CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 22-249
`
`MEDICAL REVIEW! S!
`
`

`

`CLINICAL REVIEW ADDENDUM
`
`Application Type:
`Submission Number:
`Submission Code:
`
`Letter Date:
`
`Stamp Date:
`PDUFA Goal Date:
`
`Reviewer Names:
`
`NDA
`22249
`000
`
`09/19/07
`
`09/20/07
`03/20/07
`
`Qin Ryan, MD, PhD (Efficacy)
`Virginia Kwitkowski, MS, RN, CRNP (Safety)
`
`Date of Addendum:
`
`03/18/08
`
`Established Name:
`(Proposed) Trade Name:
`Therapeutic Class:
`Applicant:
`
`bendamustine hydrochloride
`TRENDA ®
`Alkylating agent
`Cephalon
`
`Priority Designation:
`
`P
`
`Formulation:
`Dosing Regimen:
`Indication:
`
`IV
`100 mg/m2, Days 1 & 2, q28 days
`Treatment for CLL
`
`Intended Population:
`
`Chemotherapy naive patients
`
`Amendment Summary:
`
`After the completion of the NDA review, the Applicant submitted additional information
`regarding the following:
`-
`1. Study 02CLLIII financial disclosures
`2. Treatment dose modification information
`
`This amendment is to include the reviewers’ assessments of the new information.
`
`Amendments to Clinical Review sections 3.3, Financial Disclosure and 9.2 Labeling
`Recommendations are listed below.
`
`After the initial review completion, an investigation for drug—induced liver injury was
`undertaken with the results prepared as an amendment to section 7.4.2 Laboratory
`Findings.
`
`

`

`Efficacy Review Addendum
`
`In section 3.3 Financial Disclosures in the original NDA review, it was stated that the
`financial disclosures could not be obtained for the following studies: 02CLLIII,
`99CLL2E (BG), 99CLL2E (DE), 98B02, 20BEND1, 20BEN 03, 98B02W, 93BOP01,
`94BP01, 96BMF02/l, 98B03, BEO4, based on the initial NDA submission. However,
`
`upon FDA request, the applicant requested financial disclosures per the FDA
`recommended format through the original sponsor of study 02CLLIII. The collected
`disclosure information was submitted as an amendment to the NDA. Among the 45
`principal investigators (PIS), 43 of them as well as the available sub-investigators from
`their sites submitted financial disclosures indicating no personal financial interest in the
`study drug. Of the 2 remaining PIS, one was deceased and one is on vacation. Based on
`the information provided in this NDA, there were 11 patients enrolled from the sites of
`the 2 PIS whose financial disclosures are not yet available. Excluding enrollments fiom
`the deceased PI, 6 patients (or 2% of the total enrollment of study 02CLLIII) were treated
`by an investigator who has not provided financial disclosure information. The applicant
`will continue to collect this information and submit it to the Agency as soon as the last
`one is available.
`
`The available information does not suggest that the study results would be influenced by
`financial interest since no personal financial interest was reported by any of the
`investigators. Due to the small number of investigators for whom financial disclosure
`information is not available and the small number of patients enrolled by these
`investigators, it is unlikely that the information not available to date would influence
`FDA’s interpretation of the study results.
`
`Safety Review Addendum
`
`The following text is added to Section 7.4.2, Laboratory Findings:
`
`An exploration of the datasets submitted to the Cephalon NDA 22249 (Treanda for CLL)
`was undertaken to search for potential cases of Drug Induced Liver Injury (DILI) per the
`“Draft Guidance for Industry Drug—Induced Liver Injury: Premarketing Clinical
`Evaluation”. The clinical chemistry dataset was explored to identify any patients that met
`Hy’s Law definition. Briefly, Hy’s Law cases have the following three components:
`
`I. The drug causes hepatocellular injury, generally shown by more frequent 3-fold or
`greater elevations above the ULN ofALT or AST than the (nonhepatotoxic) control agent
`or placebo.
