CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`20-965
`
`CORRESPONDENCE
`
`

`

`Printed by Olga Cintron
`
`ElectronicyMail Message
`
`5
`
`Iity: COMPANY CONFIDENTIAL
`
`Date:
`From:
`
`06-Apr-1999 03:05pm
`Patricia Tuegel
`TUEGELP
`
`Dept
`TelNo:
`
`PKLN 18808
`HFD-805
`301-827-7340 FAX 301-443—9281
`
`“3:019a Cintron
`
`Subject: NDA 20- 965
`
`( CINTRONO )
`
`(out consult request for the above application has been assigned to
`Review Microbiologist Bryan Riley on 4/5/99 Please make sure the COMIS
`assignment for microbiology is updated with the correct reviewer.
`
`dicrobiology Staff, RFD-805
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`'
`
`

`

`T AN
`””‘melufifl'éfi'flm 52 3'22
`FOOD AND DRUG ADMINISTRATION
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`REQUEST FOR CONSULTATION
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`TYPE 0/ DOCUMENT
`DATE F DOCUMENT
`NDA NO.
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`. GENERAL
`
`51-1.
`
`IA E 'F D ' G
`
`PRION'TY CONSIDERATION CLASSIFICATION OF DRUG
`
`DESI“; COMPLETION DATE
`
`D NEW PROTOCOL
`D PROGRESS REPORT
`D NEW CORRESPONDENCE
`D DRUG ADVERTISING
`D ADVERSE REACTION REPORT
`D MANUFACTURING CHANGE/ADDITION
`
`D MEETING PLANNED Bv
`
`.
`
`D PRE-NDA MEETING
`D END OF PHASE II MEETING
`D RESUBMISSION
`-
`D SAFETY/EFFICACY
`D PAPER NDA
`D CONTROL SUPPLEMENT
`
`.
`
`D RESPONSE TO DEFICIENCY LETTER
`D FINAL PRINTED LABELING
`D LABELING REVISION
`D ORIGINAL NEW CORRESPONDENCE
`D FORMULATIVE REVIEW
`WHERmpu-ij below)
`
`STATISTICAL EVALUATION BRANCH
`
`STATISTICAL APPLICATION BRANCH
`
`_
`II. BIOMETRIcs
`
`‘
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`-— -
`
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`D TYPE A OR B NDA REVIEW
`D END OF PHASE II MEETING
`D CONTROLLED STUDIES
`D PROTOCOL REVIEW
`D OTHER
`
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`
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`D CHEMISTRY
`D PHARMACOLOGY
`D BIOPHARMACEUTIOS
`D OTHER
`
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`’III. BIOPHARMACEUTICS
`
`'
`
`’
`
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`LUTION
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`D
`D PHASE IV STUDIES
`
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`D DEFICIENCY LETTER RESPONSE
`._ D PROTOCOL; BIOPHAHMACEUTICS
`D IN—VIVO WAIVER REOUEST
`
`” ‘
`
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`
`——~
`
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`
`IV. DRUG EXPERIENCE
`
`“
`D PHASE IV SURVEILLANCE/EPIDEMIOLOGY PROTOCOL ""
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`3 CASE REPORTS OF SPECIFIC HEACTIONSILLT! below)
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`3 COMPARATIVE RISK ASSESSEMENT ON'GENERIC DRUG GROUP
`V. SCIENTIFIC INVESTIGATIONS
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`D REVIEW OF MARKETING EXPERIENCE, DRUG USE AND SAFETY
`D SUMMARY OF ADVERSE EXPERIENCE
`D POISON msx ANALYSIS
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`D CLINICAL
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`

`Printed by Olga Cintron
`
`ElectronicyMail Message
`
`s.
`
`.vity: COMPANY CONFIDENTIAL
`
`Date:
`From:
`
`16--Sep- 19_9__8___g<_1_:20pm
`Olga Cintron
`CINTRONO
`
`-
`
`Dept
`TelNo:
`
`CRPZ N248
`RFD-540
`301-827-2023 FAX 301-827-2075
`
`TO: Steve Hathaway
`
`( HATHAWAYSV.)
`
`CC: Wilson DeCamp
`Subject: NDA 20-965
`
`Levulan
`
`‘
`
`( DECAMP )'“’ "
`'
`
`'-'—-- “--
`
`""""
`
`‘
`
`Steve:
`
`‘"
`
`hA ‘_*
`
`If
`Please advise if a CMC micro consult is needed for this.NDA.
`that's the case,
`then we should send the consult as soon as possible.
`
`Thanks, Olga
`
`APPEARS THIS WAY”
`0N ORIGINAL
`
`, ..
`
`

