Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22—350
`
`.
`.
`Study Summary
`Pregnant SD rats (22/group for main study and 12/dose for TK) were treated with combination of
`saxagliptin/metformin dose of 5/200 and 25/200 mg/kg/d from gestation day (GD) 6 though 15.
`There were no separate arms for saxagliptin or metformin in the study. Saxagliptin was prepared
`in 0.125% Avicel/water (1 ml/kg) while metformin was prepared in water (4 ml/kg) for oral
`gavage delivery. Blood samples for hematology and clinical chemistry and TK were collected
`from the TK group on GD 14-15. The combination saxagliptin/metformin was well tolerated and
`there were no deaths. There were no adverse findings or malformations at 5/200 mg/kg/d of
`saxagliptin/metformin (20x/4x the maximum therapeutic dose of saxagliptin/metformin, based on
`AUC). However, at higher dose of saxagliptin (25/200 mg/kg/d dose of saxagliptin/metformin),
`neural tube defect was observed in 2 fetuses from one litter. Neural tube defect also known as
`craniorachischisis was marked by incomplete closure of the skull and spinal column. * The same
`two fetuses had missing renal papilla(e), mierocaudia (short tail), and one of them had cleft palate.
`The fetal and litter incidence of craniorachischisis was 0.7% and 4.5%, respectively, which
`greatly exceeds historical experience. Two additional fetuses from a second litter showed an
`increased incidence of missing or absent digits of the paws/hindlimbs. The cause of malformation
`in the combination study is not clear since both drugs were not teratogenic in embryofetal
`development studies in rats and rabbits. Since malformations were seen when the dose of
`saxagliptin was raised from 5 to 25 mg/kg/d with no change in metformin dose, the data implicate
`saxagliptin as the potential cause of malformations, possibly via a pharmacodynamic interaction
`with metformin. However, the sponsor believes that malformations were due to metformin since
`at least in one publication, 500 mg/kg/d of metformin produced an incidence of neural tube defect
`(craniorachischisis) in pregnant rats (GD 1 to 12). The author of the paper had considered
`metformin not to be strongly teratogenic. The sponsor also stated that metformin treated patients
`have been shown to have low circulating levels of folate and Vit B12, two cofactors needed for
`synthesis of methionine. Since methionine is essential for normal fetal development, the
`malformations in the combination study were likely due to metformin and not saxagliptin.
`Spontaneous incidence of craniorachischisis is very rare. According to the sponsor the historical
`control data collected from 2005 to 2007 found only one incidence of craniorachischisis. This low
`historical background further highlights the need for repeating the study in rats as well as a new
`study in rabbits. The study should include separate arms for saxagliptin and metformin in
`addition to the combination. The sponsor has agreed to do the studies but the results of the two
`studies are likely to become available post approval (late 2009).
`
`240
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22—350
`
`Historical control Data from C 7
`
`/
`
`C
`
`HISTORICAL CONTROL DATA
`RAT - CD® lGS (Crl:CD[SD]), 1996-2007
`
`ALL ROUTES or ADlVlleb IRA‘HUN
`
`EMBRYO—FETAL DEVELOPMENT STUDIES
`FETAL FJNDINGS - SUMMARY DATA
`
`M4)
`
`Parameter
`
`Minimum
`
`Maximum.
`
`GESTATION DAY 20
`
`Fetal Weight (G) _ Total
`GESTATION DAY 21
`Fetal Weight (G) — Males
`Fetal Weight (G) - Females
`Fetal Weight (G) - Total
`COMBINATION OF GESTATION DAY 20 AND 21
`Major Malformations - Litters Affected (%)
`Major Malformations - Fetuses Affected (%)
`Minor External and Visceral Anomalies — Liners Affected (%)
`Minor External and Visceral Anomalies - Feruses Affected (%)
`GESTATION DAY 20
`
`Minor Skeletal Anomalies - Litters Affected (%)
`Minor Skeletal Anomalies — Fetuses Affected (%)
`Vertebral Centmrn Variants - Fetuses Affect-ed (%)
`Stemebral Variants l to 4 - Fetuses Affected (%)
`Sternebral Variants 5 and 6 - Fetuses Affected (%)
`GESTATION DAY 21
`Minor Skeletal Anomalies - Litters Affected (%)
`Minor Skeletal Anomalies - Fctuscs Affected (%)
`Vertebral Centrum Variants (unosSified, incomplete ossification,
`bipartite, semi-bipartite) - Fetuscs Affected (%)
`Stemebral Variants l to 4 (unossified, incomplete ossification,
`bipartite, semi-bipartite) - Fetuses Affected (%)
`Stemebral Variants 5 and 6 (unossified, incomplete ossification,
`bipartite, semi—bipartite) - Fetuses Affected (%)
`
`241
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`HISTORICAL C01 'TROL DATA
`RAT - CD® 1G5 (Crl:CDlSDll. 1996-2007
`ALL ROUTES OF ADMINISTRATION
`
`b(4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE 0F FETAL EXTERNAL, VISCERAL AND SKELETAL i-TNDINGS
`MAJOR MALFORMA'HONS AND MINOR ANOMALIES
`
`I
`
`EXTERNAL (EXT)
`VISCERAL (VIS)
`SKELETAL (31(5)
`TECHNIQUE OF WILSON (WT)
`
`Liners examined
`
`1814
`1813
`1812
`1812
`
`Total no. of studies used
`82
`
`MAJOR MALFORMATIONS OTAL)
`
`SUM
`37
`
`AVERAGE %
`2.09
`
`MIN %
`0.00
`
`MAX %
`13.64
`
`H—quu—aw
`
`~
`
`Cranium: Auditory/vestibular system; absent (WT)
`Cranium: Auditory/vestibular system; reduced!"
`incomplete formation (WT)
`Cranium: Cleft palate/lip (EXT,WT)
`Cranium: Microfia (EXT)
`Cranium: Microcephaly (£XT,WT)
`Cranium: Exencephaly (EXT,SKE)
`Brain: Hydrocephaly (EXT,V\«'T)
`Brain: Cerebrum, cyst-like formation (WT)
`Brain: Lateral ventricles reduced (WT)
`Eyc(s): Anophthalmia (EXT,WT)
`Eyc(s): Exophthalmia (EXT.WT)
`Eyc(s): Microphthalmia (WT)
`Eyc(s): Open (EXT,WT)
`Eye(s): Retinal folding (WT)
`Eye(s): Aphakia (WT)
`Face: Aglossia (EXIM‘T)
`Pace: Agnathia (EXT,WT)
`Face: Astomia (EXT, WT)
`Face: Micrognathia (EXT,WT)
`Face: Mandibular micrognalhia (EXT)
`Face: Microstomia (EXT,\«\'T)
`Face: Nares; reduced (EXT,WT)
`Face: Nares opening; reduced (WT)
`Face: Nasal sepmm/mrbinate formation;
`reduced (WT)
`Face: Nasal septum; 1ack of turbinate
`formation (WT)
`Face: Palate; absent (WT)
`Face: Split tongue (WT)
`Face: Upper jaw absent (EXT)
`Face: Nares absent (EXT)
`Face: Probosis (EXT,WT)
`Heart: interventricular septal defect (V15)
`Heart: Dilatation ofascending aorta (V18)
`Heart: Right descending aorta (V15)
`
`-HHMHMVIW~NHN~O—_4§~NHWId
`
`_.
`
`242
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`HISTORICAL CONTROL DATA
`
`<
`
`n .n- nm Inc IP—l.l‘l\lcnl\ IM‘ annu
`ALLROUTES orADMINISTRATION
`EMBRYO—FETAL DEVEIDPME'NT STUDlES
`GROUP INCIDENCE 0F FETAL EXTERNAL. VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`Liners affected
`
`.- VERAGE %
`MIN %
`MAJOR MALFORMATIONS CONT'D)
`SUM
`
`.
`
`b(4)
`
`MAX %
`
`Heart: Stenosis ofascending aorta (V15)
`Heart: Transposition ofmajor vessels (V15)
`Hem: Globular hean (V15)
`Heart: Ringed aorta (V15)
`Diaphragm: Diaphragmau’c hernia (V15)
`Lungs and thymus: Lung lobes; absent (V18)
`Lungs and thymus: Lung lobes: reduced (V15)
`Vertebral column: Multiple fusion and anomalies
`in vertebral column (SKE)
`Thorax: Trunk shortened (EXT)
`Abdomen: Anal atresia (EXT,VIS)
`Abdomen: Gastroschisis (EXT)
`Abdomen: Situs inversus (V13)
`Abdomen: Omphalocele (EXT)
`Abdomen: Urogenital region fissurc (EXT)
`Abdomen: Abdominal muscles herniated (EXT)
`Abdominal cavity: Colon blind (V15)
`Abdominal cavity: Malposition stomachi
`pancreas/spleen (V15)
`Abdominal cavity: Intestine; stcnosis (V15)
`Tail: Acaudia (EXT)
`Tail: Microcaudia (EXT)
`Limb(s); Ecrrodaeryly (EXT)
`Limb(s): Bmchydactyly (EXT)
`Limb(s): Abnormal flexure of hindlimb(s) (EXT)
`Limb(s): Hindpaw(s) absent (SKE)
`Skull: Mandible shortened (SKIS)
`Skull: Maxilla shortened/Incisive bone (SKE)
`Gross exam: Anasarca (EXT)
`General: Sims inversus (V15)
`
`‘
`
`MINOR VlSCERAL- AND EXTERNAL
`ANOMALIES OTAL
`Cranium: Pinna(e); displaced (EXT)
`Cranium: Subcutaneous hemaroma (WT)
`Cranium: Cutis aplasia (EXT,WT)
`Cranium: Cyst-like formation subcutaneously (WT)
`
`i
`
`
`l
`1
`i
`
`i
`
`Cranium: Moderate dilatation ofthe third ventricle (WT)
`Cranium: Moderate dilatation ofthe lateral ventricles (WT)
`Eye(s): Masks) oval (WT)
`Eyc(s): Hematoma adjacent To eye(s) (WT)
`Face: Protruding tongue (EXT)
`Nasal septum: Reduction in turbinate formation (WT)
`Heart: lnnominate artery absent (V13)
`Heart: lunominate anery reduced (V15)
`Heart: lmiominate anery malpositioued (V15)
`Liver: Discolomtion pale (V15)
`Liver: Supemumery lobes (V15)
`Liver: Vestigial lobe (V15)
`Spleen: Small (V15)
`Kidneym: Reduction ofrenal papillae) (V15)
`Kidney(s): Reduced (V15)
`Ureter(s): Dilation (V18)
`Ureter(s): Megaureter (V15)
`Adrenal glaud(s): Hemorrhage (V15)
`Testes: Malpositioned (V15)
`Skin: Pale (EXT)
`Tail: Kinked (EXT)
`General: Subcutaneous hematoma (EXT)
`
`1
`4
`1
`1
`1
`2
`1
`3
`
`1
`4
`1
`1
`5
`1
`1
`l
`l
`
`1
`2
`4
`2
`2
`2
`l
`l
`I
`5
`4
`
`132
`
`1
`l
`l
`l
`
`3
`l
`8
`2
`1
`1
`13
`I
`1
`1
`7
`l
`1
`9
`2
`69
`22
`1
`1
`1
`3
`2
`
`243
`
`0.06
`0.22
`0.06
`0.06
`0.06
`0.1 1
`0.06
`0.17
`
`0.06
`0.22
`0.06
`0.06
`0.28
`0.06
`0.06
`0.06
`0.06
`
`0.06
`0.1 1
`0.22
`0.1 I
`0.11
`0.1 l
`0.06
`0.06
`0.06
`0.28
`0.22
`
`7.22
`
`0.06
`0.06
`0.06
`0.06
`
`0.17
`0.06
`0.44
`0.1 1
`0.06
`0.06
`0.72
`0.06
`0.06
`0.06
`0.39
`0.06
`0.06
`0.50
`0.11
`3.81
`1.21
`0.06
`0.06
`0.06
`0.17
`0.11
`
`.
