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

`

`NDA 20-965
`
`Guidelines, Incorporated
`Attention: Mr. Samuel D. Swetland
`
`Vice President, Regulatory Affairs and Compliance
`10320 USA Today Way
`
`Miramar, Florida 33025
`
`Dear Mr. Swetland:
`
`Please refer to your new drug application (NDA) dated June 29, 1998, received July 1, 1998,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for LEVULAN"
`KERASTICKm (aminolevulinic acid HCl) for Topical Solution, 20%, for use in photodynamic therapy
`with blue light irradiation using the BLU-U" Illuminator.
`
`We acknowledge receipt of your submissions dated June 21, July 7 and 28, October 1, 8 and 11,.
`November 11, and December 2 and 3, 1999 (facsimiles). Your submission of October 1, 1999,
`constituted a complete response to our June 27, 1999, action letter.
`
`This new drug application provides for the use of LEVULAN" KERAS'I'ICK"I (aminolevulinic acid
`HCl) for Topical Solution, 20%, when used with blue light irradiation using the BLU-UTM Illuminator
`for the photodynamic therapy of actinic keratoses of the face and scalp.
`
`We have completed the review of this application, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product is safe and effective for use as
`recommended in the agreed upon enclosed labeling text. Accordingly, the application is approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert,
`text for the patient package insert, carton and applicator labels). Marketing the product with FPL that
`is not identical to the approved labeling text may render the product misbranded and an unapproved
`new drug.
`
`Please submit 20 copies of the FPL as soon as it is available, in no case more than 30 days after it is
`printed. Please individually mount ten of the copies on heavy-weight paper or similar material. For
`administrative purposes, this submission s" ould be designated "FPL for approved NDA 20-965."
`Approval of this submission by FDA is not required before the labeling is used.
`
`

`

`NDA 20-965
`
`Page 2
`
`We remind you of your Phase 4 commitments specified in your submissions dated October 1, and
`December 2, 1999. These commitments, along with any completion dates agreed upon, are listed
`below:
`
`1. A commitment to characterize the potential for dermal allergenicity of LEVULAN'
`KERASTICK" (aminolevulinic acid HCI) for Topical Solution, 20%, within 24 months of
`approval.
`
`2. A commitment to characterize the safety and efficacy of LEVULAN" KERASTICK"
`(aminolevulinic acid HCl) for Topical Solution, 20%, plus blue light photodynamic therapy to assess
`the long-term recurrence rate of actinic keratosis lesions over a 12-month follow-up period. As
`part of this study, the histopathology of treated actinic keratosis lesions (including lesions that recur
`in long-term follow-up) should be characterized. Patients with Fitzpatrick skin types IV-VI should
`be included in this study. This study would be completed within 4 years of approval.
`
`3. A commitment to re-evaluate the drug substance and drug product specification limits for [
`once adequate data are available.
`
`]
`
`Protocols, data, and final reports should be submitted to your IND for this product and a copy of the
`cover letter sent to this NDA. If an IND is not required to meet your Phase 4 commitments, please
`submit protocols, data and final reports to this NDA as correspondence. In addition, under 21 CFR
`314.82(b)(2)(vii), we request that you include a status summary of each commitment in your annual
`report to this NDA. The status sumrhary should include the number of patients entered in each study,
`expected completion and submission dates, and any changes in plans since the last annual report. For
`administrative purposes, all submissions, including labeling supplements, relating to these Phase 4
`- commitments must be clearly designated "Phase 4 Commitments."
`
`Validation of the regulatory methods has not been completed. At the present time, it is the policy of the
`Center not to withhold approval because the methods are being validated. Nevertheless, we expect
`your continued cooperation to resolve any problems that may be identified.
`
`Be advised that, as of April 1, 1999, 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 (63 FR 66632). We note that you have not fulfilled the requirements of 21 CFR
`314.55 (or 601.27). We are deferring submission of your pediatric studies until December 2, 2000.
`However, in the interim, please submit your pediatric drug development plans within 120 days from the
`date of this letter unless you believe a waiver is appropriate.
`
`

