CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`202343Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`

`

`PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`NDA #fl’roduct Name:
`
`202-343/JUVISYNC (sitagliptin and simvastatin fixed-dose combination
`[FDCD
`
`PMR/PMC Description: A randomized,,double-blind. active-controlled clinical trial to study the effect
`of sitagliptin and simvastatin FDC versus sitagliptin on glycemic control in
`type 2 diabetic patients on background metformin therapy.
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`04/30/2012
`
`01/29/2015
`07/29/2015
`
`1. During application review. explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`
`E] Unmet need
`E] Life-threatening condition
`[I Long-term data needed
`[I Only feasible to conduct post—approval
`E] Prior clinical experience indicates safety
`El Small subpopulation affected
`E] Theoretical concern
`IE Other
`
`Meta-analyses in the published literature have shown increases in fasting plasma glucose and
`hemoglobin AlC in patients receiving statin therapy. including simvastatin. The applicant
`conducted a meta-analysis of clinical trial data with simvastatin in diabetic patients showing that
`there was no clinically significant worsening of glycemic control. However, this involved a limited
`number of subjects and was not a rigorous appraisal of this safety concern. The applicant is being
`required to further assess this safety signal in a dedicated clinical trial. It is understood that the
`
`individual components in this FDC are already available and are frequently being co-administered.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk Ifthe FDAAA PMR is created post-approval. describe the “new
`safety information.”
`
`The goal of the study is to conclusively demonstrate the effect of simvastatin on glycemic control in
`type 2 diabetic patients being treated with sitagliptin and simvastatin FDC on a background of
`
`metformin therapy versus type 2 diabetic patients being treated with sitagliptin.
`
`PMR/PMC Development Template
`
`Last Updated 10/6/2011
`
`Page 1 of 3
`
`Reference ID: 3025589
`
`

`

`3.
`
`If the study/clinical uial is a PMR, check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`[:1 Accelerated Approval (subpart H/E)
`E] Animal Efficacy Rule
`D Pediatric Research Equity Act
`[Z FDAAA required safety study/clinical trial
`
`-
`
`-
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`E] Assess a known serious risk related to the use of the drug?
`[Z Assess signals of serious risk related to the use of the drug?
`[I Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`D Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if such an analysis will not be sufficient to
`assess or identify a serious risk
`
`E] Analysis using pharmacovigjlance gistem?
`Do not select the above studecIinical trial type if: the new pharrnacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`D Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies). animal studies. and laboratory
`experiments?
`Do not select the above study We if. a study will not be sufficient to identify or assess a
`serious risk
`
`IX] Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`
`A randomized, double-blind, active-controlled clinical trial in Z 200 type 2 diabetic subjects per
`treatment arm on background metformin therapy randomized to sitagliptin and simvastatin FDC or
`sitagliptin alone for Z 16 weeks to assess the effect of simvastatin on glycemic control. Glycemic
`control should be assessed by the change in HbAlc (primary endpoint), change in fasting plasma
`
`glucose, and change in 2-hour postprandial glucose.
`
`Reguired
`
`E] Observational pharmacoepidemiologic study
`B Registry studies
`X Primary safety study or clinical trial
`El Pharmacogenetic or pharmacogenomic study or clinical trial ifrequired to further assess safety
`E] Thorough Q-T clinical trial
`E] Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`PMRIPMC Development Template
`
`Last Updated 1016:9011
`
`Page 2 of 3
`
`Reference ID: 3025589
`
`