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`. 0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`
`
`33.33
`
`4.17
`4.17
`4.00
`4.00
`
`4.55
`4.55
`9.52
`5.00
`5.00
`4.00
`10.53
`5.00
`4.76
`4.17
`10.00
`5.00
`4.55
`16.67
`5.00
`27.27
`13.64
`4.76
`4.76
`4.17
`4.55
`3.00
`
`

`

`Reviewer: Fred Alavi Ph.D.
`,
`
`ND
`
`A No. 22-350
`
`(1
`
`HISTORICAL CONTROL DATA
`RAT - CD® IGS (Crl:CDISD'h. 1905.2 tin-I
`
`ALL ROUTES 0F ADMINISTRATION
`GESTATION DAY 20*
`
`D
`
`I1(4)
`
`1
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`SKELETAL (SKE)
`
`
`Litters examined
`Total no. ofstudies used
`
`
`806
`36
`
`
`
`
`
`MINOR SKELETAL ANO MALIES (TOTAL)
`
`SUM
`6 1 9
`
`AVERAGE %
`76.80
`
`MIN %
`27.27
`
`MAX %
`95.83
`
`
`
`SKULL
`Frontal bone(s): Reduced ossification
`Frontal bonds): Irregular ossification
`Parietal bone(s): Reduced ossification
`Parietal bone(s): Irregular ossification
`Supraoccipital bone: Reduced ossification
`Supraoccipital bone: Irregular ossification
`Interparietal bone: Reduced ossification
`Interparietal bone: Irregular ossification
`Hyoid bone: Absent
`Hyoid bone: Reduced ossification
`Hyoid bone: Irregular ossification
`Extra suturc(s) in fi'ontaL'parietal bone(s)
`VERTEBRAL COLUMN
`Extra pro-sacral vertebra(e)
`2 S pro-sacral vertebrae
`Lumbar centrum: Bipartite
`Lumbar centrum: Semi-bipartite
`Lumbar vertebral centrum: Absent
`Lumbar vertebral arch(es): Reduced ossification
`Lumbar vertebral arch(es): Irregular ossification
`Ossification center on is! lumbar vertebra or
`14th thoracic vertebra
`Sacral vcrtcbra(c):Reduc<7.1 no.
`Sacral vertebral centrum: Absent
`Sacral vertebral centrum: Reduced ossification
`Sacral vertebral arch(es): Reduced ossification
`Caudal vertebra(e): Reduced no.
`Thoracic centrum: Misaligned
`Thoracic centrum: Reduced ossification
`Thoracic vertebral contra: Misaligned
`Thoracic vertebral centrum: Displaced
`Thoracic vertebral arch(es): Fused
`Thoracic vertebral arch(es): Absent
`Thoracic vertebral arch(es): Reduced ossification
`
`’ = last study conducted in 2003
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`4.17
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`5.26
`4.17
`23.81
`9.09
`42.86
`55.00
`77.27
`75.00
`9.52
`80.00
`12.50
`4.00
`
`5.00
`10.53
`4.17
`8.33
`4.76
`5.00
`0.00
`50.00
`
`4.17
`4.76
`5.26
`24.00
`5.26
`4.76
`4.55
`4.17
`4.55
`4.17
`4.55
`4.17
`
`
`
`uh.)—
`
`NW
`
`~N_N_~._.:"
`
`76l 6ll0
`
`I70
`
`244
`
`

`

`Reviewer: Fred Alavi, Ph.D.'
`
`NDA No. 22-350
`
`HISTORICAL CONTROL DATA
`RAT - CD® [GS {Crl:CD[SDI). 1996-2007
`
`ALL mu ma ur ADMINISTRATlON
`GESTATION DAY 20*
`
`31(4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`Litters affected
`AVERAGE %
`MIN %
`
`SUM
`
`MINOR SKELETAL ANOMALIES (CDNT’D)
`
`Reduced no. ofphalange(s) in hindpaw(s)
`
`.
`
`0.00
`0.25
`0.37
`0.50
`
`0.25
`0.12
`3 .47
`0.50
`0.87
`7.44
`0.50
`1.49
`0.99
`0.12
`1.99
`
`STERNEBRAL COLUMN
`Extra
`Fused
`Misaligned
`Sternebrae: All absent
`RIBS
`Absent
`Fused
`Reduced
`Nodule(s)
`Extra 14th rib
`Rudimentary 14th rib
`Wavy
`Ossification center(s) on 7th cervical vertebra(e)
`Rib(s) on 7th cervical vertebra(e)
`Extra 14th rib with contmlateml rudimentary rib
`Rudimentary 14th rib with contmlateral
`ossification center
`PELVIC GIRDLE
`Pubic bone(s): Absent
`Pubic bonds): Reduced ossification
`Pubic bonds): irregular ossification
`lschial bone(s): Absent
`Ischial bone(s): Reduced ossification
`Ischial bone(s): Irregular ossification
`Ilia] bonds): Reduced ossification
`LIMBS
`Reduced no. ofphalange(s) in forepaw(s)
`
`"‘ = Last study conducted in 2003
`
`245
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`C
`
`HISTORICAL CONTROL DATA
`RAT - CD® IGS (Crl:CD[SDD. 1996-2007
`.
`.
