CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Administrative Documents
`
`

`

`
`
`“:3 __-.-_- __..__.___._ _ _
`
`
`
`Patent No.
`
`Expiration Date
`
`Type of Patent
`
`Patent Owner
`
`5,912,226
`
`June 15, 2016
`
`Drug Product
`
`Eli Lilly and Company
`
`6,468,967
`
`September 24, 2019
`
`Method of Use
`
`Cubist Pharmaceuticals, Inc.
`
`65 Hayden Avenue. Lexington. MA 02421
`
`P 781.860.8660
`
`F 781.861.0566 ww w.:ubist.<om
`
`1of3
`
`

`

`
`
`DECLARATION OF TIMOTHY J. DOURos, ESQ.
`
`The undersigned declares that US. Patent No. 5,912,226 covers the formulation,
`composition, and/or method of use of daptomycin.
`.Daptomycin is the subject of this
`
`application no. 21 572 for which approval is being sought.
`
`
`
`uros
`Timothy J.‘
`Chief Intellectual Property'Counsel
`Cubist Pharmaceuticals, Inc.
`
`I;
`
`20133
`
`
`
`65 Hayden Avenue. Lexington MA 02421
`
`P 781.860.8660
`
`F 781.861.0566 ww w.c ubistxom
`
`

`

`
`
`DECLARATION or TIMOTHY J. DOURos, Esg.
`
`The undersigned declares that US. Patent No. 6,468,967 covers the formulation,
`
`composition, and/or method of use of daptomycin. Daptomycin is the subject of this
`
`application no. 21 572 for which approval is being sought.
`
`
`
`Chief Intellectua Property Counsel
`Cubist Pharmaceuticals, Inc.
`
`”m
`
`3of3
`
`
`
`65 Hayden Avenue. Lexington. MA 02421
`
`P 78l.860.8660
`
`F 781.861.0566 w ww.cubist.com
`
`

`

`EXCLUSIVITY SUMMARY for NDA #:
`
`21-572
`
`SUPPL #: N/A
`
`Trade Name:
`
`injection
`Applicant Name: Cubist Pharmaceuticals, Inc.
`
`Cubicin'm
`
`Generic Name: Daptomycin for
`
`Division: HFD- 520
`A proval Date: September 12, 2003
`
`PART I:
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1.An exclusivity determination will be made for all original
`applications, but only for certain supplements. Complete
`Parts II and III of this Exclusivity Summary only if you
`answer "YES" to one or more of the following questions about
`the submission.
`
`a) Is it an original NDA?
`
`YES/_X__/
`
`NO /
`
`/
`
`b) Is it an effectiveness supplement? YES /
`
`/
`
`NO /_X__/
`
`If yes, what
`
`type(SEl, SE2, etc.)?
`
`c) Did it require the review of clinical data other than to
`.support a safety claim or change in labeling related to
`safety?
`(If it required review_only of bioavailability
`or bioequivalence data, answer "NO.")
`
`YES /_x__/
`
`NO /
`
`/
`
`If your answer is "no" because you believe the study is a
`bioavailability study and,
`therefore, not eligible for
`exclusivity, EXPLAIN why it is a bioavailability study,
`including your reasons for disagreeing with any arguments
`made by the applicant that the study was not simply a
`'bioavailability study.
`
`
`
`
`
`If it is a supplement requiring the review of clinical
`data but it is not an effectiveness supplement, describe
`the change or claim that is supported by the clinical
`data:
`
`

`

`d) Did the applicant request exclusivity?
`
`YES /
`
`/ NO /_X__/
`
`is "yes," how many years of
`If the answer to (d)
`exclusivity did the applicant request?
`
`
`
`
`
`e)Has pediatric-exclusivity beem.granted for this Activ
`Moiety?
`'
`
`YES /_/
`
`NO /_x__/
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`2. Has a product with the same active ingredient(s), dosage form,
`strength,
`route of administration, and dosing schedule
`previously been approved by FDA for the Same use? (Rx to OTC)
`Switches should be answered No — Please indicate as such).
`
`If yes, NDA #
`
`Drug Name
`
`YES /_/
`
`NO /__x_/
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9.
`
`3.15 this drug product or indication a DESI upgrade?
`
`was /_/
`
`NO /_x_/
`
`IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9
`
`(even if a study was required for the
`
`upgrade).
`
`Page 2
`
`

