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].
`
`, x.
`
`Sincerely yours.
`
`Samuel D. Swetland
`Vice President. Regulatory Affairs and Compliance
`
`SDSIsds
`DUSMNDAWW utterance
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`SUPPL we"
`
`DUPLICATE
`
`
`
`GUIDELINES
`INCORPORATED
`
`September 30, 1998
`
`.. /“\
`
`\ 11:333.008%?21/-
`j,
`
`i
`
`Olga Cintron, Project Manager
`Division of Dermatologic and Dental Drug Products (HFD-540)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`2"“ Floor North
`.
`
`9201 Corporate Boulevard
`Rockville, MD 20850 -
`
`REFERENCE: New Drug Application for Levulan® (aminolevulinic acid HCl)
`KerastickTM for Topical Solution, 20% - NDA No. 20-965
`
`Dear Olga:
`
`Attached please find copies of two correspondences submitted regarding the
`above application. This information was provided directly to the requesting
`parties as a result of a telephone correspondence.
`In each case, no new
`information has been provided that was not available in the original NDA
`submission. These correspondences are being provided to you for informational
`purposes and to maintain a record of the NDA correspondence. Please feel free
`to call me if you have any questions regarding either of these correspondences.
`
`Sincerely yours
`
`gawqbféfi
`
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`SDS/sds
`DUSAWOAW Loo-v6.69:
`
`i0320 USA Today Way. Miramar. FL 33025. USA ' 954-433-7480 ° Fax: 954-432-905 0 E-mail: gis@gate.net
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND onus ADMINISTRATION
`
`
`
`NAMEOFAPPUCANT
`
`PPLICATION TO MARKET A NEW DRUG, BIOLOGIC, on AN mam
`ANTIBIOTIC DRUG FOR HUMAN USE
`W110” "was
`‘
`3
`I
`\V
`(771/927, CodeolFedera/Regulations, 314I: 601) mI
`—IM\
`Q. MEGA
`DISAPhamaceuticaIs
`Inc.
`w -. --
`30 1998
`\ _
`DOOR” /
`"151"?$4192;
`“a“
`m“ “3“?“ "m ”" ”W
`- APPLICANT ADDRESS (Name Shut Cary. sane, Canny, ZPCcde WWI/Coda,
`- AUTHORIZED U.S. AGENT NAME a ADDRESS (N -“- ‘“~ ' “State,
`
`
`
`
`
`(1.5. MWIWM:
`,
`ZPCadaJalephaanAXmmbad IFAPPIJCABLE
`
`
`
`Gu‘IdeI Ines, Inc.
`400 Cqurbus Avenue
`10320 USA Today Nay
`ValhaIIa, NY 10595
`
`
`
`Miranar, FL
`33025
`
`
`
`(954) 433-7480
`FAX:
`(954) 432-9015
`
`
`
`
`
`
` ' i ' ' '1 ' i ' I 0 A
`
`nusossusmssm
`
`‘
`
`‘
`
`NEW DRUG OH ANTIBIOTIC APPLICATION NUMBER. OFI BIOLOGICS UCENSE APPLICATION NUMBER (IIMy issued)
`
`20.965
`
`ESTAEUSHED NAME (0. "OPIWIIIMO, USP/USAanma)
`PROPRIETARWE (“do
`Amnolevuhmc
`1d I~CI
`-
`.7 .. Keraflckwl
`mnmmamcmo PRODUCT NAME may)
`cope NAME (lazy)
`5-arn1'no-4-oantanoic .
`.
`k
`—m mm...m
`Squt1on
`20%
`T. .
`1.
`(PROPOSED) INDICATIONS) FOR USE:
`Treatrent of{
`g actinic keratoses of the face and scaIp
`'IJCA‘ITON INFORMATION
`
`)IF ANY
`
`- -
`
`-
`
`-
`
`APPIJCATION TYPE
`(M on.)
`
`m NEW DRUG APPIJCATION (21 CFR 314.50)
`
`CI ABBREVIATED APPIJCATION (ANM MBA 21 CFR 314.94)
`
`0 BIOIDGICSUCBISEAPPUCATIONQ1CFHMM)
`
`D 507
`U 505 (b) (2)
`m 55 (b) (1)
`IF AN NOA IDENflI-Y THE APPROPRIATE TYPE
`IFANANDA. OR AADA. IDENTIFYfl-IEREFERENCEUSTEDDRUGPRODUCTTHATISTHE BASISFORTHESUBMISSION
`deDmg
`HmaAppvwodAppIW
`
`
`
`Domemmmmou Umronaommm
`BMW
`UESTWWW
`
`TYPE OF SUBMISSION
`(ch-chem)
`UPRESIMISSION
`
`aason Foa suamssuou
`
`PHOPossoMAmNGSTAmem) ammm Dmmmmm
`
`GeneraI Cares-- T-erloe
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`ESTABUSHMENT INFORMATION
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`mmmdumumwmw
`m.muwmomm.ngtmm
`
`Modalmomo. antemmmmb
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`
`See Attadment to Form FDA 3581
`
`'
`
`Mu 1:113?an (Ilst related License Appllcaflom. lNDs. NDAs. PMAs. 510003. IDEs. BMFs. and DMFI Morenced In the current
`Ice on
`.
`
`See Attadmnt to Form FDA 35191
`
`FORM FDA 356:: («7)
`
`,,
`
`7
`
`, 5“
`
`