`

`Continuation 0
`
`tion 4
`
`[:1 Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`[I Pharmacokinetic studies or clinical trials
`D Drug interaction or bioavailability studies or clinical trials
`El Dosing trials
`E] Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`[:1 Meta-analysis or pooled analysis of previous studies/clinical trials
`El Immunogenicity as a marker of safety
`[I Other (provide explanation)
`
`Agreed umn:
`
`[:1 Quality study Without a safety endpoint (e.g., manufacturing, stability)
`[I Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`El Clinical trials primarily designed to further define eflicacy (e.g., in another condition,
`difi'crent disease severity, or subgroup) that are NOT required under Subpart HIE
`E] Dose-response study or clinical trial performed for effectiveness
`E] Nonclinical study, not safety-related (specify)
`
`C] Other
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`
`E Does the study/clinical trial meet criteria for PMRs or PMCs?
`X Are the objectives clear fiom the description of the PMR/PMC?
`X Has the applicant adequately justified the choice of schedule milestone dates?
`X Has the applicant had sufficient time to review the PMRs/PMCs, ask questions. detemiine
`feasibility, and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`X This PMR/PMC has been reviewedfor clarity and consistency, and is necessary tofurther refine
`the safety, efl‘icacy, or optimal use ofa drug, or to ensure consistency and reliability ofdrug
`quality.
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 10/6f2011
`
`Page 3 of 3
`
`Reference ID: 3025589
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`10/06/2011
`
`Reference ID: 3025589
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`M E M O R A N D U M
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`____________________________________________________________________________
`
`DATE:
`
`TO:
`
`September 7, 2011
`
`
`
`FROM:
`
`Mary Parks, M.D.
`Director, Division of Metabolism and Endocrinology
`Products
`Office of Drug Evaluation
`
`Sripal R. Mada, Ph.D.
`Bioequivalence Branch
` Division of Bioequivalence and GLP Compliance
` Office of Scientific Investigations
`
`
`THROUGH: Martin K. Yau, Ph.D.
`Acting Team Leader – Bioequivalence Branch
` Division of Bioequivalence and GLP Compliance
` Office of Scientific Investigations
`
`®
`SUBJECT: Review of EIR Covering NDA 202-343,
`(Sitagliptin/Simvastatin) Tablets, 100/10 mg,
`100/20 mg, 100/40 mg, from Merck Sharp & Dohme Corp.
`
`
`At the request of the Division of Metabolism and Endocrinology
`Products (DMEP), the Division of Bioequivalence and GLP
`Compliance (DBGC) conducted inspections of clinical and
`analytical portions of the following studies:
`
`Study: 255: “A Single-Dose Study to Evaluate Definitive
`Bioequivalence of MK-0431D and Co-administration of
`Sitagliptin and Simvastatin”
`
`
`Study: 153: “A 2-Part Single-Dose Study to Evaluate a Probe
`
`Formulation of MK-0431D and Evaluate Definitive
`Bioequivalence of MK-0431D and Co-administration of
`Sitagliptin and Simvastatin”
`
`
`CLINICAL INSPECTION:
`
`The inspection of clinical portion was conducted at Icon
`Development Solutions (Icon), San Antonio, TX.
`
`Following the inspection at Icon (June 14-24, 2011), Form FDA
`483 was issued (Attachment 1). The firm’s response (dated June
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 2 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`28, 2011) was received (Attachment 2). The Form FDA 483
`observations, Icon's response to Form FDA 483 and our
`evaluations follow:
`
`
`1. Failure to retain reserve samples for Study 153 Part 1.
`
`
`Icon stated that they did not retain reserve samples, according
`to the study protocol. Icon stated that after dispensing the
`study drug into unit dosing containers, they returned the
`remaining drug product to the sponsor. Note that the lot number
`for drug product used in Study 153 Part 2 differed from product
`used in Study 153 Part 1.
`
`In response to Form FDA 483, Icon explained that Study 153
`Part 1 was initially planned and was later amended to Study 153
`Part 2 for final BE evaluation.
`
`DBGC is of the opinion that because Icon did not retain reserve
`samples for Study 153 Part 1, the authenticity of the drug
`products used in Study 153 Part 1 cannot be confirmed.
`
`
`2. Failure to randomly select reserve samples for
`Study 153 Part 2. Retention samples that were
`retained were pre-identified by the sponsor as
`"Replacement Kits." In addition, these kits were
`returned to the sponsor upon completion of the study.
`Further, the reserve samples were subsequently
`returned by the sponsor resulted in broken chain of
`custody.
`
`
`During the inspection, Icon revealed that they did not randomly
`select drug kits for dosing and reserves. The sponsor
`pre-identified kits #1001 to 1100 as "replacement kits." Icon
`dosed subjects with kits #0401 to 0500.
`
`In the response to Form FDA 483, Icon acknowledged their error
`in returning the reserve samples (pre-identified as replacement
`kits) from Protocol 153 Part 2 to the sponsor. Although this
`error was quickly identified, the return of these samples to the
`sponsor broke the chain of custody. However, in contradiction
`of the findings of the inspection, the Principal Investigator
