CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202270Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA SDN 31
`Application Number(s) 202-270
`Priority or Standard Standard
`
`Submit Date(s) 08-03-11
`Received Date(s) 08-03-11
`PDUFA Goal Date 02-03-12
`Division / Office DMEP/ODEII/OND
`
`Reviewer Name(s) Valerie S. W. Pratt, M.D.
`Review Completion Date 11-10-11
`
`Established Name Sitagliptin/metformin XR
`(Proposed) Trade Name Janumet XR
`Therapeutic Class DPP-4 inhibitor/biguanide
`Applicant Merck
`
`Formulation(s) 50/500, 50/1000, & 100/1000
`mg tablets
`Dosing Regimen Once daily
`Indication(s) Type 2 diabetes mellitus
`Intended Population(s) Adult type 2 diabetes
`
`
`
`
`
`Reference ID: 3043180
`
`

`

`Medical Officer Safety Review
`Division of Metabolism and Endocrinology Products
`
`
`
`
`NDA: 202-270 SDN 31 (Complete Response [CR])
`Date of Submission: August 3, 2011
`Name of drug: Sitagliptin/metformin fixed dose combination (FDC) tablet
`Indication: For use as an adjunct to diet and exercise to improve glycemic
`control in patients with T2DM
`Sponsor: Merck
`
`Medical Reviewer: Valerie Pratt, M.D.
`Medical Team Leader: Ilan Irony, M.D.
`
`Background: On July 22, 2011, a CR letter was issued due to deficiencies at
`the Arecibo, Puerto Rico manufacturing facility. Satisfactory resolution of the
`Chemistry, Manufacturing, and Controls (CMC) deficiencies is required before
`the application may be approved. The updated complete study report (CSR) for
`clinical pharmacology study 147-00 (147) was also required, after review of
` July 11, 2011 response to our Form FDA 483.
`
`
`Please refer to my review of NDA 202-270 which recommended approval of
`the FDC, pending resolution of the Office of Compliance, Division of
`Manufacturing and Product Quality (OC-DMPQ) issues.
`
`CR: No additional nonclinical or clinical studies of sitagliptin/metformin XR FDC
`were undertaken by the applicant. Thus, there were no additional data to submit.
`No additions or changes to the safety profile were reported by the applicant.
`
`As requested in the CR letter, however, the applicant submitted an updated CSR
`for clinical pharmacology study 147, a pivotal study that characterized the single
`dose pharmacokinetics (PK) of sitagliptin and metformin following administration
`of 50/500 mg or 100/1000 mg of the FDC in healthy subjects. (The revised CSR
`was requested because of
` July 11, 2011 response to the Form
`FDA 483 and the applicant’s submission of updated study 147 datasets in SAS
`transport files on July 21, 2011.) As described in Jee Eun Lee’s June 17, 2011
`original clinical pharmacology review, the 90% CIs of the geometric mean ratios
`for the pharmacokinetic parameters (AUC0-∞ and Cmax) for sitagliptin and
`metformin after administration of single tablet of sitagliptin/metformin XR 100
`mg/1000 mg tablet and those after administration of sitagliptin 100 mg +
`Glumetza (metformin XR) 1000 mg fell within the range of [0.80, 1.25]. Thus, the
`bioequivalence (BE) between FDC and co-administration of sitagliptin and
`Glumetza was established for two of the three dose strengths.
`
`
`Reference ID: 3043180
`
`(b) (4)
`
`(b) (4)
`
`

`

`When BE was evaluated using the updated datasets as requested in the CR
`letter, the 90% CIs of the geometric mean ratios for the pharmacokinetic
`parameters (AUC0-∞ and Cmax) for sitagliptin and metformin after administration
`of single tablet of sitagliptin/metformin XR 50/500 mg or 100 mg/1000 mg tablet
`and those after co-administration of corresponding doses of sitagliptin +
`Glumetza (metformin XR) again fell within the range of [0.80, 1.25]. Thus, the
`bioequivalence (BE) between FDC and co-administration of sitagliptin and
`Glumetza was reestablished for two strength levels. Clinical pharmacology
`concurs. Please also refer to Dr. Jee Eun Lee’s review.
