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

`

`Summary Review for Regulatory Action
`
`
`
`
`
`m_——
`
`TREANDA (bendamustine hydrochloride) for Injection
`is indicated for the treatment of patients with chronic
`lymphocytic leukemia (CLL). Efficacy relative to first
`line therapies other than chlorambucil has not been
`established.
`,
`
`
`
`
`
`
`2/ 19/08
`
`Su .lement #
`
`Established
`
`SAN Name
`
`Dosage Forms / Strength
`
`Proposed Indication(s)
`
`
`
`Single-use vial containing 100 mg of bendamustine
`HCl as l o ohilized owder
`
`Action/Recommended Action for Approval
`NME:
`
`\
`-
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Reviews
`
`Statistical Reviews
`
`Pharmacolo 1 Toxicolo_ Reviews
`CMC Review/OBP Review
`
`Microbiology Reviews
`Clinical Pharmacology Reviews
`DDMAC
`
`DSI
`
`CDTL Review
`
`OSE/DMEP
`
`OSE/DDRE
`
`3/5/08
`
`2/ 19/08
`
`2/27/08, 3/11/08
`
`2/27/08, 3/19/08
`
`12/17/07, 2/6/08
`
`2/19/08, 2/22/08
`3/3/08
`
`2/28/08
`
`3/5/08
`
`3/6/08
`
`N/A
`
`N/A
`
`OSE/DSRCS
`SEALD
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEP=Division of Medication Error Prevention
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DSRCS=Division of Surveillance, Research, and Communication Support
`CDTL=Cross—Discipline Team Leader
`
`

`

`Division Director Summary Review
`
`1. Introduction
`
`This new drug application seeks approval of TREANDA for the following indication:
`
`TREANDA (bendamustine hydrochloride) for Injection is indicated for the treatment
`of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established.
`
`The application was submitted on September 20, 2007 and the PDUFA goal date is March
`20, 2008. This review will summarize the efficacy and safety data supporting approval,
`the recommendations of each review discipline, and any outstanding issues.
`
`2. Background
`Bendamustine is a bifunctional mechlorethamine derivative. Mechlorethamine and its
`
`derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds
`with electron-rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell
`death via several pathways. The exact mechanism of action of bendamustine remains
`unknown.
`
`Bendamustine has been marketed in the German Democratic Republic since 1974, in
`Germany since 1993, and Bulgaria since 2000. It is authorized for the treatment of
`Hodgkin’s disease, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, multiple
`myeloma, and breast cancer.
`
`An IND was submitted in 2003, an end-of—phase 2 meeting was held on 9/2/04, and pre-
`NDA meetings were held on 4/12/07 and 4/27/07 (CMC). The issue of the potential
`acceptability of a single randomized trial to support approval was discussed at the EOP2
`meeting.
`
`3. CMCIDevice
`
`Chemistry Review
`The Chemistry Review of 2/27/08 made the following recommendation regarding
`approval:
`
`The application is recommended for an approval action for chemistry, manufacturing
`and controls under section 505 of the Act, provided trademark and labeling
`acceptability has been determined by Office of Drug Safety (DMETS) and provided the
`manufacturing sites are deemed acceptable for cGMP compliance. The product quality
`microbiology has recommended approval on 06-Feb-2008. The recommendation for
`Office of Compliance regarding the acceptability of the manufacturing facilities is
`pending as of the date of this review.
`
`

