CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 20-965
`
`MEDICAL REVIEW(S)
`
`

`

`Medical Officer's Review of NDA 20-965, AZ Submission
`
`DEC
`
`1
`
`1999
`
`Correspondence date: 10/01/99
`HFD540 #:
`994278
`Document ID: AZ
`
`CDER Stamp date: 10/04/99
`Review date: 11/22/99
`.— ,
`.
`
`SPONSOR: DUSA Pharmaceuticals
`
`DRUG: LEVULAN KERASTICK (aminolevulinic acid HCl) for Topical Solution, 20%
`(LEVULAN)
`.
`
`PHARMACOLOGIC CATEGORY: Anti-neoplastic photosensitizer
`
`PROPOSED INDICATION: Treatment of actinic keratoses (AKs) of the face or scalp
`
`DOSAGE FORM/ROUTE OF ADMINISTRATION: Solution, applied topically to
`actinic keratosis lesions
`-
`
`BACKGROUND:
`"On June 27, 1999, Agency notified Sponsor that NDA 20-965 was approvable. Agency
`informed Sponsor that before approval, satisfactory inspections will be required for all
`manufacturing and testing facilities, and revised drafi labeling must be submitted.
`Revised drafi labelling was submitted as part of this submission and has been reviewed
`and revised by Agency. Labeling that incorporates Agency revisions of sponsor’s drafi
`revised label is appended to the review of this submission.
`
`Four informational needs of clinical relevance were identified:-
`
`0 Characterization of the potential for dermalirritancy with LEVULAN.
`- Characterization of the potential for dermal allergenicity with LEVULAN.
`0 Characterization of the safety and efficacy of LEVULAN in an additional 70'patients.
`At least 30 of the additional patients should have Fitzpatrick skin types IV~VI.
`Follow-up at one year after treatment should be arranged to assess the long term
`recurrence rate of actinic keratoses that have resolved afier treatment.
`0 Characterization of the safety and efficacy of LEVULAN for the treatment of AKs of
`the,
`)
`.,
`
`Sponsor was also requested to update the NDA by submitting all safety information
`pertinent for LEVULAN accumulated since the date of the original NDA submission.
`
`On November 5, 1999, at a meeting ofthe Dermatologic and Ophthalmic Drug Advisory
`Committee, several committee members expressed concern that because LEVULAN
`action may cause oxidative DNA damage, and because treatment with LEVULAN does
`not always result in permanent, complete clearing of AK lesions, the possibility exists
`that LEVULAN treatment may enhance the oncogenic progression ofAK lesions that are
`
`

`

`not permanently, completely resolved by LEVULAN treatment. Several committee
`members also expressed interest in having a patient package insert prepared for the drug
`product. Agency’s revision of sponsor’s drafl patient package insert is appended to this
`submission review.
`
`AZ SUBMISSION SUMMARY:
`Sponsor has committed to characterize the potential for dermal sensitization with
`LEVULAN and characterize the safety and efficacy of LEVULAN in an additional 70
`patients, including patients with Fitzpatrick skin types IV-VI, and to assess the long term
`recurrence rate of AK lesions over a 12-month follow-up period. Sponsor has provided a'
`justification for not undertaking a characterization of the safety and efficacy of
`LEVULAN for the treatment of AKs of the back and arms, and for not undertaking a
`characterization of the potential for dermal irritancy with LBVLHLAN. Sponsor has
`submitted in tabular form safety data fi‘om the results of trials that were still ongoing at
`the time of NBA submission.
`
`.
`
`Following the Drafi Guidance Skin Irritation and Sensitization Study (Modified Draize
`Test), Sponsor plans a controlled study on LEVULAN]
`/
`
`
`l
`
`Reviewer '3 Comment;
`istudy is satisfactory, and as outlined
`The outline oftheprotocolfor theL
`wouldaddress the in ormational need to characterize theg
`l
`Sponsor is encouraged to su mtt t efina study protocol
`
`s
`
`prior to study initiation.
`
`Sponsor suggests that characterization ofthe cumulative in'itaney ofLEVULAN should
`. not be required. The most compelling consideration that sue" a study is not necessary is
`that LEVULAN is unique among dermatological drugs in that it would only be applied
`once or twice to any given skin site. The relevancy ofa cumulative irritancy studyfor
`such a product is unclear.
`
`

