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

`

`STATISTIQQ,‘ BEWEW £2 EVALQAIIQN
`
`NDA/DRUG CLASS:
`
`20-965/18
`
`MAR 2 2 i999
`
`NAME OF DRUG:
`
`Levulan Kerastick (Aminolevulinic Acid HCI)
`Topical Solution 20%
`
`APPLICANT:
`
`DUSA Pharmaceuticals, Inc.
`
`INDICATION(S):
`
`.
`
`Q
`
`-
`
`R I
`
`)Actinic Keratoses ofthe Face & Scalp
`
`TYPE OF REVIEW:
`
`‘
`
`Statistical
`
`DOCUMENTS REVIEWED:
`
`Two Controlled Studies: ALA-018 & ALA-019,
`Dated July 1, 1998
`
`MEDICAL REVIEWER:
`
`Martin Okun, M.D./HFD-54O
`
`STATISTICAL REVIEWER:
`
`Shahla-S. Farr; M.S./I-[FD-725 '
`
`I INTRODUQIIQE;
`The sponsor has submitted two identically designed (multicenter, investigator-blind,
`randomized, unbalanced, parallel group, Vehicle and blue light controlled) pivotal studies in
`patients with multiple actinic keratoses of the face and scalp. (Studies ALA-018 & ALA-019).
`
`Table I lists the two pivotal trials:
`
`
`
`Table I
`
`Summa
`
`of the Pivotal Studies
`
`
`
`
`
`# of Centers
`Subjects' Complete
`Levulan (88)
`Randomized, Multicenter,
`ALA-018
`
`
`
`.Cure Rate
`Vehicle (29)
`Investigator-Blind,
`.
`.
`a
`,
`
`
`Parallel, Vehicle-
`
`
`Controlled 8 Weeks
`
`
`
`
`Randomized, Multicentet,
`Subject’s Complete
`Levulan (93)
`
`
`
`Cure Rate
`Vehicle (33)
`Investigator-Blind.
`
`
`Parallel, Vehicle-
`
`Controlled 8 Weeks
`
`"‘
`
`11. REVI W'
`
`Obiective & Design:
`To evaluate the safety and efficacy of Levulan 20% solution and 10 J/crnz of blue light
`delivered at lOmW/ cm2 in treatment ofl
`lactinic keratoses of the face and scalp.
`
`

`

`Levulan Kerufiek (Aminolevullnlc Add 8C1), NDA 20-965
`
`' " i
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`Page 2 0'10
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`Eight centers in the United States participated in each ofthese studies. Afier qualifying for the
`study, subjects were randomized in 3:1 ratio to receive a pre-numbered kit containing either
`Levulan or Vehicle Kerastick applicators, respectively. Four to 15 target lesions on either the
`face or scalp were selected. The subjects were directed to apply the study medication or the
`vehicle to individual Actinic Keratoses (AK) lesions ofthe face or scalp. Blue light from the
`417mlight device was delivered at a power density of lOmW/cm2 to a total light dose of 10
`J/cmrl—ti-l8 hours after Levulan Topical Solution application.
`
`performed efficacy and cosmetic evaluations at Weeks 4, 8 and 12.
`
`Patient Population, Primafl Endpoint Variables. §amplg §ize & §tatjstigal Methods:
`Men and non-pregnant women, over the age'of 18, who had a minimum of4 discrete non—
`hyperkeratotic lesions on either the face or scalp participated in these trials. Patients could
`have up to 15 discrete target regions treated as long as they were confined to either the face or
`the scalp.
`
`
`
`Based on the sponsor’s submission, the efficacy results were analyzed as the percent reduction
`in lesion count (CR rate) and the percentage ofpatients with at least a 75% reduction in lesion
`counts. The treatment groups were compared with respect to each parameter with the data
`stratified by center. The primary time point was Week 8. Treatment differences with respect
`to the patient's cosmetic evaluations'Were assessed at Week 12 using ridit analysis. Treatment
`differences with reSpect-to the proportions of lesions with pigmentary changes relative to
`baseline were evaluated using a Mantel-Haenszel test. The studies sought to show a
`statistically significant difference between Levulan solution and Vehicle with respect to the
`proportions ofpatients with a CR at Week 8 based onper-protocolpopulation.
`
`However, in this review the primary endpoint parameter is based on the percent of subjects
`who were completely cleared of all targetedlesions at Week-8 based on Intent-to-Treat
`population.
`
`In order to calculate the sample size, the sponsor is assuming CR rates of 80% in the Levulan
`group and 20% in the Vehicle group at a 1% significance level and 95% power, requiring a
`sample size of 24 lesions per treatment group. Assuming 4 lesions per patient, 6 patients were
`
`

