saxagliptin
`
`Page 1 of 2
`
`Hartford, Rachel
`MW
`
`From:
`
`Hartford, Rachel
`
`'nt:
`
`Monday, June 22, 2009 1:46 PM
`
`a:
`
`'Smith, Pamela'
`
`Subject: FW: saxagliptin
`
`Pam.
`
`We have reviewed the clarification below and are still unclear.
`
`it is stated that 80 patients in Study —039 and 22 patients in Study -O38 had a frozen A1c sample used in the calculation of change
`from baseline to Week 24 (LOCF). This seems to be at odds with the statement below that only 8 patients were excluded from -
`039 and no patients were excluded from -038 for calculating the change from baseline in HbA1c.
`
`Are you stating in the last paragraph that frozen A1 c samples from these 102 patients would be classified as "missing" for
`calculating the primary efficacy endpoint of change from baseline in HbA1c?
`-
`
`Rachel
`"Mmmmm
`
`From: Smith, Pamela [mailtozpamela.smith@bms.com]
`Sent: Tuesday, June 09, 2009 12:13 AM
`To: Hartford, Rachel
`Subject: RE: saxagliptin
`
`Dear Rachel,
`
`Please see below for our clarification Response regarding your query regarding the number patients/samples used in the
`ilation of the primary endpoint in the studies in which patients from Russia were enrolled and for which samples were
`an:
`
`Appendix 1.1 and Appendix 2.1 of the response to Question 2 of May 11 reports the number of subjects with at least one sample ‘
`that was frozen as a result of the Russian export suspension and subsequently used in the calculation of change from baseline to
`Week 24 (LOCF). A total of 80 subjects from study CV181039 had at least one frozen sample and 22 subjects from study
`CV181038 had at least one frozen sample.
`
`Tables 1 and 2 of the response to Question 3 of May 11 reports the change from baseline in A1C including all data (top panel)
`and excluding data from the frozen samples (bottom panel) to illustrate the impact on excluding the frozen samples. The
`number of subjects data that were totally excluded from the analysis of A1C change from baseline due to the exclusion of the
`frozen samples was 8 from study CV181039, and no subject data were totally excluded from study CV181038. The analysis of
`A1C change from baseline (LOCF) excluding the frozen samples applied the same rules as in the Clinical Study Reports, ie, the last
`value prior to Week 24, prior to rescue, was used. Thus, the majority of subjects who had at least one frozen sample had A1C
`data from other (non frozen) samples that were used in the LOCF analysis.
`
`I hope this is helpful. Please let me know if we should formally submit this clarification response to the NDA.
`
`Thanks,
`
`Pam
`
`. rom: Hartford, Rachel [mailto:Rachel.Hartford@fda.hhs.gov]
`Sent: Thursday, June 04, 2009 5:27 PM
`To: Smith, Pamela
`Subject: RE: saxagliptin
`
`6/29/2009
`
`

`

`saxagliptin
`
`Good Afternoon Pam,
`
`-
`
`'
`
`Page 2 of 2
`
`Please clarify the n in Tables 1 and 2 under Response 3. These "n" do not appear consistent with the Response to question 1
`where it states that 80 patients in CV181039 had a frozen Aic sample used in the calculation of the primary endpoint and tha’
`patients in CV181038 had a frozen Aic sample used in the calculation of the primary endpoint.
`‘
`
`Thank you,
`
`Rachel
`
`WF
`
`'
`
`rom: Smith, Pamela [mailtozpamela.smith@bms.com]
`Sent: Tuesday, June 02, 2009 10:25 AM
`To: Hartford, Rachel
`Subject: RE: saxagliptin
`
`Hi Rachel,
`
`Attached please find Responses to Question 1, 2, and 3 ofthe May 11 query about lab samples involved in the suspension of
`shipment of samples from Russia We will formally submit the Responses to all 3 questions this week.
`
`Pam
`
`
`From: Hartford, Rachel [mailtozRacheLHartford@fda.hhs.gov]
`sent: Monday, May 11, 2009 9:40 AM
`To: Smith, Pamela
`Subject: saxagliptin
`
`Good Morning Pam,
`
`We have a few additional information requests regarding the suspension of samples from Russia:
`
`1. Is there evidence to show that the freezing and thawing of samples did not affect reliability of the data?
`2. How many samples (total and by study) used for the efficacy analyses were affected as a result of the suspension?
`3. If the affected samples were excluded, would the efficacy results be consistent?
`
`Thanks,
`
`Rachel
`
`W a. Wad
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@£da.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`6/29/2009
`
`

