CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`206073Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`January 8, 2015
`
`Jean-Marc Guettier, MD
`Director
`Division of Metabolism and Endocrinology Products
`(DMEP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`Barbara Fuller, RN, MSN, CWOCN
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Karen Dowdy, RN, BSN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`Kendra Y. Jones
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Review of Patient Labeling: Medication Guide (MG)
`
`GLYXAMBI (empagliflozin and linagliptin)
`
`tablets, for oral use
`NDA 206073
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`Drug Name (established
`name):
`Dosage Form and Route:
`Application
`Type/Number:
`Applicant:
`
`
`
`
`
`
`
`
`
`Reference ID: 3684301
`
`
`
`

`

`INTRODUCTION
`On January 30, 2014, Boehringer Ingelheim Pharmaceuticals, Inc. submitted for the
`Agency’s review an original New Drug Application (NDA) 206073 for GLYXAMBI
`(empagliflozin and linagliptin) tablets indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus when treatment
`with both empagliflozin and linagliptin is appropriate.
`This collaborative review is written by the Division of Medical Policy Programs
`(DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a
`request by the Division of Metabolism and Endocrinology Products (DMEP) on June
`23, 2014, and January 6, 2015, respectively, for DMPP and OPDP to review the
`Applicant’s proposed Medication Guide (MG) for GLYXAMBI (empagliflozin and
`linagliptin) tablets.
`
` MATERIAL REVIEWED
`• Draft GLYXAMBI (empagliflozin and linagliptin) tablets MG received on
`December 17, 2014, and received by DMPP and OPDP on December 22, 2014.
`• Draft GLYXAMBI (empagliflozin and linagliptin) tablets Prescribing Information
`(PI) received on January 30, 2014, revised by the Review Division and the
`Applicant throughout the review cycle, and received by DMPP and OPDP on
`December 22, 2014.
`• Approved TRADJENTA (linagliptin) tablets comparator labeling dated May 22,
`2014.
`• Approved JARDIANCE (empagliflozin) tablets comparator labeling dated August
`1, 2014.
`
`1
`
` 2
`
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th 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 Guidelines for Prescription Labeling and Consumer Medication
`Information for 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.
`In our collaborative review of the MG we have:
`simplified wording and clarified concepts where possible
`•
`ensured that the MG is consistent with the Prescribing Information (PI)
`•
`removed unnecessary or redundant information
`•
`
`
`
`
`
`Reference ID: 3684301
`
`
`
`

`

`•
`
`•
`•
`
`•
`
`ensured that the MG is free of promotional language or suggested revisions to
`ensure that it is free of promotional language
`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
`
`4 CONCLUSIONS
`The MG is acceptable with our recommended changes.
`
` 5
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`correspondence.
`• Our collaborative review of the MG is appended to this memorandum. Consult
`DMPP and OPDP 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: 3684301
`
`
`
`14 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/
`----------------------------------------------------
`
`KAREN M DOWDY
`01/08/2015
`
`KENDRA Y JONES
`01/08/2015
`
`BARBARA A FULLER
`01/08/2015
`
`LASHAWN M GRIFFITHS
`01/08/2015
`
`Reference ID: 3684301
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`January 7, 2015
`
`
`To:
`
`
`
`
`
`From:
`
`
`
`Subject:
`
`Callie Cappel-Lynch, Regulatory Project Manager
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Kendra Y. Jones, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`NDA 206073
`OPDP labeling comments for GLYXAMBI® (empagliflozin and
`linagliptin) tablets, for oral use
`
`
`
`OPDP has reviewed the proposed draft prescribing information (PI) and carton
`container labels for GLYXAMBI® (empagliflozin and linagliptin) tablets, for oral
`use (Glyxambi) submitted for consult on January 6, 2015.
`
`Prescribing Information
`OPDP’s comments on the proposed draft PI are based on the version sent from
`Callie Cappel-Lynch (RPM) on December 22, 2014, and are provided directly on
`the marked version below.
`
`Carton/Container Labels
`We have no further comments on the draft carton and container labeling
`(provided directly below) at this time.
`
`Medication Guide
`OPDP’s comments on the proposed draft medication guide will be provided
`under separate cover in conjunction with Division of Medical Policy Programs
`(DMPP) at a later date.
`
`Thank you for the opportunity to comment on the proposed draft labeling.
`
`If you have any questions, please contact Kendra Jones at 301.796.3917 or
`Kendra.jones@fda.hhs.gov.
`
`
`
`
`Reference ID: 3683908
`
`1
`
`26 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/
`----------------------------------------------------
`
`KENDRA Y JONES
`01/07/2015
`
`Reference ID: 3683908
`
`