`

`
`
`0 Characterization of the safety and efficacy of LEVULAN for the treatment of AKs of
`the:
`
`Sponsor notes that the drug dose-ranging and light dose-ranging studies that were
`undertaken to establish the treatment parameters related to LEVULAN use were designed
`for treatment of AKs of the face or sea]
`and ma not be 0 timal for treatment of lesions
`
`
`
`at other body sites. In particular,
`-
`_
`____—__—______J
`/'—
`
`
`[lhe sponsor states that
`
`--_
`
`
`
`Reviewer ’5 Comment:
`Because the sponsor makes several compelling arguments that characterization ofthe
`safety and efi'icacy ofLEVULANfor treatment ofAKs ofthe
`’
`'s not
`
`warranted at this time, withdrawal of the request by Agencyfofil
`
`
`
`is appropriate at this time.
`
`,
`
`0 Characterization of the risk'of malignant'progression of AK lesions that do not
`undergo complete, permanent clearing after treatment with LEVULAN.
`
`Numerous epidemiologic studies, as well as the clinicalexperience of dermatologists,
`have established that AKs are pre-cancerous skin lesions, with a low risk of malignant
`progression to squamous cell carcinoma of the skin. The theoretical possibility cannot be
`excluded that LEVULAN-induced Oxidative DNA dainage may promote the malignant
`progression of AKs-that are incompletely cleared or that recur after LEVULAN
`treatment. As part of the approval letter, sponsor should be asked to address this
`possibility by committing to perform a clinical study involving long-term (at least 12
`month followup) of treated patients. A goal of this study should include characterization
`of the recurrence rate at 12 months of AK lesions that cleared by the primary endpoint
`(e.g., 8 weeks). .In addition, this study should also characterize the histopathology of AK
`lesions in long-term follow-up. The following discussion concerning the histopathology
`of different grades of AK lesions is based on the article “Incipient Intraepidermal
`Cutaneous Squamous Cell Carcinoma: A Proposal for Reclassifying and Grading Solar
`(Actinic) Keratoses”, by Yantos et al., Semin. Cutan. Med. and Surg., Vol. 18, No. 1,
`3/99, pp. 3-14.
`-
`
`

`

`All AK lesions are characterized by atypical keratinocytic proliferation in the epidermis.
`AK lesions that are hypothesized to have undergone comparatively less malignant
`progression are characterized by atypical keratinocytic proliferation confined to the lower
`one~third or lower two-thirds of the epidermis. AK lesions that are hypothesized to have
`undergone comparatively more malignant progression are characterized by atypical
`keratinocyte proliferation involving the full thickness ofthe epidermis including adnexal
`structures. Lesions in which there is extension ofneoplastic Cells from the epidermis into
`the papillary or reticular dermis are considered squamous cell carcinoma of the skin.
`The hypothesis that sponsor’s study should be designed to reject is that AK lesions that
`are (a) completely cleared; (b) completely cleared but recur during follow-up; and (c) not
`completely cleared carry an increased risk of either (1) atypical keratinocyte proliferation
`involving the full thickness of the epidermis including adnexal structures, or (2)
`squamous cell carcinoma of the skin. Sponsor should estimate the spontaneous incidence
`of progression of actinic keratoses to squamous cell carcinoma of the skin based on a
`review of the relevant scientific literature, and based on this estimate, should characterize
`the histopathology of enough treated lesions to preclude thepossibility 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 as a consequence of treatment.
`
`,
`
`0
`
`Sponsor’s update of NDA, with submission of all safety information pertinent for
`LEVULAN accumulated since the date of the original NDA submission.
`
`
`Sponsor submitted the safety results from
`
`bugging}
`
`
`
`