`ALL ROUTEb 0F ADMINISTRATION
`GESTATION DAY 21
`
`3
`
`W3
`
`
`
`
`
`SKELETAL (SKIS)
`
`EMBRYO~FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`
`
`
`Litters examined
`Total no. of studies used
`
`
`1006
`46
`
`
`
`Liners affected
`
`
`AVERAGE %
`MIN %
`-‘IAX %
`MINOR SKELETAL ANOMALIES OTAL
`75.15 45.45755 95.45
`
`
`
`
`
`
`
`
`SKULL
`
`
`Frontal bonc(s): Incomplete ossification
`
`
`Parietal bone(s): Incomplete ossification
`
`[Parietal bone(s): Reduced ossification]
`
`[Parietal bone(s): Irregular ossification]
`Supraoccipital bone: Incomplete ossificalion
`
`
`[Supraoccipital bone: Reduced ossification]
`
` .4:— \J
`
`Lu
`
`Interparictal bone: Incomplete ossification
`
`{lnterparietal bone: Reduced ossification]
`10
`
`
`
`3
`Hyoid bone: Unossified
`
`
`
`399
`Hyoid bone: Incomplete ossification
`
`
`{Hyoid bone: Reduced ossification]
`9
`
`
`Extra. suture(s) in frontab’parietal bone(s)
`0
`Nasal bone(s): Incomplete ossification
`2
`
` VERTEBRAL COLUMN
`Cervical vertebral arcii(es): Fused
`1
`l
`
`Cervical vertebral arch(es): Incomplete ossification
`l
`4.17
`
`
`
`Cervical Vertebral arch(es): Absent
`2
`8.33
`
`
`l
`Cervical 7111 and moracic lst vertebral arch(es): Fused
`4.17
`
`
`l l
`Extra pre-sacral vertebra(c)
`8.70
`
`25 prc-sacral vertebrae
`4.00
`
`Lumbar eentmrn: Bipanite
`4.55
`
`Lumbar centrum: Semi-bipartite
`4.76
`
`Lumbar vertebral centmm: Absent
`0.00
`Lumbar vertebral arch(cs): Irregular ossification
`5.00
`
`Ossification center on Is: lumbar vertebra or
`72.73
`
`14th thoracic vertebra
`
`Sacral vertebra(e): Reduced no.
`
`Caudal vertebra(e): Reduced no.
`
`Caudal vertebra(e): Bipanite
`
`Thoracic ccntrum: Misaligned
`
`Thoracic vertebral contra: Misaligned
`
`Thoracic vertebral centrum: Displaced
`
`Thoracic vertebral centrum: Fused
`
`[ ] = Terminology/grading changed in 2002/2003
`
`
`
`l
`
`I
`
`.
`'
`
`l
`
`'
`
`0.00
`0.00
`4.76
`4.55
`
`0.00
`5.00
`
`4.l7
`
`246
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`C
`
`HISTORICAL CONTROL DATA
`1:: AT - CD® IGS fCrI:CDiSDI). 1996-2007
`ALL ROUTES or ADMINISTRATION
`crsmrron DAY 21
`
`11(4)
`
`9
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE Of FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`MINOR SKELETAL ANOMALIES (CONT’D
`
`
`
`
`
`
`
`
`
`MAX %
`AVERAGE %
`
`
`
`VERTEBRAL COLUMN (CONT’D)
`
`
`Thoracic vertebral arch(es): Fused
`
`Thoracic vertebral aroma): Absent
`
`Thoracic vertebral arch(es): Reduced ossification
`
`Thoracic vertebral arch(es): Incomplete ossification
`STERNEBRAL COLUMN
`Extra
`
`Fused
`Misaligned
`
`Stemcbrae: All absent
`
`RIBS
`
`
`Absent
`
`Fused
`3.00
`
`Reduced
`8.33
`Nodule(s)
`14
`9.09
`
`
`
`
`Extra 14th rib
`5
`9.52
`
`Rudimentary 14th rib
`31.82
`Wavy
`8.33
`
`Ossification ccnter(s) on 7th cervical venebm'c)
`.
`20.00
`
`Ossification centcr(s) on 51h cervical venebra(e)
`0.00
`4.17
`
`
`Rib(s) on 7th cervical vertebra(e)
`
`
`Rib(s) Incomplete ossification
`
`Extra I4th rib with contralaterai rudimentary rib
`
`Rudimentary 14th rib with contralaterdl'
`
`ossification center
`
`PELVIC GIRDLE
`Pubic bone(s): Incomplete ossification
`
`Ischial bonds): Incomplete ossification
`
`LIMBS
`Reduced no. ofphalangqs) in forepaw(s)
`
`Reduced no. of phalange(s) in hindpaw(s)
`
`
`1
`i
`i
`.
`i
`
`247
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`HISTORICAL CONTROL DATA
`RAT - cn® IGS (Crl:CD|SDl), 1996-2007
`ALL “UU I DO Ul" flui'lll‘lall‘flllul‘
`
`5
`
`3
`
`bib!)
`
`EM BRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`
`MAJOR MALFORMATIONS AND MINOR ANOMALlES
`
`
` Felmes examined
`EXTERNAL (EXT)
`25228
`
`
`12781
`VISCERAL (V13)
`
`
`SKELETAL (SIG-2)
`12762
`
`12630
`TECHNIQUE OF WILSON (WT)
`
`82
`
`Total no. of studies used
`
`l
`
`l
`
`-
`
`l
`
`SUM
`39
`
`l
`2
`
`.
`
`MAX % '
`1.00
`
`0.53
`0.67
`
`0.34
`0.33
`0.41
`0.36
`0.66
`0.53
`0.53
`0.41
`0.27
`0.58
`0.27
`0.65
`0.65
`0.64
`0.64
`0.41
`0.32
`
`0.36
`0.27
`0.27
`0.63
`0.63
`
`0.67
`1.27
`
`'
`
`l
`‘
`|
`'
`1
`i
`i
`f
`l
`I
`I
`'
`l
`i
`‘
`
`I
`‘
`1
`
`.
