply a small amount of Solaraze® Gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.

The following table summarizes the rates of complete clearance of AK lesions 30 days post treatment (all locations) for the three treatment protocols:

Solaraze® Gel Vehicle p-value

Overstatement of Efficacy

Promotional materials are misleading if they contain representations or suggestions that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience.

The flashcard contains numerous claims and presentations that misleadingly overstate the efficacy of Solaraze in treating actinic keratoses. For example, the flashcard includes the following statement regarding the efficacy of Solaraze up to 1 year post-treatment:

• “The power to deliver... 95% clearance at 1 year posttreatment”

This statement is followed by a graph entitled “Mean clearance of target lesions” with the following data points plotted on it:

• 27% clearance at 30 days (~4 weeks)
• 62% clearance at 60 days (~8 weeks)
• 83% clearance at 90 days (~12 weeks)
• 90% clearance at 30 days posttreatment (~16 weeks)
• 95% clearance at 1 year posttreatment

The flashcard also presents the following presentation and claim:

• Graph titled, “> 75% clearance of target lesions” displaying the percentage of patients

with > 75% clearance of target lesions 30 days posttreatment (85%) and 1 year posttreatment (91 %).

The flashcard references articles by Nelson et. al .1, 2 to support these claims and presentations. These articles describe the preliminary and follow-up efficacy results of an uncontrolled, open-label study in patients with actinic keratoses. Results from a single open- label trial with no control group do not constitute substantial evidence or substantial clinical experience to support these, or any other, efficacy claims.

In addition, page 2 of the flashcard includes the following presentation:

• Graph titled, “100% clearance of target lesions” displaying the percentage of patients with complete clearance of lesions 30 days posttreatment (58%) and 1 year posttreatment (79%).^1,2

This presentation misleadingly overstates the efficacy of Solaraze and is inconsistent with the efficacy results demonstrated in the Clinical Studies section of the approved PI. It is clear from the well-controlled, double-blinded, placebo-controlled trials listed in the PI that the highest proportion of subjects to experience complete clearing 30 days post-treatment was 47%. Therefore, the claims that Solaraze provides 100% clearance in 58% of patients 30 days post-treatment and 100% clearance in 79% of patients 1 year post-treatment is inconsistent with the efficacy results in the PI and significantly overstates the effectiveness of Solaraze.

Moreover, the approved PI specifically states that “No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence,” and we are not aware of substantial evidence to support claims that Solaraze has a long-lasting treatment effect after use has been discontinued. Therefore, claims regarding the efficacy of Solaraze at 1 year post-treatment are inconsistent with the PI and overstate the efficacy of the drug.

In addition, the flashcard presents the following claims:

• “Effectively treats subclinical lesions within target area”¹
• “Effective in treating subclinical lesions within the target area.”¹

These claims are misleading because the efficacy of Solaraze was not studied for subclinical lesions; i.e., lesions that cannot be seen by the naked eye or magnifying glass and cannot be palpated. FDA is not aware of any substantial evidence to support that Solaraze is effective in treating subclinical lesions. As stated above, the cited reference was a single-arm, open- label study, which is not considered substantial evidence to support any efficacy claims. Therefore, these claims misleadingly overstate the efficacy of Solaraze.

The flashcard includes the claim, "Delivers the clearance. Preserves the appearance." This claim misleadingly suggests that Solaraze has been demonstrated to prevent recurrence of AKs. We are unaware of substantial evidence or substantial clinical experience that supports the claim that Solaraze prevents the recurrence of AKs. Furthermore, this claim is inconsistent with the PI which states, "No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence."

Minimization of Risk

Promotional materials are misleading it they suggest that a drug is safer than has been demonstrated by substantial evidence. The flashcard includes the claim that Solaraze is “well-tolerated.” This claim is misleading because it minimizes the adverse events associated with Solaraze use and is not supported by the PI. The PI for Solaraze states, “Of the 211 patients treated with Solaraze, 172 (82%) experienced adverse reactions involving skin and the application site. . . .” Additionally, the PI states that “Eighteen percent of Solaraze® treated patients and 4% of vehicle-treated patients discontinued from the clinical trials due to adverse events. . . . These discontinuations were mainly due to skin irritation or related cutaneous adverse reaction.” Given such a high percentage of patients experiencing adverse events, it is misleading to state that Solaraze is “well-tolerated.”

Misleading Patient Compliance Claim

The claim, “Majority of patients were compliant with treatment”1 is misleading because it is not supported by substantial evidence or substantial clinical experience. The reference cited to support this claim is an open-label study designed to assess the efficacy of Solaraze for the treatment of actinic keratoses. This study did not assess patient compliance with Solaraze. Claims that imply an impact of treatment on patient compliance require support with adequate and well-controlled studies of compliance endpoints, including side effects, effectiveness, dosing schedule, dosage form, and cost.

Conclusion and Requested Action

For the reasons discussed above, your promotional piece misbrands Solaraze in violation of the Federal Food, Drug and Cosmetic Act (the Act), 21 U.S.C. 352(a) Cf. 21 CFR 202.1(e)(5)(i), (e)(6)(i) & (e)(7)(i).

DDMAC requests that Nycomed immediately cease the dissemination of violative promotional materials for Solaraze such as those described above. Please submit a written response to this letter on or before July 1, 2011, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Solaraze 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 ID 20126 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 Solaraze comply with each applicable requirement of the Act and FDA implementing regulations.

Sincerely,

Emily Baker, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications