CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022406Orig1s000
`
`SUMMARY REVIEW
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`
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`

`

`
`Subject
`NDA/BLA #
`
`Su lement #
`
`Applicant Name
`Janssen Pharmaceuticals, Inc.
`Date of Submission
`1/04/11
`
`PDUFA Goal Date
`
`7/03/11
`
`Proprietary Name /
`Established
`S .
`
`Name
`
`Xarelto/rivaroxaban
`
`Dosa _e Forms / Stren_ h
`
`Immediate Release Oral Tablets/ 10 m film-coated
`
`Proposed Indication(s)
`
`For the prophylaxis of deep vein thrombosis and
`pulmonary embolism in patients undergoing hip
`replacement surgery or knee replacement surgery
`
`Action/Recommended Action for Approval
`NME:
`
`0ND Action Packa - e. includin- :
`
`
`
`Yash Chopra. PhD./Adebayo Laniyonu. PhD. and Patricia Harlow.
`PhD./ Thomas P u . ian. PhD.
`
`Joyce Crich. PhD/Janice Brown. PhD. and Tapash Ghosh.
`PhD/Patrick Marroum. PhD.
`
`Microbioloa Review
`Clinical Pharmacolo; Review
`DDMAC
`
`Jos - h Grillo. Ph.D./Julie Bullock. PhD.
`
`_ Susan Thompson. M.D.fTejashari Purohit Sheth. M.D.lLeslie Ball.
`
`MD.
`
`——
`
`Other — Pediatrics
`
`Elizabeth L. Durmowicz. M.D.[Hari C. Sachs M.D.[Lisa Mathis.
`MD.
`
`Maternal Health Team
`
`Dr. Upasana Bhatnagar. MD/ Karen Feibus. M.D.l Lisa Mathis.
`MD.
`
`Other— Pharmacometlics
`
`Nitin Mehrotra. PhD/Christine Gamett. Ph.D.
`
`0ND=0ffice ofNew Drugs
`DDMAC=Drvision ofDrug Marketing, Advertising and Comanmication
`OSE= Office of Surveillance and Epidemiology
`
`Reference ID: 2968673
`
`

`

`Signatory Authority Review Template
`
`2
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`
`
`1. Introduction
`Xarelto is an oral Factor Xa inhibitor. Johnson and Johnson Pharmaceutical Research
`and Development LLC initially submitted this NDA on July 22, 2008 for the
`prophylaxis of deep vein thrombosis and pulmonary embolism in patients undergoing
`hip replacement surgery or knee replacement surgery. However the application could
`not be approved during the first cycle due to the need to clarify chemistry,
`manufacturing and control issues, need for additional understanding of potential
`safety issues and need for additional clarification of data integrity issues. The
`applicant was sent a complete response letter on May 27, 2009. The applicant
`responded to the complete response letter on January 4, 2011.
`
`Xarelto has been approved by the European Medicines Agency since May 6, 2009.
`2. Background
`The FDA has approved four drugs for use in the prevention of venous
`thromboembolism (VTE) in the setting of hip and/or knee replacement surgery. All
`these drugs are administered parenterally (enoxaparin, fondaparinux, dalteparin and
`unfractionated heparin). Warfarin is the only FDA-approved oral anticoagulant
`approved for the prophylaxis of venous thrombosis and its extension pulmonary
`embolism in general. However, warfarin, is not specifically indicated for use in the
`prevention of VTE in the perioperative period but is widely used and numerous
`publications have cited use in this setting.
`
`Unlike warfarin, rivaroxaban does not require anticoagulation parameter monitoring of
`the prothrombin time (PT). However, rivaroxaban does prolong the partial
`thromboplastin time (PT) and partial thromboplastin time (PTT). Additionally there is a
`linear relationship between exposure and PT prolongation. Dose dependent inhibition
`of Factor Xa was observed in clinical pharmacology trials.
`
` A
`
` single dose of 10 mg daily is recommended for all patients. However, the clinical
`pharmacology review team recommended and continues to recommend the
`development of a lower strength formulation for dose modification to be used in
`certain populations of patients who may be more sensitive to rivaroxaban.
`
`The original submission had four major trials submitted (RECORD 1, 2, 3, and 4) in
`support of the application. These trials were reviewed and the review team
`determined the trials supported an efficacy determination. However, during the first
`review cycle a number of deficiencies were identified in the areas of chemistry,
`manufacturing and control, clinical safety, and data integrity issues. The text in italics
`below is from the May 2009 complete response letter.
`
`
`Reference ID: 2968673
`
`

`

`Chemistg Manufacturing and Control Issues
`
`pm) is inadequate in support ofthis NDA.
`3. DIMF
`4. DlllF mm is inadequate in support ofthis NDA.
`5. DMF mm is inadequate in support ofthis NDA.
`6. The drug substance information is not adequate in that it does not meet 21 CFR
`314. 50(d)(1)(ii). Insuflicient information is provided to confirm nomenclature, description,
`physicochemicalproperties, specifications, the primary stability protocol, the post-approval
`stability commitment andprimary stability data.
`7. The drugproduct specification, as provided by Bayer HealthCare Pharmaceuticals, Inc.
`is inadequate because it does notpropose analytical methodsfor testparameters
`Additionally, the proposed acceptance criteriafor uniformity ofdosage units do not
`meet the current USP requirements.
`8. The proposed acceptance criteriafor uniformity ofdosage units and dissolution are
`difl'erent between Bayer HealthCare Pharmaceuticals and Janssen Ortho
`Pharmaceuticals. Justify this diflerence or alternatively, resolve the discrepancy.
`9. The currently-proposed acceptance criterionfor dissolution is not acceptable and is
`recommended to be Q: nu) at 15 minutes.
`10. The container and closure system is not adequately described.
`I I. The proposed stability study is inadequate in that no stability data are submittedfor
`pilot or commercial batches. In addition, a postapproval stability protocol and stability
`commitment were not submittedfor Bayer Pharmaceuticals, Inc.
`
`Data Integrig Issues
`
`1. Investigator audits ofa total of I I clinical investigator sites, yourfirm as the applicant, and
`Bayer Pharmaceuticals as the sponsor ofthe "RECORD" studies (RECORD 1, 2, 3, and 4),
`were undertaken to evaluate the conduct ofthesefour studies. These studies supplied most
`ofthe clinical data in support ofthe requested indication.
`
`Clinical Investigator Inspections
`A total ofeight clinical investigator inspections by FDA, two eachfor thefollowing studies,
`have been completed as part ofthe data auditfor this NDA: RECORD 1, 2, 3, and 4. For
`the RECORD 1 study, datafrom the two clinical investigators audited by FDA are
`considered reliable in support ofthis NDA. For the RECORD 2 study, datafrom one oftwo
`clinical investigators audited by FDA are not considered reliable in support ofthis NDA (Dr.
`Qingming Yang). For the RECORD 3 study, one oftwo investigators audited, Dr. Bing‘ang
`Zeng, had afield classification ofOflicial Action Indicated (0A1), indicating that serious
`deficiencies were noted which raised concerns regarding human subjects protection,
`although the data appeared acceptablefor use in support ofthe NDA. For the RECORD 4
`study, datafrom one oftwo audited clinical investigators are not considered reliable in
`support ofthis NDA (Dr. Michael Illurray).
`
`In addition to these eight clinical investigator inspections that were conductedfollowing the
`NDA submission, two additional clinical investigators were inspectedprior to the NDA
`submission as a result ofcomplaints. These complaints pertained to the RECORD 2 study
`
`Reference ID: 2968673
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`