`
`2. Among subjects showing such aminotransferase (AT) elevations, often with ATS much
`greater than 3xULN, some subjects also show elevation ofserum total bilirubin (TBL) to
`>2xULN, without initialfindings ofcholestasis (serum alkaline phosphatase (ALP)
`activity >2xULN).
`
`

`

`3. No other reason can be found to explain the combination ofincreased AT and TBL,
`such as viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug
`capable ofcausing the observed injury.
`
`In the dataset exploration, no cases that met these criteria were found.
`
`These results do not exclude the potential for DILI due to the small sample size, but no
`evidence for DILI was identified during this data exploration.
`
`The following text is added to Section 9.2, Labeling Recommendations:
`
`The original proposed product information label that was submitted by Cephalon \
`A ,recommendations for dose reductions in the case of toxicities. FDA proposed the
`
`following language for the Dosage and Administration section ’
`
`
`u
`
`Cephalon expressed concern that if these recommendations were followed verbatim,
`patients would be undertreated. Cephalon proposed the following text for the label:
`
`0
`
`“Dose modifications for hematologic toxicity: consider a 50% dose reduction for
`Grade 3 or greater toxicity; if Grade 3 or greater toxicity recurs, consider a 75% dose
`reduction. (2.2)
`0 Dose modifications for non-hematologic toxicity: 50% dose reduction for clinically
`significant Grade 3 toxicity. (2.2)
`0 Dose re-escalation may be considered. (2.2)”
`
`FDA asked Cephalon to provide an evaluation of how the dose reductions were handled
`in the 02CLLIII protocol to justify the above labeling recommendations.
`
`Cephalon provided the following evaluation summary:
`
`The main findings from this analysis were as follows:
`
`1. The occurrence of Grade 2 and Grade 3/4 hematologic toxicities, as graded by the
`standard NCI-CTC, did not result in dose reduction for the majority of patient-cycles. Of
`the patient-cycles with Grade 2 and Grade 3/4 hematologic toxicity, 69% and 64% of the
`subsequent cycles were administered at >90% of the planned dose, respectively. Of the
`patient-cycles with Grade 2 and Grade 3/4 hematologic toxicity excluding leucopenia and
`lymphocytopenia (which are both related to disease), 58% and 53% of the subsequent .
`cycles were administered at >90% of the planned dose, respectively.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`
`
`Virginia Kwitkowski
`3/18/2008 05:02:59 PM
`MEDICAL.OFFICER
`
`Signing as Acting Clinical Team Leader
`
`Qin Ryan
`3/18/2008 05:15:59 PM
`MEDICAL OFFICER
`
`

`

`2. The most common form of dose reduction was 50%, and the degree of dose reduction
`did not vary appreciably with the severity of the toxicity. Just over half the dose
`reductions were to 50% of the planned dose and approximately one third were to 25% of
`the planned dose (75% dose reduction). The remainder were to 75% of the planned dose
`(25% dose reduction).
`
`3. Cheson/NCI-WG graded toxicity was only recorded in the hematology listing in the
`case of Grade 3/4 toxicity. Of the patient-cycles with Grade 3/4 hematologic toxicity,
`53% of the subsequent cycles were administered at >90% of the planned dose. The extent
`of dose reduction was broadly as described for the NCI—CTC analysis, with just over half
`the dose reductions being 50% of the planned dose, and just over a third being 25% of the
`planned dose.
`
`Applicant Recommendation
`
`The following recommendation for dose modification is based on the findings from the
`analysis of the NCI-CTC graded toxicities since the Cheson/NCI-WG criteria are not
`used in routine clinical practice.
`
`Dose modifications for hematologic toxicity: consider a 50% dose reduction for Grade 3
`or greater toxicity; if = grade 3 toxicity recurs, consider a 75% dose reduction.
`
`Given the findings of this evaluation, the Applicant’s proposal for dose modification for
`hematologic toxicities for labeling is: "Dose modifications for hematologic toxicity:
`consider a 50% dose reduction for Grade 3 or greater toxicity; if > grade 3 toxicity recurs,
`consider a 75% dose reduction."