`

`The review listed the following deficiencies:
`
`1. The following agreement should be placed in the action letter.
`
`We remind you of your agreement in an amendment dated 12-Feb-2008 to initiate
`change controls for all the documents impacted by the revision to the maximum hold
`
`time not to exceed
`.
`.
`and to submit
`appropriate post-approval correspondence reflecting this change.
`
`2. The company should commit to the following phase 4 commitment:
`
`Provide an agreement to study the physico-chemical compatibility of the drug product
`with commonly used diluents such a: A,“ ind submit the data
`within six months from the date of approval of this NDA.
`
`‘
`CMC Branch Chief Memo
`The CMC Branch Chief Memo of 3/1 9/08 made the following overall recommendation:
`
`All pending issues subsequent to completion of the primary CMC review have been
`resolved satisfactorily. The Office of Compliance made an acceptable cGMP
`recommendation for the NDA on March 17, 2008. The DDMAC and DMETs reviews
`on labels and labeling were completed and the combined CMC/DMETs comments on
`labels and labeling were satisfactorily addressed by the firm. An approval
`recommendation is made for this NDA. A statement on grantable expiration dating
`period and reminders on a CMC post-marketing commitment and a CMC agreement,
`listed at the end of this memo, have been included in the action letter.
`
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`
`4. Nonclinical Pharmacology/Toxicology
`
`Pharmacology/Toxicology Review and Evaluation
`The Pharmacology/Toxicology Review and Evaluation dated February 27, 2008 made the
`following recommendations:
`
`A. Recommendation on approvability: The non-clinical studies submitted to this NDA
`provide sufficient information to support the use of Treanda ® (bendamustine
`hydrochloride) for the treatment of patients with chronic lymphocytic leukemia (CLL).
`B. Recommendation for nonclinical studies: No additional non-clinical studies are
`
`‘
`required.
`C. Recommendations on labeling: A separate review will be conducted.
`
`The pharmacology/toxicology labeling review was completed on March 11, 2008.
`
`

`

`Secondary and Tertiary Pharmacology/Toxicology Reviews
`The secondary and tertiary reviews concurred that the pharmacology and toxicology data
`support approval and that there are no outstanding nonclinical issues.
`
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`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Clinical Pharmacology Review
`The Clinical Pharmacology Review of February 19, 2008 made the following
`recommendations:
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 5 has
`reviewed the information contained in the NDA 22-249.
`
`This NDA is considered to be deficient from a clinical pharmacology perspective due
`to the lack of data available regarding pharmacokinetics at the proposed dose, dose
`proportionality, human excretion and metabolism, effect on QT prolongation, in-vivo
`drug-drug interactions, and in-Vitro p-glycoprotein screens.
`
`The NDA will be considered acceptable pending the sponsor’s agreement to the
`following Phase 4 commitments:
`
`Phase IV commitments
`
`1. Submit the completed report and data sets for the mass-balance evaluation. Results
`from this study may indicate a need for dedicated renal and/or hepatic organ
`impairment studies.
`
`2. The potential for bendamustine to affect the QT interval needs to be investigated.
`
`3,-The influence of CYP1A2 inhibitors (fluvoxamine) on bendamustine
`pharmacokinetics needs to be evaluated in-vivo.
`
`4. The influence of CYP1A2 inducers (smoking) on bendamustine pharmacokinetics
`needs to be evaluating in-vivo.
`
`5. In-vitro p-glycoprotein screens need to be completed to determine if bendamustine is
`an inhibitor or substrate of p—glycoprotein.
`
`W
`
`

`

`Acting Team Leader Memo
`The Acting Team Leader memo of February 22, 2008 concurred with these
`recommendations.
`
`Clinical Pharmacology NDA Review Amendment
`The subsequent Clinical Pharmacology NDA Review Amendment of March 11, 2008
`agreed with the sponsor’s request to delete the last phase 4 commitment for a -\—
`A.
`
`_
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`
`6. Clinical Microbiology
`
`The final Product Quality Microbiology Review of February 6, 2008 recommended
`approval.
`
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`
`7. ClinicallStatistical-Efficacy
`
`The following brief summary of the clinical trial design and efficacy results is excerpted
`from the agreed upon labeling.
`
`The safety and efficacy of TREANDA were evaluated in an open-label, randomized,
`controlled multicenter trial comparing TREANDA to chlorambucil. The trial was
`conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I -
`IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic
`insufficiency, B-symptoms, rapidly progressive disease or risk of complications from
`bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune
`thrombocytopenia, Richter’s syndrome, or transformation to prolymphocytic leukemia
`were excluded from the study.
`
`The patient populations in the TREANDA and chlorambucil treatment groups were
`balanced with regard to the following baseline characteristics: age (median 63 vs. 66
`years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B),
`lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48%
`vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%),
`lymphocyte count (mean 65.7X109/L vs. 65. 1x109,/L) and serum lactate dehydrogenase
`concentration (mean 370. 2 vs. 388.4 U/L). Ninety percent of patients in both treatment
`groups had1mmuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or
`CD20 or both).
`
`

