CENTER FOR IDRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Statistical Review(s)
`
`

`

`STATISTICAL REVIEW AND EVALUATION: 45 DAY MEETING REVIEW
`(COMPLETED REVIEW FOR INTERNAL DISTRIBUTION ONLY)
`
`NDA:
`NAME OF DRUG:
`APPLICANT:
`
`21-572
`CIDI-ICIN® (Daptomycin for Injection)
`Cubist Pharmaceuticals Inc.
`
`SUBMISSION DATE:
`
`December 19, 2002
`
`INDICATION(S):
`
`Complicated Skin and Skin Structure Infections (CSSSI)
`
`NUMBER AND TYPE OF
`CLINICAL:
`
`Two completed phase III studies
`
`STATISTICAL REVIEWER:
`CLINICAL REVIEWER:
`PROJECT MANAGER:
`
`Joel Jiang, PhD.
`Susan Thompson, MD.
`LTJG Raquel Peat, M.S., M.P.H, HFD-520
`
`45 DAY MEETING DATE:
`USER FEE DATE:
`
`February 13, 2003
`June 20, 2003
`
`I. ORGANIZATION AND DATA PRESENTATION
`
`YES NO
`
`N/A
`
`A.
`
`Is there a comprehensive table of contents
`with adequate indexing and pagination?
`
`Are the original protocols, protocol
`amendments and proposed label
`provided?
`
`Adverse event listings by center and time
`of occurrence relative to enrollment date.
`
`Are adverse events from cited sources
`
`(foreign and domestic) provided?
`
`Is a CANDAR or an electronic submission of
`
`the data necessary?
`
`

`

`YES NO
`
`N/A
`
`E.
`
`If the data have been submitted electronically,
`has adequate documentation of the data sets
`been provided?‘
`
`Reviewer’s comment: Formatfiles are not found in sponsor '5
`SAS data set package, which may have difliculty to reference
`formals or identifi) codes ofvariables in using SAS.
`
`F.
`
`Are inclusion/exclusion (evaluability) criteria
`adequately coded and described:
`
`Are there discrepancies between CRF information
`and CANDAR/Jacket data?
`
`If the data have been submitted electronically,
`can laboratory data be easily merged across
`studies and indications?
`
`lfnot, can you estimate the time required
`_to correct problems?
`
`I]. STATISTICAL METHODOLOGY
`
`A.
`
`Are all primary efiicacy studies of appropriate
`design to meet basic approvability requirements,
`within current Divisional policy statements or
`to the extent agreed upon previously with the
`sponsor by the Division?
`'
`
`For each study, is there a comprehensive
`statistical summary ofthe efiicacy analyses
`which covers the intent-to-treat population,
`evaluable subject population and other
`applicable sub populations (age, gender,
`race/ethnicity, etc.)?
`
`If subset analyses were not done, was an
`acceptable explanation of why given?
`
`

`

`Based on the summary analyses of each study,
`do you believe:
`'
`
`The analyses are appropriate for the type data
`collected, the study design, and the study
`objectives (based on protocol and proposed
`label claims)?
`
`Ifthere are multiple endpoints, has this
`been adequately addressed?
`
`Intent-to-treat (HT and MITI') analyses are
`properly performed?
`-
`
`Sufficient and appropriate references were
`included for novel statistical approaches?
`
`If interim analyses were performed, were they
`planned in the protocol and were appropriate
`significance level adjustments made?
`
`Are there studies which are incomplete or
`
`,
`
`ongoing?
`
`ls there a comprehensive, adequate analysis
`of safety data as recommended in the
`Clinical/Statistical Guideline?
`
`Is there anything significant yet regarding
`safety or AE evaluations?
`-
`
`YES NO
`
`N/A
`
`V
`
`V
`
`V
`
`V
`
`Ill. FILEABILITY CONCLUSIONS
`
`From a statistical perspective is this submission, or indications
`therein, reviewable with only minor further input fi'om the sponsor?
`
`This submission is fileable. However the sponsor needs to clarify some issues in electronic
`submitted data files.
`
`._ “.4
`_-~.--
`
`