`(PI) stated that she randomly selected bottles to be used for
`dosing, and considered all remaining drug products as reserve
`samples. She stated that no bottles were pre-identified as
`retention samples.
`
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 3 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`Icon failed to meet the regulatory requirements for retention of
`reserve samples for bioavailability or study (21 CFR 320.38 and
`320.63). The sponsor is not an "independent third party" as
`specified by the regulation.
`
`Icon failed to randomly select drug products for dosing and
`reserves, and failed to maintain custody of the unused drug
`products. Therefore, the authenticity of drug products cannot
`be verified for Study 153 Part 2.
`
`
`3. Failure to randomly select reserve samples for Study
`255. Retention samples that were retained were pre-
`identified by the sponsor as Replacement Kits.
`
`
`During the inspection, Icon revealed that they did not randomly
`select drug kits for dosing and reserves. The sponsor pre-
`identified kits #1001 to 1100 as "replacement kits." Icon dosed
`subjects with kits #001 to 100.
`
`In response to Form FDA 483, Icon stated that they received 100
`kits for randomized subjects and 100 kits for replacement
`subjects in six containers with two of each test and reference
`product. However, the purpose of the “replacement subjects”
`kits is unclear. The Principal Investigator (PI) stated that
`she randomly selected bottles to be used for dosing, and
`considered all remaining drug products as reserve samples. She
`stated that no bottles were pre-identified as retention samples.
`
`Icon failed to randomly select drug products for dosing and
`reserve. Therefore, the authenticity of drug products cannot be
`verified for Study 255.
`
`
`4. Source study records show employees performed certain
`key study tasks of the study, however; were not listed
`on the "Site Signature Log" as being delegated by you
`to perform those key delegated study tasks.
`
`
`In the response to Form FDA-483, Icon acknowledged this
`observation and identified the delegation process in use is
`deficient. Icon developed corrective actions instituted on May
`25, 2010.
`
`
`5. Failure to follow SOP CPU132, Maintenance and
`Organization of the "Investigator File," as during
`review of the study files it was discovered that not
`all significant study related e-mails were included in
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 4 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`the "General Correspondence" section of the study
`file.
`
`
`In response to Form FDA 483, Icon acknowledged this observation
`and stated they will re-train all staff on SOP CPU132, to be
`completed by August 31, 2011. The inspection audited the
`available e-mails and suggested that they be transferred to the
`study file.
`
`ANALYTICAL INSPECTION:
`
`The inspection of analytical portion was conducted at
`
`
`
`
`
`, Form
`Following the inspection at
`FDA 483 was issued (Attachment 3). The firm’s response dated
`July 11, 2011 was received on July 11, 2011, and the response
`dated July 21 was received on July 28, 2011 (Attachment 4). The
`Form FDA 483 observations,
` responses to Form FDA
`483, and our evaluations follow:
`
`
`1. Failure to provide adequate security for electronic
`source records. Specifically,
`(a) A common access procedure is used to access the
`computer workstation and the "Analyst" software
`used for analytical data integration.
`(b) Technical writers who do not work in the
`bioanalytical laboratory were given inappropriate
`permission to edit chromatograms in the "Analyst"
`software.
`
`
` that these practices were not
`DBGC explained to
`recommended during the conduct of any bioequivalence studies.
`This objectionable practice is related to DBGC’s concern
`discussed below under Form FDA-483, Item 4, regarding modifying
`chromatographic integration parameters. The observation tends
`to confirm a complaint received by OSI that unauthorized
`individuals at
` had edited various
`records of clinical trials. Currently,
` has updated
`their operating procedures to restrict the common computer
`access procedure and not granting permission to technical
`writers edit chromatograms in future studies.
`
`
`2. Failure to conduct long term freezer stability and
`freeze/thaw stability at -200C for samples containing
`MK-0431, simvastatin and simvastatin hydroxy acid.
`Specifically, subjects in studies #255-00 and 153-01
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 5 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`were treated with both MK-0431 and simvastatin and the
`analyses determined the plasma concentrations of
`MK-0431, simvastatin and simvastatin hydroxy acid.
`
`
`3. Failure to evaluate long term freezer stability of
`simvastatin and simvastatin hydroxy acid in plasma at
`-200C and -800C.
`
`
`
` had
` acknowledged the above observations.
`previously prepared freeze/thaw and long-term frozen storage
`stability test samples containing MK-0431, simvastatin and
`simvastatin hydroxy acid, and stored them at -200C. These
`samples were analyzed during the inspection.
`
` submitted stability data
`In response to Form FDA 483,
`for freeze/thaw and long-term frozen storage (Attachment). The
`results are acceptable and adequate to cover sample handling
