1 division of anti-infective and ophthalmology products advisory committee meeting for difluprednate...

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Division of Anti-Infective and Division of Anti-Infective and Ophthalmology Products Ophthalmology Products

Advisory Committee Meeting Advisory Committee Meeting

for Difluprednatefor DifluprednateSonal D. Wadhwa, MDSonal D. Wadhwa, MD

US Food and Drug AdministrationUS Food and Drug AdministrationMedical OfficerMedical OfficerMay 29, 2008May 29, 2008

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Applicant InformationApplicant Information

Applicant: Applicant: Sirion TherapeuticsSirion Therapeutics

3110 Cherry Palm Drive, 3110 Cherry Palm Drive, Suite 340Suite 340

Tampa, FL 33619Tampa, FL 33619

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Introduction and Introduction and BackgroundBackground

ST-601 is a topical ST-601 is a topical ophthalmic emulsion ophthalmic emulsion formulation of difluprednate formulation of difluprednate for ocular instillation. for ocular instillation.

Difluprednate (6α, 9-Difluprednate (6α, 9-

difluoro-11β,17,21,-difluoro-11β,17,21,-trihydroxypregna-1,4-diene-trihydroxypregna-1,4-diene-3,20-dione 21 acetate 17-3,20-dione 21 acetate 17-butyrate) is a synthetic, butyrate) is a synthetic, glucocorticoid receptor glucocorticoid receptor agonist, a difluorinated agonist, a difluorinated derivative of prednisolone derivative of prednisolone that has anti-inflammatory that has anti-inflammatory activity. activity.

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Applicant Proposed Applicant Proposed IndicationIndication

Topical corticosteroid indicated for Topical corticosteroid indicated for the treatment of inflammation and the treatment of inflammation and pain associated with ocular surgery.pain associated with ocular surgery.

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Drug InformationDrug Information Proposed Proprietary Name: DurezolProposed Proprietary Name: Durezol

Established name: difluprednate ophthalmic Established name: difluprednate ophthalmic emulsionemulsion

NDA Drug Classification: P (NDA Drug Classification: P (Priority designation Priority designation because this is first steroid with the proposed because this is first steroid with the proposed indication of treatment of pain with ocular indication of treatment of pain with ocular surgery)surgery)

Pharmacologic Category: SteroidPharmacologic Category: Steroid

Dosage Form and Route of Administration: topical Dosage Form and Route of Administration: topical ophthalmic emulsionophthalmic emulsion

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Clinical Trials Which Clinical Trials Which Support Efficacy of Support Efficacy of

DifluprednateDifluprednate

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Description of Clinical Description of Clinical Trials Which Support Trials Which Support

Efficacy of DifluprednateEfficacy of Difluprednate Two Phase 3 clinical trials were reviewed to support efficacy Two Phase 3 clinical trials were reviewed to support efficacy

(Studies ST-601A-002a and ST-601A-002b) and seven studies (Studies ST-601A-002a and ST-601A-002b) and seven studies were reviewed to support safety. were reviewed to support safety.

The efficacy studies (Studies 002a and 002b) were double-The efficacy studies (Studies 002a and 002b) were double-masked, randomized, placebo-controlled clinical trials masked, randomized, placebo-controlled clinical trials evaluating ST-601 in the treatment of inflammation and pain evaluating ST-601 in the treatment of inflammation and pain following ocular surgery. following ocular surgery.

Each study was conducted under an identical but separate Each study was conducted under an identical but separate protocol. protocol.

As specified in the protocol and the Statistical Analysis Plan, As specified in the protocol and the Statistical Analysis Plan, the analysis was to be conducted strictly geographically, with the analysis was to be conducted strictly geographically, with sites located north of latitude 37° in Study 002b and sites sites located north of latitude 37° in Study 002b and sites located south of latitude 37° in Study 002a. located south of latitude 37° in Study 002a.

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Efficacy of DifluprednateEfficacy of Difluprednate In each study, the efficacy and safety of ST-601, In each study, the efficacy and safety of ST-601,

dosed either BID or QID for 14 days, was dosed either BID or QID for 14 days, was compared with vehicle in subjects who had compared with vehicle in subjects who had undergone unilateral ocular surgery. undergone unilateral ocular surgery.