`

`Patients were randomly assigned to receive either TREANDA at 100 mg/mz,
`administered intravenously over a period of 30 minutes on Days 1 and 2 or
`chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and
`15 of each 28-day cycle. Efficacy endpoints of objective response rate and
`progression-free survival were calculated using a pre-specified algorithm based on NCI
`working group criteria for CLL.
`
`The results of this open-label randomized study demonstrate superior efficacy for
`TREANDA treatment as compared with chlorambucil treatment with a higher rate of
`overall response and a longer progression—free survival (see Table 3). Survival data are
`not mature.
`
`
`
`
`
`
`
`90 (59)
`(5103,6662)
`13(8)
`4(3)
`__—
`73 (48) ——
`
`——
`
`(95% CI)
`Com alete response (CR)*
`Nodular oartial response (nPR)**
`Partial response (PR) T
`Progression-Free Survival”
`6 (5.6, 8.6)
`18 (11.7, 23.5)
`Median, months (95% CI)
`0.27 (0.17, 0.43)
`Hazard ratio (95% CI)
`
`
`*CR was defined as peripheral lymphocyte count 5 4.0 x 109/L, neutrophils 2 1.5 x 109/L, platelets >100 x 109/L, hemoglobin >
`110g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes 5 1.5 cm, < 30% lymphocytes without
`nodularity in at least a nomrocellular bone marrow and absence of “B” symptoms. The clinical and laboratory criteria were
`required to be maintained for a period of at least 56 days.
`**nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.
`tPR was defined as 250% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either 250%
`reduction in lymphadenopathy, or 250% reduction in the size of spleen or liver, as well as one of the following hematologic
`improvements: neutrophils 21.5 x 109/L or 50% improvement over baseline, platelets >100 x 109/L or 50% improvement over
`baseline, hemoglobin >110g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.
`fiPFS was defined as time from randomization to progression or death from any cause
`
`Table 3: Efficac Data
`
`MAN
`(N=153
`(N=148
`
`Res . onse Rate 11 %
`——
`Overall res onse rate
`
`
`
`
`
`—_
`
`Kaplan-Meier estimates of progression-flee survival comparing TREANDA with
`chlorambucil are shown in Figure 1.
`
`Figure 1. Progression-Free Survival
`
`
`
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`
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`15
`Progrelsion-FreeSurvival (months)
`MTreamert ——mm "W
`
`35
`
`4o
`
`45
`
`

`

`Clinical Review
`
`The Clinical Review was completed on March 5, 2008 and made the following
`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.
`
`“TREANDA (bendamustine hydrochloride) for Injection is an alkylating agent
`indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).
`Efficacy relative to first line therapies other than chlorambucil has not been
`established.”
`
`In addition to the phase 4 commitments recommended by Clinical Pharmacology, the
`Clinical Review recommended that “The applicant should continue to follow subjects of
`study 02CLLHI for survival outcome.”
`
`Clinical Review Addendum
`
`A Clinical Review Addendum was completed on 3/18/08. The addendum reviewed the
`updated financial disclosure information provided by the applicant, provided an analysis of
`drug-induced liver injury, and evaluated the data submitted by the applicant to support
`their labeling recommendations for dose modifications for toxicity.
`
`The applicant was able to obtain financial disclosure information from all but two
`investigators. One was deceased and the other on an extended vacation. The review
`reached the following conclusions regarding financial disclosure:
`
`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.
`
`Cross-Discipline Team Leader Review
`The Cross-Discipline Team Leader Review was completed on March 5, 2008. The review
`recommended the following regulatory action:
`
`Pending reviews of DMETS and DDMAC, all disciplines recommend approval of
`Treanda for CLL. A statistically significant improvement in response rate, and
`progression free survival was observed. The adverse event profile is acceptable.
`
`Statistical Review and Evaluation
`
`The Statistical Review and Evaluation was completed on February 20, 2007 and made the
`following conclusions and recommendations:
`
`