`

`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
`
`____________________________________________________________________________
`
`CLINICAL INSPECTION SUMMARY
`
`DATE: October 6, 2014
`
`TO:
`
`FROM:
`
`
`
`THROUGH:
`
`William H. Chong, M.D., Clinical Reviewer
`Richard Chiang, Regulatory Project Manager
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Cynthia F. Kleppinger, M.D.
`Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`Janice Pohlman, M.D., M.P.H.
`Team Leader
`Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`Kassa Ayalew, M.D., M.P.H
`Branch Chief
`Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`SUBJECT:
`
`Evaluation of Clinical Inspections
`
`NDA: 206073
`
`APPLICANT:
`
`Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI)
`
`DRUG:
`
` Empagliflozin/linagliptin fixed dose combination tablets
`
`NME:
`
`THERAPEUTIC CLASSIFICATION: Standard Review
`
`No
`
`INDICATIONS:
`
`As an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus when treatment with both empagliflozin
`
`
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 2
` NDA 206073 empagliflozin/linagliptin
`
`and linagliptin is appropriate.
`
`CONSULTATION REQUEST DATE: March 31, 2014
`CLINICAL INSPECTION SUMMARY GOAL DATE: October 6, 2014
`DIVISION ACTION GOAL DATE: January 30, 2015
`PDUFA DATE: January 30, 2015
`
`I. BACKGROUND
`
`Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) is seeking approval of
`empagliflozin/linagliptin fixed-dose combination (FDC) tablets as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment
`with both empagliflozin and linagliptin is appropriate. Inspections were requested for the
`following clinical study:
`
` Protocol1275.1 “A Phase III Randomized, Double-Blind, Parallel Group Study to
`Evaluate the Efficacy and Safety of Once Daily Oral Administration of BI 10773 25
`mg/Linagliptin 5 mg and BI 10773 10 mg/Linagliptin 5 mg Fixed Dose Combination
`Tablets Compared with the Individual Components (BI 10773 25 mg, BI 10773 10 mg,
`And Linagliptin 5 mg) for 52 Weeks in Treatment Naïve and Metformin Treated
`Patients with Type 2 Diabetes Mellitus with Insufficient Glycaemic Control”
`
`This multi-center trial was conducted in 212 sites in 22 countries. There were 2504 subjects
`screened and 1363 subjects enrolled. The first subject was enrolled August 31, 2011 and the
`last subject visit was September 10, 2013. The primary endpoint was the change from baseline
`in HbA1c (%) after 24 weeks of treatment.
`
`These inspections were conducted as part of the routine PDUFA pre-approval clinical
`investigation data validation in support of NDA 206073 in accordance with Compliance
`Program 7348.811. General instructions were also provided with this assignment.
`
`NOTE: During the inspections, it was discovered that BIPI had not obtained any 1572s from
`the foreign sites. Although the sites were listed in the site selection tool as being conducted
`under an Investigational New Drug Application (IND), in the application BIPI requested a
`waiver from certain requirements outlined in 21 CFR 312.120 related to foreign clinical studies
`not conducted under an IND.
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 3
` NDA 206073 empagliflozin/linagliptin
`
`II.
`
`RESULTS (by Site):
`
`Name of CI/ Site #
`
`Protocol 1275.1 / # of
`Subjects Randomized
`
`Inspection
`Date
`
`Preliminary
`Classification
`
`Naresh Aggarwal
`Site #20001
`Diego Aizenberg
`Site #54005
`Georgina Sposetti
`Site #54004
`Lawrence Levinson
`Site #1088
`Mandeep Oberoi
`Site #1013
`Farid Marquez
`Site #1063
`Key to Classifications
`
`30
`
`33
`
`23
`
`6
`
`7
`
`26 subjects
`
`6/09-
`6/13/2014
`6/09-
`6/13/2014
`6/16-
`6/19/2014
`7/14-
`7/22/2014
`7/21-
`8/01/2014
`9/08-pending
`close out
`
`No Action Indicated
`(NAI)
`No Action Indicated
`(NAI)
`No Action Indicated
`(NAI)
`No Action Indicated
`(NAI)
`Voluntary Action
`Indicated (VAI)
`Official Action
`Indicated (OAI)
`
`NAI = No deviation from regulations
`VAI = Deviation(s) from regulations
`OAI = Significant deviations from regulations; data unreliable.
`Pending = Preliminary classification based on information in 483, preliminary communication
`with the field, and review of EIR; final classification is pending letter to site.
`
`1. Naresh Aggarwal, M.D.
`490 Bramalea Road
`Suite 201
`Brampton, ON L6T 0G1
`Canada
`
`a. What was inspected: The inspection focused on 100% review of informed
`consent documents (ICDs), institutional review board (IRB) correspondence,
`Form FDA 1572, financial disclosures, training records, delegation forms,
`monitoring reports, inclusion/exclusion criteria checklist, enrollment logs,
`subject source documents including medical history records, drug
`accountability, concomitant medication records, and adverse event reports.
`There were 26 subject charts reviewed. Source data was verified with data line
`listings for 16 subjects (15 who completed and one who had withdrawn).
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 4
` NDA 206073 empagliflozin/linagliptin
`
