CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205103Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`NDA: 205103
`Submission Date(s): 03/14/2016, 5/2/2016, 7/20/2016
`Submission Type; Code
`Resubmission
`Brand Name
`Yosprala
`Aspirin Delayed Release/Omeprazole Immediate Release
`Generic Name
`Reviewer
`Dilara Jappar, Ph.D.
`Team Leader
`Sue-Chih Lee, Ph.D.
`OCP Division
`Division of Clinical Pharmacology 3
`Division of Gastroenterology and Inborn Errors Products
`(DGIEP)
`POZEN, Inc
`Tablet, 81 mg or 325 mg Aspirin/40 mg Omeprazole
`Use in the secondary prevention of cardiovascular and
`cerebrovascular events in patients at risk of developing
`aspirin-associated gastric ulcers
`Proposed Dosing Regimen Once Daily tablet
`09/14/2016
`PDUFA Goal Date:
`
`OND Division
`
`Sponsor
`Formulation; Strength(s)
`
`Proposed Indication
`
`Table of Contents
`
`Table of Contents...........................................................................................................................................1
`1
`Executive Summary...............................................................................................................................2
`1.1
`Recommendation.............................................................................................................................2
`1.2
`Summary of Clinical Pharmacology and Biopharmaceutics Findings............................................2
`2
`Question Based Review .........................................................................................................................3
`2.1
`What are the differences in aspirin API from the two suppliers?....................................................3
`2.2
`Is the aspirin (acetylsalicylic acid) component of Yosprala from the two suppliers bioequivalent
`at the proposed dosages?................................................................................................................................5
`2.3
`What is the relative bioavailability of omeprazole in PA8140 compared to reference product
`Prilosec? .......................................................................................................................................................10
`3
`Appendix..............................................................................................................................................12
`3.1
`Individual reviews .........................................................................................................................12
`
`Reference ID: 3971976
`
`1
`
`

`

`1 Executive Summary
`
`This is a 505(b)(2) application for Yosprala (Delayed Release Aspirin/Immediate Release
`
`omeprazole) tablets referencing Ecotrin® (EC-Aspirin) and Prilosec® (EC-Omeprazole). The
`
`proposed product is an oral fixed dose combination product containing 81 mg or 325 mg aspirin
`
`in the inner enteric coated core (delayed release) smrounded by 40 mg omeprazole in the
`
`immediate—release film coat to release the active ingredients in a sequential fashion.
`
`The original application was submitted on 03/25/2013. A full clinical pharmacology review was
`
`conducted during the lSt review cycle and application was acceptable from clinical pharmacology
`
`perspective.
`
`Please see Clinical Pharmacology review dated 04/18/2014. However,
`
`this
`
`application was issued a Complete Response (CR) action letter on 04/25/2014 due to facility
`inspection deficiencies at
`(m4) manufacturing facility, which was a supplier to
`aspirin drug substance used to manufacture Yosprala tablets. There were no deficiencies from
`
`clinical pharmacology perspective.
`
`The sponsor submitted a response to the Complete Response action letter (resubmission) on June
`
`30, 2014. There was no new clinical pharmacology study in that submission. Please see clinical
`
`pharmacology review dated 11/24/2014. That submission was issued another Complete
`
`Response (CR) action letter on 12/16/2014 due to facility inspection deficiencies at aspirin
`substance supplier
`(our manufacturing facility again.
`
`In this 3‘‘1 submission, the sponsor submitted another response to Complete Response action
`letter
`(resubmission) on March 14, 2016.
`In this submission,
`in order to address its
`manufacturing facility deficiency,
`the sponsor had changed the supplier for aspirin
`(m4)
`component from the previous supplier
`6"(4) to a new supplier
`(5x4)
`(also referred to as
`«0(0)
`«0(4) The omeprazole for Yosprala
`Tablets and the manufacturing process for Yosprala Tablets remain completely unchanged. To
`support these changesin aspirin supplier, in addition to in—vitro testing, the sponsor submitted
`two relative BA/BE study comparing the aspirin components of PA32540 and PA8140 (hm
`(hm)
`
`1.1 Recommendation
`
`The application is acceptable from the clinical pharmacology perspective provided that a mutual
`
`agreement is reached on the labeling languages.
`
`1.2
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`Aspirin Supplier Comparison:
`
`In this submission, the sponsor changed API aspirin supplier source from
`M” (also referred to as
`aw)
`
`(5X4) t0
`
`). In addition, aspirin
`
`Reference ID: 3971976
`
`

