`RESEARCH
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`APPLICATION NUMBER:
`022406Orig1s000
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`CROSS DISCIPLINE TEAM LEADER REVIEW
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`Cross Discipline Team Leader Review
`NBA 22-406/ resubmission
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`Cross-Discipline Team Leader Review
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`
`Date
`June 14, 2011
`
`Kath M. Robie Suh, M.D., PhD.
`From
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`22—406 2" review c cle
`
`Johnson & Johnson
`
`Date of Submission
`December 31, 2010
`
`PDUFA Goal Date
`July 3, 2011
`
`indicated
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`Established
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`S ‘
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`names
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`rivaroxaban
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`Dosa _e forms / Stren h
`Proposed Indication(s)
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`Recommended:
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`10 111
`Oral tablets
`for prophylaxis of deep vein thrombosis ODVT) and
`puhnonary embolism (PE) in patients lmdergoing hip or
`knee re 0 lacement sur - e
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`Approval, with agreed upon revisions to sponsor’s
`proposed labeling and post-marketing commitments as
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`1. Introduction
`
`
`Patients undergoing total hip replacement surgery or total knee replacement surgery are at
`increased risk for venous thromboembolic events (VTE) including deep vein thrombosis
`(DVT) and pulmonary embolism (PE). Current practice recommends anticoagulant
`thromboprophylaxis following these procedures. Consideration for thromboprophylaxis seeks
`to balance risk of VTE and risk of bleeding. Several anticoagulant drug products are currently
`approved and marketed in the U.S. for thromboprophylaxis in hip and/or knee replacement
`surgery. These include: Lovenox (enoxaparin sodium)(hip replacement and knee
`replacement), Arixtra (fondaparinux sodium) (hip replacement, knee replacement, and hip
`fracture surgery) and Fragmin (dalteparin sodium)(hip replacement). All these products are
`administered subcutaneously. In addition heparin sodium is labeled generally for
`subcutaneous administration for prophylaxis of DVT. Coumadin (warfarin sodium)
`administered orally is approved generally “for the prophylaxis and/or treatment of venous
`thrombosis and its extension and pulmonary embolism”.
`
`Xarelto (rivaroxaban) Tablets is an orally administered Factor Xa inhibitor being developed as
`an anticoagulant for several indications. Relevant IND applications include IND 64,892
` for
`(rivaroxaban, BAY 59-7939) for antithrombotic indications and
`cardiovascular indications including stroke prevention in non-valvular atrial fibrillation and
`use in acute coronary syndromes. In the current NDA application the sponsor is seeking initial
`U.S. marketing approval of rivaroxaban for the indication: “for the prophylaxis of deep vein
`thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing knee or hip
`replacement surgery”. The proposed dose is 10 mg orally once daily with a treatment duration
`of 14 days for knee surgery and 35 days for hip surgery. Xarelto was approved for this
`indication in Europe and Canada in September 2008 and has been approved in some other
`countries also.
`
`If approved, rivaroxaban would be the first oral anticoagulant approved in the U.S. for the
`indication being sought and the second oral anticoagulant approved in the U.S. for any
`indication since approval of warfarin in 1954. [Pradaxa (dabigatran), an orally administered
`antithrombin inhibitor, was approved on October 19, 2010 in the U.S. for the indication “to
`reduce the risk of stroke and systemic embolism in patients with non-valvular atrial
`fibrillation”]. Other indications for which phase 2 or 3 clinical investigations of rivaroxaban
`are ongoing include: for treatment of deep vein thrombosis (DVT) and pulmonary embolism
`(PE), for thromboprophylaxis in hospitalized medically ill patients, and in patients with acute
`coronary syndromes (ACS). Concurrent with the current resubmission of NDA 22-406 the
`sponsor has submitted a separate application (NDA 202439) on January 4, 2011 (received
`January 6, 2011) for long-term use of rivaroxaban for the prevention of stroke and systemic
`embolism in patients with chronic non-valvular atrial fibrillation. That application is currently
`under review by the Division of Cardiovascular and Renal Products (DCRP).