`

`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW.CHEMICAL ENTITIES
`
`(Answer either #1 or #2, as appropriate)
`
`1 i
`
`.§in le active in redient
`
`roduct.
`
`Has FDA previously approved under section 505 of the Act any
`drug product containing the same active moiety as the drug
`under consideration? Answer "yes" if the active moiety
`(including other esterified forms, salts, complexes, chelates
`or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g.,
`this particular
`ester or salt
`(including salts with hydrogen or coordination
`bonding) or other non-covalent derivative (such as a complex,
`chelate, or clathrate) has not been approved.
`'Answer "no" if
`the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug)
`to produce
`an already approved active moiety.
`
`YES /
`
`/ NO /_X__/
`
`If "yes," identify the approved drug product(s) containing the
`active moiety, and, if known,
`the NDA #(s).
`
`NDA #
`
`NDA #
`
`NDA #
`
`2.Combination product.
`
`If the product contains more than one active moiety (as
`defined in Part II, #1), has FDA previously approved an
`application under section 505 containing __y one of the active
`moieties in the drug product?
`If, for example,
`the
`.combination contains one never-before-approved active moiety
`and one previously approved active moiety, answer "yes."
`(An
`active moiety that is marketed under an OTC monograph, but
`that was never approved under an NDA,
`is considered not
`previously approved.)
`
`YES /
`
`/
`
`NO /_X__/
`
`g;
`
`Page 3
`
`

`

`If "yes," identify the approved drug product(s) containing the
`active moiety, and,
`if known,
`the NDA #(s).
`
`NDA #
`
`NDA #
`
`NDA #
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO
`
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`.
`III.
`
`IF "YES," GO TO PART
`
`PART III: THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or
`supplement must contain "reports of new clinical investigations
`(other than bioavailability studies) essential to the approval of
`the application and conducted or sponsored by the applicant."
`This section should be completed only if the answer to PART II,
`Question 1 or 2, was "yes."
`'
`
`1. Does the application contain reports of clinical
`investigations?
`(The Agency interprets "clinical
`investigations" to mean investigations conducted on humans
`other than bioavailability studies.)
`If the application
`contains clinical investigations only by Virtue of a right of
`reference to clinical investigations in another application,
`answer "yes," then skip to question 3(a).
`If the answer to
`3(a)
`is "yes" for any investigation referred to in another
`application, do not complete remainder-of summary for that
`investigation.
`
`YES
`
`/
`
`/
`
`No /
`
`/
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`2. A clinical investigation is "essential to the approval" if the
`Agency could not have approved the application or supplement
`without relying on that investigation. Thus,
`the
`investigation is not essential to the approval if 1) no
`clinical investigation is necessary to support the supplement
`or application in light of previously approved applications
`(i.e.,
`information other than clinical trials, such as
`bioavailability data, would be sufficient to provide a basis
`- “._.
`
`Page 4
`
`

`

`for approval as an ANDA or 505(b)(2) application because of
`what is already known about a previously approved product), or
`2)
`there are published reports of studies (other than those
`conducted or sponsored by the applicant) or other publicly
`available data that independently would have been sufficient
`to support approval of the application, without reference to
`the clinical investigation submitted in the application.
`
`For the purposes of this section, studies comparing two
`products with the same ingredient(s) are considered to be
`bioavailability studies.
`
`(a)
`
`is a
`In light of previously approved applications,
`clinical investigation (either conducted by the
`applicant or available from some other source,
`including the published literature) necessary to
`support approval of the application or supplement?
`
`YES /_/
`
`NO /
`
`/
`
`If "no," state the basis for your conclusion that a
`clinical trial is not necessary for approval AND GO
`DIRECTLY TO SIGNATURE BLOCK ON Page 9:
`
`(b) Did the applicant submit a list of published studies
`relevant to the safety and effectiveness of this drug
`product and a statement that the publicly available
`data would not
`independently support approval of the
`application?
`
`YES /__/
`
`NO /
`
`/
`
`(1)
`
`is "yes," do you personally
`If the answer to 2(b)
`know of any reason to disagree with the applicant's
`conclusion?
`If not applicable, answer NO.
`
`YES /__/
`
`NO /___/
`
`If yes, explain:
`
`
`Page 5
`
`