`

`from this new supplier
`
`00(4)
`
`m A
`
`W" was
`spirin components of PA8140 and PA32540 from the new supplier
`bioequivalent to that of previous supplier
`M0 based on two separate BE studies (PA8140-
`104 and PA32540-119) that had used partial reference-replicate3-way study design with a
`reference—scaled average BE approach.
`
`081 inspection:
`
`An inspection for bioequivalence (BE) studies PA8140-104 and PA32540—1 19 for both clinical
`
`site and bioanalytical site was requested on 06/21/2016. However, the Division of New Drug
`
`Bioequivalence Evaluation (DNDBE) within the Office of Study Integrity and Surveillance
`(OSIS) recommends accepting data without an on-site inspection
`am) as 0818
`
`recently inspected these sites and the inspectional outcome from the inspections was classified as
`
`No Action Indicated (NAI).
`
`Relative BA of omeprazole component of PA8 140 vs Prilosec :
`
`Based on bridged cross-study comparisons, the plasma exposure of IR omeprazole 40 mg from
`
`PA8140 was lower than that of Prilosec 40 mg, Prilosec®. Cmax and AUC of IR omeprazole 40
`
`mg from PA8140 were estimated to be 90% and 75%, respectively, of that from an EC
`
`formulation omeprazole 40 mg, Prilosec 40 mg following a repeat dose administration for 7
`
`days.
`
`2 Question Based Review
`
`2.1 What are the differences in aspirin API from the two suppliers?
`
`@(4)
`
`to
`In this submission, the sponsor changed API aspirin supplier source from
`@(4) (also referred to as
`M"). In addition, aspirin
`(m4)
`
`from this new supplier
`
`Table I: Comparison ofASA
`(m4) (New Source)
`
`(hm) Sourced From
`
`om) (Current Source) and 8
`
`0:) (4)
`
`Table 2: Comparison of PA8140 Aspirin Core Tablet Formulation
`
`| Components
`
`I
`
`Quantity per unit (mg/tablet)
`
`l
`
`(um
`
`I
`
`Reference ID: 3971976
`
`

`

`9
`Table 3: Com arison o PA32540 As irin Core Tablet Formulation—
`
`
`
`Reference ID: 3971976
`
`

`

`2.2
`
`Is the aspirin (acetylsalicylic acid) component of Yosprala from the two suppliers
`bioequivalent at the proposed dosages?
`(m4) was
`Yes, aspirin components of PA8140 and PA32540 from the new supplier
`bioequivalent to that ofprevious supplier
`(but) based on two separate BE studies (PA8140-
`104 and PA32540—119) that had used partial reference-replicate3-wa_v studv design with a
`reference-scaled average BE approach.
`
`Bioeguivalence for Aspirin component for PA8140:
`
`Study PA8140-104 compared relative bioavailability of aspirin component of Yosprala tablets
`PA8140 produced from
`on» aspirin. This study was designed as an open—
`label, randomized, single—center, single-dose, 3-way crossover study in 36 healthy adult subjects
`comparing two aspirin formulations
`(m4) of PA8140 using the partial
`reference replicated 3-way design. Each subject was to receive the reference product (Treatment
`B), 3 tablets of PA8140 (dosed concurrently) as Formulation l
`(be) twice, and the test
`product (Treatment A), three tablets (dose concrurently) of PA8140 one as Formulation 2, once
`in a randomized crossover fashion over 3 treatment periods based on the treatment sequence of
`BBA, BAB, or ABB. The study drugs were administered following an overnight fasting of at
`least 10 hours prior to dosing. Subjects received a standardized breakfast an hour after the
`dosing. The study drug was to be swallowed as whole and was not to be broken, crushed, or
`chewed. There was at least a 4— day of washout period between the treatments. PK blood samples
`were collected for up to 8.5 hours in each treatment period to determine the plasma
`concentrations of acetylsalicylic acid.
`
`Figure I: Mean Plasma Acetylsalicjvlic Acid Concentration vs. Time Curves (Treatment A and
`Average of Treatments BI and B2)
`
`1000
`
`800
`
`+11
`-E+ Bavg
`
`MeanAcetylsallcyllcAcid
`
`Concentration
`
`(ng/mL)
`
`600
`
`400
`
`200
`
`A=Test product: three tablets (dosed concurrently) of PA814C 0’)(4) (Formulation 2). Bflg=average concentration of Treatment Bl
`(first occurrence) and Treatment Bl (second occurrence) for subjects who had completed both BI and B2. reference product of
`PA8140
`W0.
`
`Time (h)
`
`Table 4: Summarv ofAcetylsalicvlic Acid Pharmacolrinetic Parameters
`
`Treatment
`
`Statistics
`
`n
`
`Cm
`
`11 mL
`
`31
`
`tm"
`
`hr
`
`31
`
`5
`
`Reference ID: 3971976
`
`tug"
`
`1'
`
`31
`
`AUCM
`
`AUCO—inf
`
`r*n mL
`
`r*n mL
`
`31
`
`31
`
`t‘/z
`
`1'
`
`31
`
`

