CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203085Orig1s000
`
`MEDICAL REVIEW(S)
`
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`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 203085
`Priority or Standard Priority
`
`Submit Date(s) April 27, 2012
`Received Date(s) April 27, 2012
`PDUFA Goal Date October 27, 2012
`Division / Office Division of Oncology Products
`2 / Office of Hematology
`Oncology Products
`
`Reviewer Name(s) Shan Pradhan, MD
`Kaushik Shastri, MD
`Review Completion Date September 5, 2012
`
`Established Name Regorafenib
`Trade Name Stivarga
`Therapeutic Class Multikinase inhibitor
`Applicant Bayer Health Care
`Pharmaceuticals, Inc.
`
`Formulation(s) 40 mg oral tablet
`Dosing Regimen 160 mg (four 40 mg tablets)
`taken orally once daily for 21
`days of a 28-day cycle
`Indication(s) Treatment of patients with
`metastatic colorectal cancer
`
`
`
`
`
`Reference ID: 3185412
`
`

`

`
`
`who have been previously
`treated with fluoropyrimidine-,
`oxaliplatin-, and irinotecan-
`based chemotherapy, an anti-
`VEGF therapy, and, if KRAS
`wild type, an anti-EGFR
`therapy
`Intended Population(s) Adults ≥ 18 years of age
`
`
`
`Template Version: March 6, 2009
`
`
`
`Reference ID: 3185412
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`