`
`Table 1. Statistical comparison of plasma PK parameters of sitagliptin and metformin after
`administration of a single 50/500 or 100/1000 mg FDC tablet and co-administration of
`corresponding doses of sitagliptin and Glumetza (metformin XR) in healthy adults
`
`Sita/met XR FDC Tablets vs. Co-administration of sitagliptin
`and Glumetza (metformin XR)
`Parameter Sita/met XR FDC 50/500 mg
`Sita/met XR FDC 100/1000 mg
`Sitagliptin
`
`
` AUC0-∞
`1.00 (0.99, 1.02)
`1.01 (0.99, 1.03)
` Cmax
`0.96 (0.92, 1.01)
`1.00 (0.96, 1.05)
`Metformin
`
`
` AUC0-∞
`1.07 (1.01, 1.13)
`0.96 (0.91, 1.01)
` Cmax
`1.08 (1.03, 1.14)
`1.14 (1.09, 1.19)
`Source: CSR 147-00 Tables 11-1 and 11-2
`
`Recommendation: I recommend approval of sitagliptin/metformin XR FDC,
`pending resolution of the Office of Compliance, Division of Manufacturing and
`Product Quality (OC-DMPQ) issues.
`
`
`Reference ID: 3043180
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`VALERIE S PRATT
`11/10/2011
`
`ILAN IRONY
`11/10/2011
`I concur with Dr. Pratt's review and recommendation for approval, pending OC/OMPQ
`recommendation.
`
`Reference ID: 3043180
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`
` Date 7/20/20] 1
`
`Ilan Iron , M.D.
`From
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`202270 Original Submission
`Sun lement#
`
`Date of Submission
`
`PDUFA Goal Date
`
`9/23/2010
`
`7/23/2011
`
`Com o lete Res 001188 letter
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Janumet XR / sitagliptin metformin XR
`
`Dosa_e forms / Stren_ h
`
`Tablets / 50/500, 50/1000 and 100/1000 mo
`
`Proposed Indication(s)
`
`Recommended:
`
`As adjunct to diet and exercise to improve glycemic
`control in atients with pe 2 diabetes mellitus
`
`Page 1 of 14
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`Cross Discipline Team Leader Review
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`1. Introduction
`
`This is the Cross Discipline Team Leader (CDTL) review of NDA 202270, a sitagliptin/
`metformin extended release OCR) fixed-dose combination (FDC) for the treatment of Type 2
`diabetes mellitus (T2DM) submitted under 505 (b)(2), with Glumetza (metformin XR) being
`the reference listed drug (RLD).
`
`Reviewer comment: During the review cycle, the team uncovered that the applicant hadfill]
`right ofreference to Depomed ’s Glumetza, its Prescribing Information and supporting data.
`All disciplines stated that there were no additional data (beyond Merck’s sitagliptin,
`sitagliptin / innnediate—release metformin FDC and Depomed ’s Glumetza) necessary to
`support approval ofthe product under this application; therefore we deem the NDA to be a
`505(b)(1) and the applicant has revised the NDA classification accordingly.
`
`2. Background
`
`This is a NDA for a fixed-dose combination of two approved oral drug products. The
`components are sitagliptin (tradename Januvia), a dipeptidyl peptidase inhibitor approved in
`October 2006, and metformin formulated for extended-release. The comparator for the latter is
`Glumetza, the RLD, approved in June 2005. Another fixed-dose combination containing
`sitagliptin and metformin immediate-release has been approved in March 2007, under the
`tradename Janumet, for twice—daily administration. So the product reviewed under this NDA is
`only expected to bring the convenience of once-daily dosing.
`The proposed dosing regimen is sitagliptin/metfonnin XR 50 mg/500 mg and 50 mg/1000 mg
`to be given as two tablets once daily and sitagliptin/metformin XR 100 mg/ 1000 mg to be
`given as one tablet once daily.
`
`3. CMC/Device
`
`0 General product quality considerations
`
`The CMC review team had initially recommended approval, pending acceptable
`recommendations from Biopharmaceutics (biowaiver for the 50/ 1000 mg strength tablet),
`Office of Compliance Worm 483 inspection findings, see below) and Office of Surveillance
`and Epidemiology (labeling). Of note, the Biopharmaceutics review team, found the
`application acceptable and granted the biowaiver for the middle strength tablet of sitagliptin
`50/ metformin 1000 mg strength (refer to further details under the Clinical Pharmacolo
`section of this memo).
`
`)(4)
`
`Sitagliptin/metformin XR tablets are film-coated tablets containing an immediate-release dose
`of sitagliptin phosphate surrounding a core of extended-release dose of metformin
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`Cross Discipline Team Leader Review
`
`hydrochloride for once dail use. A 01
`
`eric film coatin over the active sitagliptin coating
`
`s s1ta pt me ormm XR FDC NDA 202270 use
`
`is appliedtoWBoth sitaglipt me ormm IR FDC an
`metformin drug substance fronfi (DMF-). The release specification
`
`criterion for sitagliptin in sitaglip met ormm XR FDC is wider (92.5- 107.5%) relative to
`sitagliptin/metformin IR FDC (95.0 - 105%). However, as pivotal clinical pharmacology study
`P147 demonstrated bioequivalence, the change in the specification criterion is acceptable.
`The expiration dating period grantable for the sitagliptin/metformin XR tablets in 7-, 14-, 30—,
`60, 90-, 180-, and 1000-count HDPE bottles is 24 months with stora e conditions of 25°C
`
`(77°F); excursions permitted to 15- 30°C (59-86°F). For theh, when
`
`the container is subdivided, the repackaged container should be moisture resistant and tightly
`closed. CMC recommended that this be included in the action letter.
`The applicant will submit data to s port a site change for the metformin_ operation
`
`only, whichoccurs#withthe modifiedrelease excipient (hypromellose), as a
`
`e submission will include 3 months of accelerated stability
`CBE-30 after NDA approv .
`data for three batches tested in each strength (long term data will be sent to the annual report),
`dissolution data, and cGMP certification for the new site. Even though the drug product is a
`modified-release product, the site change will require supportive data as described in the
`Scale-up and Post-Approval Changes Guidance for Immediate-release Products (SUPAC-IR).
`
`0 Facilities review/inspection
`
`FDA conducted inspections of the manufacturing site in Puerto Rico on 3/28/11 and 4/14/11,
`and concluded there were multiple findings that support a “Withhold” recommendation at this
`
`
`
`These findings were reviewed by the Central Office of Compliance (0C) and referred to
`Merck for response and action.
`With the withhold recommendation by DC, CMC recommended a Complete Response action
`(see Memo to File by the CMC review team, dated 5/25/1011).
`Merck responded to the findings in their manufacturing site in Arecibo, Puerto Rico. Afier
`review of the responses, the Division of Manufactlu‘ing and Product Quality maintained that
`
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`Cross Discipline Team Leader Review
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`the response to Observation 1 (i.e.,
`
`”(0
`was inadequate, and
`maintained the recommendation to Withhold (based on verbal communication to DMEP; no
`review filed in DARRTS at the time of writing this CDTL memo).
`
`4. Nonclinical Pharmacology/Toxicology
`
`(I!) (4)
`
`Please refer to Dr. Patricia Brundage’s Pharmacology / Toxicology review for details. The
`applicant conducted a 3-month toxicity study in rats and two in vitro genotoxicity studies
`(microbial mutagenesis assay and chromosomal aberration assay) in order to qualify an
`degradate of sitagliptin identified in sitagliptin/metformin XR at the proposed
`m” which exceeds the qualification threshold (ICH Q3B(R2)). Microbial
`limit of
`mutagenesis and in vitro chromosomal aberration assays using an
`(m4) batch of
`sitagliptin containing
`(51(4) and
`“mlysis degradation products
`were negative supporting a
`"m limit for the
`(m4) degradation2product. A
`3-month rat toxicity study, in which rats were administered a 60 mg/kg (360 mg/m ) dose of
`sitagliptin with and without the two
`one degradation products
`(m4)
`showed that the hydrolysis
`degradatesbggd no toxicological effect. Given that the expected level of degrade at
`m4)
`associated with the MHRD of sitagliptin (100 mg; 62 mg/m2) is approximately
`6-fold less than the level assessed in the 3-month toxicity study in rats, the
`(m4)
`(modegradate is not expected to cause a toxicological effect in humans. Collectively,
`the findings of the 3—month toxicity study in rats and two negative in vitro genotoxicity studies
`(microbial mutagenesis assay and chromosomal aberration assay) support the
`one limit for
`mmdegradation product of sitagliptin.
`The Pharmacology/ Toxicology review team recommends approval of this NDA, with
`proposed labeling language referring to the metformin component to comply with the
`Glumetza PI language under Section 8.] Pregnancy and under Section 13.1 Carcinogenicity,
`Mutagenesis, Impairment of Fertility.
`
`5. Clinical Pharmacologleiopharmaceutics
`
`Please refer to the Dr. Jee Eun Lee’s clinical pharmacology review for more detail. The
`discipline team recommends approval of the NDA, for the three dose strengths of fixed-dose
`combinations between sitagliptin and extended-release metformin.
`Prior studies conducted by this applicant have assessed the effects of metformin and sitagliptin
`
`on incretin hormones. Sitagliptin stabilizes and increases active GLP-1 and GIP
`concentrations, while metformin administration results in increased to_tal GLP-l. When
`metformin and sitagliptin were given in combination, the effects on active GLP-l levels were
`complementary, with active GLP-l levels about 4-fold higher compared with levels observed
`for placebo and about 2-fold higher compared with levels observed for sitagliptin alone. While
`this study was conducted in healthy volunteers, a similar study conducted in subjects with
`T2DM confnmed these results. There is no drug-drug interaction regarding PK parameters for
`sitagliptin and metformin.
`
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`Cross Discipline Team Leader Review
`
`
`The clinical pharmacology program includes a pivotal bioequivalence (BE) study to compare
`the final market composition (FMC) of sitagliptin / metformin XR to the co-administration of
`sitagliptin and an approved metformin XR product (Glumetza). Demonstration of BE was
`needed to bridge the existing safety and efficacy data from trials with sitagliptin, metformin
`XR and the combination of sitagliptin and metformin IR to sitagliptin / metformin XR.
`
`Study 147 (BE Study)
`Briefly, this was an open label, randomized sequence, 5-period crossover study in 48 healthy
`adult volunteers who received study drug after an overnight fast and 30 minutes after
`consumption of a high fat breakfast.
`The 5 treatments were:
`Treatment A: Co-administration of sitagliptin 50 mg and Glumetza 500 mg
`Treatment B: Administration of a single sitagliptin /metformin XR 50 mg/500 mg tablet
`Treatment C: Co-administration of sitagliptin 100 mg and Glumetza 1000 mg
`Treatment D: Administration of a single sitagliptin /metformin XR 100 mg/1000 mg tablet
`Treatment E: Administration of two sitagliptin /metformin XR 50 mg/500 mg tablets
`
`The three PK comparisons were between:
`1. Sitagliptin 50 mg co-administered with Glumetza 500 mg versus single dose of sitagliptin /
`metformin XR 50 mg / 500 mg;
`2. Sitagliptin 100 mg co-administered with Glumetza 1000 mg versus single dose of
`sitagliptin / metformin XR 100 mg / 1000 mg and
`3. Sitagliptin / metformin XR 50 mg/ 500 mg (2 tablets administered once) versus sitagliptin /
`metformin XR 100 mg / 1000 mg, following FDA’s recommendation at the End of Phase 2
`meeting.
`
`
`The PK results are shown in Table 1 (for sitagliptin data) and Table 2 (for metformin data).