`conditions during the study.
`
`
` also submitted stability data at -20°C for long-term
`stability of simvastatin and simvastatin hydroxy acid alone in
`plasma for 7 days and 9 days, respectively.
` submitted
`stability data at -80°C for simvastatin and simvastatin hydroxy
`acid alone in plasma for 122 days, adequate to cover the study
`sample storage time (77 days).
`
`The newly submitted data are acceptable, and
`response is adequate.
`
`
`
`
`4. Integration parameters from most analytical runs in
`the validation and production for studies # 255-00 and
`153-01 were modified and were different from the
`method SOP. These changed integration parameters were
`not applied to all samples in the respective runs.
`
`
`Integration parameters for many chromatograms in validation and
`analytical runs were modified. The reasons for modifying
`integration parameters were not documented in records or an
`audit trial.
`
` reintegrated all
`In the response to Form FDA 483,
`chromatograms generated during method validation and production
`runs, using a revised uniform automatic integration process.
`Also,
` compared the re-integrated chromatographic data
`with original data in summary tables (see Attachment 4). DBGC's
`review of the comparative data found no significant differences.
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 6 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`However, the OCP reviewer should re-evaluates the bioequivalence
`statistics using the uniformly re-integrated data.
`
`
`5. Failure to demonstrate lack of carry-over during the
`simvastatin assay validation. Although two of six
`blank samples in validation run #5 contain simvastatin
`peaks >20% of LLOQ, the run was accepted for the
`evaluation of precision and accuracy.
`
`
` stated that the
`In response to Form FDA-483,
`interfering peak was an artifact not caused by instrumental
`carryover. Their source was not identified.
`
`
` response is adequate, in that the interferences do
`not significant affect measurements of Cmax and AUC.
`
`Conclusions:
`
`Following the inspection, DBGC recommends the following:
`
`
`• The analytical data generated at
` are
`acceptable for review. However, the OCP reviewer should
`re-evaluate bioequivalence statistics using the
`uniformly re-integrated data.
`
`• The studies fail to meet the regulatory requirements for
`retention of reserve samples for bioavailability or study
`(21 CFR 320.38 and 320.63). The Final Rule for Retention of
`Bioavailability and Bioequivalence Testing Samples (Federal
`Register, Vol. 58, No. 80, Pages 25918-25928, 1993)
`clarifies that:
`
`“The study sponsor should provide to the testing
`facility batches of the test product and reference
`standard packages such that the reserve samples can be
`randomly selected to ensure that they are in fact
`representative of the batches provided by the study
`sponsor…”
`
`Since, Icon did not randomly select reserve samples
`and maintain custody of them; DBGC cannot verify the
`authenticity of the study drugs tested (see Clinical
`Form FDA-483 items 1, 2 and 3).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3011627
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`® (Sitagliptin/Simvastatin) Tablets
`Page 7 - NDA 202-343,
`100/10 mg, 100/20 mg, 100/40 mg
`
`DBGC is of the opinion that studies 255 and 153 (Part 1 and 2)
`are not acceptable for review.
`
`After you have reviewed this transmittal memo, please append it
`to the original NDA submission.
`
`
`Sripal R. Mada, Ph.D.
`Bioequivalence Branch, DBGC, OSI
`
`
`
`Final Classifications:
`
`VAI –
`
`
`
`
`
`
`
`OAI – Icon Development Solutions, San Antonio, TX
`FEI: 3007158681
`
`(DBGC is considering regulatory letters to Icon Development
`Solutions and Merck Sharp & Dohme Corp for the regulatory
`violations involving reserve samples).
`
`
`cc:
`OSI/Ball
`OSI/DBGC/Salewski/Dejernett/Matthews
`OSI/DBGC/BB/Mada/Yau/Haidar
`OCP/DCP2/Sahajwalla/Lee/Vaidyanathan/Chung
`ODE2/DMEP/Parks/Chiang
`HFR-SW1540/Martinez
`HFR-SW350/Kuchenthal
`Draft: SRM 09/02/2011
`Edit: MFS 09/02/2011; MKY 09/07/2011
`DSI: BE6185; O:\Bioequiv\EIRCover\202343.mer.juv.doc
`Complaint: 3299/Chu
`FACTS: 1266778
`
`
`
`Reference ID: 3011627
`
`79 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SRIPAL R MADA
`09/07/2011
`
`MARTIN K YAU
`09/07/2011
`
`Reference ID: 3011627
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`PATIENT LABELING REVIEW
`
`September 1, 2011
`
`
`
`
`
`
`
` Mary Parks, M.D., Director
`Division of Metabolism and Endocrinology Products (DMEP)
`
`
`LaShawn Griffiths, RN, MSHS-PH, BSN
`Acting Team Leader, Patient Labeling Reviewer
`Division of Risk Management (DRISK)
`
`Robin Duer, RN, BSN, MBA
`Senior Patient Labeling Reviewer
`Division of Risk Management
`
`Twanda Scales, RN, BSN, MSN/Ed.
`Patient Labeling Reviewer
`Division of Risk Management
`
`
`
`
`
`
`
`
`
`
`
`DRISK Review of Patient Labeling (Medication Guide)
`
` (sitagliptin and simvastatin)
`
`
`
`
`Date:
`
`To:
`
`
`
`
`
`Through:
`
`
`
`
`From:
`
`
`
`
`
`
`
`
`
`
`
`
`Subject:
`
`Drug Name(s):
`
`Dosage Form
`and Route:
`
`
`Application
`Type/Number:
`
`Applicant/Sponsor: Merck & Co., Inc.
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`Tablets
`
`
`
`
`NDA 202343
`
`2011-302
`
`
`
`Reference ID: 3009470
`
`1
`
`(b) (4)
`
`