`
`Discussions within the review team identified a lack of clarity about whether or not
`the 75% dose reduction should be taken from the original dose or the reduced dose.
`This led the team to decide that a clearer way to communicate these
`recommendations would be:
`
`“Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce
`the dose to 50 mg/m2 on Da 3 1' and 2 of each cycle; if Grade 3 or greater toxicity recurs,
`reduce the dose to 25 mg/m on Days 1 and 2 of each cycle.
`Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or
`greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.
`Dose re-escalation in subsequent cycles may be considered at the discretion of the
`treating physician.”
`
`This plan should provide sufficient doses for efficacy without adversely effecting
`safety.
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Submission Number
`
`NDA
`
`22249
`
`Submission Code
`
`000
`
`1 Letter Date
`
`Stamp Date
`PDUFA Goal Date
`
`September 19, 2007
`September 20, 2007
`March 20,‘ 2008
`
`. Reviewer Name
`
`Qin Ryan, MD, PhD (efficacy)
`Virginia Kwitkowski, MS, RN,
`CRNP (safety)
`
`Review Completion Date
`
`February 26, 2008
`
`Established Name
`
`bendamustine
`
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`Treanda
`
`Alkylating agent
`Cephalon
`
`Priority Designation
`
`P
`
`Formulation
`
`Dosing Regimen
`Indication
`Intended PopulatiOn
`
`IV
`,
`100 mg/mz, days 1 and 2, q28days
`treatment for CLL
`
`chemotherapy na’1’ve patients
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Table of Contents
`
`l
`
`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ..........................................................................7
`
`1.1
`1.2
`1.3
`1.4
`1.5
`
`Recommendation on Regulatory Action..................................................................................................... 7
`Risk Benefit Analysis ................................................................................................................................. 7
`Recommendations for Risk Evaluation and Mitigation Strategies ............................................................. 7
`Recommendations on Post Marketing Activities/Phase 4 Commitments ................................................... 7
`
`‘
`Summary of Clinical Findings .................................................................................
`Brief Overview of Clinical Program ...................................................................................................... 8
`
`Efficacy....
`
`Safety ....................................................
`
`Dosing Regimen and Administration....
`Drug-Drug Interactions ........................................................................................................................ 10
`Special Populations .............................................................................................................................. 10
`
`1.5.1
`1.5.2
`1.5.3
`1.5.4
`1.5.5
`1.5.6
`
`INTRODUCTION AND REGULATORY BACKGROUND ....................................................................... 12
`
`2.1
`
`Product Information .................................................................................................................................. 12
`
`2.2
`. 2.3
`2.4
`2.4.1
`
`Tables of Currently Available Treatments for Proposed Indications........................................................ 13
`Availability of Proposed Active Ingredient in the United States ......................................................_........ 13
`
`Important Safety Issues with Consideration to Related Drugs ............. 13
`General Class Toxicities ...................................................................................................................... 13
`
`2.4.2
`
`Alkylating Agent Specific Toxicities ................................................................................................... 14
`Summary of Presubmission Regulatory Activity Related to Submission ...................................... 14
`2.5
`
`
`Other Relevant Background Information ...................................................................................... 15
`2.6
`Development history ............................................................................................................................ 15
`2.6.1
`2.6.2 Marketing history ................................................................................................................................. 15
`
`ETHICS AND GOOD CLINICAL PRACTICES ......................................................................................... 16
`
`3.1
`3.2
`3.3
`
`Submission Quality and Integrity ............................................................................................................. 16
`Compliance with Good Clinical Practices ................................................................................................ 17
`Financial Disclosures ................................................................................................................................ 17
`
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ...... 18
`
`4.1
`4.2
`4.3
`4.4
`
`Chemistry Manufacturing and Controls ................................................................................................... 18
`
`Clinical Microbiology.................................................................................. 19
`Preclinical Pharmacology/Toxicology ...................................................................................................... 19
`Clinical Pharmacology ............................................................................................................................. 19
`4.4.1 Mechanism of Action................................................................................................................ 20
`
`Pharmacodynamics .............................................................................................................................. 20
`Pharmacokinetics ................................................................................................................................. 20
`
`4.4.2
`4.4.3
`
`SOURCES OF CLINICAL DATA ......;..........................................................................................................21
`
`5.1
`
`5.2
`5.3
`
`Tables of Clinical Studies ......................................................................................................................... 21
`
`Review Strategy .................................................................................................................................... 24
`
`Discussion ofIndividual Studies
`.......................................................... 24
`
`5.3.1
`
`Study 02CLLIII Protocol ..................................................................................................................... 24
`
`REVIEW OF EFFICACY ...............................................................................................................................38
`
`6.1
`
`Indication .................................................................................................................................................. 3 8
`
`
`6.1.1 Methods ......................................................................................................................................... 38
`Patient Baseline Characteristics and Demographics .................................................................'........... 38
`6.1.2
`6.1.3
`Patient Disposition .......................................p........................................................................................ 3 9
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Protocol deviation andviolation ..................................41
`6.1.4
`
`Analysis of Primary Endpoint(s) ........................