`

`Table ofthe Studies:
`
`APPENDIX
`
`Com - arator
`
`CSR-DAP-
`9801
`3/15/99 —
`8/2/01
`
`Daptomycin: 4 mg/ltg
`administered l.V. q.d. for 7 to 14
`days
`
`'
`
`Phase 111, active-
`controlled, randomized
`(1:1 ratio), investigator-
`blinded,
`Multicenter (69)
`
`Vancomycm: 1 g administered
`l.V. BIDx7 to 14 days
`Or selected semi-synthetic
`penicillins:
`Nafcillin 4 to 12 g l.V. q.d. in
`equally divided doses for 7 to 14
`days
`Cloxacillin 4 to 12 g l.V. q.d. in
`equally divided doses for 7 to 14
`days
`Oxacillin 4 to 12 g l.V. q.d. in
`equally divided doses for 7 to 14
`days.
`
`Duration of treatment: Maximum study duration from Prc-therapy to Post~Srudy was to be 44 days. Study drug was to be administered
`for 7 to 14 days, followed by TOC and Post-Study visits conducted 7 to 12 and 21 to 28 days, respectively, after the last dose of study
`dm . Theta-v could be extended bevond 14 davs with the a- .roval of the Medical Monitor.
`
`Primary efficacy: The primary outcome variable was the Sponsor-Defined Clinical Outcome, which was based on the lnvesugator’5
`evaluation of Clinical Res-onse at the TOC visit, with ad'ustment for s-ecific events e. -. rem0\al sur-cn' and e\aluabilin criteria.
`Objecrjve: The primary objectives of this study were to compare the safety and'to demonstrate the equivalent efficacy of l.V.
`Daptomya'n to that of l.\'. Vancomycin or selected l.V. semi-synthetic penicillins in the treatment of c5551 due to Gram-positive
`bacteria.
`
`
`
`CSR-DAP-
`9901
`3/17/00 —
`12/28/00
`
`Daptomycm: 4 trig/kg
`administered l.V. q.d. for 7 to 14
`days
`
`Phase II], active-
`controlled, randomized
`(1:1 ratio), investigator-
`blinded,
`Multicenter (67)
`
`Vancomycin: 1 g administered
`l.V. BIDx7 to 14 days
`Ot selected semi-synthetic
`penicillins:
`Oxacillin 4 to 12 g I.\'. q.d. in
`equally divided doses for 7 to 14
`days
`Cloxacillin 4 to 12 g l.V. q.d. in
`equally divided doses for 7 to 14
`days
`Flucloxacjllin 4 to 12 g l.V. q.d.
`in equally dinded doses for 7 to
`14 days.
`
`Duration of treatment: see Study CSR-DAP-9801.
`
`f.“ Number ofall enrolled and randomized; " Number of safety (as trench-J Number of HT; 0 Number of MTl'l'; v Number of clinically
`evaluable: a Number ofmicrobiolot-icallv fl‘aluable
`
`

`

`_This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Joel Jiang
`2/20/03 09:52:06 AM
`BIOMETRICS
`
`Daphne Lin
`2/20/03 10:00:07 AM
`BIOMETRICS
`
`

`

`OFFICE OF BIOSTATISTICS
`
`US. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACOEPIDEMIOLOGY AND STATIanAL SCIENCE
`
`Sept, 12 y 2003
`
`Statistical Review and Evaluation
`
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`21-572
`
`Drug Name: Cubicin" (Daptomycin for Injection)
`
`Indication: Complicated Skin and Skin Structure Infections (CSSSI)
`
`Sponsor: Cubist Pharmaceuticals, Inc.
`
`Dates: Submission Date: 12/19/2002; Received Date:
`
`12/20/2002; PDUFA Date: 9/20/2003; Review Completion
`Date: 9/12/2003
`
`Review Status: Priority Review
`
`Biometrics Division: Division of Biometrics III (HFD-725)
`
`Statistical Reviewer:
`
`joeljiang, Ph.D.
`
`Concurring Reviewers: Daphne Lin, Ph.D., Statistical Team Leader
`
`Mohammad Huque, Ph.D., Statistical Division Director
`
`Medical Division: Division ofAnti—infective Drug Division (HFD-SZO)
`
`Clinical Team: Medical Officer: Sumathi Nambiar, M.D.
`
`Medical Officer: Susan Thompson, M.D.
`
`Medical team leader: David Ross, M.D.
`
`Medical Division Directorzjanice Soreth, M.D.
`
`Project manager: LTJG Raquel Peat, M.S., M.P.H., HFD-520
`
`Keywords: NDA review, clinical studies, efficacy evaluation, Statistical
`analysis
`
`..-M.,
`._“.,
`
`

