`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202895Orig1s000
`
`MICROBIOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`
`Review Number:
`
`Dates of Submission(s) Covered by this Review
`Submit
`Received
`Review Request
`29 MAR 2011
`30 MAR 2011
`20 APR 2011
`15 JUN 2011
`15 JUN 2011
`N/A
`
`Prezista®.
`Darunavir.
`
`1.
`
`Assigned to Reviewer
`21 APR 2011
`N/A
`
`Tibotec, Inc.
`1125 Trenton-Harbourton Rd.
`Tutusville, NJ 08560
`Charles Zezza, Ph.D.
`908-707-3451
`
`John W. Metcalfe, Ph.D.
`
`Recommend approval.
`
`Product Quality Microbiology Review
`
`09 August 2011
`
`
`202-895/N-000
`
`
`NDA:
`
`Drug Product Name
`Proprietary:
`Non-proprietary:
`
`
`
`Applicant/Sponsor
`Name:
`Address:
`
`Representative:
`Telephone:
`
`
`Name of Reviewer:
`
`Conclusion:
`
`
`Reference ID: 2998329
`
`

`

`NDA 202-895/N-000
`
`
`
`Product Quality Microbiology Data Sheet
`
`A.
`1.
`TYPE OF SUBMISSION: 505(b)(1) NDA.
`
`2.
`
`Microbiology Review #1
`
`
`SUBMISSION PROVIDES FOR: A pediatric formulation based on an
`approved tablet formulation (reference is made to NDA 21-976).
`
`MANUFACTURING SITE:
`Janssen Pharmaceutica NV
`Turnhoutseweg 30
`Beerse B-2340
`Belgium
`
`3.
`
`
`4.
`
`B.
`
`C.
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY:
`(cid:190) Suspension.
`(cid:190) Oral.
`(cid:190) 100 mg/mL.
`
`METHOD(S) OF STERILIZATION: The drug product is not sterile.
`
`PHARMACOLOGICAL CATEGORY: Antiviral.
`
`
`5.
`
`6.
`
`SUPPORTING/RELATED DOCUMENTS: None.
`
`REMARKS:
`The subject NDA is submitted electronically in the CTD format.
`
` A
`
` Microbiology Information request was forwarded to the applicant by the
`ONDQA Project Manager on 25 May 2011. Following is the reviewer comments
`and information requests:
`
`
`Reference is made to Table 1 (Specifications for the drug Product (F052))
`of Module 3.2.P.5.1 which states the following regarding the product
`specification and microbiological testing, “monitoring frequency based on
`microbiological risk assessment”. Further reference is made to Section 1.8
`of Module 3.2.P.5.6 (Justification of Specifications) which states, “the
`drug product is tested and validated for microbiological purity according
`to the requirements of current USP<61> and <62>”.
`
`This microbiology reviewer notes that the microbiological risk assessment
`referenced in the Product Specification was not provided in the
`application. In addition, the application lacks verification studies
`demonstrating the suitability of use of the stated microbial limits tests with
`the subject drug product. Finally, for aqueous non-sterile dosage forms,
`
`
`
`
`
`Reference ID: 2998329
`
`
`
`Page 2 of 11
`
`
`
`

`

`NDA 202-895/N-000
`
`
`Microbiology Review #1
`
`
`
`
`Burkholderia cepacia is considered to be an objectionable microorganism,
`in addition to the objectionable organisms listed in USP<1111>.
`(cid:190) Clarify whether microbial limits testing will be performed as part of
`the release testing of every product batch.
`(cid:190) Provide the microbial test methods and data sets which verify the
`suitability of use of these tests (both microbial enumeration and
`specified microbes) with the subject drug product.
`(cid:190) It is understood that the product specification references USP<1111>
`regarding microbial limits acceptance criteria. Modify the product
`specification to specify the numerical limits and identities of each of
`the organisms that will be tested for regarding microbial limits
`acceptance criteria.
`(cid:190) Provide test methods and acceptance criteria to demonstrate the
`product is free of the objectionable microorganism Burkholderia
`cepacia. We recommend that potential sources are examined and
`sampled as process controls, and these may include raw materials and
`the manufacturing environment. A risk assessment for this species in
`the product and raw materials is recommended to develop sampling
`procedures and acceptance criteria. Your test method should be
`validated and a discussion of those methods should be provided. Test
`methods validation should address multiple strains of the species and
`cells that are acclimated to the environments (e.g., warm or cold water)
`that may be tested.
`
`The applicant amended the application with responses to this Information Request
`on 15 June 2011. Applicant responses are summarized and reviewed in
`appropriate sections of this review.
`
` A
`
` second Microbiology Information Request was forwarded to the applicant on
`27 June 2011 by the OND Project Manager. Following is the Information
`Request:
`
`
`Reference is made to the FDA Information Request dated 25 May 2011
`regarding microbial limits testing for Prezista®. Further reference is made to
`Tibotec’s responses to this request submitted on 15 June 2011.
`
`Tibotek’s responses to FDA Request # 1, and 2 are acceptable. Regarding
`FDA Request #3, add “absence of Burkholderia cepacia” to the list of
`Specified Microorganisms identified in the product specification. With
`regard to FDA Request #4, Tibotec has not demonstrated the ability to
`recover the objectionable organism Burkholderia cepacia from the subject
`drug product, nor has Tibotec provided a validated test for the detection of
`this organism, as requested. Provide a test method for detecting B. cepacia
`similar to the one you have provided for the specified organism, Escherichia
`coli. The original FDA Request #4 is copied below for Tibotec’s
`convenience.
`
`
`
`Page 3 of 11
`
`
`
`
`
`
`
`
`
`Reference ID: 2998329
`
`

`

`NDA 202-895/N-000
`
`
`Microbiology Review #1
`
`
`
`
`Provide test methods and acceptance criteria to demonstrate the product is
`free of the objectionable microorganism Burkholderia cepacia. We
`recommend that potential sources are examined and sampled as process
`controls, and these may include raw materials and the manufacturing
`environment. A risk assessment for this species in the product and raw
`materials is recommended to develop sampling procedures and acceptance
`criteria. Your test method should be validated and a discussion of those
`methods should be provided. Test methods validation should address
`multiple strains of the species and cells that are acclimated to the
`environments (e.g., warm or cold water) that may be tested.
`
`The applicant amended the application with responses to Microbiology Information
`Request #2 on 29 July 2011. Applicant responses are summarized and reviewed in
`appropriate sections of this review.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`File Name: N202895N000R1.doc
`
`
`
`
`
`Reference ID: 2998329
`
`
`
`Page 4 of 11
`
`
`
`

`

`NDA 202-895/N—000
`
`Microbiology Review #1
`
`Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability — NDA 202-895/N-000 is
`recommended for approval on the basis of product quality
`microbiology.
`
`B.
`
`Recommendations on Phase 4 Commitments and/or
`
`Agreements, if Approvable — Not applicable.
`
`II.
`
`Summary of NIicrobiology Assessments
`
`A.
`
`Brief Description of the Manufacturing Processes that relate to
`Product Quality Microbiology -
`mm
`
`B.
`
`C.
`
`Brief Description of Microbiology Deficiencies — There are no
`microbiology deficiencies identified.
`
`Assessment of Risk Due to Microbiology Deficiencies — Not
`applicable.
`
`III.
`
`Administrative
`
`A.
`
`Reviewer's Signature
`
`John W. Metcalfe, Ph.D.
`
`B.
`
`Endorsement Block
`
`Bryan S. Riley, Ph.D.
`
`C.
`
`CC Block
`
`N/A
`
`6 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 2998329
`
`Page 5 of 11
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN W METCALFE
`08/10/2011
`
`BRYAN S RILEY
`08/10/2011
`I concur.
`
`Reference ID: 2998329
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS
`OFFICE OF NEW DRUGS
`VIROLOGY REVIEW
`NDA: 202,895 SN: 000 DATE REVIEW COMPLETE: 4/29/11
`Virology Reviewer: Lisa K. Naeger, Ph.D.
`
`
`
`Serial #: 000
`
`
`NDA#: 202,895
`
`
`
`
`Reviewer's Name: Lisa K. Naeger, Ph.D.
`
`Sponsor’s Name and Address:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tibotec-Virco, USA
`2505 Meridian Parkway
`Suite 350
`Durham, NC 27713
`
`
`
`
`
`
`Important Dates:
`Correspondence Date:
`March 28, 2011
`CDER Receipt Date:
`March 30, 2011
`Assigned Date:
`
`March 30, 2011
`Review Complete Date: April 29, 2011
`PDUFA Date:
`
`September 30, 2011
`
`
`
`Amendments: none
`Related/Supporting Documents: IND-62477, NDA-21976 SN000, NDA-21976 SN006,
`SN007 and SN009
`
`
`Product Name(s)
`
`Proprietary: PREZISTA/rtv
`
`Non-Proprietary/USAN: Darunavir/rtv; darunavir
`
`Code Name/Number: TMC114
`
`Empirical formula: C27H37N3O7S .C2H5OH
`Chemical Name: {3-[(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-
`propyl}-carbamic acid hexahydro-furo-[2,3-b]furan-3-yl
`ester.ethanolate
`
`
`Molecular mass: Relative molecular mass: 547.656 (active moiety) + 46.068 (ethanol,
`EtOH) = 593.724 (TMC 114-ethanolate)
`
`
`
`Structural Formula:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Darunavir
`Drug category: antiviral for HIV infection
`Dosage Form(s): Oral; co-administration with ritonavir
`Route(s) of Administration: Oral
`
`
`
`Reference ID: 2951349
`
`1
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS
`OFFICE OF NEW DRUGS
`VIROLOGY REVIEW
`NDA: 202,895 SN: 000 DATE REVIEW COMPLETE: 4/29/11
`Virology Reviewer: Lisa K. Naeger, Ph.D.
`Dispensed: Rx X OTC
`
`
`Abbreviations: ABC, abacavir; APV, amprenavir; ATV, atazanavir; AZT, zidovudine;
`Control, comparator PI arm; ddI, didanosine; d4T, stavudine; DRV, darunavir; EFV,
`efavirenz; ETR, etravirine; FTC, emtricitabine; HAART, highly active antiretroviral
`therapy; HIV-1, human immunodeficiency virus-1; IC, inhibitory concentration; IDV,
`indinavir; LAM, lamivudine; LPV, lopinavir; NFV, nelfinavir; NVP, nevirapine; NNRTI,
`non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase
`inhibitor; OBT, optimized background therapy; PBMC, peripheral blood mononuclear
`cells; PCR, polymerase chain reaction; PI, protease inhibitor; /rtv, ritonavir-boosted; RT,
`reverse transcriptase; SQV, saquinavir; ENF, enfuvirtide; TDF, tenofovir; TPV, tipranavir
`
`________________________________________________________________
`
`EXECUTIVE SUMMARY
`
`Darunavir (DRV) is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage
`of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation
`of mature virus particles. It was approved June 23, 2006 for combination antiretroviral
`treatment of HIV-1 infected treatment-experienced adult subjects. The supplemental
`NDA with 96-week data of DRV/r treatment from studies of treatment-experienced
`subjects and 48-week data of DRV/r treatment from studies of treatment-naïve subjects
`was approved October 21, 2008. DRV is currently approved for treatment-experienced
`HIV-1 infected children >6 years old. This supplemental pediatric NDA seeks approval
`for treatment-experienced children 3 to <6 years old.
`
`This submission contains Week 24 efficacy, safety and PK data from the open-label
`Phase II trial TMC114-C228 (ARIEL) to support the selected pediatric doses of darunavir
`with low-dose ritonavir (DRV/r), by body weight, in combination with other antiretroviral
`(ARV) products, in treatment-experienced HIV-1-infected children from 3 to <6 years of
`age and weighing between 10 and <20 kg. Approximately 24 children, on a stable ARV
`treatment for ≥12 weeks but who needed to change their ARV regimen because it was
`currently failing (plasma viral load >1,000 copies/mL), and who had <3 DRV resistance-
`associated substitutions, were planned to be included in the trial with ≥10 and maximally
`14 children for each of the 2 following weight bands: 10 to <15 kg and 15 to <20 kg.
`Subjects were initially to be given a dose of DRV/r 20/3 mg/kg twice daily, together with
`an OBR consisting of ≥2 active ARVs with available pediatric dose recommendations.
`
`At baseline, 2 subject isolates harbored DRV substitutions (PID 228-0009 had L33F and
`L76V, and PID 228-0015 had L76V). Both subjects responded virologically (HIV-1 RNA
`<50 copies/mL) at Week 24.
`
`Post-baseline resistance testing was performed on samples with plasma viral load ≥50
`copies/mL. There were 11 (41%) never-suppressed subjects, when using the virologic
`response parameter plasma viral load <50 copies/mL (TLOVR non-VF censored) over
`time (1 subject discontinued due to an AE). When using the virologic response
`parameter confirmed plasma viral load <400 copies/mL (TLOVR non-VF censored), 9
`out of these 11 never-suppressed subjects were considered responders, of whom 7 had
`
`
`
`Reference ID: 2951349
`
`2
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS
`OFFICE OF NEW DRUGS
`VIROLOGY REVIEW
`NDA: 202,895 SN: 000 DATE REVIEW COMPLETE: 4/29/11
`Virology Reviewer: Lisa K. Naeger, Ph.D.
`achieved an unconfirmed undetectable plasma viral load (<50 HIV-1 RNA copies/mL) on
`treatment. The 2 subjects (PID 228-0012 and 228-0033) considered never-suppressed
`when using the virologic response parameter plasma viral load <400 copies/mL had no
`relevant baseline resistance characteristics.
`
`Paired baseline/endpoint genotypes (all Week-24 samples) were available for 6
`subjects, 5 of whom did not achieve a confirmed undetectable viral load (plasma viral
`load <50 copies/mL). No development of any IAS-USA PI or NRTI substitutions was
`detected. All 6 subjects with paired baseline/endpoint phenotypes were susceptible to all
`commercially available PIs and NRTIs in the OBR at baseline and remained susceptible
`to those PIs and NRTIs post-baseline.
`
`This NDA for DRV/r is approvable with respect to virology for combination antiretroviral
`treatment of HIV-1-infected treatment-experienced children 3 to <6 years old. There are
`no virology post-marketing commitments or requirements for this approval and there are
`no virology changes to the package insert.
`
`RECOMMENDATIONS
`
`
`Recommendation and Conclusion on Approvability
`
`
`This NDA for DRV/r is approvable with respect to virology for combination
`antiretroviral treatment of HIV-1-infected treatment-experienced children 3 to <6
`years old.
`
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable.
`
`There are no virology post-marketing commitments or requirements for this
`approval.
`
`
`
`ADMINISTRATIVE
`3.1. Reviewer’s Signature(s)
`
`
`____ Lisa K. Naeger __________
`Lisa K. Naeger, Ph.D.
`Sr. Microbiologist, HFD-530
`
`3.2. Concurrence
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2951349
`
`
`HFD-530/Micro TL__________________________Signature____________Date
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LISA K NAEGER
`05/24/2011
`
`JULIAN J O'REAR
`05/25/2011
`
`Reference ID: 2951349
`
`