`

`Hartford, Rachel
`
`M P
`
`rom:
`5ent:
`To:
`Subject:
`
`'
`
`Hartford, Rachel
`Thursday, June 04, 2009 5:30 PM
`'Smith. Pamela'
`Lymphocyte request
`
`Hello again,
`
`Please conduct the following subgroup analyses on the phase 2/3 data for lymphocyte counts (mean changes, shifts,
`outliers):
`
`1. Patients on strong'CYP3A4 inhibitors (e.g., Ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole,
`nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin)
`
`2. Patients on moderate CYP3A4 inhibitors (e.g., Diltiazem, aprepitant, erythromycin, fluconazole, fosamprenavir,
`verapamil, amprenavir)
`
`3. Asians
`
`Thanks,
`
`Rachel
`
`mam
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`1Tood and Drug Administration
`sachel.hartfordga;fda.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`saxagliptin
`
`Page 1 of 2
`
`Hartford, Rachel"mm—MW
`
`From:
`
`Hartford, Rachel
`
`nt:
`
`Thursday, June 04, 2009 5:27 PM
`
`.0:
`
`'Smith, Pamela'
`
`Subject: RE: saxagliptin
`
`Good Afternoon Pam,
`
`Please clarify the "n" in Tables 1 and 2 under Response 3. These "n" do not appear consistent with the Response to question 1,
`where it states that 80 patients in CV181039 had a frozen A1c sample used in the calculation of the primary endpoint and that 22
`patients in CV181038 had a frozen Aic sample used in the calculation of the primary endpoint.
`
`Thank you,
`
`Rachel
`
`WWW
`
`From: Smith, Pamela [mailto:pamela.smith@bms.com]
`Sent: Tuesday, June 02, 2009 10:25 AM
`To: Hartford, Rachel
`Subject: RE: saxagliptin
`
`Hi Rachel,
`
`Attached please find Responses to Question 1, 2, and 3 ofthe May 11 query about lab samples involved in the suspension of
`shipment of samples from Russia We will formally submit the Responses to all 3 questions this week.
`
`
`
`
`
`From: Hartford, Rachel [mailtozRacheLHartford@fda.hhs.gov]
`Sent: Monday, May 11, 2009 9:40 AM
`To: Smith, Pamela
`Subject: saxagliptin
`
`Good Morning Pam,
`
`We have a few additional information requests regarding the suspension of samples from Russia:
`
`1. Is there evidence to show that the freezing and thawing of samples did not affect reliability of the data?
`2. How many samples (total and by study) used for the efficacy analyses were affected as a result of the suspension?
`3. If the affected samples were excluded, would the efficacy results be consistent?
`
`Thanks,
`
`'
`
`Rachel
`
`mew
`Regulatory Project Manager
`"ision of Metabolism and Endocrinology Products
`iter for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.gov
`301—796-0331 (phone)
`
`6/29/2009
`
`

