CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
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`Cross Discipline Team Leader Review
`
`Cross—Discipline Team Leader Review
`
`
`Date
`April 9, 2012
`From
`Susan Limb, MD
`m_ Cross-Disci o line Team Leader Review
`NDA/BLA #
`NDA 202-236/ SN000
`
`Su vlement#
`
`Date of Submission
`
`Aril 1, 2011
`
`Meda Phannaceuticals, Inc.
`
`
`
`Ma 1,2012
`PDUFA Goal Date
`——
`Proprietary Name /
`Dymista Nasal Spray (azelastine hydroehloride/ fluticasone
`Established
`S 1
`.ro ionate
`
`names
`
`Dosage forms / Strength
`
`Pro I osed Indication s
`
`Azelastine hydrochloride 137 meg/fluticasone propionate
`50 megper spray (0.l%/0.037%)
`1. Seasonal aller 'c rhinitis in atients 12 ears and older
`
`1. Introduction
`
`Meda Pharmaceuticals, Inc. submitted a 505(b)(2) new drug application (NDA #202-236) on
`April 1, 2011, for a fixed—dose combination nasal spray containing azelastine hydrochloride
`0.1% and flutieasone propionate 0.03 7% for the treatment of symptoms of seasonal allergic
`rhinitis (SAR) in patients 12 years of age and older. Each actuation of the nasal spray pump
`delivers 137 meg azelastine and 50 meg fluticasone propionate. The proposed dosing regimen
`is 1 spray to each nostril twice daily, so that the total daily dose is 548 meg azelastine
`hydrochloride and 200 mcg fluticasone propionate. The proposed tradename is Dymista. The
`drug product represents the first fixed-dose combination nasal spray for an allergic rhinitis
`indication. The individual components, azelastine hydrochloride and fluticasone propionate,
`are each approved for various rhinitis indications and are currently marketed in several
`different formulations.
`
`The application was initially submitted on April 1, 2011, and was filed as a standard review.
`The Applicant submitted an amendment on December 7, 2011, containing CMC information
`on the pharmaceutical characteristics of the novel monocomparators used in the key efficacy
`trials. As this information was critical for the interpretation of the clinical trial results, the
`amendment was considered to be a major amendment, and the review clock was extended by
`three months.
`
`Throughout this memo, the drug product for this application will be referred to as azelastine
`hydrochloride/fluticasone propionate (azelastine/FP). This memo will provide an overview of
`the application with a focus on the data that support the contribution of each monocomponent
`to the efficacy and safety of the fixed-dose combination. As part of this discussion, the memo
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`Cross Discipline Team Leader Review
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`will discuss the regulatory background for the program, given its status as the first fixed-dose
`combination nasal spray.
`2. Background
`
`
`Azelastine hydrochloride
`Azelastine hydrochloride is a selective, H1 antihistamine, and is approved in the US in an
`ophthalmic solution, Optivar, and in two nasal spray solutions, Astelin Nasal Spray and
`Astepro Nasal Spray. Astelin Nasal Spray (azelastine hydrochloride 0.1%) was originally
`approved in the US in November 1996 for the treatment of SAR and is approved and marketed
`for the treatment of symptoms of allergic rhinitis in more than 80 countries worldwide and has
`nonprescription status in many of these countries. According to the Applicant, there have been
`no marketing withdrawals, suspensions, failure to obtain renewal, restrictions on distribution,
`or clinical trial suspensions worldwide.
`
`Astelin Nasal Spray is currently approved for the following indications in the US:
`(cid:120) Seasonal allergic rhinitis (SAR)
`o Children 5 to 11 years - 1 spray per nostril BID
`o Adults and children 12 years of age and older -1 or 2 sprays per nostril BID
`(cid:120) Vasomotor rhinitis (VMR) in adults and children 12 years of age and older - 2 sprays
`per nostril twice daily
`
`
`Azelastine hydrochloride is characterized by a bitter aftertaste. To mask the taste, Meda also
`developed a formulation of azelastine hydrochloride nasal spray which contained two
`additional excipients, sucralose and sorbitol. The sweetened formulation is marketed under the
`tradename Astepro Nasal Spray 0.1% and 0.15% (NDA 22-203 and 22-371). Astepro 0.1%
`was approved in 2008 for SAR in patients 12 years and older in 2008, and Astepro 0.15% was
`approved for SAR and perennial allergic rhinitis (PAR) in patients 12 years and older in 2010.