`

`is "no," are you aware of
`If the answer to 2(b)
`(2)
`published studies not conducted or sponsored by the
`applicant or other publicly available data that
`could
`independently demonstrate the safety and effectiveness
`of this drug product?
`'-
`
`YES /__/
`
`NO /
`
`/
`
`If yes, explain:
`
`(c)
`
`If the answers to (b)(l) and (b)(2) were both "no,"
`
`identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`Investigation #1, Study #
`
`Investigation #2, Study #
`
`Investigation #3, Study #
`
`investigations must be "new
`3.In addition to being essential,
`to support exclusivity.
`The agency interprets "new clinical
`investigation" to mean an investigation that 1) has not been
`relied on by the agency to demonstrate the effectiveness of a
`previously approved drug for any indication and 2) does not
`duplicate the results of another investigation that Was relied
`on by the agency to demonstrate the effectiveness of a
`previously approved drug product, i.e., does not redemonstrate
`something the agency considers to have been demonstrated in an
`already approved application.
`
`I!
`
`(a)
`
`For each investigation identified as "essential to the
`approval," has the investigation been relied on by the
`agency to demonstrate the effectiveness of a previously
`approved drug product?
`(If the investigation was relied
`on only to support the safety of a previously approved
`drug, answer "no.")
`
`Investigation #1
`
`.
`
`Investigation #2
`
`Investigation #3
`
`YES /
`
`YES /
`
`YES /
`
`/
`
`/
`
`/
`
`NO /
`
`NO /
`
`NO /
`
`/
`
`/
`
`/
`
`“on“
`
`If you have answered "yes" for one or more
`investigations,
`identify each such investigation and the
`‘NDA in which each was relied upon:
`__ “v
`
`Page 6
`
`

`

`NDA #
`NDA #
`NDA #
`
`Study #
`Study #
`Study #
`
`(b)
`
`For each investigation identified as "essential to the
`approval,” does the investigation duplicate the results
`of another investigation that was relied on by the agency
`to support
`the effectiveness of a previously approved
`drug product?
`
`Investigation #1
`
`Investigation #2
`
`YES /
`
`YES /
`
`/
`
`/
`
`NO /
`
`NO /
`
`Investigation #3
`
`YES /
`
`./
`
`NO /
`
`/
`
`/
`
`/
`
`If you have answered "yes" for one or more
`investigations,
`identify the NDA in which a similar
`investigation was relied on:
`
`NBA #
`
`NDA #
`
`NDA #
`
`'
`
`Study #
`
`Study #
`
`Study #
`
`(c)
`
`identify each
`If the answers to 3(a) and 3(b) are no,
`"new" investigation in the application or supplement that
`is essential to the approval (i.e.,
`the investigations
`listed in #2(c),
`less any that are not "new"):
`
`Investigation #_;, Study #
`
`Investigation #__, Study #
`
`Investigation #__, Study #
`
`a new investigation that is
`. To be eligible for exclusivity,
`essential to approval must also have been conducted or
`sponsored by the applicant.
`An investigation was "conducted
`.or sponsored by" the applicant if, before or during the
`conduct of the investigation, 1)
`the applicant was the sponsor
`of the IND named in the form FDA 1571 filed with the Agency,
`or 2)
`the applicant
`(or its predecessor in interest) provided
`substantial support for the study. Ordinarily, substantial
`support will mean providing 50 percent or more of the cost of
`the study.
`
`Page 7
`
`

`

`(a)
`
`For each investigation identified in response to
`question 3(c): if the investigation was carried out
`under an IND, was the applicant identified on the FDA
`1571 as the sponsor?
`
`Investigatibn #1
`
`IND #
`
`YES
`
`/
`
`/
`
`NO /
`
`/ Explain:
`
`Investigation #2
`
`IND #
`
`YES /
`
`‘/
`
`NO /
`
`/ Explain:
`
`(b)
`
`For each investigation not carried out under an IND or
`for which the applicant was not identified as the
`sponsor, did the applicant certify that it or the
`applicant's predecessor in interest provided
`substantial support for the study?
`
`Investigation #1
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`Investigation #2
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`22“;
`
`Page 8
`
`