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`2. Background
`
`
`This is the second review cycle for this drug product. See my Medical Team Leader/CDTL
`review dated 5/27/2009 for background and summary of cycle 1 review findings. Briefly, the
`database consisted of four trials (the RECORD 1, 2, 3, and 4 studies), each comparing
`rivaroxaban to enoxaparin (different regimens) with two studies for knee surgery and two
`studies for hip surgery. All four studies were multinational, randomized (1:1), double-blind,
`double-dummy, active control (enoxaparin), parallel groups design. The studies were
`conducted by Bayer but the right of reference for use of the studies was transferred to Johnson
`& Johnson (J & J) just prior to NDA submission and J & J is the sponsor of the NDA. The
`efficacy findings of the first cycle review found statistically significant evidence for efficacy in
`all 4 studies with incidence rates for the primary efficacy endpoint (“total VTE”) for the
`rivaroxaban and enoxaparin arms, respectively, in the studies as follows: 1.1% (18/1595) and
`3.7% (58/1558) in RECORD 1; 2.0% (17/864) and 9.3% (81/869) in RECORD 2; 9.6%
`(79/824) and 18.9% (166/878) in RECORD 3; and 6.9% (67/965) and 10.1% (97/959) in
`RECORD 4. A meeting of the Cardiovascular and Renal Drugs Advisory Committee on
`March 19, 2009 concluded that favorable benefit-risk profile had been demonstrated for use of
`rivaroxaban in the prophylaxis of venous thromboembolism (VTE) in patients undergoing hip
`or knee replacement surgery, but voiced some concerns about the strength of the signals for
`hepatotoxicity and the feasibility of long-term studies to further elucidate the hepatotoxicity
`potential. Subsequent to the advisory committee meeting, findings of the Division of
`Scientific Investigations (DSI) inspections of several sites, particularly in RECORD 4,
`identified deficiencies with regard to compliance with study procedures, completeness in
`reporting of adverse events and other irregularities during the conduct of the RECORD studies
`raising questions about the adequacy of study monitoring by Bayer and necessitating further
`examination of the integrity of the studies by DSI.
`
`On May 27, 2010 the Agency issued a Complete Response (CR) letter to Johnson & Johnson
`(Appendix B) citing results from the DSI clinical investigator inspections indicating that some
`sites may be unreliable and results from the sponsor (Bayer) inspection revealing that “the
`sponsor failed to 1)ensure proper monitoring of the study, 2)to ensure that 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.”
`The sponsor was requested to provide a detailed report of their clinical quality assurance (QA)
`audit plan including plan for securing investigator compliance, audit findings, corrective
`actions including termination of investigators, oversight of CROs and Bayer handling of
`review information obtained from the CROs. The sponsor was asked to plan and perform an
`additional audit and provide a full report.
`
`Also, in the CR letter the sponsor was informed that the supplied clinical data were insufficient
`to fully characterize a potential risk for serious liver toxicity. The sponsor was asked to
`provide additional long-term safety data from the studies of rivaroxaban in patients with atrial
`fibrillation (ROCKET srtudies), post-marketing experience outside the U.S., final reports for
`other completed long-term treatment studies and summary of post-marketing studies initiated
`outside the U.S.
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`Finallly, the CR letter included deficiencies identified by Chemistry, Manufacturing and
`Controls (CMC) review including problems with dissolution specifications, inadequate
`information about the drug substance, significant DMF deficiencies and issues regarding the
`proposed labels.
`
`In the resubmission the sponsor has provided a full response to the CR letter.
`3. CMC/Device
`
`
`The product is an immediate release 10 mg tablet. During this review cycle upon
`recommendation by ONDQA Biopharmaceutics review (Tapash K. Ghosh, Ph.D., 3/23/2011)
`the sponsor revised the dissolution specifications and method adequately (see review by
`Tapash K. Ghosh, Ph.D., 5/2/2011). The CMC review completed by Joyce Z. Crich, Ph.D.
`(signed 6/2/2011) found the additional submitted materials and response acceptable from a
`CMC standpoint and recommended approval of Xarelto with 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
`under specified conditions. The Office of Compliance has given an overall acceptable
`recommendation for the facilities and from a CMC standpoint, this NDA is recommended for
`approval (CMC Review #3, Janice Brown, Ph.D., 6/14/2011). There were no
`recommendations for Phase 4 commitments or risk management measures.