On Day 15, after completion of the planned On Day 15, after completion of the planned treatment course, subjects who had an anterior treatment course, subjects who had an anterior chamber cell grade of “0” (defined as chamber cell grade of “0” (defined as ≤1 cell) ≤1 cell) or or who had responded satisfactorily to treatment as who had responded satisfactorily to treatment as judged by the investigator began graduated judged by the investigator began graduated tapering of the study drug, which successively tapering of the study drug, which successively halved the number of doses per day at each step. halved the number of doses per day at each step.

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Efficacy of DifluprednateEfficacy of Difluprednate Beginning at Day 15, the subjects who were initially Beginning at Day 15, the subjects who were initially

assigned to the QID dosing group instilled study assigned to the QID dosing group instilled study medication BID from Days 15 to 21, and QD from medication BID from Days 15 to 21, and QD from Days 22 to 28. Days 22 to 28.

Beginning at Day 15, the subjects who were initially Beginning at Day 15, the subjects who were initially assigned to the BID dosing group instilled study assigned to the BID dosing group instilled study medication QD from Days 15 to 28. medication QD from Days 15 to 28.

If further tapering was required after Day 28, the If further tapering was required after Day 28, the investigator discontinued study drug and prescribed investigator discontinued study drug and prescribed a suitable drug, as deemed appropriate. a suitable drug, as deemed appropriate.

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Inclusion CriteriaInclusion Criteria

Unilateral ocular surgery on the day prior to study Unilateral ocular surgery on the day prior to study enrollmentenrollment

Anterior chamber cell grade ≥ “2” (defined as 11-20 Anterior chamber cell grade ≥ “2” (defined as 11-20 cells) on the day after surgery (Day 1)cells) on the day after surgery (Day 1)

Age 2 years or older on the day of consentAge 2 years or older on the day of consent Negative urine pregnancy test on Day 1 for post-Negative urine pregnancy test on Day 1 for post-

menarchal subjects; negative urine pregnancy test for menarchal subjects; negative urine pregnancy test for pre-menarchal subjects at the investigator’s discretionpre-menarchal subjects at the investigator’s discretion

Provide signed written consent prior to entering the Provide signed written consent prior to entering the study or signed written consent from parent or legal study or signed written consent from parent or legal guardian if subject is a minor and signed assent from guardian if subject is a minor and signed assent from minor subjectminor subject

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Protocol Defined Analysis Protocol Defined Analysis PopulationsPopulations

Safety/Intent to Treat (ITT) population-All randomized Safety/Intent to Treat (ITT) population-All randomized subjects that received at least 1 dose of the study drug. subjects that received at least 1 dose of the study drug. Subjects were analyzed according to the treatment they Subjects were analyzed according to the treatment they were assigned to at randomization, irrespective of were assigned to at randomization, irrespective of compliance or any deviations from the study protocol. compliance or any deviations from the study protocol.

Per Protocol (PP) population-All randomized subjects who Per Protocol (PP) population-All randomized subjects who had no protocol violations (i.e. subjects who complied with had no protocol violations (i.e. subjects who complied with the protocol sufficiently to ensure that the data exhibited the the protocol sufficiently to ensure that the data exhibited the effects of the active substance when administered as effects of the active substance when administered as intended). According to the study protocol, the term intended). According to the study protocol, the term “protocol violations” denoted those deviations from the “protocol violations” denoted those deviations from the protocol that led to the exclusion of the subject from the PP protocol that led to the exclusion of the subject from the PP analysis, while “protocol deviations” subsumed minor analysis, while “protocol deviations” subsumed minor deviations that had no impact on the PP analyses. Protocol deviations that had no impact on the PP analyses. Protocol violations included violation of entry criteria, lack of violations included violation of entry criteria, lack of compliance, and the use of prohibited medications. compliance, and the use of prohibited medications.