`b. General observations/commentary: There were 48 subjects screened at the
`site and 30 enrolled (three subjects withdrew consent before randomization).
`Four subjects withdrew consent after randomization. There were 23 subjects
`that completed the study. The study was overseen by Institutional Review Board
`Services.
`
`The investigator did not complete an FDA 1572, Statement of Investigator, but
`did complete the Canadian Qualified Investigator Undertaking.
`
`The primary efficacy endpoint was verifiable. There was no under-reporting of
`adverse events (only one adverse event of bronchitis found which was not
`reported for Subject 93130. The antibiotic Zithromax was also not recorded on
`the concomitant medication log).
`
`The inspection revealed adequate adherence to the regulations and the
`investigational plan. There were no objectionable conditions noted and no Form
`FDA-483, Inspectional Observations, issued.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was
`submitted for review. Data from this site appear acceptable. The audit did not indicate
`serious deviations/findings that would impact the validity or reliability of the submitted
`data.
`
`2. Dr. Diego Aizenberg
`Clinical Research Director
`Centro Médico Viamonte
`Avda Córdoba 2019
`Ciudad Autónoma de Buenos Aires
`C1120AAC
`Argentina
`
`a. What was inspected: The inspection focused on informed consent documents
`(ICDs), ethics committee (EC) correspondences, investigator agreements,,
`financial disclosures, protocol deviations, delegation forms, monitoring reports,
`inclusion/exclusion criteria checklist, enrollment logs, subject source documents
`including medical history records, drug accountability, concomitant medication
`records, and adverse event reports. Seven subject’s records were reviewed with
`data line listings compared to source documents.
`
`b. General observations/commentary: There were 37 subjects screened and 33 subjects
`enrolled. All the documents were organized, complete, and accurate. The records were
`all hand-written in Spanish and were difficult to read. The Spanish consents had all the
`elements of informed consent and were very comprehensive. All the subject’s records
`showed they were consented appropriately.
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 5
` NDA 206073 empagliflozin/linagliptin
`
`The eligibility criteria were met in all the subject’s records that were reviewed. The
`blinding of the study was followed and maintained throughout the duration of the study,
`with no unblinding during rescue. The primary efficacy endpoint was verifiable and
`there was no under-reporting of adverse events.
`
`The logs for the test article accountability were reviewed. There was an isolated
`incident where the wrong kit was given to a subject (#098474). The incident was
`thoroughly investigated and corrected by the clinical investigator’s personnel and study
`monitor. There was documentation of the investigation. This issue was brought to the
`attention of the clinical investigator as a discussion issue.
`
`The inspection revealed adequate adherence to the regulations and the
`investigational plan. There were no objectionable conditions noted and no Form
`FDA-483, Inspectional Observations, issued.
`
`Dr. Aizenberg sent an email follow-up on July 17, 2014 to address some of the
`discussion items of the FDA field investigator. One item was to evaluate the use
`of electronic or systematized medical charts in order to make them more legible.
`Dr. Aizenberg stated that he will evaluate the use of computerized systems or
`electronic medical histories as a substitute for paper records. Based on that
`evaluation, a final decision will be made, in accordance with the characteristics
`of the systems available on the market, budget issues, and site infrastructure.
`Another discussion item was to perform and document a root cause analysis for
`protocol violations. The site team was re-trained in the use of different tools and
`how to document the issues and findings on June 23, 2014.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was not
`available for review. Preliminary inspection results were communicated by the FDA
`ORA field investigator. Data from this site appear acceptable. The audit did not
`indicate serious deviations/findings that would impact the validity or reliability of the
`submitted data.
`
`3. Georgina Sposetti, M.D.
`Diabetes and Metabolism Department, Head
`Instituto de Investigaciones Clínicas
`Av Colon 3364
`B7600FZN Mar del Plata, Buenos Aires
`Argentina
`
`a. What was inspected: The inspection included review of subjects’ medical
`records, informed consents, laboratory results, case report forms, source
`documents, monitoring logs, drug accountability and data listings. In addition,
`the inspection also covered the regulatory binder and ethics committee
`correspondences. Five subject records were fully reviewed.
`
`b. General observations/commentary: There were 35 subjects screened, 23
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 6
` NDA 206073 empagliflozin/linagliptin
