CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202155Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 202155
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`COMPLETE RESPONSE
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`Bristol-Myers Squibb
`ATTENTION: Linda Gambone, Ph.D.
`Associate Director, Global Regulatory Sciences
`P.O. Box 4000
`Princeton, NJ 08543-4000
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`Dear Dr. Gambone:
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`Please refer to your New Drug Application (NDA) dated September 28, 2011, received September 28,
`2011, submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Eliquis
`(apixaban) tablets.
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`We also refer to your submissions dated October 4, 7, 13, 14, 19, and 28; November 4, 10, 17, 18, and 22;
`December 2, 7, 9, 15, 19, 21, 22, 23, 28, and 30, 2011; and January 4, 5, 10, 11, 17, 20, 25 26, 30, and 31;
`February 2, 7, 8, 9, 10, 13, 14, 17, 21, 23, 24, 27, 28, and 29; March 21, 22, 23, 26, 27, and 28; April 2, 3,
`5, 10 (two), 13, 20, and 27; and May 9, 2012.
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`We have completed our review of this application, as amended, and have determined that we cannot
`approve the application in its present form. We have described our reasons for this action below and
`provided recommendations to address these issues.
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`1. As you are aware, some subjects in ARISTOTLE were given the wrong study drug (e.g. active
`instead of placebo and vice-versa). Knowledge of the study drugs actually dispensed to subjects is
`crucial to understanding the outcomes of the study. While we recognize your efforts to better define
`the rate and nature of dosing errors, which suggest a lower rate than initially reported, we believe the
`information you have submitted for us to review has not adequately characterized the frequency of
`errors in dispensing study drugs. Before we can approve your NDA you will need to submit reliable
`information regarding the following:
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` The frequency of a subject in ARISTOTLE receiving the wrong study medication, specifically:
`a. dispensing active warfarin instead of placebo warfarin to a subject randomized to
`apixaban;
`b. dispensing active apixaban instead of placebo apixaban to a subject randomized to
`warfarin;
`c. dispensing placebo apixaban instead of apixaban to a subject randomized to apixaban;
`d. dispensing placebo warfarin instead of warfarin to a subject randomized to warfarin, and
`e. dispensing the wrong dose of apixaban to a subject randomized to apixaban
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` 
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` The frequency of dispensing to a subject a bottle with a serial number other than the one assigned
`by the interactive voice response system (IVRS).
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`Reference ID: 3149976
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`NDA 202155 – Complete Response Letter
`Page 2
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` The frequency with which the serial number on the tear-off label from a study drug bottle did not
`match the IVRS assigned serial number.
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` The frequency with which the IVRS assigned serial number did not match each of the following
`and any one of the following: the eCRF entry of the serial number of dispensed study drug
`bottles, the eCRF entry of the serial number of returned study drug bottles, and the eCRF entry of
`the serial number of study drug bottles brought in to a visit but not returned.
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`You should use whatever sources of information you have available to respond to our requests. We
`believe that that the best source of information for responding to the first two bulleted items requested
`above is the tear off labels on which are printed the serial numbers of the study drug bottles. You
`may choose to collect all of these labels from investigative sites. However you recently submitted to
`us a summary report (but not the full report) you prepared for the European Medicines Agency
`(EMA), detailing your assessment of the errors in dispensing study drugs in a random 12% sample of
`subjects. The full report of this assessment might constitute an adequate response to our requests
`above, or may serve as a template for designing a response to our requests. A brief review of the
`summary report raises some questions that will need to be addressed if the full report is used to
`respond to our requests. For example, your analysis included only legible labels whereas it seems to
`us that a bottle with a difficult to read label is more likely to be dispensed in error.
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`You assert in the report you prepared for EMA that the frequency of a wrong study drug being
`dispensed to a subject was less than 0.1%. If the frequency is much greater than that, we may have
`additional requests for information. One of those will be identification of all primary endpoint events,
`deaths, and ISTH major bleeds that occur at times a subject may have been on two active study drugs
`or no active study drug. Another will be determining the frequency with which site monitoring
`identified and did not identify a subject whose eCRF indicates they may have been dispensed a bottle
`with an incorrect serial number.
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`2. Investigators in the ARISTOTLE study were supposed to report all instances in which they scratched
`off a coating on the tear-off labels to unblind a subject. We do not believe you have checked tear-off
`labels to verify that all instances of unblinding by investigators were reported in the 12% sample. If
`you have not done so, submit a plan to us to determine the frequency of unblinding by the investigator
`not reported to you. If the frequency is more than minimal, we may have additional requests.
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`3. In submissions to your NDA, you describe the intensity with which certain eCRF fields were
`monitored and checked during the conduct of ARISTOTLE. For example, you have told us that the
`entry on the eCRF listing the serial number of the bottle dispensed was subjected to more intense
`monitoring and edit checks than the entry listing the serial number of the bottle returned. To help us
`understand these different procedures, you need to provide us with all plans used to monitor and
`verify the accuracy of the entries on the eCRF. We note that the final monitoring plan you submitted
`in your NDA was dated after data-lock, and so may not have been a working plan actually used
`during the conduct of ARISTOTLE. You should provide the initial monitoring plan with all
`subsequent changes to that plan, both formal and informal. Indicate when and how changes in
`monitoring were implemented. Include all communications to sites, and identify the organizations
`responsible for all monitoring in the original monitoring plan, and any changes made.