`

`The sponsor submitted this application to evaluate the efficacy of Treanda
`(Bendamustine) compared with chlorambucil in the initial treatment of patients with
`chronic lymphocytic leukemia (CLL) in Binet stage B or Binet stage C requiring
`treatment. The applicant is seeking approval based on the primary efficacy endpoints,
`overall response rate (OR) and progression-free survival (PFS). OR was the
`proportion of patients in each treatment group with a best response of CR, nPR, or PR.
`Progression-free survival (PFS) was defined as the time from randomization to
`progressive disease (PD) or death for any cause, whichever occurred first. The primary
`analyses were based on the Independent Committee for Response Assessment (ICRA)
`adjudicated responses and adjudicated event time points. This application was based
`primarily on data from a Phase III pivotal study (02CLLIII). This was an open-label,
`randomized, Phase 3 study. Patients were randomly assigned (with stratification by
`Binet stage and study center) to either the bendamustine or chlorambucil treatment
`group at a ratio of l: 1
`
`A total of 302 patients were screened and 301 were randomly assigned to treatment (1
`patient was not assigned to a treatment group due to refusal) at 45 centers throughout 8
`countries. The sponsor reported that the proportion of patients with ORR was 62% in
`the bendamustine treatment group compared with 33% in the chlorambucil treatment
`group (p<0.0001) as determined by the Independent Committee for Response
`Assessment (ICRA). The primary PFS analysis showed that the bendamustine
`treatment was superior to chlorambucil treatment (median 21 vs. 9 months, hazard ratio
`(HR) 0.23, p<0.0001). Based on the data submitted by the sponsor these results‘ were
`confirmed by this reviewer and the data support the efficacy claim.
`
`Whether the endpoints and the sizes of the effects on these two endpoints in this phase
`III study are adequate for apprOval is a clinical decision.
`
`Statistical Team Leader’s Memo
`
`The statistical team leader’s memo of 2/25/08 made the following conclusion and
`recommendation:
`
`This is Team Leader’s memo of the New Drug Application (NDA) submission seeking
`approval for bendamustine (Treanda) as the first line treatment of chronic lymphocytic
`leukemia (CLL) based on one randomized study comparing to chlorambucil in
`previously untreated adults with symptomatic Binet stage B or stage C CLL requiring
`treatment. I concur with the primary reviewer, Dr. Tang’s conclusion that the data
`submitted supports the claim that bendamustine has demonstrated superior overall
`response rate (ORR) and progression-free survival (PFS) compared to chlorambucil
`(ORR of 59% vs. 26% and PFS HR = 0.52, p-value < 0.0001). Please refer to the
`primary review by Dr. Tang for the details of the study and the results.
`
`Progression-free survival was assessed by a panel of three independent expert
`hematologic oncologists and also objectively calculated using an algorithm based on
`NCI working group criteria. According to the sponsor, in performing the review the
`members of the independent panel were allowed to exercise clinical judgment in
`
`

`

`determining response and did not include bone marrow evaluations as required by the
`NCI working group criteria. The FDA reviewers were able to verify the calculated
`response rates and PFS, but could not verify the same as determined by the
`independent panel due the subjective nature of the independent evaluation. Therefore,
`it is recommended that the calculated response rates and PFS estimates be included in
`the product label.
`
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`
`8. Safety
`
`The safety profile of bendamustine is summarized in the following excerpts from the
`agreed upon package insert:
`
`Adverse reactions were reported according to NCI CTC v. 2.0. In the randomized CLL
`clinical study, hematologic adverse reactions (any grade) in the TREANDA group that
`occurred with a frequency greater than 15% were neutropenia (28%),
`thrombocytopenia (23%), anemia (19%), and leukopenia (18%). Non-hematologic
`adverse reactions (any grade) in the TREANDA group that occurred with a frequency
`greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).
`
`Other adverse reactions seen frequently in one or more studies included asthenia,
`fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation;
`headache; mucosal inflammation and stomatitis.
`
`Worsening hypertension was reported in 4 patients treated with TREANDA in the
`randomized CLL clinical study and none treated with chlorambucil. Three of these 4
`adverse reactions were described as a hypertensive crisis and were managed with oral
`medications and resolved.
`
`The most frequent adverse reactions leading to study withdrawal for patients receiving
`TREANDA were hypersensitivity (2%) and pyrexia (1%).
`
`