`
`AVERAGE %
`0.16
`
`MIN %
`0.00
`
`
`
`MAJOR MALFORMATIONS TOTAL
`
`
`
`Cranium: Auditory/vestibular system; absent (WT)
`
`
`Cranium: Auditorylvestibular system; reduced/
`
`
`incomplete formation (WT)
`
`3
`Cranium: Cleft palate/lip (EXIWT)
`
`
`1
`Cranium: Microtia (EXT)
`
`Cranium: Microeephaly (EXT,WT)
`2
`
`
`Cranium: Exencephaly (EXT,SKE)
`1
`
`
`
`
`Brain: Hydrocepha1y(EXT,WT)
`4
`Brain: Cerebrum, cyst—like formation (WT)
`1
`
`
`Brain: Lateral ventricles reduced (WT)
`l
`
`
`
`
`Eyc(s): Anophthalmia (EXT,WT)
`6
`
`
`Eye(s): Exophthalmia (EXT, WT)
`1
`Eye(s): Microphthalmia (WT)
`2
`
`
`Eyc(s): Open (EXT,W’1‘)
`l
`
`
`Eye(s): Retinal folding (WY)
`2
`
`
`Eye(s): Aphakia (WT)
`1
`
`
`Face: Aglossia (EXT,WT)
`3
`
`
`Face: Agnathia (EXTAV‘I)
`s
`
`
`Face: Astomia (EXT,WT)
`3
`
`
`Face: Micrognathia(EXT,WT)
`l
`
`
`5
`Face: Mandibular micrognathia (EXT)
`
`
`1
`Face: Microstomia (EXT,\V1‘)
`
`
`1
`Face: Nares; reduced (EXT,WT)
`Face: Nures opening; reduced (WT)
`1
`
`
`Face: Nasal septum/turbinatc formation;
`1
`
`reduced (WT)
`
`Face: Nasal septum; lack of turbinate
`1
`
`
`formation (WT)
`
`Face: Palate; absent (WT)
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.86
`1
`Face: Split tongue (WT)
`0.41
`2
`Face: Upper jaw absent (EXT)
`0.32
`1
`Face: Nares absent (EXT)
`0.41
`1
`Face: Probosis (EXTMIT)
`0.73
`2
`Heart: [nterventricular septal defect (V13)
`0.63
`1
`Heart: Dilatation of ascending aorta (V15)
`
`
`
`1Heart: Right descending aorta (V15) 0.66
`
`
`QA'd 20-Feb—09
`10m? Wfifi
`
`248
`
`

`

`
`
` Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`C
`
`HISTORICAL CONTROL DATA
`RAT . rum [CS mmr‘nmnn ransom-r
`ALL RUU 1 L5 U1" ADMIN15'] RA] [UN
`
`2
`
`“(4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE 0F FETAL EXTERNAL, VlSCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`Fetuses affected
`AVERAGE %
`
`MAJOR MALFORMATlONS comm)
`
`MAX %
`
`Heart: Stenosis of ascending aorta (VIS)
`Heart: Transposition ofmajor vessels MS)
`Heart: Globular heart (V15)
`Heart: Ringod aorta (VIS)
`Diaphragm: Diaphragmatic hernia (VlS)
`Lungs and thymus: Lung lobes; absent (V15)
`Lungs and thymus: Lung lobes; reduced (V15)
`Vertebral column: Multiple fusion and anomalies
`in vertebral column (SKE)
`Thorax: Trunk shortened (EXT)
`Abdomen: Anal atrcsia (EXT,VIS)
`Abdomen: Gastroschisis (EXT)
`Abdomen: Situs inversus (VlS)
`Abdomen: Omphaloeele (EXT)
`
`é Abdomen: Urogenital region fissure (EXT)
`Abdomen: Abdominal muscles herniated (EXT)
`1 Abdominal cavity: Colon blind (V18)
`Abdominal cavity: Malposition stomach/
`pancrms’spleen (VIS)
`Abdominal cavity: intestine; stenosis (VlS)
`Tull: Acaudia (EXT)
`Tail: Micmcaudia (EXT)
`Limb(s): Ectrodactyly (EXT)
`Limb(s): Brachydactyly (EXT)
`Limb(s): Abnormal flexure ofhindlimb(s) (EXT)
`Limb(s): Hindpaw(s) absent (SKI-2)
`Skull: Mandible shortened (SKE)
`Skull: Maxilla shortened/Incisive bone (SKE)
`Gross exam: Anasarca (EXT)
`General: Sims inversus (VIS)
`
`Cranium: Pinna(c); displaced (EXT)
`Cranium: Subcutaneous hematoma (WT)
`Cranium: Cutis aplasia (EXEWT)
`Cranium: Cyst—like formation subcutaneously (WT)
`
`Cranium: Moderate dilatation ofthe third ventricle (WT)
`Cranium: Moderate dilatation ofthe lateral ventricles (WT)
`' Eye(s): Lens(es) oval (WT)
`Eye(s): Hemawma adjacent to eyc(s) (WT)
`Face: Pronuding tongue (EXT)
`Nasal septum: Reduction in turbinatc formation (WT)
`Heart: lnnominate artery absent (VIS)
`Heart: lnnominate artery reduced (VIS)
`Heart: lnnominare anery malpositioned (VlS)
`Liver: Discoloration pale (VlS)
`Liver: Supcmrtmery lobes (VlS)
`Liver: Vestigial lobe (VlS)
`Spleen: Small (V[8)
`Kidney(s): Reduction ofrenal papilla(e) (VlS)
`Kidney(s): Reduced (V18)
`Urctcr(s): Dilation (VlS)
`Ureter(s): Megatn'cter (V13)
`Adrenal gland(s): Hemorrhage (VIS)
`Testes: Malpositioned (Vl S)
`Skin: Pale (EXT)
`Tail: Kinked (EXT)
`General: Subcutaneous hematoma (EXT)
`
`au-—NNH§N—4
`0.54
`
`0 00
`
`0.00
`0.00
`0 00
`
`'0.00
`0.00
`
`0.00
`0.00'
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.32
`0.63
`0.27
`0.53
`
`0.66
`0.64
`2.07
`0.67
`0.36
`0.53
`2.07
`0.72
`0.6:?