`6.1.5
`Analysis of Secondary Endpoints(s) .................................................................................................... 55
`6.1.6
`REVIEW OF SAFETY ....................................................................................................................................61
`
`7
`
`7.1
`
`Methods .................................................................................................................................................... 62
`
`7.1.1
`7.1.2
`7.1.3
`
`7.2
`
`7.3.1
`7.3.2
`7.3.3
`7.3.4
`7.3.5
`
`7.4.1
`7.4.2
`7.4.3
`7.4.4
`7.4.5
`7.4.6
`
`Clinical Studies Used to Evaluate Safety .................................................................................. 63
`
`Adequacy of Data ..................................................................................................................... 63
`
`Pooling Data Across Studies to Estimate and Compare Incidence ........................................... 69
`Adequacy of Safety Assessments ............................................................................................................. 71
`Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations............ 71
`7.2.1
`Explorations for Dose Response .......................................................................................................... 74
`7.2.2
`Special Animal and/or In Vitro Testing .................................................................................... 76
`7.2.3
`Routine Clinical Testing ...................................................................................................................... 77
`7.2.4
`7.2.5 Metabolic, Clearance, and Interaction Workup ................................................................................... 77
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .............................. 78
`7.2.6
`
`Major Safety Results ..................................................................................................................... 78
`Deaths .................................................................................................................................................. 78
`Nonfatal Serious Adverse Events ........................................................................................................ 81
`Dropouts and/or Discontinuations ....................................................................................................... 86
`Significant Adverse Events ............................................................................................................... 87
`
`Submission Specific Primary Safety Concerns .......................................................................... 90
`
`Supportive Safety Results ............................................................................................................... 91
`Common Adverse Events .................................................................................................................... 91
`Laboratory Findings ............................................................................................................................. 94
`Vital Signs ......................................................................................................................................... 105
`Electrocardiograms (ECGs) ............................................................................................................... 107
`Special Safety Studies ........................................................................................................................ 108
`Immunogenicity ................................................................................................................................. 108
`Other Safety Explorations ...................................................................................................................... 108
`Dose Dependency for Adverse Events.................................................................................... 108
`
`Time Dependency for Adverse Events .............................................................................................. 108
`Drug-Demographic Interactions ........................................................................................................ 108
`Drug-Disease Interactions .................................................................................................................. 109
`Drug-Drug Interactions ...................................................................................................................... 109
`Additional Safety Explorations.................'...........................................-................................................... 109
`...109
`Human Carcinogenicity .......................................................................................................