`

`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT (S. PRADHAN / K.
`SHASTRI)................................................................................................................. 8
`1.1 Recommendation on Regulatory Action ............................................................. 8
`1.2 Risk Benefit Assessment.................................................................................... 9
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 10
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 10
`INTRODUCTION AND REGULATORY BACKGROUND (S. PRADHAN)............. 11
`2.1 Product Information .......................................................................................... 11
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 11
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 11
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 11
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 13
`2.6 Other Relevant Background Information .......................................................... 14
`3 ETHICS AND GOOD CLINICAL PRACTICES (S. PRADHAN) ............................. 14
`3.1 Submission Quality and Integrity ...................................................................... 14
`3.2 Compliance with Good Clinical Practices ......................................................... 14
`3.3 Financial Disclosures........................................................................................ 15
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES (S. PRADHAN)................................................................................ 15
`4.1 Chemistry Manufacturing and Controls ............................................................ 16
`4.2 Clinical Microbiology......................................................................................... 16
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 16
`4.4 Clinical Pharmacology...................................................................................... 18
`4.4.1 Mechanism of Action.................................................................................. 18
`4.4.2 Pharmacodynamics.................................................................................... 18
`4.4.3 Pharmacokinetics....................................................................................... 19
`5 SOURCES OF CLINICAL DATA (S. PRADHAN).................................................. 20
`5.1 Tables of Studies/Clinical Trials ....................................................................... 20
`5.2 Review Strategy ............................................................................................... 20
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 21
`6 REVIEW OF EFFICACY (S. PRADHAN) ............................................................... 27
`Efficacy Summary...................................................................................................... 27
`6.1
`Indication .......................................................................................................... 28
`6.1.1 Methods ..................................................................................................... 28
`6.1.2 Demographics............................................................................................ 28
`6.1.3 Subject Disposition..................................................................................... 31
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 32
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`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 33
`6.1.6 Other Endpoints ......................................................................................... 35
`6.1.7 Subpopulations .......................................................................................... 35
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 36
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 36
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 37
`7 REVIEW OF SAFETY (K. SHASTRI)..................................................................... 37
`Safety Summary ........................................................................................................ 37
`7.1 Methods............................................................................................................ 39
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 39
`7.1.2 Categorization of Adverse Events.............................................................. 41
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 41
`7.2 Adequacy of Safety Assessments .................................................................... 41
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 41
`7.2.2 Explorations for Dose Response................................................................ 41
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 42
`7.2.4 Routine Clinical Testing ............................................................................. 43
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 43
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 43
`7.3 Major Safety Results ........................................................................................ 44
`7.3.1 Deaths........................................................................................................ 44
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 44
`7.3.3 Dropouts and/or Discontinuations .............................................................. 45
`7.3.4 Significant Adverse Events ........................................................................ 46
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 48
`7.4 Supportive Safety Results ................................................................................ 58
`7.4.1 Common Adverse Events .......................................................................... 58
`7.4.2 Laboratory Findings ................................................................................... 58
`7.4.3 Vital Signs .................................................................................................. 58
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 61
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 61
`7.4.6
`Immunogenicity.......................................................................................... 61
`7.5 Other Safety Explorations................................................................................. 61
`7.5.1 Dose Dependency for Adverse Events ...................................................... 61
`7.5.2 Time Dependency for Adverse Events....................................................... 61
`7.5.3 Drug-Demographic Interactions ................................................................. 62
`7.5.4 Drug-Disease Interactions.......................................................................... 63
`7.5.5 Drug-Drug Interactions............................................................................... 63
`7.6 Additional Safety Evaluations ........................................................................... 63
`7.6.1 Human Carcinogenicity.............................................................................. 64
`7.6.2 Human Reproduction and Pregnancy Data................................................ 64
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`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 64
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 65
`7.7 Additional Submissions / Safety Issues............................................................ 65
`8 POSTMARKET EXPERIENCE (S. PRADHAN) ..................................................... 65
`9 APPENDICES (S. PRADHAN / K. SHASTRI)........................................................ 66
`9.1 Literature Review/References .......................................................................... 66
`9.2 Labeling Recommendations ............................................................................. 67
`9.3 Advisory Committee Meeting............................................................................ 69
`
`
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`Reference ID: 3185412
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`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`Table of Tables
`
`Table 1 Regorafenib Product Information...................................................................... 11
`Table 2 NDA 203085 Key Regulatory Background ....................................................... 13
`Table 3 DSI Clinical Inspections.................................................................................... 15
`Table 4 Demographics - Age......................................................................................... 29
`Table 5 Demographics .................................................................................................. 29
`Table 6 Baseline Characeristics.................................................................................... 30
`Table 7 Stratification Factors......................................................................................... 30
`Table 8 Patient Disposition............................................................................................ 31
`Table 9 Protocol Violations by Category ....................................................................... 32
`Table 10 Overall Survival .............................................................................................. 33
`Table 11 Progression Free Survival - FDA’s Analysis................................................... 34
`Table 12 Progression Free Survival - Applicant's Analysis............................................ 34
`Table 13 Objective Response Rate............................................................................... 35
`Table 14 Subgroup Analyses of Overall Survival .......................................................... 36
`Table 15 Supportive Phase I and II studies................................................................... 40
`Table 16 Duration of treatment...................................................................................... 42
`Table 17 Demographics: Safety Population of Study 14387 ......................................... 42
`Table 18 Overview of deaths during treatment and within 30 days post-treatment ....... 45
`Table 19 Serious Adverse Events ................................................................................. 46
`Table 20 AEs leading to permanent discontinuations (≥ 1%) ........................................ 46
`Table 21 AEs leading to dose reductions (≥ 1%) .......................................................... 47
`Table 22 AEs leading to dose interruptions (≥ 1%) ....................................................... 48
`Table 23 Hepatic Failure, Fibrosis, cirrhosis and other liver damage (SMQ) ................ 49
`Table 24 Hepatotoxicity: Laboratory Evaluation ............................................................ 49
`Table 25 Incidence of Hemorrhage (SMQ).................................................................... 52
`Table 26 Skin and subcutaneous tissue disorders (incidence >5%): ............................ 53
`Table 27 Thromboembolic events ................................................................................. 56
`Table 28 Common Adverse Events (≥10% incidence in regorafenib arm) .................... 58
`Table 29 Hematology Laboratory Evaluation ................................................................ 59
`Table 30 Liver Function Tests ....................................................................................... 59
`Table 31 Laboratory tests: Chemistries and urinalysis.................................................. 60
`
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`Reference ID: 3185412
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`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`Table of Figures
`
`Figure 1 Trial 14387 Design .......................................................................................... 22
`Figure 2 Schedule of Assessments (copied from CSR) ................................................ 24
`Figure 3 K-M Curves of Overall Survival ....................................................................... 33
`Figure 4 K-M Curves of PFS ......................................................................................... 35
`
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`