`0.57
`1.74
`0.69
`0.64
`2.58
`0.66
`8.00
`2.76
`0.69
`0.69
`0.28
`0.32
`
`i
`l
`l
`l
`
`1
`4
`1
`l
`l
`3
`1
`3
`
`l4ll5lll1
`
`.
`
`249
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`c
`
`HISTORICAL CONTROL DATA
`
`"
`
`RAT - CD® lGS (Crl:CD[SDl),-1996-2007
`ALL rum 1 no or ADD/1mm] KA’I‘IUN
`GESTATION DAY 20*
`
`3
`
`m4)
`
`
`
`EMBRYO FETAL DEVELOPMENT STUDIES
`‘ GROUP INCIDENCE OF FETAL EXTERNAL, VISCE-RAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`
`
`‘
`
`SKELETAL (SKE)
`
`MINOR SKELETAI. ANOMALIES OTAL
`
`Total no. of studies used
`Fetuses examined
`
`
`36
`595]
`
`Fetuses affected
`AVERAGE %.
`MIN %
`28.92
`6.63
`
`
`SUM
`1721
`
`
`
`
`
`
`
`SKULL
`
`Frontal bone(s): Reduced ossification
`
`Frontal bonds): Irregular ossification
`Parietal bonds): Reduced ossification
`Parietal bone(s): Irregular ossification
`Supraoccipital bone: Reduced ossification
`
`Supraoccipital bone: irregular ossification
`
`lnterparietal bone: Reduced ossification
`
`lnterparietal bone: Irregular ossification
`
`Hyoid bone: Absent
`
`Hyoid bone: Reduced ossification
`
`Hyoid bone: Irregular ossification
`
`Extra sumre(s) in frontal/parietal bonc(s)
`
`
`VERTEBRAL COLUMN
`
`
`Extra pro-sacral vertebra(e)
`25 ore-sacral vertebrae
`Lumbar centrurn: Bipartite
`Lumbar ccntrum: Semi-bipartite
`
`Lumbar vertebral centmm: Absent
`
`Lumbar vertebral arch(es): Reduced ossification
`
`Lumbar vertebral arch(es): Irregular ossification
`
`Ossification center on lst lumbar vertebra or
`
`14th thoracic vertebra
`
`Sacral vertebra(e): Reduced no.
`
`
`
`Sacral vertebral centrum: Absent
`(MN-—
`
`Sacral vertebral centrum: Reduced ossification
`
`Sacral vertebral arch(es): Reduced ossification
`
`
`
`
`--L'JAW
`Caudal vertebra(e): Reduced no.
`
`Thoracic ccntrum: Misaligned
`
`
`Thoracic centrum: Reduced ossification
`
`
`Thoracic vertebral centra: Misaligned
`
`
`
`Thoracic vertebral cenrrum: Displaced
`Thoracic vertebral arch(es): Fused
`Thoracic vertebral arch(es): Absent
`
`
`Thoracic vertebral arch(es): Reduced ossification
`
`
`‘ = Last study conducted in 2003
`
`
`
`
`
`
`
`
`h—N‘IQWN-fl
`
`QA’d 20-Feb-09
`
`[QM/r god/1.2690]
`
`250
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No.22-350
`
`C
`
`HISTORICAL CONTROL DATA
`RAT - rm mg (mmnlsnn 1006:2007
`ALL KUU 1. LS Ul" ADD/[WIS] RA 1 [UN
`
`2'
`
`“(4)
`
`EMBRYO—FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE 0F FETAL EXTERNAL, VlSCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATlONS AND MINOR ANOMALIES
`Fetuses afi'ected
`AVERAGE %
`
`MAJOR MALFORMATIONS comm
`
`MAX %
`
`w~u-agu
`~r-_~u......—4;_
`
`l24222lll54
`
`Heart: Stenosis ofascending aorta (V[5)
`Heart: Transposition ofmajor vessels (VlS)
`Heart: Globular heart (V15)
`Heart: Riugcd aorta (VlS)
`Diaphragm: Diaphragmatic hernia (VlS)
`Lungs and thymus: Lung lobes; absent (VlS)
`Lungs and thymus: Lung lobes; reduced (VlS)
`Vertebral column: Multiple fusion and anomalies
`in vertebral column (SKE)
`Thorax: Trunk shortened (EXT)
`Abdomen: Ana] aucsia (EXT,VIS)
`Abdomen: Gastroschisis (EXT)
`Abdomen: Situs inversus (VlS)
`Abdomen: Omphalocele (EXT)
`Abdomen: Urogenital region fissure (EXT)
`Abdomen: Abdominal muscles herniated (EXT)
`Abdominal cavity: Colon blind (VlS)
`Abdominal cavity: Malposition stomach]
`pancreas’spleen (VlS)
`Abdominal cavity: intestine: stenosis (VIS)
`Tuil: Acaudia (EXT)
`Tail: Microcaudia (EXT)
`Limb(s): Ectrodactyly (EXT)
`Limb(s): Brachydactyly (EXT)
`Limb(s): Abnormal flexure ofhindlimb(s) (EXT)
`Limb(s): Hindpaw(s) absent (SKE)
`Skull: Mandible shortened (SKE)
`Skull: Maxilla shortened/Incisive bone (SKE)
`Gross exam. Anaarca (EXT)