`

`1
`
`INTRODUCTION
`
`On December 3, 2010 Merck Sharp & Dohme Corp, a subsidary of Merck & Co.,
`Inc. (Merck), submitted a New Drug Application (NDA) for
`0x0 a fixed-dose
`combination tablet containing sitagliptin phosphate and simvastatin.
`M0 is
`indicated as
`
`(m4)
`
`This review is written in response to a request by the Division of Metabolic and
`Endocrine Products (DMEP) for the Division of Risk Management ODRISK) to
`review the Applicant’s proposed Medication Guide (MG) for
`(we) (sitagliptin
`and simvastatin) Tablets.
`
`2 MATERIAL REVIEWED
`
`W" (sitagliptin and simvastatin) Medication Guide OVIG) received on
`o Drafi
`December 7, 2010, revised by the review division throughout the review cycle
`and sent to DRISK on August 18, 2011.
`
`(I'm (sitagliptin and simvastatin) Prescribing Information (PI)
`o Drafi
`received December 7, 2010, revised by the Review Division throughout the
`current review cycle and received by DRISK on August 18, 2011.
`
`0 Approved JANUMET (sitagliptin/metformin hydrochloride) comparator labeling
`dated May 13, 2011.
`
`0 Approved JANUVIA (sitagliptin) comparator labeling dated April 14, 2011.
`
`3 REVIEW NIETHODS
`
`To enhance patient comprehension, materials should be written at a 6m to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the MG the target
`reading level is at or below an 8th grade level.
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelinesfor Prescription Labeling and Consumer Medication
`Informationfor People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`
`accessible for patients with vision loss. We have reformatted the MG document
`using the Verdana font, size 11.
`
`In our review of the MG we have:
`
`0
`
`0
`
`simplified wording and clarified concepts where possible
`
`ensured that the MG is consistent with the prescribing information (PI)
`
`Reference ID: 3009470
`
`

`

`•
`•
`•
`
`•
`
`removed unnecessary or redundant information
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`ensured that the MG meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`ensured that the MG is consistent with the approved comparator labeling where
`applicable.
`
` CONCLUSIONS
`
` 4
`
`
`
`The MG is acceptable with our recommended changes.
`
`5 RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DRISK on the
`correspondence.
`• Our annotated versions of the MG are appended to this memo. Consult DRISK
`regarding any additional revisions made to the PI to determine if corresponding
`revisions need to be made to the MG.
`
`
` Please let us know if you have any questions.
`
`
`
`
`
`Reference ID: 3009470
`
`3
`
`19 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TWANDA D SCALES
`09/01/2011
`
`LASHAWN M GRIFFITHS
`09/01/2011
`
`Reference ID: 3009470
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`
`August 29, 2011
`
`
`To:
`
`
`
`
`From:
`
`
`Pooja Dharia, Regulatory Project Manager,
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Samuel Skariah, Regulatory Review Officer
`Kendra Jones, Regulatory Review Officer
`Division of Drug Marketing, Advertising, and Communications (DDMAC)
`
`NDA 202343
`
`DDMAC labeling comments for
`
`
`
`™ (sitagliptin and simvastatin) Tablets
`
`
`Subject:
`
`
`
`
`
`
`
`
`
`
`
`
`
`DDMAC has reviewed the proposed Prescribing Information (PI) and Medication Guide (Med
`Guide) for
` accessed from the eRoom on August 27, 2011.
`
`General Comment
`
`Comments regarding the PI and the Med Guide are provided in the marked version below.
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions on the PI, please contact Samuel Skariah at 301. 796. 2774 or
`Sam.Skariah@fda.hhs.gov.
`
`If you have any questions on the MedGuide, please contact Kendra Jones at 301.796.3917 or
`Kendra.Jones@fda.hhs.gov.
`
`
`
`
`Reference ID: 3007952
`
`1
`
`55 Pages of Draft Labeling Have Been Withheld in Full As b4 (CCI/TS) Immediately Following
`This Page
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KENDRA Y JONES
`08/29/2011
`
`Reference ID: 3007952
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name(s) and
`Strength:
`Application
`Type/Number:
`Applicant:
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2962868
`
`June 20, 2011
`Mary Parks, MD, Director
`Division of Metabolism and Endocrinology Products
`
`Lubna Merchant, PharmD, M.S., Team Leader
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`Anne C. Tobenkin, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Label and Labeling Review
` (Sitagliptin and Simvastatin) Tablets
`100 mg/10 mg, 100 mg/20 mg, 100 mg/40 mg
`NDA 202343
`
`Merck
`2011-300
`
`
`
`1
`
`(b) (4)
`
`