`

`Printed by Olga Cintron
`
`ElectronicyMail Message
`
`1.
`
`my: COMPANY CONFIDENTLAL»
`
`- ,1 1' ".--.1 I
`
`23--Apr--1999 02:51pm
`M. Date:
`_ From: _‘_Mar_tin O_kun__
`L—
`> ~. -. n OKUW ,‘ —— ~
`
`CRPZ N241
`Qgpt:
`. HFD-_5_4_o‘
`TelNo:
`301- 827— 2021 FAX"301- 827- 2075
`
`0: Olga Cintron
`
`( CINTRONCET_—
`
`abject: Re: NBA 20-965
`
`Levulan
`
`0 concerns
`
`V
`
`V
`
`N1 ~—_* .,_______1_.-_ __ ‘"'_ 7.1..
`
`_ 1.
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`7.
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`
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`~
`
`>
`
`5-
`
`-
`
`* --—-*-—----—--—~—--—r
`
`-, ~~-
`
`informed me that no inspections will be
`from the 081,
`Dr. Carrera's,
`issued for this NDA. Do you have any concerns?—— ,_
`»-
`..
`.___‘,
`
`Olga
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`.~ A sham: .
`
`V
`
`_-
`
`~ ~
`
`'1' :r—«m—tm-r-I‘nw-g -.« — w"w"‘ --- "rm .
`
`

`

`GUIDELINES, INC.”
`
`
`
`FACSIMILE TRANSMITTAL SHEET
`
`
`FROM:
`‘
`3 _CIntron
`Sam Swetland
`
`W:
`DATE:
`DDP/ODEV/FDA
`December 3. 1999
`«A _. .—~
`
`MBER;
`TOTAL No. OF PAGES INCLUDING COVER:
`
`4327-2075
`5
`
`NUMBER:
`RE:
`
`327-2023
`NDA 20-965
`
`
`NT
`
`l3 FOR REVIEW Cl PLEASE COMMENT
`
`[3 PLEASE REPLY [3 PLEASE RECYCLE
`
`
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`lga,
`
`As‘tog? :ouerhone convérsation. attached is lhe.cover letter of the NDA
`Amt" ment agreeing to the labeling changes.
`"9
`wetland
`
`a.
`Sam .
`
`10320 USA'LToday Way;
`Miramar. Florida 33025 -
`(954) 433—7480. Fax_(954)432-9015
`
`

`

`MOO318l8$0d1$38
`
`
` , mGUIDELINES ‘_
`
`_
`I‘ JCORPORATED :
`
`Sent Via Facsimile .
`
`.»
`
`_
`
`Decer 3er3, 1999 _
`
`Jonatl .in Wilkin, MD. Director
`Divisic ‘l of Dermatologic and Dental ‘Dmg Products
`Centc for-.Drug'Evaluation and Research
`Food , 1d Drug Administration
`Docur ant Control Reom
`2“ Fit N North (HFD-540)
`"rom-
`.
`9201'! orporate Boulevard--
`Rock» a. MD 208501;“: 3; 35‘5““: :",.‘..~;.'
`
`.--_--..
`;
`,_
`
`,
`
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`
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`
`REFE ENCE: NDA..AM.ENDMENT - New Drug Application for LEVULAN'
`KERASTIGKW— (aminolevulinic acid HCI) for Topical Solution.
`20% - NDA No. 20-965
`
`.-
`
`...r
`...*
`
`..
`s-
`
`---.v- »....-
`
`.
`
`—_4
`
`.Av
`
`Dear l
`
`‘. lNllkin:
`
`:,~'!r“ Kn... ann.~.
`
`On b¢ ~ah‘ of our client. DUSA Phamiaoeuticals. Inc.. we herewith amend the
`subjer application in order to respond to the Agency's Facsimile Transmission
`from ( ga Cintron dated December 3. 1999.
`
`DUSA i’harmaceuticals. Inc.. agrees to the labeling modifications proposed by
`the ’A‘encyjor‘the LEVULANHKERASTICK for Topical Solution. 20% as
`comm nicated ’in the‘FaaimileTra'nsmission dated December 3. 1999.
`
`We m .t that this commitment is adequate and the application may be approved.
`it you eed any further information, please feel free to contact me at (954) 433-
`7480.
`
`isider” ail the information contained in this application proprietary and
`We c:
`confid: wtial. Please be advised that the confidentiality of all enclosed information
`is pro-. jed for under 18 USC. Section 1905 and/or USC. Section 331].
`
`0320 US Today Way. Miramar. FL 33025. USA ' 954-433-7480 ° Fax: 954-432-905 ' E-mailz gi5@9‘3-"¢‘
`
`

`

`
`
`
`
`AdOOEI'IHISSOd1338 i
`
`Since 2ly yours.
`(2;, ”13/5.W
`
`Samu ID. Swetland
`
`Wu: F esident. Regulatory Affairs and Compliance
`
`50530:
`Enamel
`
`_~
`
`
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`*_—
`
`
`
`