`

`A
`
`PA8140 9""
`
`Bl
`
`PA8140
`
`First Dose
`
`Mean“
`
`%CV
`GeoMean
`
`Min
`
`Max
`
`n
`
`Mean*
`
`%CV
`
`2377.00
`
`54
`2079.91
`
`647
`
`5400
`
`32
`
`2185.59
`
`41
`
`GeoMean
`
`2023.50
`
`3.05
`
`43
`3.25
`
`1.75
`
`6.50
`
`32
`
`4.00
`
`43
`
`3.55
`
`1.57
`
`60
`ND
`
`0.00
`
`5.25
`
`32
`
`1.88
`
`57
`
`2.37
`
`2551.22
`
`38
`2346.99
`
`592.14
`
`4777.49
`
`32
`
`2572.60
`
`38
`2373.37
`
`615.69
`
`4789.75
`
`30
`
`2491.13
`
`2564.43
`
`36
`
`36
`
`2327.49
`
`2399.79
`
`0.40
`
`30
`0.38
`
`0.27
`
`0.79
`
`30
`
`0.39
`
`15
`
`0.38
`
`Min
`929
`1.75
`1.25
`735.44
`747.74
`0.29
`
`Max
`4590
`7.00
`6.50
`4963.52
`4987.27
`0.54
`
`B2
`
`n
`
`Mean*
`
`34
`
`2095.65
`
`34
`
`3.29
`
`34
`
`2.25
`
`34
`
`33
`
`2488.95
`
`2469.96
`
`33
`
`32
`
`33
`
`0.37
`
`15
`
`PA8140
`
`%CV
`
`42
`
`Second Dose
`
`GeoMean
`
`1922.50
`
`Average of
`BI and B2
`
`Min
`
`Max
`
`n
`
`Mean“
`%CV
`
`GeoMean
`
`Min
`
`Max
`
`863
`
`3990
`
`31
`
`2067.88
`36
`
`1955.02
`
`1045.79
`
`4148.80
`
`44
`
`3.50
`
`1.50
`
`7.53
`
`31
`
`3.74
`38
`
`3.47
`
`1.73
`
`7.26
`
`56
`
`2.29
`
`0.50
`
`6.50
`
`31
`
`2.29
`50
`
`2.28
`
`0.79
`
`6.50
`
`2335.90
`
`790.43
`
`4080.23
`
`31
`
`2450.29
`33
`
`2314.21
`
`770.36
`
`4413.32
`
`2327.10
`
`805.21
`
`4095.16
`
`28
`
`2459.87
`30
`
`2342.37
`
`770.36
`
`4413.32
`
`0.37
`
`0.29
`
`0.55
`
`28
`
`0.38
`11
`
`0.37
`
`0.31
`
`0.46
`
`GeoMean = geometric mean. *: Median for tmax.and tlag.. na = not applicable
`
`The Swr (intra-subject variability) value for Cmax of acetylsalicylic acid for the reference
`
`treatment (Treatment B) was determined using the Referenced-Scaled Average Bioequivalence
`
`(RSABE) evaluable population (N=28), who had adequate blood sampling to assess the PK
`
`parameters for acetylsalicylic acid for both Cmax and AUC values for all three periods. The Swr
`
`value for Cmax was 0.384, indicating a “highly variable” drug product for this parameter.
`
`Therefore, reference-scaled average bioequivalence (RSABE) approach was used for comparison
`
`of acetylsalicylic acid Cmax.
`
`The Swr values for AUCO-t and AUCO-inf of acetylsalicylic acid for the reference treatment
`
`(Treatment B) were determined in 31 subjects and 28 subjects, respectively, using the BE
`
`evaluable population and whose both periods of Treatment B were measurable. The Swr values
`
`for AUCO-t and AUCO-inf were below 0.294, (0.261 and 0.270, respectively). Therefore,
`
`average bioequivalence approach was used for comparison of AUCO—t and AUCO—inf of
`
`acetylsalicylic acid.
`
`Table 5: Summary ofStatistical Analysis Results ofAcetvlsaliquic Acid PK Parameters:
`— Referenced Sealed Average Bioequivalence (RSABE)
`
`Reference ID: 3971976
`
`