`

`INCORPORATED
`
`GUIDELINES
`
`September 30, 1998
`
`Richard Felten, PhD
`Division of General and Restorative Devices
`
`Office of Device Evaluation
`
`Center for Device and Radiological Health
`Food and Drug Administration
`HFZ-410, Room 310K
`9200 Corporate Boulevard
`Rockville, MD 20850
`
`REFERENCE: DESK COPY—
`
`New Drug Application for Levulan® (aminolevulinic acid HCI)
`-.W vWWWVWWWWKerastickI!rfmIopicaLSommmWNDANorms—WWAW..
`
`Dear Dr. Felten:
`
`On behalf of our client, DUSA Pharmaceuticals, Inc., and pursuant to our phone
`conversation yesterday regarding the above referenced NDA, attached please
`find additional copies of the following NDA volumes:
`
`1. Volume1.1.1
`
`2. Volume1.10.1
`
`3. Volume1.10.2
`
`If you require any further information please feel free to call me.
`
`Sincerely yours.
`
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`CC: NDA 20-965
`SDSlsds
`DUSAWDAWLM-llu
`
`l0320 USA Today Way, Miramar. FL 33025. USA ' 954—433-7480 ° Fax: 954-432-905 ' E-mail: gis@gate.net
`
`

`

`
`
`seaside
`
`September 18, 1998 ,
`
`so
`
`Jose Carreras, MD
`Division of Scientific Investigations (HFD-344)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`_
`Metro Park North 1, Room 125
`7520 Standish Place
`
`_,
`
`’
`
`Rockville, MD 20855
`
`REFERENCE: New Drug Application for _Lev_ulanQ(aminolevulinic acid HCl)
`KerastickTM for Topical Solution, 20% - NDA No. 20-965
`
`Dear Dr. Carreras:
`
`
`-
`
`-
`
`.j_...:.:.
`
`(F béhalf can? client, DUSA Pharmaceuticals, inc, and pursuant to our phone
`conversation yesterday/"regarding the above-’referenCed NDA, attached please
`find the requested information as outlined below.
`
`investigators who
`the clinical
`the names and addresses of
`1. A list of
`participated in thePhase-lllclinidirialsfimiocols ALA-018 and ALA-O19).
`
`2. The number of patients enrolled ineach center (Protocols ALA-018 and ALA-
`019) by treatment arm.
`3. A list of all seriousadversereactIonsforProtocols ALA-O18 and ALA-O19.
`
`Please note that the page numbers on the bottom right comer of each page
`reference the location of this dataIn the original NDA submission.
`If you require
`any further information please feelfreeto call me.
`Sincerely yours,. W
`
`Samuel D. Swetland
`
`Vice President, Regulatory Affairs and Compliance
`
`SOS/eds
`DUSAWOAW Leaving:
`
`l0320 USA Today Way. Hiramar. FL 33025. USA ° 954-433-7480 ' Fax1954-432-90l5 ° E-mail: gis@gate.net
`
`

`

`Protocol ALA-O18
`
`
`
`

`

`DUSA Pharmaceuticals, inc.
`LevulanO Keraslickm 20% MIN
`NDA No. 20-965
`
`Protocol ADA-018
`
`TABLE 6.1
`List of Principal investigators
`
`Princl - al lnvestl - ator
`Mary Gail Mercurio. MD
`
`Scott D. Glazer. MD
`
`Daniel J. Piacquadio. MD
`
`J. Richard Taylor, MD
`
`8. Elizabeth Whitmore. MD
`
`John Goodman. MD
`
`Harold Farber. MD
`'
`
`
`
`Department of Dermatology
`Clinical Pharmacology Unit
`Columbia Presbyterian Medical Center
`161 Fort Washington Ave. Room 750
`New York. NY 10032
`
`Director. Clinical Pharmacology Unit
`Emory University Hospital
`1364 Clifton Rd., Room 6408
`Atlanta. GA 3032
`
`VA Medical Center
`Dermatology Service
`1201 N. 16 Street
`Miami. FL 33125
`Johns Hopkins University
`Department Dermatology
`550 Building. Suite 1002
`550 N. Broadway
`Baltimore. MD 21205
`Hill Top Research. Ltd.
`900 Osceola Drive
`West Palm Beach. Fl 33409
`Hill Top Research Ltd.
`Einstein Center One
`9880 Bustleton Ave, Suite 203
`Philadel- ia. PA 19115
`
`b.
`
`Statistician:
`
`
`
`c.
`
`Clinical Trial Supply Management:
`
`i.
`
`ii.
`
`Guidelines. Inc. was responsible for the packaging. labeling and
`shipping of all clinical supplies used in this study.
`A central laboratoryl;
`was used to analyze all hematology.
`chemistry and urine parameters. Instructions and supplies for handling
`the sam les were provided to the investigators prior to study initiation.
`nalyzed the samples and the test results were to be reported
`to the investigator within 48 hours of receipt. Copies of laboratory
`
`xxiv
`
`