`4. Nonclinical Pharmacology/Toxicology
`
`
`The application was found acceptable for approval from a Non-clinical
`Pharmacology/Toxicology viewpoint during the first cycle. No new non-clinical data are
`provided in the CR submission for NDA 22-406. However, the sponsor has provided full
`reports of carcinogenicity studies in the NDA 202-439 application for long-term use of
`rivaroxaban in patients with atrial fibrillation. The non-clinical carcinogenicity studies are not
`required for approval of the drug for the short-term thromboprophylaxis use proposed in NDA
`20-406. However, review of those studies has been completed (Patricia P. Harlow, Ph.D.,
`06/13/2011). Two year carcinogenicity studies were performed in CD-1 mice and Wistar rats.
`The review found no significant evidence of neoplasia related to rivaroxaban in either rats or
`mice. The Executive Carcinogenicity Assessment Committee also concluded that there were
`no clear drug-related neoplasms in either study. The review concluded that the results of the
`carcinogencity studies support approvability of rivaroxaban. Dr. Harlow’s review also
`provided recommendations for section 13.1 of the labeling based on the results of the
`carcinogenicity studies.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Though no Clinical Pharmacology deficiencies precluding approval were included in the CR
`letter, the letter did request that the sponsor provide a description of its plans to develop a
`lower strength formulation to be used for dose modification in certain special populations.
`The sponsor’s response included a study synopsis and proposal to conduct a Phase 1 drug
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`interaction study (RIVAROXACS1001) in patients with mild or moderate renal impairment
`concomitantly receiving erythromycin, a moderate CYP3A4/moderate P-gp inhibitor. The
`FDA Clinical Pharmacology Review (Joseph Grillo, Pharm.D., 6/3/2011) agreed with the
`sponsor’s planned study. For other populations the sponsor’s submission provided discussion
`regarding the sponsor’s belief that a lower dose formulation was not needed for patients with
`Child Pugh class B patients without coagulopathy or for patients concurrently receiving
`Xarelto and a P-gp and strong CYP3A4 inhibitors. FDA Clinical Pharmacology was not
`persuaded by the sponsor’s arguments and the Dr. Grillo’s review of the resubmission
`concluded: “From a clinical pharmacology perspective, this resubmission of the original
`application is ACCEPTABLE provided that the applicant and the Agency come to a mutually
`satisfactory agreement regarding the language in the package insert and the applicant commits
`to the following post marketing commitments addressing clinical pharmacology related safety
`concerns with rivaroxaban treatment.” The following were listed as post-marketing
`commitments: (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, and (2)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. Also, the review recommended that the sponsor
`evaluate the effect of a P-gp inhibitor with limited CYP3A4 inhibitory activity (e.g., quinidine)
`on the pharmacokinetics, pharmacodynamics, and safety of rivaroxaban in healthy subjects to
`explore the involvement of P-gp in rivaroxaban elimination.
`
`The Clinical Pharmacology review provided detailed recommendations for the labeling. It
`also recommended that, until the sponsor has developed a lower dose formulation for use in
`patients with Child Pugh class B hepatic impairment without coagulopathy and in patients with
`concurrent rivaroxaban use with a P-gp and strong CYP3A4 inhibitor, avoidance language
`should be included in the labeling for these populations.
`
`
`6. Clinical Microbiology
`The product is an oral formulation. No clinical microbiology information was submitted for
`this application.
`
`7. Clinical/Statistical- Efficacy
`
`
`This is the second review cycle for this supplemental application. During the first review
`cycle Clinical Review (Min Lu, M.D., M.P.H., signed 4/2/2009) concluded that efficacy of
`rivaroxaban had been demonstrated. The review stated: “Overall, rivaroxaban demonstrates
`efficacy in prophylaxis of total VTE in patients undergoing elective hip or knee replacement
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`surgeries. The absolute risk reduction of rivaroxaban for total VTE was 2.6% for total hip
`replacement surgery (RECORD 1 study), and 3.2% for total knee replacement surgery
`(RECORD 4 study) compared to currently available product (enoxaparin) with the similar
`treatment duration. The difference between the two treatments was mostly due to
`asymptomatic DVT. These results were based on 67% of all randomized population. There
`was no significant difference for the symptomatic VTE between the two treatments in these
`two studies based on 97% of randomized population.” Statistics Review (Qing Xu, Ph.D.,
`5/8/2009) of the original application during the first review cycle found, “Statistical analysis
`results, based on the data of the 4 pivotal studies, demonstrate the drug efficacy using
`Rivaroxaban in the treatment of major VTE when compared with Enoxaparin control. Findings
`from using different approaches to deal with missing data issues with the primary endpoint
`consistently concluded the robustness of the primary efficacy results.” After completion of the
`reviews, information from Division of Scientific Investigations (DSI) inspections of sites in
`the RECORD studies, raised concerns regarding data integrity for the studies. (See section 11
`below). Therefore, for the clinical review of the resubmission efficacy was re-evaluated
`considering the results of the more extensive auditing of the studies that was conducted in
`response to the CR letter.
