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Rx Development Resources, LLC

   

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

Barry Butler, MBA
President, Chief Executive Office
Sirion Therapeutics, Inc.
9314 East Broadway Avenue
Tampa, FL 33619

RE: NDA 22-212
Durezol™ (difluprednate ophthalmic emulsion) 0.05%
MACMIS# 17586

WARNING LETTER

Dear Mr. Butler:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a professional sales aid (DIF8-015E) (sales aid) and a professional z-card (DIF8-037B) (z-card) for Durezol™ (difluprednate ophthalmic emulsion) 0.05% (Durezol) submitted by Sirion Therapeutics, Inc. (Sirion) under cover of Form FDA-2253. The sales aid and z-card are false or misleading because they omit and minimize important risk information associated with Durezol, overstate the efficacy of Durezol, promote an unapproved dosing regimen for the drug, and make unsubstantiated claims. Thus, the sales aid and z-card misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (f)(1); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1) & 201.128; cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (xvii) & (xviii). These violations are concerning from a public health perspective because they suggest that Durezol is safer and more effective than has been demonstrated.

Background

According to the FDA-approved product labeling (PI), Durezol “is indicated for the treatment of inflammation and pain associated with ocular surgery.”

The following safety information is provided in the PI, in pertinent part:

Contraindications

The use of Durezol, as with other ophthalmic corticosteroids, is contraindicated in most active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal disease of ocular structures.

Warnings and Precautions

….IOP [intraocular pressure] Increase
Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored.

….Cataracts
Use of corticosteroids may result in posterior subcapsular cataract formation.

….Delayed healing
The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

….Bacterial infections
Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

….Viral infections
Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex).

….Fungal infections
Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal culture should be taken when appropriate…..

Adverse Reactions
Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

Ocular adverse reactions occurring in 5–15% of subjects in clinical studies with Durezol included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis….

The Clinical Studies section of the PI states:

Postoperative Ocular Inflammation and Pain
Clinical efficacy was evaluated in 2 randomized, double-masked, placebo-controlled trials in which subjects with an anterior chamber cell grade ≥ “2” (a cell count of 10 or higher) after cataract surgery were assigned to Durezol or placebo (vehicle) following surgery. One drop of Durezol or vehicle was self instilled either 2 (BID) or 4 (QID) times per day for 14 days, beginning the day after surgery. The presence of complete clearing (a cell count of 0) was assessed 8 and 15 days post-surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of both studies, a significant benefit was seen in the QID Durezol-treated group in ocular inflammation and reduction of pain when compared with placebo. The consolidated clinical trial results are provided below.

 

Ocular inflammation and Pain Endpoints (Studies Pooled)
 

Durezol QID

N = 107

Vehicle

N = 220

Day 8 15 8 15
Anterior Chamber cell clearing (% subjects)

24

(22%)*

44

(41%)*

17

(7%)

25

(11%)

Pain free (% subjects)

62

(58%)*

67

(63%)*

59

(27%)

76

(35%)

* Statistically significantly better than vehicle, p<0.01

The Dosage and Administration section of the PI states:

Instill one drop into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response.

Omission/Minimization of Risk Information

Sales Aid

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 16-page sales aid presents numerous efficacy claims on both its front and back covers and on pages 1-12 but fails to convey any risk information specific to Durezol on these pages. The only specific risk disclosure is relegated to the end of sales aid on page 14. Promotional materials must
include risk information in each part as necessary to qualify any safety or effectiveness claims made in that part (Cf. 21 CFR 202.1(e)(3)(i)). We note the statement, “Please see page 14 for Important Safety Information” is included on several pages of the sales aid; however this does not mitigate this misleading omission of risk information.

Furthermore, the risk presentation included on page 14 presents adverse reactions associated with Durezol, but fails to communicate some of the more serious risks associated with the product, including the Contraindication that Durezol is not to be used in most viral diseases of the cornea and conjunctiva, mycobacterial infections of the eye, and fungal diseases of ocular structures, and the Warning and Precaution related to delayed healing and bleb formation.

Furthermore, page 13 of the sales aid consists of a misleading safety presentation, which includes the following claims and graphics (emphasis in original; footnote omitted):

“PROVEN SAFETY PROFILE”
“Low incidence of IOP rise in Phase 3 Pivotal trials”

o “97.2% of patients experienced no clinically relevant effects on IOP [intraocular pressure]”

• “2.8% of patients experienced a criterion increase in IOP with Durezol compared with 0.9% with placebo”

• “IOP criterion increase defined as an observed value of ≥ 21 mmHg and a change from baseline of ≥ 10 mmHg.”