`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`This clinical review team recommends approval of new drug application (NDA) 203085
`for regorafenib tablets for the treatment of patients with metastatic colorectal cancer
`(mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and
`irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-
`EGFR therapy.
`
`This NDA is primarily supported by a single, multicenter, randomized (2:1), double-blind,
`placebo-controlled trial, Trial 14387, in a total of 760 patients with previously treated
`mCRC. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and
`irinotecan-based chemotherapy and with bevacizumab, and all but one patient with a
`KRAS wild type tumor received panitumumab or cetuximab. Patients were randomized
`to receive 160 mg regorafenib orally once daily (n=505) plus best supportive care (BSC)
`or placebo (n=255) plus best supportive care for the first 21 days of each 28-day cycle.
`Treatment continued until disease progression, unacceptable toxicity, or death.
`
`The assessment of benefit in this application is based on the primary endpoint of overall
`survival. This recommendation for approval is based on review of the clinical data,
`which support the conclusion that regorafenib prolongs overall survival in patients who
`have failed standard chemotherapy (a population for whom no other therapy is currently
`approved). A statistically significant, clinically meaningful prolongation in overall
`survival was observed in patients randomized to receive regorafenib; median survival
`was 6.4 months in the regorafenib arm (95% CI: 5.8, 7.3) compared to 5.0 months in the
`placebo arm (95% CI: 4.4, 5.8), with a hazard ratio of 0.77 (95% CI: 0.64, 0.94;
`p=0.0102).
`
`Supportive efficacy outcome measures in Trial 14387 were progression free survival
`and overall response rate. The PFS benefit observed was modest, with a median PFS
`of 2.0 months in the regorafenib arm (95% CI: 1.9, 2.3) compared to 1.7 months in the
`placebo arm (95% CI: 1.7, 1.8), with a hazard ratio of 0.49 (95% CI: 0.42, 0.58;
`p<0.0001). The overall response rate was low, consisting of 5 patients (1%) in the
`regorafenib arm and 1 patient (0.4%) in the placebo arm.
`
`The FDA Guidance for Industry entitled “Providing Clinical Evidence of Effectiveness for
`Human Drug and Biological Products” states that for approval, “reliance on only a single
`study will generally be limited to situations in which a trial has demonstrated a clinically
`meaningful effect on mortality, irreversible morbidity, or prevention of a disease with a
`potentially serious outcome, and confirmation of the result in a second trial would be
`practically or ethically impossible”. Trial 14387 was a large randomized trial which
`demonstrated robust and consistent results across most patient subsets and achieved
`
`Reference ID: 3185412
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`

`

`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`more than one endpoint including a clinically meaningful, statistically significant overall
`survival benefit in a population for whom no other therapy is approved, providing
`sufficient basis for approval as set forth in the guidance.
`
`1.2 Risk Benefit Assessment
`
`Trial 14387 included 500 patients who received regorafenib at the proposed dose (160
`mg orally once daily for the first 21 days of each 28-day cycle until disease progression,
`unacceptable toxicity, or death) and 253 patients who received placebo.
`
`The mean duration of therapy was 12 weeks for the regorafenib group and 8 weeks for
`placebo. Treatment emergent adverse events resulted in dose interruptions in 61% of
`patients receiving regorafenib and 38% of patients had their dose reduced. In the
`placebo group, dose interruptions and dose reductions occurred in 22% and 3% of
`patients, respectively.
`
`
`The most significant toxicities observed with regorafenib were drug induced liver injury,
`hemorrhage, dermatologic toxicity (palmar-plantar erythrodysesthesia and rash),
`hypertension, cardiac ischemic events, and gastrointestinal perforation.
`
`Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100
`regorafenib-treated patients (across all clinical trials). In Trial 14387, fatal hepatic
`failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the
`placebo arm. All patients with hepatic failure had metastatic disease in the liver. Liver
`biopsy findings in 2 cases showed hepatocyte necrosis and lymphocyte infiltration. This
`review team recommended inclusion of a boxed warning for hepatotoxicity in the
`regorafenib product label.
`
`The overall incidence (Grades 1-5) of hemorrhage was 21% among regorafenib-treated
`patients compared to 8% among placebo-treated patients. Fatal hemorrhage occurred
`in 4 of 500 (0.8%) regorafenib-treated patients and involved respiratory, gastrointestinal,
`and genitourinary tracts.
`
`The overall incidence of palmar-plantar erythrodysesthesia (PPE) (45% versus 7%) and
`the incidence of Grade 3 PPE (17% versus 0) were increased in regorafenib-treated
`patients compared to placebo. The overall incidence of rash (26% versus 4%) and the
`incidence of Grade 3 rash (6% versus <1%) were also higher in regorafenib-treated
`patients. The onset of dermatologic toxicity occurred in the first cycle of treatment in
`most patients and frequently required dose modification.
`
`Hypertension occurred in 30% of regorafenib-treated patients versus 8% of placebo-
`treated patients. The onset of hypertension occurred during the first cycle of treatment
`in most patients.
`
`
`Reference ID: 3185412
`
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`

