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ISTA Pharmaceuticals Inc

   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Silver Spring, MD 20993

TRANSMITTED BY FACSIMILE

Vicente Anido Jr., Ph.D.
President and Chief Executive Officer
ISTA Pharmaceuticals
15295 Alton Parkway
Irvine, CA 92618

RE: NDA #21-664
XIBROM™ (bromfenac ophthalmic solution) 0.09%
MACMIS #17933

WARNING LETTER

Dear Dr. Anido:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a professional sales aid (XIB556-12/08) for XIBROM™ (bromfenac ophthalmic solution) 0.09% (Xibrom) submitted by ISTA Pharmaceuticals (ISTA) under cover of Form FDA 2253. The sales aid is false or misleading because it presents unsubstantiated superiority claims, broadens the indication of Xibrom, overstates its efficacy, omits and minimizes important risk information for the drug, makes misleading patient preference claims, and omits other material facts. Thus, the sales aid misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(5); (6)(i), (ii) & (vii); (7)(vi) & (viii). These violations are concerning from a public health perspective because they suggest that Xibrom is safer or more effective than has been demonstrated.

Background

According to the Indications and Usage section of the FDA approved product labeling (PI):

XIBROM ophthalmic solution is indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction.

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

WARNINGS
Contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people….

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

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

PRECAUTIONS
General: All topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

Use of topical NSAIDS may result in keratitis. In some susceptible patients, continued use of topical NSAIDS may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.

Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients.

Postmarketing experience with topical NSAIDs also suggests that use more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for the occurrence and severity of corneal adverse events.

It is recommended that XIBROM ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.

In addition, the Dosage and Administration section of the PI states:

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of XIBROM ophthalmic solution should be applied to the affected eye(s) two times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.

Finally, the Clinical Trials section of the PI states (in pertinent part):

Clinical efficacy was evaluated in two randomized, double-masked, vehicle-controlled U.S. trials in which subjects with a summed ocular inflammation score ≥3 after cataract surgery were assigned to XIBROM or vehicle in a 2:1 ratio following surgery. One drop of XIBROM or vehicle was self-instilled in the study eye twice a day for 14 days, beginning the day after surgery. The primary endpoint was reduction of ocular inflammation (to trace inflammation or clearing) assessed 14 days post-surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of both studies, a significant effect of XIBROM on ocular inflammation after cataract surgery was demonstrated (62-66% vs. 40-48%).

Unsubstantiated Superiority Claims

The sales aid is false or misleading because it suggests that Xibrom is superior to other drugs in its class when this has not been demonstrated by substantial evidence or substantial clinical experience. Page two of the sales aid presents the claims, “XIBROM: Greater Potency . . .” and “Bromfenac has up to 4x greater inhibition of the COX-2 enzyme.”1 These claims are followed by a chart of in vitro data comparing the IC50 (concentration of drug necessary for 50% inhibition of the COX-2 enzyme) and relative potency of bromfenac to those of the ocular NSAIDs amfenac (active metabolite of nepafenac), ketorolac, and diclofenac. Bromfenac is shown with the lowest IC50 and highest relative potency of all the agents, implying that bromfenac is the most clinically effective. However, in vitro data are not a reliable predictor of the level of activity in the anterior chamber of the eye and no clinical significance of this data has been demonstrated. Additionally, the COX-2 in vitro assay is highly variable between laboratories and types of assays used. FDA is not aware of any adequate and well-controlled head-to-head comparison trials between Xibrom and any other ophthalmic NSAID that demonstrate the clinical superiority of Xibrom compared to other ocular NSAIDs. The footnoted claim “In vitro study, the clinical significance is unknown” does not mitigate the overwhelming misleading impression created by the claims and chart that Xibrom is superior to other drugs in its class.

Broadening of Indication

The sales aid is false or misleading because it suggests that Xibrom is effective in a broader range of patients and conditions than has been demonstrated by substantial evidence or substantial clinical experience. The sales aid prominently claims “XIBROM: Rapidly Relieves Pain and Inflammation with Just Two Days of Treatment,”2 and “XIBROM: Patients’
Convenient Choice for Rapid Relief of Pain and Inflammation.” These prominent claims suggest that Xibrom can be used for any ocular pain and inflammation. Xibrom, however, is only indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction. The reference cited to support the first claim discusses the results of a study on the use of Xibrom for pain and inflammation after cataract extraction. The study does not support the use of Xibrom for any ocular pain and inflammation.