The above claims are presented in conjunction with a bar graph entitled “Mean IOP in Phase 3 Pivotal trials” (emphasis in original), which compares the mean IOP for Durezol QID
(n=107) to placebo (n=220) at day 0, 3/4, 8, 15, and 29. The claim, “Mean IOP remained similar to baseline measures in Phase 3 Pivotal trials through Day 29,” is presented below the graph. This presentation implies that IOP rise is not a significant concern with Durezol treatment, and serves to minimize the serious risk of IOP increase reflected in Durezol’s PI. According to the Warnings and Precautions, IOP Increase section of Durezol’s PI, “Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. . . . If this product is used for 10 days or longer, intraocular pressure should be monitored” (emphasis added). This implication is especially concerning as patients who use Durezol based on the PI’s recommended dosing and administration will most likely use this product for longer than 10 days, thus requiring IOP monitoring (according to the Dosage and Administration section of Durezol’s PI, one drop of the drug should be instilled “into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response). Furthermore, according to the Adverse Reactions section of the PI, “Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera” (emphasis added).

This presentation is particularly concerning because it suggests the use of Durezol for as long as 29 days, while indicating IOP rise is not a significant concern during such prolonged use and while failing to reveal other significant risks associated with such use. As stated above, prolonged use of Durezol is associated with serious risks related to IOP increase, and according to the Warnings and Precautions section of Durezol’s PI related to bacterial and fungal infections, “Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated” (emphasis added), and “Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application.” Additionally, the Warnings and Precautions section of the PI related to delayed healing states, “The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation . . . . The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.” The piece fails to disclose any of this risk information relating to prolonged use.

Z-Card

Similarly, the promotional spread of the z-card presents numerous efficacy claims for Durezol, such as (emphasis in original), “Hit post-op inflammation with a powerful force,” “Tame the Flame,” and “Introducing the first and only powerful steroid with proven pain relief,” as well as an assurance of safety – “Demonstrated safety profile” – but fails to include any risk information for Durezol. We note that the statement “Please see full prescribing information for Important Safety Information” is included on the promotional spread of the unfolded z-card, and that the PI for Durezol is printed on the back side of the unfolded z-card; however, this is not sufficient to provide appropriate qualification or pertinent information for the claims made in the promotional spread of the piece. As indicated above, promotional materials must contain risk information in each part as necessary to qualify any safety or effectiveness claims made (Cf. 21 CFR 202.1(e)(3)(i)).

Overstatement of Efficacy/Promotion of Unapproved Dosing Regimen

Sales Aid

The sales aid is false or misleading because it implies that Durezol is more effective than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the sales aid presents the following claims and presentations (bolded and italicized emphasis in original; underlined emphasis added; footnotes omitted):

• “Significant reduction in cells and flare

o “71.0% of patients receiving Durezol experienced ocular inflammation clearing as defined by cell count of ≤ 5 and grade 0 flare at Day 15 (P<.0001 vs placebo). . . .”
o The above claims are presented in conjunction with a bar graph entitled
Patients with clearing of ocular inflammation (cell count ≤ 5 and grade 0flare),” which compares the percentage of patients using Durezol QID (n=107) to patients using placebo (n=220) at day 3/4 (15.1% on Durezol vs. 4.7% on placebo), 8 (42.1% on Durezol vs. 18.9% on placebo), and 15 (71.0% on Durezol vs. 27.1% on placebo).

• “Significant clearing of anterior chamber cells

o “62.6% of patients receiving Durezol experienced a clearing (cell count ≤ 1) of anterior chamber cells at Day 15 (P<.0001 vs placebo).”
o The above claims are presented in conjunction with a bar graph entitled
Patients with clearing of anterior chamber cells (cell count ≤ 1),” which compares the percentage of patients using Durezol QID (n=107) to patients using placebo (n=220) at day 3/4 (6.6% on Durezol vs. 1.9% on placebo), 8 (34.6% on Durezol vs. 9.2% on placebo), and 15 (62.6% on Durezol vs. 16.1% on placebo).

