CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
` 022406Orig1s000
`
`OTHER ACTION LETTER(s)
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`
`
`
`NDA 22-406
`
`
`
`
`
`
`
`
`
`
`
`
`
`COMPLETE RESPONSE
`
`
`
`Johnson and Johnson Pharmaceutical Research and Development
`Attention: Andrea F. Kollath, DVM
`Director, Regulatory Affairs
`920 Route 202, P.O. Box 300
`Raritan, NJ 08869
`
`
`Dear Ms. Kollath:
`
`Please refer to your new drug application (NDA) dated July 28, 2008, received July 28, 2008,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for XareltoTM
`(rivaroxaban) tablets.
`
`We acknowledge receipt of your amendments dated August 11, October 15, November 4, 5, 21,
`24, and 25, December 1,16, 18, 19, and 24, 2008; January 6, 13, 23(3), 28(2), 27, 29, and 30,
`February 2(2), 13, 20, 24, and 25(2), March 2, 3, 4, 6, 11(2), 18(2), 25, and 26, April 1(2), 7, 17,
`24, 27, and 30(2), May 1, 5(2), 11, 18, 20(2) and 21, 2009.
`
`We have completed the review of your application, and have determined that we cannot approve
`this application in its present form. We have described below our reasons for this action and,
`where possible, our recommendations to address these issues.
`
`CLINICAL
`
`1.
`
`
`
`
`
`Investigator audits of a total of 11 clinical investigator sites, your firm as the applicant, and
`Bayer Pharmaceuticals as the sponsor of the "RECORD" studies (RECORD 1, 2, 3, and 4),
`were undertaken to evaluate the conduct of these four studies. These studies supplied most
`of the clinical data in support of the requested indication.
`
`Clinical Investigator Inspections
`
`A total of eight clinical investigator inspections by FDA, two each for the following studies,
`have been completed as part of the data audit for this NDA: RECORD 1, 2, 3, and 4. For
`the RECORD 1 study, data from the two clinical investigators audited by FDA are
`considered reliable in support of this NDA. For the RECORD 2 study, data from one of two
`clinical investigators audited by FDA are not considered reliable in support of this NDA (Dr.
`
`