`

`Table 1 contains the treatment emergent adverse reactions, regardless of attribution,
`that were reported in 25% of patients in either treatment group in the randomized CLL
`clinical study.
`
`Table 1: Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least
`5% of Patients
`
`System organ class
`Preferred term
`
`.
`
`Total number of patients with at least 1 adverse
`reaction
`Blood and lymphatic system disorders
`Neutropenia
`Thrombocytopenia
`Anemia
`Leukopenia
`Lymphopenia
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`‘ General disorders and administration site
`conditions
`Pyrexia
`Fatigue
`Asthenia
`Chills
`Immune system disorders
`Hypersensitivity
`Infections and infestations
`Nasopharyngitis
`Infection
`Herpes simplex
`Investigations
`Weight decreased
`Metabolism and nutrition disorders
`Hyperuricemia
`Respiratory, thoracic and mediastinal disorders
`Cough
`Skin and subcutaneous tissue disorders
`Rash
`Pruritus
`
`TREANDA
`1N=1532
`
`Number 1%) of patients
`
`Chlorambucil
`(N=143!
`
`All Grades
`
`Grade 3/4 '
`
`All Grades
`
`Grade 3/4
`
`136 (89)
`
`43 (28)
`35 (23)
`29 (19)
`28 (18)
`10 (7)
`
`31 (20)
`24 (16)
`l4 (9)
`
`36 (24)
`14 (9)
`13 (8)
`9 (6)
`
`7 (5)
`
`10 (7)
`9 (6)
`5 (3)
`
`11 (7)
`
`11 (7)
`
`6(4)
`
`12 (8)
`8 (5)
`
`88 (58)
`
`36 (24)
`20 (13)
`4(3)
`23 (15)
`10 (7)
`
`1 (<1)
`1 (<1)
`2 ( 1)
`
`6 (4)
`2 (1)
`0
`0
`
`2 (1)
`
`0
`3 (2)
`O
`
`0
`
`3 (2)
`
`1 (<1)
`
`4 (3)
`0
`
`113 (79)
`
`44 (31)
`
`20 (14)
`28 (20)
`16(11)
`4 (3)
`0
`
`21 (15)
`9 (6)
`5 (3)
`
`8 (6)
`8 (6)
`6 (4)
`1 (<1)
`
`3 (2)
`
`12 (8)
`1 (<1)
`7 (5)
`
`5 (3)
`
`2(1)
`
`7 (5)
`
`7 (5)
`2 (1 b
`
`’
`
`13 (9)
`11 (8)
`0
`2 (l)
`0
`
`1 (<1)
`O
`0
`
`2 (1)
`0
`O
`0
`
`O
`
`0
`1 (<1)
`0
`
`O
`
`0
`
`1 (<1)
`
`3 (2)
`0
`
`The Grade 3 and 4 hematology laboratory test values by treatment group in the
`randomized CLL clinical study are described in Table 2. These findings confirm the
`myelosuppressive effects seen in patients treated with TREANDA. Red blood cell
`transfusions were administered to 20% of patients receiving TREANDA compared
`with 6% of patients receiving chlorambucil.
`
`10
`
`

`

`Table 2—Incidence of Hematology Laboratory Abnormalities in Patients Who
`Received TREANDA or Chlorambucil in the Randomized CLL Clinical Stud
`
`TREANDA
`n=150
`
`Chlorambucll
`N=141
`
`Laboratory Abnormality
`
`All Grades Grade 3/4
`11 (%)
`n (%)
`
`All Grades Grade 3/4
`n (%)
`n (%)
`
`
`
`Decreased
`
`Decreased
`
`Decreased
`
`nhoc es Decreased
`L
`Neutrohils Decreased
`
`102 68
`113 (75
`
`70 47)
`65 43
`
`27 19)
`86 61)
`
`30 (21
`
`In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some
`without associated significant elevations in AST and ALT. Grade 3 or 4 increased
`bilirubin occurred in 3% of patients. Increases in AST and ALT of grade 3 or 4 were
`limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may
`also have changes in their creatinine levels. If abnormalities are detected, monitoring of
`these parameters should be continued to ensure that significant deterioration does not
`occur.
`
`The package insert also includes the following Warnings and Precautions:
`
`0 Patients treated with TREANDA are likely to experience myelosuppression. In the
`randomized CLL clinical study, patients receiving TREANDA experienced Grade 3 or
`4 neutropenia (24%), febrile neutropenia (3%), red blood cell transfusions (20%), and
`platelet transfusions (<1 %). ..
`
`0
`
`0
`
`Infection, including pneumonia and sepsis, has been reported in patients in clinical
`trials and in post-marketing reports. Infection has been associated with hospitalization,
`septic shock and death. . .
`
`Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms
`include fever, chills, pruritus and rash. In rare instances severe anaphylactic and
`anaphylactoid reactions have occurred, particularly in the second and subsequent
`cycles of therapy. . .
`
`. Tumor lysis syndrome associated with TREANDA treatment has been reported in
`patients in clinical trials and inpost—marketing reports. The onset tends to be within the
`first treatment cycle of TREANDA and, without intervention, may lead to acute renal
`failure and death. Preventive measures include maintaining adequate volume status,
`close monitoring of blood chemistry, particularly potassium and uric acid levels, and
`
`11
`
`