`

`DUSA Pharmaceuticals. Inc.
`LevulanO Kerastick" 20% wlv
`NDA No. 20-965
`
`10.
`
`STUDY PATIENTS
`
`10.1 Disposition of Patients.
`
`Protocol ALA-018
`'
`
`..
`
`A total of 117 patients were randomized to either Levulan or Vehicle. As may be
`seen. 88 patients received Levulan and 29 received Vehicle. The number of patients
`by center is presented in Table 10.1.1 and summary Table 1.1.
`
`Table 10.1.1
`Number of Patients Enrolled by Center
`
`
`
`
`
`
`
`
`
`'W-m Vehicle
`GEE—““1-
`[HIE—“n.2-
`Imam-“n“.
`——__—_
`IBM—“n“.
`——_-—-_
`—-I‘-_'_-E-‘
`
`———-—_
`——_-.
`
`—_m_—l_‘
`
`
`
`
`
`
`As specified in the protocol. each patient had to have a minimum of 4 target lesions
`on the face or scalp for entry into the study. The number of lesions by center and
`treatment is presented in Table 10.1.2 and summary Table 1.2.
`
`.
`
`. Table,140.1.2
`..
`Number of Lesions by Center
`
`
`
`
`
`
`
`
`
`Imm- Vehicle _
`mun—IE-
`—-m--I_—H-
`mama-“n“
`-:--3_—___
`_“—-E-
`__m-I-I—
`“ha-.1:-
`—-§-—___
`__—_
`”mi-m2-
`
`
`
`
`
`
`24
`
`

`

`DUSA Pharmaceuticals. Inc.
`Levulan® Kerastick" 20% w/v
`NDA No. 20-965
`
`Protocol ALA-018
`
`The data are summarized in summary Table 41.2 and listed by
`patient in Patient Data Listing 19.
`
`12.3 Deaths, Other Serious Adverse Events
`
`12.3.1 Listings of Deaths, Other Serious Adverse Events, and
`Other Significant Adverse Events
`
`12.3.1.1
`
`Deaths
`
`There were no deaths reported during the study.
`
`Other Serious Adverse Events
`12.3. 1.2
`There was only one patient with a serious adverse event. Patient
`18219 was hospitalized for an elective neurosurgical procedure for the
`treatment of a familial tremor refractory to medical therapy.
`
`12.3. 1.3
`
`Other Significant Adverse Events
`
`Two patients (18515 and 18517) had their light treatment terminated
`early due to discomfort.
`
`7‘ MM_
`
`_1_2;§.;2_Lqi‘!ratiY§_QfJJ_eath§thher. SetwusAdversefivthsT-andGertain—
`Other Significant Adverse Events
`
`18515
`Patient Number:
`# 5, Richard Taylor. MD
`Site/Investigator:
`Reason for Narrative: Light treatment terminated
`Protocol:
`ALA-018
`Treatment Group:
`Levulan 20 %
`
`Patient 18515 was first diagnosed with actinic keratoses (AK) in 1996 and had
`not received any treatment prior to coming on study.
`
`At the Screening visit on 4/22/97. medical history was significant for
`hypertension (HTN). peptic ulcer disease (PUD). anemia, osteomyelitis with
`prior arthroplasty of the left knee, chronic obstructive pulmonary disease.
`cataract and diminished hearing, renal calculi and constipation. Physical
`examination and Vitals were WNL and the patient was determined to have
`Type I skin. Medications included acetaminophen 500 mg. PRN
`(osteomyelitis). Doxazosin 8 mg. QHS (HTN). psyllium 1 tbs. after meals
`(prophylaxis constipation), simethicone 80 mg after meals (PUD) and
`sunscreen for sun protection. Serum creatinine was slightly elevated at
`baseline (1.6 Range (R): 0.5 - 1.5 meq/L) and judged not clinically significant.
`Other laboratory parameters were WNL.
`
`80
`
`