`

`C...x (N=28)
`
`swr [>=0.294]
`
`Point Estimate [0.80, 1.25]
`
`USE RSABE: Criteria Met
`
`0.384
`
`1.0292
`
`Critical Bound
`
`l<=01
`-0.0650
`
`
`
`AUCo.t (N=35)
`
`5... [<0.294]
`
`Ratio (%)
`
`90% CI Lower
`
`90% CI Upper
`
`USE UNSCALED ABE: s... < 0.294
`
`0.261
`
`99.75
`
`90.59
`
`109.84
`
`— A.....B,
`90% CI Upper
`AUCO.in1(N=35)
`Sm- [<0.294]
`Ratio (%)
`90% CI Lower
`
`USE UNSCALED ABE: S." < 0.294
`0.270
`99.44
`90.32
`109.49
`
`Reviewer’s Comment:
`
`0
`
`Ihe within-subject standard deviation (Swr) of acetylsalicvlic acid PK parameters from the
`reference product, PA8140, was estimated to be:
`0 0.384 (38.4%) for Cmax, appropriate for reference-scaled average bioequivalence
`approach,
`0 0.261 (26.1%) for AUCO—t and 0.270 (27.0%) for AUCO—inf appropriate for average
`bioequivalence approach notfor (RSABE).
`The reference-scaled average bioequivalence assessment showed that the point
`o Cmax:
`estimate of the geometric least squares mean ratios, PA8146 01(4) vs. PA8140, for Cmax of
`acetylsalicvlic acid were within the interval of 0.80-1.25. In addition,
`the upper bound
`(critical bound) of the 95% confidence intervalfor the diflerence between PA8140 00(4) and
`PA8140 treatments, adjusted for the estimated intrasubject variability of the PA8140
`treatment was less than zero, indicating that PA8140 M" is bioequivalent to PA8140 in
`terms ofCmar ofacetvlsalicvlic acid
`0 AUC. Ihe average bioequivalence assessment showed that the 90% confidence interval for
`the geometric least squares mean ratios, PA8146 00(4) vs. PA8140, for AUCO-t and AUCO—inf
`of acetvlsalzcvhc acid were within the bioequivalence interval of 80%—I25% indicating that
`PA8146 M0 is bioequivalent to PA8140 in terms ofA UC ofacetvlsalzcvhc acid.
`0 Overall, PA8140— M" is bioequivalent to PA8140 in terms of Cmax, AUCO-t and AUCO-inf
`ofacetylsalicvlic acid.
`
`Bioeguivalence for Aspirin component for PA32540:
`
`Study PA32540— 119 compared relative bioavailability of aspirin component of Yosprala tablets
`PA32540 produced from
`00(4) aspirin. This study was designed as an open-
`label, randomized, single-center, single-dose, 3-way crossover study in 48 healthy adult subjects
`comparing two aspirin formulations
`W" of PA32540 using the partial
`reference replicated 3-way design. Each subject was to receive the reference product (Treatment
`B), PA32540 as Formulation 1
`(m4), twice, and the test product (Treatment A), PA32540-
`moas Formulation 2, once 111 a randomized crossover fashion over 3 treatment periods based on
`the treatment sequence of BBA, BAB, or ABB. The study drugs were administered following
`an overnight fasting of at least 10 hours prior to dosing and an additional 4 hours of fasting post-
`dose. The study drug was to be swallowed as whole and was not to be broken, crushed, or
`
`Reference ID: 3971976
`
`

`

`chewed. There was at least a 4- day of washout period between the treatments. PK blood samples
`were collected for up to 10 hours in each treatment period to determine the plasma
`concentrations of acetylsalicylic acid.
`
`Figure 2: Mean Plasma Acetylsalicylic Acid Concentration vs. Time Curves (Treatment A and
`Average of Treatments B1 and B2)
`
`A
`PA32540
`
`B1
`PA32540
`First Dose
`
`Table 6: Summary of Acetylsalicylic Acid Pharmacokinetic Parameters
`t½
`AUC0–inf
`Cmax
`tmax*
`tlag*
`AUC0-t
`Treatment
`Statistics
` (ng/mL) (hr) (hr) (hr*ng/mL) (hr*ng/mL) (hr)
`n
`47
`47
`47
`47
`46
`46
`Mean*
`3034.09
`4.33
`2.67
`3323.83
`3380.04
`0.40
`%CV
`54
`32
`29
`44
`43
`24
`GeoMean
`2446.94
`4.22
`2.48
`2945.69
`3011.98
`0.39
`Min
`227
`2.00
`1.50
`467.07
`497.72
`0.29
` Max 6540 9.50 4.33 7529.72 7542.91 0.88
`n
`48
`48
`48
`48
`46
`46
`Mean*
`2645.63
`4.33
`2.52
`2973.79
`3059.22
`0.46
`%CV
`60
`35
`44
`48
`45
`54
`GeoMean
`1991.25
`4.35
`ND
`2433.41
`2633.54
`0.42
`Min
`121
`2.33
`0.00
`88.05
`378.15
`0.28
` Max 5780 10.00 8.00 5697.51 5709.12 1.80
`n
`48
`48
`48
`48
`47
`47
`Mean*
`2631.44
`4.40
`2.68
`3078.07
`3122.77
`0.44
`%CV
`50
`33
`35
`45
`45
`34
`GeoMean
`2237.64
`4.53
`2.55
`2688.55
`2732.46
`0.42
`Min
`548
`2.00
`0.75
`596.88
`607.34
`0.27
` Max 5760 10.05 4.33 6089.81 6107.11 1.22
`n
`48
`48
`48
`48
`45
`45
`Mean*
`2479.22
`4.46
`2.66
`2903.62
`3019.53
`0.43
`
`B2
`PA32540
`Second Dose
`
`Average of
`
`Reference ID: 3971976
`
`8
`
`(b) (4)
`
`

