`RESEARCH
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`Exhibit 1058
`IPR2017-00807
`ARGENTUM
`
`000001
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`
`
`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Review
`
` Date April 9, 2012
`
`From
`Susan Limb, MD
`Subject
`Cross-Discipline Team Leader Review
`NDA 202-236/ SN000
`NDA/BLA #
`Supplement#
`
`Date of Submission
`PDUFAGoalDate
`
`Meda Pharmaceuticals, Inc.
`April 1, 2011
`May
`I, 2012
`
`
`
`a P
`
`roprietary Name/
`names
`Established
`(USAN)
`Dosage forms / Strength
`
`Proposed Indication(s
`
`Dymista Nasal Spray (azelastine hydrochloride/ fluticasone
`propionate
`Azelastine hydrochloride 137 mcg/fluticasone propionate
`50 megper spray (0.1%/0.037%)
`1. Seasonalallergic rhinitis in patients 12 years and older
`[Approval
`Approval
`
`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 fluticasone propionate 0.037% for the treatment of symptoms of seasonalallergic
`rhinitis (SAR) in patients 12 years of age and older. Each actuation of the nasal spray pump
`delivers 137 mcg azelastine and 50 mcg fluticasone propionate. The proposed dosing regimen
`is 1 spray to each nostril twice daily, so that the total daily dose is 548 mcg azelastine
`hydrochloride and 200 mcgfluticasone propionate. The proposed tradename is Dymista. The
`drug productrepresents the first fixed-dose combination nasal spray for an allergic rhinitis
`indication. The individual components, azelastine hydrochloride and fluticasone propionate,
`are each approvedfor various rhinitis indications and are currently marketed in several
`different formulations.
`
`The application wasinitially submitted on April 1, 2011, and wasfiled as a standard review.
`The Applicant submitted an amendment on December7, 2011, containing CMC information
`on the pharmaceutical characteristics of the novel monocomparators used in the key efficacy
`trials. As this information wascritical for the interpretation of the clinical trial results, the
`amendment wasconsidered 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 memowill 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. Aspart of this discussion, the memo
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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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`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 andcorticosteroid, respectively. The drug product
`is a Suspension nasal spray, supplied in a multi-dose, amberglass bottle and fitted with a
`metered
`©® spray pump. Eachspray delivers 137 mcg azelastine (equivalent to 125
`meg azelastine base) and 50 mcgfluticasone propionate. The drug contains an isotonic,
`© aqueous formulation of 0.1% azelastine hydrochloride and suspended, micronized
`0.037% fluticasone propionate USP with a pH 6.0
`©©® The excipients consist of
`glycerin, microcrystalline cellulose and carboxymethylcellulose sodium
`mt)
`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 mimimum 28 sprays after priming (sample pack). The
`submitted CMC data support a 24-month expiry period whenthe productis stored at 20°-25°C
`(68°-77°F).
`
`Initial review of the CMCdata noted deficiencies in the proposed specifications, analytical
`methods, andstability data for the drug productas described in the June 13, 2011, 74-day
`filing letter. In addition, the review team expressed concerns regarding the ruggednessof 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 acceptancecriteria for
`spray weight, spray content uniformity, droplet size distribution, and the microscopic method
`for particle size distribution. The original proposed expiry period
`©® 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 performanceof the drug product before andafter the
`changeswill be submitted in the first annual report. The CMCreview team has concluded that
`the deficiencies have been addressed by the Applicant’s responses, and that the proposal for
`follow-up information is acceptable.
`
`e Facilities review/inspection
`
`The Establishment Evaluation Request (EER) for this NDAis pendingat the timeofthis
`memorandum. Azelastine hydrochloride is manufactured by
`and fluticasone propionate is manufactured by
`The drug product is manufactured by Cipla Ltd. in Goa, India. Acceptable status is
`indicated in the EES for the
`©® ‘Voluntary Action Indicated (VAI)
`status is listed in the EES for the azelastine hydrochloride drug substance manufacturingsite
`© The cGMP inspection was completed at this
`establishment in July 2011, with a FDA Form 483issued.
`
`(b) (4)
`
`(b) (4)
`
`e Other notable issues (resolved or outstanding)
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`Given the requirements outlined by the Combination Rule in 21CFR 300.50, characterization
`of the monocomponentsin 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 0.037% nasal spray monocomparator
`products specifically for use in the key factorial design clinicaltrials.
`
`Dose performance comparison data for the combination and monotherapy products were
`reviewedand found to be comparable.