`

`GUIDELINES, INC?
`
`
`
`FACSIMILE TRANSMITTAL SHEET
`
`To:
`FROM:
`Olga Cintron
`Sam Swetland
`
`COMPANY:
`DATE:
`_
`__
`DDDDPIODEVIFDA
`December 2. 1999 -
`
`FAX NUMBER:
`TOTAL no. or mess mcwoms coven:
`301.327.2075 .
`7
`
`PHONE NUMBER:
`
`RE;
`
`301-827-2023
`
`NDA 20-965
`
`M D
`
`URGENT D FOR REVIEW B PLEASE COMMENT 0 PLEASE REPLY 0 PLEASE RECYCLE
`
`
`MOTEQCOMHENTS:
`
`Dear Olga.
`
`As per our phone conversation. attached is the cover letter of the NDA
`~ WWW—“Amendmentto—resteting the Phase—A—eommitments. The original of this
`Submission (in duplimte) was submitted today for delivery on Friday 12-3-99.
`
`Ify/ogdjd not receive this shipment. please let me know. Thanks
`
`Sarn-éwettand
`
`APPEARS THIS WAY
`on ORIGINAL
`
`M 1
`
`0320 USA Today Way.
`- Miramar. Florida 33025
`(954) 433-7480, Fax (954)432-9015
`
`

`

`INCORPORATED
`
`GUIDELINES
`
`December 2. 1999
`
`Sent Via Facsimile
`
`‘
`Jonathan lMlkin. MD. Director
`Division of Dermatologic and Dental Drug Products
`Center for Dmg Evaluation and Research
`Food and Drug Administration
`Document Control Room
`2"“ Floor North (HFD—540)
`9201 Corporate Boulevard
`Rockville. MD 20850
`
`REFERENCE: NDA AMENDMENT - New Drug Application for LEVULANo
`KERASTICK'“ (aminolevulinic acid HCl) for Topical Solution.
`”TOW-WK No. 20-965
`
`Dear Dr. Wilkin:
`
`On behalf of our client. DUSA Pharmaceuticals. Inc. we herewith amend the
`subject application in order to respond to the Agency's request for restatement of
`Phase 4 clinical commitments as communicated in the Facsimile Transmission
`from Olga Cintron dated December 2. 1999.
`
`DUSA Pharmaceuticals. he. agrees to perform the following Phase 4 studies.
`
`1. A study to characterize the potential for derrnel allergenicity of LEVULAN®
`KERASTlCKT“ (aminolevulinic acid HCI) for Topical Solution. 20%. This
`study will be completed within 24 months of approval.
`
`2. A study to characterize the safety and efficacy of LEVULAN KERASTICK for
`Topical Solution. 20%. plus blue light photodynamic therapy in an additional
`70 patients in which at least 30 patients should have Fitzpatrick skin type N-
`Vl. Patients will be seen in follow-up at one year afler treatment to assess the
`long-term recurrence rate of actinic keratoses that have resolved after
`treatment. This study will be completed within 4 years of approval.
`
`3. A clinical study involving long-term (at least 12 months) follow-up of treated
`patients to characterize the recurrence rate of AK lesions that cleared by the
`primary endpoint (e.g.. 8 weeks) and to characterize-the histopathology of AK
`
`'0310 USA Today Way. Hiram-r. FL 33025. USA . 95443337450 - Fax: 954432-90”: - E-mail; gis@g'afeiiii
`
`

`

`’-
`
`In this regard. the study will be designed to
`lesions in long-term follow-up.
`reject the hypothesis that AK lesions that are (a) assessed as completely
`cleared by clinical evaluation; (b) assessed as completely cleared by clinical
`examination but recm during follow-up; and (c) assessed as not completely
`cleared by clinical'examination carry an increased risk of either (1) atypical
`keratinocyte proliferation involving the full thickness of the epidermis including
`adnexal structures at 12 month follow-up. or (2) squamous cell carcinoma of
`the skin at 12 month follow-up. DUSA will estimate the spontaneous
`incidence of progression of actinic keratoses to full thickness epidermal atypia
`or squamous cell carcinoma of the skin based on a review of the relevant
`scientific literature. and based on this estimate. will characterize the
`histopathology of enough treated lesions to preclude the possibility that a
`' clinically significant fraction of completely cleared. completely cleared but
`recurrent, or not completely cleared lesions undergo malignant progression to
`full thickness epidermal atypia or to squamous cell carcinoma of the skin
`during long-term follow-up.
`ibis study will be completed within 4 years of
`approval.
`
`As noted in the December 2, 1999 Facsimile Transmission. the commitments in
`items 2 and 3 above may be accomplished in a single study. Furthermore.
`DUSA will confer with the Agency regarding the design and acceptability of the
`Abpwposedphaseatstudiesfk-
`
`We trust that this information adequately responds to the requested information.
`If you need any further information. please feel free to contact me at (954) 433-
`7480.
`
`We consider all the information contained in this application proprietary and
`confidential. Please be advised that the confidentiality of all enclosed information
`is provided for under 18 USC, SeCtion 1905 and/or USC. Section 331j.
`
`Sincerely yours.
`(”W/a 5%
`
`Samuel D. Swetland
`\fice President. Regulatory Affairs and Compliance
`
`WE
`
`ndosun:
`
`wean-mm“
`
`APPEARS nus WAY
`on ORIGINAL
`
`