`
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`Cross Discipline Team Leader Review
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`Table 1. Summary statistics and statistical comparisons for plasma PK parameters of sitagliptin after
`administration of a single sitagliptin / metformin XR (MK-0431A XR) 50 mg/500 mg or 100 mg/1000 mg
`tablet, co-administration of corresponding doses of sitagliptin and metformin XR (Glumetza), or two
`sitagliptin / metformin XR 50 mg/500 mg tablets in healthy volunteers
`
`Source: Study P147 synopsis
`
`
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`Cross Discipline Team Leader Review
`
`Table 2. Summary statistics and statistical comparisons for plasma PK parameters of metformin after
`administration of a single sitagliptin / metformin XR (MK-0431A XR) 50 mg/500 mg or 100 mg/1000 mg
`tablet, co-administration of corresponding doses of sitagliptin and metformin XR (Glumetza) or two
`sitagliptin / metformin XR 50 mg/500 mg tablets in healthy volunteers
`
`Source: Study P147 synopsis
`
`
`Thus, the 90 % confidence intervals of geometric mean ratios of AUC0-inf and Cmax for both
`sitagliptin and metformin were within the pre-specified bounds of 0.8 to 1.25, and therefore
`met the BE criteria.
`
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`Cross Discipline Team Leader Review
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`Of the 48 subjects randomized, 39 completed, while 9 were discontinued for the following
`reasons: five for AEs (including one SAE of urinary retention with hospitalization, With past
`history of urethral stricture), two for protocol deviation and two for consent withdrawal.
`
`The Division of Bioequivalence and GLP Compliance (DBGC), within the newly formed
`Office of Scientific Investigations investigated the clinical and analytical sites of the pivotal
`BE study 147. The clinical site and anal
`'cal sites are the Covance Clinical Research Unit Inc.
`(Dallas, Texas) an
`respectively. DBGC’s memo in
`DARRTS, dated 7/15/11, did not reveal significant issues at the clinical site. On the other
`hand, one of the deficiencies cited in their FDA Form 483 and conveyed to Merck and to
`- had not been completed addressed. This is the text ofthe deficiency cited:
`
`
`
`The assigned DBGC inspector reviewed
`change the last sentence to bold type for emp as15 :
`
`response and concluded (the CDTL
`
`
`
`However, the OCP reviewer should ask the sponsor to repeat the bioequivalence
`determination using the new reintegrated data and reevaluate the study outcomes.”
`
`DBGC maintained that the lack of a repeat BE determination using the new reintegrated data
`submitted to the NDA would support their decision to recommend “Withheld”.
`
`OCP and DMEP, in response to this recommendation, agreed to ask for these data and a
`revised study 147 report as a “major amendmen ”, With possible extension of the review clock
`(if Merck’s response came before the PDUFA goal date). However, the manufacturing
`deficiency uncovered by DMPQ and not adequately addressed by Merck precluded any timely
`review of these new BE data in this review cycle.
`Since our decision was to issue a CR letter based on the manufacturing deficiency noted above
`(as of this writing, 7/20/2011), we will include the lack of the repeat BE determination as a
`second deficiency to be addressed as part of the applicant’s Complete Response.
`
`Stu
`
`P164
`
`ood Efi'ect Bioavailabili Stu
`
`The submission also includes a food efl'ect study, where the PK characteristics of the FDC
`components are assessed with or Without a standardized high fat breakfast. The results
`indicated that there was a significant food eflect on metformin PK following administration of
`sitagliptin / metformin XR. Afler administration of two sitagliptin / metformin XR 50 mg/1000
`mg tablets following consumption of a high-fat breakfast, the AUCo.inf for metformin increased
`by 62% compared with the fasted state. The AUCo_inf and Cm for sitagliptin and the Cm for
`
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`Cross Discipline Team Leader Review
`
`metformin decreased by approximately 6%, 17%, and 9%, respectively, compared with the
`fasted state. This effect of food on the PK of metformin was generally consistent with the
`effect of food for marketed metformin XR formulations (e.g., Glucophage XR: fed state
`metformin AUC increased by 50%, no food effect on Cmax).