`
`Fluticasone propionate
`Fluticasone propionate is a corticosteroid available as an intranasal formulation (Flonase,
`NDA 20-121, approval date 1994, GSK) and as an orally inhaled formulation (Flovent Diskus,
`NDA 20-833; Flovent HFA, NDA 21-433).
`
`Flonase Nasal Spray is currently approved for SAR, PAR, and nonallergic rhinitis (NAR) in
`patients 4 years and older at the following doses:
`(cid:120) Adults and children 12 years and older:
`o 2 sprays per nostril QD (200 mcg/day)
`o 1 spray per nostril BID (200 mcg/day)
`o In some patients, the dose may be decreased to 1 spray per nostril QD (100
`mcg/day)
`(cid:120) Children 4 to 11 years
`o 1 spray per nostril once daily (100 mcg/day)
`o Some pediatric patients may require 200 mcg/day, delivered as 1 spray per
`nostril BID or 2 sprays per nostril QD
`
`
`
`
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`Cross Discipline Team Leader Review
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`A combination nasal spray containing azelastine hydrochloride and fluticasone propionate
`(Duonase) at the same nominal doses is currently marketed in India, but the formulation differs
`from the proposed azelastine/FP product which is the subject of this application.
`
`Regulatory background
`As noted in the Introduction, azelastine/FP will be the first fixed-dose combination nasal spray
`approved for allergic rhinitis. The development of an intranasal antihistamine/corticosteroid
`combination raised certain issues that had not been previously encountered in development
`programs for single-component nasal sprays. Early in development, the Division highlighted
`the need to satisfy the requirements of the Combination Rule outlined in 21CFR 300.50.
`Specifically, the Division expressed concerns regarding the following: 1) identification of an
`appropriate patient population for the proposed product; 2) the loss of dose titration flexibility;
`3) the use of two components to treat the same symptoms of allergic rhinitis; and 4) the need
`for pharmaceutically comparable monocomparators to be used in the key factorial-design trials
`(May 21, 2007 written communication; September 10, 2007 Type A Meeting Minutes; January
`31, 2008 SPA No Agreement Letter).
`
`Given the multiple issues surrounding the interpretation of the Combination Rule in the
`azelastine/FP program, the Agency held a Regulatory Briefing on April 17, 2009. Based on
`the feedback received in this internal discussion, the Division communicated to the Applicant
`in an April 23, 2009, teleconference, that the Agency would accept a fixed-dose combination
`product where each monotherapy component treats the same symptoms of allergic rhinitis.
`Furthermore, the demonstration of a statistically significant difference between azelastine/FP
`and each of the monocomparators would be accepted as evidence of a patient population
`requiring concurrent therapy, provided that the effect sizes were of reasonable magnitude and
`each monocomparator also demonstrated superiority to placebo. The Division noted that
`statistical significance driven by a large sample size with a marginal treatment effect would
`likely be inadequate.
`
`In addition, the Division reiterated the requirement for demonstrating that there were no
`pharmaceutical differences between the combination product and each monocomponent. Due
`to the pharmaceutical differences between the corresponding commercial monoproducts and
`the azelastine/FP combination formulation, the Applicant was compelled to develop
`monocomparators specifically for the azelastine/FP program. As the monocomparators
`developed specifically for the azelastine/FP program were novel products, replicate evidence
`of efficacy for each monocomparator versus placebo was also expected.
`
`
`3. CMC/Device
`
`
`The application is recommended for Approval from a CMC perspective, provided that the
`Office of Compliance issues an acceptable recommendation for all manufacturing and testing
`sites.
`
`
`(cid:120) General product quality considerations
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`The drug product, azelastine hydrochloride/fluticasone propionate (A/FP), is a fixed-dose
`combination of an intranasal antihistamine and corticosteroid, respectively. The drug product
`is a suspension nasal spray, supplied in a multi-dose, amber glass bottle and fitted with a
`metered
`(m4) spray pump. Each spray delivers 137 mcg azelastine (equivalent to 125
`meg azelastine base) and 50 meg fluticasone propionate. The drug contains an isotonic,
`m4) aqueous formulation of 0.1% azelastine hydrochloride and suspended, micronized
`0.03 7% fluticasone propionate USP with a pH 6.0
`m” The excipients consist of
`glycerin, microcrystalline cellulose and carboxymethylcellulose sodium
`(m4)
`polysorbate 80, edetate disodium (EDTA), benzalkonium chloride (0.1 mg/g), phenylethyl
`alcohol (2.5 mg/g), and purified water.