`

`o
`
`Sponsor’s literature review relevant to LEVULAN
`
`Sponsor notes the publication of a case report describing a patient believed to have
`developed contact sensitization from S-aminolevulinic acid. The patient described in this
`case report (Gniazdowska et al., Contact Dermatitis, 1998, Vol. 38: 348-349) was
`receiving photodynamic therapy for Bowen’s disease ofthe vulva. The patient had a
`positive patch test reaction to S—aminolevulinic acid. In sponsor’s comment on this
`article, it was noted that the ALA was formulated as a gel rather than a solution, which
`may have made it more sensitizing, that vulva may be more sensitizing than glabrous
`skin, and that over 600 patients have been tested by sponsor with a variety of S-ALA
`formulations and concentrations, with no reports of contact dermatitis developing in these
`patients. As mentioned above, sponsor has committed to perform a contact sensitization
`study of LEVULAN Topical Solution.
`
`REGULATORY CONCLUSIONS
`Approvability Issues:
`0
`Sponsor’s agreement to the labeling for the drug product and the patient package
`insert will be required before this application may be approved.
`7 V,_sg-- "The theoretical possibility cannot be excluded that LEVULAN—induced oxidative
`DNA damage may promote the malignant progression of AKs that are incompletely
`cleared or that recur after treatment. As part of a post-approval commitment, sponsor
`is requested to address this possibility by committing to perform a clinical study
`involving long-term (at least 12 month follow-up) of treated patients. A goal of this
`study should include characterization of the recurrence rate at 12 months of AK
`lesions that cleared by the primary endpoint (e.g., 8 weeks). In addition, this study
`should also characterize the histopathology of AK lesions in long-term follow-up. In
`this regard, the hypothesis that sponsor’s study should be designed to reject is that
`AK lesions that are (a) completely cleared; (b) completely cleared but recur during
`follow-up; and (c) not completely cleared carry an increased risk of either (1) atypical
`keratinocyte proliferation involving the full thickness of the epidermis including
`adnexal structures, or (2) squamous cell carcinoma of the skin. Sponsor shoirld
`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, should 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 as a consequence of treatment.
`Sponsor is encouraged to submit the final study protocol prior to study initiation.
`
`The following -omments pertain to the informational needs identified in the June 27,
`1999 letter to sponsor, and how sponsor has addressed these needs:
`.
`.
`.
`.
`.
`.
`cal/yr (“way
`0 Characterization of the potential for dermal rrntancy and for dermal
`wrth
`LEVULAN KERASTICK (aminolevulinic acid HCI) for Topical Solution, 20%.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`’ i A
`
`

`

`The outline of the protocol for the skin sensitization study is satisfactory, and as outlined
`would address the informational need to characterize the potential for dermal
`sensitization by LEVULAN. Sponsor is encouraged to submit the final study protocol
`prior to study initiation. The induction phase of the sensitization study, which entails
`repeated exposures of skin to LEVULAN over a period of several weeks, is de facto a
`type of dermal irritation study. If sponsor submits to Agency the dermal irritation scores
`during the induction phase along with data analysis, this may potentially obviate a need
`for a separate dermal irritancy study.
`
`0 Characterization of the safety and efficacy of LEVULAN in an additional 70 patients.
`At least 30 of the additional patients should have Fitzpatrick skin types IV-VI.
`Follow-up at one year afier treatment should be arranged to assess the long term
`recurrence rate of actinic keratoses that have resolved after treatment.
`
`Sponsor has agreed to address this informational need. This informational need partly
`overlaps with the approvability issue relating to characterization of the recurrence rate at
`12 months ofAK lesions that cleared by the primary endpoint and characterization_ofthe
`histopathology of AK lesions in long-term follow-up. A single clinical study may
`potentially address the approvability issue and the informational need.
`
`0 Characterization of the safety and efficacy of LEVULAN for the treatment of AKs of
`thd
`}
`
`, Because the sponsor makes several compelling arguments that characterization of the
`safety and efficacy of LEVULAN for treatment ofAKs of the
`iis not
`warranted at this time, withdrawal of the request by Agency for a commitment to
`
`‘
`
`I-
`[
`
`$8
`
`n/zz/fiq
`
`I M
`
`artin M. Okun, MD, Ph.D.
`Medical Reviewer
`
`cc:
`
`Archival NDA
`
`RFD-540
`
`HFD-540/DivisionDirector/Wilkin G\t 7/470]
`
`HFD-540/Dermatology Team Leader/Walke
`r_,,\
`I-IFD-540/Medical Reviewer/01am
`HFD-725/Biostatistics Team Leader/Srinivasar?
`HFD-725/Biostatistician/Farr
`-
`HIFD-SSO/Biopharm/Noory
`I-IFD-540/Pharm/Nostrandt
`I-IFD-540/Chemistry/Hathaway
`HFD-540/Project Manager/Cintron
`
`N4?
`
`t ’1—
`
`