`
`Study P165 (PK of sitagliptin and metformin after multiple doses)
`Study P165 was conducted to evaluate the safety, tolerability and PK of sitagliptin / metformin
`XR at the clinical dose for sitagliptin and the highest proposed total daily dose for metformin
`(two sitagliptin / metformin XR 50 mg/1000 mg tablets, or a total dose of 100 mg of sitagliptin
`and 2000 mg of metformin). Twelve subjects received this dose with the evening meal for 7
`days and PK, safety and tolerability were assessed. This is consistent with the FDA guidance,
`which recommends that “a steady-state study on the highest strength is to be performed for
`modified-release products.” Steady-state for sitagliptin and metformin was reached by Day 4
`and 5, respectively. The PK of sitagliptin / metformin XR 50 mg / 1000 mg tablets qd X 7 days
`were consistent with what would be predicted from the PK parameters after administration of a
`single sitagliptin / metformin XR tablet at the same tablet strength, and suggests that there are
`no time-dependent non-linearities for sitagliptin and metformin after multiple-dose
`administration of MK-0431A XR.
`
`Biopharmaceutics Review
`
`The applicant requested a biowaiver of the in vivo BE requirements for the sitagliptin /
`metformin XR 50/1000 mg strength based on dissolution profile comparisons of all strengths
`in different media.
`The Biopharmaceutics reviewer, Dr. Sandra Sharp, focused on:
`• Acceptability of the dissolution method and specifications
`• The in vitro alcohol interaction study
`• Acceptability of a waiver request supporting the approval of the 50/1000 mg strength;
`• Acceptability of a biowaiver request supporting the approval of the manufacturing process
`change
`• The role of dissolution in Quality by Design (QbD): this was applicable to the metformin
`component only.
`The Biopharmaceutics team found the dissolution methods and the alcohol interaction study
`acceptable and granted the waiver for the intermediate dose strength (50/1000 mg) and the
`biowaiver requested.
`6. Clinical Microbiology
`
`
`Not applicable.
`7. Clinical/Statistical- Efficacy
`
`
`As stated in the Dr. Pratt’s clinical review, the pivotal study to support this NDA is a clinical
`pharmacology study, P147, to establish BE between the final market formulation tablet of
`sitagliptin / metformin XR and the co-administration of sitagliptin and metformin XR.
`
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`Cross Discipline Team Leader Review
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`Dr. Pratt reviewed data from Study P053, a trial of sitagliptin versus placebo added to a
`background of metformin in subjects with T2DM conducted in 2006 and 2007 that had not
`been previously reviewed by FDA. The main difference between this trial and a prior pivotal
`trial of sitagliptin added on to metformin background (Study P020) is that in Study P053,
`subjects had to have moderate degrees of hyperglycemia (HbA1c between 8 and 11 % at
`randomization, fasting glucose between 130 and 280 mg/dL), despite near maximal metformin
`dose of ≥ 1500 mg qd in order to be deemed eligible. The applicant did not propose to include
`data from this trial in the Januvia, Janumet or this product’s label.
`
`Trial P053 – Design
`
`This was a multicenter, double-blind, placebo-controlled, randomized (1:1), parallel group trial
`of 30 weeks duration. The primary efficacy endpoint was the placebo-subtracted change in
`HBA1c from baseline to week 18 in the Full Analysis Set population. The trial continued with
`the same randomized groups to week 30, and the change in HbA1c from baseline at week 30
`was one of the secondary endpoints. The other important secondary endpoints were change in
`fasting and post-prandial (MMTT) glucose from baseline to week 18.
`
`Trial P053 – Results
`
`The trial was conducted from 8/21/2006 to 8/27/2007 at 24 sites, being half of these located in
`the US and the others distributed in Israel, Mexico, Peru and Austria. Of 544 subjects
`screened, 190 were enrolled meeting the glycemic range criterion mentioned above. Of the 190
`subjects enrolled, 159 completed the 30-week treatment period (87%) with similar rates of
`discontinuation among the placebo and sitagliptin groups. The groups were well balanced with
`regard to demographic and baseline disease characteristics. The mean baseline HbA1c for the
`combined groups was 9.2%, higher than most recent trials in T2DM.
`Those subjects in either group who met protocol-specified thresholds of hyperglycemia in the
`course of the trial were rescued with glipizide.
`
`Table 3 shows a summary of the results reported for Trial P053.