`

`(b), are
`Notwithstanding an answer of "yes" to (a) or
`there other reasons to believe that the applicant
`should not be credited with having "conducted or
`sponsored" the study?
`(Purchased studies may not be
`used as the basis for exclusivity. However, if all
`rights to the drug are purchased (not just studies on
`the drug),
`the applicant may be considered to have
`sponsored or conducted the studies sponsored or
`conducted by its predecessor in interest.)
`
`If yes, explain: ““—
`
`YES /_/
`
`NO /
`
`/
`
`LT Raguel Peat, MS, MPH
`Signature of Preparer
`Title: Regulatory Health Project Manager
`
`October 8, 2003
`Date
`
`
`Janice Soreth, M.D.
`Signature of Division Director
`
`October 9, 2003
`Date
`
`cc:
`
`Archival NDA
`
`HFD- 520 /Division File
`HFD- Peat
`/RPM
`
`HFD-6lO/Mary Ann Holovac
`HFD—lO4/PEDS/T.Crescenzi
`
`Form OGD-011347
`
`Revised 8/7/95; edited 8/8/95; revised 8/25/98, edited 3/6/00
`
`Page 9
`
`

`

`
`
`DEBARMENT CERTIFICATION
`
`Cubist Pharmaceuticals, Inc. hereby certifies that it did not\ and will not use in any
`capacity the services of any person debarred under Section 306 of the Federal Food,
`Drug, and Cosmetic Act in connection with this application.
`
`
` MKIIIICI \\'. BunncyiPrcsident and
`
`r
`
`/
`
`
`
`65 Hayden Avenue. Lexington. MA 02421
`
`P 781.860.8660
`
`F 781.861.0566
`
`v- .. .- z «.- :-x'.'
`
`r c. r:
`
`

`

`NDA 21-572
`
`Office/Division Director Memo for Cubicin (daptomycin for injection)
`
`Indication: Complicated Skin and Soft Tissue Infections
`
`September 11, 2003
`
`The pre-clinical and clinical reviewers have done an excellent job of detailing the issues
`in their disciplines and in the safety and efficacy of this product. There is clearly a need
`for additional products to treat severe infections due to Gram-positive organisms
`including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
`enterococcal (VRE) infections. This submission addresses some but not all ofthese issues
`and needs.
`l will only very briefly mention preclinical findings, efficacy and safety, and
`then identify what I see as currently unresolved issues.
`
`Preclinical:
`
`The major target organs of daptomycin toxicity toxicity in rat, dog, and monkey were
`muscle and peripheral nerves. Muscle damage consisted of muscle degeneration/
`regeneration and usually resolved within 1 month of cessation oftreatment. Muscle
`changes were sometimes accompanied by increases in creatine phosphokinase (CPK).
`Peripheral nerve damage occurred at higher doses and included loss of patellar/gag
`reflexes, loss ofpain perception, decreases in nerve conduction velocity, and axonal
`degeneration. The dosing interval (quh v. q24h) appeared to play a role in the
`development of muscle toxicity in animals, favoring q24h.
`
`Efficacy:
`
`Two multicenter, multinational, randomized, active control studies were conducted by
`Cubist in hospitalized patients with serious skin infections, with over 500 patients
`receiving daptomycin.
`I agree with the overall conclusions as stated in the Medical
`Officer Reviews. In these two adequate and well-controlled trials in complicated skin
`and skin structure infections (cSSSI), daptomycin performed in a similar fashion to
`appropriate controls. Infections included major abscesses, post-surgical wound
`
`infections, and infected ulcers. The data were insufficient to demonstrate efficacy in
`Analyses of various subgroups based upon age, sex, underlying
`disease and severity ofinfection did not show any convincing trend favoring either
`daptomycin or control. Analyses looking at efficacy based upon infecting organism also
`showed comparability across the relevant organisms. Sufficient data exist to support
`clinical efficacy for cSSSI due streptococci of Groups A, B, and C. While a breakpoint
`of 0.5 uyml. can be justified by strict application ofa Mngo plus one rule, a l ug/mL
`breakpoint can be supported by the MIC distribution data, a lack of resistance, and
`clinical efficacy data. Sufficient data exist to include MRSA with the indication of
`cSSSI. Not surprisingly, however, there were insufficient numbers of VRE to include
`.. “q—~.--
`
`