`

`1 EXECUTIVE SUMMARY ............................................................................................................ 3
`
`1.1 CONCLUSIONS AND RECOMMENDATIONS............... 3
`1.2 BRIEF OVERVIEW OF CLINICAL STUDIES .......................................................... 3
`1.3 STATISTICAL ISSUES AND FINDINGS .................................................................... 4
`
`2 INTRODUCTION .......................................................................................................................... 7
`
`2:1 OVERVIEW ......................................................................................................................... 7
`2.2 DATA SOURCES ................................................................................................................ 8
`
`3 STATISTICAL EVALUATION ................................................................................................. 10
`
`3.1 EVALUATION OF EFFICACY .......................................... 10
`3.2 EVALUATION OF SAFETY ........................................................................................ 26
`
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ................................................. 29
`
`4.1 GENDER, RACE ANDAGE ....................................................... 29
`4.2 OTHER SPECIAL SUBGROUP POPULATIONS ................................................... 31
`
`5 SUMMARY AND CONCLUSIONS ......................................................................................... 42
`
`5.1 COLLECTIVE EVIDENCE .......................................................................................... 42
`5.2 CONCLUSIONS AND RECOMMENDATIONS .................................................... 43
`
`6 APPENDICES ............................................................................................................................... 44
`
`Reviewer? Note: Tbrougbout tbe renew, tbefollouing term: are abbreviated and referred to at:
`AE = atlI'erIe event; BID = twee daib'; CE = :lim'talb' evaluable; Comparator = Vanrong'a'n or Jemi-
`g'ntbetz'r Panza/Hm; Daptonya'n = Cubia'n 7” (Daptong'a'n for Injection)
`(n'proflxan'n 0.3% and
`dexan/etbamne 0.7% otir :quenJI'on); {555] = tonlplitated :kin and Jkin mudune iryertiom; ECT = end
`of treatment; HT = intent-to—fieat; I. V. = intral'enom; ME = mitrobialogiralb evaluable; MI’IT =
`modg/ied intent-to-treat; 1W0 = Mediral Ofieer, QD = ante daily; TOC = text of cure; 50C = g'JtenI
`organ (lag.
`Coryidenre intervalxflr a'lfi’renm in outeorne rate: (Daptonytin minu: tontml) are r¢orted a: ,,_,2(l, u)p,fl,
`n'bere n, i: tbe number ofDap/ong'n‘n .rubjertx, n2 1': tbe number of[antral :ubjertx, land u are tbe lower and
`tgbper bound: oftbe 95% ton/Eden” interval, regaem'zleb', p, i: tbe reIponIe rate in Daptonyrn'n :ubjerte, and
`pz 1': tbe regbonye rate in rontml .Iuly'ertx.
`
`..-~..,
`
`

`

`NDA 21-572
`
`Cubicinm (Daptomycin for lniection)
`
`Statistical Review and Evaluation
`
`Error! Not a valid link.
`
`1 EXECUTIVE SUMMARY
`
`1.1 CONCLUSIONS AND RECOMMENDATIONS
`
`This NDA submission supported by two pivotal studies was to evaluate the efficacy and
`safety of Daptomycin in the treatment of cSSSI.
`
`Both studies 980] and 990] showed therapeutic non—inflriority to the approved comparator.
`These studies support approval of Daptomycin (4 mg/kg I.V. QD x 7 to 14 days) for the cSSSl
`indication.
`
`In addition, both
`ivotal studies demonstrated that Da tomvcin and its com arator
`.
`.
`P
`«
`P
`prowded substantially comparable safety profiles.
`
`Based on the above findings, it is the opinion of this reviewer to conclude that the accessible
`data from two pivotal studies of this submission supported the use of Daptomycin with
`proposed treatment regimen in the treatment of c555] and the trial provided sufficient
`evidence to confirm that Daptomycin as an effective and safe medicine in this indication.
`
`1.2 BRIEF OVERVIEW OF CLINICAL STUDIES
`
`The sponsor submitted this NDA in order to obtain approval to market its Daptomycin (4
`mg/kg I.V. QD x 7 to 14 days) for thetreatment of cSSSI. Daptomycin is a novel cyclic
`lipopeptide antibiotic being developed for treatment of serious and life-threatening Gram—
`positive infections, and it is claimed to be rapidly bactericidal in vitro against most clinically
`significant Gram-positive pathogens, including drug-resistant strains such as Methicillin-
`resistant staphylococci. Daptomycin is said to be effective against clinical isolates in several
`different animal models ofinfection and the data from Phase II clinical trials also suggested
`that Daptomycin might be effective in treating such infecdon. This Phase III clinical trial
`was designed to compare the safety and efficacy of Daptomycin with that of current
`conventional therapy in the treatment of cSSSI.
`
`The two studies were multicenter, investigator-blinded, randomized, comparative, Phase III
`trials to compare I.V. Daptomyciri (4 mg/kg I.V. QD) with either I.V. Vancomycin (1 g I.V.
`BID) or selected I.V. semi-synthetic Penicillin in the treatment of cSSSI known or suspected
`to be due to Gram-positive bacteria. Study 9801 was conducted primarily in the United
`States and South Africa, and Study 9901 was conducted in non-US sites only. Both studies
`were similar in design, but differed in subject characteristics including history of diabetes and
`peripheral vascular disease.
`
`_.. “ -.—
`
`