`
`Table 3. Summary results in Trial P053: Least square mean changes in HbA1c from baseline to week 18
`(primary endpoint) and to week 30 (secondary endpoint) and in changes in fasting and 2-hour postprandial
`glucose from baseline to week 18 (secondary endpoints) – Full Analysis Set
`
`Source: Applicant’s Table under Efficacy in the Synopsis
`
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`Cross Discipline Team Leader Review
`
`The placebo-adjusted mean glycemic effect of sitagliptin in Trial P053 (assessed by HbA1c,
`fasting or postprandial glucose) at week 18 and week 30 is greater than seen in prior trials
`where the mean HbA1c at baseline was lower (8.0 to 8.5%).
`
`The analyses of glycemic parameters in the completers population yielded almost identical
`results (Table 4).
`
`Table 4. Between groups difference in the change in HbA1c and fasting plasma glucose from baseline to
`week 18 in the Completers population
`Between Treatment Difference: Sitagliptin 100 mg
`versus placebo
`HbA1c (%)
`Fasting Plasma Glucose (mg/dL)
`
`These effects were also consistent among subgroups of the Full Analysis Set, based on
`demographic and disease baseline characteristics.
`
`Other secondary and exploratory endpoints will not be discussed in this memo, but are
`discussed in Dr. Pratt’s clinical review.
`
`
`p-value
`
`<0.001
`<0.001
`
`Difference in LS Means (95% CI)
`
`-1.0 (-1.3, -0.6)
`-25 (-37, -13)
`
`8. Safety
`
`
`No new safety issues are noteworthy from the clinical pharmacology studies and the newly
`reviewed clinical trial P053 submitted under this NDA.
`
`In the BE study P147, of the 48 subjects enrolled, there were no deaths. One SAE was
`reported: a 36 year old male hospitalized due to urinary retention four days after receiving
`sitagliptin / metformin XR 50/500 mg, who had a past medical history of urethral stricture.
`This subject was discontinued from the study. Four other subjects were discontinued from the
`study due to AEs: one subject with abdominal pain, two subjects due to rash and one subject
`due to urticaria. Common AEs were balanced among the groups. There were no laboratory-
`related AEs.
`
`In the clinical trial P053, there were no deaths or SAEs among the 96 subjects randomized to
`sitagliptin; one subject on placebo died of myocardial ischemia and four other SAEs were
`reported for placebo-treated subjects. Two subjects on placebo discontinued due to clinical
`AEs, and two subjects on sitagliptin discontinued due to lab-related AEs: one with “blood
`creatinine increased” on day 169 and one with “alanine aminotransferase increased” on day
`131. There is no new, noteworthy pattern of common AEs reported in this trial. Seventy nine
`subjects treated with sitagliptin 100 mg qd completed the 30-week trial.
`
`With the 4-month safety update, three additional clinical study reports were submitted. Dr.
`Pratt and I focused only on safety data from these trials. The safety of sitagliptin / metformin
`FDC (Janumet) in trials P066, P068 and P079 is consistent with the experience already
`reviewed for this product, and does not change the risk / benefit profile of sitagliptin or
`sitagliptin / metformin FDC.
`
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`Cross Discipline To- Leader Review
`
`9. Advisory Committee Meeting
`
`This application was not discussed before an advisory committee for the following reasons:
`
`0
`0
`
`0
`
`0
`
`it is not a first-in—class anti-diabetic therapy;
`the indication sought is based on a well-established efficacy endpoint relied upon for
`approval of other drugs across the 11 classes of anti-diabetic therapies;
`
`clinical trials assessing eflicacy and safety are typical of diabetes programs evaluated
`by FDA for approval of other anti-diabetic therapies;
`
`no unexpected safety concerns were identified in the nonclinical or clinical
`development program.
`
`10.
`
`Pediatrics
`
`Afier completing a PK study with sitagliptin 25 mg, 50 mg and 100
`the
`atnc
`ulation, Merck lans to conduct Stud 083 entitled:
`
`at sin e doses in
`
`
`
`
`ting
`is e y mcon
`Mer
`the sitagliptin approval letter.