`

`Qingming Yang). For the RECORD 3 study, one of two investigators audited, Dr. Bingfang
`Zeng, had a field classification of Official Action Indicated (OAI), indicating that serious
`deficiencies were noted which raised concerns regarding human subjects protection,
`although the data appeared acceptable for use in support of the NDA. For the RECORD 4
`study, data from one of two audited clinical investigators are not considered reliable in
`support of this NDA (Dr. Michael Murray).
`
`In addition to these eight clinical investigator inspections that were conducted following the
`NDA submission, two additional clinical investigators were inspected prior to the NDA
`submission as a result of complaints. These complaints pertained to the RECORD 2 study
`(Dr.
`) and the RECORD 4 study (Dr.
`). Based upon the inspection findings,
`the data from both of these sites are considered unreliable.
`
`The data from the five sites listed above are considered unreliable for the following reasons:
`
`• Failure to conduct the study according to the signed investigator statement and the
`investigational plan [21 CFR 312.60].
`• Failure to report adverse events to the sponsor [21 CFR 312.64].
`• Failure to prepare or maintain adequate and accurate case histories with respect to
`observations and data pertinent to the inspection [21 CFR 312.62 (b)].
`• Failure to obtain adequate informed consent [21 CFR 50]
`• Failure to maintain drug accountability records [21 CFR 312.62 (a)]
`• Failure to report to the IRB all unanticipated problems involving risk to human subjects
`[21 CFR 312.66].
`
`Bayer Pharmaceuticals informed us of data integrity issues pertaining to an additional
`RECORD 4 study clinical investigator, Dr. Ricardo Esquivel in Naulcapan, Mexico. These
`issues included an inability to confirm that study medication was administered consistent
`with protocol expectations, due to a systematic discarding of medical records documenting
`study drug administration.
`
`Sponsor Inspection
`
`Inspection of Bayer Pharmaceuticals as the sponsor of the four RECORD 4 studies revealed
`that the sponsor failed to 1) ensure proper monitoring of the study, 2) to ensure the study was
`conducted in accordance with the protocol and/or investigational plan, and 3) to ensure that
`FDA and all investigators were promptly informed of significant new adverse effects or
`risks.
`
`In order to address the issues outlined above we request that you:
`
`NDA 22-406
`Page 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 3
`
`
`
`
`a.
`
`
`
`Provide the following information regarding your clinical data quality assurance (QA)
`audit program that was in place for the four RECORD studies:
`
`i. A report of your QA audit plan, including your plan for securing compliance from
`non-compliant clinical investigators. Include copies of any Standard Operating
`Procedures (SOPs) that were in place during conduct of the study to address the
`means by which corrective actions were to be taken if or when you or the applicable
`contract research organization (CRO) identified noncompliant clinical investigators.
`
`
`ii. A report of your audit findings, including any corrective actions taken and final
`outcomes for the Yang, Murray,
`, and Esquivel sites and for all other
`sites you audited under your QA program.
`
`
`iii. A description of any clinical investigators terminated for non-compliance. Provide
`a list of these clinical investigators, their sites, the specific violations, and whether
`the data were included in the NDA submission.
`
`b. Describe Bayer’s QA program with respect to the oversight of CROs that were hired
`to monitor the clinical sites, including
` for the RECORD 4
`study. Describe the procedures implemented to make sure that the CROs adequately
`monitored the clinical sites. In your response, include the following information:
`
`i. How was Bayer kept apprised by the CROs concerning monitoring of the clinical
`sites during the course of the study? Specifically, what information did the CROs
`provide? Provide a list of non-compliant clinical study sites reported by the CROs.
`
`
`ii. How did Bayer review the information obtained from the CROs, during the course
`of the study and at the end of the study? What monitoring information was kept at
`the end of the study?
`
`
`iii. What actions did Bayer take based on the monitoring reports?
`
`c.
`
`Provide assurance that the clinical data obtained from the RECORD 1, 2, 3, and 4
`studies are reliable. Specifically, perform an additional audit and supply the results of
`this audit within your response to this letter. Within your response, include:
`
`
`
`i. A copy of your audit plan, including the following information:
`
`• How many clinical sites were to be audited, how many subject records were
`examined, and a description of the process for selection of the audited sites.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 4
`
`
`
`•
`
`
`
`If not all subject records at a given clinical site were to be audited, describe
`how subject records were sampled and how the specific data from each
`subject were audited.
`
`ii. The timeline for completion of your audit (plan finalization, start date, completion
`date, report finalization date).
`
`
`iii. In addition to any other information within your audit report, address the following
`questions or requests:
`
`• At each site audited, how many violations involved each of the following
`specific issues? For each specific violation, list the clinical sites involved and
`provide a breakdown by treatment group for each site and overall for the four
`RECORD studies.
`
`
`
`o Enrollment of subjects that did not meet study eligibility criteria.
`
` Failure of the Principal Investigator to ensure that all associates and
`colleagues assisting in the investigation were meeting the commitments
`of the study protocol.
`
` o
`
`
`
`o Failure to report adverse events and serious adverse events
`
`o Failure to randomize subject preoperatively
`
`o Failure to obtain informed consent from all subjects
`
`
`• List all clinical sites where either Bayer or CRO monitoring is determined to
`be ineffective, either in identifying significant violations or in taking actions
`towards securing compliance (such as notifying the sponsor).
`
`The supplied clinical data are insufficient to fully characterize a potential risk for serious
`liver toxicity. We request the following information:
`
`a. A report that assesses the potential signal for severe liver toxicity in your major on-going
`clinical studies of patients with atrial fibrillation (the "ROCKET" studies). Provide this
`report in a manner that does not compromise the analytical integrity of these studies. Base
`this report upon the findings from a data safety monitoring board's review of the clinical
`information for patients reported to have serum alanine aminotransferase (ALT) values
`greater than three times the upper limit of normal along with serum total bilirubin values
`greater than twice the upper limit of normal. The board's review should, at a minimum,
`consist of the review of all available clinical data for the index patients along with the
`treatment assignment. In reviewing these data, the board should consider any possible
`imbalance in the occurrence of the liver test abnormalities as well as each patient's clinical
`
`
`
`
`
`
`
`
`2.
`
`
`
`
`
`