`

`
`
`4
`
`). Based upon the inspection findings,
` and the RECORD 4 study (Dr.
`(Dr.
`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:
`
`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
`
`Reference ID: 2968673
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`
`
`5
`
` for the RECORD 4
`to monitor the clinical sites, including
`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.
`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.
`• 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.
`• Failure to report adverse events and serious adverse events
`• Failure to randomize subject preoperatively
`• 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).
`
`
`
`
`
`
`
`
`
`Reference ID: 2968673
`
`(b) (4)
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`
`6
`
`Clinical Safety Issues
`
`2. 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 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" postmarketing
`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.
`
`
`
`
`Additionally in the Complete Response Letter, the sponsor was asked to address the
`following:
`
`Clinical Pharmacology:
`
`Provide a description of your plans to develop a lower strength formulation to be used for
`dose modification in certain special populations of patients.
`
`Carton and Container:
`Please submit draft labeling revised as follows.
`a. Revise the established name on the bulk container label (30 tablets) to include the
`dosage form as follows:
`
`b. 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
`
`
`
`
`
`
`
`Reference ID: 2968673
`
`(b) (4)
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`7
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`
`
`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
`statement as it crowds the principal display panel on the container label and carton
`labeling.
`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.
`3. CMC/Device
`Drs. Crich, Brown, and Pope-Miksinski reviewed this supplement. Dr. Lostritto has
`also reviewed this supplement. In their reviews they state the following:
`
`From a Chemistry, Manufacturing and Controls standpoint, this NDA is recommended
`for approval a 30 month shelf life for the drug product in HDPE bottles and a 18 month
`shelf life for the drug product in blisters, when stored at 20°-25°C (68°F - 77°F) or
`room temperature; excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP
`Controlled Room Temperature].
`4. Nonclinical Pharmacology/Toxicology
`Drs. Chopra and Laniyonu performed the first cycle review and did not identify any
`issues that would preclude approval. Drs. Harlow and Papoian reviewed the 2 year
`carcinogenicity studies in CD-1 Mice and Wistar rats. A slight increase in tumors was
`noted in the Wistar rats study; however, this increase was not statistically significant.
`The observed increase does not affect the approvability of this NDA which is for short-
`tem use.
`5. Clinical Pharmacology/Biopharmaceutics
`The recommended dose is 10 mg per day with or without food. Dose modification is
`suggested for those who will take rivaroxaban with a strong PgP and CYP 3A4
`inducer.
`
`From the first cycle review:
`
`
`Dose-dependent inhibition of FXa activity and prolongation of the prothrombin time
`(PT), activated partial thromboplastin time (aPTT) and HepTest® were observed in
`humans. The offset of the pharmacodynamic effect (24-48 hours) parallels the
`pharmacokinetic halflife. The relationship between exposure and PT prolongation
`appears linear.
`
`There are no issues which would preclude approval of rivaroxaban based on the
`clinical pharmacology reviews. However, the clinical pharmacology review team
`recommends the following post-marketing commitment and requirement from their
`second cycle review:
`
`Reference ID: 2968673
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`8
`
`
`Commitment
`1) Develop and propose a 5 mg dosing form (tablet) or scored 10 mg tablet to allow
`for proper dose titration when rivaroxaban needs to be co-administered in patients at
`risk for clinically relevant changes in rivaroxaban exposure. The 5 mg dose form
`should be sufficiently distinguishable from the 10 mg tablet. Full chemistry,
`manufacturing and controls (CMC) information for the 5 mg dosage form including the
`batch data and stability data, labels, updated labeling, and updated environmental
`assessment section is required in a prior approval supplement.
`
`Requirement
`2) The applicant should evaluate the effect of renal impairment (i.e., mild, moderate,
`severe) plus the concurrent use of P-gp and moderate inhibitors of CYP3A4 on the