`
`Human Reproduction and Pregnancy Data ........................................................................................ 109
`Pediatrics and Effect on Growth ........................................................................................................ 109
`Overdose, Drug Abuse Potential, Withdrawal and Rebound ............................................................. 110
`
`7.3
`
`7.4
`
`7.5
`
`7.6
`
`7.5.1
`7.5.2
`7.5.3
`7. 5 .4
`7.5.5
`
`7.6.1
`7.6.2
`7.6.3
`7.6.4
`
`POSTMARKETING EXPERIENCE ........................................................................................................... 1 10
`
`APPENDICES ................................................................................................................................................ 111
`
`9.1
`9.2
`9.3
`
`Literature Review/References ................................................................................................................ l 11
`
`Labeling Recommendation .......................................................................................................... 113
`Advisory Committee Meeting ................................................................................................................ 113
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`TABLE OF TABLES
`
`Table 2-1: Currently available first line treatments for proposed indication ................................ 13
`Table 5-1: Studies included in NDA 22249 .................................................................................. 22
`
`................................................................................ 27
`Table 5-2: 02CLLIII study treatments
`Table 5-3: Dose modification for study 02CLLIII ....................................................................... 28
`Table 5-4: Study landmark and amendments ................................................................................ 28
`Table 5-5: Efficacy and safety evaluation ......................................................... 30
`Table 5-6: Rule for response evaluation (part 1) .......................................................................... 33
`Table 5-7: Rule for response evaluation (part 2) .......................................................................... 34
`Table 5-8: Rule for response evaluation (part 3) ...................................................................... 34
`Table 5-9: Deriving a date of progression or censoring for PFS analysis (02CLLIII ITT) .......... 35
`Table 6-1: Study 02CL LIII patient baseline characteristics and demographics (ITT) ................ 38
`Table 6-2: Major protocol deviations or violations ...................................................................... 41
`Table 6-3:Overall response rate based on ICRA assessment (ITT) .............................................. 42
`Table 6-4: Investigator assessed overall response (ITT) .............................................................. 43
`Table 6-5: Overall response rate based on ICRA (ITT excluding centers 1 & 2) ........................ 43
`Table 6-6: Overall response assessment comparison between ICRA and investigator (ITT) .....,, 44
`Table 6-7: Comparison of assessments by ICRA, investigator, and applicant calculation .......... 45
`Table 6-8: The concordant analyses within tumor response assessment of ICRA, calculated and
`investigators. ................................................................................................................................. 45
`Table 6-9: Concordant rates between ICRA and calculated response assessments: response (CR,
`nPR, PR) versus none (unconfirmed response, SD, PD, NE) ....................................................... 46
`Table 6-10: PFS based on ICRA assessment (ITT) ...................................................................... 46
`Table 6-11: PFS analysis based on the calculated assessment (ITT) ............................................ 48
`Table 6-12: PFS based on ICRA (ITT Excluding Centers 1 and 2) ............................................. 49
`Table 6-13: Concordance between the calculated and ICRA PFS assessments ........................... 50
`
`Table 6-14: Tumor assessment interval between the two treatment arms (ITT) .......................... 51
`Table 6-15: Reasons or outcomes for missing assessment. ......................................................... 53
`Table 6-16: Duration of response by ICRA assessment (ITT) ..................................................... 56
`Table 6-17: Duration of each type of response (ITT, IRCA assessment) ..................................... 57
`Table 6-18: Duration of response by calculated assessment (ITT) ............................................... 57
`Table 6-19: Duration of each type of response (ITT, calculated assessment) .............................. 58
`Table 6-20: TTP by ICRA assessment (ITT) ................................................................................ 59
`Table 6-21: Overall survival (ITT) ............................................................................................... 59
`Table 7-1 Randomized Trial Providing Main Safety Population for Bendamustine .................... 65
`Table 7-2 Trials Providing Additional Safety Population for Clinical Studies of Intravenous -
`Bendamustine ................................................................................................................................ 65
`
`Table 7-3 Other Trials Providing Supportive Safety Information ............................................... 66
`Table 7-4 Extent of Exposure (Applicant Table) .......................................................................... 73
`Table 7-5 Dose Delays and Reductions by Treatment Group (Treated Analysis Set) (Applicant