Furthermore, the claim, “Bromfenac concentration available in all ocular tissues, with detectable levels through 24-hours”3 (emphasis added), along with a corresponding graphic representation showing concentration of bromfenac over time in the cornea, iris-ciliary body, and all other ocular tissues, misleadingly suggests that Xibrom is effective for the treatment of pain and inflammation in all ocular tissues when this is not the case. Xibrom has only been demonstrated to be effective in treating inflammation and associated pain following cataract surgery. Cataract surgery may lead to inflammation and pain in the cornea and irisciliary body. However, Xibrom is not indicated for inflammation or pain involving all other ocular tissues. The graph depicts the concentration of bromfenac over time in all other ocular tissues as very similar to the concentration over time in the iris-ciliary body, misleadingly suggesting that Xibrom will exhibit similar efficacy throughout the rest of the eye as it does in the iris-ciliary body. Additionally, the graph is based on animal data, which are not a reliable predictor of the level of activity or the penetration of Xibrom in the human eye. Moreover, the graph and claim suggest efficacy of Xibrom for 24 hours after a single dose, which is inconsistent with Xibrom’s approved twice-daily dosing. The statement beneath the graph, “In vitro study, the clinical significance is unknown,” does not mitigate this misleading presentation.

Additionally, the sales aid prominently claims that Xibrom is “The Preferred Choice” and “Xibrom: Your Patients’ Choice for NSAID Therapy,” in conjunction with a graph of patient
dosing preference comparing the twice daily dosing of Xibrom to the dosing of other ocular NSAIDs. The sales aid also presents a chart, described above, comparing the potency of
bromfenac to ketorolac and diclofenac. The totality of these claims and presentations implies that Xibrom is a safe and effective alternative, and one that is preferred by patients, for any of the uses of these other ocular NSAIDS when this is not the case. Ketorolac is indicated for the reduction of ocular pain and burning/stinging following corneal refractive surgery, and diclofenac, in addition to being indicated for treatment of postoperative inflammation in patients who have undergone cataract extraction, is indicated for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery. Cataract surgery and corneal refractive surgery are two distinct and separate ocular surgeries.

We note that the approved indication for Xibrom is provided at the bottom of the first page of the sales aid. However, it is presented without prominence in very small font compared to the large, bold, and colorful claims and graphs suggesting that Xibrom can be used for any ocular pain and inflammation. Thus, the presentation of the approved indication does not mitigate the misleading impression created by the claims and presentations described above that Xibrom is effective in a broader range of patients and conditions than has been demonstrated by substantial evidence or substantial clinical experience.

Overstatement of Efficacy

The sales aid is misleading because it suggests that Xibrom is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The claim “XIBROM: Rapidly Relieves Pain and Inflammation with Just Two Days of Treatment”2 is misleading because it implies that patients receiving Xibrom experienced significant relief of inflammation after two days of treatment when this has not been demonstrated by substantial evidence or substantial clinical experience. Xibrom therapy does not completely relieve inflammation after two days of treatment. While a statistically significant difference between Xibrom and placebo in reduction of inflammation was demonstrated as early as three days after surgery (two days after treatment was initiated), as shown in the graphs titled “Anterior Chamber Cells Grade” and “Anterior Chamber Flare Grade,” the reference cited for the claim reports that only 8.4% of subjects receiving bromfenac had cleared or trace ocular inflammation on day 3. Additionally, the PI reports that only 62-66% of patients receiving Xibrom experienced reduction of ocular inflammation to trace inflammation or clearing by 14 days post-surgery. Therefore, few patients experienced relief of inflammation two days after treatment initiation and many patients did not experience clearing of inflammation after 2 weeks.

Omission and Minimization 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. Although the sales aid contains information regarding the most commonly reported adverse events and a precaution about keratitis, it fails to communicate the most serious warnings and the most serious precautions associated with the use of Xibrom. The sales aid omits serious and important warnings regarding the potential for allergic reactions to sodium sulfite, including anaphylaxis and potentially life-threatening asthmatic episodes, cross-sensitivity reactions, and increased bleeding times. It also omits the most serious precautions regarding slowed or delayed healing, increased risk for corneal adverse events in certain patient populations, and limitations on dosing. By omitting the most serious risks associated with the drug, the sales aid misleadingly suggests that Xibrom is safer than has been demonstrated.

The sales aid also misleadingly minimizes the risks associated with the use of Xibrom by failing to present risk information with a prominence and readability that is reasonably comparable to the efficacy claims. Efficacy claims are presented using large font, bolded, colorful headers and colorful graphics. In contrast, the incomplete risk information is relegated to the end of the aid and is presented in block paragraph format, without the use of headers or other signals to alert readers to its significance, and in a smaller font than the efficacy claims.

Misleading Patient Preference Claims

The sales aid is misleading because it implies that patients prefer Xibrom to other ophthalmic NSAIDs in the absence of substantial evidence or substantial clinical experience. Specifically, the sales aid includes the following presentations:

• Headline claim, “The Preferred Choice”
• “XIBROM™: Your Patients’ Choice for NSAID Therapy”
• “99% of physicians reported in a multi-center postmarketing survey involving 12,000 patients that their patients preferred the ease of use of XIBROM”4
• “90% of patients (1,707 patients) preferred twice daily dosing over other dosing regimens”5
• Graph titled, “*Patient Dosing Preference,” displaying the percentage of patients preferring twice daily (90.0%), three times daily (6.7%), or four times daily (4.3%) regimens.