`

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`APPLICANT INFORMATION
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`400 Colusws Aveme
`10320 USA Today Hay
`Valhalla, NY 10595
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`Him, FL 33325
`
`
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`Phone: (954) 437%
`
`Fax: (954) 432-9015
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`ATTACHMENT TO FORM FDA 356h
`
`ESTABLISHMENT INFORMATION:
`
`Drug Substance
`
`i
`
`The drug substance will be manufactured, packaged. controlled and shipped by
`ithe drug substance manufacturer. Stability studies of the dmg substance will
`con ucted b
`‘YW
`
`Name and Address of Manufacturing Site:
`
`Establishment Registration No.:
`
`Not Applicable
`
`Contact Person and Phone No.:
`
`Site Keenan by FDk
`
`This facility has been inspected.
`
`Maggot
`
`The dmg product will be manufactured. packaged, labeled. controlled and shipped by
`North Safety Products will be responsible for the manufacture of the bulk solution
`vehicle, filling and sealing of the glass ampules and assembly of the Levulan Kerastick.
`North Safety Products is responsible for the in-process testing of the bulk Levulan
`Topical Solution Vehicle.
`
`Name and Address of the Manufacturing Site:
`
`North Safety Products
`2000 Plainfield Pike
`Cranston. RI 02921
`
`Establishment Registration No.:
`
`-—
`
`#1217998
`
`Contact person and Phone No.:
`
`Jonny Smith
`Manager. Business Quality
`(401) 9464400
`
`Site Inspection by FDA:
`
`This facility has been inspected.
`.
`
`

`

`Contract Laboratories
`
`The raw materials, process intermediates and finished products are analyzed by a
`contract analytical laboratory. The finished product stability studies are also conducted
`by the contract laboratory listed below:
`
`Guidelines Analytical Laboratories. Inc. (GAL)
`10320 USA Today Way
`Miramar. FL 3
`5
`DMF No.1?
`'
`
`Establishment Registration No.:
`
`Contact Person and Phone No.:
`
`#1052961
`
`Mike Ray
`President
`
`(954) 433-7480
`
`Site Inspection by FDA:
`
`This facility is ready for inspeCtion.
`
`The finished product is tested for microbial content by the contract microbiological
`testing laboratory listed below:
`
`‘
`
`i
`
`i.
`
`Establishment Registration No.: 3
`Contact Person and Phone No.:
`‘
`'
`
`Site Inspection by FDA:
`
`This facility is ready for inspection.
`
`CROSS REFERENCES:
`
`DUSA's IND for Aminolevulinic Acid HCI:
`GAL's DMF:
`
`iND # i‘
`DMF #’
`
`
`
`

`

`4"
`"‘ 'WNiaiao
`: INCORPORATED
`
`GUIDELINES
`
`November 11. 1999
`
`Jonathan Wilkin. MD, Director
`Division of Dermatologic and Dental Drug Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Document Control Room
`2"‘1 Floor North (HFD-540)
`9201 Corporate Boulevard
`Rockville, MD 20850
`
`
`
`REFERENCE: NDA AMENDMENT - New Drug Application for LEVULANQ
`KERASTICKT" (aminolevulinic acid HCl) for Topical Solution.
`
`20% - NDAJJQ; 2929,65
`
`Dear Dr. Wilkin:
`
`On behalf of our client. DUSA Pharmaceuticals. Inc.. we herewith amend the
`subject application in accordance with 21CFR §314.60.
`This amendment
`provides the draft Patient Package Insert (PPI) as agreed to following the recent
`Advisory Committee meeting. Four copies of the draft PPI and an electronic
`copy are provided for your review.
`
`./
`
`Additionally, in conversations with Richard Felten. he recommended that DUSA
`review both the Physician's lnsert and the device Operating Instructions to
`assure that
`the sections referring to the device trade name and patient
`positioning during light
`treatment utilize consistent
`language.
`Therefore,
`attached is a red-lined version of the Physician’s Insert (revision date October 1.
`1999) modified to be consistent with the device labeling. This Physician's Insert
`does not include changes resulting from the DODAC meeting as it was our
`agreement that DDDDP would be making such revisions. Please incorporate the
`minor changes provided in the attached into the insert that DDDDP is drafting.
`
`If you need any further information. please feel free to contact me at (954) 433-
`7480.
`
`1
`
`l0320 USA Today Way. Mir-amt. FL 33025. USA . 954-433-7480 msmssuzz-ms .. E-rnail: mtgkwm _
`
`-
`
`