`
`The fill weight of 23 g delivers at the minimum 120 sprays after priming (commercial pack),
`and the fill weight of 6 g delivers at the minimum 28 sprays after priming (sample pack). The
`submitted CMC data support a 24-month expiry period when the product is stored at 20°-25°C
`(68°-77°F).
`
`Initial review of the CMC data noted deficiencies in the proposed specifications, analytical
`methods, and stability data for the drug product as described in the June 13, 2011, 74-day
`filing letter. In addition, the review team expressed concerns regarding the ruggedness of the
`container closure device, noting that the actuator detached easily from the glass vial during
`removal of the dust cap. Subsequently, the Applicant proposed new acceptance criteria for
`spray weight, spray content uniformity, droplet size distribution, and the microscopic method
`for particle size distribution. The original proposed expiry period
`(m4) was not
`adequately supported given out-of-trend instability changes for several tested attributes, so the
`expiry period was modified to 24 months. Manufacturing changes were also implemented to
`seat the actuator more securely on the glass vial. As the changes are not anticipated to
`substantially impact dose performance, the proposed changes were considered acceptable, and
`comparative data comparing the dose performance of the drug product before and after the
`changes will be submitted in the first annual report. The CMC review team has concluded that
`the deficiencies have been addressed by the Applicant’s responses, and that the proposal for
`follow-up information is acceptable.
`
`0 Facilities review/inspection
`
`The Establishment Evaluation Request (EER) for this NDA is pending at the time of this
`memorandum. Azelastine hydrochloride is manufactured by
`and flutieasone propionate is manufactured by
`The drug product is manufactured by Cipla Ltd. in Goa, India. Acceptable status is
`indicated in the EES for the
`(m4) Voluntary Action Indicated (VAI)
`status is listed in the EES for the azelastine hydrochloride drug substance manufacturing site
`mm The cGMP inspection was completed at this
`establishment in July 2011, with a FDA Form 483 issued.
`
`(b) (4)
`
`(I!) (4)
`
`o Other notable issues (resolved or outstanding)
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`Cross Discipline Team Leader Review
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`Given the requirements outlined by the Combination Rule in 21CFR 300.50, characterization
`of the monocomponents in the fixed-dose combination for potential pharmaceutical
`interactions as well as characterization of the monocomparators used in the key efficacy and
`safety trials was a focus of the CMC review for this application. While azelastine and
`fluticasone propionate are marketed as individual products, the formulation of the
`commercially available products differs from the formulation of the combination. In the
`combination, azelastine is solubilized in the drug product formulation while the fluticasone
`propionate is micronized and in suspension. Therefore, the Applicant developed novel
`azelastine 0.1% nasal spray and fluticasone propionate 0.03 7% nasal spray monocomparator
`products specifically for use in the key factorial design clinical trials.
`
`Dose performance comparison data for the combination and monotherapy products were
`reviewed and found to be comparable.
`mm)
`
`the overall dose performance results were
`considered to be within the acceptable range of variations of NMT (m4) Based on the in vitro
`data, the CMC review team has concluded that there are no significant pharmaceutical
`interactions, which would potentially impact the interpretation of the clinical results.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The recommendation from the Nonclinical Pharmacology/1'oxicology review is Approval.
`There are no outstanding issues from a pharmacology/toxicology perspective at this time.
`
`The nonclinical program for azelastine/FP is based upon complete toxicology programs
`conducted for the individual active drugs, including single dose toxicology, subchronic
`toxicology, chronic toxicology, reproductive toxicology, genotoxicity, and carcinogenicity
`studies. These studies were previously reviewed under NDAs 20-114 and 20-121. The
`Applicant conducted 14-day intranasal toxicology studies in rats and dogs and a 3—month
`intranasal toxicology study in rats with azelastine/FP. In general, these toxicology studies did
`not indicate any potential additive or synergistic toxic effects of the combination. Mast cells
`were noted to be increased in the mandibular lymph nodes of both male and female rats in the
`azelastine/FP group compared to control, vehicle, and the monoproducts, but the toxicological
`significance of this finding is uncertain given that high background levels in the
`tracheobronchial lymph nodes of control males were also observed. Azelastine/FP is
`categorized as Pregnancy Category C.
`
`5. Clinical PharmacologyIBiopharmaceutics
`
`The application is deemed acceptable from a Clinical Pharmacology perspective. No issues
`are outstanding at this time.
`
`The clinical pharmacology program for this application included two single-dose relative
`bioavailability trials in healthy volunteers to assess for potential drug-drug interactions and
`formulation issues O(-03065-3282 and X-03065-3283). These trials demonstrated that co-
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`administration of azelastine and fluticasone does not affect the systemic exposure of either.
`Systemic exposure for azelastine in combination is within ±20% exposure of the commercially
`marketed azelastine product, Astelin. In contrast, systemic exposure for FP in combination is
`44 to 61% higher than exposure from a commercially marketed, generic FP nasal spray
`product at the same nominal dose. However, the systemic exposure of FP from the
`azelastine/FP combination is below the systemic exposure from higher doses of commercially
`marketed FP nasal spray (Flonase 200 mcg once daily or 400 mcg twice daily), which has been
`reported to have no effect on adrenal responses and is described in the current Flonase package
`insert. While a HPA-axis study has not been conducted specifically for azelastine/FP, the
`information regarding relative systemic exposures suggests that the higher systemic exposure
`observed for FP in azelastine/FP is not likely to pose new systemic safety concerns.
`Previously, at the Pre-NDA meeting held on August 17, 2010, the Division had agreed that if
`systemic exposure from azelastine/FP were equal or less than systemic exposures from the
`corresponding commercially marketed monotherapies, then a separate HPA axis trial would
`not be required.
`
`Information on drug interactions, intrinsic factors, demographic interactions, and QT
`assessment are based on clinical pharmacology data for the commercially marketed
`monocomponent drugs that are described in the respective package inserts. No dose
`adjustments are recommended for renal or hepatic impairment or for geriatric patients. The
`application references previous trials that evaluated potential cardiac effects of both intranasal
`and oral azelastine; no QT effect was observed with intranasal azelastine, while mean changes
`in QTc of 7.2 msec and 3.6m msec have been observed following multiple-dose, oral
`administration of azelastine 4 mg and 8 mg twice daily, respectively. The clinical program for
`azelastine/FP did not include a thorough QT assessment.
`
`
`6. Clinical Microbiology
`Clinical microbiology is not applicable for this NDA.
`7. Clinical/Statistical- Efficacy
`
`
`The main clinical program for azelastine/FP consisted of five efficacy and safety trials: 4001,
`4002, 4004, 4006, and 4000 (Table 1). Trial 4000 was a long-term safety trial and is discussed
`separately in the following Section 8 on safety. The clinical program also included two
`clinical pharmacology trials (X-03065-3282 and X-03065-3283), which were discussed
`previously in Section 5 Clinical Pharmacology/Biopharmaceutics. This section focuses on the
`trials which demonstrated the contribution of azelastine and FP to the efficacy of the
`combination product and which form the basis for the recommended regulatory decision,
`namely, trials 4002, 4004, and 4006.
`
`The results of 4001 are of clinical interest, however, 4001 is viewed as secondary support due
`to the use of Astelin and commercially marketed FP as monocomparators. Given
`pharmaceutical differences between the commercial formulations and the azelastine/FP
`formulation, the commercial monoproducts are not appropriate comparators for the purpose of
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`Cross Discipline Team Leader Review
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`addressing the Combination Rule. For this reason, the results of 4001 will be summarized
`briefl but Will not be a focus of this section.
`
`Table l Azelastine/FF effica
`
`and safe
`
`trials
`
`Trial
`Trial dates
`
`Design
`
`Treatmen
`
`Endpoints
`
`2—week. R, DB, PC. AC trial
`in patients 12 years and
`older with SAR (Texas
`Dec 2007 to Feb 2008 Mountain Cedar
`
`153 Azelastine/FP
`153 Astelin
`153 Commercial FP
`151
`Placebo
`
`Change from
`baseline in rTNSS
`
`Change from
`baseline in rTNSS
`
`Change from
`baseline in rTNSS
`
`Change from
`baseline in rTNSS
`
` W
`
`2—week. R, DB. PC, AC,
`trial in patients 12 years and
`older with SAR
`
`2-week. R. DB. PC, AC trial
`in patients 12 years and
`older with SAR
`
`2-week. R. DB. PC. AC trial
`in patients 12 years and
`older with SAR
`
`207 Azelastine/PP
`208 Azelastine
`207
`FP
`210
`Placebo
`
`195 Azelastine/FP
`194 Azelastine
`189
`PP
`201
`Placebo
`
`451 Azelastine/PP
`449 Azelastine
`450 FP
`451
`Placebo
`
`Mar 2008 to Jun 2008
`
`Au ' 2008 to Nov 2008
`
`n" 2009 to Au ' 2009
`
`4000
`
`Jan 2008 to Jun 2009
`
`12-month. R. 0L. AC trial
`in patients 12 to 80 years of
`a - e with PAR or VMR
`
`405 Azelastine/FP
`207 Commercial FP2
`
`Safety
`
`W
`
`number randomized
`
`2 All treatments administered as 1 spray per nostril BID except in Trial 4000. where the commercial FP active
`control was administered as 2 sprays per nostril BID.