`

`NDA Zl-572
`Cubicinm (Daptomycin for Injection)
`
`I
`
`Statistical Review and Evaluation
`Error! Not a valid link.
`
`Adult subjects with a diagnosis of cSSSI who met all of the inclusion criteria and none of the
`exclusion criteria could be enrolled in the study. Baseline evaluations were performed within
`48 hours prior to the first dose of study medication. Eligible subjects who gave informed
`consent were randomized on a 1:1 basis to receive either Daptomycin or comparator
`(Vancomycin or semi-synthetic Penicillins). During the treatment phase, subjCCts were
`monitored daily for treatment—emergent adverse events and concurrent medications. At Day
`3 or 4 of treatment the blinded investigator conducted an on-therapy evaluation. Duration
`of therapy for both regimens was 7 to 14 days as clinically indicated.
`It was anticipated that
`most subjects would receive I.V. study therapy for the duration of their
`treatment.
`However, subjects could be switched to oral therapy if certain conditions were met and the
`medical monitor had given permission.
`Post-treatment visits included an EOT visit
`conducted up to 3 days after the last dose of study drug (or at early termination); a TOC visit
`conducted 7 to 20 days post-treatment; and a Post-Study visit conducted 21 to 28 days post-
`treatment.
`For subjects who received both I.V. study medication and oral
`therapy
`administered per protocol, the last day of oral therapy was defined as the end of treatment.
`The EOT and TOC visits were performed for all subjects. The Post-Study visit was
`performed only for those subjects who were considered cured or improved by the blinded
`investigator at the TOC visit.
`.
`
`The primary objectives were to compare the safety and to demonstrate equivalent efficacy of
`Daptomycin to that of Vancomycin or selecred serni~synthetic Penicillin in the treatment of
`cSSSl.
`
`Efficacy was assessed for clinical response based on evaluations of the clinical signs and
`symptoms of the infection at baseline, during treatment, and in the post-treatment period;
`and for microbiologic response by cultures conducted concurrently. Efficacy analyses were
`conducted on 4 subjecr populations defined as HT, MITI', CE, and ME.
`
`Safety was assessed by monitoring for treatment-emergent adverse events and use of
`concomitant medications, and by assessing changes from baseline in vital signs and clinical
`laboratory test results. All subjects who received at least one dose of study medication were
`included in the safety population.
`
`1.3 STATISTICAL ISSUES AND FINDINGS
`
`The comparisons of statistical interest in this study were conducted between Daptomycin
`and its comparator. The reviewer employed the following methodologies in primary
`statistical analyses of efficacy and safety for two pivotal studies.
`
`The variable in statistical evaluation of efficacy was the success rate of clinical or
`microbiologic outcomes.
`
`

`

`NDA 21-572
`CubicmTM (Daptomycin for Injection)
`
`Statistical Review and Evaluation
`Error! Not a valid link.
`
`_
`
`A two-sided 95% confidence interval was constructed for the difference in proportions of
`clinical or microbiologic outcomes between Daptomycin’s group and its comparator’s group.
`The confidence intervals were computed using a normal approximation to the binomial, and
`included a continuity correction. The evaluation of whether non-inferior in efficacy was
`declared was judged based upon the lower confidence limit for the difference in proportion
`(Daptomycin — its comparator) and the delta value.
`\Y’ith respect to this indication, the delta
`value 0.] is considered a clinically acceptable non~inferiority margin. The assessment of
`clinical response was primarily performed on CE and HT populations, and microbiologic
`response on ME and MTI'T populations. Subgroup analyses by demographic, baseline,
`prognosdc and geographic characteristics were also performed for primary efficacy variables.
`Homogeneity of treatment effect was evaluated by Breslgw-Day’s test.
`
`Safety evaluation was primarily conducted on the following variables: the rates as per at least
`one AE, treatment related. AEs, severeAEs, serious AEs, died, discontinuation'dtie to AE,
`discontinuation due to treatment related AEs. Fisher’s exact test was employed to compare
`the safety variables between the two treatment groups.
`
`this reviewer assessed the comparability of the
`Prior to performing efficacy analyses,
`treatment groups with respect
`to pretreatment characterisrics of randomized subjects.
`Quantitative variables were assessed using the t-test, and qualitative variables were assessed
`using chi-square test.
`
`All tests were two-sided and used a 5% level 'of significance. A 15% level of significance was
`applied to the test of homogeneity.
`
`Study 9801
`
`For CE population, a total of 158/208 (76.0%) Daptomycin subjects were considered
`clinical success, while 158/206 (76.7%) comparator subjects were considered clinical success.
`The efficacy results demonStrated therapeutic non-inferiority of Daptomycin to its
`comparator (-O.7%, 95%CI: -9.4%, 7.9%).
`
`For TIT population, a tom] of 165/264 (62.5%) Daptomycin subjecrs were considered
`clinical success, while 162/266 (60.9%) comparator subjects were considered clinical success.
`The efficacy results demonsrrated therapeutic non-inferiority of Daptomycin to its
`comparator (1.6%, 95% Cl: -7.l%, 10.3%).
`
`Study 9901
`
`For CE population, a total of 214/238 (89.9%) Daptomycin subjects were considered
`clinical success, while 226/250 (90.4%) comparator subjects were considered clinical success.
`The efficacy results demonstrated therapeutic non-inferiority of Daptomycin to its
`comparator (-0.5%, 95%CI: -6.2%, 5.2%).
`
`'For ITT'population, a total of 217/270 (80.4%) Daptomycin subjeCts were considered
`clinical success, while 235/292 (80.5%) comparator subjects were considered clinical success.
`
`_.. A... ...
`__ “u.
`
`