`Clinical Review
`
`8. Pradhan I K. Shastri
`
`NDA 203085
`
`RegorafeniblStivarga
`
`The incidence of myocardial ischemia or infarction was higher in regorafenib-treated
`patients (1.2 % versus 0.4%) compared to placebo. Gastrointestinal perforation or
`fistula occurred in 0.6% of 1100 patients treated with regorafenib (across all clinical
`trials). A single case of reversible posterior leukoencephalopathy (RPLS) was observed
`among the 1100 patients.
`
`The most frequently observed adverse reactions (occurring in 2 30% of patients) with
`regorafenib were asthenialfatigue, decreased appetite and food intake, palmar—plantar
`erythrodysesthesia (PPE), diarrhea, mucositis, weight loss, infection, hypertension, and
`dysphonia.
`
`The safety profile of regorafenib is similar to drugs with similar mechanisms of action
`including other multikinase inhibitors. This clinical review team concludes, based on the
`overall survival benefit observed in Trial 14387, that regorafenib has demonstrated an
`acceptable risk-benefit profile in the proposed population of patients with refractory
`metastatic colorectal cancer.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`None. The proposed USPI contains patient counseling information for prescribing
`physicians (oncologists) and a patient information leaflet.
`
`The Applicant also included a Risk Management Plan in the submission which
`referenced the ongoing Expanded Access Study (Treatment Protocol 15967) under IND
`75642.
`In response to an information request from this clinical review team, the
`Applicant stated that should regorafenib be approved, the Applicant plans to
`"'m’
`
`“m" patients will be recruited to the
`The Applicant further stated that a minimum 01
`study and that the clinical study report is projected to be complete by October 31, 2014.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`No specific new studies were recommended by the clinical review team.
`
`See Clinical Pharmacology review for recommendations from the clinical pharmacology
`review team for postmarket requirements and commitments.
`
`The Pediatric Review Committee granted a full waiver of the requirements under the
`Pediatric Research Equity Act (PREA) because the rarity of colorectal cancer in the
`pediatric population renders conduct of the necessary studies impossible or highly
`impractical.
`
`Reference ID: 3185412
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`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`2 Introduction and Regulatory Background (S. Pradhan)
`The trade name for regorafenib is Stivarga. Regorafenib is a small molecule inhibitor of
`multiple kinases (including BRAF, VEGFR 1/2/3, TIE2, PDGFR, FGFR, RET, and KIT)
`involved in normal cellular functions and in pathologic processes such as oncogenesis
`and tumor angiogenesis.
`
`2.1 Product Information
`
`Table 1 Regorafenib Product Information
`Generic Name:
`Trade Name:
`Pharmacologic Category:
`Drug Class:
`Route of Administration:
`Storage:
`Drug Product:
`
`Dose and Regimen:
`
`
`
`Regorafenib
`Stivarga
`Multikinase inhibitor
`Small molecule
`Oral
`Store at 25˚C (77˚) in the original container
`Tablets in packages containing 3 bottles,
`with each bottle containing 28 tablets
`160 mg (four 40-mg tablets) orally once
`daily for the first 21 days of each 28-day
`cycle
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`There are no (FDA) approved products for the treatment of patients with mCRC for
`whom treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based
`chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy,
`has failed.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Regorafenib is a new molecular entity and is not currently marketed in the United
`States.
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`) is a small molecular inhibitor of
`Regorafenib (BAY 73-4506,
`multiple kinases including BRAF, VEGFR 1/2/3, TIE2, PDGFR, FGFR, RAF-1, KIT and
`RET. Regorafenib interferes both with tumor-cell proliferation and tumor angiogenesis.
`Multi-kinase agents that inhibit at least 3 of the main tyrosine kinases targeted by
`regorafenib (VEGFR, PDGFR and KIT) include sorafenib (Nexavar), sunitinib (Sutent)
`and pazopanib (Votrient).
`
`Reference ID: 3185412
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`(b) (4)
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`