`

`DUSA Pharmaceuticals, lnc.
`Protocol No: ALA—019
`Levulan’ Kerastickm 20%
`NBA No. 20-965
`
`Table 6.1
`
`,
`
`Principal Investigators
`
`
`Diana Chen. M.D.
`'
`
`
`
`
`
`Joseph Fowler. MD.
`
`Northwestern University Medical School
`Department of Dermatology
`222 East Superior Avenue, 3rd Floor
`Chica o. lL 60611
`
`Family and Occupational Dermatology
`310 East Broadway. Suite 100
`
`
`
`
`
`
`
`Luciann Hruza. MD.
`
`Tania Phillips. MD.
`
`Washington University School of Medicine
`1040 North Mason Road. Suite 120
`St. Louis. MO 63141
`
`Boston University
`
`
`Department of Dermatology
`
`
`609 Albany Street. 4th Floor
`
`
`Boston. MA 021 18
`
`
`
` . Tena Rallis. M.D.
`University of Utah
`
`Department of Derrnatclogy
`
`50 North Medical Building
`
`
`
`.Salt Lake Ci
`. UT 84132
`
`
`
`David Tashjian. M.D.
`Hilltop Research. inc.
`
`
`
` .. WrthFresnoSbeetSnitetm ,7
`r
`r
`'
`Fresno. CA 93710
` Chartes Taylor. MD.
`
`Weiiman Laboratories of Photomedicine
`Department of Dermatology. BHX-630
`
`Massachusetts General Hospital
`
`50 Blossom Street
`
`Boston, MA 02114
`
`
`
` Gerald Weinstein. MD.
`University of Califomia, lrvine
`
`
`Department of Dermatology
`
`
`Medical Sciences. I—C340
`Irvine. CA 92717
`
`
`Obligations for monitoring were shared by DUSA and'.
`
`Obligations for data management. statistical analysis. and report writing were
`transferred tci
`iThe following is a list of the organizations that were key with
`respect to the conduct of the clinical trial.
`
`i
`
`APPEARS mrs WAY
`on ORlGlllAl.
`
`cacusnrsrousmrmusnboc Much to. ma.
`
`1 5
`
`

`

`DUSA Pharmaceuticals. Inc.
`Protocol No.: ALA-019
`Levulan’ Kerastick'“ 20%
`NDA No. 20-965
`
`10. STUDY PATIENTS
`
`10.1 DISPOSITION OF PATIENTS
`
`A total of 126 patients were randomized to have either Levulan or Vehicle applied. The
`number of patients randomized by each center is presented in the table below (Table
`10.1.1). As shown in Table 10.1.2. 93 patients were randomized to receive Levulan,
`and 33 patients were randomized to receive Vehicle.
`
`Table 10.1.1
`Number of Patients Enrolled by Investigator
`
`
`
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`czlcueursmusmrmusazooc m 10. um
`
`55
`
`

`

`DUSA Pharmaceuticals. Inc.
`Protocol No.: ALA-019
`Levulano Kerastick'"I 20%
`NBA No. 20-965
`
`12.2.4
`
`LISTING OF ADVERSE EVENTS BY PATIENT
`
`A listing of all adverse events. sorted by treatment group and investigator, are
`presented by patient in Patient Data Listing 13. which is located in Appendix 16.2.7 of
`this report. Both the verbatim and the coded COSTART term. as Well as the day of
`onset. duration, intensity, relationship to study drug, and treatment required are
`presented.
`
`12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER
`SIGNIFICANT ADVERSE EVENTS
`
`12.3.1
`
`LISTING OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND
`OTHER SIGNIFICANT EVENTS .
`
`12.3.1.1
`
`Deaths
`
`One patient (Pt. No. 19410) died during participation in the study. The
`relationship for the serious adverse events (jaundice, carcinoma of liver. liver
`WWWWWWQE to be 'remOte." A patient
`narrative is presented in Section 12.3.2.
`
`12.3.1.2
`
`Other Serious Events
`
`Five patients had other serious adverse events during the study. All were from
`the Levulan treatment group. The severity of these SBI‘IOUS adverse events
`ranged from mild to severe with an outcome of “recovered" for all 5 patients. The
`relationship to study medication for these serious adverse events was judged to
`be “not related' for all five patients. These adverse events are presented in
`Table 12.3.1.2.1.
`
`The patient narratives are presented in Section 12.3.2.
`
`There were no serious adverse events reported during the study in the Vehicle
`treatment group.
`
`QCLIENTSVDUSMOWIDUSAZDOC Marat 1c, mo
`
`97
`
`

`

`DUSA Pharmaceuticals. Inc.
`Protocol No.: ALA-O19
`Levulan‘ Kerastick'" 20%
`NDA No. 20-965
`
`. u ‘
`
`Serious Adverse Events
`
`
`Table 12.3.1 .2.1
`
`
`
`
`
`—N
`
`ot Related
`
`Not Related
`
`
`
`
`
`
`Jaundicel Jaundice
`Carcinoma of Liver]
`
`Liver
`FailurelHepatocellular
`
`Carcinoma
`
`Pneumonia!
`
`Pneumonia
`Chest Pain/
`
`
`Chest Pain
`
`Accidental Injury!
`Taylor
`Not Related
`
`
`Automobile Accident
`
`
`Pain 8. Bmisin .
`‘
` Bradycardial
`
`__
`
`Disc. = Discontinued from the study.
`
`'
`' Relative to the day of initial treatment.
`" Relative to the day of retreatment Visit 5 (Week 8). if applicable.
`
`
`7 Data Source: End-of-Text Table 33: Patient Data Listin 13: and CRF
`
`
`
`1 2.3.1.3
`
`Other Significant Adverse Events
`
`No patient discontinued from the study because of adverse events.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`c \cuenrsxouumwuwcoc Mara- 10. me
`
`98
`
`