`

`NDA 22-406
`Page 5
`
`
`
`
`
`features, particularly those related to liver abnormalities. We welcome a discussion with
`you to address the most appropriate method to report the board's findings to us.
`
`b. A report of the safety findings from the rivaroxaban post-marketing experience outside the
`United States. Include tabular and text summaries of spontaneously reported adverse
`events and an estimate of the numbers of patients exposed in the market place.
`
`c. A report that provides a summary of post-marketing studies initiated outside the United
`States, to include a description of the study designs, a status update (e.g., date of initiation,
`numbers of enrolled subjects) as well as a summary of adverse events detected in these
`studies. Additionally, provide a copy of the protocol for the "observational" post-
`marketing study you cited at the March 19, 2009, Advisory Committee.
`
`
`d.
`
`Provide a final report for the "ATLAS ACS TIMI 46" study, including electronic
`datasets sufficient to verify the safety and efficacy data.
`
`
`PRODUCT QUALITY
`
`3. DMF
`
`4. DMF
`
`5. DMF
`
`6.
`
`
`
`
`
`
`7.
`
` is inadequate in support of this NDA.
`
` is inadequate in support of this NDA.
`
` is inadequate in support of this NDA.
`
`The drug substance information is not adequate in that it does not meet 21 CFR
`314.50(d)(1)(ii). Insufficient information is provided to confirm nomenclature, description,
`physicochemical properties, specifications, the primary stability protocol, the post-approval
`stability commitment and primary stability data.
`
`The drug product specification, as provided by Bayer HealthCare Pharmaceuticals, Inc.
`is inadequate because it does not propose analytical methods for test parameters
`Additionally, the proposed acceptance criteria for uniformity of dosage units do not
`meet the current USP requirements.
`
`
`
`8.
`
`The proposed acceptance criteria for uniformity of dosage units and dissolution are
`different between Bayer HealthCare Pharmaceuticals and Janssen Ortho
`Pharmaceuticals. Justify this difference or alternatively, resolve the discrepancy.
`
`The currently-proposed acceptance criterion for dissolution is not acceptable and is
`recommended to be Q=
` at 15 minutes.
`
`10. The container and closure system is not adequately described.
`
`
`9.
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`NDA 22-406
`Page 6
`
`
`11. The proposed stability study is inadequate in that no stability data are submitted for
`pilot or commercial batches. In addition, a postapproval stability protocol and stability
`commitment were not submitted for Bayer Pharmaceuticals, Inc.
`
`
`CLINICAL PHARMACOLOGY
`
`We have the following additional comment for you to address in your response to this letter. This
`clinical pharmacology request is not a basis for our inability to approve your application.
`However, we request a response to facilitate our review of the proposed labeling and the need for
`any post-marketing expectations.
`
`12. Provide a description of your plans to develop a lower strength formulation to be used for
`dose modification in certain special populations of patients.
`
`
`LABELING
`
`
`Package Insert
`
`13. We reserve comment on the Package Insert 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/oc/datacouncil/spl.html.
`
`
`Container Label and Carton Labeling
`
`14. Please submit draft labeling revised as follows.
`
`
`d.
`
`Provide a more specific description (e.g., color, shape, size, resin) for bottles used as containers
`(NDC 50458-580-30) in the How Supplied section. In addition, include the carton as a
`container for
` blister packs, and provide a description in the How Supplied
`Section (section 16) of the package insert labeling.
`
`
`
`
`
`
`
`a.
`
`
`b.
`
`Revise the established name on the bulk container label (30 tablets) to include the dosage form
`as follows: ‘rivaroxaban tablets’.
`
`The size of the graphic on the principal display panel is more prominent than the size of the
`established name and proprietary name. The proprietary name, established name and strength
`should be the most prominent information on the container label and carton labeling.
`
`
`c. Delete or relocate to the side panel the
`itcrowds the principal display panel on the container label and carton labeling.
`
` statement as
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`NDA 22-406
`Page 7
`
`
`SAFETY UPDATE
`
`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.
`
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`• Present new safety data from the studies 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.
`•
`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.
`
`
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating
`the drop-outs from the newly completed studies. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical study or who did not complete a study because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`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.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`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.
`
`8. Provide English translations of current approved foreign labeling not previously submitted.
`
`

`

`
`
`NDA 22-406
`Page 8
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will consider
`your lack of response a request to withdraw the application under 21 CFR 314.65. 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.
`
`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. If you wish to have such a
`meeting, submit your meeting request as described in the FDA Guidance for Industry Formal
`Meetings With Sponsors and Applicants for PDUFA Products, February, 2000
`(http://www.fda.gov/cder/guidance/2125fnl.htm).
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`If you have questions, contact Marcus Cato, Regulatory Project Manager, at (301) 796-3903.
`
`
`
`
`
`
`
`
`Sincerely,
`
`
`
`
`
`
`
`
`
`
`
`{See appended electronic signature page}
`
`Richard Pazdur, MD
`Director
`Office of Oncology Drug Products
`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.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Richard Pazdur
`5/27/2009 03:44:28 PM
`
`