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Efficacy StudiesEfficacy Studies

In Studies 002a and 002b the total In Studies 002a and 002b the total number of subjects included in the number of subjects included in the Safety/ITT population was 438. Safety/ITT population was 438.

ST-601 BID: 111ST-601 BID: 111 ST-601 QID: 107ST-601 QID: 107 Vehicle: 220Vehicle: 220

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Disposition of Patients in Disposition of Patients in Study 002aStudy 002a

Safety/ITT PopulationSafety/ITT PopulationST-601 BIDST-601 BID

N=57N=57ST-601 QIDST-601 QID

N=55N=55VehicleVehicle

N=107N=107

Completed Completed StudyStudy

52 (91.2%)52 (91.2%) 51 (92.7%)51 (92.7%) 68 (63.6%)68 (63.6%)

Total subjects Total subjects withdrawn withdrawn earlyearly

55 44 3939

Adverse eventAdverse event 00 22 33

Lack of Lack of efficacyefficacy

44 11 3333

Lost to f/uLost to f/u 00 00 22

Protocol Protocol violationviolation

00 00 00

Withdrew Withdrew consentconsent

11 00 11

Early Early termination of termination of studystudy

00 11 00

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Disposition of Patients in Disposition of Patients in Study 002bStudy 002b

Safety/ITT Population Safety/ITT PopulationST-601 BIDST-601 BID



N=113N=113

Completed Completed studystudy

48 (88.9%)48 (88.9%) 48 (92.3%)48 (92.3%) 56 (49.6%)56 (49.6%)

Total Total subjects subjects withdrawn withdrawn earlyearly

66 44 5757

Adverse Adverse eventevent

00 00 11

Lack of Lack of efficacyefficacy

55 22 5454

Lost to f/uLost to f/u 11 00 00

Protocol Protocol violationviolation

00 11 11

Withdrew Withdrew consentconsent

00 11 11

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Subjects in the Analysis Subjects in the Analysis Populations by Treatment Group: Populations by Treatment Group:

ST-601A-002aST-601A-002a

ST-601 ST-601 BIDBID

N=58N=58

ST-601 ST-601 QIDQID

N=55N=55

VehicleVehicle

N=107N=107

RandomizRandomizeded

5858 5555 107107

Safety/Safety/ITT ITT PopulatioPopulationn

5757 5555 107107

PP PP PopulatioPopulationn

5757 5252 105105

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Subjects in the Analysis Subjects in the Analysis Populations by Treatment Group: Populations by Treatment Group:

ST-601A-002bST-601A-002b


N=54N=54


N=52N=52

VehicleVehicle

N=114N=114

RandomizRandomizeded

5454 5252 114114

Safety/Safety/ITT ITT PopulatioPopulationn

5454 5252 113113

PP PP PopulatioPopulationn

5454 5151 113113

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Primary Efficacy EndpointPrimary Efficacy Endpoint

The primary efficacy endpoint for Studies 002a The primary efficacy endpoint for Studies 002a and 002b was the proportion of subjects with an and 002b was the proportion of subjects with an anterior chamber cell grade of “0” on Day 8 as anterior chamber cell grade of “0” on Day 8 as compared between the ST-601 QID and placebo compared between the ST-601 QID and placebo groups.groups.

Since the Agency considers that a clinically Since the Agency considers that a clinically meaningful endpoint would be complete meaningful endpoint would be complete clearing of anterior chamber cells where a grade clearing of anterior chamber cells where a grade 0=0 cells in the anterior chamber, the Agency 0=0 cells in the anterior chamber, the Agency utilized complete clearing of anterior chamber utilized complete clearing of anterior chamber cells where a grade 0=0 cells in the anterior cells where a grade 0=0 cells in the anterior chamber in our efficacy determinations.chamber in our efficacy determinations.