`

`NDA 21-57
`
`CubicinTM (Daptomycin for Injection)
`
`Statistical Review and Evaluation
`
`Error! Not a valid link.
`
`The efficacy results demonstrated therapeutic non-inferiority of Daptomycin to its
`comparator (-0.1%, 95% CI: -7.0%, 6.8%).
`
`It is noteworthy that 'Study 9901 (international study without site in the United States) had
`always better efficacy outcomes than Study 9801 (79.2% in CE subjects and 81.7% in 1T1"
`subjects from the Unites States sites). Divergence in the pretreatment status and baseline
`characteristics of enrolled subjects could cause the differences in efficacy outcome between
`the two studies.
`
`
`
`4.7% (4.47.. 13%)
`
`
`
`1.6% (4.17., 1047.)
`
`
`CE Sub'pcu a! Sludy ”0|
`
`I11 swig“. cl SKI-d" not
`
`
`
`
`4).“. “2-1., 5.2%)
`
`CE Subicm a! Study M)
`
`In Subjmu cf Sludy ’90]
`4.1% (-7.070, ‘17-)
`
`
`.ls-n-DJI-IIJI-OJJAJ‘JJ-lI l
`a It I A? l ‘nnnuuu
`
`Difference in Clinill Succu- Illtt ('/-)
`(Diplomyein - Comp-nun)
`
`__- u _,
`._ “_,
`
`

`

`Statistical Review and Evaluation
`NDA 21-572
`Cubicin‘m (Daptomycin for lniection) Introduction A
`
`
`
`
`
`2 INTRODUCTION
`
`2.] OVERVIEW
`
`The sponsor submits this NDA in order to obtain approval to market Daptomycin for the
`treatment of cSSSI. Two pivotal phase 111 controlled studies were completed and presented
`as evidence to support that Daptomycin was safe and efficacious for the indication when
`compared with its comparator. Statistical review focuses on these comparative clinical trials
`which formed the basis of this application.
`
`Study 9801
`
`Erimary Objectives
`
`The primary objective of this Study was to compare the safety and to demonstrate the
`equivalent efficacy of I.V. Daptomycin to that of I.V. Vancomycin or selected I.V. semi—
`synthetic Penicillin in the treatment of cSSSl due to Gram-positive bacreria.
`
`Study Design
`
`investigator-blinded study of cSSSl known or
`a multicenter, multinational,
`This was
`suspected to be due to Gram-positive bacteria. Subjects were randomized on a 1:1 basis to
`receive Daptomycin 4 mg/ltg QD or a comparator agent (Vancomycin, Nafcillin, Cloxacillin
`or Oxacillin). Baseline evaluations were performed within 48 hours prior to treatment start.
`An On—Therapy evaluation of pertinent clinical signs and symptoms of infection was
`conducted on Study Day 3 or 4. Post treatment \isits included an EOT visit conducred up
`to 3 days after the last dose of Study drug (whether per protocol or due to early termination);
`a TOC visit conducted 7 to 20 days post treatment; and a Post-Study visit conducted 21 to
`28 days pOSt treatment. Subjects previously assessed as clinical failure were not required to
`attend the Post—Study visit.
`
`The study was conducted at 69 Study sites in the United States (64 sites) and South Africa (5
`Sites). It was initiated on March 15, 1999 and completed on August 2, 2001.
`
`Five hundred subjecrs were enrolled into this study to ensure 400 subjects (200 in each
`treatment group) were clinically evaluable. SubjCCIS were stratified by presence or absence of
`a diagnosis ofinfected diabetic ulcer. A total of 547 subjects were randomized into the study
`and 530 received at least one dose of study medication.
`
`Study 9901
`
`Primarv Ob‘ecu’ves
`
`"aw.
`
`_ H.“
`_ h..-
`
`