`

`this organism with the indication. There were sufficient data to include vancomycin-
`susceptible Enrerococcusfaecalis.
`
`Safety:
`
`I agree with the
`Clinical data for over 1400 patients given daptomycin were evaluated.
`overall conclusions as stated in the reviews and as described in product labeling. The
`overall safety profile ofthis product is similar to that ofthe control regimens. Skeletal
`muscle appears to be a target organ for toxicity as demonstrated in pre-clinical studies as
`well as in the clinical trials, and this is likely to be a problem that will require on-going
`assessment and potential re-evaluation in the post-mfrketing period. The manifestations
`ofthis are both laboratory and clinical. The overall difference in frequency of CPK
`elevations is not great between daptomycin and control, but higher-grade elevations are
`slightly more common on daptomycin. There have been several cases with clinical
`symptoms including one with myositis that resolved after therapy was discontinued. At
`present, there is no information regarding risk factors such as age or baseline CPK that
`might predispose to this toxicity. Since the overall number of patients that have been '
`exposed to daptomycin is in the 1000+ range, it is likely that the frequency and severity
`ofthis toxicity and potential antecedent factors will not be better defined until actual use
`in practice, in conjunction with post marketing studies in vivo and in vitro.
`
`Both pre-clinical and some early clinical trial data suggest that peripheral neuropathy
`may be an adverse event associated with daptomycin use. The pre-clinical information
`suggested that higher exposures were necessary for this toxicity to be expressed and the
`Phase 3 clinical trials did not show clear—cut evidence ofthis toxicity. These latter studies
`were conducted in a patient population with underlying diabetes and/or significant limb
`infection that could make such assessment difficult. Again post-marketing information
`may better define the significance ofthis toxicity.
`
`To date, neither liver nor cardiac electrophysiologic (Q-T prolongation) toxicity appears
`to be an issue. There was no excess of transaminase increases or alkaline phosphatase
`elevations in daptomycin-treated patients.
`
`Unresolved Issues:
`
`There is a continued need for new products to treat serious Gram positive infections, and
`daptomycin, with its unique mechanism of action and its spectrum of activity, would
`appear to be an important new product in the therapeutic armamentan'um. Tempering this
`enthusiasm are the results of studies conducted in other serious conditions beyond the
`current indication. In a pilot study of patients with either Staphylococcus aureus
`bacteremia or actual endocarditis conducted by Lilly, the original developer of this
`product, unexpectedly lower efficacy for daptomycin was seen. It would appear that
`lower peak levels in the BID dosing regimen used in this trial and possibly insufficient
`penetration into vegetations with the may have contributed to this finding. In a
`Community Acquired Pneumonia trial conducted by Cubist daptomycin performed also
`performed less well than would have been expected. It is believed that reduced
`.__-~_.,
`
`

`

`penetration into the lung was a factor in these results. The pneumonia data was
`sufficiently convincing that a statement appears in the Indications and Usage section of
`the product label that daptomycin is not indicated for community acquired pneumonia.
`
`Additional study ofdaptomycin in serious illness is clearly necessary. A small study of
`right sided bacterial endocarditis using the to be approved 4 mg/kg OD regimen is
`currently underway. Results of this study are to be monitored after the first thirty patients
`are enrolled. Ideally it would also be appropriate to evaluate the usefulness ofthis
`- product in serious enterococcal infections. The company does not currently have such a
`trial underway and the possibility of doing this should be the subject of further
`discussion.
`
`Finally, the optimal dose for patients with renal insufficiency needs to be determined.
`Dose adjustment for patients with CrCL of: SOmL/min, including patients on dialysis
`(hemodialysis and CAPD), needs to be determined in a Phase 4 study. Cubist has agreed
`to perform such a study. In the meantime, the basis for current dosing recommendations
`rests upon the clinical efficacy and safety data in patients with normal renal function
`combined with limited data in subjects and patients with renal impairment.
`
`._- M .,
`__ _.,
`
`

`

`This is a representation Of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Janice Soreth
`9/12/03 05:24:25 PM
`MEDICAL OFFICER
`
`Office/Division Director Memo
`Ready for sign—off
`
`Mark Goldberger
`9/12/03 05:26:12 PM
`MEDICAL OFFICER
`
`