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Complete Clearing of Anterior Complete Clearing of Anterior Chamber Cell Chamber Cell

Study 002a [Grade 0 = 0 cells] Study 002a [Grade 0 = 0 cells] (ITT Population)(ITT Population)

SubjectSubjects s ClearedCleared


N=57N=57


N=55N=55

Vehicle Vehicle (N=107(N=107))

BID BID dosingdosing

P valueP value

QID QID dosing dosing

P valueP value

Day 3Day 3 33 44 00 0.01800.0180 0.00750.0075

Day 8 Day 8 (LOCF)(LOCF)

99 1313 1111 0.35840.3584 0.03020.0302


2525 2525 1515 <0.0001<0.0001 <0.001<0.001


3535 3232 2626 <0.0001<0.0001 <0.001<0.001

Follow-Follow-upup

3535 3636 5151 0.22000.2200 0.01480.0148

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Complete Clearing of Anterior Complete Clearing of Anterior Chamber Cell Chamber Cell

Study 002b [Grade 0 = 0 cells] Study 002b [Grade 0 = 0 cells] (ITT Population)(ITT Population)

SubjectSubjects s ClearedCleared


N=54N=54


N=52N=52



P valueP value


P valueP value

Day 3Day 3 11 11 22 0.87060.8706 1.01.0


1010 1111 66 0.00750.0075 0.00120.0012


2020 1919 1010 <0.0001<0.0001 <0.0001<0.0001


2929 3333 2020 <0.0001<0.0001 <0.0001<0.0001

Follow-Follow-upup

3333 3232 4848 0.02090.0209 0.01010.0101

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Analysis of Secondary Endpoints-Study 002a: Analysis of Secondary Endpoints-Study 002a: Proportion of Patients with a Pain/Discomfort Proportion of Patients with a Pain/Discomfort

Score of 0 (ITT Population)Score of 0 (ITT Population)


N=57N=57


N=55N=55



P valueP value


P valueP value

Day 3Day 3 2323 2727 2929 0.0770.07722

0.0020.00266


2323 3838 3232 0.2250.22500

<0.00<0.000101


3636 4242 4747 0.0200.02099

0.0000.00011

Follow-Follow-upup

4141 4444 7575 0.3960.39611

0.2510.25166

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Analysis of Secondary Endpoints-Study 002b: Analysis of Secondary Endpoints-Study 002b: Proportion of Patients with a Pain/Discomfort Proportion of Patients with a Pain/Discomfort

Score of 0 (ITT Population)Score of 0 (ITT Population)


N=54N=54


N=52N=52



P valueP value


P valueP value

Day 3Day 3 1919 2121 2525 0.0800.08000

0.0110.01166


2323 2424 2727 0.0120.01211

0.0020.00277


2323 2525 2929 0.0150.01500

0.0020.00211

Follow-Follow-upup

3030 3636 5656 0.4280.42822

0.0080.00888

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Studies Used to Evaluate Studies Used to Evaluate SafetySafety

Sirion Post-Sirion Post-surgical surgical StudiesStudies

Study 1: ST-601A-Study 1: ST-601A-002a002a

USUS 5555

Study 2: ST-601A-Study 2: ST-601A-002b002b

USUS 5252

Senju Post-Senju Post-surgical surgical StudiesStudies

Study 3: SJE2079/3-03Study 3: SJE2079/3-03 JapanJapan 100100

Study 4: SJE2079/2-Study 4: SJE2079/2-03-PC03-PC

JapanJapan 1111

Senju Senju Anterior Anterior Uveitis/PanuUveitis/Panuveitis veitis StudiesStudies


JapanJapan 6969

Study 7: SJE2079-2-Study 7: SJE2079-2-02-PC02-PC

JapanJapan 88


JapanJapan 1919

Total No. of Total No. of Patients Patients Treated with Treated with ST-601 QID ST-601 QID for at least for at least 14 days14 days

314314

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Integrated Review of SafetyIntegrated Review of Safety

Seven clinical trials were used to evaluate Seven clinical trials were used to evaluate safety of difluprednate. safety of difluprednate.

In Studies 3, 4, 6, and 7, the comparator In Studies 3, 4, 6, and 7, the comparator drug was betamethasone ophthalmic drug was betamethasone ophthalmic emulsion 0.1%, which is used for the emulsion 0.1%, which is used for the treatment of ocular inflammation in treatment of ocular inflammation in countries outside of the US. countries outside of the US.