`

`saxagliptin
`
`301-796—97 12 (fax)
`
`Page 2 of 2
`
`6/29/2009
`
`

`

`PreApproval Safety Conference
`Overview of Meeting
`
`MEETING DATE:
`
`June 2, 2009
`
`V TIME:
`
`8:00 — 9:30am
`
`LOCATION:
`
`FDA - Federal Research Facility
`White Oak Building 22, Rm 3270
`10903 New Hampshire Avenue
`Silver Spring, MD
`
`APPLICATION:
`
`NDA 22-350 Onglyza (saxagliptin) tablet
`
`ATTENDEES (alphabetic): (Title and Office/Division)
`
`Fred Alavi, Ph.D.
`Pharmacology/Toxicology Reviewer, Division of Metabolism and Endocrinology Products
`(DMEP)
`
`Ali Al Hakim, Ph.D.
`
`-
`
`Chief, Division of Pre-Marketing Assessment I (DPA-l)
`
`Lina Aljuburi, Pharm.D.
`Chief, Project Management Staff, DMEP
`
`Todd Bourcier, Ph.D.
`»
`Supervisor, Phannacology/Toxicology, DME
`
`Jessica Diaz, RN, BSN
`Patient Product Information Reviewer, Division of Risk Management
`
`Amy Egan, MD.
`Deputy Director for Safety, DMEP
`
`Rachel Hartford
`
`Regulatory Project Manager, DMEP
`
`John Hill, Ph.D.
`Chemistry Reviewer, DPA-I
`
`Hylton Joffe, M.D., M.M.Sc.
`Clinical Diabetes Team Leader, DMEP
`
`

`

`ADDITIONAL ITEMS:
`
`1. Status of Labeling Reviews
`PLR format review — complete
`High-level DRISK review — complete
`DDMAC initial review — complete
`DMEPA initial review — complete
`CMC initial review — complete
`
`9999‘?
`
`2. D81 Inspection: Clinical Inspection Summary — complete
`
`3. Sign—off procedure and schedule
`Action Package due to the Division Director — 2-2Jun09
`Action Package due to the Immediate Office — 9Jul09
`Action Letter due to SRT — l3Ju109
`
`5199‘?
`
`PDUFA goal date — 31Ju109
`
`Supervisory Concurrence:
`Lina Aljuburi
`Chief, Project Management Staff
`
`

`

`SmeiSSiO”
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22350
`
`ORIG 1
`
`' BRISTOL MYERS
`SQUIBB CO
`
`SAXAGLIPTIN
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`RACHEL E HARTFORD
`
`07/30/2009
`
`

`

`Hartford, Rachelm
`
`‘rom:
`sent:
`To:
`Subject:
`
`Hello Pam,
`
`Hartford, Rachel
`Tuesday, May 12, 2009 1:37 PM
`'Smith, Pamela'
`Request
`
`We have an additional request:
`
`Provide an analysis of pancreatitis cases occurring with saxagliptin and comparators in your controlled phase 2/3 clinical
`trials. Present data by individual study and for the placebo-controlled pooled safety populations. lnclude a description of
`how events were identified.
`
`Thank you,
`
`Rachel
`
`mama
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`rachel.hartford@fda.hhs.aov
`
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Rachel E Hartford
`5/12/2009 01:39:37 PM
`CSO
`
`

`

`Hartford, Rachelm
`
`‘rom:
`Jent:
`To:
`Subject:
`
`Hartford, Rachel
`Monday, May 11, 2009 9:40 AM
`'Smith, Pamela'
`saxagliptin
`
`Good Morning Pam,
`
`We have a few additional information requests regarding the suspension of samples from Russia:
`
`1. ls there evidence to show that the freezing and thawing of samples did not affect reliability of the data?
`2. How many samples (total and by study) used for the efficacy analyses were affected as a result of the
`suspension?
`3. if the affected samples were excluded, would the efficacy results be consistent?
`
`Thanks,
`
`Rachel
`
`W£.9£aatfiaxd
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford®fda.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Rachel E Hartford
`
`5/11/2009 02:38:37 PM
`CSO
`
`

`

`
`
`wé DEPARTMENTOFHEALTH & HUMAN SERVICES MP”93"“Sewice
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 22-350
`
`Bristol-Myers Squibb Company
`Attention: Pamela Smith, MD.
`Group Director, Global Regulatory Strategy
`PO. Box 4000 '
`
`Princeton, NJ 08543-4000
`
`Dear Dr. smith:
`
`Please refer to your June 30, 2008, new drug application (NDA) submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for Onglyza (saxagliptin) tablet, 2.5 mg and 5 mg.
`
`On April 15, 2009, we received your April 15, 2009, amendment to this application. This
`submission contains BMS study report DN08072: Saxagliptin (EMS-477118) and Metformin
`(BMS-207150): Oral Combination Study of Embryo-Fetal Development in Rats. This is a
`major amendment. The receipt date is within three months of the user fee goal date. Therefore,
`we are extending the goal date by three months to provide time for a full review of the
`submission. The extended user fee goal date is July 30, 2009.
`
`If you have any questions, call Rachel Hartford, Regulatory Project Manager, at 301-796-0331.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mary H. Parks, MD.
`Director
`
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`Mary Parks
`4/20/2009 11:50:43 AM
`
`