`

`NDA REGULATORY FILING REVIEW
`
`(Includes Filing Meeting Minutes)
`
`NDA Number, Requested Trade Name, Generic Name and Strengths (modify as needed for an efficacy
`supplement and include type): NDA 21-572, Cidecin® (daptomycin for injection), 4mg/‘kg.
`
`Applicant: Cubist Pharmaceuticals
`
`Date of Application: December 19, 2002
`Date of Receipt: December 20, 2002
`Date of Filing Meeting: February 13, 2003
`Filing Date: February 18, 2003
`
`Indication(s) requested: complicated Skin and Skin Structure Infections (cSSSI) including those complicating
`diabetic foot and decubitus ulcers caused by susceptible strains of the following Gram-positive
`microorganisms: Staphylococcus aureus (including methicillin-tesistant strains), Streptococcus pyogenes,
`Streptococcus agaiactiae, Streptococcus dysgalacn‘ae subsp. equisimilis, Enterococcusfaecilis (vancomycin-
`susceptible strains only)
`-—-—
`
`Type of Application:
`
`Full NDA
`Supplement
`X
`
`(b)(l) ___.X
`(b)(Z) ._.
`[If the Original NDA of the supplement was a (b)(2), all subsequent supplements are
`(b)(2)s; if the Original NDA was a (b)(l), the supplement can be either a (b)(l) or
`(b)(2)l
`
`If you believe the application is a 505(b)(2) application, see the 505(b)(2) requirements at the end of this
`summary.
`
`P_X
`Therapeutic Classification: S_
`Resubmission after a withdrawal or refuse to file __N/A__
`Chemical Classification: (1,2,3 etc‘.)_1___.
`Other (orphan, OTC, etc.) N/A_
`
`
`
`Has orphan drug exclusivity been granted to another drug for the same indication?
`
`YES NO I/
`
`If yes, is the drug considered to be the same drug according to the orphan drug definition of sameness
`[2] CFR 316.3(b)(13)]?
`
`YES NOV
`
`If the application is affected by the application integrity policy (AIP), explain.
`
`
`User Fee Status: PAID (December 23, 2002) Waived (e.g., small business, public health) _no
`
`Exempt (orphan, government) _no
`-
`Form 3397 (User Fee Cover Sheet) submitted: YES_X
`User Fee D#
`4484
`
`NO
`
`Clinical data? YES ____X
`Date clock started after UN
`
`NO
`
`Referenced to NDA# _N/A
`
`User Fee Goal date:
`
`_June 20, 2003
`
`Action Goal Date (optional) _June 20, 2003
`
`0 Does the submission containy accurate comprehensive index?
`
`YESV
`
`NO
`
`

`

`Form 356h included with authorized signature?
`If foreign applicant, the US. Agent must countersign.
`
`-
`
`NDA 21-572
`
`NDA Regulatory Filing Review
`Page 2
`
`-
`
`YESV
`
`NO
`
`Submission complete as required under 21 CFR 314.50?
`Ifno, explain:
`'
`
`YES!
`
`NO
`
`0
`
`0
`
`0
`
`If electronic NDA, does it follow the Guidance?
`
`YESV
`
`NO
`
`If an electronic NDA: all certifications must be in paper and require a signature.
`
`If Common Technical Document, does it follow the guidaice?
`
`YES
`
`NO NA/
`
`Patent information included with authorized signature?
`
`YESV
`
`NO
`
`0
`
`0
`
`NOV
`years
`YES; If yes,
`'
`Exclusivity requested?
`0
`Note: An applicant can receive exclusivity without requesting it, therefore, requesting exclusivity is not a
`requirement.
`
`0 Correctly worded Debarrnent Certification included with authorized signature?
`If foreign applicant, the US. Agent must countersign.
`
`YESV
`
`NO
`
`Debannent Certification must have correct wording, e.g.: “I, the undersigned, hereby certify that
`Co. did not and will not use in any capacity the services of any person debarred under
`section 306 of the Federal Food, Drug and Cosmetic Act in connection with the studies listed in Appendix
`__.” Applicant may not use wording such as, “ To the best of my knowledge, ....”
`
`Financial Disclosure included with authorized signature?
`(Forms 3454 and/or 3455)
`If foreign applicant, the US. Agent must countersign.
`
`YESV
`
`NO
`
`Has the applicant complied with the Pediatric Rule for all ages and indications?
`If no, for what ages and/or indications was a waiver and/or deferral requested:
`
`YES
`
`NO NAV
`
`Field Copy Certification (that it is a true copy of the
`CMC technical section)?
`
`YESV
`
`NO
`
`Refer to 2] CFR 314.101(d) for Filing Requirements
`
`NO
`YESV
`PDUFA and Action Goal dates correct in COMJS?
`If not, have the document room staff correct them immediately. These are the dates EES uses for calculating
`inspection dates.
`
`Drug name/Applicant name correct in COMIS? Ifnot, have the Document Room make the corrections.
`
`List referenced IND numbers: IND 57,693 and IND 27,627
`
`'
`End-of-l’hase 2 Meeting?
`If yes, distribute minutes before filing meeting.
`
`'
`
`Date: May 9, 2000
`
`g. .,
`Pre-NDA Meeting(s)?
`If yes, distribute minutes before filing meeting.
`
`Date(s) November 9, 200l and December 3, 200]
`
`Version: 3/27/2002
`
`