The above claims and presentations overstate the efficacy of Durezol because they are inconsistent with the efficacy information provided in the Durezol PI and misrepresent the definition of inflammation clearing. The studies cited in the Clinical Studies section of Durezol’s PI defined clearing of inflammation as an anterior chamber cell count of 0 cells and flare grade of 0. FDA used these criteria as the basis for Durezol’s approval, as well as for other similar products in this drug class. Consequently, the PI reflects that at day 15, for patients using Durezol, the clearing of ocular inflammation in the anterior chamber cell was 41%, not 71.0% or 62.6% as claimed in the sales aid. Similarly, the PI states that at day 8 the clearing of ocular inflammation in the anterior chamber cell was 22%, not 42.1% or 34.6% as shown in the sales aid. While these claims in the piece are derived from the trials reflected in the Clinical Studies section of Durezol’s PI, they are based on cell count definitions (cell count ≤ 5 and grade 0 flare, cell count ≤ 1) that are not consistent with the standard FDA-defined criteria for clearing of inflammation. Therefore, the above percentages of patients with clearing of inflammation presented in the sales aid significantly overstate the demonstrated efficacy of Durezol.


Moreover, the sales aid presents the following claims and presentations (bolded and italicized emphasis in original; underlined emphasis added; footnotes omitted):


• “In a clinical study of patients receiving Durezol QID starting one day prior to surgery. . .”

o “Demonstrated efficacy in managing inflammation

• “81.3% of patients receiving Durezol achieved clearing of ocular inflammation vs 25.0% of placebo patients at Day 14 (P<.0001).”

o The above claims are presented in conjunction with a bar graph entitled
Patients with clearing of ocular inflammation (cell count ≤ 5 and grade 0 flare),” which compares the percentage of patients using Durezol QID (n=83) to patients using placebo (n=41) at day 3/4, 7, 14, and 28.

• “Power to reduce inflammation”

o “91.3% of patients receiving Durezol achieved a cell count ≤ 5 vs 30.0% with placebo at Day 14 (P<.0001).”
o The above claims are presented in conjunction with a bar graph entitled
Patients with clearing of anterior chamber cells (≤ 5 cells),” which compares the percentage of patients using Durezol QID (n=83) to patients using placebo (n=41) at day 3/4, 7, 14, and 28.

• “Significant clearing of anterior chamber flare”

o “81.3% of patients receiving Durezol experienced a clearing of anterior chamber flare (grade 0) vs 37.5% with placebo at Day 14 (P<.0001).”

Grade 0 flare defined as complete absence

o The above claims are presented in conjunction with a bar graph entitled
Patients with clearing of anterior chamber flare (grade 0),” which compares the percentage of patients using Durezol QID (n=83) to patients using placebo (n=41) at day 3/4, 7, 14, and 28.

The above claims and presentations are derived from a clinical study1 using an unapproved dosing regimen for Durezol; as such, this study does not constitute substantial evidence to support claims of efficacy for the drug. Specifically, these presentations are derived from a clinical study of patients receiving Durezol QID one day prior to surgery; however, Durezol is only approved for use following surgery. According to the Dosage and Administration section of Durezol’s PI, one drop of the drug should be instilled “into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response” (emphasis added).

In addition to suggesting that Durezol is approved for use prior to surgery, these presentations overstate the efficacy of the drug. The above claims and presentations suggest that at day 14, 81.3% of patients using Durezol experienced a clearing of ocular inflammation, 91.3% of patients using Durezol experienced a clearing of anterior chamber cells, and 81.3% of patients using Durezol experienced a clearing of anterior chamber flare. These results are inconsistent with the PI, which states that at day 15, for patients using Durezol, the clearing of ocular inflammation in the anterior chamber cell was 41%. Furthermore, as stated above, the cell count definitions used to arrive at the percentages cited above (cell count ≤ 5 and grade 0 flare, cell count ≤ 5, grade 0 flare) are not consistent with the FDA-defined criteria for clearing of inflammation. As noted above, the approval of Durezol was based on clearing of inflammation defined as an anterior chamber cell count of 0 cells and flare grade of 0. Therefore, the above percentages of patients with clearing of inflammation presented in the sales aid significantly overstate the demonstrated efficacy of Durezol.