`
`Dose selection
`
`The proposed dose of 1 spray to each nostril twice daily delivers a total daily dose of 548 mcg
`azelastine and 200 mcg fluticasone propionate. Azelastine/FP is viewed as a combination of
`convenience, and formal dose-ranging trials of the combination were not conducted. Dose
`selection for each component of azelastine/FP is based on the approved dosing for each
`individual component and supported by the efficacy and safety data obtained in the Phase 3
`program.
`
`As mentioned in the preceding Background section, the Division had initial concerns that
`patients may be exposed to doses higher than necessary to treat their symptoms, since the
`fixed-dose formulation would eliminate the option for dose titration that is recommended for
`FF. This issue is discussed in further detail in Section 12 on Labeling.
`
`Trial design
`Trials 4001, 4002, 4004, and 4006 were 2—week, randomized, double—blind, placebo— and
`active-controlled trials in patients 12 years and older with seasonal allergic rhinitis. The trials
`had a fill] factorial design, intended to demonstrate the contribution of each monocomponent
`to the combination to satisfy the requirements of the Combination Rule. Afier a 7-day, single-
`blind, placebo lead-in period, patients 12 years of age and older with a minimum 2—year
`history of SAR to a relevant local allergen and a positive skin test were randomized 1:1:l:l to
`azelastine/FP, azelastine, FF, or vehicle placebo administered 1 spray per nostril twice daily.
`Patients were required to have a minimum symptom score and a demonstration of compliance
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`with the placebo spray during the run-in period in order to be randomized. Information
`regarding patients’ history of prior experience with azelastine or FP nasal sprays was not
`specifically queried.
`
`During the 14-day treatment period, patients recorded reflective and instantaneous total nasal
`symptom scores (TNSS) twice daily. The TNSS was defined as the sum of the nasal symptom
`scores of itchy nose, nasal congestion, runny nose, and sneezing, rated on a 4-point scale from
`0 to 3 (0 = no symptoms, 1 = mild symptoms, 2= moderate symptoms, and 3 = severe
`symptoms). In addition to the rTNSS and iTNSS, patients scored reflective and instantaneous
`total ocular symptom scores (TOSS), defined as the sum of the ocular symptoms of itchy eyes,
`watery eyes, and eye redness on a 4-point scale (0 = no symptoms, 1 = mild symptoms, 2=
`moderate symptoms, and 3 = severe symptoms). Patients who were 18 years or older also
`completed a Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ), a 28-item
`questionnaire that scores the subjective impact of SAR symptoms on quality of life. A change
`from baseline of (cid:149)0.5 units is considered to be a minimum clinically important difference
`(MCID) for the RQLQ, and a treatment difference of (cid:149)0.5 units between comparator arms is
`also expected.
`
`In general, the patient population, trial design, and assessments were consistent with the
`recommendations outlined in the Draft Guidance for Industry, Allergic Rhinitis: Clinical
`Development Programs for Drug Products (April 2000) and the clinical trials conducted for
`other allergic rhinitis programs. The primary endpoint was the change from baseline over the
`14-day treatment period in the combined AM and PM rTNSS. Instantaneous TNSS was also
`assessed to confirm the dosing interval as well as to establish the onset of action. In Trials
`4004 and 4006, the change from baseline over the 14-day treatment period in the combined
`AM and PM rTOSS was designated as a key secondary endpoint. The change from baseline in
`the RQLQ was assessed as an additional secondary endpoint in all the trials.