`
`subjects enrolled into the study and 20 subjects who completed the study. In the
`Province of Buenos Aires, it is mandatory that all informed consent forms are
`witnessed. The informed consents that were reviewed were all witnessed and
`signed by the subjects and witnesses before any study related procedures were
`performed.
`
`All the documents were in Spanish. They were well organized, accurate, and
`complete. Part of the source documents were printed from a database that was at
`the investigational center. Some other documents were written by hand, such as
`the Drug Accountability Log, the Delegation Log, Subject Enrollment Logs,
`and the Training Logs. A review of the study records revealed that all inclusion
`criteria were met and none of the exclusion criteria was met by the study
`subjects. In some of the records it was briefly mentioned that the exercise and
`dietary counseling had taken place.
`
`The primary and secondary efficacy endpoints were verifiable. There was no
`under-reporting of adverse events.
`
`The inspection revealed adequate adherence to the regulations and the
`investigational plan. There were no objectionable conditions noted and no Form
`FDA-483, Inspectional Observations, issued.
`
`During the close out meeting, the FDA field investigator stressed the
`importance of detailed documentation of all the procedures of the protocol,
`instructions and events related to the subject visits. For example, it could be
`inferred that the food intake diary was given to the subjects from other
`information consigned in the subject notes but it was not specifically
`documented that the diaries were given to them.
`
`Dr. Sposetti responded to the discussion items via an email dated July 15, 2014.
`His site has implemented a check list describing the procedures to be performed
`as well as the materials to be used in each protocol visit. After the visit
`completion, the coordinator will check with the patient whether or not the
`required materials were given to him/her. If necessary, other useful tools will
`be implemented, including alert signs in the appointment book, flowcharts
`describing the procedures, etc. There is also a new staff member in charge of
`Quality Control tasks, especially focused on protocol critical procedures,
`trainings, preventive measures and corrective actions.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was not
`available for review. Preliminary inspection results were communicated by the FDA
`ORA field investigator. Data from this site appear acceptable. The audit did not
`indicate serious deviations/findings that would impact the validity or reliability of the
`submitted data.
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 7
` NDA 206073 empagliflozin/linagliptin
`
`4. Lawrence S. Levinson, M.D.
`Tipton Medical & Diagnostic Center
`4371 East Pleasant Valley Boulevard
`Tipton, PA 16684
`
`a. What was inspected: Records reviewed included the investigator agreements,
`1572s, financial disclosures, drug accountability logs, study
`enrollment/screening logs, consent forms, case report forms, source documents,
`sponsor correspondence, monitoring visit correspondence, ethics committee
`correspondence, and training records. All six enrolled subjects’ records were
`reviewed.
`
`b. General observations/commentary: There were 13 subjects screened and 6
`subjects enrolled at the site. All subjects completed the study. Some subjects
`had initially signed the incorrect version of consent. This was caught by the
`sponsor, corrected by the firm and reported to the IRB.
`
`The primary efficacy endpoint was verifiable and there was no under-reporting
`of adverse events.
`
`The inspection revealed adequate adherence to the regulations and the
`investigational plan. There were no objectionable conditions noted and no Form
`FDA-483, Inspectional Observations, issued.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was not
`available for review. Preliminary inspection results were communicated by the FDA
`ORA field investigator. Data from this site appear acceptable. The audit did not
`indicate serious deviations/findings that would impact the validity or reliability of the
`submitted data.
`
`5. Mandeep S. Oberoi, M.D.
`240 Williamson Street
`Suite 305
`Elizabeth, NJ 07202
`
`a. What was inspected: The inspection focused on 100% review of informed
`consent documents (ICDs), IRB correspondence, training, 1572s, financial
`disclosures, delegation forms, randomization, monitoring reports,
`inclusion/exclusion criteria, enrollment logs, subject source documents
`including medical history records, drug accountability, concomitant medication
`records, and adverse event reports. Eleven subject records were reviewed.
`
`b. General observations/commentary: Eleven subjects were screened, seven
`subjects were randomized, and six completed the study. Study was overseen by
`. The informed consent was
`approved for an English and Spanish version. The Regulatory Binder was neat
`
`Reference ID: 3639585
`
`(b) (4)
`
`