`

`_-\_ Page(s) Redacted
`
`

`

`ADDENDUM TO MEDICAL OFFICER’S REVIEW OF NDA# 20-965
`
`JUNél 2 I999
`
`Information Reviewed:
`NDA Amendment, date of submission 3/11/99, CDER stamp date 3/12/99
`NDA Amendment, date of submission 4/16/99, CDER stamp date 4/19/99
`NDA Amendment, date of submission 4/26/99, CDER stamp date 4/27/99
`NDA Amendment, date of submission 4/30/99, CDER stamp date 5/03/99
`NDA Amendment, date of submission 4/30/99, CDER stamp date 5/03/99
`NDA Amendment, date of submission 3/31/99, CDER stamp date 4/01/99
`
`9‘3"?pr
`
`'
`
`Addendum Date: May 08, 1999
`
`Sponsor: DUSA Phannaceuticals
`
`Proposed trade name: LEVULAN® (aminolevulinic acid HCl) KERASTICK'”M for
`Topical Solution, 20%
`
`DRUG: aminolevulinic acid HCl
`
`PHARMACOLOGIC CATEGORY: Anti-neoplastic photosensitizer
`
`PROPOSED INDICATION:
`
`treatment of}
`
`iactinic keratoses of the face and Scalp
`
`DOSAGE FORM AND ROUTE OF ADMINISTRATION: solution, applied topically to
`actinic keratoses.
`
`BACKGROUND
`
`Amendments 1 through 6 pertain to: (1) NDA safety update on 19 patients treated under
`INDijsubsequent to the NDA analyses; (2) labeling update; (3) information
`frequested by medical officer regarding whether lesions on cars were treated; (4)
`fi’equency of use of chin rest during light treatment; (5) case report of allergic contact
`dermatitis resulting from photodynamic therapy with aminolevulinic acid (not the
`sponsor’s formulation); and (6) CVs of unblinded investigators.
`
`,
`:
`.
`,
`,,
`AMENDMENTS
`l. The only clinical study performed under INDC:}since-NDA 20-965 was
`submitted is Protocol ALA-012, “A Phase I/II study of Photodynamic Therapy with
`Levulan (S-Aminolevulinic Acid HCl) Topical Solution and Visible Red Light for the
`Removal of Hair”. This study has enrolled nineteen patients. Safety information for
`these patients is now available.
`Reviewer '3 Comrnent:
`- The adverse event profile among these patients was not substantially dtfi'erent than
`the adverse event profile seen in the clinical studies submitted to support the
`indication oftreatment ofactinic keratoses oftheface and scalp.
`0 No deaths or serious adverse events were noted among the nineteen patients.
`
`