`

`
`
`-~- GUIDELINES
`INCORPORATED
`
`.GfilG atrium
`
`"—1
`
`0Rl§lNAL
`
`t/‘ii
`'
`
`'
`
`August 20. 1998
`
`Jonathan Wilkin. MD, Director
`Division of Dermatologic and Dental Drug Products (HFD-540)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Central Documents Room
`12229 \Mlkins Avenue
`Rockville, MD 20852
`
`,
`
`
`PEG D
`’l
`"
`AUG 2 131993}
`
`f. n00
`
`
`
`
`REFERENCE: New Drug Application for Levulan® (aminolevulinic acid HCI)
`KerastickTM for Topical Solution, 20% - NDA No. 20-965
`
`Dear Dr. Wilkin:
`
`On behalf of our client, DUSA Pharmaceuticals. Inc, we herewith amend the
`subject application in accordance with 21CFR §314.60 to provide the following
`information requested by the Division during a telephone conversation on 20
`August 1998.
`i
`
`As stated in the Device Manufacturing Documentation Section of the above
`referenced NDA (Section X.
`the final ins 'e tion and QC
`Testing of the clinical devices was conducted by
`on behalf of
`DUSA Pharmaceuticals, Inc. As indicated in our phone conversation, we confirm
`that the facilities and documentation to support the QC Testing of the clinical
`devices by‘
`)are ready for FDA inspection. This facility has not
`been inspected previously by FDA}.
`‘)address is as follows:
`
`, 710320 USA Today Way. Miramar. FL 33025. USA - 9544334430 - Fax; 954432.905 - E-mail: ges@ga:e.net~
`
`

`

`conversation, DUSA
`phone
`out
`pointed
`as
`Additionally,
`However, this will not impact
`Pharmaceuticals, Inc. is acquiring
`the availability of the site and dochrnentation for inspection.
`
`during
`
`our
`
`We trust that this information is satisfactory and that the application will be found
`acceptable for filing.
`
`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.
`awe/D.W
`
`Samuel D. Swetland _
`Vice President, Regulatory Affairs and Compliance
`
`SDS/sds
`DUSAwoA Dean-mmM
`
`m, ,,
`
`APPEARS THIS WAY
`0N ORIGINAL '
`
`'
`
`

`

`GUIDELINES
`
`August 18, 1998
`
`INCORPORATED AUG 2 0 1998
`
`
`a) MEGA DOC RM .1-
`-
`9
`“9’9
`$
`
`”Jami-y
`
`7
`Jonathan Vlfilkin, MD, Director
`Division of Derrnatologic and Dental Drug Products (HFD-540)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Central Documents Room
`12229 \erkins Avenue
`Rockville, MD 20852
`
`REFERENCE: New Drug Application for Levulan® (aminolevulinic acid HCl)
`Kerastick‘" for Topical Solution, 20% - NDA No. 20-965
`
`Dear Dr. Vlfilkin:
`
`On behalf of our client, DUSA Pharmaceuticals, Inc.. we herewith amend the
`subject application in accordance with 21CFR §314.60 to provide information
`requested by the Division during a telephone conversation with Sam Swetland on
`18 August 1998. The following information is provided.
`
`j
`
`The Cover Page (page 10-002) of the Device Manufacturing Documentation
`submitted in the above referenced NDA stated that the device manufacturing
`facility:
`3 would be available for FDA
`inspection in February of 1999. This statement referred to the anticipated date
`when the commercial design,
`the 4170 Blue Light Photodynamic Therapy
`llluminator. would be complete and the manufacturing procedures for this design
`would be in place at the commercial device manufacturer's facility.
`
`As pointed out by Richard Felten during ou.r rbone conversation. an inspection of
`the documentation for the manufacture of the clinical devices will be necessary
`as part of the NDA review. We confirm that the documentation to support the
`
`I0320 USA Today Way. Mirarnar. FL 33025. USA ' 954-433-7480 ' Fax: 954-432-905 ' E-mail: gis@gate.net
`
`‘ "W
`
`

`

`design and manufacture of the clinical devices is aVallablé'at
`for FDA inspection.
`
`Lrand is ready
`
`We trust that this clarification is satisfactory and that the application will be found
`acceptable for filing.
`
`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, Secti
`on 331 j.
`
`Sincerely yours,
`
`’5‘MM D 59%?“ 5.
`Samuel D. Swetland
`Vice President, Regulatory Affairs and Compliance
`
`SDS/sds
`DUSAWDA Doumomsm Lotta-3 doc
`
`_
`
`APPEARS THIS WAY
`
`._._. ..
`
`won ORIGINAL
`
`