`

`
`
` é DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`Food and Drug Administration
`Rockville, MD, 20857
`
`3/Q5/0?
`
`IND63,634
`c
`,r
`NDA 22-35
`
`W!)
`
`Bristol-Myers Squibb Company
`Attention: Pamela Smith, MD.
`Group Director, Global Regulatory Strategy
`PO. Box 4000
`
`Princeton, NJ 08543-400
`
`Dear Dr. Smith:
`
`Please refer to your Investigational New Drug Applications (INDs) submitted under section
`505(i) of the Federal Food, Drug, and Cosmetic Act for saxagliptin tablet and
`saxagliptin/metformin XR fixed—dose combination’tablets and your new drug application (NDA)
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for saxagliptin
`tablet, 2.5 mg and 5 mg.
`
`) dated March 6, 2009, containing a
`We also refer to your amendments to INDs 63,634 L ‘
`15 day non—clinical safety report. The safety report contains information regarding results of
`neural tube defects and other malformations in rats during the embryofetal development study.
`
`M4)
`
`We do not agree that the current data are sufficient to exclude a potential interaction of the
`saxagliptin/metformin combination in causing the teratogenic effect observed in this study. We
`therefore request that you take the following actions:
`
`1. Submit the full report of the rat embryofetal development study with the
`saxagliptin/metformin combination along with relevant historical incidence data as soon
`as it becomes available.
`
`2. Repeat the rat embryofetal development study with a design that includes separate arms
`for metformin alone, saxagliptin alone, and the combination of saxagliptin + metformin.
`We also ask that you conduct an embryofetal development study in rabbits with a similar
`study design.
`
`

`

`3. Because saxagliptin would be commonly used in conjunction with metformin if it
`receives marketing approval, propose language that discloses the teratogenic finding in
`the marketing label for saxagliptin (NDA 22-350).
`
`As sponsor of this IND, you are responsible for compliance with the Federal Food, Drug, and
`Cosmetic Act and the implementing regulations (Title 21 of the Code of Federal Regulations).
`These responsibilities include (1) reporting any unexpected fatal or life-threatening adverse
`experience associated with use of the drug by telephone or fax no later than 7 calendar days after
`initial receipt of the information [21 CFR 312.32(c)(2)]; (2) reporting any adverse experience
`associated with use of the drug that is both serious and unexpected in writing no later than 15
`calendar days after initial receipt of the information [21 CFR 3 12.32(c)( 1)]; and (3) submitting
`annual progress reports (21 CFR 312.33).
`
`If you have any questions, call Rachel Hartford, Regulatory Project Manager, at (301) 796-0331.
`
`Sincerely,
`
`{See appended eleclronic signature page}
`
`Mary H. Parks, MD.
`Director
`
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic recOrd that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Todd Bourcier
`3/25/2009 01:09:39 PM
`Signing for Dr. Parks
`
`