In Studies 1 (002a) and 2 (002b), vehicle In Studies 1 (002a) and 2 (002b), vehicle was selected as the control treatment. was selected as the control treatment.

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Integrated Review of Integrated Review of SafetySafety

In Studies 002a and 002b, subjects also In Studies 002a and 002b, subjects also could be randomized to receive 1 drop could be randomized to receive 1 drop BID for 14 days.BID for 14 days.

Safety assessments in these 7 studies Safety assessments in these 7 studies included: palpebral injection, corneal included: palpebral injection, corneal endothelial cell density, IOP, BCVA, slit endothelial cell density, IOP, BCVA, slit lamp examination, ophthalmoscopy, and lamp examination, ophthalmoscopy, and the collection of AEs. the collection of AEs.

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Integrated Review of Integrated Review of SafetySafety

Between the 7 studies there were 314 Between the 7 studies there were 314 patients in the safety database in which patients in the safety database in which patients received ST-601 QID for at patients received ST-601 QID for at least 14 days. least 14 days.

All of these trials were randomized, All of these trials were randomized, multi-center, double-masked, parallel-multi-center, double-masked, parallel-group, and comparative, except for group, and comparative, except for Study 11, which was an open-label trial. Study 11, which was an open-label trial.

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Mean Duration of Exposure Mean Duration of Exposure to Study Drug (ITT to Study Drug (ITT

Population)Population) Study 002aStudy 002a

ST-601 BID (N=57): 26.3 daysST-601 BID (N=57): 26.3 days ST-601 QID (N=55): 26.5 daysST-601 QID (N=55): 26.5 days Vehicle (N=107): 20.1 daysVehicle (N=107): 20.1 days

Study 002bStudy 002b ST-601 BID (N=54): 26.1 daysST-601 BID (N=54): 26.1 days ST-601 QID (N=52): 26.2 daysST-601 QID (N=52): 26.2 days Vehicle (N=113): 17.9 daysVehicle (N=113): 17.9 days

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Study 002a: Distribution of Study 002a: Distribution of Exposure Durations to Study Drug Exposure Durations to Study Drug

(ITT Population)(ITT Population)Exposure Exposure Time Time (Days)(Days)


N=57N=57


N=55N=55

VehicleVehicle

N=107N=107

0-4 Days0-4 Days 22 00 2020

5-11 5-11 DaysDays

11 33 1212

12-18 12-18 DaysDays

22 00 44


5151 5252 7171

>33 Days>33 Days 11 00 00

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Study 002b: Distribution of Study 002b: Distribution of Exposure Durations to Study Drug Exposure Durations to Study Drug

(ITT Population)(ITT Population)Exposure Exposure Time Time (Days)(Days)


N=54N=54


N=52N=52

Vehicle Vehicle

N=113N=113

0-4 Days0-4 Days 22 22 2323

5-11 5-11 DaysDays

33 00 2222


00 33 1010


4848 4747 5858

>33 Days>33 Days 11 00 00

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Integrated Summary of Exposure Integrated Summary of Exposure (7 Safety Studies): Safety (7 Safety Studies): Safety

PopulationPopulationSirion post-Sirion post-surgical studies surgical studies

(US-002a and (US-002a and 002b)002b)

ST-601 QIDST-601 QID

N=107N=107

Senju post-Senju post-surgical studies surgical studies

(Japan-Studies (Japan-Studies 3 &4)3 &4)

ST-601 QIDST-601 QID

N=111N=111

Senju uveitis Senju uveitis studies ST-601 studies ST-601 QID QID

(Japan-Studies (Japan-Studies 6, 7, and 11)6, 7, and 11)

N=96N=96

Mean ExposureMean Exposure 26.926.9 13.213.2 14.014.0

Median Median ExposureExposure

28.028.0 14.014.0 14.014.0

Min/MaxMin/Max 2/342/34 0/160/16 12/1712/17

Duration of Duration of ExposureExposure

0-4 Days0-4 Days 22 66 00

5-11 Days5-11 Days 33 00 00

12-18 Days12-18 Days 33 104104 9595

>=19 Days>=19 Days 9999 00 11

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Fatal and Nonfatal Serious Fatal and Nonfatal Serious AEs in Clinical TrialsAEs in Clinical Trials