`

`B1 and B2
`
`28
`42
`45
`35
`26
`51
`%CV
`0.42
`2729.01
`2557.80
`ND
`4.44
`2110.85
`GeoMean
`0.28
`736.59
`353.94
`0.00
`2.33
`438.62
`Min
` Max 5125 7.32 5.66 5708.72 5722.88 0.87
`
`The Swr values for Cmax and AUC0-t of acetylsalicylic acid for the reference treatment
`(Treatment B) were determined using the 47 subjects who had adequate plasma concentrations to
`assess the PK parameters for acetylsalicylic acid for both Cmax and AUC0-t values for all three
`periods (RSABE1 evaluable population). The Swr value for AUC0-inf of acetylsalicylic acid for
`the reference treatment (Treatment B) was determined in 43 subjects who had adequate plasma
`concentrations to assess the PK parameters for acetylsalicylic acid for AUC0-inf values for all
`three periods (RSABE2 evaluable population).
`Intrasubject standard deviation (Swr) values for Cmax, AUC0-t and AUC0-inf of acetylsalicylic acid
`for the Reference treatment (Treatment B) were greater than 0.294, indicating that EC-Aspirin
`PK parameters qualify for the reference-scaled average BE approach to establish bioequivalence
`of AUCs and Cmax between two formulations.
`
`Table 7: Summary of Statistical Analysis Results of Acetylsalicylic Acid PK Parameters:
`Referenced Scaled Average Bioequivalence (RSABE)
`Critical Bound [<=0]
`Swr [>=0.294]
`Point Estimate [0.80, 1.25]
`-0.2055
`0.677
`1.1760
`Cmax (N=47)
`-0.1386
`0.588
`1.1669
`AUC0-t (N=47)
`-0.0785
`0.475
`1.1675
`AUC0–inf (N=43)
`Swr: within-subject standard deviation of the PK parameter from the Reference product.
`
`Reviewer’s Comment:
` The within-subject standard deviation of acetylsalicylic acid pharmacokinetic parameters
`from the reference product PA32540 was estimated to be 0.677 for Cmax and 0.588 for
`AUCt and 0.475 for AUC0-inf, which are all greater than 0.294, confirming that EC-aspirin
`formulations are considered to be highly variable drug products and EC-Aspirin PK
`parameters qualify
`for
`the reference-scaled average BE procedure
`to establish
`bioequivalence of AUCs and Cmax between two formulations.
` The reference-scaled average bioequivalence assessment showed that the point estimates of
`the geometric least squares mean ratios, PA32540
` vs. PA32540, for all bioavailability
`parameters of acetylsalicylic acid were within the interval of 0.80-1.25. In addition, the
`upper bound (critical bound) of the 95% confidence interval for the difference between
`PA32540
` and PA32540 treatments (adjusted for the estimated intrasubject variability of
`PA32540) was less than zero.
` is bioequivalent to PA32540 in terms of Cmax, AUC0-t and AUC0-inf of
` PA32540
`acetylsalicylic acid based on the reference-scaled average bioequivalence approach for
`highly variable drug products.
`
`Reference ID: 3971976
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`2.3 What is the relative bioavailability of omeprazole in PA8140 compared to reference
`product Prilosec?
`Based on cross-study comparison, Cmax and AUC of IR omeprazole 40 mg from PA8140
`following repeat dose administration for 7 days were 90% and 75%, respectively, of that from an
`EC formulation of omeprazole 40 mg from Prilosec 40 mg.
`
`In all submission for NDA 205103 thus far, the exposure of omeprazole from PA8140 has not
`been directly compared with Prilosec 40 mg. The sponsor had compared the exposure of
`omeprazole from PA32540 with Prilosec 40 mg in study PA32540-112 on Day 1, 5 and 7 (also
`in study PA32540-113 only on Day 1) and compared the exposure of omeprazole from PA32540
`to that of PA8140 in study PA8140-103 on Day 7 only. Please refer to clinical pharmacology
`review d Clinical Pharmacology review dated 04/18/2014 for further details on this omeprazole
`exposure comparison.
`
`Table 8: Cross-study Comparison of Omeprazole Exposure from PA8140, PA32540 and Prilosec
`40 mg on Day 7
`
`AUC0-24
`(hr*ng/mL)
`30
`3063
`101
`1920
`30
`2288
`91
`1513
`26
`2187
`88
`1446
`26
`2985
`59
`2558
`
`Source
`(study #)
`
`PA8140-103
`
`PA8140-103
`
`PA32540-112
`
`PA32540-112
`
`Cmax
`(ng/mL)
`30
`1488
`71
`1094
`30
`1385
`73
`1051
`26
`1196
`71
`903
`26
`1345
`44
`1218
`
`Statistics
`
`NM
`
`ean
`%CV
`GeoMean
`
`NM
`
`ean
`%CV
`GeoMean
`
`nM
`
`ean
`%CV
`GeoMean
`
`nM
`
`ean
`%CV
`GeoMean
`
`Treatment
`
`PA8140
`
`PA32540
`
`PA32540
`
`Prilosec 40 mg +
`Ecotrin 325 mg
`
`With this available cross-study data, the agency requested the sponsor to approximate the
`geometric mean ratio and its associated confidence interval comparing Cmax and AUC of
`omeprazole from PA8140 to Prilosec 40. The requested analysis compared omeprazole
`exposure from one tablet of PA8140 administered once daily for 7 consecutive days on Day 7 in
`study PA8140-103 to one tablet of EC-ASA (Ecotrin®) 325 mg and one capsule EC omeprazole
`(Prilosec®) 40 mg administered once daily for 7 consecutive days on Day 7 in study PA32540-
`112 utilizing cross-study data. Please note that the PK studies used in this cross-study
`
`Reference ID: 3971976
`
`10
`
`