`

` 1
`
`
`INTRODUCTION
`This review summarizes the Division of Medication Error Prevention and Analysis’
`(DMEPA’s) evaluation of the proposed container labels and carton and insert labeling for
` (Sitagliptin and Simvastatin) Tablets for NDA 202343 for areas of vulnerability
`that could lead to medications errors. The review responds to a request from the Division
`of Metabolism and Endocrinology Products (DMEP) to review the container labels and
`carton labeling for this Application. The proposed proprietary name is currently being
`evaluated under OSE review # 2011-1129.
`2 MATERIAL REVIEWED
`Using Failure Mode and Effects Analysis, the Division of Medication Error Prevention
`and Analysis (DMEPA) evaluated the product labels submitted on December 7, 2010 to
`identify vulnerabilities that may lead to medication errors. See the Appendix for samples
`of the draft container labels and carton labeling.
`Additionally, Merck, the Applicant for this NDA, standardized the label design for the
`container labels of their oral solid dosage forms. DMEPA reviewed and provided
`recommendations for the revised labels of the effected products included in a bundled
`supplement in OSE reviews # 2010-628 dated August 13, 2010 and # 2010-628-1 dated
`April 11, 2011. DMEPA considered these recommendations during the evaluation of the
`labels and labeling for this product to ensure consistency across the Merck products.
`3 CONCLUSIONS AND RECOMMENDATIONS
`Our Label Risk Assessment indicates that the presentation of information on the labels
`and labeling introduces vulnerability to confusion that could lead to medication errors.
`The risks we have identified can be addressed and mitigated prior to drug approval, and
`thus we provide recommendations in the following sections that aim at reducing the risk
`of medication errors. We request the recommendations in Section 3.2 be communicated
`to the Applicant prior to the approval of this NDA.
`Please copy the Division of Medication Error Prevention and Analysis on any
`communication to Merck. with regard to this review. If you have further questions or
`need clarifications, please contact Margarita Tossa, OSE Project Manager, at 301-796-
`4053.
`3.1 COMMENTS TO THE DIVISION
`A. Highlights Sections; Dosage and Administration and Dosage Forms and Strengths
`Revise the strength statements so that they are expressed with the mg after each
`ingredient, for example, 100 mg/20 mg. Also, revise all strength statements
`throughout the insert to reflect this presentation.
`
`
`
`
`
`
`
`
`Reference ID: 2962868
`
`2
`
`(b) (4)
`
`

`

`
`3.2 COMMENTS TO THE APPLICANT
`A. Physician Sample Carton Labeling (All strengths)
`1. Revise the presentation of the established name so that the established name is
`printed in letters that are at least half as large as the letters comprising the
`proprietary name or designation with which it is joined, and the established
`name shall have a prominence commensurate with the prominence with which
`such proprietary name or designation appears, taking into account all pertinent
`factors, including typography, layout, contrast, and other printing features, per
`21 CFR 201.10(g)(2).
`2. Revise the strength presentation so that the unit of measure “mg” is on the
`same line as the numeric strengths and in the same size font to improve
`readability. Currently, the unit of measure appears as a superscript.
`4. Revise the contents statement so that it reads;
`7 tablets per bottle
`Carton contains 2 bottles
`5. The contents and sample statements should appear on more then one panel to
`ensure that this information is conveyed regardless of how it is stored on
`shelves.
`6. De