`

`.
`
`~
`
`EA: 914.747.7563 June 29, 1998
`
`DusA PHARMACEUTICALS. luc.
`
`400 Coumaus Avenue
`
`VALHALLA. NY 10595
`
`TEL 9 1 4.7471300
`
`WWW.DUSAPHARMA.COM
`
`#5:}.‘Sfiz ‘31,. _.
`
`’,
`
`Jonathan Wilkin. MD, Director
`Division of Dermatologic and Dental Drug Products (HFD-540)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Central Documents Room
`12229 Vtfilkins Avenue
`
`Rockville, MD 20852
`
`Kerastick” for Topical Solution, 20% - NDA No. 20-965
`
`Dear Dr. Vlfilkin:
`
`Pursuant to Section 505(b) of the Federal Food. Drug and Cosmetic Act, and in
`accordance with Title 21 of the Code of Federal Regulations. Section 314.50.
`DUSA Pharmaceuticals, Inc. herewith submits an original New Drug Application
`(NDA) for Levulan® (aminolevulinic acid HCl) Kerastick” for Topical Solution,
`20%, for use in the treatment of multiple actinic keratoses (AKs) of the face and
`scalp.
`'
`
`the
`The Levulan Kerastick for Topical Solution. 20% contains Levulan®,
`hydrochloride salt of aminolevulinic acid. a naturally occurring 5-carbon
`aminoketone. When applied topically, Levulan photosensitizes AKs
`for
`‘ photodynamic therapy with the Model 4170 Blue Light Photodynamic Therapy
`llluminator (Blu-UT").
`
`The Levulan Kerastick is a two component applicator in which Levulan and
`Topical Solution Vehicle are admixed to produce a 20% wlv solution just prior to
`administration. The applicator consists of a plastic tube containing two sealed
`glass ampules and an applicator tip. One ampule contains 1.5 mL of a
`
`m
`
`inuovA‘non m Puo‘roovvumc Tut-A" Extcu‘nvz OF'lCE$. 1.1 Umvtnsl‘rv AVENUE. surf! IZOD. ToRONYo. ONTARIO MSH 3M7
`
`

`

`hydroalcoholic solution vehicle (ethanol content = 48% v/v). comprised of alcohol,
`water, laureth-4, isopropyl alcbhol, and polyethylene glycol. The other ampule
`contains 354 mg of Levulan drug substance. The applicator tube is covered with
`a protective cardboard sleeve.
`
`The Levulan Kerastick and Ble Illuminator comprise a drug/device combination
`product which has been assigned to the administrative jurisdiction of the Center
`for Drug Evaluation and Research. Accordingly, information covering the design
`and manufacture of the illuminator is being provided within the NDA. At the
`request of the Center for Devic s and Radiological Health. the NDA contains
`information on the Model 4170
`lluminator. the blue light illuminator used in the
`Phase Ill clinical trials conducted by DUSA Pharmaceuticals.
`Information on the
`proposed commercial device, the Model 4170 Blu-U, will be included in an NBA
`'Amendment to be submitted in February, 1999.
`L/
`
`At the 4 November 1996 End of Phase II Meeting, the Chemistry Reviewer
`indicated that samples of the container closure system shduld be provided with
`the NDA since the Levulan Kerastick is a novel packaging configuration.
`Therefore, appended to this cover letter (Archival Copy and Chemistry Review
`Copy only) are samples of the finished dosage form as used in the Phase Ill
`clinical
`trials.
`Please note that
`these samples have been labeled for
`
`demonstration purposes only. and do not reflect proposed commercial labeling or
`A];—————previouselinieal—labelingfifiirrm
`
`At the 22 October 1997 Pre-NDA Meeting, the Division of Biometrics requested
`that the Phase lll clinical data be submitted on computer disk, and instructions on
`the type and format of the data files were provided. Appended to this letter
`(Archival Copy and Statistical Review Copy only) are one set of disks containing
`the Phase III data formatted as requested, a listing of the data provided, and
`instructions for the extraction of the data from the zipped files.
`
`A large number of photographs (as 35 mm slides) were taken to document the
`clinical findings of the Phase lll
`trials. While these slides have not been
`submitted as part of the NDA. they are all available for review, and will be
`provided upon Agency request.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`We consider alt 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.
`
`DUSA PHARMACEUTICALS. INC.
`
`//Z’2%
`
`Stuart L. Marcus. MD, PhD
`Senior Vice President. Scientific Affairs
`and Chief Scientific Officer
`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`

`

`BEST POSSIBLE COPY
`
`my 23 l998
`
`FORWARD PLANNING MEETING MINUTES
`
`NDA 20-965
`
`Levulan (aminolevulinic HCI) Kerastick for Topical Solution,
`20%
`
`Date:
`Sponsor:
`Authorized Rep.:
`Pharmacologic class:
`Type:
`Indication:
`Active ingredient:
`Filing Date:
`Regulatory Due Date:
`User Fee Due Date:
`
`'
`
`August 18, 1998.
`DUSA Pharmaceuticals
`Guidelines, Inc.
`Photodynamic Therapy Photosensitizer
`IS
`\actinic keratoses of the face and scalp
`Treatment of:-
`arninolevulinic acid HCl
`August 30, 1998.
`December 28, 1998.
`May 1, 1999.
`
`_
`
`Attendees:
`
`» Jonathan Wilkin, M.D., Division Director, HFD-S40
`Martin Okun, M.D., Medical Officer, HFD-S40
`Assadollah Noory, Pharmacokineticist, HFD-880
`Dennis Bashaw, Pharm. D., Team Leader Biopharmaceutics,
`HFD-88O
`Amy NostrandtTPhd-Dfilharmacologist, HFD-54O
`Norman See, Ph.D., Pharmacologist, HFD-540
`Steve Hathaway. Ph.D., Chemist, HFD-830
`Wilson DeCamp, Ph.D., Team Leader/Chemistry, RFD-830
`y
`R. Srinivasan, Ph.D., Team Leader/Biostatistics, HFD-725
`6‘
`Shahla Farr, M.S., Biostatistics, RFD-725
`Leif71,5 ‘3 M'
`Richard Felten, Chemist, CDRH, HJFZ-410
`Mary Jean Kozma-Fomaro, Supv. Project Manager, RFD-540 V4
`I"L
`
`_
`
`Discussion:
`
`The meeting was convened to determine the adequacy of NDA 20-965 for filing. All sections of
`the New Drug Application (NDA) were evaluated in terms of general content and format
`requirements.
`
`From a preliminary evaluation of the general content and format as well as the non clinical
`pharmacology and toxicology, human pharmacokinetics, clinical data, chemistry, statistical, and
`device sections of the application, it was recommended that NDA 20-965 be filed.
`
`All disciplines stated that no additional information from the Sponsor is needed at this time with
`the exception of Devices.
`_It was not clear if the commercial device manufacturing site was ready
`for inspection. During the meeting, the Sponsor we? contacted to clarify statements regarding
`
`readiness for inspection of the manufacturing site of the commercial device. The Sponsor
`
`indicated that the‘
`1 is ready for inspection. Details of this
`telephone conversation are attached.
`
`

