Bhavana Desai
Senior Director, Advertising and Promotional Compliance
Allergan, Inc.
2525 Dupont Drive
P.O. Box 19534
Irvine, CA 92623-9534

RE:  NDA #022427
       AcuvailTM (ketorolac tromethamine ophthalmic solution) 0.45%
       MACMIS #18420

Dear Ms. Desai:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a professional journal advertisement (APC02ZD09) (ad) for AcuvailTM (ketorolac tromethamine ophthalmic solution) 0.45% (Acuvail) submitted by Allergan, Inc. (Allergan) under cover of Form FDA 2253. The ad is false or misleading because it makes unsubstantiated superiority claims, overstates the efficacy of Acuvail, broadens its indication, and omits important risk information for the drug. Thus, the ad misbrands Acuvail in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(n) & 321(n), and FDA implementing regulations. 21 CFR 202.1(e)(5)(i) & (iii); (e)(6)(i), (ii), & (xviii).

Background

According to its FDA-approved product labeling (PI), Acuvail is indicated for the treatment of pain and inflammation following cataract surgery. The CLINICAL STUDIES section of the PI reports that the drug’s efficacy was demonstrated versus vehicle.

The PI describes many WARNINGS AND PRECAUTIONS associated with use of Acuvail, including risks related to delayed healing, potential for cross-sensitivity, increased bleeding time, and corneal effects. For example, the PI states:

With some NSAIDS, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

ACUVAILTM should not be administered while wearing contact lenses.

Unsubstantiated Superiority Claims/Overstatement of Efficacy

Promotional materials are misleading if they contain representations or suggestions that a drug is safer or more effective than another drug when this has not been demonstrated by substantial evidence or substantial clinical experience. Furthermore, 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 journal ad prominently claims, “A NEW SHAPE IN NSAID THERAPY” and presents 4 diamond-like stones. The first stone is dull and uncut, while the remaining stones get progressively larger, more cut, and more polished until the final stone, which is the largest and most brilliant. This presentation is accompanied by the claims, “THE KETOROLAC MOLECULE ENHANCED, THE NSAID ADVANCED” and “Optimal outcomes, enhanced patient comfort, and simple BID dosing. ACUVAIL has arrived.” (bolded emphasis in original) Additionally, the product logo in the lower right corner of the ad prominently states, “Your Next NSAID.” The totality of this presentation misleadingly suggests that Acuvail confers more therapeutic benefits and has been “enhanced” in comparison to other ocular ketorolac products or other ocular non-steroidal anti-inflammatory drugs (NSAIDs). Although differences exist in certain aspects of Acuvail’s chemical properties and within the composition of its solution, FDA is not aware of any substantial evidence or substantial clinical experience to support claims implying that Acuvail has been “enhanced” in any way or is superior to other ocular ketorolac products or other ocular NSAIDs in treating pain and inflammation following cataract surgery, or in any other outcomes, including enhanced patient comfort. If you have any evidence to support these claims, please submit it to FDA for review.

In addition to suggesting superiority over other NSAIDs in the context of the claims in this ad, the broad nature of the “Optimal outcomes” claim misleadingly suggests that Acuvail will beneficially impact, and actually optimize, all clinically relevant outcomes of cataract surgery (e.g., cystoid macular edema, an adverse event associated with cataract surgery). However, FDA is not aware of substantial evidence or substantial clinical experience to support such claims. Also, the claim “enhanced patient comfort” (bolded emphasis in original) implies that Acuvail will have a positive impact on patient comfort. However, we are not aware that such an impact has been demonstrated by substantial evidence or substantial clinical experience. The Acuvail PI is cited to support this claim; however, it does not include any supportive evidence. In fact, the Adverse Reactions section of the PI specifically states that patients using Acuvail experienced adverse events, such as ocular pain, headache, and blurred vision (1-6% of patients), which could undermine patient comfort. Generally, claims concerning the impact of drug treatments on patient comfort must be supported by adequate and well-controlled clinical trials that utilize well-developed instruments to measure this outcome. If you have such data to support these claims, please submit them to FDA for review.

Broadening of Indication

Promotional materials are misleading if they contain representations or suggestions that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.

The ad includes several prominent claims comparing Acuvail to ketorolac and other NSAIDs. These claims include:

“A NEW SHAPE IN NSAID THERAPY”
“THE KETOROLAC MOLECULE ENHANCED, THE NSAID ADVANCED” “YOUR NEXT NSAID”

These comparisons to other NSAID products are misleading because they imply that Acuvail is safe and effective for any of the approved uses of other ocular ketorolac products or other ocular NSAIDs, when this has not been demonstrated by substantial evidence or substantial clinical experience. Acuvail is only indicated for pain and inflammation following cataract

surgery. It is not indicated for any of the other uses for which other ocular NSAIDs are approved. For example, approved uses of other ocular ketorolac products include reduction of ocular pain and burning/stinging following corneal refractive surgery (a separate and distinct surgery from cataract surgery) and temporary relief of ocular itching due to seasonal allergic conjunctivitis. Additionally, ocular diclofenac is an NSAID indicated for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery. Therefore, the ad misleadingly broadens the indication for the drug. The presentation of the indication in the middle of the ad does not mitigate the misleading impression created by these claims.

Omission of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made or with respect to the consequences that may result from the use of the drug as recommended or suggested in the materials. The ad claims that, “With some NSAIDs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation.” However, this statement does not fully capture the risk information concerning increased bleeding time because it fails to include important, related information from the WARNINGS AND PRECAUTIONS section of the PI regarding how this adverse event could manifest with ocular NSAID use. Specifically, it omits that, “There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.” Additionally, the ad fails to reveal the warning and precaution that Acuvail should not be administered while wearing contact lenses.

Conclusion and Requested Action

For the reasons discussed above, the ad misbrands Acuvail in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(n) & 321(n), and FDA implementing regulations. 21 CFR 202.1(e)(5)(i) & (iii); (e)(6)(i), (ii), & (xviii).

DDMAC requests that Allergan immediately cease the dissemination of violative promotional materials for Acuvail such as those described above. Please submit a written response to this letter on or before September 9, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Acuvail 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 #18420 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 Acuvail comply with each applicable requirement of the Act and FDA implementing regulations.

Sincerely,

Lynn Panholzer, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications