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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 21-572/S-008
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`Cubist Pharmaceuticals, Inc.
`Attention: Francis P. Tally, MD
`Senior Vice President and Chief Scientific Officer
`65 Hayden Avenue
`Lexington, MA 02421
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`Dear Dr. Tally:
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`Please refer to your supplemental new drug application dated September 22, 2005, received September
`26, 2005, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for CUBICIN®
`(daptomycin for injection) Intravenous, 500 mg/vial.
`
`We also acknowledge receipt of your submissions dated October 24, 2005, November 14, 2005,
`November 16, 2005, December 22, 2005, December 28, 2005, January 3, 2006, January 19, 2006,
`January 23, 2006, January 24, 2006 (2), January 25, 2006 (2), January 26, 2006 (2), January 31, 2006,
`February 3, 2006, February 10, 2006, February 21, 2006, February 22, 2006 (2), February 24, 2006 (2),
`February 28, 2006, March 1, 2006, March 3, 2006, March 13, 2006 (2), March 15, 2006, March 22,
`2006, and March 27, 2006.
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`Your submissions of April 14, 2006, April 18, 2006, April 19, 2006, April 20, 2006, May 18, 2006,
`May 22, 2006 and May 24, 2006 constituted a complete response to our March 24, 2006 action letter.
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`This supplemental new drug application provides for the use of CUBICIN® (daptomycin for injection)
`Intravenous, 500 mg/vial, for the treatment of Staphylococcus aureus bloodstream infections
`(bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible
`and methicillin-resistant isolates.
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`We completed our review of this application, as amended, and it is approved, effective on the date of
`this letter, for use as recommended in the agreed-upon labeling text.
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`The final printed labeling (FPL) must be identical to the enclosed labeling. Marketing the product with
`FPL that is not identical to the approved labeling text may render the product misbranded and an
`unapproved new drug.
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`NDA 21-572/S-008
`Page 2
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`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “FPL for approved NDA 21-572/S-008.” Approval of this submission by FDA is not
`required before the labeling is used.
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`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`deferring submission of your pediatric studies for ages 0 to 18 years until December 31, 2011.
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`Your deferred pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA)
`are considered required postmarketing study commitments. The status of this postmarketing study shall
`be reported annually according to 21 CFR 314.81. This commitment is listed as follows:
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`1. Deferred pediatric study under PREA for the treatment of Staphylococcus aureus bloodstream
`infections (bacteremia), including those with right-sided infective endocarditis, caused by
`methicillin-susceptible and methicillin-resistant isolates.
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`Final Report Submission: December 31, 2011
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`Submit final study reports to this NDA. For administrative purposes, all submissions related to this
`pediatric postmarketing study commitment must be clearly designated “Required Pediatric Study
`Commitments”.
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`We also remind you of your postmarketing study commitments, in your submission dated May 25,
`2006. These commitments are listed below:
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`Clinical:
`1. Description of Commitment: Conduct a study to evaluate the potential impact of daptomycin
`used in combination therapy in the treatment of S.aureus infective endocarditis.
`Protocol Submission:
`by
`November, 2006
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`Study Start
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`by
`April, 2007
`Final Report Submission
`by
`June, 2010
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`Microbiology:
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`2. Description of Commitment: Perform studies to assess penetration of daptomycin into
`vegetations using simulated endocarditis vegetations in vitro and in animals.
`Protocol Submission:
`by
`September, 2006
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`Study Start
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`by
`October, 2006
`Final Report Submission
`by
`December, 2007
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`NDA 21-572/S-008
`Page 3
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`3. Description of Commitment: Perform in vitro studies to evaluate potential factors affecting
`daptomycin potency including vancomycin exposure and the susceptibility of vancomycin
`intermediate S. aureus (VISA) strains to daptomycin.
`Protocol Submission:
`by
`July, 2006
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`Study Start
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`by
`August, 2006
`Final Report Submission
`by
`December, 2006
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`by
`by
`by
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`September, 2006
`December, 2006
`April, 2007
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`4. Description of Commitment: Perform studies of the activity and penetration of daptomycin in
`biofilms.
`Protocol Submission:
`Study Start
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`Final Report Submission
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`5. Description of Commitment: Evaluate the efficacy of daptomycin in combination with other
`antibiotics in vitro and in animal models of bacterial endocarditis.
`Protocol Submission:
`by
`September, 2006
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`Study Start
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`by
`October, 2006
`Final Report Submission
`by
`December, 2007
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`We also remind you that you have agreed to collect the following information:
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`Clinical:
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`1. Monitor outcomes of patients with S. aureus bacteremia and infective endocarditis from the
`ongoing Cubicin Outcome Registry and Experience (CORE) database. Summarize data in
`annual report for 2 years.
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`Microbiology:
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`1. Monitor reports of resistance and collect isolates for determination of daptomycin and
`vancomycin minimum inhibitory concentration (MIC) when possible. Submit findings in
`periodic safety update reports (PSUR).
`2. Perform surveillance studies to monitor the activity of daptomycin for a period of no less than 2
`years. A summary of findings are to be included in each year’s annual report.
`3. Collect organisms that become resistant to daptomycin and perform studies to characterize the
`mode(s) of resistance, including genetic changes.
`4. Determine cross-resistance of daptomycin resistant bacteria to other antimicrobials.
`5. Evaluate the impact of sub-inhibitory concentrations of daptomycin on the development of
`resistance and the results of serial passage experiments.
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`NDA 21-572/S-008
`Page 4
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`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
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`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`Please submit one market package of the drug product when it is available.
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
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`If you have any questions, call J. Christopher Davi, Regulatory Project Manager at (301) 796-0702.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Janice M. Soreth, MD
`Director,
`Division of Anti-Infective and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`Enclosure: Approved labeling dated May 25, 2006
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
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` /s/
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`Janice Soreth
`5/25/2006 06:45:10 PM
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