`

`Expected date of draft review:
`
`Chemistry
`Pharmacology
`Biopharmaceutics
`Biostatistics
`
`Clinical
`
`12/98
`2/99
`1 0/98
`2/99
`
`2/99
`
`It was agreed that an action on this application should be issued by 5/99.
`
`APPEARS THIS WAY
`0N ORlGlNAL
`
`Attachments: Checklists, Memo of Telecon dated 8/18/98.
`
`

`

`cc:
`
`Original NDA 20-965
`HFD-540/DIV FILE
`
`HFD-540/CHEM/Hathaway
`HFD-540/SR CHEM/DeCamp
`HFD-540/PHARM/Nostrandt
`HFD—540/SR PHARM/Jacobs
`HFD-725/BIOSTAT/Farr
`HFD-725/SR BIOSTAT/Srinivasan
`HFD—540/MO/Okun
`
`HFD-880/PK/Noory
`HFD-880/SR BIOPHARM/Bashaw
`HFD-540/SU'PV PROJ MGR/Kozma-Fomaro
`HFD-540/PROJ MGR/Cintron
`
`
`
`APPEARS THIS WAY
`0N ORiGINAL
`
`

`

`MEMORANDUM OF TELEPHONE CONFERENCE
`
`DATE:
`NBA:
`DRUG:
`SPONSOR:
`
`August 18, 1998
`20-965
`Levulan (aminolevulinic HCI) Kerastick for Topical Solution, 20%
`Guidelines Incorporated
`Sam Swetland
`
`FDA:
`
`Dr. Alan Gollup
`Dr. Jonathan Wilkin, DD, RFD-S40
`
`\ U“
`(—- ,
`Mr. Richard Felten, Reviewer, CDRH
`Mary Jean Kozma-Fornaro, C, PMS, HFD-SW /S l0 l
`
`SUBJECT:
`
`Inquiry on Commercial Device -
`
`During the filing meeting for NBA 20-965, Sponsor was contacted to clarify statements
`regarding the commercial device for this NDA. Sponsor stated that the commercial device
`
`manufacturing site,
`__1 is ready for inspection.
`
`The official statement of above was faxed into the division and also formally submitted.
`This allowed the NDA to be filed.
`
`Conversation ended amicably.
`
`CC:
`
`NDA 20-965
`
`HFD—S40/Div File
`HFD-S40/Cintron
`HFZ-410/Felten
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`
`(I
`
`Meeting Minutes
`
`_
`
`/S/
`
`A
`
`M
`
`Date: November 4, 1996
`
`Time:
`
`1PM
`
`Location: N-225
`
`IND:(
`
`j Levulan(5-aminolevulinic acid HCL)Topical Solution
`
`Type of meeting:
`
`End of Phase 2
`
`Meeting Chair:
`
`Linda Katz, M.D., Deputy Director, BED—540
`
`Meeting Recorder: M.J.Kozma-Fornaro,Supv. Proj. Mgr.,HFD-54O
`Olga Cintron, Project Manager, RFD-540
`
`FDA Attendees:
`
`R.Srinivasan, Ph.D.,Team Leader, Biostatistics, RFD-725
`Cheryl Dixon, Ph.D., Biostatistics, BED-540
`Robin Anderson, R.N., MBA, Project Manager, RFD-540
`Abby Jacobs, Ph.D., Team Leader, Pharmacology, RFD-540
`Amy Nostrandt, Ph.D., Pharmacologist, RFD-540
`Ramzy Labib, M.D., Medical Officer, RFD-540
`Wilson DeCamp, Ph.D., Team Leader, Chemistry, RFD-540
`Janet Higgins, Chemist,.HED-S4D
`r
`Bonnie B. Dunn, Deputy Director, RFD-830
`Linda Katz, M.D., Deputy Director, BED-540
`M.J.Kozma-Fornaro,R.N., M.S.A., Supv.Project Manager, RFD-540
`Olga Cintron, R. Ph., Project Manager, RFD-540
`
`Sponsor Attendees:
`
`Samuel Swetland, Consultant, Regulatory Affairs, Guidelines,
`Stuart L. Marcus, M.D., Ph.D., DUSA Pharmaceuticals, Inc.
`Russell 8. Sobel, M.S., DUSA Pharmaceuticals,
`Inc.
`
`Inc.
`
`i4
`
`‘
`
`
`lyn Golub, Ph.D.,Technical/Regu atory Affairs, Guidelines, Inc.
`Geoffrey Shulman, M.D., President/CEO, DUSA Pharmaceuticals,
`Inc.
`
`5)
`
`Meeting Objectives:
`
`To discuss the completeness of the pharmacology,
`1.
`and chemistry, manufacturing and controls information.
`
`toxicology
`
`To evaluate the adequacy of the Phase 2 studies and the
`2.
`adequacy of the proposed Phase 3 protocols to establish safety
`and effectiveness fo.
`the claimed indication.
`
`