`

`MICROBIOLOGY FILING CHECKLIST FOR NDA or Supplement
`
`Applicant: Tibotec
`NDA Type: Pediatric
`
`Stamp Date: March 29, 2011
`
`
`
`NDA Number: 202-895
`Drug Name: Prezista
`(darunavir)
`
`On initial overview of the NDA application for filing:
`
`
`
`
`1
`
`Content Parameter
`Is the virology information (nonclinical and clinical)
`provided and described in different sections of the NDA
`organized in a manner to allow substantive review to
`begin?
`
`Is the virology information (nonclinical and clinical)
`indexed, paginated and/or linked in a manner to allow
`substantive review to begin?
`Is the virology information (nonclinical and clinical)
`legible so that substantive review can begin?
`4 On its face, has the applicant submitted cell culture data in
`necessary quantity, using necessary clinical and non-
`clinical strains/isolates, and using necessary numbers of
`approved current divisional standard of approvability of the
`submitted draft labeling?
`5 Has the applicant submitted any required animal model
`studies necessary for approvability of the product based on
`the submitted draft labeling?
`6 Has the applicant submitted all special/critical studies/data
`requested by the Division during pre-submission
`discussions?
`7 Has the applicant submitted the clinical virology datasets in
`the appropriate format as described in the relevant guidance
`documents and are the datasets complete?
`8 Has the applicant used standardized or nonstandardized
`methods for virologic outcome measures? If
`nonstandardized methods were used, has the applicant
`included complete details of the method, the name of the
`laboratory where actual testing was done and performance
`characteristics of the assay in the laboratory where the
`actual testing was done?
`9 Has the applicant submitted draft labeling consistent with
`current regulation, divisional and Center policy, and the
`design of the development package?
`10 Has the applicant submitted annotated microbiology draft
`labeling consistent with current divisional policy, and the
`design of the development package?
`
`11 Have all the study reports, published articles, and other
`
`2
`
`3
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`
`
`Yes No
`X
`
`
`Comments
`
`
`
`
`
`
`
`n/a
`
`n/a
`
`n/a
`
`
`
`
`
`
`
`
`
`
`
`X
`
`n/a
`
`
`
`
`
`
`
`
`
`n/a
`
`
`
`n/a
`
`n/a
`
`File name: 5_Microbiology Filing Checklist for a NDA or Supplement 010908
`
`Reference ID: 2938339
`
`

`

`MICROBIOLOGY FILING CHECKLIST FOR NDA or Supplement
`
`
`
`
`
`Content Parameter
`references been included and cross-referenced in the
`annotated draft labeling or summary section of the
`submission?
`12 Are any study reports or published articles in a foreign
`language? If yes, has the translated version been included
`in the submission for review?
`
`Yes No
`
`Comments
`
`
`
`X
`
`
`
`
`IS THE MICROBIOLOGY SECTION OF THE APPLICATION FILEABLE? __Yes____
`
`If the NDA is not fileable from the microbiology perspective, state the reasons and provide
`comments to be sent to the Applicant.
`
`
`
`
`
`
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
`
`Lisa K. Naeger
`Reviewing Microbiologist
`
`
`Microbiology Team Leader
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4/26/11
`Date
`
`Date
`
`
`
`
`
`
`
`
`
`
`
`
`File name: 5_Microbiology Filing Checklist for a NDA or Supplement 010908
`
`Reference ID: 2938339
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LISA K NAEGER
`04/26/2011
`
`JULIAN J O'REAR
`04/26/2011
`
`Reference ID: 2938339
`
`