`

`NDA 21-572
`
`CubicinTM (Daptomycin for Injection)
`
`Statistical Review and Evaluation
`
`Introduction
`
`The primary objectives of this study were to compare the safety and to demonstrate the
`equivalent efficacy of I.V. Daptomycin to that of I.V. Vancomycin or seleaed I.V. serni—
`synthetic Penicillin in the treatment of cSSSI due to Gram-positive bacteria.
`
`Studv Design
`
`investigator-blinded study of cSSSI known or
`international,
`This 'was a multicenter,
`suspected to be due to Gram-positive bacteria. Subjects were randomized on a 1:1 basis to
`receive Daptomycin 4 mg/kg QD or a comparator agent (Vancomycin or semi—synthetic
`Penicillin). Baseline evaluations were performed within 48 hours prior to treatment start.
`An On—Therapy evaluation of pertinent clinical signs and symptoms of infection was
`conducted on Study Day 3 or 4. Post treatment visits included an EOT visit conducted up
`to 3 days after the last dose of study drug (or at early termination); 2 TOC visit conducted 7
`to 20 days post treatment; and a Post-Study visit conducted 21 to 28 days post treatment.
`. SubjeCts prexiously assessed as clinical failure were not required to attend the Post—Study
`visit.
`
`The study was conducted at 67 study sites in Europe (42 sites), South Africa (20 sites), and
`Australia (5 sites). It was initiated on March 17, 2000 and completed on December 28, 2000.
`
`Five hundred subjects were enrolled into this study to ensure 400 subjects (200 in each
`treatment group) were clinically evaluable. Subjects were stratified by presence or absence of
`a diagnosis ofinfected diabetic ulcer. A total of 571 subjects were randomized into the study
`and 562 received at leasr one dose of study medication.
`
`2.2 DATA SOURCES
`
`This submission contains data from two pivoral studies performed by the sponsor, 9801 and
`9901, to support the cSSSI indication. All data files are maintained at specific network path
`location.
`
`The submitted datasets for Studies 9801 and 9901 can be found respectively under:
`33Cdsesub1§N21572§N 00032002—12—193crt3datasets§dapsst9801,
`35Cdsesub1§N21572§N 00032002-12—19Scrtfidatasetsxdapsst9901
`
`All the resubmitted datasets due to correcdon, revision, and modification are listed under:
`33Cdsesub1§N21572§
`
`The two pivoral studies are described in Table 1.
`
`-_-~._-’
`._--_,
`
`

`

`NDA 21-572
`
`CulzzicinTM (Dapzomycin for Injection)
`
`Statistical Review and Evaluation
`
`Introduction
`
`TABLE1”11ST1NG OF CLINICALTRIALS
`7'
`Men and women 18 to 85
`Daptomycin: 4 mg/kg 1.V QD x 7 to
`272 Daptomycin
`years of age,—inclusive, who
`14 days
`275 Comparator
`required hospitalization for Vancomycin: 1 g].\’. BID it 7 to 14
`clinical signs and symptoms
`days
`of cSSSl were specific
`Or selected semi-synthetic penicillins:
`candidates for the study.
`Nafcillin 4 to 12 g I.V. QD in equally
`divided doses x 7 to 14 days
`Cloxacillin 4 to 12 g I.V. QD in
`equally divided dogs at 7 to 14 days
`Oxacillin 4 to 12 g I.V. QD in equally
`divided doses x 7 to 14 davs.
`
`
`
`277 Daptomycin
`294 Comparator
`
`Daptomycin: 4 mg/kg I.V. QD x 7 to
`Men and women 18 to 85
`14 days
`years of age, inclusive, with
`clinical signs and symptoms Vancomycin: 1 g I.V. BID x 7 to 14
`of cSSSI were specific
`days
`candidates for the study.
`Or selected semi—synthetic penicillins:
`Nafcillin 4 to 12 g I.V. QD in equally
`divided doses x 7 to 14 days
`Cloxacillin 4 to 12 g I.V. QD in
`equally divided doses x 7 to 14 days
`Oxacillin 4 to 12 g I.V. QD in equally
`divided doses x 7 to 14 days.
`
`A review by random sample method of at leasr 10% of the CRF stratified by treatment
`group was conducted to validate the sponsor’s efficacy data and to check for agreement with
`im'estigators’ evaluabiliry and outcome assessments. The MO did not concur with some
`efficacy outcomes assessed by the sponsor, and also disagreed with some aspects of
`evaluability evaluated by the sponsor. Please refer to MO’s review for detailed descriptions.
`
`....M.,
`
`