`General: Sit-us'mversus (VlS)
`
`ANOMALIES TOTAL
`
`Cranium: Pinna(c); displaced (EXT)
`Cranium: Subcutaneous hematoma (WI)
`Cranium: Cutis aplasia (EXT.WT)
`Cranium: Cyst-like formation subcutaneously (\Vl')
`
`Cranium: Moderate dilatation ofthe third ventricle (WT)
`Cranium: Moderate dilatation ofthe lateral ventricles (WT)
`' Eye(s): Lens(es) oval (WT)
`Eye(s): Hemnmma adjacent to eyc(s) (WT)
`Face: Protruding tongue (EXT)
`Nasal septum: Reduction in turbinatc formation (WT)
`Heart: lnnominate arteryabsent (VIS)
`Heart: lnnominate artery reduced (VIS)
`Heart: lnnominate artery malpositioned (VlS)
`Liver: Discolomtion pale (V15)
`Liver: Supernumerylobes(VlS)
`
`Liver: Vestigial lobe (VlS)
`Spleen: Small (V[5)
`Kidney(s): Reduction ofrenal papilla(e) (Vl5)
`Kidney(s): Reduced (V18)
`Urclcr(s): Dilation (VlS)
`Ureter(s): Megaureter (VlS)
`Adrenal gland(s): Hemorrhage (V15)
`Testes: Malpositioned (V13)
`Skin: Pale (EXT)
`Tail: Kinked (EXT)
`General: Subcutaneous hematoma (EXT)
`
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`000
`O.00
`
`0.32
`0.63
`0.27
`0.53
`
`0.66
`0.64
`2.07
`0.67
`0.36
`0.53
`2.07
`0.72
`0.68
`0.57
`1.74
`
`0.69
`0.64
`2.58
`0.66
`8.00
`2.76
`0.69
`0.69
`0.28
`0.32
`0.54
`
`i
`l
`
`l
`i
`
`0.00
`0.01
`0.00 _
`0.01
`
`0.02
`(WI
`0.08
`0.02
`0.00
`0.01
`0.11
`0.0l
`0.0l
`0.0]
`0.06
`
`0.0l
`0.01
`0.08
`0.02
`0.73
`0.20
`0.01
`0.01
`0.00
`0.0]
`0.01
`
`i
`
`'
`i
`I
`'
`i
`
`l
`1
`l
`l
`
`3
`]
`lo
`2
`1
`1
`14
`1
`]
`1
`8
`
`l
`l
`10
`2
`93
`25
`1
`1
`1
`3
`2
`
`249
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22~350
`
`C.
`
`HISTORICAL CONTROL DATA
`
`“
`
`RAT - CD® IGS (Crl:CD[SD]),01996-2007
`ALL rum 1 Lb ur AJJMINISI RAMON
`GESTATION DAY 20*
`
`3
`
`M4)
`
`
`
`
`EMBRYO FETAL DEVEDOPMENT STUDIES
`‘ GROUP INCIDENCE OF FETAL EXTERNAL, VISCB-RAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`
`
`
`‘
`
`
`
`SKELETAL (SKE)
`
`wo-m~oN \O
`
`
`
`
`
`Total no. of studies used
`Fetuses examined
`36
`595]
`
`Fetuses affected
`
`MAX%
`-AVERAGE%.
`MIN %
`MINOR SKELBTAI. ANOMALIES OTAL
`50.00
`1721
`28.92
`i
`6.63
`
`
`SKULL
`
`
`Frontal bone(s): Reduced ossification
`
`Frontal bonds): Irregular ossification
`
`Parietal bone(s): Reduced ossification
`
`Parietal bone{s): Irregular ossification
`
`Supraoccipital bone: Reduced ossification
`Supraoccipital bone: Irregular ossification
`
`Interparietal bone: Reduced ossification
`
`Interparietal bone: Irregular ossification
`
`Hyoid bone: Absent
`
`Hyoid bone: Reduced ossification
`
`Hyoid bone: Irregular ossification
`
`Extra suture(s) in frontal/parietal bone(s)
`
`
`VERTEBRAL COLUMN
`
`
` \l
`Extm pre—sacral vertebra(e)
`
`
`25 pre-sacral vertebrae
`
`Lumbar centrum: Bipurlite
`
`
`Lumbar ccntrum: Semi-bipartite
`Lumbar vertebral centrurn: Absent
`
`
`Lumbar vertebral arch(es): Reduced ossification
`Lumbar vertebral atch(es): Irregular ossification
`Ossification center on 15! lumbar vertebra or
`
`
`
`14th thoracic vertebra
`
`Sacral vertebra(e): Reduced no.
`
`
`
`Sacral vertebral cemrum: Absent
`uh.)—
`
`Sacral vertebral centrum: Reduced ossification
`
`Sacral vertebral arch(es): Reduced ossification
`
` ...L..IAla!
`
`Caudal vertebra(e): Reduced no.
`Thoracic ccntrum: Misaligned
`
`
`Thoracic centrum: Reduced ossification
`
`
`Thoracic vertebral centra: Misaligued
`
`
`Thoracic vertebral cemrum: Displaced
`Thoracic venebral arch(es): Fused
`Thoracic vertebral arch(es): Absent
`
`
`Thoracic vertebral arch(es): Reduced ossification
`
`“ = Last study conducted in 2003
`
`HN—Alng—a
`
`QA’d 20-Feb-09
`
`[61% Scar—290a;
`
`250
`
`

`

`NDA No. 22-350
`Reviewer: Fred Alavi Ph.D.