`
`DSI review of the resubmission concluded that RECORD 4 was unreliable and the data should
`not be used. (Susan D. Thompson, M.D., 5/25/2011). This leaves the RECORD 1 and 2
`studies for thromboprophylaxis in total hip replacement and a single study RECORD 3 for
`thromboprophylaxis in total knee replacement. For each of these three studies, one or more
`audited sites also were found to be unreliable. FDA Statistics conducted analysis by excluding
`all unreliable sites for RECORD 1, 2, and 3 identified by DSI; and the results did not alter the
`original efficacy conclusion (Qing Xu, Ph.D., final signature 5/27/2011). In her current
`Clinical Review (signed 6/3/2011) of the resubmission Dr. Lu states, “Rivaroxaban has been
`shown to reduce the rate of total venous thromboembolic events (VTE) inpatients undergoing
`hip or knee replacement surgery as compared to the control (enoxaparin or enoxaparin
`followed by placebo).” Secondary clinical review (Kathy Robie Suh, M.D.,Ph.D., 6/13/2011)
`after considering the impact of the unreliable sites concludes that, “With regard to efficacy,
`overall, the results support that rivaroxaban is effective in reducing VTE events in patients
`undergoing hip or knee surgery. However, considering the shortcoming in the monitoring
`adequacy in the studies, quantitative expression of that effectiveness as compared to the
`enoxaparin comparator in these studies may not be reliable. I would not conclude superiority
`of rivaroxaban over enoxaparin for the indication based on the results of these studies.”
`
`
`8. Safety
`
`
`The major clinical safety concerns identified during the first cycle review were bleeding
`(increased risk for major bleeding) and possible hepatotoxicity. (See Clinical Review by Min
`Lu, M.D., M.P.H., signed 4/2/2009; Medical Team Leader/CDTL review by Kathy Robie Suh,
`M.D., Ph.D., dated 5/27/2009; Statistical Review and Evaluation of the clinical studies for
`possible liver toxicity by Chava Zibman, Ph.D., 2/26/2009; and Office of Surveillance and
`Epidemiology (OSE), Division of Epidemiology (DEPI) review by Kate Gelperin, M.D.,
`M.P.H., 2/13/2009). Dr. Lu’s Clincal Review mentioned limitations of short-term studies for
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`evaluation of safety and recommended that, “Additional safety data of rivaroxaban from
`ongoing ROCKET-AF studies and recently completed trial of ATLAS ACS TIMI 46 6-months
`trial should be submitted for evaluation of the risk for hepatotoxicity to allow assessment of
`benefit and risk of rivaroxaban for the proposed indication.” Dr. Zibman’s Statistical Review
`and Evaluation of the clinical studies for possible liver toxicity during the first cycle
`commented, based on the aggregate data from the RECORD studies, “In summary, according
`to the data evaluated in this memorandum, it might be difficult to differentiate between
`Rivaroxaban and Enoxaparin patients based on signals of liver toxicity in the data. In fact, a
`smaller proportion of Rivaroxaban patients than Enoxaparin patients have elevated enzyme or
`TBL levels or experience hepatobiliary adverse events.” Dr. Gelperin’s review concluded, “A
`potential signal for severe liver injury associated with rivaroxaban therapy has not been fully
`characterized at this time. Complete risk assessment, fully evaluating safety data from long
`term clinical trials, should be undertaken in order to inform decisions about the balance of
`therapeutic benefit versus risk with rivaroxaban.”
`
`In the resubmission long-term safety data from the completed studies of rivaroxaban in non-
`valvular atrial fibrillation and other long-term studies were reviewed.
`
`Statistical Review of the safety data for evaluation of potential hepatotoxicity was done by
`John Yap, Ph.D. (6/10/2011). The review assessed liver toxicity based on the results of five
`trials of rivaroxaban at dose of 10-30 mg daily for chronic use (>35 days and up to 4 years) for
`stroke prevention in patients with atrial fibrillation (ROCKET and J-ROCKET studies), and
`for treatment in patients with deep venous thrombosis (EINSTEIN-DVT study or pulmonary
`embolism (EINSTEIN-PE) and extended DVT/PE treatment (EINSTEIN Extension study).