`

`NDA 20-965
`
`Page 3
`
`If you believe that this drug qualifies for a waiver of the pediatric study requirement, you should submit
`a request for a waiver with supporting information and documentation in accordance with the provisions
`of 21 CFR 314.55 within 60 days from the date of this letter. We will notify you Within 120 days of
`receipt of your response whether a waiver is granted. If a waiver is not granted, we will ask you to
`submit your pediatric drug development plans within 120 days from the date of denial of the waiver.
`
`Pediatric studies conducted under the terms of section 505A of the Federal Food, Drug, and
`Cosmetic Act may result inadditional marketing exclusivity for certain products (pediatric exclusivity).
`You should refer to the Guidancefor Industry on Qualifyingfor Pediatric Exclusivity (available on
`our web site atWe) for details. If you wish to qualify for pediatric exclusivity
`you should submit a "Proposed Pediatric Study Request" (PPSR) in addition to your plans for pediatric
`drug development described above. We recommend that you submit a Proposed Pediatric Study
`Request within 120 days from the date of this letter. If you are unable to meet this time frame but are
`interested in pediatric exclusivity, please notify the division in writing. FDA generally will not accept
`studies submitted to an NDA before issuance of 3 Written Request as responsive to a Written Request.
`Sponsors should obtain a Written Request before submitting pediatric studies to an NDA. If you do
`not submit a PPSR or indicate that you are interested in pediatric exclusivity, we will proceed with the
`pediatric drug development plan that you submit and notify you of the pediatric studies that are required
`under section 21 CFR 314.55. Please note that satisfaction of the requirements in 21 CFR 314.55
`alone may not qualify you for pediatric exclusivity. FDA does not necessarily ask a sponsor to
`complete the same scope of studies to qualify for pediatric exclusivity as it does to fulfill the
`requirements of the pediatric rule.
`
`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock-up form, not final
`print. Please send one copy to the Division of Dermatologic and Dental Drug Products and two copies
`of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD—40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314. 80 and 314. 81.
`
`

`

`NDA 20-965
`
`Page 4
`
`If you have any questions, contact Olga Cintron, Project Manager, at (301) 827-2020.
`
`Sincerely,
`
`Robert J. DeLap, M.D., Ph.D.
`Director
`
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

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

`

`( DEPARTMENTOF HEALTH&HUMANSERVICES
`
`PuhlicHealthService
`
`
`
`Division of Dermatologic and Dental Drug Products
`
`Center for Drug Evaluation and Research
`Food and Drug Administration
`9201 Corporate Boulevard, HFD-S4O
`Rockville, MD 20850
`
`FACSIMILE TRANSMISSION
`
`Number of Pages (including cover sheet) 29
`DATE: June 28, 1999.
`TO: Mr. Samuel Swetland, Vice President, Regulatory Affairs and Compliance
`COMPANY: Guidelines, Inc.
`,
`NUMBER: 954-432-9015
`
`MESSAGE: RE: NDA 20-965
`
`LEVULAN KERASTICK (aminolevulinic acid HCl) for Topical Solution,:20%: ;
`
`Please find approvable letter for this NDA with revised draft labeling.
`
`»-
`
`NOTE: We are providing the attached information via telefacsimile for your convenience. Please
`feel free to contact me if you have any questions regarding the contents of this transmission.
`
`FROM : Olga Cintron, R.Ph.
`TITLE: Project Manager
`TELEPHONE: 301- 827-2020
`
`‘
`
`FAX NUMBER: 301-827-2075
`
`THIS DOCUMENT lS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED. CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW. Ifyou
`are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination, copying, or other action based on the content ofthis communication is not authorized. If you have received this document in error,
`please immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`C c '. fl/o/I 52w 96$
`”0- syn/om N“ T
`
`

`

`.’
`
`m
`
`g. ( DEPARTMENT OF HEALTH 8. HUMAN SERVICES
`'=. C
`3.“Due
`
`
`
`Food and Drug Administration
`Rockville MD 20857
`
`JUN 2 7 I999
`
`N'DA 20-965
`
`Guidelines, Incorporated
`Attention: Mr. Samuel D. Swetland
`Vice President, Regulatory Afi‘airs and Compliance"
`10320 USA Today Way
`Miramar, Florida 33025
`
`Dear Mr. Swetland:
`
`Please refer to your new drug application (NDA) dated June 29, 1998, received July 1, 1998,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for LEVULAN‘”
`KERASTICK" (aminolevulinic acid HCl) for Topical Solution, 20%, for use in photodynarnic
`therapy with blue light irradiation using the BLU-U"'M Illuminator.
`'
`
`We acknowledge receipt of your submissions dated August 18 and 20, September 30, October
`14, November 4, and December 1, 1998; February 17 and 26, March 11, 15 and 31, April 16, 26
`and 30 (two), and June 2, 1999.
`
`-
`
`We have completed the review of this application, and it is approvable. Before this application
`may be approved, however, it will be necessary for you to address the following:
`
`1. During a recent pre-approval inspection, your manufacturer of 5-aminolevulinic acid
`hydrochloride was found to be non-compliant with our current Good Manufacturing Practices
`regulations. Satisfactory inspections will be required for all manufacturing and testing
`facilities before this application may be approved.
`
`2. Submit drafi labeling for the drug product revised as recommended in the enclosed revised
`draft labeling (text for the package insert, carton and applicator labels). Should additional
`information relating to the safety or effectiveness of this drug become available, revision of
`the labeling may be required.
`1
`
`Although not approvability issues, you should address the following informational needs.
`
`Clinical:
`
`a. Characterization of the potential for demial irritancy with LLVULANo KERASTICK"
`(aminolevulinic acid HCl) for Topical Solution, 20%.
`
`