`

`2. Sponsor has submitted an amended label replacing “picture text boxes” with digital
`photographs to show the activation steps of the Levulan Kerastick.
`Reviewer 's Comment:
`
`The digital photographs are acceptable.
`
`3.
`
`Sponsor conducted a review of case report forms for clinical studies ALA-018 and
`ALA-019 for the purpose of determining the number of target lesions located on
`patients’ ears. Six target lesions were located on the ears, half of which were on
`patients enrolled in the active arm of the studies. The lesion clearance rate was 67%
`for ear lesions receiving active treatment and 0% for ear lesions receiving vehicle
`treatment.
`
`Reviewer '3 Comment:
`
`The number ofear lesions receiving active treatment was too low to permit a reliable
`estimate ofthe efi’icacy oftreatment with LEVULAN at this anatomic site. Given that
`patients with ear lesions were enrolled in the study, it would be appropriate not to
`exclude ear lesionsfifom treatment in the package label.
`
`For the pivotal Phase 3 clinical trials, sponsor provided to investigators a chin rest
`designed for patient use during the approximately 16 minute duration of light
`treatment. It was unclear from sponsor’s initial submission whether patients did
`actually use the provided chin rest. At the. request of the medical reviewer, sponsor
`7”“ ------u - performed a retrospective evaluation to estimate the percentage ofpatients who
`utilized the chin rest supplied by sponsor. Based on responses, more than 50% of the
`patients in the Phase 3 trials used the chin rest. Sponsor has agreed to include
`wording for the operating device that states that “A chin rest, available from DUSA,
`may be used to provide support for the patient’s head during treatment.” The sponsor
`_ is submitted a PMA Amendment pToviding—device design and manufacturing
`information for the chin rest used in the Ehase 3 trials.
`Reviewer 's Comment:
`.0
`
`These changes are satisfactory.
`
`5.
`
`This is a case report of a patient who developed allergic contact dermatitis following
`photodynamic therapy With, an aminolevulinic acid solution different than
`LEVULAN® KERASTICKTM. The allergic contact dermatitis resolved with
`treatment with topical corticosteroids. On patch testing, the patient was found to be
`reactive to 20% aminolevulinic acid solution.
`.
`.
`Reviewer '5 Comment:
`This case report points out the needfor dermal sensitization studies with
`LE VULAN®, which have not yet been performed.
`
`This is a listing of the curriculum vita of all unblinded investigators in the two pivotal
`clinical studies, ALA-018 and ALA-019. In these studies, the unblinded investigators
`interviewed patients to elicit adverse events and characterized the adverse events on
`the CRFs.
`
`Reviewer '3 Comment:
`
`The information was reviewed.
`
`

`

`Martin M. Okun, M.D., PhD.
`
`cc:
`
`Archival NDA
`
`RFD-540
`
`HFD-540/Division Director/Wilkin
`HFD--540/Dennatology Team Leader/Walker
`HFD-540/Mcdical Reviewer/01mm
`
`2"/67
`
`HFD-S40/ProjectManager/Cintron @411[2.1/77
`
`"
`
`i
`
`_ APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`APR
`
`3l999
`
`Medical Officer’s Review of NDA 20-965
`
`—Iand_l uuN—|
`
`General Information
`
`NDA submission number 000
`
`Applicant identification
`1.2.1 Name
`
`DUSA Pharmaceuticals, Inc.
`1.2.2 Address and telephone number.
`400 Columbus Avenue
`
`Valhalla, N.Y., 10595
`1.2.3 Name of company official or contact person:
`Samuel D. Swetland .
`
`Vice President, Regulatory Affairs and Compliance
`Guidelines, Inc.
`10320 USA Today Way
`Miramar, FL 33025
`
`(Ph.) 954-433-7480; (Fax) 954-432-9015
`Submission/review dates
`
`1 .3
`
`1.3.1 Date of submission (date of applicant’s letter)
`June 29, 1998
`1.3.2 CDER stamp date
`July 01, 1998
`1.3.3 Date submission received by reviewer
`July 28, 1998
`1.3.4 Date review begun
`August 11, 1998
`1.3.5 Date review completed
`April 1, 1999
`
`_
`
`1.4 Drug identifications .
`1.4.1 Generic name
`
`Aminolevulinic Acid HCl
`
`1.4.2 Proposed trade name
`LEVULAN® Kerastickm
`
`'
`
`1.4.3 Chemical name
`
`5-amino-4—oxopentafioic acid
`1.4.4 Chemical structure:
`
`, O
`
`o
`
`NH3+ CI'
`
`