`The proportions of patients with elevated alanine aminotransferase (ALT) at predefined
`multiples of the upper limit of normal (ULN) were generally balanced between the
`rivaroxaban and warfarin arms in the atrial fibrillation trials and were lower in some cases in
`the rivaroxaban arm as compared to the enoxaparin arm in the VTE studies. Occurrence of
`“Hy’s Law cases” (concurrent values of ALT>3x ULN and total bilirubin >2x ULN) in the
`atrial fibrillation studies was similar in the rivaroxaban (0.45%; 34/7618) and warfarin (0.47%;
`36/7650) arms. In the DVT/PE treatment studies overall Hy’s Law cases were 0.17% (6/3560)
`with rivaroxaban ttreatment and 0.17% (6/3487) with enoxaparin. In the DVT extended
`treatment study there were no Hy’s Law cases. The review states,
`
`“In conclusion, findings from this review suggest that the liver toxicity profile based on
`assessment of evaluated ALT, TBL [total bilirubin], and of reported hepatic events, of
`rivaroxaban is comparable to active controls, warfarin and enoxaparin, studied across
`four randomized clinical trials. No notable differences in these outcomes were
`identified in a single placebo-controlled trial versus rivaroxaban. Lastly, the incidence
`of Hy’s Law cases were similar between the rivaroxaban and warfarin arms in the
`Rocket trials; however, these events occurred earlier (within the first year) in the
`warfarin arm compared to the rivaroxaban arm.”
`The review noted, however, that the dose (10 mg/daily) and duration (up to 35 days) of
`rivaroxaban studied in the RECORD 1-4 trials was lower and shorter, respectively, compared
`to the dose and duration of rivaroxaban studied in the ROCKET and EINSTEIN studies.
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`Rivaroxaban is approved in Canada and the European Union (September 2008) for
`prophylaxis of VTE in patients undergoing hip or knee replacement surgery and is also
`approved in some other countries. Post-marketing safety information and safety information
`from an observational post-marketing safety study were included in the resubmission. The
`most common serious adverse events reported were bleeding events. Other serious adverse
`events in the reports were cerebral hemorrhage (9 cases, 3 deaths), agranulocytosis (3 cases; 1
`death), hypersensitivity reactions (3 cases; no deaths) anaphylactic shock (2 cases; no deaths);
`anaphylactic reaction (2 cases; no deaths); Stevens-Johnson syndrome (2 cases; no deaths).
`(See Dr. Min Lu’s Clincal Review, completed 6/3/2011 for details).
`
`Dr. Lu’s Clincal Review states, “The overall benefit of rivaroxaban treatment is considered to
`outweigh the risk for the proposed use in the intended population.”
`9. Advisory Committee Meeting
`
`
`There was no Advisory Committee meeting held for this resubmission.
`10.
`Pediatrics
`
`
`No pediatric information is included in this resubmission. See the first review cycle Medical
`Team Leader Secondary Review/CDTL Review by Kathy Robie Suh, signed 5/27/2009 for a
`summary of comments from the Pediatric group of the Maternal and Pediatric Health Team
`(PMHS) regarding the potential for use of rivaroxaban in pediatric patients. For this
`resubmission the PMHS was consulted to provide comments and recommendations for
`labeling regarding use in pediatric patients and use in pregnant women and nursing mothers.
`Pediatric Review of the resubmission for proposed pediatric labeling (Elizabeth Durmowicz,
`M.D., 6/10/2011) agreed with a full waiver of PREA studies for this application since studies
`would be impossible or highly impractical because there are too few children with the
`disease/condition, i.e. pediatric patients undergoing hip or knee replacement surgery. Because
`studies have not been conducted in pediatric patients and no specific pediatric safety concerns
`have been identified, the review agreed that the statement, “Safety and effectiveness in
`pediatric patients have not been established” should be included under the Pediatric Use
`section of the label.
`
`Also, the Maternal Health Team provided review and recommendations for wording in the
`labeling regarding use and risks for the use of rivaroxaban in pregnancy and nursing mothers.