`

`NDA 20-965
`
`Page 2
`
`b. Characterization of the potential for dermal allergenicity with LEVULAN“
`KERASTICK" (aminolevulinic acid HCl) for Topical Solution, 20%.
`
`c. Characterization of the safety and efficacy of LEVULAN° KERASTICKm
`(aminolevulinic acid HCl) for Topical Solution, 20%, plus blue light photodynamic
`therapy when used in the manner described in the proposed labeling in different skin
`types. At least 70 patients should be enrolled. The investigators should be qualified health
`care professionals. To assess the safety profile in patients with Fitzpatrick skin types IV-
`VI, at least 30 of the enrolled patients should have Fitzpatrick skin types IV-VI. The
`safety evaluation should include laboratory evaluations ofhernatocrit and levels of
`urinary aminolevulinic acid, before and after treatment. Patients should be seen in
`follow-up at one year after treatment to assess the long term recurrence rate of actinic
`keratoses that have resolved after treatment with LEVULAN" KERASTICK"
`(aminolevulinic acid HCl) for Topical Solution, 20%, plus blue light photodynamic
`therapy.
`
`d. Characterization of the safety and efficacy of LBVULAN" KERASTICKm
`(aminolevulinic acid HCl) for Topical Solution, 20%, plus blue light photodynamic
`therapy for the treatment of actinic keratoses of the back and arms.
`
`Chemistry:
`
`In order to conform with the conventions set forth in the ICH Q3A guidance document
`"Impurities in New Drug Substances", the drug substance specificationf
`\
`hould be revised as!
`”and
`The limit fori
`'lshould be set at "less than or equal to
`
`-
`
`-
`
`a.
`
`b.
`
`i
`.3
`
`(
`
`In order to conform with the conventions set forth in the ICH Q3B guidance document
`"Impurities in New Drug Products", the dru
`roduct re
`atory ecificatio
`hould berevised asr'
`.
`-
`e limit forJ'
`
`,4
`
`and
`should be set at "less than or equal to
`
`_
`
`Under 21 CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all
`safety information you now have regarding your new drug. Please provide updated information
`as listed below. The update should cover all studies and uses ofthe drug including: (1) those
`involving indications not being sought in the present submission, (2) other dosage forms, and (3)
`other dose levels, etc.
`
`1. Retabulation of all safety data including results of trials that were still ongoing at the time
`
`

`

`NDA 20-965
`
`Page 3
`
`ofNBA submission. The tabulation can take the same form as in your initial submission.
`Tables comparing adverse reactions at the time the NDA was submitted versus now will
`certainly facilitate review.
`
`Retabulation ofdrop-outs with new drop-outs identified. Discuss, ifappropriate.
`
`Details of any significant changes or findings.
`
`Summary ofworldwide experience on the safety ofthis drug.
`
`Case report forms for each patient who died during a clinical study or who did not
`complete a study because of an adverse event.
`
`English translations of any approved foreign labeling not previously submitted.
`
`Information suggesting a substantial difference in the rate of occurrence of common, but
`less serious, adverse events.
`
`Within 10 days afier the date ofthis letter, you are required to amend the application, notify us of
`your intent to file an amendment, or follow one of your other options under 21 CFR 314.1 10. In
`the absence of any suCh action FDA may proceed to withdraw the application. Any amendment
`should respond to all the deficiencies listed. We will not process a partial reply as a major
`amendment nor will the review clock be reactivated until all deficiencies have been addressed.
`
`Under 21 CPR 314.102(d) ofthe new drug regulations, you may request an informal or telephone
`conference with this Division to discuss what firrther steps need to be taken before the
`application may be approved.
`‘
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`Ifyou have any questions, contact Olga Cintron, Project Manager, at (301) 827-2020.
`
`Sincerely
`
`/S/
`
`Robert J. DeLap, M.D., PhD.
`Director
`
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`

`

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