`

`Discussion points:
`
`CHEMISTRY, MANUFACTURING AND CONTROLS:
`
`The following comments were provided to the sponsor with respect
`to CMC:
`
`1.
`
`Proposed specifications:
`
`(A)Drug Substance
`
`Additional parameters that should be considered are; pH,
`
`specifications of'
`'
`,identified on page 265-6 ( namel"%
`Sandx
`f
`>MW__/ and a test for residual solvent should be provided, if
`;\
`applicable.
`
`h... lira—~-
`The UV spectra for the drug substance and key related substances
`
`that are potentialg
`7 mmm
`A
`ishould also
`be provided.
`“
`”
`
`Since there is no NDA for this drug substance, a full
`rmw7_eficharaeterizatieneef—the—drug-substance should be provided; TEE'
`sponsor may refer to February 1987 guidelines for submitting
`documentation in drug applications for the manufacture of the
`drug substance or may reference to a DMF which contains this
`information.
`
`Please note that the drug substance manufacturer has no
`inspection history according to the sources consulted.
`
`(B) Drug product and intermediates
`
`The specifications provided on page 274-5 seem to be adequate at
`this time. However, examination of the full tests methods and the
`NDA as a whole will need to be performed before a full evaluation
`can be rendered.
`
`2.
`
`Stability protocol:
`
`(A) Drug substance
`
`One set of regulatory specifications should be provided. The
`statement regarding to related substances specifications, also
`applies to this section.
`
`Stability at 25 C/60% RH: An initial time point should
`
`2
`
`

`

`be provided. The two weeks and one month time period could be
`eliminated.
`'
`
`)An initial time point should be
`Stability atW_ __
`provided and a two month time period should be added. The two
`week station could be eliminated.
`
`the drug substance should be stressed under a1
`Also,
`protocol.
`
`-jstress
`
`(B) Drug product
`
`The stability specifications were not described on page 281-7.
`The sponsor should clarify if they will be the same as the
`release specifications.
`'
`
`The sponsor should clarify if the product is tested in both
`states,
`the vehicle and drug substance and the reconstituted drug
`product.
`-
`
`The stability of activated applicators should be provided in the
`NDA.
`
`Additional comments:
`3.
`
`Labeling- The first paragraph of the DESCRIPTION section does not
`belong in this section. Also,
`this product, should not be labeled
`as a topical solution.
`
`Please note the changes of light delivery system on page 239—40
`of the package.
`
`Letters of authorization should be provided for all DMF’s
`referenced in the NDA.
`
`PHARMACOLOGY/TOXICOLOGY
`
`The following comments were provided to the sponsor by the
`pharmacologist:
`
`including an in vitro cytogenetic test in mammalian cells,or cite
`studies addressing this from the literature. An in vivo test for
`test for chromosomal damage in rodent hematopoietic cells should
`be performed if significant systemic exposure is demonstrated
`after topical administration.
`
`

`

`Photogenotoxicity testing should be performed.
`
`Transdermal absorption should be performed, as part of the
`clinical trials to-estimate systemic exposure. If this is
`minimal,
`then further toxicity testing may not be necessary.
`If there is significant systemic exposure,
`then the sponsor
`should perform testing in animals for:
`teratogenicity and ocular
`effects (e.g.
`tissue concentrations and photosensitivity).
`Alternatively,
`the sponsor may provide relevant clinical data.
`
`*
`
`The sponsor stated that genotoxicity and photogenotoxicity
`testing will be performed. Also,
`that some human (systemic)
`pharmacokinetic and in vitro transdermal absorption data was
`available as well as clinical data from patients with
`porphyrias that will be submitted. The pharmacologist
`clarified that if these data demonstrate lack of significant
`systemic absorption and/or adequately address the toxicity
`issues,
`they will be acceptable.
`
`CLINICAL:
`
`The following comments were provided by the medical officer:
`
`The protocol included on page 152 and page 158 of the package is
`not clear whether the same patient may be treated on