The sales aid references Donnenfeld et al.4, which describes a survey undertaken to evaluate physician and patient satisfaction with Xibrom and its comfort profile in normal clinical practice, in support of these patient preference claims. The survey asked about overall patient satisfaction, control of inflammation, ease of use, compliance, comfort upon instillation, and safety. This survey does not provide substantial evidence to support claims that patients prefer Xibrom for ophthalmic NSAID therapy for several reasons. First, the survey only included subjects on Xibrom. Without comparator products, there is no way to determine patient preference for Xibrom over other ophthalmic NSAID treatments. Second, patient preference is a patient-reported outcome that implies a measurement of an aspect of a patient’s health status that comes directly from the patient (i.e., from the patient’s perspective, without the interpretation of the patient’s responses by a physician or anyone else). The responses to the survey questions were based only on the physicians’ determinations (not the patients’ determinations) for the six categories surveyed. These responses may, therefore, have been unduly influenced by the assessments or judgments of the physician. Third, the broad concept of overall patient preference is not adequately measured by just the six items in the survey because these items do not adequately address other important determinants of patient preference such as convenience, dosing, dosage form, efficacy, and adverse events.

In addition to broad patient preference claims, the sales aid includes “patient dosing preference” claims and presentations that imply that patients prefer Xibrom to other ophthalmic NSAIDs that are dosed more frequently. The sales aid references the Trial Card Patient Survey5 (data on file) in support of these presentations. This survey was conducted via a coupon that asked, “If you could pick a prescription eye drop, which best fits your needs?” The results from this survey do not support claims that patients prefer Xibrom over more frequently dosed ophthalmic NSAIDs because responses to a general hypothetical question are not sufficient to assess patient preference for one particular dosing regimen over another. Moreover, patient preference is influenced by more than just the dosing regimen of a drug. Patient preference claims should be supported by well-designed and controlled head-to-head studies using well-developed instruments that can evaluate all determinants of patient preference.

Furthermore, the claim, “XIBROM: Patients’ Convenient Choice for Rapid Relief of Pain and Inflammation,” which appears as a tagline near the end of the sales aid, is misleading because it broadly asserts that, overall, treatment with Xibrom will be “convenient” for patients. When considering all aspects of convenience, including the risks associated with the drug (some of which may be sight-threatening) and the method of administration of Xibrom, it is not self-evident that this broad claim of overall convenience is supported. If you have evidence to support the above claim, please submit it to FDA for review.

Omission of Material Fact

The sales aid is misleading because, while it states that Xibrom is administered twice daily, it fails to reveal important limitations to its dosing. Specifically, the sales aid fails to reveal that Xibrom should be applied beginning 24 hours after cataract surgery and only continued through the first 2 weeks of the postoperative period. This omission is concerning because, according to the Precautions section of the PI, use of topical NSAIDs beyond 14 days postsurgery may increase patient risk for the occurrence and severity of corneal adverse events.

Conclusion and Requested Action

For the reasons discussed above, the sales aid misbrands Xibrom in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(5); (6)(i); (ii) & (vii); (7)(vi) & (viii).

DDMAC requests that ISTA immediately cease the dissemination of violative promotional materials for Xibrom such as those described above. Please submit a written response to this letter on or before March 24, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Xibrom that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional 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, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #17933 in addition to the NDA number. We remind you that only written communications are considered official. If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.

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

Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,
/S/

Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications

_______________________________________________________________

1 Kida T, et al. Evaluations of the human COX-2 inhibition for amfenac, bromfenac, diclofenac, and ketorolac. Poster presented at: 2007 American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting; April 27-May 2, 2007; San Diego, CA.
2 Donnenfeld ED, et al. Bromfenac Ophthalmic Solution 0.09% (XIBROM) Study Group. Bromfenac ophthalmic solution 0.09% (XIBROM) for postoperative ocular pain and inflammation. Ophthal 2007;114(9):1653-1662.
3 Baklayan GA, et al. 24-hour evaluation of the ocular distribution of 14C-labeled bromfenac following topical instillation into the eyes of New Zealand White rabbits. J Ocular Pharmacol Ther 2008;24(4):398-404.
4 Donnenfeld ED, Donnenfeld A. Global experience with XIBROM (bromfenac sodium ophthalmic solution) 0.09%: the first twice daily ophthalmic nonsteroidal anti-inflammatory drug. Int Ophthal Clin. 2006;46:21-40. Survey conducted 2005-2006.
5 Trial Card Patient Survey, ISTA Pharmaceuticals Inc. Data on file January 7, 2009. Survey conducted Jun 2008-Jan 2009.