`
`The trials were similar in conduct and size, with the exception of Trials 4001 and 4006. As
`noted, Trial 4001 used corresponding commercial products for the monocomparator arms.
`Trial 4006 enrolled 1801 patients, which was more than double the size of the other Phase 3
`trials. The Applicant stated in the August 17, 2010, pre-NDA meeting that the trial was
`powered based on the magnitude of effect observed in the preceding Trial 4002
` This
` is discussed in further detail
`
`below.
`
`Efficacy results
`
`Reflective TNSS
`The key trials, Trials 4002, 4004, and 4006, demonstrated a statistically significant decrease in
`the combined AM and PM rTNSS scores over the 14-day treatment period for the comparison
`of azelastine/FP to placebo (Table 2). Comparisons of the azelastine and FP monocomparators
`to placebo were also statistically significant (p<0.001; results not shown in table). The
`factorial comparisons of azelastine/FP to the individual monocomparators, azelastine and FP,
`were also statistically significant, with the exception of the borderline results in Trial 4004 for
`the comparison of azelastine/FP to FP alone (p=0.06; Table 2). These results provide replicate
`
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`Cross Discipline Team Leader Review
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`evidence of the contribution of each individual component to the efficacy of the combination,
`satisfying the requirements of the Combination Rule and demonstrating the advantage of the
`combination over each individual component. The magnitude of the treatment differences was
`similar to the differences observed in other clinical programs for allergic rhinitis, and the
`results based on last-observation-carried—forward (LOCF) imputed and non-imputed results
`were also similar. The pre-specified analysis was based on a repeated-measures analysis using
`the last observation carried forward (LOCF) method for imputation of missing data. As there
`are some concerns regarding the use of LOCF imputation in this setting, the results presented
`here are based on observed data without imputation (Table 2). The issue of imputation and
`different sensitivity analyses are discussed in flnther detail in the biostatistical review.
`
`Table 2 Results of change from baseline in rTNSS over 2 weeks (observed data)
`
`Treatment
`
`Baseline
`LS Mean
`
`Change from baseline
`LS Mean
`
`Treatment Difference from Azelastine/FP
`95% CI
`
`
`
`—-—————
`
`I_-————
`—--m-—__
`4004
`
`—-—————
`
`I_-————
`—lm———I__
`4006
`
`—-—————
`
`I_m——-E-_I—
`—--E!-—I__
`
`Results for the comparison of azelastine/FP to placebo for each of the individual rhinitis
`symptoms (itchy nose, nasal congestion, runny nose, and sneezing) were also statistically
`significant (p<0.001).
`
`Results for Trial 4001, the trial that used commercial azelastine and PP, were similar to the
`
`results observed for the other efficacy trials. Statistically significant differences for the
`comparison of azelastine/FP to placebo, Astelin, and generic commercial FP were observed.
`
`Instantaneous TNSS
`
`The key trials demonstrated a statistically significant decrease in instantaneous TNSS for
`azelastine/FP compared to placebo and for each of the monocomparators compared to placebo,
`supporting the proposed dosing interval of twice daily (Table 3).
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`Table 3 Results of change from baseline in ITNSS over 2 weeks (observed data)
`
`--n Change from baseline
`
`LS Mean
`
`LS Mean
`
`Treatment Difference from Placebo
`
`95% CI
`
`P—value
`
`LS Mean
`
`
`
`17.16
`16.84
`16.84
`17.26
`
`17.16
`17.28
`17.19
`16.84
`
`17.91
`18.00
`17.82
`17.90
`
`-5.21
`-3.91
`-4.54
`-2.66
`
`-2.55
`
`-1.89
`
`-3.35, -1.76
`-1.96, -0.55
`-2.60, -1.18
`
`-3.43, -1.82
`-2.36, -0.78
`-2.64, -1.02
`
`-2.49, -1.35
`-1.76, -0.68
`
`lillI'll
`
`<0.001
`<0.001
`<0.001
`
`<0.001
`<0.001
`<0.001
`
`<0.001
`<0.001
`<0.001
`
`\l
`Azelastine/FP
`—-
`Azelastine
`—-
`I_-
`Placebo
`—-
`4004
`Azelastine/FP
`Azelastine
`
`0 0 0
`
`\OW
`
`H...000cow
`
`Placebo
`4006
`Azelastine/FP
`Azelastine
`
`Placebo
`
`3
`
`iii!