`

`We consider all the information contained in this application proprietary and
`confidential. Please be advised that the confidentiality of all enclosed information
`is provided for under 18 USC, Section 1905 and/or USC. Section 331j.
`
`Sincerely yours.
`
`aims/D.W
`
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`SDS/sds
`Enclosure:
`Patient Package Insert
`Diskette containing Electronic Labeling
`DUSMFn-l NDAmm Letter-27.“
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`~ GUIDELINES
`
`INCORPORATED
`October 11. 1999
`
`Jonathan Wilkin, MD. Director
`Division of Derrnatologic and Dental Drug Products
`Center for Drug Evaldation‘and'Besearch
`’
`Food and Drug Administration
`Document Control Room
`2" Floor North HFD-540
`(
`)
`9201 Corporate Boulevard
`Rockville. MD 20850
`
`"
`
`,,
`
`7-
`
`Z 52 ]
`i
`'
`“ .
`.
`_
`- W ‘M':m,4flt‘.'-
`
`*z
`
`-
`
`-
`
`REFERENCE:‘NDA"AMENDMENTM- New Drug Application for LEVULAN”
`KERASTICKW (aminblevulinic acid HCI) for Topical Solution,
`20% - NDA No. 20-965
`
`Dear Dr. Wilkin:
`
`Inc.._ we herewith amend the
`On behalf _of our client, DUSA Pharmaceuticals.
`subject application in accordance With 21CFR §314.60.
`This amendment
`incorporates by reference a Dru Master File amendment submitted by the drug
`substance manufacturer;
`i
`-
`—
`,
`
`On August 11. 1999
`lsubmitted anamendment to their Type II DMF for
`
`5-aminolevulinic acid HCl. DMF No;
`ihis amendment contains responses
`to the comments forwarded to:’
`y the Office of New Drug Chemistry
`as a result of the CMC reviewwof the above NDA application. The amendment
`also includes updated stability data and minor changes such as. use of Purified
`Water EP versus Purified Water USP, use of new identical manufacturing
`equipment, a new packaging container size and clarifications to the specifications
`for the processing ingredients. These changes are considered minor and do not
`affect the quality of the drug substance.
`
`A summary of the new information is provided in the attached document provided
`by the DMF holder. For more details regarding this DMF amendment, please
`refer to DMFi
`iA letter authorizing the FDA to review DMF(
`Jon behalf of
`
`l0320 USA Today Way. Miramar, FL 33025. USA ' 954-433-7480 ' Fax: 954-432-905 ° E-ma'l: gis@gate.net
`
`g
`
`ORIGINAL
`
`

`

`this NDA was provided in the original NDA submission and a copy is attached to
`this submission for ease of review.
`
`if you need any further information, please feel free to contact me at (954) 433»
`7480.
`
`We consider all the information contained in this application proprietary and
`confidential. Please be advised that the confidentiality of all enclosed information
`is provided for under 18 USC, Section 1905 and/or USC, Section 331].
`
`Sincerely yours.
`
`cam/kW
`
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`SDSIsds
`Enclosure:
`Summary oLDMF Update
`
`DUSMFM NDA Doom-um Loner-26.00::
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`W if
`
`GUIDELINES
`
`INCORPORATED
`October 8. 1999
`
`Jonathan Wilkin, MD, Director
`Division of Dennatologic and Dental Drug Products
`Centerfor Drug Evaluation and Research
`Food and Drug Administration
`Document Control Room
`2"“ Floor North (HFD-540)
`9201 Corporate Boulevard
`Rockville, MD 20850
`
`KERASTICKT"
`LEVULANO
`for
`REFERENCE: New Drug Application
`(aminolevulinic acid HCI) for Topical Solution, 20% -
`NDA No. 20-965
`
`
`Dear Dr. Wilkin:
`
`On behalf of our client, DUSA Pharmaceuticals, Inc., enclosed please find the
`information requested during a telephone ‘ conversation on 7 October 1999
`between Olga Cintron of your Division and Sam Swetland of Guidelines. Inc.
`
`As requested. electronic copies of the revised draft labeling provided in the 1
`October 1999 NBA Amendment is being provided to aid in the review of the
`application. This labeling includes the Package insert, Carton Labels (cartons of
`1. 4, 6 and 12 units) and individual Applicator Label (cardboard sleeve label).
`The requested files are provided as detailed below.
`
`/
`
`
`.m File Description
`Diskette Title
`Package insert 10-1-99.doc Draft Package insert
`LEVULAN’ KERASTICK'”
`
`
`Kerastick Labels 10-99.doc
`Draft LEVULAN' KERASTlCK'”
`gggbpeffufggbe'mg
`
`
`
`'
`Carton labeling (cartons of 1. 4.
`
`6, and 12 applicators) and
`
`Applicator label
`
`Additionally. Ms Cintron requested 5 desk copies of the October 1. 1999 NBA
`Amendment. These desk copies are being provided as part of this submission.
`
`|0320 USA Today Way. Miramar. FL 33025. USA 0 954-433-7480 ' Fax: 954-432-9015 ' E-mail: gis@gate.neL ,,
`
`

`

`If you need any further information regarding these documents, please feel free
`to contact me.
`
`We consider all the information contained in this application proprietary and
`confidential. Please be advised that the confidentiality of all enclosed information
`is provided for under 18 USC, Section 1905 and/or USC, Section 331].
`
`Sincerely yours,
`
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`Enclosure:
`
`1 Diskette — Levulan Kerastick Draft Product Labeling, October 1, 1999
`5 Desk Copies — October 1‘. 1999 NDA Amendment
`
`SDS/sds
`DUSAWDAWW Law-25.00:
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`