`pharmacokinetics, pharmacodynamics, and safety of rivaroxaban in volunteers so that
`appropriate dosing recommendations can be developed in these populations following
`the development of the 5 mg tablet formulation.
`
`
`6. Clinical Microbiology
`Not applicable
`
`
`7. Clinical/Statistical-Efficacy
`I have read the first cycle clinical reviews from Drs. Rieves, Robie-Suh, and Lu. Drs.
`Lu’s and Robie-Suh’s primary concerns regarding the application were safety, not
`efficacy. They were concerned that insufficient safety information on hepatotoxicity
`was available to assess the full-risk benefit profile. Dr. Lu concluded the Executive
`Summary of her first cycle review by stating the following:
`
`Overall rivaroxaban demonstrates efficacy in the prophylaxis of total VTE in patients
`undergoing elective hip or knee replacement surgeries.
`
`The RECORD 1, 2, 3, and 4 trials provided the efficacy and safety database for the
`both indications:
`the prophylaxis of deep vein thrombosis and pulmonary embolism in patients
`undergoing hip replacement surgery and
`the prophylaxis of deep vein thrombosis and pulmonary embolism in patients
`undergoing knee replacement surgery.
`
`
`All four trials were international, randomized, double-blind, double-dummy, active
`control (enoxaparin), parallel group design enrolling patients undergoing elective
`surgery for hip replacement (RECORD 1 and RECORD 2) or for knee replacement
`(RECORD 3 and RECORD 4).
`
`From Dr. Lu’s first cycle review:
`
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`Reference ID: 2968673
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`9
`
` Four multi-center, randomized controlled trials (RECORD 1-4) were conducted to support
`the currently proposed indication for the prophylaxis of deep vein thrombosis and pulmonary
`embolism in patients undergoing hip or knee replacement surgeries. RECORD 1 and 2 studies
`were conducted in patients undergoing hip replacement surgery (THR) and RECORD 3 and 4
`studies were in patients undergoing knee replacement surgery (TKR). In all 4 RECORD trials,
`rivaroxaban 10 mg once daily administered orally at least 6 to 8 hours after surgery was
`compared with enoxaparin administered subcutaneously. The enoxaparin dosing regimen was
`40mg once daily starting 12 hours preoperatively in RECORD 1-3 studies and was 30 mg
`twice daily starting 12 to 24 hours postoperatively in RECORD 4 study. The durations of
`active treatment for rivaroxaban and enoxaparin were similar in the RECORD studies with the
`exception of RECORD 2, in which treatment duration of Rivaroxaban was much longer than
`enoxaparin control (rivaroxaban 35 days versus enoxaparin 13 days). The dose regimen of
`enoxaparin (40 mg once daily) control in RECORD 3 study is not a recommended dose
`regimen of enoxaparin for the prophylaxis of DVT in patients undergoing TKR in the United
`States.
`Altogether a total of 12,729 patients (6356 in the rivaroxaban group and 6373 in the
`enoxaparin group were randomized in 4 RECORD studies and 8,512 (67%) (4248 in the
`rivaroxaban group and 4264 in the enoxaparin group) were included in the Modified Intent to
`Treat (MITT) population for the primary efficacy analysis. About 30-39% of randomized
`patients in RECORD studies were excluded from MITT population mainly due to no adequate
`assessment of DVT.
`The primary efficacy endpoint was a composite endpoint of total VTE consisting of any DVT
`(proximal and/or distal), non-fatal PE, or death from all causes at the end of treatment in all 4
`RECORD studies.
`
`The statistical analyses supporting approval from the statistical team’s review are in
`the table below.
`
`Table 1. Summary of Primary Efficacy Endpoint Analysis Results (Total VTE)
`Study
`Rivaroxaban %
`Enoxaparin %
`ARR
`p-value
`(n/N)
`(n/N)
`1.1% (18/1595) 3.7% (58/1558) 2.6%
`
`RECORD 1
`
`RECORD 2
`
`2.0% (17/864)
`
`9.3% (81/869)
`
`7.3%
`
`p<0.0001
`
`p<0.0001
`
`p<0.0001
`
`p=0.012
`
`RECORD 3
`
`9.6% (79/824)
`
`RECORD 4
`
`6.9% (67/965)
`
`18.9%
`(166/878)
`10.1% (97/959)
`
`
`9.3%
`
`3.2%
`
`ARR=Absolute Risk Reduction
`Statistical Review Team table
`
`The Division of Scientific Investigation identified some problematic sites and
`investigators during their inspection and assessment. Thus, the statistical review team
`also performed sensitivity analyses excluding the known unreliable sites. The
`statistical review team reanalyzed the data removing these sites where there were
`drug accountability and other issues. For each RECORD trial, the sensitivity analysis
`
`Reference ID: 2968673
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`