`

`1.4.5 Molecular formula
`
`C,NO,H,-HC1
`1.4.6 Molecular weight
`167.59
`
`1.5
`
`1.6
`
`Pharmacological Category
`Anti-neoplastic photosensitizer
`
`Dosage Form
`Solution
`
`1.7
`
`Route of Administration
`
`Topical
`
`Proposed Indication 8: Usage section:
`1.8
`Treatment of=\
`actim'c keratoses of the face and scalp
`
`1.9
`
`Proposed Dosage & Administration section:
`
`From the proposed label: 1
`
`1.10 Related Drugs
`None
`
`'1.1 1 Material Reviewed
`
`1. 1 1.1 NDA volumes reviewed
`
`NDA Volumes Reviewed and their Contents
`
`
`
`_—
`
`
`
`
`
`
`
`1 71
`
`1.70
`
`
`
`Integrated Summary of Efficacy,
`Integrated Summary of Safety
`Retrospective Study of Clinical
`History in Patients with
`Erythropoietic Protopon ~thyria
`and Acute Intermittent Porphyn‘a
`
`
`
`
`

`

`1.11.2 Regulatory Documents Reviewed
`Minutes of End of Phase 2 meeting, minutes of Pre-NDA meeting.
`1.11.3 Non—Regulatory Documents Reviewed
`Literature Search on the Epidemiology of Actinic Keratosis
`
`1.12 Regulatory Background
`December 1, 1992: Sponsor files 1ND
`November 4, 1996: End of Phase 2 Meeting, Clinical comments
`Patients will have only one site (either the face or the scalp) treated
`Photographs should be taken to back up investigator's evaluation, and photographs
`should be taken for each patient that has been retreated at a specific site
`. Each center will have a list of investigators who are blinded and unblinded before
`starting the study
`The primary efficacy criteria is the percentage ofpatients who have greater than 75%
`complete response of their lesions
`Pigmentary changes (hypo or hyperpigmentation) are considered adverse events
`Laboratory evaluations will be performed at 4 weeks
`Extent of goggle use should be defined in the protocol
`Sponsor should clarify whether hyperkeratotic lesions are target lesions
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`2 Table of Contents
`
`‘
`
`4
`
`1
`
`General Information ............................................................................................................................. l
`1.1
`NDA submission number 000 .................................................................................................. I
`1.2 Applicant identification.............................................................................................................. 1
`1.2.2
`Address and telephone number: .............................................................................................. 1
`1.2.3
`Name of company official or contact person:........;................................................................ 1
`1.3
`Submission/review dates .......................................................................................................... 1
`1.3.1
`Date of submission (date of applicant’5 letter) ....................................................................... 1
`1.3.2
`CDER stamp date.................................................................................................................... 1
`1.3.3
`Date submission received by reviewer ................................................................................... 1
`1.3.4
`Date review begun .................................................................................................................. 1
`1.3.5
`Date review completed ........................................................................................................... 1
`1.4
`Drug identification ...................................................................................................................... 1
`1.4.1
`Generic name .................................................................................................................... ...... 1
`1.4.2
`Proposed tradename‘............................................................................................ 1
`1.1.3
`Chemical name ............................................................................. '.......................................... 1
`1. 1 .4
`Chemical structure: .......................................................................................................... 1
`1.1.5
`Molecular formula ...........................................e ...................................................................... 2
`1.1.6
`Molecular weight .................................................................................................................... 2
`1.5
`Pharmacological Category ........................................................................................................ 2
`1.6 Dosage Form ................................................................................................................................ 2
`1.7
`Route of Administration ............................................................................................................ 2
`”v ’7 77777.8 Proposed Indication & Usage section: ................................................................................... 2
`.1 .9
`Proposed Dosage-&.Administrationsection: ........................................................................ 2
`1.10
`Related Drugs .......................................................................................................................... 2
`1.1 1
`Material Reviewed .................................................................................................................. 2
`1.11.1
`NDA volumes reviewed.......................................................................................................... 2
`1.11.2
`Regulatory Documents Reviewed........................................................................................... 3
`1.11.3
`Non-Regulatory Documents Reviewed .................................................................................. 3
`1.12
`Regulatory Background ......................................................................................................... 3
`Table of Contents ................................................................................................................................. 4
`2
`Chemistry/Manufacturing Controls........................................................................................ 5
`3
`Animal Pharmacology/Toxicology...................................................................................................... 6
`4
`Devices .......................................................................................................................................................... 6
`6
`Human Pharrnacokinetics/Pharrnacodynamics ............................................................................... 6
`7
`Human Clinical Experience................................................................................................................. 7'
`7.1
`Foreign Experience ..................................................................................................................... 7
`7.2
`Post-Marketing Experience ....................................................................................................... 8
`Clinical Studies ..................................................................................................................................... 8
`8.1
`Introduction ...........................................f...................................................................................... 8
`8.1.1
`Clinical and Histological Features ................................................................................... 8
`8.1.2
`Epidemiology ........................................................................................................................ 8
`8.1.3
`Indications for treatment ............................................ 9
`8.1.4 Human Studies Submitted in NBA 20-965 .................................................................. 9
`8.2
`Dermal Toxicity Studies .......................................................................................................... 12
`8.3
`Indication #1 .............................................................................................................................. 12
`8.3.1
`Trial #1: ALA-018 ........................................................................................................... 12
`8.3.1.1 Objective/Rationale........................................................................................................ 12
`8.3.1.2 Design ............................................................................................................................... 12
`83.1.3
`Protocol Overview .......................................................................................................... 13
`
`8
`
`