`

`NDA 21-572
`NDA Regulatory Filing Review
`Page 3
`
`Project Management
`
`Copy of the labeling (PI) sent to DDMAC?
`
`YESV
`
`NO
`
`Trade name (include labeling and labels) consulted to ODS/Div. of Medication Errors and Technical Support?
`YESV
`,NO NA
`
`MedGuide and/or PPl consulted to ODS/Div. of Surveillance, Research and Communication Support?
`YES NO
`NAM
`
`OTC label "comprehension studies, Pl & PPI consulted to ODS/ Div. of Surveillance, Research and
`Cominunication Support?
`YES
`NO NAV
`
`Advisory Committee Meeting needed?
`
`_
`
`YES, date if known
`
`NOV
`
`
`Clinical
`
`o
`
`If a controlled substance, has a consult been sentlto the Controlled Substance Staff?
`YES
`
`NOV
`
`Chemistrv
`
`0 Did sponsor request categorical exclusion for environmental assessment?
`If no, did sponsor submit a complete environmental assessment?
`If EA submitted, consulted to Nancy Sager (HFD-357)?
`
`0
`
`0
`
`Establishment Evaluation Request (EER) package submitted?
`
`Parenteral Applications Consulted to Sterile Products (HEB-805)?
`
`YES“
`YES
`YES
`
`YESV
`
`YESV
`
`NO-
`NO
`NO
`
`NO
`
`NO
`
`If 505(b)(2), complete the following: N/A
`
`Describe the change from the listed drug(s) provided for in this (b)(2) application (for example, ”This
`application provides for a new indication, otitis media” or “This application provides for a change in dosage
`form, from capsules to solution”).
`
`Name of listed drug(s) and NDA/ANDA #:N/A
`
`is the application for a duplicate of a listed drug and eligible for approval under section 5050)?
`(Normally, FDA will refuse-to—file such applications.)
`
`YES
`
`NO NAV
`
`Is the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action less
`than that of the reference listed drug (RLD)?
`If yes, the application must be TCfiJSCd for filing under 314.54(b)(l)
`
`NO NAI/
`
`YES
`
`Is the rate at which the product’s active ingredient(s) is absorbed or otherwise made available to the site of
`action unintentionally less than that of the RLD?
`
`YES
`
`NO NAV
`
`If yes, the application must beieiiilsed for filing under 314.54(b)(2)
`
`Version: 3/27/2002
`
`

`

`NDA 2l-572
`
`NDA Regulatory Filing Review
`Page 4
`
`Which of the following patent ceru'fications does the application contain? Note that a patent certification must
`contain an authorized signature.
`
`2] CFR 3]4.50(i)(l)(i)(A)(l): The patent information has not been submitted to FDA.
`
`2] CFR 314.50(i)(l)(i)(A)(2): The patent has expired.
`
`_X_ 21 CFR 314.50(i)(l)(i)(A)(3): The date on which the patent will expire.
`
`2} CFR 314.50(i)(])(i)(A)(4): The patent is invalid, unenforceable, or will not be infi'inged by
`the manufacture, use, or sale of the drug product for which the application is submitted.
`
`Iffiled, and Ifthe applicant made 0 '“Paragraph IV " certification [2] CFR
`314.500) (l)(t)(A)(4)], the applicant must submit a signed certification that the patent holder
`was notified the NDA wasfiled [2] CFR 314.52(b)]. Subsequently, the applicant must submit
`documentation that the patent holder(s) received the notification ([21 CFR 3 J4.52(e)].
`‘
`
`2] CFR 3]4.50(i)(l)(ii): No relevant patents.
`
`2] CFR 3]4.50(i)(l)(iii): Information that is submitted under section 505(b) or (c) of the act and
`2] CFR 314.53 is for a method of use patent, and the labeling for the drug product for which the
`applicant is seeking approval does not include any indications that are covered by the use patent.
`
`21 CFR 314.54(a)(l)(iv): The applicant is seeking approval only for a new indication and not
`for the indication(s) approved for the listed drug(s) on which the applicant relies.
`
`Did the applicant:
`
`.0
`
`0
`
`Identify which parts of the application rely on information the applicant does not own or to which the
`applicant does not have a right of reference?
`
`YES NO
`
`NAV
`
`Submit a statement as to whether the listed drug(s) identified has received a period of marketing
`exclusivity?
`
`YES NO
`
`NAV
`
`Submit a bioavailability/bioequivalence (BA/BE) study comparing the proposed product to the listed drug?
`YES NO
`NAV
`
`Has the Director, Div. of Regulatory Policy I], HEB-007, been notified of the existence of the (b)(2) application?
`
`YES NO
`
`NAV
`
`Version: 307/2002
`
`