`

`
`
`GUIDELINES
`INCORPORATED
`
`October 1. 1999
`
`Jonathan \Mlkin. MD. Director
`Division of Dermatologic and Dental Drug Products
`Center for DnIg Evaluation and Research
`Food and Drug Administration
`Document Control Room
`2"“ Floor North (HFD-540)
`9201 Corporate Boulevard
`Rockville. MD 20850
`
`REFERENCE: NDA AMENDMENT- New Drug Application for LEVULAN”
`KERASTICKT“ (aminolevulinic acid HCI) for Topical Solution.
`20% - NDA No. 20-965
`
`Dear Dr. Wilkin:
`
`On behalf of our client DUSA Pharmaceuticals. Inc. we herewith amend the
`subject applicationIn accordance with 21CFR §314. 110. responding to the June
`27 1999 action letter issued by the Office of Drug Evaluation V for LEVULAN°
`KERASTICK‘" (aminolevulinic acid HCI) for Topical Solution. 20% The attached
`amendment provides a complete response to each item listed in the _June 27
`1999 action letter and contains the fellowing' infbrmation:
`
`Information to support that all manufacturing and testing facilities have
`received satisfactory pre-approval
`inspections or have adequate
`inspectional histories to conclude that the facilities are in substantial
`confonnanoe with current Good Manufacturing Practices regulations.
`
`Revised _draft labeling reflecting the recommendations provided by the
`Agency in the June' 27. 1999 Approvable_Letter_.
`
`A commitment to characterize the potential for dermal sensitization of
`LEVULAN KERASTICK for Topical Solution. 20%.
`
`1.
`
`2.
`
`3.
`
`4.
`
`Va”.9»
`
`to characterize the safety and efficacy of LEVULAN
`A commitment
`KERASTICK for Topical Solution. 20% plus blue light photodynamic
`therapy“In different skin types. including Fitzpatrick skin types N-Vl and to
`
`
`(r
`I0320USATodayVVay. Mimnar, FL33025. USA 0 954433-7480' Fax: 954-432-905. Email: use _. te.net
`
`iyfl’I'fi
`(”b/5:“
`{M
`
`S u
`
`REC-'0
`
`
`
`
`

`

`5.
`
`6.
`
`7.
`
`8.
`
`assess the long term recurrence rate of AK lesions over a 12-month
`follow—up period.
`
`A justification for not undertaking characterization of the safety and
`efficacy of LEVULAN KERASTICK for Topical Solution. 20% plus blue
`light photodynamic therapy. delivered by the BLU-U‘“ blue
`light
`photodynamic therapy illuminator. for the treatment of actinic keratoses of
`the back and arms.
`
`Revised drug substance and dmg product specifications to oonfonn to the
`lCl-l 03A and Q38 uidance with respect to the nomenclature for(
`nd a commitment
`to re-evalua e
`' nce adequate data is available.
`
`spe Ication limits fo
`
`e
`
`”1
`
`'
`
`Updated safety lnforrnation including data obtained from indications.
`dosage forms and dosage levels other than those currently being sought
`in the subject application.
`
`Additional information to support the inclusion of an applicator cap as a
`tertiary component of the container-closure system to protect
`the
`applicator tip during the distribution. storage. and admixing of the
`LEVULAN KERASTICK in the physician's office.
`
`r—Wsav- ——*~Wetmstthatthisinformatiorradequately responds to all items listed In the action
`letter. and request that the review of this application be reopened. Based on the
`infomtation provided. we believe that this resubmission meets the requirements
`of a Class 1 Resubmission under CDER's Manual of Policies and Procedures
`(MAPP 5020.4) and.
`therefore.
`request
`that
`it be assigned a 2—rnonth
`performance goal.
`If you need any further information. please feel free to contact
`me at (954) 433-7480.
`
`We consider all the information contained in this application proprietary and
`confidential. Please be advised that the confidentiality of all enclosed information
`is provided for under 18 USC. Section 1905 and/or USC. Section 331].
`
`Samuel D. Swetland
`
`Vice President, Regulatory Affairs and Compliance
`
`SDSIIds
`Endoun:
`
`WWWW
`
`APPEARS THIS WAY
`ou ORIGINAL
`
`

`

`INCORPORATED
`
`GUIDELINES
`
`28 July , 1999
`
`ORIGINAL
`
`“C“
`
`
`
`Jonathan WIIkin. MD, Director
`Division of Dermatologic and Dental Drug Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Document Control Room
`2"" Floor North (HFD-540)
`9201 Corporate Boulevard
`Rockville, MD 20850
`
`NEW CORRESP
`
`Reference: Request for Agency Opinion - New Drug Application for Levulan”
`Kerastick" (aminolevulinic acid HCI) for Topical Solution, 20% - NDA No.
`20-965
`
`Dear Dr. \NIlkin:
`
`As requested by Mary Jean Kozma-Fornaro on July 27, 1999, and on behalf of our
`client, DUSA Pharmaceuticals,
`Inc. we herewith submit copies of the attached
`correspondence, previously fowvarded to the Agency by telefax on July 7, 1999 and July
`13, 1999.
`
`We consider all the information contained in this application proprietary and confidential.
`Please be advised that-the confidentiality of all enclosed information is provided for
`under 18 USC, Section 1905 and/or USC,.A$ection 331j.
`
`APPEARS THlSWAY
`0” ORIGINAL
`
`—
`
`Sincerely yours,
`
`. x
`
`Allyn L.
`Chairman
`
`ub, PhD
`
`m
`
`ALG/b
`
`'
`Enclosures
`
`|0320 USA Today Way. Himmar. FL 33025. USA ' 954-433-7480 ' Fax: 954-432-903 0 E-mail: gis@gatc.net
`
`”W,
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`
`APPLICATION TO MARKET A NEW DRUG, BIOLOGIC, OR AN
`ANTIBIOTIC DRUG FOR HUMAN USE
`
`(Title 21, Code 0/ Federal Regulations. 314 a 6‘0 7)
`
`APPLICANT INFORMATION
`
`NAME OF APPUCANT
`
`DUSA Phamaceuticals, Inc.
`TELEPHONE NO. (mm: Am Coda)
`'
`A
`A
`I
`4‘...
`APPLICANT ADDRESS (Nunbar, sum, City. State. Canny, ZPCoda arMafl Coda.
`(1.5. bun.” mint-EM 330010:
`
`400 Colurbus Avenue
`
`Valhalla, NY
`
`10595
`
`
`
`
`
`
`'3.- 7/28/99
`
`
`
`
`Guidelines, Inc.
`
`
`
`10320 USA Today Way
`
`
`Miramar, FL
`33025
`
`Phone: (954) 433-7480
`Fax:
`(954) 432-9015
`
`
`DATE OF SUBMISSION \ '
`
`
`,
`
`-
`
`AUTHORIZED U.S. AGENT NAME A ADDRESS (Number, 57ml. City, State,
`2P Coda. telephone I! FAX nunbar) IF APPUCABLE
`
`NEW DRUG OR ANTIBIOTIC APPUCATION NUMBER. OR BIOLOGICS UCENSE APPUCAT'ION NUMBER (II previously issued)
`
`20-965
`
`-
`
`ESTABUSHED NAME (9.9., Pmpornama, USP/USANnnmo)
`PROPRIETARY NAME (Magma) IF ANY
`Annnolevuhm .
`.
`TM
`'I -I
`.- .
`'
`CHEMICAL/BIOCHEMICAUBLOOD PRODUCT NAME filmy)
`CODE NAME (Illny)
`5-am1no—4-ox- - -ntan01c acid
`5-ALA HCl
`5-
`.
`.
`
`
`
`
` I
`DOSAGE FORM:
`ROUTE OF ADMINISTRATION:
`
`
`Ali.
`-
`~
`. ncal
`III—PROPOSED) INDICTION(S) FOR use
`.
`Treatment om actin'lc keratoses of the face and scalp
`APPLICATION INFORMATION
`
`fl
`
`APPUCATION TYPE
`(Check one)
`
`C] ABBREVIATED APPLICATION (ANDA. AADA. 21 CFR 314.94) El BIOLOGICS UCENSE APPLICATION (21 CFR pan 601)
`
`“KNEW DRUG APPIJCATION (21 CFR 314.50)
`
`E] 507
`D 505 (b) (2)
`m 505 (b) (1)
`IF AN NDA IDENTIFY THE APPROPRIATE TYPE
`IF AN ANDA~ OR AADA. IDENTIFY THE REFERENCE USTED DRUG PRODUCT THAT IS THE BASIS FOR THE SUBMISSION
`Name of Drug
`HoIdor of Appmved Applicafion
`
`TYPE OF SUBMISSION
`(Check one)
`
`[3 ORIGINAL APPLICATION
`
`DMENOMENT TO A PENOINO APPLICATION
`
`E] REsuaMISSION
`
`D SUPAC SUPPLEMENT D EFFICACY SUPPLEMENT
`
`C] PRESUBMISSION
`
`El ANNUAL REPORT
`
`E] ESTABLISHMENT DESCRIPTION SUPPLEMENT
`
`l3 IAaEuNC SUPPLEMENT
`
`D CHEMISTRY MANUFACTURING AND CONTROLS SUPPLEMENT
`
`UOTNER
`
`
`
`REASON FOR SUBMISSION
`
`.
`.
`Request for Agency 0p1n10n
`
`PROPOSED MARKEUNG STATUS (dtodt one)
`
`u PREMIPTION PRODUCT (Rx)
`
`D OVER THE COUNTER PRODUCT (OTC)
`
`l
`NUMBER OF VOLUMES SUBMITTED________
`ESTABLISHMENT INFORMATTON
`I
`
`THIS APPLICATION Is
`
`I1 PAPER
`
`I] PAPER ANO ELECTRONIC D ELECTRONIC
`
`
`
`
`
`
`
`Pmmmummmm.memmmmmmwmmmmmmmmmmumy). lnCIUdanm.
`awrm.mmbhpmmm.m¢mmW(CFN).DMFnum.mmmm steps Worrypooltesting(o.g. FmaI dosagolonn. SubIIIIy tostIrIg)
`conductodltflnsilo. Pmmmmmmhmmmmummumnumdy.
`‘
`
`
`
`
`
`See Attachment to Form FDA 3581
`
`as: Reference; (Ilst related [Jeense Applications. INDs. NDAC. PMAs. 51000:. IDES, BMFS, and DMFS reierenced In the current
`appllcatlon)
`
`
`
`See Attacment to Form FDA 356h
`
`FORM FDA 356h (”97)
`
`"FF ,
`
`