`me)
`
`the overall dose performanceresults were
`considered to be within the acceptable range ofvariations ofpNUT ™® Basedon thein vitro
`data, the CMCreview team has concludedthat there are no significant pharmaceutical
`interactions, which would potentially impact the interpretation ofthe clinical results.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The recommendation from the Nonclinical Pharmacology/Toxicology review is Approval.
`There are no outstanding issues from a pharmacology/toxicology perspectiveat 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. Mastcells
`were noted to be increased in the mandibular lymph nodes of both male and female rats in the
`azelastine/FP group comparedto control, vehicle, and the monoproducts, but the toxicological
`significance ofthis finding is uncertain given that high backgroundlevels in the
`tracheobronchial lymph nodes of control males were also observed. Azelastine/FP is
`categorized as Pregnancy Category C.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The application is deemed acceptable from a Clinical Pharmacology perspective. No issues
`are outstandingatthis time.
`
`Theclinical pharmacology program for this application included twosingle-doserelative
`bioavailability trials in healthy volunteers to assess for potential drug-drug interactions and
`formulation issues (X-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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`addressing the Combination Rule. Forthis reason, the results of 4001 will be summarized
`briefly but will not be a focus of this section.
`
`Table 1 Azelastine/FP efficacy
`Trial
`Trial dates
`
`and safety
`Design
`
`trials
`
`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
`2-week, R. DB, PC, AC,
`Azelastine/FP
`Change from
`trial in patients 12 years and
`Azelastine
`baseline in rTNSS
`older with SAR
`
`baseline in rTNSS
`
` a
`
`Mar2008 to Jun 2008
`
`Aug 2008 to Nov 2008
`
`2-week, R, DB, PC, ACtrial
`in patients 12 years and
`older with SAR
`
`2-week. R. DB, PC. ACtrial
`in patients 12 years and
`older with SAR
`
`Azelastine/FP
`Azelastine
`
`Change from
`baseline in rTNSS
`
`Change from
`baseline in rTNSS
`
`Apr 2009 to Aug 2009
`4000 405|Azelastine/FP12-month, R, OL. ACtrial Safety
`
`
`
`in patients 12 to 80 years of|207|Commercial FP”
`Jan 2008 to Jun 2009
`age with PAR or VMR
`
`number randomized
`> All treatments administered as 1 spray per nostril BID exceptin Trial 4000, where the commercial FP active
`control was administered as 2 sprays per nostril BID.
`
`Doseselection
`The proposed dose of 1 spray to each nostril twice daily delivers a total daily dose of 548 mcg
`azelastine and 200 mcgfluticasone propionate. Azelastine/FP is viewed as a combination of
`convenience, and formal dose-rangingtrials of the combination were not conducted. Dose
`selection for each componentof azelastine/FP is based on the approved dosing for each
`individual componentand supported by the efficacy and safety data obtained in the Phase 3
`program.
`
`As mentioned in the preceding Backgroundsection, the Division hadinitial concerns that
`patients may be exposedto doses higher than necessary to treat their symptoms, since the
`fixed-dose formulation would eliminate the option for dosetitration that is recommended for
`FP. 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 seasonalallergic rhinitis. Thetrials
`had a full factorial design, intended to demonstrate the contribution of each monocomponent
`to the combination to satisfy the requirements of the Combination Rule. After 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 relevantlocal allergen and a positive skin test were randomized 1:1:1:1 to
`azelastine/FP, azelastine, FP, 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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`evidence of the contribution of each individual componentto the efficacy of the combination,
`satisfying the requirements of the Combination Rule and demonstrating the advantage of the
`combination over each individual component. The magnitudeof the treatment differences was
`similar to the differences observedin other clinical programs for allergic rhinitis, and the
`results based on last-observation-carried-forward (LOCF) imputed and non-imputedresults
`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 concernsregarding the use of LOCF imputationin 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 further detail in the biostatistical review.
`
`Table 2 Results of change from baseline in rTNSS over 2 weeks (observed data)
`
`-0.06)|0.030_|
`
`
`
`Treatment Baseline|Change from baseline|Treatment Difference from Azelastine/FP
`LS Mean
`LS Mean
`95% CI
`
`|AzelastineFP_|207|18.27|5.64|
`
`[FP207*||8.22|47|-0.971.80,-0.24)|0.022|
`
`
`|Placebo|209|18.61|2.94|-2.71YT3.49.-1.92)|<0.001_|
`4004
`|AzelastineFP_|193|18.28|5.54
`
`[FPiss|is64|466|-0.881.79.0.04)|0.060_|
`
`
`[Placebo|199|18.24|3.12|-2-413.24,-1.58)|<0.001__|
`4006
`|AzelastineFP_|448|19.34|555
`
`[FP450|9.4|T00641.21,
`
`Results for the comparison of azelastine/FP to placebo for each of the individual rhinitis
`symptoms (itchy nose, nasal congestion, runny nose, and sneezing) werealsostatistically
`significant (p<0.001).
`
`Results for Trial 4001, the trial that used commercial azelastine and FP, 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 demonstrateda statistically significant decrease in instantaneous TNSSfor
`azelastine/FP compared to placebo and for each of the monocomparators comparedto placebo,
`supporting the proposed dosing interval of twice daily (Table 3).
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`Table 3 Results ofchange from baseline in iTNSS over 2 weeks (observed data)
`
`
`
`Treatment Baseline|Change from baseline Treatment Difference from Placebo
`
`LS Mean
`LS Mean
`95% CI
`
`<0.001
`-1.76
`-3.35,
`-5.21
`17.16
`20
`Azelastine/FP
`<0.001|-1.25
`-1.96, -0.55
`-3.91
`16.84
`0
`
`[FP (20 -1.18)|<0.00116.84 4.54 -2.60,
`
`
`
`0
`17.26
`
`-2.66 p= |po
`
`4004
`
`
`|<0.001_||(3.43,-1.82)|<0.001
`Azelastine/FP
`9
`17.16
`-3.43, -1.82
`.
`17.28
`-4.14
`-2.36, -0.78
`<0.001
`
`[FPti(“(i‘COé‘*”L:#COLQ 17.19 -4.40 -2.64, -1.02 <0.001
`
`
`
`16.84
`-2.57 p=
`po
`
`4006
`
`-2.49,
`5.01
`17.91
`
`
`18.00 -4.31|1.22|1.76,-0.68)|<0.001_|
`
`re 17.82 -4.73|1.64|(-2.19.-1.09)|<0.001_|
`
`448|17.90 3.09 eeeeeee
`
`-1.35)|<0.001_|<0.001
`efficacy endpoint,
`
`The iINSSscores were also usedto characterize the onset of action, defined as the first time
`pointafter initiation of treatment when azelastine/FP demonstrateda statistically significant
`difference from placeboin terms of the reduction in iTNSS whichproved 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 rTOSSfrom baseline over the 14-day treatment period wasassessed as
`
`
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`RQLQ
`The change from baseline in RQLQ overthe 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 threetrials
`and crossed the MCID threshold of >0.05 units; these replicate results are considered adequate
`to support inclusion of RQLQ information in the product label.
`
`Table 5 Results ofchange from baseline in RQLQ over 2 weeks (ITT population, excluding patients with
`missing baseline value
`
`PrevementLS[sirens|MSSten”FSteePoser]PateLS Mean
`
`LS Mean
`
`Cross Discipline Team Leader Review
`-0.72, -0.39)|<0.001
`
`|Azelastine/FP_|176|3.87|-1.64|
`
`|Azelastine|174|3.80|136|0.29 (0.54,-0.03)|0.029|
`
`[FPO C“‘L:«SCS4#COT3.76|3-001 (-0.36,0.23)|0.907__|
`
`|Placebo|169|3.87|0.85|-0.80_ (1.05.-0.55)|<0.001|
`4004
`|Azelastine/FP_|176|3.76|1.68|
`
`|Azelastine|172,|3.83|140-028 (0.53.-0.03)|0.031__|
`
`[FPO C“‘L:C‘CMS|3-78-4020 (-0.46.0.05)|0.123
`
`4006
`|Azelastine/FP_|381|3.87|-159|
`
`
`
`|FpoCT384|387|SS -0.04|(0.20. 0.12 0.629
`
`Summary ofefficacy
`The application contains adequate data to support the efficacy of azelastine/FP for the
`treatment of symptoms of seasonalallergic rhinitis in patients 12 years and older. The three
`keytrials (4002, 4004, and 4006) demonstratedstatistically 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 similar between the
`efficacy trials and the safety trial, the clinical review concluded that the results of 4000 were
`relevant to a US population. Furthermore, local toxicity is the primary AE of interest for this
`class of drug products and is not expected to vary substantially among different ethnic/racial
`groups. Overall, the size of the safety database and the safety parameters are considered
`adequate for characterizing the safety of azelastine/FP.
`
`Deaths, SAEs, and discontinuations due to AEs
`There were no deaths in the clinical program. A total of 5 SAEs were reported among patients
`who received azelastine/FP, and these events did not