`

`
`
`10
`
`using the modified ITT population demonstrates a statistically significant difference in
`favor of rivaroxaban for the primary endpoint. The results are provided in table 2
`below.
`
`Table 2. Summary of Primary Efficacy Endpoint Analysis Results (Total VTE)
`Excluding Unreliable Sites
`Enoxaparin %
`Study
`Rivaroxaban %
`(n/N)
`(n/N)
`1.1% (17/1513) 3.9% (57/1473)
`
`RECORD 1
`
`ARR
`
`2.8%
`
`p-value
`
`p<0.0001
`
`p<0.0001
`
`p<0.0001
`
`p=0.0174
`
`RECORD 2
`
`2.1% (17/828)
`
`8.4% (70/830)
`
`6.3%
`
`RECORD 3
`
`9.7% (79/813)
`
`18.8% (164/871)
`
`9.1%
`
`RECORD 4
`
`7.1% (53/742)
`
`10.8% (79/731)
`
`
`3.7%
`
`ARR=Absolute Risk Reduction
`
`Removing the problematic investigators/sites suggested that the results are still
`supportive of efficacy claims. However, the Agency has additional concerns
`regarding the study conduct and data collected in RECORD 4 which are discussed
`later.
`
` I
`
` concur with the conclusions of the clinical and statistical review teams regarding the
`demonstrations of efficacy for both indications.
`8. Safety
`During the first review cycle, the review team identified several areas for rigorous
`safety review: bleeding events, cardiovascular events, hepatotoxicity, and renal
`toxicity.
`
`Bleeding Events:
`Review of the bleeding events revealed an increase in major bleeding events for the
`rivaroxaban treated patients; however the difference was not statistically significant. In
`subgroup analyses, for Asian subjects and those subjects with body weight ≤ 50 kg or
`≥ 110 kg the bleeding risk appeared to be higher for those subjects with rivaroxaban
`treatment.
`
`Cardiovascular Events:
`No statistically significant differences were noted between treatment groups during
`treatment. However, a slightly higher incidence of ischemic stroke was noted after
`subjects stopped rivaroxaban treatment. The significance of this increase is unclear.
`
`
`
`
`
`Reference ID: 2968673
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`

`

`
`
`11
`
`Hepatotoxicity:
`The clinical team’s greatest concern during the first cycle review was for
`hepatotoxicity. The review team requested additional long term follow-up data from
`the ROCKET studies where rivaroxaban was used for stroke prophylaxis in patients
`with atrial fibrillation. In addition to the clinical and statistical review teams, two other
`teams analyzed the rivaroxaban safety data for hepatoxicity: Drs. Senior and Gelperin
`from OSE and Drs. Yap, Tracy and Chakravarty from statistics. The longer term data
`did not reveal a significantly different liver toxicity profile compared with warfarin and
`enoxaparin.
`
`Renal toxicity:
`There were slightly higher incidences of creatinine and urea elevations in the
`rivaroxaban treated subjects compared with the active control subjects.
`
`Dr. Lu concluded in her second cycle review the following:
`
`The other adverse events reported more frequently with rivaroxaban as compared to the
`control were pruritus, wound healing complications, pain in extremity, increased muscle tone
`and cramping, wound secreation, blister, syncope, and dysuria in clinical trials. Other
`significant adverse events reported associated with rivaroxaban treatment in post-marketing
`spontaneous reports were cerebral hemorrhage, epidural hematoma, hypersensitivity
`reactions including anaphylactic shock, agranulocytosis, and Steven-Johnson syndrome.
`
` concur with the conclusions of the clinical and statistical review teams.
`
`One of the safety issues associated with rivaroxaban use is the lack of knowledge
`about a method to reverse anticoagulation (including excessive anticoagulation). This
`information would be crucial for practicing physicians to have. The division will request
`from the sponsor a method to amass cases of major bleeding seen post-approval,
`collect information on rivaroxaban dosing, outcome of major bleeding, and any
`treatment for the major bleeding.
`
`
` I
`
`9. Advisory Committee Meeting
`This product was discussed at a Cardiovascular and Renal Advisory Committee
`meeting on March 19, 2009. The Committee voted 15 (yes) to 2 (no) that the available
`clinical data demonstrate a favorable risk-benefit profile for rivaroxaban in the
`prophylaxis of venous thromboembolism in patients undergoing hip or knee
`replacement surgery.
`10.
`Pediatrics
`The applicant requested a full waiver and the pediatric review committee concurred.
`
`Reference ID: 2968673
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`