`

`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`
`The package insert for Nexavar contains the following potentially serious adverse
`events in warnings and precautions: cardiac ischemia/infarction, hemorrhage,
`hypertension, dermatologic toxicity, GI perforation, elevation in INR when taking
`warfarin, wound healing complications, increased mortality in squamous cell lung
`cancer when co-administered with carboplatin/paclitaxel and gemcitabine/Cisplatin, QT
`prolongation, and fetal harm. The most common adverse reactions (≥20%), which were
`considered to be related to Nexavar are fatigue, weight loss, rash/desquamation, hand-
`foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.
`
`The package insert for Sutent contains the following potentially serious adverse events
`in warnings and precautions: hepatotoxicity, fetal harm, left ventricular dysfunction, QT
`prolongation and torsades de pointes, hypertension, hemorrhagic events, osteonecrosis
`of the jaw, tumor lysis syndrome, thyroid dysfunction, wound healing, adrenal
`insufficiency (in patients undergoing stress such as surgery, trauma or severe infection).
`The most common adverse reactions (≥2 0%) are fatigue, asthenia, fever, diarrhea,
`nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation,
`hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin,
`hair color changes, altered taste, headache, back pain, arthralgia, extremity pain,
`cough, dyspnea, anorexia, and bleeding.
`
`The package insert for Votrient contains the following potentially serious adverse events
`in warnings and precautions: hepatotoxicity, QT prolongation and torsades de pointes,
`cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, GI
`perforation and fistula, RPLS, hypertension, hypothyroidism, wound healing, proteinuria,
`infection, and increased toxicity with other cancer therapies. The most common
`adverse reactions in patients with advanced renal cell carcinoma (≥20%) are diarrhea,
`hypertension, hair color changes (de-pigmentation), nausea, anorexia, and vomiting.
`The most common adverse reactions in patients with advanced soft tissue sarcoma
`(≥20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, decreased
`appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache,
`dysgeusia, dyspnea, and skin hypo-pigmentation.
`
`
`Reference ID: 3185412
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`Clinical Review
`
`S. Pradhan l K. Shastri
`
`NDA 203085
`
`Regorafenib/Stivarga
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`The following table summarizes key regulatory background for this application.
`
`Table 2 NBA 203085 Key Regulatory Background
`
`End-of-Phase 2 meetin
`
`SPA No Ao reement letter issued
`
`Seotember 2009
`
`Janua
`
`2010
`
`Aril 2010
`
`June 2011
`
`Au 0 ust 2011
`
`Pre-NDA meetino
`
`Res onse to Toe A meetin o
`
`o uestions issued
`
`Fast Track desi. nation 0 ranted
`
`September 2009 End of Phase 2 Meeting
`
`0
`
`FDA recommended overall survival as the primary efficacy endpoint for Trial
`14387.
`
`0
`
`FDA stated that placebo plus best supportive care would be acceptable as the
`control arm treatment, provided patients experienced disease progression after
`all approved therapies for mCRC.
`o Bayer proposed a new study design with OS as the primary endpoint and two
`formal interim analyses for efficacy; FDA stated that this proposal was
`acceptable.
`FDA agreed to the use of RECIST “M" for tumor response assessments.
`FDA stated that the stratification factors proposed (ECOG performance status,
`prior targeted therapy, and geographic region) were acceptable.
`
`0
`0
`
`Januam 2010 SPA No Agreement Letter Issued
`
`0
`
`FDA stated that whether a 15-month increment in median OS would be clinically
`relevant would be a review issue.
`
`0
`
`0
`
`FDA stated that any subgroup analyses would be considered exploratory and
`may not be included in labeling.
`FDA stated that Bayer would need to ensure enrollment of a population that is
`representative of the US population.
`0 Bayer proposed testing PFS, ORR, and DCR
`
`“m
`
`April 2010 Response to Type A Meeting Questions
`0
`FDA stated that whether the population ultimately enrolled in Trial 14387 is
`representative of the US population would be a review issue.
`
`Reference ID: 3185412
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`