`
`esepe atnc stu es, accor
`
`tedin
`
`The applicant’s rationale—As discussed in detail
`in Dr. Pratt’s review, the applicant will lave one or two pediatric post—marketing
`requirement (PMR) studies to evaluate dosing, safety, and eflicacy of sitagliptin/metformin
`XR in pediatric patients 10 through 17 years (inclusive) of age With T2DM. This PMR will
`include:
`(1)A- pharmacokinetic stud ofJanumet XR in
`ears inclusive of a e with T2DM.
`
`' tric atients 10 through 17
`
`Page 12 of 14
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`Reference ID: 2976469
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`Cross Discipline To- Leader Review
`
`to evaluate the
`
`
`
`double-blind, placebo-controlled stu
`
`efficacy and safety ofJanumet XR vs. metformin
`in
`
`pediatric patients who are inadequatel controll As art 0
`e sw owa ility
`s stu
`,
`of the formulation will be evaluated.
`
`
`
`
`
`
`1. PK study: submission 1 year after approval; trial completion 15 months later,
`submission 1 year after completion.
`2. Safety and Eflicacy Study: submission 6 month alter a
`submission 8 months after co
`letion
`
`roval; co
`
`letion 4 ears later;
`
`move
`tes
`ere ore FDA’s propos
`submission of the final report up to the end of 2016, pending the date ofNDA approval.
`
`FDA discussed in a teleconference with the applicant the pediatric lan for the sitagliptin/
`metformin XR FDC, and explained the rationale for the requir
`safety and
`efficacy trialin pediatric patients on J1me 28"12011 The applicant inquired whether we
`can accept the final report on the safety and efficacy of sitagliptin / metformin XRin the
`pediatric population prior to the completion of the trial with sitagliptin in monotherapy, as
`they anticipate enrollment will be faster for a trial of the FDC compared to sitagliptin
`monotherapy. FDA concurred. At the time of writing this CDTL memo, FDA is waiting
`for the revised PREA PMR to be received by the applicant, based on this discussion.
`
`1 1.
`
`Other Relevant Regulatory Issues
`
`As stated in the Introduction to this CDTL memo, the applicant submitted the NDA under 505
`(b)(2), with the listing of Glumetza as the RLD. Since the applicant has full right of reference
`to Depomed’s Glumetza, the application was reclassified as 505(b)(1).
`
`Although FDA had asked the applicant in December 2010 to submit a REMS with Medication
`Guide (similar to the REMS for Januvia and Janumet), after issuance of the FDA guidance
`allowing Medication Guide-only products to be approved without a REMS, the REMS
`requirement was waived for this product, and for the other sitagliptin-based products as well.
`
`12.
`
`Labefing
`
`With the ori '
`
`NDA submission,
`
`Page 13 of 14
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`Cross Discipline Team Leader Review
`
`The proprietary name is still under review by DMEPA (medications errors) at the time of
`writing this CDTL memo. DDMAC had no objection to this proprietary name, regarding the
`potential for promotion.
`
`The product will have a Medication Guide to convey to patients the risks of pancreatitis,
`
`(but)
`
`and Janumet.
`
`These are the same issues covered in the Medication Guides for Januvia
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`0 Recommended Regulatory Action
`
`At the time of writing this CDTL memo, I recommend a Complete Response letter to the
`applicant, listing the manufacturing deficiency noted by DMPQ during inspection and the
`DBGL deficiency (lack of BB determination based on reanalysis of reintegrated data).
`
`0 Risk Benefit Assessment
`
`Pending resolution of the manufacturing issues, the risk benefit assessment for sitagliptin/
`metformin XR is favorable, similar to sitagliptin / metformin immediate-release.
`
`0 Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`This application will not need a REMS. Risks will be managed by appropriate professional
`labeling, a Medication Guide and continued pharmacovigilance.
`
`0 Recommendation for other Postmarketing Requirements and Commitments
`
`The requirement for PREA-related PMRs is discussed in Section 10 of this memo and in Dr.
`Pratt’s clinical review.
`
`0 Recommended Cements to Applicant
`
`Labeling (package insert and Medication Guide) discussions with the applicant are ongoing at
`this time, as are timelines for the pediatric studies. No other comments need to