`

`Statistical Review and Evaluau'on
`NDA 21-572
`
`Cubicinm (Daptomycin for Injection) Statistical Evaluation
`
`
`
`3 STATISTICAL EVALUATION
`
`3.1 EVALUATION OF EFFICACY
`
`Study 9801
`
`The statistical objective of this study was to demonstrate the non-inferiority of Daptomycin
`to its comparator in clinical response at TOC.
`
`Efficacy analyses were performed on four subject populations as ITI', MITI' , CE, and ME.
`Subjects were analyzed for efficacy according to randomization, regardless of treatment
`administered.
`Subjects who were randomized but never received any study drug were
`excluded from all efficacy analyses.
`
`The clinical outcome was defined as the basis for the primary efficacy variable. The
`outcomes success (cure, clinical
`improvement),
`failure, and-non—evaluable were based
`primarily on the invescigator’s assessment of clinical response at the TOC evaluation.
`. The
`MO redefined these populations and reclassified efficacy outcomes after checking for
`agreement with investigators’ evaluability and outcome assessments according to the
`protocol. The primary outcome measures under analysis were the clinical success rates at
`TOC for the CE and ITT populations.
`
`The number and the proportion of subjects included in each evaluation group are presented
`in Table 2. A total of 547 subjects were randomized to study treatment; 272 received
`Daptomycin and 275 received comparator as designated by the investigator prior to
`randomization. Seventeen of the 547 randomized subjects discontinued from the study
`prior to receiving any study treatment due to “Other Infection Stratum” or “Diabetic Ulcer
`Stratum”. Among the 530 subjects who received at least one dose of study drug, 264 to the
`Daptomycin arm and 266 to the comparator arm. One subject was randomized to receive
`comparator; but was adminisrered one dose of Daptomycin in error. This subject was
`referred to as misrandornizt:d. In all efficacy analyses, data for this subject were tabulated as
`randomized; in all safety analyses, data for this subject were tabulated as treated. Thirteen
`treated subjects, who were found not to have cSSSI and were designated as “rejected” and-
`excluded from the efficacy analyses by the sponsor, were included by the MO in the ITI‘
`analysis. MO’s CE population included approximately 78% of subjects in both treatment
`groups. The most common reason for exclusion was “CPK > 50% above ULN; require i.m.
`injections; rhabdomyolysis; receiving statins”.
`
`.-""'\
`
`10
`
`

`

`NDA 21-572
`
`CubicinTM (Daptomycin for Injection)
`
`Statistical Review and Evaluation
`Statistical Evaluation
`
`
`
`
`
`
` TABLE 2: STUDY 9801: NUMBER OF SUBJECTS INCLUDED IN EACH
`EVALUATION GROUP
`
`
`Exaluation——_Group _umberSub—ensof
`Da-tom\cin Corn.arator
`272
`275
`265
`265
`
`AllRandomizedSubjects
`Safetx (as treated)
`MO’s ITT Subjects
`
`Sponsor’s ITT Subjects
`MO’s MITT SUbjCCtS
`
`Sponsor’s MI'IT Subjects
`MO’sCE Subjects
`
`| Sponsor’s CE Subjects
`MO’s ME Subjects
`Sponsor’s ME Subjects
`
`.
`
`
`
`
`264 (100%)
`266 (100%)
`256 (97.0%)
`261 (98.1%)
`
`
`215 (81. 4%)
`216 (81.2%)
`
`
`209(7.92%)
`212 (79.7%)
`
`
`208‘(78. 8%)
`206 (77.4%)
`
`
`223 (84. 5%)
`222 (83.5%)
`
`
`174 (65.9%)
`176 (66.2%)
`
`
`187 (70.8%
`
`189 (71.1%
`
`Data for baseline demographics and disease characteristics are described for MO’s ITT
`subjects in Tables 3 and 4. The two treatment groups were comparable and no statistically
`significant differences were detected with regard to these characterisdcs.
`
`TABLE 3: STUDY 980]: BASELINE DEMOGRAPHICS IN ITT SUBJECTS BY
`MO
`r‘_-—.'_
`
`j
`
`Vanables
`
`Daptomycin
`I =264
`
`Comparator
`‘=266
`
`'
`
`0.5366
`
`Age Q'rs.)
`Range (Min, Max)
`Mean i SD
`Distribution
`
`< 65 years
`2 65 vears
`
`Weight (kg)
`Range (Min, Max)
`Mean i SD
`
`(1 8,. 91)
`55.2 i 17.6
`
`(18, 94)
`55.5 i 17.7 '
`
`173 (65.5%)
`91 (34.5%)
`
`183 (68.8%)
`83 (31.2%)
`
`143 (54.2%)
`121 45.8%
`
`177 (67.1%)
`50 (18.9%)
`37 (14.0%
`
`148 (55.6%)
`118 (44.4%
`
`167 (62.8%)
`60 (22.6%)
`39 (14.7%
`
`(36, 274)
`87.6 i 33.5
`
`(44, 193)
`87.0 i 27.7
`
`0.7334
`
`‘ B\' t test. All others in the table, b\' chi-s-uare test.
`
`..->\‘
`
`._ “a
`
`ll
`
`