`

`5
`
`_
`
`Population, procedures ............................................................................................... 13
`8.3.1.3.]
`8.3.1.3.2 Evaluability criteria .................................................................................................... 20
`8.3.1.3.3 Endpoints defined (clinical & microbiology) ............................................................. 21
`83.1.3.4 Statistical considerations............................................................................................. 21
`8.3.1.4
`Study Results ................................................................................................................... 22
`8.3.1.4.] Demographics, Evaluability........................................................................................ 22
`8.3.1.4.2 Efficacy....................................................................................................................... 24
`8.3.1.421
`Primary Efficacy Results ..................................................................................... 24
`8.3.1.422 Secondary Efficacy Resuls ................................................................................. 27
`8.3.1.5
`Safety.............................................................................................................................. 28
`8.3.1.5.] Extent of Exposure..................................................................................................... 28
`83.1.5.2 Discontinuations ......................................................................................................... 28
`83.1.5.3 Adverse Events(Sponsor's Assessment) ..................................................................... 28
`8.3.1.8 Reviewer’s Comments/Conclusions of study results ........................................................ 37
`8.3.2
`Trial #2—ALA—019 ........................................................................................................... 38
`8.3.2.1 Objective/Rationale/Design ............................................................................................ 38
`8.3.2.2
`Protocol Overview .......................................................................................................... 38
`8.3.2.3
`StudyResults................................I.................................................................................. 40
`8.3.2.3.1 Demographics, Evaluability........................................................................................ 40
`8.3.2.3.2 Primary Efficacy Results ............................................................................................ 42
`8.3.2.3.3
`Secondary Efficacy Results ........................................................................................ 45
`83.2.3.4 Safety .......................................................................................................................... 46
`8.3.2.4 Reviewer’s Comments/Conclusions of study results .................................................... 52
`9 Overview of Efficacy—Comparative results between and across studies ................................. 53
`—-—10—f)verviewuf'Safety ......................................................................................................................... 55
`10.1
`Significant/Potentially Significant Events........................................................................ 55
`10.1.1
`Deaths ................................................................................................................................... 55
`10.1.2
`Other Significant/Potentially Significant Events .................................................................. 56
`10.1.3
`Overdosage exposure ............................................................................................................ 56
`10.2
`Other Safety Findings .......................................................................................................... 56
`10.2.1
`ADR IncidenceTables .................................................. 56
`10.2.2
`Laboratory Findings, Vital Signs; ECGs
`.............................................. 61
`
`'
`10.2.3
`Special Studies ..................................... LI.................................'....’....:.'.
`Drug-Demographic Interactions ................................................................................. 63
`10.2.4
`10.2.5
`Drug-Disease Interactions ........................................................................................... 64
`10.2.6
`Drug-Drug Interactions...................................................................... 64
`10.2.7 Wit