`
`HISTORICAL CONTROL DATA
`RAT - CD® IGS (Crl:CDlSDD. 1996-2007
`
`ALL ROUTES UF ADMINISTRATION
`GESTATION DAY 20*
`
`J
`
`M4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`Femsm affected
`AVERAGE “/9
`
`SUM
`
`MINOR SKELETAL ANOMALIES CONT’D
`
`MAX %
`
`
`
`STEKNEBRAL COLUMN
`Extra
`Fused
`Misaligned
`Stemebrae: All absent
`
`Nodule(s)
`Extra 14th rib
`Rudimentary 14m rib
`Wavy
`Ossification center(s) on 7th cervical vencbra(e)
`Rib(s) on 7th cervical vertebra(e)
`Extra 14m n'b with oontralatcral rudimentary rib
`Rudimentary l4th rib with contralatcral
`ossification center
`PELVlC GlRDLE
`Pubic bonds): Absent
`Pubic bone(s): Reduced ossification
`Pubic bone(s): Irregular ossification
`lschial bone(s): Absent
`lschial bone(s): Reduced ossification
`Ischial bone(s): Irregular ossification
`llial bone(s): Reduced ossification
`LIMBS
`Reduced no. of phalange(s) in forepaw(s)
`Reduced no. ofphalange(s) in hindpaw(s)
`
`’ = Last study conducted in 2003
`
`QA’d 20-Feb-09
`
`(mm "Mljwfi
`
`251
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`C
`
`HISTORICAL CONTROL DATA
`1: AT - r'nrs: [CS (Prtsrfntsmx 1996-2007
`
`ALL ROUTES 0F ADMINISTRATION
`CESTATION DAY 2]
`
`D
`'
`
`[1(4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE 0F FETAL EXTERNAL, VISCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`SKELETAL (SKIS)
`
`-
`
`Fctuses examined
`68] l
`
`Total no. of studies used
`46
`
`--o4:-—N
`
`SUM
`1925
`
`AVERAGE %
`28.26
`
`MIN °/o
`9.32
`
`MAX %
`46.67
`
`gum—.—
`
`MINOR SKELETAL ANOMALIES OTAL
`SKULL
`Frontal bone(s): Incomplete ossification
`Parietal bonds): Incomplete ossification
`[Parietal bonc(s): Reduced ossification]
`[Parietal bone(s): Irregular ossification]
`Supraoccipital bone: Incomplete ossification
`[Supraoccipital bone: Reduced ossification]
`Interparietal bone: Incomplete ossification
`[lntcrparictal bone: Reduced ossification]
`Hyoid bone: Unossified
`Hyoid bone: Incomplete ossification
`[Hyoid bone: Reduced ossification]
`Extra suture(s) in frontal/parietal bone(s)
`Nasal bone(s): Incomplete ossification
`VERTEBRAL COLUMN
`Cervical vertebral arch(es): Fused
`Cervical vertebral arch(es): Incomplete ossification
`Cervical vertebra] arch(es): Absent
`Cervical 7th and thoracic lst Vertebral arch(es): Fused
`Extra pro-sacral venebra(e)
`25 pre—sacral vertebrae
`Lumbar centrum: Bipartite
`Lumbar oentrum: Semi-bipartite
`Lumbar vertebral centrum: Absent
`Lumbar vertebral arch(es): Irregular ossification
`Ossification center on Is! lumbar vertebra or
`14th thoracic vertebra
`Sacral vertebra(e): Reduced no.
`Caudal vertebra(e): Reduced no.
`Caudal vertebrae); Bipartite
`'Ilioracic centrum: Misaligned
`Thoracic vertebral contra: Misaligned
`Thoracic vertebral ccntrum: Displaced
`Thoracic vertebral centrum: Fused
`
`33
`= Tcrminolo 'lgrading changed in 2002/2003
`
`QA‘d 20—Feb-09
`
`racemes
`
`252
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`HISTORICAL CONTROL DATA
`RAT - CD® IGS (CrkCDlSDl), 1996-2007
`ALL .KUU l L) Ul‘ AUNUJNIB I .KA 1 Jun
`CESTATJON DAY 2]
`
`C
`
`>
`
`“(4)
`
`EMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VlSCERAL AND SKELETAL FINDINGS
`MAJOR MALFORMATIONS AND MINOR ANOMALIES
`
`Fetuses examined
`Total no, of studies used
`
`
`6811
`46
`
`
`
`SKELETAL (SKE)
`
`
`
`
`
`
`
`
`
`
`
`MINOR SKELETAL ANOMALIES OTAL
`
`1925
`
`Fetuses affected
`AVERAGE %
`MIN %
`28.26
`9.32
`
`
`MAX %
`46.67
`
`SKULL
`
`
`Frontal bone(s): Incomplete ossification
`
`
`Parietal bone(s): Incomplete ossification
`
`[Parietal bonds): Reduced ossification]
`
`[Parietal bone(s): Irregular ossification]
`Supraoccipital bone: incomplete ossification
`
`[Supraoccipital bone: Reduced ossification]
`
`Ilnterpan'etal bone: incomplete ossification
`
`[lntcrparictal bone: Reduced ossification]
`
`Hyoid bone: Unossified
`
`Hyoid bone: Incomplete ossification
`
`[Hyoid bone: Reduced ossification]
`
`Extra suture(s) in frontal/parietal bonds)
`
`Nasal bone(s): Incomplete ossification
`
`
`VERTEBRAL COLUMN
`
`
`Cervical vertebral arch(cs): Fused
`
`Cervical vertebral arch(es): Incomplete ossification
`
`Cervical vertebra] arch(es): Absent
`Cervical 7th and thoracic lst vertebral memes): Fused
`
`Extra prc-sacral vertebra(e)
`
`25 prc-sacral vertebrae
`
`Lumbar centrum: Bipartite
`
`Lumbar centrum: Semi-bipartite
`
`Lumbar vertebral centnim: Absent
`
`Lumbar vertebral arch(es): Irregular ossification
`
`Ossification center on 15: lumbar vertebra or
`
`14th thoracic vertebra
`
`Sacral venebra(e): Reduced no.
`
`Caudal vertebra(e): Reduced no.
`
`Caudal vertebra(e): Bipartite
`
`Thoracic centmm: Misaligned
`
`Thoracic vertebral contra: Misaligned
`
`Thoracic vertebral centrum: Displaced
`
`Thoracic vertebral ccntrum: Fused
`
`[ ] = Terminology/grading changed in 2002/2003
`
`QA‘d 20—Feb-09
`
`iii/m $373,693
`
`253
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`C'
`
`'
`
`HISTORICAL CONTROL DATA
`RAT - CD® IGS (CrkCDISDll. 1996-2007
`ALL nuu‘l Eb Ul" ADMINISTRATION
`GESTATION DAY 21
`
`h 4)
`
`
`
`
`
` BMBRYO-FETAL DEVELOPMENT STUDIES
`GROUP INCIDENCE OF FETAL EXTERNAL, VISCERAL AND SKELETA