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`4. You recently informed us that manual changes were made to a dataset containing the serial numbers
`of bottles assigned by the IVRS to subjects in ARISTOTLE. You stated that these changes were
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`made in response to information provided by investigators directly to the IVRS vendor,
`ensure that a bottle dispensed in error would be removed from inventory so it could not be assigned.
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`Reference ID: 3149976
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`(b) (4)
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`NDA 202155 – Complete Response Letter
`Page 3
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`Manual changes to the IVRS concern us because of the possibility of alterations to the randomization
`dataset. You therefore should provide the following:
` All agreements between BMS and
` concerning the role of
`ARISTOTLE.
` All SOPs from
` related to the conditions under which manual changes to data from the
`IVRS could be made and the documentation required to do so.
` An IVRS dataset that flags all subjects whose original IVRS-assigned bottle serial number was
`later changed, the serial number originally assigned and the altered serial number, and the reason
`for the change. Original IVRS datasets with codes to create the dataset (kitassgn) that was
`provided to the Agency may be helpful.
` Most importantly, an audit trail of the changes indicating who, when and why manual changes
`were made to the data set containing IVRS assigned bottle serial numbers. If the changes were
`made in response to information provided by an investigative site, please include the
`communication from the site documenting the information provided.
` A statement signed by responsible individuals that no changes were made to the randomization
`dataset.
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`5. We are concerned that the trial datasets submitted in your NDA do not accurately reflect the
`information in the eCRFs. In our brief review of your medication error dataset (smed.xpt) (used for
`most of your medication error analyses), we identified an observation with a valid date in the eCRF
`that was misrepresented by a period in the dataset, indicating that a valid date was missing. We also
`found medication data (indicating that drug was dispensed and taken until the end of treatment) for
`which there were no corresponding eCRFs in one subject. We can provide more details concerning
`these mismatches on request.
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`We are concerned about these errors because they were found after a cursory examination of these
`datasets, leading us to believe that there may be important errors in the datasets used for critical
`analyses. You should explain how these and similar errors, if any, occurred. If you believe that the
`datasets for important analyses are accurate, please provide the basis for your belief.
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`6. Some subjects have a unique adverse event listed multiple times as both non-serious and serious.
`This appears to be because the site personnel completed a non-serious AE CRF and a serious adverse
`event (SAE) CRF for the same event. You should prepare an adverse event analysis dataset
`(adae.xpt) in which all adverse events are listed a single time with the correct designation as serious
`or non-serious.
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`We expect that you will anticipate and answer any reasonable questions we are likely to have after
`reviewing the information you submit in your complete response.
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`LABELING
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`We reserve comment on the proposed labeling until the application is otherwise adequate. If you revise
`labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured
`product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`Reference ID: 3149976
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 202155 – Complete Response Letter
`Page 4
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`As described in our letter dated February 3, 2012, in accordance with section 505-1 of the FDCA, we
`have determined that a risk evaluation and mitigation strategy (REMS) is necessary for Eliquis to ensure
`that the benefits of the drug outweigh the increased risk of thrombotic events, including stroke, if Eliquis
`is discontinued.
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`We note that your February 13, 2012, amendment contained a response to our February 3, 2012, letter;
`this amendment was not reviewed for this action. We will continue discussion of your proposed REMS
`after your complete response to this action letter has been submitted.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical
`studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows:
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` Present new safety data from the studies/clinical trials for the proposed indication using the
`same format as the original NDA submission.
` Present tabulations of the new safety data combined with the original NDA data.
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`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
` For indications other than the proposed indication, provide separate tables for the frequencies
`of adverse events occurring in clinical trials.
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`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-
`outs from the newly completed trials. Describe any new trends or patterns identified.
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`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`trial or who did not complete a trial because of an adverse event. In addition, provide narrative
`summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects,
`person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously submitted.
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`Reference ID: 3149976
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`NDA 202155 – Complete Response Letter
`Page 5
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`OTHER
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`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what
`steps you need to take before the application may be approved. We strongly encourage you to schedule
`this meeting with us to discuss your plans for providing us with the additional information we have
`requested.
`Please submit your meeting request as described in the FDA’s “Guidance for Industry - Formal Meetings
`Between the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1532
`22.pdf.
`Within one year after the date of this letter, you are required to resubmit or take other actions available
`under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a
`request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in
`which to resubmit the application. A resubmission must fully address all the deficiencies listed. A partial
`response to this letter will not be processed as a resubmission and will not start a new review cycle.
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`The drug product may not be legally marketed until you have been notified in writing that this application
`is approved.
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`If you have any questions, please call:
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`Alison Blaus
`Regulatory Project Manager
`(301) 796-1138
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`{See appended electronic signature page}
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`Sincerely,
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`Robert Temple, M.D.
`Deputy Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Reference ID: 3149976
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`ROBERT TEMPLE
`06/22/2012
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`Reference ID: 3149976
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