`

`comparison of exposure of omeprazole were conducted by same sponsor with similar
`bioanalytical method at the same bioanalytical site
`
`The relative bioavailability of omeprazole from PA8140 to Prilosec® was estimated by
`performing a parametric analysis of variance (ANOVA) using a mixed-effects model based on
`natural log transformed PK parameters for plasma omeprazole (Cmax, AUC0-t and AUC0-24). The
`mixed-effects model included a fixed effect for treatment and a random effect of subject-within-
`treatment. A 90% confidence interval (CI) around the geometric least-squares mean ratio of Cmax,
`AUC0-t and AUC0-24 was calculated for each pairwise comparison (test vs. reference) as
`summarized in Table 2 below. Statistical Team leader Dr. Yeh-Fong Chen stated that the
`statistical approach was reasonable.
`
`Parameter
`
`Table 9: Geometric Mean Ratios and 90% Confidence Intervals for Cmax, AUC0-t, and AUC0-24 of
`Omeprazole from PA8140 to Prilosec® on Day 7 based on Bridged Cross-Study Comparisons
`PA81401 vs Prilosec 40 mg2 on Day 7
`GLSM Ratio % (90% Confidence Interval)
`89.76 (64.79-124.36)
`74.97 (50.92-110.36)
`75.05 (51.00-110.44)
`
`Cmax (ng/mL)
`AUC0-t (hr*ng/mL)
`AUC0-24 (hr*ng/mL)
`GLSM = geometric least-squares mean.
`1: PA8140 is from study PA8140-103 Treatment A: One tablet of PA8140 (delayed-release aspirin 81 mg and
`immediate release omeprazole 40 mg) administered once daily for 7 consecutive days.
`2: Prilosec 40 mg is from study PA32540-112 Treatment B: One tablet of EC-ASA (Ecotrin®) 325 mg and one
`capsule EC omeprazole (Prilosec®) 40 mg administered once daily for 7 consecutive days.
`
`Reviewer’s Comment:
` Based on bridged cross-study comparisons, the plasma exposure of IR omeprazole 40 mg
`from PA8140 was lower than that of Prilosec 40 mg, Prilosec®. Cmax and AUC of IR
`omeprazole 40 mg from PA8140 were 90% and 75%, respectively, of that from an EC
`formulation of omeprazole 40 mg, Prilosec 40 mg following repeat dose administration for 7
`days.
` Based on result of study PA32540-112 with direct head-to-head comparison, Cmax and AUC
`of IR omeprazole 40 mg from PA32540 were 74% and 57%, respectively, of that from an EC
`formulation of omeprazole 40 mg, Prilosec 40 mg following repeat dose administration for 7
`days.
` Based on result of study PA8140-103 with direct head-to-head comparison, omeprazole
`exposure (AUC) from PA8140 was 27% higher than that of PA32540 where the Cmax was
`very similar between PA8140 and PA32540 following repeat dose administration for 7 days.
`
`Reference ID: 3971976
`
`11
`
`(b) (4)
`
`