The overall incidence of SAEs in the 7 The overall incidence of SAEs in the 7 clinical studies was 11 of 425 subjects clinical studies was 11 of 425 subjects (2.6%) exposed to ST-601 (This includes (2.6%) exposed to ST-601 (This includes patients on BID and QID dosing)patients on BID and QID dosing)

Of the 329 subjects who were treated with Of the 329 subjects who were treated with ST-601 in the combined Senju and Sirion ST-601 in the combined Senju and Sirion post-surgical studies, SAEs were reported post-surgical studies, SAEs were reported for 8 subjects (2%), 1 SAE each. for 8 subjects (2%), 1 SAE each.

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Nonfatal Serious Adverse Nonfatal Serious Adverse EventsEvents

In the Sirion post-surgical studies (Studies In the Sirion post-surgical studies (Studies 002a and 002b)002a and 002b) 1 of 111 subjects (<1%) treated with ST-601 BID 1 of 111 subjects (<1%) treated with ST-601 BID

experienced 1 SAE (syncope)experienced 1 SAE (syncope)

4 of 107 subjects (3.7%) treated with ST-601 QID 4 of 107 subjects (3.7%) treated with ST-601 QID had 1 SAE each (syncope, UTI, HA, and had 1 SAE each (syncope, UTI, HA, and pneumonia)pneumonia)

2 of 220 subjects (<1%) in the placebo group had 2 of 220 subjects (<1%) in the placebo group had 1 SAE (respiratory distress secondary to anxiety 1 SAE (respiratory distress secondary to anxiety attack and CVA)attack and CVA)

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Nonfatal Serious Adverse Nonfatal Serious Adverse EventsEvents

In the Senju post-surgical studies (Studies 3 In the Senju post-surgical studies (Studies 3 and 4)and 4) 3 of 110 subjects (3%) treated with ST-601 QID 3 of 110 subjects (3%) treated with ST-601 QID

reported 1 SAE each (maculopathy secondary to reported 1 SAE each (maculopathy secondary to hypotony, retinal detachment, and iris adhesions)hypotony, retinal detachment, and iris adhesions)

In the Senju uveitis studies (Studies 6, 7, and In the Senju uveitis studies (Studies 6, 7, and 11)11) 3 of 96 subjects (3%) treated with ST-601 QID 3 of 96 subjects (3%) treated with ST-601 QID

reported 1 SAE each (monoarthritis, corneal reported 1 SAE each (monoarthritis, corneal perforation-in on-study eye secondary to reactivation perforation-in on-study eye secondary to reactivation of know HSV keratitis, and necrotizing retinitis)of know HSV keratitis, and necrotizing retinitis)

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Treatment-Emergent Adverse Events Occurring in ≥2%

of Subjects

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Special Safety Special Safety Studies/IOPStudies/IOP

An increase in IOP is a common treatment-An increase in IOP is a common treatment-related AE resulting from corticosteroid related AE resulting from corticosteroid use, especially with the use of topical use, especially with the use of topical ophthalmic steroids. ophthalmic steroids.

It is important to note though that in the It is important to note though that in the immediate post-operative period there may immediate post-operative period there may be other factors which contribute to be other factors which contribute to elevations in IOP.elevations in IOP.

Also, cataract surgery itself can decrease Also, cataract surgery itself can decrease the IOP, so following cataract surgery the the IOP, so following cataract surgery the IOP may be decreased from baseline.IOP may be decreased from baseline.