`

`Hartford, Rachelm
`
`‘rom:
`Sent:
`To:
`Subject:
`
`Hello Pam,
`
`,
`Hartford, Rachel
`Wednesday, March 18, 2009 2:01 PM
`'Smith, Pamela'
`Saxagliptin statistical request
`
`The interpretation of the cardiovascular events is dependent on the observed confidence intervals. in turn, the size of the
`confidence interval is dependent on the statistical method used. For example, in your response to the FDA January 2009
`request, you computed an incidence rate ratio of 0.48 with 95% confidence interval of 0.24 to 0.96 for Custom MACE
`(ST+LT); in your briefing document, you present an incidence rate ratio of 0.48 with 95% confidence interval of 0.25 to
`0.90. Clearly the interpretation of these results do not differ. However it is important to us to understand precisely the
`methods that led to the differing intervals.
`
`Please provide us with the name of the software packages you used and an example of the coding you used for the
`following methods:
`
`0 Cox proportional hazards model for computing the overall stratified risk ratio
`
`0
`
`0
`
`Exact procedure for computing the overall stratified risk ratio
`
`Exact procedure for Poisson processes for computing the overall stratified incidence rate ratio
`
`0 Mantel-Haenszel method for computing the overall stratified incidence rate ratio
`
`0 Mantel-Haenszel method for computing the overall stratified risk difference
`
`Ne have applied some of these methods in our analyses of the CV data and so this information will help us in comparing
`our programs to yours.
`
`Please provide a response timeframe.
`
`Thank you,
`
`Rachel
`
`M a.W
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`Hartford, RachelM
`
`'-'rom:
`Sent:
`To:
`Subject:
`
`Hartford, Rachel
`Wednesday, March 18, 2009 3:13 PM
`“Smith, Pamela'
`Integrated Summary of Safety Appendix request
`
`Good Afternoon Pam,
`
`Please see our request below and provide a response as soon as possible.
`
`Certain laboratory analyses could not be located in the Integrated Summary of Safety Appendix. For the pooled
`monotherapy studies:
`1. Please provide the location of the following labs (expressed as change from baseline to endpoint) : basophils (%),
`eosinophils (%), erythrocytes (%), hematocrit, hemoglobin, lymphocytes (%), monocytes (%), leukocytes (%), neutrophils
`(%), direct bilirubin, BUN, chloride, potassium, sodium, uric acid, and urinalysis (creatinine, microalbumin,
`microalb/creatinine ratio, pH, SG).
`If these have not been provided, please do so for the pooled monotherapy population
`only.
`.
`2. In addition, please provide the location for shift tables for the following labs for the pooled monotherapy studies:
`hemoglobin, hematocrit, WBCs, sodium, potassium, creatinine (please provide if not submitted).
`
`Thank you,
`
`Rachel
`
`W€.Wd
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.g0v
`301-796-0331 (phone)
`' 301—796-9712 (fax)
`
`

`

`Hartford, Rachel
`mum—“WM
`
`Page 1 of 1
`
`From:
`
`Hartford. Rachel
`
`int:
`
`Friday, March 13, 2009 9:10 AM
`
`.0:
`
`'Smith, Pameia'
`
`Subject: RE: One more CMC Clarification
`
`Pam,
`
`The wording below is acceptable.
`
`Thanks,
`
`Rachel
`
`
`
`From: Smith, Pamela [mailtozpamela.smith@bms.com]
`Sent: Thursday, March 12, 2009 4:02 PM
`To: Hartford, Rachel
`Subject: One more CMC Clarification
`
`Dear Rachel,
`
`Just one (hopefully) last CMC clarification, re spelling, ca pltalization, etc. Please see below for the exact proposed wording to
`confirm acceptability:
`
`Each tablet contains 2.79 mg saxagliptin hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin.
`
`,n tablet contains 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin.
`
`Thanks in advance,
`
`Pam
`
`3/13/2009
`
`

`

`Hartford, Rachel
`
`WWW-"WWW
`From:
`Hartford, Rachel
`
`Page I of 2
`
`ant:
`
`Thursday, March 12, 2009 8:49 AM
`
`.0:
`
`'Smith, Pamela'
`
`' Subject: RE: CMC Clarification
`
`Pam,
`
`We found the alternative proposal acceptable. Sorry for the confusion. Thus the labeling will read:
`
`Each tablet contains 2.79 mg saxagliptin HCl (anhydrous) equivalent to 2.5 mg saxagliptin,
`' or
`
`Each tablet contains 5.58 mg saxagliptin HCl (anhydrous) equivalent to 5 mg saxagliptin
`
`Thanks,
`
`Rachel
`
`From: Smith, Pamela [mailtozpamela.smith@bms.com]
`Sent: Wednesday, March 11, 2009 10:12 PM
`To: Hartford, Rachel
`Subject: CMC Clarification
`
`Dear Rachel,
`
`1 “er our conversation, here is the CMC item for which we would like clarification. Please see below.
`.ks,
`
`Pam
`
`PS: I also have a followup question about the Tradename approval letter. I will call you on Thursday.
`
`Clarification Request:
`The Agency indicated that our response to Question 12 of the December 11 FDA CMC questions was acceptable. However, we
`repeated our original proposal as our preferred option:
`(1)
`
`Each tablet contains 2.5 mg saxagliptin (as saxagliptin hydrochloride),
`or
`
`Each tablet contains 5 mg saxagliptin (as saxagliptin hydrochloride)
`
`And we also proposed this alternative if the original proposed wording was not acceptable:
`(2)
`
`("I
`é;
`
`/
`/1
`
`.
`
`M4)
`
`Uur preference would be to used the originally proposed language:
`(1)
`
`3/12/2009
`
`