`
`The iTNSS scores were also used to characterize the onset of action, defined as the first time
`point after initiation of treatment when azelastine/FP demonstrated a statistically significant
`difference from placebo in terms of the reduction in iTNSS which proved durable from that
`timepoint. An onset of action of 30 minutes was demonstrated in replicate in 4004 and 4006;
`the onset of action in 4002 was 45 minutes.
`
`Reflective TOSS
`
`The change in mean rTOSS from baseline over the l4—da
`efficac end oint,
`
`treatment eriod was assessed as
`
`
`
`
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`
`
`RQLQ
`The change from baseline in RQLQ over the 14-day treatment period was an additional
`secondary endpoint, and the Applicant proposes inclusion of RQLQ information in the product
`label. The comparison of azelastine/FP to placebo was statistically significant in all three trials
`and crossed the MCID threshold of 20.05 units; these replicate results are considered adequate
`to support inclusion of RQLQ information in the product label.
`
`Table 5 Results of change h'om baseline in RQLQ over 2 weeks (111‘ population, excluding patients with
`.. mu _ baselinevalne
`
`--n Change from baseline
`
`LS Mean
`
`LS Mean
`
`
`
`Treatment Difference from Azelastine/FP
`
`95% CI
`
`—-—-E_———
`-0.54, -0.03
`0.029
`IE—IEl——— -0.36, 0.23
`0.907
`mm“ -1.05, -0.55
`<0.001
`4004
`
`—-—-E_———
`-0.53, -0.03
`0.031
`IE—IEI——— -0.46, 0.05
`0.123
`-0.97, -0.45
`<0.001
`
`4006
`
`—-—-E-———
`-0.33, -0.01
`0.043
`I_-——-m- -0.20, 0.12
`0.629
`-0.72, -0.39
`<0.001
`
`Summary of efficacy
`The application contains adequate data to support the efficacy of azelastine/FP for the
`treatment of symptoms of seasonal allergic rhinitis in patients 12 years and older. The three
`key tn'als (4002, 4004, and 4006) demonstrated statistically significant results for the pre-
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`specific efficacy endpoint, the change from baseline in mean rTNSS over the 14-day treatment
`period. While there is no agreed-upon MCID for the rTNSS, the magnitude of the treatment
`effect observed was fairly consistent across the three trials as well as in comparisons with
`other allergic rhinitis clinical programs. Two of the three trials (4004 and 4006) also provided
`robust, statistically significant demonstration of factorial contribution of azelastine and FP to
`the combination. These results address the requirements for a combination product as outlined
`in the Combination Rule and provide justification for the use of the combination product in
`lieu of the individual monoproducts. Data from secondary endpoints, iTNSS and RQLQ,
`provide secondary support for efficacy, and the iTNSS data confirm the twice-daily dosing
`interval as well as the proposed onset of action of 30 minutes. Data from the rTOSS endpoint
`are also generally supportive of efficacy but are not sufficient to support inclusion of rTOSS
`data in the label. These conclusions are consistent with the views expressed in the primary
`clinical review and biostatistics review.
`
`At this time, there are no outstanding clinical issues in terms of efficacy.
`
`
`8. Safety
`
`
`The evidence of safety of azelastine/FP is based on the clinical trials outlined in Table 1, as
`well as the known systemic safety profiles of the commercially marketed azelastine and FP
`products. This memorandum focuses on the key efficacy trials – 4002, 4004, and 4006 – and
`the long-term safety trial, 4000. Data from 4001 were also reviewed and were found to be
`similar to the results of the other trials, but 4001 was not included in the pooled safety
`database, given the use of different monotherapy comparators. The pooled database includes a
`total of 1257 patients: 853 patients 12 years and older with SAR treated with azelastine/FP for
`up to 2 weeks and 404 patients with PAR or VMR treated for up to 12 months.
`
`Safety assessments in the clinical program included adverse events, vital signs, and focused
`head and neck examinations to evaluate for local toxicity. The design and conduct of the
`efficacy trials was previously described in Section 7. Trial 4000, the long-term safety study,
`was an open-label, active controlled trial comparing the safety profiles of azelastine/FP 1 spray
`per nostril BID to commercial FP 2 sprays per nostril BID. Of note, while the 2-week SAR
`trials were conducted in the US, the 12-month safety trial was conducted in India. The
`generalizability of the long-term safety study results was raised as a review issue in the 74-day
`filing letter. As the nature and frequency of adverse events was fairly