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Study 002a: Proportion of Subjects Study 002a: Proportion of Subjects With Increase in IOP of 10 mmHg With Increase in IOP of 10 mmHg

or Moreor MoreVisitVisit ST-601 BIDST-601 BID

N=54N=54ST-601 QID ST-601 QID


N=113N=113

Visit 2 (Day Visit 2 (Day ¾)¾)

00 00 00

Visit 3 (Day Visit 3 (Day 8)8)

11 11 22


00 11 00


00 00 00

Visit 6 Visit 6 (Follow-up)(Follow-up)

00 00 00

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Study 002b: Proportion of Subjects Study 002b: Proportion of Subjects With Increase in IOP of 10 mmHg With Increase in IOP of 10 mmHg

or Moreor MoreVisitVisit ST-601 BIDST-601 BID


N=55N=55Vehicle Vehicle

N=107N=107

Visit 2 (Day Visit 2 (Day ¾)¾)

00 11 00


11 11 22


11 11 00


11 22 00

Visit 6 Visit 6 (Follow-up)(Follow-up)

00 11 00

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Safety Studies/Corneal Safety Studies/Corneal Endothelial Cell CountEndothelial Cell Count

Another special safety study performed was Another special safety study performed was corneal endothelial cell counts at baseline and corneal endothelial cell counts at baseline and at Visit 6. at Visit 6.

This measurement was only performed in This measurement was only performed in Studies 002a and 002b.Studies 002a and 002b.

The Agency recommends performing corneal The Agency recommends performing corneal endothelial cell counts at baseline and at 3 endothelial cell counts at baseline and at 3 months because if performed sooner there months because if performed sooner there may not be sufficient time to observe changes.may not be sufficient time to observe changes.

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Corneal Endothelial Cell Count Change from Corneal Endothelial Cell Count Change from Baseline (Integrated Data from Studies 002a Baseline (Integrated Data from Studies 002a

and 002b)and 002b)

Mean Corneal Mean Corneal endothelial endothelial cell count ST-cell count ST-601 BID601 BID

N=111N=111

Mean Corneal Mean Corneal endothelial endothelial cell count ST-cell count ST-601 QID601 QID

N=107N=107

Mean Corneal Mean Corneal endothelial endothelial cell count cell count VehicleVehicle

N=220N=220

Visit 1 (Day 0)Visit 1 (Day 0) 2301.7 +/- 2301.7 +/- 493.7493.7

2213.4 +/- 2213.4 +/- 639.4639.4

2279.9 +/- 2279.9 +/- 526.9526.9

Visit 6 (Follow-Visit 6 (Follow-up)up)

2288.6 +/- 2288.6 +/- 633.9633.9

2180.1 +/- 2180.1 +/- 592.5592.5

2250.5 +/- 2250.5 +/- 633.2633.2

Change From Change From BaselineBaseline

78.8 +/- 529.378.8 +/- 529.3 14.3 +/- 464.414.3 +/- 464.4 36.3 +/- 521.536.3 +/- 521.5

P value based P value based on the on the difference difference between ST-between ST-601 and vehicle601 and vehicle

0.280.28 0.720.72

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Post-marketing Post-marketing ExperienceExperience

Because ST-601 is not marketed in Because ST-601 is not marketed in any country, no sources of AE any country, no sources of AE information exist, except for clinical information exist, except for clinical study reports of the trials that were study reports of the trials that were conducted for its development. conducted for its development.

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Questions for the Advisory Questions for the Advisory CommitteeCommittee

Do you think difluprednate ophthalmic emulsion Do you think difluprednate ophthalmic emulsion should be approved for the treatment of ocular should be approved for the treatment of ocular inflammation and pain following cataract surgery?inflammation and pain following cataract surgery?

If no, what additional studies should be performed?If no, what additional studies should be performed?

If yes, any additional Phase 4 studies should be If yes, any additional Phase 4 studies should be performed?performed?

Do you have any suggestions concerning the Do you have any suggestions concerning the labeling of the product?labeling of the product?

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Division of Anti-Infective and Division of Anti-Infective and Ophthalmology Products Ophthalmology Products

Advisory Committee Meeting Advisory Committee Meeting

for Difluprednatefor DifluprednateSonal D. Wadhwa, MDSonal D. Wadhwa, MD

US Food and Drug AdministrationUS Food and Drug AdministrationMedical OfficerMedical OfficerMay 29, 2008May 29, 2008

1 division of anti-infective and ophthalmology products advisory committee meeting for difluprednate...

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