`Clinical Review
`S. Pradhan / K. Shastri
`NDA 203085
`Regorafenib/Stivarga
`
`August 2011 Pre-NDA Meeting
`• Bayer proposed including the text portion of the ISS and ISE in Module 2 and
`agreed to include tables, figures, appendices, and datasets in Module 5. FDA
`stated that this plan was acceptable.
`• FDA stated that CRFs for SAEs should be submitted.
`• FDA requested that narratives for all SAEs except those related to disease
`progression be submitted.
`• FDA stated that the differential between the data cutoff date for the 120 day
`safety update and submission of the 120-day safety update should not be greater
`than 6 months.
`
`2.6 Other Relevant Background Information
`
`None.
`
`3 Ethics and Good Clinical Practices (S. Pradhan)
`
`3.1 Submission Quality and Integrity
`
`Electronic datasets were submitted in CDISC format as requested by the Division.
`Adverse events (AE) from a subset of case report forms for Trial 14387 were reviewed
`and compared to the datasets in order to confirm accuracy of the data transfer.
`Verbatim terms for all Grade 3, 4, or 5 (NCI CTCAE v3.0) AEs in Trial 14387 were
`compared to the corresponding MedDRA lower level terms and AE coding was deemed
`adequate.
`
`The submission was of adequate quality and integrity to allow for review of the clinical
`trial pertaining to the proposed indication.
`
`3.2 Compliance with Good Clinical Practices
`
`The submission [module 2, section 2.5 (Clinical Overview), page 39)] contained a
`statement that Trial 14387 was conducted in accordance with the Declaration of
`Helsinki and the ICH Good Clinical Practice (GCP) Guideline.
`
`Because Stivarga is an NME, an OSI consult was requested for the clinical inspection of
`4 trial sites. Sites were selected based upon analyses of site-specific efficacy data,
`numbers and types of protocol violations, patient enrollment per site, and investigator
`financial conflict of interest disclosures.
`
`
`Reference ID: 3185412
`
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`

`Clinical Review
`
`S. Pradhan l K. Shastri
`
`NDA 203085
`
`Regorafenib/Stivarga
`
`Table 3 DSI Clinical Inspections
`
`.
`
`Number of
`
`Dr. Alfredo Falcone
`
`A.O.U. Pisana, Oncologia
`Medica 2
`
`ITALY
`
`22005
`
`22004
`
`28001
`
`14001
`
`Dr. Eric Van Cutsem
`
`UZ Leuven Gasthuisberg
`BELGIUM
`
`Dr. Axel Grothey
`Mayo Clinic - Rochester
`USA
`
`Dr. Salvatore Siena
`
`A.O. Osp Niguarda Ca.
`Granda,
`Oncologia Medica Falck
`ITALY
`
`34
`
`22
`
`Clinical inspection results were not available at the time of completion of this review.
`
`3.3 Financial Disclosures
`
`The submission included a Form 3454 (Certification: Financial Interests and
`Arrangements of Clinical Investigators) completed by the Applicant. All financial
`disclosure materials in section 1.3.4 (Financial Disclosure) were reviewed.
`
`“’"6’, was listed as holding
`One sub-investigator for Trial 14387,
`disclosable financial interest. A Form 3455 (Disclosure: Financial Interests and
`Arrangements of Clinical Investigators) completed by the Applicant and naming Dr.
`m” was included in the application.
`
`“‘6’
`
`m” and the steps
`A Statement of Actions to Minimize Bias was submitted for
`taken by the Applicant were acceptable. Additionally, the primary endpoint of Trial
`14387 (and the basis for the assessment of benefit in