Furthermore, the sales aid misleadingly presents data from this same off-label study regarding Durezol’s effect on pain. Specifically, the sales aid presents the following claims and presentations (emphasis in original; footnote omitted):

• “In a clinical study of patients receiving Durezol QID starting one day prior to surgery. . . ” (pages 9-10). . . .

o “Significantly more patients free from pain

"72.5% of patients receiving Durezol were pain free (score of 0 on a 0 to 100 VAS) compared to 40.0% of patients receiving placebo at Day 14 (p=.0006)"

o The above claims are presented in conjunction with a bar graph entitled
Patients free from pain (score of 0 on a 0-100 VAS),” which compares the percentage of patients using Durezol QID (n=83) to patients using placebo (n=41) at day 3/4, 7, 14, and 28.

These claims, which are again derived from a study1 that used an unapproved treatment regimen, are not supported by substantial evidence. As stated above, Durezol is not approved for use prior to surgery, and is only approved for use beginning 24 hours after surgery. Furthermore, according to the Clinical Studies section of the PI, at day 15, for patients using Durezol, the percentage of patients who were pain free was 63%. These presentations thus misleadingly overstate the efficacy of Durezol in managing pain, and (as noted above) also suggest the drug is approved for use prior to surgery when this is not the case.

Sales Aid and Z-card

The sales aid and z-card include the following claims and presentations (emphasis in original; footnotes omitted):

• “Hit post-op inflammation with a powerful force” (both covers and page 1 of sales aid, and front cover and front side of unfolded z-card);
• “Introducing the first and only powerful steroid with proven pain relief” (page 2 and back cover of sales aid, and back cover and both sides of unfolded z-card);
• “Powerful anti-inflammatory efficacy to clear cells and flare” (page 2 and back cover of sales aid, and front side of unfolded z-card);
• “Tame the FlameTM” (both covers and pages, 1, 3, 5, 7, 9, 11, and 13 of sales aid, and both covers of z-card); and
• Picture presentation of flames being engulfed by clear-blue water (both covers and pages 1 and 2 of sales aid, and front cover and front page of unfolded z-card).

The totality of the above claims and presentations misleadingly suggests that patients treated with Durezol will achieve complete resolution of inflammation and pain. The Durezol PI does not include evidence to support claims of completely clearing inflammation or pain in all patients. The Clinical Studies section of the PI reports on two clinical efficacy endpoints - the percentage of subjects that had anterior chamber cell clearing (a cell count of 0) and that were pain free at day 8 and day 15. Only 22% of patients using Durezol QID had anterior chamber cell clearing (a cell count of 0) at day 8, and 41% of patients using Durezol QID had anterior chamber cell clearing (a cell count of 0) at day 15. The PI also reports that 58% of patients using Durezol QID were pain free at day 8, and 63% of patients using Durezol QID were pain free at day 15. The claims and presentations suggesting that Durezol will completely resolve inflammation and pain thus considerably overstate the demonstrated efficacy that Durezol has on these endpoints.

Unsubstantiated Claims

Furthermore, the sales aid presents the following claims (emphasis in original):

• “DESIGNED FOR PATIENTS” (pages 3-4). . . .

o “Formulated for patient comfort”2

"Emulsion formulation with no shaking required"

"Durezol is a BAK-free product."

The above claims imply that there are characteristics of Durezol (e.g., emulsion formulation and BAK-free) that will have a positive impact on patient comfort with Durezol treatment. However, we are not aware that such an impact has been demonstrated by substantial evidence or substantial clinical experience. These claims also suggest that Durezol is superior to other ocular products that are not emulsion formulations or are not BAK-free, when we are not aware that this has been demonstrated by substantial evidence or substantial clinical experience. The Durezol PI is cited to support the claim that the drug is formulated for patient comfort; however, the PI does not include any evidence to support this claim. In fact, the Adverse Reactions section of the PI specifically states that patients using Durezol experienced eye pain, photophobia, blepharitis, etc., as the most commonly reported adverse events (5-15% of patients), any of which would undermine patient comfort. Generally, claims concerning the impact of drug treatments on patient comfort, and claims implying superiority to other products, 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.

Conclusion and Requested Action

For the reasons discussed above, the sales aid and z-card misbrand Durezol in violation of the Act, 21 U.S.C. 352(a) & (f)(1); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1) & 201.128; cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (xvii) & (xviii).

DDMAC requests that Sirion immediately cease the dissemination of violative promotional materials for Durezol such as those described above. Please submit a written response to
this letter on or before March 4, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Durezol 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 violations, 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 ID #17586, 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 Durezol 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,
{See appended electronic signature page}
Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications

_______________________________________________________

1 Data on file, Sirion Therapeutics, Inc.
2 Durezol Prescribing Information, Sirion Therapeutics, Inc. 2008.