`

`-
`
`12
`
`NDA 21-572 '
`
`Cubicln‘"M (Daptomycin for Injection)
`
`Statistical Review and Evaluation
`
`Statistical Evaluation
`
`TABLE 4: STUDY 9801: BASELINE DISEASE CHARACTERISTICS IN ITT
`
`SUBIECTS BY MO
`Daptomycin
`Comparator -
`
`
`
`\V'ound Infecuon
`116 (43.6%)
`99 (37.5%)
`3 Major Abscess
`43 (16.2%)
`55 (20.8%)
`
`; Infected Diabetic Ulcer
`41 (15.4%)
`38 (14.4%)
`
`
`
`{ Infected Ulcer (non-diabetic)
`33 (12.5%)
`34 (12.8%)
`
`
`
`3 Other Infection
`' Bv chi-s - uare test.
`
`
`1
`
`l
`
`Parameters
`
`.
`
`(N =264)
`
`(N =266
`
`0.4591
`
`The primary analyses are presented in Tables 5, 6, 7, and 8 for the clinical responses of CE
`and II I subjects as per MO’s and sponsor’s at the TOC visit, respectively. The confidence
`interval results demonstrated Daptomycin was non-inferior to its comparator with respect to
`clinical success rates at TOC.
`
`l
`'
`
`l
`|
`
`._
`
`{i
`
`TABLE 5: STUDY 9801: CLINICAL RESPONSES OF CE
`SUBlECTS AT TOC VISIT BY MO
`
`Clinical Response
`
`Daptomycin
`(N2208
`
`Comparator
`1:206
`
`Clinical Success
`158 (76.7%)
`158 (76.0%)
`Clinical Failure
`48 23.3%
`50 24.0%
` Difference in Success Rate
`
`Da utomvcin vs. Com carator:
`-0.7%, 95% c1: 94%, 7.9%
`
`
`
` TABLE 6: STUDY 9801: CLINICAL RESPONSES OF CE
`
`SUBIECTS AT TOC VISIT BY SPONSOR
`
`
`
`:
`Clinical Response
`'
`
`
`(N=223
`
`Comparator
`(N=222
`
`
`l
`
`
`Clinical Success
`166 (74.8%)
`Clinical Failure
`56 25.1%
`56 25.2%
`: Difference in Success Rate
`.— 0.1%, 95% C.I.: 84%, 8.6%
`
`
`
`
`1
`!
`!
`
`_j
`
`

`

`NDA 21-572
`CuliicinTM (Daptomycin for Injection)
`
`_
`
`-
`
`Statisu'cal Review and Evaluation
`Sratisn'cal Evaluation
`
`TABLE 7: STUDY 9801: CLINICAL RESPONSES OF I'I'I‘ SUBIECTS AT TOC VISIT BY MO
`
`Clinical Response
`
`
`
`Clinical Suc'cess
`Clinical Failure
`Difference in Success Rate
`
`Da tomvcin vs. Com -arator:
`
`Daptomycin
`(N =264)
`
`165 (62.5%)
`99 (37.5%)
`
`Comparator
`‘ =266)
`
`162 (60.9%)
`104 39.1%
`
`1.6%, 95% C.I.: -7.1%, 10.3%
`
`TABLE 8: STUDY 9801: CLINICAL RESPONSES OF ITT
`
`SUBIECTS AT TOC VISIT BY SPONSOR
`
`Daptomycin
`(N =256)
`
`-
`
`Comparator
`(N=261)
`
`|
`
`1
`
`E
`
`i
`i
`
`—-_
`Clinical Failure
`89 (34.8%
`95 36.4%
`I
`Difference in Success Rate
`‘
`
`1.6%, 95% C.I.: -7.0%, 10.3%Da-tomvcin vs. Com narator: ’
`
`
`
`The secondary analyses are presented in Tables 9, 10, 11, and 12 for the clinical responses of
`ME and MITT subjects as per MO’s and sponsor’s at the TOC visit, respectively. The
`confidence interval
`results
`showed Daptomycin was
`therapeutically non-inferior or
`marginally non-inferior to its comparator with respect to clinical success rates at TOC.
`
`TABLE 9: STUDY 9801: CLINICAL RESPONSES OF ME
`
`
`
`
` Clinical Respbnse
`
`SUBIECTS AT TOC VISIT BY MO
`
`
`Clinical Success
`
`
`Clinical Failure
`
`
`Difference in Success Rate
`
`
`Da tomvcin vs. Com uarator:
`-1 .4%, 95% C.I.: -10.8%, 8.0%
`
`
`
`Daptomycin
`1:174
`
`133 (76.4%)
`41 23.6%
`
`Comparator
`‘=176
`
`137 (77.8%)
`39 22.2%
`
`i
`4
`
`a
`
`
`
`
`
`._ u”,
`._-._.r
`
`13
`
`

`

`NDA 21 -572
`Cubicinm (Dapromycin for Injection)
`
`Statistical Review and Evaluation
`Statistical Evaluation
`
`
`
`
`TAB__L___E10: STUDY 9801: CLINICAL RESPONSES OF ME
`SUBIECTS AT TOC VISIT BY SPONSOR
`
`Comparator
`
`(N=189)
`
`
`142 (75.1%)
`47 24.9%
`
`
`
`Daptomxcin
`1=18
`
`140 (74.9%)
`47 (25.1%
`
`-0.3°/o, 950/0 C. I.: -9 6°/o, 9.00/0
`
`Clinical Response
`,
`
`Clinical Success
`Clinical Failure
`
`
`' Difference in Success Rate
`
`
`Da-tomvcin vs.