`

`3 Appendix
`
`3.1
`
`Individual reviews
`
`3.1.1
`
`Study PA32540-119
`
`TITLE:
`
`A Single-Dose Randomized Crossover Study to Assess the Intrasubject Variability
`of Acetylsalicylic Acid from Administration of PA32540 and to Evaluate the
`Relative Bioavailability of Two Formulations of PA32540 with the Partial
`Reference-Replicated 3-Way Design and
`the Reference-Scaled Average
`Bioequivalence Approach
`
`STUDY SITE:
`Sponsor:
`Clinical Site:
`Analytical Site:
`Study Data:
`
`POZEN Inc. Chapel Hill, NC
`PPD, Phase I Clinic, Austin, Texas 78744
`
`1/28/2016 through 2/17/2016
`
`PHASE OF STUDY: Phase 1 study
`
`OBJECTIVE:
`Primary: The primary objective was to assess the intrasubject variability of acetylsalicylic acid following
`repeated single-dose administration of PA32540 as Formulation 1 and evaluate
`the relative
`bioavailability/bioequivalence of two PA32540 formulations (Formulation 1 and Formulation 2) with the
`partial reference replicated 3-way design and the reference-scaled average bioequivalence approach.
`Secondary: To evaluate the safety of each of the treatments.
`
`Background:
`The current study was performed to determine the relative bioavailability of ASA from two formulations
`of PA32540. The formulations differed
`
`
`STUDY DESIGN:
` Treatment A (Test product): One (1) tablet of PA32540
` (Formulation 2)
` Treatment B (Reference Product): One (1) tablet of PA32540 (Formulation 1),
`
`This study was an open-label, randomized, single-center, single-dose, 3-way crossover study in 48
`healthy adult subjects (16/treatment sequence) evaluating two PA32540 formulations. There was at least
`a 4-day of washout period between the treatments. Each subject was to receive the reference product
`(Treatment B), PA32540 as Formulation 1, twice, and the test product (Treatment A), PA32540
` as
`Formulation 2, once in a randomized crossover fashion over 3 treatment periods based on the treatment
`sequence of BBA, BAB, or ABB.
`
`Treatment Sequences
`Number of
`Sequence
`Subjects
`
`Treatment
`Period 1
`
`Treatment
`Period 2
`
`Treatment
`Period 3
`
`Reference ID: 3971976
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`I
`II
`III
`
`16
`16
`16
`
`A
`B
`B
`
`B
`A
`B
`
`B
`B
`A
`
`The study drug(s) was administered with 240 mL of water in the morning following an overnight fasting
`of at least 10 hours prior to dosing and an additional 4 hours of fasting post-dose. The tablets were not to
`be broken, crushed or chewed. Subjects received standardized meals at appropriate times during the
`study, which were scheduled at the same time in each treatment period of the study. Pharmacokinetic
`(PK) blood samples were collected for up to 10 hours in each treatment period to determine the plasma
`concentrations of acetylsalicylic acid.
`
`Study Population: The study included healthy males and non-pregnant, non-lactating female ages
`between 18-55 with good health with a BMI between 19-29 kg/m2. This study had 48 healthy volunteers
`enrolled and all of them completed the study as planned by completing all three treatments periods.
`
`Key exclusion criteria:
`Ingestion of any PPIs, H2-receptor antagonists, anticholinergics, over-the-counter anti-ulcer
`
`medications, gastric-altering compounds, ASA or salicylate-containing products, or selective
`serotonin reuptake inhibitors within 14 days prior to the first dose in Treatment Period 1 until after the
`last blood draw in the last Treatment Period.
`Significant history of acid-related GI symptoms, including peptic ulcer disease.
`
` Known allergy, hypersensitivity or intolerance to omeprazole or other PPIs (e.g., lansoprazole).
` Any GI disease, abnormality or gastric surgery that may have interfered with gastric emptying,
`motility, or drug absorption.
` Known allergic reaction, hypersensitivity or intolerance to ASA, and any subject in whom ASA or
`non-aspirin NSAIDs induce the symptoms of asthma, rhinitis and nasal polyps.
`Ingestion of grapefruit or grapefruit juice within the 10 days of dosing or during the study.
`
`
`
`Concomitant Therapy
`The following medications were not permitted within 14 days prior the treatment and throughout the
`study: antibiotics, Pepto Bismol, PPIs or gastroprotective agents, (including H2-receptor antagonists,
`misoprostol-containing preparations, sucralfate, and antacids), ASA or non-aspirin NSAIDs (including
`cyclooxygenase-2 selective and non-selective agents), bisphosphonates, steroids, anticoagulants,
`anticholinergic agents, and selective serotonin reuptake inhibitors.
`
`Pharmacokinetic:
`PK Blood Samples:
`PK blood samples (2mL) were collected in each treatment period at pre-dose and at 0.75, 1.5, 2, 2.33,
`2.67, 3, 3.33, 3.67, 4, 4.33, 4.67, 5, 5.33, 5.67, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, and 10 hours post dose to
`determine the plasma concentration of only acetylsalicylic acid.
`
`PK Analysis:
`Pharmacokinetic parameter estimates for acetylsalicylic acid (ASA) were calculated using Phoenix®
`WinNonlin 6.3 with non-compartmental methods.
`
`Reference ID: 3971976
`
`13
`
`