`

`the use of allopurinol during the first one to two weeks of TREANDA therapy in
`patients at high risk...
`
`0 A number of skin reactions have been reported in clinical trials and post-marketing
`safety reports. These events have included rash, toxic skin reactions and bullous
`exanthema. ..
`
`o TREANDA can cause fetal harm when administered to a pregnant woman.
`
`Clinical Review Addendum
`
`As noted in section 7 above, the review of drug-induced liver injury identified no cases
`that met Hy’s law. The review also evaluated the applicant’s analysis of dose
`modifications for toxicity that were utilized in the trial and recommended labeling
`revisions which were accepted by the applicant.
`
`Cole/fleet: Me size oftfle may data/ease [Ir adequate/0r tflzir [haired/1'01; Me .mfeg/ data
`flow [fie eim’ee/lrz’els’ were J'zzpp/e/Ize/ztee’éy 120/7-USpay/merl'e/z'lzg.refegz data. M
`M/I/J'e/‘e reenmmezze’ee’e/ [£13 lime. flere are 120 altar/012021457 .refegz Jim/es Met would
`preclude app/'0V01
`
`9. Advisory Committee Meeting
`
`This application was not referred to the Oncologic Drugs Advisory Committee because the
`improvements in response rate and progression-free survival with bendamustine compared
`to chlorambucil were clinically and statistically robust and the safety profile is comparable
`to other therapies used for the treatment of CLL.
`
`10.
`
`Pediatrics
`
`PREA is not applicable because the applicant has orphan drug exclusivity for the use of
`bendamustine in CLL.
`'
`
`Other Relevant Regulatory Issues
`11.
`The Clinical Inspection Summary was completed on February 28, 2008 and provided the
`following overall assessment of findings and recommendations:
`
`-—/
`,/ and Dr.
`The study data collected by Dr. M Dr. / V Dr. .‘
`appear reliable. The inspection of Cephalon Inc., did not identify any critical issues.
`Only the sponsor inspection has completed the EIR and provided that to DSI for
`support of the CIS. The 4 C15 final reports (EIRs) have not been completed to date.
`While 2 of the 4 clinical investigators inspected were issued Form FDA 483 inspection
`observations, it does not appear that the compliance deviations would significantly
`alter overall study outcome.
`
`The 2 C15 that were issued Form FDA 483s appeared to have problems with protocol
`compliance, appropriate use of the study drug and the timely reporting of serious
`Adverse Events. The deliberate use of altered dosing levels in certain subjects for both
`
`12
`
`

`

`the study drug and comparator drug at Dr. 3 / site does not appear to give the
`study drug a favorable advantage (personal communication with the review division
`medical officer, Qin Ryan). According to the final establishment inspection report for
`the sponsor the site deliberately altered drug dosing levels for “safety reasons.”
`
`Regarding study sites 01 and 02, the FDA inspectional findings described in this report
`are not sufficient to make a determination of data reliability associated with those data
`generated at study sites 01 and 02. The sponsor-described findings of protocol non-
`
`compliance and possible human use ethics Violations at these foreign sites are very
`concerning.
`\_
`
`/,.._.\
`
`_
`
`Observations noted above are based in part on the preliminary communications
`provided the field investigators. Only the findings at the sponsor, Cephalon Inc., are
`based on a final EIR. An inspection summary addendum will be generated if
`conclusions change significantly upon receipt and review of the final remaining EIRs.
`
`Because of the problems identified by both the applicant and DSI with study sites 01 and
`02, the applicant conducted a sensitivity analysis excluding patients fiom these sites. The
`results of this analysis are discussed in the Clinical Review:
`
`The PFS analysis is still statistically significant after excluding sites 1 and 2. The
`clinical and statistical reviewers verified applicant’s sensitivity analysis and agree that
`the impact of sites 1 and 2 to the progression free survival is minimal.
`
`DDMAC comments on draft labeling were completed on 3/3/08 and were considered
`during the labeling discussions.
`
`6'01721726121: Here are 120 o/éer leil’éJ’O/Védl’e/éVd/Z/ regal/glow [I’m/ex
`
`12.
`
`Labefing
`
`Proprietary name: OSE/DMEP had no objections to the use of TREANDA as the
`proprietary name.
`
`Physician labeling: Agreement has been reached on the physician labeling. The major
`issues were the appropriate efficacy analysis to include in the label and the inclusion of
`dose modifications for toxicity. The applicant objected to 74%
`
`WW
`
`The applicant provided an
`analysis which supported their proposed dose modifications.
`Carton and immediate container labels: CMC and OSE/DMEP recommendations for
`
`changes in the carton and container labels were communicated to and accepted by the
`applicant. Revised labels were submitted and are acceptable.
`Patient labeling/Medication guide: not applicable.
`
`13
`
`