`

`
`
`12
`
`Other Relevant Regulatory Issues
`11.
`Maternal Health was consulted and provided labeling recommendations which were
`incorporated into labeling.
`
`Office of Surveillance and Epidemiology was consulted including DMEPA who
`provided labeling input.
`
`Division of Scientific Investigation (DSI)
`As listed in section 2 above, at the conclusion of the first review cycle, DSI identified a
`number of items that they requested the company address based on their initial
`investigation and inspections. These items are listed in the May 2009 Complete
`Response letter. DSI has reviewed the applicant’s responses to Agency requests. DSI
`agrees that the company did respond to all their requests and outstanding issues.
`
`From their review, the DSI review team states that they believe the data from
`RECORD trials 1, 2, and 3 are reliable and that the data from RECORD 4 are not.
`The data integrity concerns for RECORD 4 involve the following areas:
`
`1. Post-operative Randomization
`DSI inspection discovered that some patients in the RECORD trials were post-
`operatively randomized to a particular treatment group. Based on the inspection, the
`percentage of patients was less than 1% for the RECORD trials 1, 2, and 3. However,
`for RECORD 4 this percentage was approximately 39%. Why the post-operative
`randomization was so high for RECORD 4 is not understood. When this error was
`discovered the company did attempt to educate the sites to randomize pre-
`operatively. Despite the high percentage of post-operative randomization, post-
`operative randomization is unlikely to have introduced any bias in favor of rivaroxaban
`over enoxaparin for efficacy or safety.
`
`
`2. Unreported Adverse Events
`All four RECORD trials had unreported adverse events. The trial with the highest
`number of unreported adverse events was RECORD 4. In the
` audit, RECORD
`4 trial had 265 unreported adverse events. The next highest total for unreported
`adverse events was observed with RECORD 2 trial where there were 131 unreported
`adverse events. In the
`l audit, RECORD 4 trial had 504 unreported adverse
`events.
`
`The applicant analyzed the safety data including and excluding RECORD 4 data and
`the percentages for each adverse event/reaction did not change significantly.
`
`3. Drug Accountability Issues
`Drug accountability issues were identified in 27-33% of the audited sites. These
`issues were observed for all RECORD trials. Drug accountability issues identified by
`the inspection fall into different categories:
`
`
`
`Reference ID: 2968673
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`13
`
`Medication return
`For both treatment groups, greater or less treatment medication (tablet or injections)
`were returned by trial participants than would have been expected. Review of the
`inspection reports revealed that these types of returns occurred for both treatment
`arms.
`
`
`Timing of Administration
`Problems with record keeping for timing of administration included discrepancies in
`the timing of administration, who and when administered and medication given at
`home. These discrepancies were noted on case report forms, medical records, and as
`well as site logs.
`
`4. Inadequate Monitoring
`
`DSI inspection of Bayer did uncover problems with the monitoring of the 4 RECORD
`trials. An inspection of Johnson & Johnson did not uncover similar problems.
`
`The issues uncovered during the Bayer inspection include failure 1) to ensure proper
`monitoring of the study, 2) to ensure the study was conducted in accordance with the
`investigational plan, and 3) to ensure that the FDA and all investigators were promptly
`informed of significant new adverse events or risks. Failure to ensure proper
`monitoring of the study includes the fact that Bayer’s monitoring program did not
`detect what should have been major violations at sites. Failure to ensure that the
`study was conducted in accordance with the investigational plan includes the fact that
`39% of RECORD 4 audited sites had post-operative randomization. Failure to ensure
`that the FDA and all investigators were promptly informed of significant new adverse
`events or risks includes the large number of unreported adverse events mentioned
`above for RECORD 4.
`
`Bayer acknowledged the problems with monitoring. Also noted is the fact that Bayer
`did inform the FDA about problems with 2 investigators in RECORD 4: Dr.
` and
`Dr. Esquivel more than a year prior to submission of the NDA and one investigator in
`RECORD 2: Dr.
`
`
`Based on the DSI inspection, the two inspected sites for RECORD 1 received no
`action indicated (NAI) letters with no recommendations for any action and the two
`inspected sites for RECORD 3 received voluntary action indicated (VAI) letters with
`recommendations for improvement. One investigator (Dr.
`) in RECORD 2
`received an Official Action Indicated letter and that data was deemed not usable.
`Based on the DSI inspection, one site for RECORD 3 received an untitled Official
`Action Indicated letter and three additional sites received VAI letters with
`recommendations for improvement. One investigator (Dr.
`) in RECORD 4
`received an Official Action Indicated and had a Notice of Initiation of Disqualification
`Proceedings and an