`

`GUIDELINES,
`
`INC‘.‘
`
`
`
`OLGA CINTRON
`Sam Swetland
`
`
`DATE:
`COMPANY:
`DDDDPIODEVIFDA
`July 7' 1999
`
`FAX NUMBER:
`TOTAL No. OF PAGES lNCLUDlNG COVER:
`
`301-827-2075
`-
`’2’
`/
`
`
`PHONE NUMBER:
`
`RE:
`
`
`
`301-827-2023 Questions For The CMC Reviewers
`
`D URGENT
`
`E] FOR REVIEW l3 PLEASE COMMENT
`
`El PLEASE REPLYU PLEASE RECYCLE
`
`
`NOTES/COMMENTS:
`
`As per our phone conversation. we are in the process of responding to the
`
`recent Approvable Letterjor DUSA's NDA 20-965. To expedite this process, we
`would appreciate the opportunity to discuss the following issues with the CMC
`reviewers for NBA 20-965.
`
`1.
`
`In the drug substance manufacturing process (synthesis and purification). will
`it be acceptable to utilize purified water that meets the EP specifications for
`Purified Water revised 7/1/99) instead of "Purified Water USP".
`If
`acceptable)
`)will amend their Type II DMF to include the EP
`specification and test data for “Purified Water EP”.
`
`2. Vifill it be possible to respond to the Approvable Letter, reopening the review
`clock, pendingtfie scheduling 'and re—inspection of the drug substance
`manufacturer? Additionally. will'the Agency request an inspection of the
`microbial testing facility during this time.
`
`As the answer toghese. questionswill affect our ability to respond to the
`deficiencies in the Approvable Letter, we would appreciate the opportunity to
`discuss these issues with the Agency as soon as possible. Thanks for your
`assistance in this matter.
`
`¢éfi
`
`Sam Swetland
`
`
`
`10320 USA Today Way.
`Miramar, Florida 33025
`(954) 433-7480, Fax (954)432-9015
`
`

`

`GUIDELINES,
`
`INC"...
`
`Féfialtj
`
`
`
`
`
`
`
`
`FACSIMILE TRANSMITTAL SHEET
`
`
`Sam Swetland
`- OLGA CINTRON
`
`COMPANY:
`DATE:
`DDDDP/ODEVIFDA
`July 13. 1999
`
`FAX NUMBER:
`TOTAL NO. OF PAGES INCLUDING COVER:
`
`3
`301-827-2075
`——————.—._____—_—__
`PHONE NUMBER:
`RE'
`301-327-2023
`.lnformation for Chemist's Review
`
`M E
`
`] URGENT
`
`El FOR REVIEW B PLEASE COMMENT
`
`[3 PLEASE REPLY E] PLEASE-RECYCLE
`
`
`
`NOTES/COMMENTS:
`
`Dear Olga,
`
`the following is
`requested during our phone conversation yesterday.
`As
`irivfiaelditional information regarding the acceptability of Purified Water EP in the
`manufacture of the drug substance.
`
`The USP specification for Purified Water has changed several times over the last
`4 years (see Table 1).
`It has evolved from strictly off-line chemical tests to a
`mixture of off-line chemical tests and on-line tests, and finally to the current
`specification of all on-line testing (Total Organic Carbon and Conductivity).
`
`The EP specification for Purified Water has also been recently revised (see
`attached translation of EP monograph - effective. 7/1/1999 and French original).
`A comparison of the USP and EP Purified Water Specifications are provided on
`the attached table. The primary difference between the two pharrnacopeial
`monographs is the conductivity specification. The USP specifies a Conductivity
`limit of 1.1 pS/cm at 20° C while the EP specifies a limit of 4.3 uS/cm at 20° C.
`
`Other minor differences between the pharrnacopeial monographs are, the use of
`the Total Organic Carbon (T00) test
`for the USP versus the Oxidizable
`Substances Test or TOC for the EP. The addition of limits testing for Heavy
`Metals and Nitrates are also in the EP.
`
`The EP monograph specifies tests and limits for Microbial Contamination where
`the USP does not. However, the USP implies that Purified Water is protected
`from microbial contamination and appropriate microbial monitoring shall be done.
`
`W
`
`2.2222,,
`
`,.
`
`10320 USA Today Way,
`Miramar, Florida 33025
`,(954) 433-7480. Fax (954)432-9015
`
`

`

`i
`
`
`The Purified Water EP proposed for use by the drug substance manufacturer,
`1 is produced from the municipal l
`_
`A water supply.
`The
`conductivity of the incoming water is approxima ely 270 pS/cm mainly due to Ca,
`Mg. COB and $04. The water is first Soflened over NaCl to replace the Ca, Mg.
`
`i
`and etc. ions with Na and Cl ions. Finally, the water passes through a
`
`l. Chloride ions are carried through the system thus causing the /
`k.
`conductivity to_b_e_inthe,.range ofi: ,JSlcmat 20‘? C.
`.
`. __.._.--..-. -
`r,
`The estimated chloride content of water meeting the US