`

`13.
`
`Decision/Actioanisk Benefit Assessment
`
`Regulatory Action: approval
`
`Risk Benefit Assessment: The improvements in response rate and PFS with
`bendamustine compared to chlorambucil were clinically and statistically robust. The
`overall response rates were 59% for bendamustine and 29% for chlorambucil
`(p<0.001). The hazard ratio for PFS was 0.27 (p<0.001) and the median PF S was 18
`months for bendamustine and 6 months for chlorambucil. This was achieved with an
`
`acceptable safety profile as noted above.
`
`Recommendation for Postmarketing Risk Management Activities
`
`None
`
`Recommendation for other Postmarketing Study Commitments
`
`The applicant has agreed to the following postmarketing study commitments:
`
`1. Cephalon commits to providing an updated study report of Protocol 02CLLIII titled
`“Pflayelll, Open—label [Pail/017212651 Mlllz'ce/z/erfiflrbdcy a/zdSa/égz 152/110} of
`flefla’dmzzJ/z'lze [Ej/drocfl/arz'de Versus Cé/oraméz/CIY1'12 flea/mefll-Mfi/e [Dd/1291213"
`szfl $12231 fldge 19/6) 5’- CZZ Requzn’zzg Mara/y” at data cut off date in May
`2008. Response rate, progression-free survival, overall survival and safety updates
`will be provided in this study report.
`
`Protocol Submission: N/A
`
`Study Start: N/A
`Final Report Submission: February, 2009
`
`Cephalon commits to submitting the results and data from the ADME Study 1039
`titled "An Open-Label Study to Investigate the Pharmacokinetics (Distribution,
`Metabolism, and Excretion) of Bendamustine Hydrochloride Following
`Intravenous Infusion of [14C] Bendamustine Hydrochloride in Patients with
`Relapsed or Refractory Malignancy (Hematologic or Nonhematologic)". Results
`from this study may indicate a need for dedicated renal and/or hepatic organ
`impairment studies.
`
`Protocol Submission: May, 2008
`Study Start: December, 2008
`Final Report Submission: PK report— December, 2009
`Final report with safety data: March, 2010
`
`Cephalon commits to conducting a study to assess the potential for bendamustine to
`prolong the QT interval in patients. The QT plan will be submitted prior to initiation
`for IRT review and concurrence.
`
`14
`
`

`

`Protocol Submission: July, 2008
`Study Start: December, 2008
`Final Report Submission: June, 2010
`
`. Since bendamustine is a CYP1A2 substrate 1'12 VIZ/'0, Cephalon agrees to perform an
`1’12 Viva drug interaction study of the ability of fluvoxamine (CYP1A2 inhibitor) to
`alter the pharmacokinetics of a single dose of bendamustine. The necessity to
`conduct this study will be predicated upon the results from Study 1039.
`
`Protocol Submission: March, 2010
`Study Start: September, 2010
`Final Report Submission: PK report - January, 2012
`Final report with safety data: July, 2012
`
`. Since bendamustine is a CYP1A2 substrate ['12 VIZ/’0, Cephalon agrees to perform an 1'}:
`Viva drug interaction study of the ability of smoking (CYP1A2 inducer) to alter the
`pharmacokinetics of a single dose of bendamustine. The necessity to conduct this
`study wil