`The review (Bhatnagar Upasana, M.D., 6/10/2011) recommended Pregnancy Class C
`designation for the drug, indicating that studies have not been conducted in pregnant women
`but commenting that preliminary results suggest that animal reproduction studies show no
`increased risk of structural malformations but an increased risk of post-implantation pregnancy
`loss in rabbits. The review voiced concern about the risk for obstetric-related bleeding and
`possible emergent delivery and noted the lack of an antidote for rivaroxaban and no
`monitoring for degree of anticoagulation. The review recommended language for warnings
`and precautions in the labeling regarding these risks. For nursing mothers the review
`recommended that the labeling indicate that it is not known if rivaroxaban or its metabolites in
`found in human milk but that it appears in rat milk. The review commented that because of
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`the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision
`should be made whether to discontinue nursing or discontinue the drug, taking into account the
`importance of the drug to the mother. Women of childbearing potential who require
`anticoagulation should discuss pregnancy planning with their physician.
`
`
`Other Relevant Regulatory Issues
`11.
`The Division of Scientific Investigations (DSI) review of the resubmission (Susan D.
`Thompson, 5/25/2011) provided a thorough evaluation of the data and materials submitted in
`response to the concerns regarding the quality of monitoring and oversight for the RECORD
`studies. The resubmission included audit information from inspections of 4.9% (30/619) sites
`and encompassing 7.4% (945/12729) of patients. The review found one or more of the audited
`sites within each of the RECORD studies to be unreliable. These included three sites in
`RECORD 1 (Lenart, Porvaneckas, and Slappendel), four sites in RECORD 2 (
`, Yang,
`Naraffete, Ono) and one site in RECORD 3 (Brabants). For RECORD 4 the review found that
`deficiencies in the audited sites were sufficiently severe and pervasive as to render the entire
`study unreliable. The review summarized the findings as follows:
`
`“ In summary given the pervasive findings of deficient clinical trial monitoring, high number
`of clinical investigator sites with data assessed as unreliable, failure to follow the protocol
`including postoperative randomization, and deficient clinical trial conduct including failure to
`report significant adverse events and SAEs, DSI cannot provide a favorable assessment of
`RECORD 4 data reliability for the remaining unaudited sites based on extrapolation of the
` audit findings. Although some issues exist with the study conduct of RECORD 1, 2,
`and 3, they are not sufficiently pervasive to recommend an unfavorable assessment of data
`reliability. Therefore, the data from RECORD 1, 2, and 3, with exception of select sites as
`identified earlier, are considered reliable in support of the application. The data from RECORD
`4 are not considered reliable in support of the respective indication.”
`
`
`The impact of the DSI review findings on the clinical assessment of the application are
`discussed in more detail in the Clinical Review by Min Lu, M.D., 6/3/2011 and in my Medical
`Team Leader Secondary Review (6/13/2011). Efficacy and safety results excluding the
`RECORD 1, 2, and 3 sites found to be unreliable appeared similar to the overall results for the
`studies.
`
`Division of Medication Error Prevention and Analysis (DMEPA) evaluation of the proposed
`proprietary name Xarelto did not identify concerns that would render the name unacceptable
`based on the product characteristics and safety profile known at the time of the review (Denise
`V. Baugh, PharmD., 5/12/2011).
`12.
`Labeling
`
`The sponsor included proposed labeling in the resubmission. Exact wording for the labeling is
`being developed by the review team incorporating the recommendations from each of the
`review disciplines and consulting review divisions.
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`The Division of Drug Marketing, Advertising, and Communications (DDMAC) (J. Dvorsky,
`6/8/2011) provided comments and recommendations on the draft Package Insert for Xarelto.
`
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`
`The sponsor has provided adequate demonstration of efficacy and an acceptable benefit/risk
`profile for rivaroxaban for the desired indication. Based on review of the resubmission of this
`NDA, the application is acceptable for approval for the indication prophylaxis of deep vein
`thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip replacement
`surgery and in patients undergoing knee replacement surgery, with labeling as discussed and
`agreed upon internally assuming successful negotiation with the sponsor.
`
`The approval should include requirements for post-marketing commitments as recommended
`by Clinical Pharmacology (section 5 above). Also, consideration should be given to focused
`post-marketing surveillance for the serious adverse events of agranulocytosis and Stevens-
`Johnson syndrome.
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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.
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`KATHY M ROBIE SUH
`06/14/2011
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`Reference ID: 2960701
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