`Table) ............................................................................................................................................ 74
`Table 7-6 Demographic Information (Treated Analysis Set; Applicant Table) .......................... 75
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Table 7-7 Grade 3 and 4 Adverse Reactions Occurring in Either Treatment Group by System
`Organ Class, Preferred Term, and Severity (Treated Analysis Set; Applicant Table) ................. 82
`Table 7-8 Serious Adverse Reactions Occurring in Either Treatment Group by System Organ
`Class and Preferred Term (Treated Analysis Set; Applicant Table) ............................................. 85
`Table 7-9 Adverse Reactions Leading to Withdrawal From Study Drug Treatment By Treatment
`Group (Applicant Table) ............................................................................................................... 87
`Table 7-10 Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Group
`by System Organs Class and Preferred Term (ITT; Applicant Table) ......................................... 92
`Table 7-11 Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Group
`by System Organs Class and Preferred Term (Excluding Centers 1 & 2) .................................... 93
`Table 7-12 Overview of Adverse Reactions in the Safety Population of Study 02CLLIII ......... 94
`Table 7-13 Worst CTC Grades for Serum Chemistry Laboratory Tests Results Overall by
`Treatment Group (Treated Analysis Set; Applicant Table) .......................................................... 97
`Table 7-14 Worst CTC Grades 3 & 4 Hematology Laboratory Tests Results by Treatment Group
`(Treated Analysis Set) ................................................................................................................... 99
`Table 7-15 Growth Factors by Cycle and Treatment Group (Treated Analysis Set; Applicant
`Table) .......................................................................................................................................... 100
`Table 7-16 Blood Products by Cycle (Treated Analysis Set; Applicant Table) ........................ 100
`Table 7-17 Hematologic Nadir Values by Treatment Group (Treated Analysis Set; Applicant
`Table) .......................................................................................................................................... 102
`Table 7-18 Actual Values and Changes From Baseline to Endpoint for Patients with Both a
`Baseline and Endpoint Immunoglobulin Value by Treatment Group (Treated Analysis Set;
`Applicant Table) ......................................................................................................................... 104
`Table 7—19 Patients with Grade 4 Serum Chemistry Values (Treated Analysis Set; Applicant
`Table).............» ............................................................................................................................. 104
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`TABLE OF FIGURES
`
`Figure 1: Chemical structure of bendamustine ............................................................................. 18
`Figure 2 Study 02CLLIII Scheme ................................................................................................. 24
`Figure 3: Study landmark flow chart ............................................................................................ 29
`Figure 4: Steps of sample estimation during study 02CLLIII ...................................................... 31
`Figure 5 Applicant’s data reorganization ...................................................................................... 32
`Figure 6: Study 02CLLIII patient disposition (ITT, Mar 26, 2006 cut-off) ................................. 40
`Figure 7: Progression free survival by ICRA assessment (ITT) ................................................... 47
`Figure 8: Applicant estimated PFS analysis - Kaplan-Meier curve (ITT) .................................... 48
`Figure 9: Response duration by Kaplan-Meier estimation (ITT, ICRA) ...................................... 56
`Figure 10: Response duration by Kaplan-Meier estimation (ITT, calculated assessment) .......... 58
`Figure 11: Overall Survival by Kaplan-Meier Estimation (ITT) .................................................. 60
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`1. Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`The efficacy and safety reviewers recommend approval of Treanda for the following indication,
`if the applicant can provide adequate financial disclosure information.
`
`indicated for the
`___=_
`“TREANDA (bendamustine hydrochloride) for Injection is
`treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established.”
`
`1.2 Risk Benefit Analysis
`
`The approval recommendation is based on the statistically significant improvement in response
`rate and progression free survival of Treanda compared to chlorambucil in a randomized study in
`CLL patients. The survival analysis was immature at the time of the study 02CLLIII final report;
`because only 11% death events occurred at the final analysis and 18.5% death had occurred at
`the 4 months follow up. The safety profile of Treanda is acceptable for the proposed indication.
`
`1.3 Recommendations for Risk Evaluation and Mitigation Strategies
`
`None
`
`1.4 Recommendations on Post Marketing Activities/Phase 4 Commitments
`
`The following areas have been identified forvpost-marketing commitments(PMC). For final
`PMCs, please see the approval letter.
`
`1. The applicant should continue to follow subject of study 02CLLIII for survival outcome.
`
`2. Submit the completed report and data sets for the mass-