`

` Clinical Inspection Summary
`Page 8
` NDA 206073 empagliflozin/linagliptin
`
`and organized with all documents present. During the course of the inspection,
`it was found that several worksheets provided by the sponsor did not have the
`study subject’s initials or subject study number. The primary efficacy endpoint
`was verifiable. There were no issues with randomization or drug accountability.
`It was noted that several adverse events (AEs) failed to be recorded into the case
`report forms. These AEs were not discovered by the monitor.
`
`At the conclusion of the inspection, a Form FDA-483, Inspectional
`Observations, was issued for the following deficiency:
`
`1. An investigation was not conducted in accordance with the investigational
`plan.
`
`Specifically, not all adverse events and concomitant medications were
`entered into the electronic data capture system for four out of the seven
`randomized subjects (#90442, #90444, #90446, #90447).
` Subject 90442 sustained a motor vehicle accident with pain to multiple
`extremities requiring Relafen and Zoloft. No AE or medications were
`reported.
` Subject 90444 was diagnosed with a urinary tract infection and
`prescribed ciprofloxacin. No AE or medications were reported.
` Subject 90446 sustained a motor vehicle accident with pain to multiple
`extremities requiring Motrin and Flexeril. No AE or medications were reported.
`The subject later complained of mild dizziness and occasional headaches. No
`AEs were reported. The subject was prescribed Mobic for joint pains and
`Cozaar. No AE or medications were reported.
` Subject 90447 was diagnosed with urinary tract infection and prescribed
`ciprofloxacin. No AE or medication was reported. Subject also had a complaint
`of gastro-esophageal reflux and bloating. No AEs were reported.
`
`Dr. Oberoi responded to the Form FDA-483 in a letter dated August 14, 2014.
`The response was acceptable.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was
`submitted for review. Although regulatory violations were noted as described above,
`they are unlikely to significantly impact primary safety and efficacy analyses. Data
`from this site appear acceptable. The audit did not indicate serious deviations/findings
`that would impact the validity or reliability of the submitted data.
`
`6. Farid Marquez, M.D.
`Palm Springs Research Institute, Inc.
`1490 West 49 Place
`Suite 205
`Hialeah, Florida 33012
`
`Reference ID: 3639585
`
`