`

`When calculating summary (descriptive) statistics, plasma concentrations below the LLOQ for
`acetylsalicylic acid (0.02 μg/mL) were treated as a zero value. The mean/median value at a time point
`with one or more concentrations below LLOQ (below quantifiable limit [BQL] value) was reported unless
`the resulting mean/median values was below the LLOQ, in which case the value was assigned as BQL. A
`high proportion of BQL values would affect the SD estimate; thus, if more than 30% of values were
`imputed, SD was not displayed.
`
`For PK analysis, plasma concentrations below the LLOQ in individual profiles of each analyte were
`handled for PK analysis as follows. If the value occurred in a profile during the absorptive phase (i.e.,
`before the maximum concentration in a profile was observed), it was assigned a value of zero. Any one
`BQL values that occurred between measurable concentrations, not in absorptive phase of a profile, was
`excluded from analysis. If two values below the LLOQ occurred in succession post peak time (or during
`the terminal phase), the profile was determined to have terminated at the last time point with measurable
`analyte concentration. Pharmacokinetic parameters were calculated for each analyte using the actual
`sampling times.
`
`Within-Subject Variability and Analysis for Bioequivalence
`The within-subject standard deviation (Swr) of acetylsalicylic acid PK parameters following replicate
`administration of the reference product (PA32540 [Formulation 1]) was estimated for AUCs and Cmax,
`respectively based on the procedures described in the Food and Drug Administration (FDA) Draft
`Guidance for Progesterone Bioequivalence Assessment, February 2011.
`If Swr was < 0.294, BE was to be determined using the conventional analysis of variance (ANOVA)
`
`on the natural logarithmic (ln)- transformed PK parameters,AUC0-t, AUC0-inf and Cmax, followed
`by two one-sided t-tests to assess the relative bioavailability of acetylsalicylic acid between
`treatments. The ANOVA model included sequence, period and treatment as fixed effects, and subject
`within sequence as a random effect.
`The geometric least-squares means ratios between treatments and the associated 90% CIs for AUCs
`and Cmax were to be calculated.
`Treatment A was considered to be bioequivalent to Treatment B when 90% CI was within 0.8-1.25.
`If Swr ≥ 0.294 for ASA PK parameters, the reference-scaled average BE procedure (FDA Draft
`Guidance for Progesterone Bioequivalence Assessment, 2011) was to be used to determine
`bioequivalence of AUCs and Cmax between the test and reference treatment.
`The adjusted point estimates (the point estimate of treatment difference adjusted for the within-
`subject variability of the Treatment B) and the upper bound of the 95% confidence interval for the
`adjusted point estimate were calculated.
`
`
`
`Two conditions were to be met for Treatment A to be considered bioequivalent to Treatment B in a
`highly variable drug product:
`a) The geometric least-squares mean ratio of Treatment A vs. Treatment B was to be within the limits
`of 80 to 125%.
`b) The upper bound of 95% confidence interval for the adjusted point estimate was to be ≤ 0
`
`Sample Size:
`From a previous bioequivalence (BE) study for PA32540 (PA32540-115), the intra-subject variability
`(CV%wr) in PK parameter AUCs and Cmax for acetylsalicylic acid was 37% and 41%, respectively.
`
`Reference ID: 3971976
`
`14
`
`

`

`With the assumption of CV%wr and assuming expected geometric mean ratio of 0.90 for AUCs and
`Cmax, a sample size of 37 completed subjects was estimated to provide at least 80% power to
`demonstrate BE of two PA32540 Formulations using the reference-replicated 3- way design and the
`reference- scaled average bioequivalence approach (Tothfalusi 2011, Karalis 2011). Considering a non-
`evaluable rate of 23%, a total of 48 subjects were randomized in this study.
`
`Bioanalytical Method:
` Method
` Concentrations of acetylsalicylic acid in human plasma wer