`

`Each tablet contains 2.5 mg saxagliptin (as saxagliptin hydrochloride),
`or
`
`Each tablet contains 5 mg saxagliptin (as saxagliptin hydrochloride)
`
`Does the Agency agree that this will be acceptable?
`
`' Page 2 of2
`
`3/12/2009
`
`

`

`slswu-
`3.0(I
`
`pll
`
`s)a
`s?
`5
`‘b4.
`(“an
`
`g DEPARTMENTOFHEALTH&HUMANSERVICES
`
`E‘
`
`Public Health Servtce
`
`Food and Drug Administration
`Rockville, MD 20857
`
`.
`
`,
`
`.
`
`IND 63,634
`NDA 22-350
`
`Bristol-Myers Squibb Company
`
`Attention: Pamela Smith, MD.
`
`Group Director, Global Regulatory Strategy
`PO. Box 4000
`
`PROPRIETARY NAME REQUEST
`- CONDITIONALLY ACCEPTABLE
`
`5/l//0 7
`
`Princeton, NJ 08543-400
`
`Dear Dr. Smith:
`
`Please refer to your Investigational New Drug application (IND) submitted under 505(i) of the
`Federal Food, Drug, and Cosmetic Act and your New Drug Application (NDA) submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act, for saxagliptin tablet, 2.5 mg and 5 mg.
`
`We also refer to your May 30, 2008, correspondence to IND 63,634, received June 2, 2008, requesting
`review of the proposed proprietary name, Origlyza. This proposed proprietary name also applies to
`NDA 22-350, submitted and received on June 30, 2008.
`
`We have completed our review of Onglyza and have concluded that it is acceptable.
`
`Onglyza will be re-reviewed 90 days prior to the approval of the NDA. If we find the name
`unacceptable following the re-review, we will notify you.
`I
`
`If gig of the proposed product characteristics as stated in your May 30, 2008, submission are altered
`prior to approval of the marketing application, the proprietary name should be resubmitted for review.
`
`If you have any questions, call Rachel Hartford, Regulatory Project Manager, at (301) 796—033 1.
`
`Sincerely,
`
`{See appended eleclronic sigI-miur'e page}
`
`Mary H. Parks, MD.
`Director
`
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Mary Parks
`3/11/2009 11:27:38 AM
`
`