`

` Clinical Inspection Summary
`Page 9
` NDA 206073 empagliflozin/linagliptin
`
`a. What was inspected: The inspection focused on informed consent documents
`(ICDs), the regulatory binder, medical chart review for all subjects, and
`verifying the authenticity of the medical records used by the site to support the
`inclusion of subjects into the clinical trial.
`
`b. General observations/commentary: Enrollment at this site took place between
`10/5/2011 thru 2/3/2012. There were 38 subjects screened and 26 subjects
`enrolled. There were 22 subjects active at the time of the site’s termination. It
`was identified during a routine monitoring visit and noted in the monitoring
`report that six subjects’ medical charts contained very similar documents from
`different physicians (#92450, #92451, #92452, #92467, #92468, #92462).
`Fraudulent activity was suspected and then confirmed by an independent
`auditor. The findings of this investigation led to the sponsor’s decision to end
`the site’s participation in the 1275.1 trial. All data was excluded from all
`analyses. The site closure letter for Dr. Marquez was submitted to the FDA on
`April 9, 2012 to IND 108388. BIPI submitted a follow-up letter to the Agency
`on May 7, 2012. In closing this site, BIPI also discontinued the site’s
`participation in Study 1275.25 being conducted under IND
`.
`
`The current inspection disclosed that medical notes and medical records
`supposedly from the subjects’ private physicians contained false information
`such as physicians’ signatures, letter heads, patient names, and outpatient
`clinics’ visit dates. Because past medical records needed to be obtained as
`required by the protocol, this documentation was used in part by the site’s staff
`to confirm a type 2 diabetes mellitus diagnosis and treatment of various subjects
`enrolled in the study. Furthermore, some of the referenced medical notes
`supposedly written by the private physician to confirm eligibility after subjects
`were enrolled into the trial are dated with dates preceding subjects’ consenting
`date. The referenced documentation pertains to Subjects 92450, 92451, 92452,
`92455, 92462, and 92468.
`
`As part of the inspection, the FDA field investigators interviewed Dr. Marquez
`and his study staff. The site claimed the fraudulent records were brought by the
`patients to the site. The FDA field investigators interviewed the outside
`physicians who confirmed the medical records in question were not signed by
`them and/or were not generated at their corresponding clinics. The FDA field
`investigators were able to locate a subject who was able to confirm that she did
`not bring the medical records and medical notes to the site. The FDA field
`investigators also went to addresses listed in the medical records and could not
`find the subjects at those addresses.
`
`Additionally, the inspection disclosed that the site notified some of the subjects’
`physicians of their participation in the study against the subjects’ expressed will.
`The form used by the research site to request medical records from the subjects'
`physician states, “Your patient is undergoing an Investigational Trial in our
`Facility.” This statement is not in agreement with the directive expressed at the
`
`Reference ID: 3639585
`
`(b) (4)
`
`

`

` Clinical Inspection Summary
`Page 10
` NDA 206073 empagliflozin/linagliptin
`
`time of consenting by Subjects 92459, 92464, 92469, 92470, 92471, 92474,
`92477, 92475, 92476, 92462, 92468, 92478.
`
`On the initial submission dated 7/26/2011 made to the IRB requesting study
`approval, the site failed to disclose the occurrence of the FDA audit conducted
`on 6/6-7/5/2011 and findings listed on the Form FDA-483.
`
`Further affidavits are being gathered. The investigation is still pending close-
`out. A Form FDA-483, Inspectional Observations, will be issued for the
`following deficiencies:
`
`1. Failure to prepare or maintain adequate and accurate case histories with
`respect to observations and data pertinent to the investigation.
`2. An investigation was not conducted in accordance with the signed statement
`of investigator and investigational plan.
`3. Failure to assure that an IRB was responsible for the initial and continuing
`review and approval of a clinical study.
`
`c. Assessment of data integrity: The full Establishment Inspection Report (EIR) was not
`available for review. Preliminary inspection results were communicated by the FDA
`ORA field investigator. The audit indicates serious deviations/findings that would
`impact the validity and reliability of the submitted data. OSI is in agreement with the
`sponsor that data from this site are considered not reliable.
`
`III. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS
`
`The inspection for this NDA consisted of three domestic and three foreign clinical sites.
`
`Observations noted above for Drs. Aggarwal and Oberoi are based on the preliminary review
`of the Establishment Inspection Reports. Observations noted above for Drs. Aizenberg,
`Sposetti and Levinson are based on communications from the field investigator. Observations
`noted above for Dr. Marquez are based on communications from the field investigator and
`review of the Form FDA-483. An inspection summary