`

`NDA 2l-572
`
`NDA Regulatory Filing Review
`Page 5
`
`ATTACHMENT
`
`MEMO OF FILING MEETING
`
`DATE: February 13, 2003
`
`BACKGROUND
`
`The Applicant submitted a New Drug Application (NDA) on December 20, 2002 for Cidecin® (daptomycin
`for injection) for the treatment of complicated Skin and Skin Structure Infections (cSSSI) including those
`complicating diabetic foot and decubitus ulcers caused by susceptible strains of the' following Gram-positive
`microorganisms: Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes,
`Sn'eptococcus ago/actiae, Streptococcus dysgalacn'ae subsp. equisimilis, Enterococcusfaecilis (vancomycin-
`susceptible strains only)
`,__..
`
`The daptomycin clinical program consisted of studies conducted by both Eli Lilly and Company
`(Lilly) and Cubist Pharmaceuticals, Inc. (Cubist). Lilly conducted primarily Phase I single and
`multiple dose safety and pharmacokinetic studies and a small Phase 2 program which consisted of
`two studies. Cubist obtained worldwide marketing rights for daptomycin from Lilly and filed its own
`IND application in December, 1998. The pre-clinical data previously generated by Lilly was used to
`support Cubist's initial Phase 2 and 3 clinical trials. Cubist has modified Lilly‘s clinical strategy of
`administering divided daily doses of daptomycin to emphasize once-daily dosing of daptomycin. This
`was done based on preclinical studies, clinical data analysis, and modeling that show that once-daily
`dosing maximizes antibacterial efficacy while minimizing adverse effects,
`
`ATTENDEES: Mark Goldberger, Janice Soreth, David Ross, Susan Thompson, Sumathi Nambiar, Philip
`Colangelo, Charles Bonapace, Terry Peters, Wendelyn Schmidt, Joel liang, Daphne Lin, Albert Sheldon, Peter
`Coderre, Bonnie Dunn, Zi Qiang Gu, Alfred Sorbello, Paul Buehler, Brenda Friend, Edward Cox, Elizabeth
`DuvallMiller, David Roeder and Raquel Peat
`
`ASSIGNED REVIEWERS:
`
`Reviewer
`Discipline
`Susan Thompson and Surnathi Nambiar
`Medical:
`David Ross
`Secondary Medical:
`Joel liang
`Statistical:
`Wendelyn Schmidt
`Pharmacology:
`N/A
`Statistical Pharmacology:
`Zi Quang Gu
`Chemist:
`Karyn Campbell
`Environmental Assessment (if needed):
`Charles Bonapace
`Biopharmaceutical:
`Peter Cooney
`Microbiology, sterility:
`Microbiology, clinical (for antimicrobial products only): Peter Coderre
`DSI:
`Ni Aye Khin and Brenda Friend
`Project Manager:
`Raquel Peat
`Other Consults:
`ODS
`
`Per reviewers, all pans in English, or English translation?
`
`YES_X_ NO—
`
`CLINICAL —
`
`'
`
`File ___X__
`
`Refuse to file
`
`Version: 3/27/2002
`
`

`

`NDA 21-572
`
`NDA Regulatory Filing Review
`Page 6
`
`0 Clinical site inspection needed:
`
`YES_ X __ NO_
`
`
`
`MICROBIOLOGY CLINICAL -
`
`File___X_
`
`Refuse to file
`
`STATISTICAL —
`
`"
`
`File _x__ -
`
`Refuse to file
`
`BIOPHARMACEUTICS -
`
`File __X____
`
`Refuse to file
`
`0 Biopharm. inspection Needed:
`
`YES
`
`NO ____X______
`
`PHARMACOLOGY ._
`
`File _X___
`
`Refuse to file
`
`CHEMISTRY —
`
`o
`
`Establishment(s) ready for inspection? '- YES,X_NO_ File_X_ Refuse to file __
`
`ADDITIONAL COMMENTS:
`
`It was decided that the sponsor would be granted a priority review with a user fee goal date of June 20, 2003.
`The