`

`Hartford, Rachel
`
`From:
`Sent:
`To:
`Subject:
`
`Hartford. Rachel
`Monday, March 09, 2009 9:18 AM
`'pamela.smith@bms.com'
`Label Comments
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Pam,
`
`The Division of Medication Error Prevention and Analysis developed the following label comments.
`
`1. 2.5 mg; 30 and 90 Count Container Label
`
`Revise the prominence of the established name to ensure that it is V: the size of the proprietary name, taking into
`account all pertinent factors, including typography, layout, contrast, and other printing features in accordance
`with 21 CFR 201.10 (g)(2) which will improve the prominence of the established name.
`
`2. Sample Blister Folder Label and Sample Tray
`
`a. Relocate the dosage form and strength to be in accordance with CFR 21 CFR 201 .57(a)(2) so that it is not
`located between the proposed proprietary name and the established name. We also recommend increasing the
`prominence of the 5 mg per tablet statement by increasing the size and font on the primary display panel. This
`will increase the visibility of the strength and dosage form and make this pertinent information more readily
`accessible to practitioners.
`
`'b. The dosage form should directly follow the established name, i.e. Saxagliptin Tablets.
`
`c. Improve the readability of the proprietary name, Onglyza, by removing the lighter font on the middle letters,
`gly. We recommend replicating the presentation of the name on the trade container label.
`
`d. Delete the numbered days on the blister folder as they are presented in a nonintuitive manner (i.e., vertical
`rather then horizontal). The tablets in this packaging configuration do not have to be taken in a specific order
`and thus do not require the numbered days of the week which may be confusing to the patients.
`
`Regards,
`
`Rachel
`
`mama
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartf0rd@fda.hhs.g0v
`301~796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`Hartford, Rachel
`
`From:
`Sent:
`Toi
`Subject:
`
`Hartford, Rachel
`Monday, March 09, 2009 6:47 AM
`'pamela.smith@bms.com'
`Feedback on the CMC Reponses
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Good Morning Pam.
`
`We have evaluated your dissolution testing proposal (February 26, 2009) submitted in response to CMC deficiency #5
`(December 11. 2008). We cannot accept your proposal in light of the 21 CFR 211.165 requirement that each batch of
`drug product be evaluated for conformance to specifications. include dissolution testing as part of routing lot release and
`stability testing for all strengths of the saxagliptin drug product.
`
`Your responses to the other CMC deficiencies communicated in the December 11, 2008 letter have been evaluated and
`deemed to be adequate.
`
`We recognize that there could be possible alternative approaches to ensure bioavailability of the drug product. We would
`be willing to discuss alternatives approaches to dissolution testing. Because of the review timelines, such discussion may
`be more appropriate post-approval.
`
`Thank you,
`
`Rachel
`
`WEW
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`Hartford, RachelM
`
`From:
`Sent:
`To:
`Subject:
`
`Hartford, Rachel
`Friday, March 06, 2009 12:09 PM
`'pamela,smith@bms.com'
`Location Request
`
`Follow Up Flag:
`Flag Status:
`
`-
`
`Follow up
`Purple
`
`Pam,
`
`We have the following request and would like a response today if possible:
`
`Please specify the location of the dataset for subjects with MAs of lymphocytes (should include Day of event).
`
`Thank You,
`
`Rachel
`
`mew
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.0,=0v
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`Hartford, Rachel
`
`rom:
`Sent:
`To:
`Cc:
`Subject:
`
`a F
`
`Hartford, Rachel
`Thursday, February 05, 2009 2:59 PM
`'pamela.smith@bms.com'
`'joseph.lamendola@bms.com'; Patrice E Todd
`CMC Request
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Pam,
`
`We have an additional CMC request. Please provide COA's (including specifications for specific activity) for r,
`and ‘7
`V
`) in the planned February 20, 2009 CMC response.
`
`:3
`
`b(4)
`
`Thanks,
`
`Rachel
`
`mafia/(that
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.l1hs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`Hartford, Rachel
`
`' From:
`Sent:
`To:
`Subject:
`
`Hartford, Rachel
`Friday, January 30, 2009 2:27 PM
`'pamela.smith@bms.corn'
`Baseline Comorbidity Information Question
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Pam,
`
`One more question:
`
`Aside from the baseline demographic and diabetes characteristics provided in the Appendix to the Summary of
`Clinical Safety, where can baseline comorbidity information (hypertension, CAD, dyslipidemia, etc.) be found?
`
`Hope you have a great weekend,
`
`Rachel
`
`mama
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.gov
`301-796-0331 (phone)
`501-796—9712 (fax)
`
`

`

`Hartford, Rache
`
`From:
`Sent:
`To:
`Cc:
`Subject:
`
`Hartford, Rachel
`Wednesday, January 28, 2009 1:26 PM
`'pamela.smith@bms.com'
`'joseph.lamendola@bms.com'; Patrice E Todd
`Saxagliptin MACE request
`'
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Hello Pam,
`
`Please respond to the following ASAP:
`
`1. It appears that terms that were not listed as "Custom MACE" terms by the Division were used in your Custom
`MACE analysis. Examples include "pulmonary embolism " and "cardiac failure congestive". Please clarify this
`apparent discrepancy.
`
`2. Provide narratives for the following subjects with the PT "infarction": 181039-199-581, 181040-39-1735,
`181013-231-335.
`
`Thanks,
`
`Rachel
`
`mama
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartford@fda.hhs.gov
`301-796-0331 (phone)
`301-796-9712 (fax)
`
`

`

`
`
`Hartford, Rachel ‘m
`
`From:
`Sent:
`To:
`Subject:
`
`Hartford, Rachel
`Thursday, January 15, 2009 10:29 AM
`'pamela.smith@bms.com‘
`NDA 22-350 Information Request
`
`Follow Up Flag:
`Flag Status:
`
`Follow up
`Purple
`
`Good Morning Pam,
`
`l have a Clinical Pharmacology question for you. Were any drug interaction studies of saxagliptin with rifampin and oral
`contraceptive conducted? If so, please submit the study reports to the NDA.
`
`Thank you,
`
`Rachel
`
`W€.W
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`rachel.hartfordgagfdahhsgov
`301-796-0331 (phone) .
`301—796-97 12 (fax)
`
`

`

`- Hartford, Rachel
`
`Page 1 of 2
`
`From:
`
`ant:
`
`. o:
`
`Cc:
`
`Hartford, Rachel
`
`Tuesday, January 13, 2009 12:01 PM
`
`'pamela.smith@bms.com’
`
`Aljuburi, Lina
`
`Subject:
`
`RE: Clarification Request
`
`Follow Up Flag: Follow up
`
`Flag Status:
`
`Purple
`
`Pam,
`
`Our responses to your clarification requests are inserted into the text of your email below (Bold Blue).
`
`Sincerely,
`
`Rachel
`
`
`
`From: pamela.smith@bms.com [mailto:pamela.smith@bms.com]
`Sent: Monday, January 12, 2009 11:01 PM
`To: Hartford, Rachel; Aljuburi, Lina
`Subject: Clarification Request
`
`Dear Rachel
`
`(and Lina)
`
`=er my telephone conversation Monday evening January 12 with Lina, please see below for our urgent request for
`c...r'ification of two items in the Information Request Letter issued by the Agency January 11, 2009 for Saxagliptin
`NDA 22-350. We hope these queries can be quickly clarified so that we can complete and submit our responses by
`January 21, as requested in the Agency's letter. We are available for a teleconference on Tuesday if needed.
`
`Thanks very much to both of you for your assistance,
`
`Pam
`
`Question IB Re the "additional analysis population": The Sponsor proposes to provide analyses using the 120-day
`safety update database, as this version is the most complete and up-to-date version of the saxagliptin data that has been
`submitted to the FDA for its review of the NDA. Does the Agency agree?
`
`Yes, the additional analysis should use the 120-safety update database. Please note that the analysis of the short-term
`period should exclude data from patients after initiation of rescue (these patients move directly into the long-term
`extension and their additional data should be included in the second analysis (13.)).
`
`Question 11. Re MACE events to be included in the analysis: The sponsor acknowledges the FDA request (e-mail
`correspondence, December 19, 2008) to "resubmit the table of MACE events incorporating these subjects:
`
`—CV181011-10—459: narrative uses the term “acute coronary syndrome”
`-CV181038-87-81 1: narrative describes discharge diagnosis “extensive AW STEMI”
`
`Sponsor also acknowledges the FDA request (letter issued January 9, 2009)
`or nonfatal events, use MedDRA Preferred Terms as they were originally assigned in the NDA submission” and to
`“...not use post hoc adjudication for nonfatal events.”
`
`The sponsor proposes, in accordance with the FDA recommendation (December 19 email) that subject CV181038—
`
`3/9/2009
`
`

`

`878-811 should be designated as having had a MACE event and should be included in the MACE analysis requested
`January 11, 2009
`
`Page 2 of 2
`
`Additionally, the Sponsor proposes that the AB for subject CV181011-10-459 (“Chest Pain and ECG abnormalities”)
`does not qualify as a MACE event and should not be included in the analysis requested in the letter issued January 1’
`2009 for the following reasons: The narrative reflects the fact that the investigator clearly documented his amended
`opinion that the event did not represent an “acute coronary syndrome”. In response to this question he further provided
`to BMS the medical record documents which were available at the site support