`

`Levulan Kerlsfldt (Aminolmllnlc Add ECI), NBA 20-965
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`. c ‘
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`Page 3 of 10
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`5.-
`
`have a minimum of 4 target lesions,' the active treatment group would have at least 300 lesions
`and the vehicle group would have at least 100 lesions.
`
`The sponsor is basing the sample size calculations on the percentage of lesions cured and not
`on the percentage of subjects who were completely cured. The method of sample size
`calculation is not acceptable by this reviewer.
`
`Comparability of the two treatment groups with respect to demographic and baseline
`characteristics was assessed using a univariatc analysis of variance (ANOVA), with treatment
`effect for continuous variables and the Cochran-Mantel-Haenszel (CMH) test for discrete
`variables.
`
`For the purpose ofmvestigating the differences between the age groups, the variable age was
`categorized between two groups: younger than 60 or 60 and older.
`
`Per-Subject Analysis:
`
`Study ALA-018: '
`
`Demographics:
`#* ~714rteta¥efalllsubjects fromeigl'n‘cerlters were enrolled into this study, Where 88 subjects we’re " ’
`randomized into the Levulan and 29 into the Vehicle arm.
`
`“ ”’ ‘
`
`Two centers had less than 10 subjects enrolled (Piacquadio, n=7 and Scher, n=4). For the
`purpose of the analyses, these twocenters werecombined._.
`.
`.__ .
`.
`
`Three (3%) subjects in the Levulan arm and one (3%) in the vehicle group dropped out.
`
`Table H summarizes the demographics of these subjects.
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`Levulan Ker-stick (Arnlnolevnliale Add 3C1). NDA 20-965
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`‘
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`str POSSIBLE 1;on
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`P!!! 4 0110
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`,
`
`Table I1
`Demographics & Baseline Characteristics
`All Randomized Subjects
`Stud ALA-018
`Levulan
`n=88
`
`
`
`Whole Population
`=11
`
`
`
`Vehicle
`n-29
`
`98 83.8%
`
`117 100%
`66.4 :1: 10.4
`180.4 i 37.2
`
`73 83%
`
`88 100%
`67.1 :1: 9.7
`179.7 t 35
`
`25 86%
`
`-
`
`29 100%
`Em—
`182.6 1 43.8
`
`
`
`
`
`P-Value
`
`0.7
`
`V
`
`'
`
`
`
`
`
`
`
`Gender.
`
`Male
`Race:
`
`-White
`
`;
`Location of Lesions:
`
`
`
` ii
`
`
`
`93 (79.5%)
`Face
`
`Scal-
`
`SkinType:
`
`9 (31%)
`19 (22%)
`28 (24%)
`
`
`
`10 (34%)
`45 (52%)
`56 (48%)
`
`
`
`30 (26%)
`21 (24%)
`9 (31%)
`
`
`
`
`72 (82%)
`16 18%
`
`21 (72%)
`8 28%
`
`
`
`
`10 (34%)
`17 (19%)
`27 (23%)
`
`
`3 (10%)
`29 (33%)
`32 (27%)
`
`
`
`3 (10%)
`7, " V '9fi0%)
`12(10%)~'
`
`
`
`1 (3%)
`3 (3%)
`4 (3%)
`
`
`
`3 (10%)
`5 (6%)
`8 (7%)
`
`
`
`1 (3%)
`2 (2%)
`3 (3%)
`
`
`
`404%)
`10(ll%)
`14 (12%)
`
`
`
`1 (3%)
`2 (2%)
`3 (3%)
`
`
`
`2 (7%)
`4 (5%)
`6 (5%)
`
`
`
`
`
`0 (0%)
`3 (3%)
`3 (3%)
`
`
`0 (0%)
`0 (0%)
`0 (0%)
`l4
`
`
`
`
`l 3%
`4 5%
`5 4%
`15
`
`
`-—IIE—_—
`Investigator:
`
`
`
`
`
`7 (8%)
`10 (8.5%)
`3 ( 10%)
`Farber
`
`
`
`18 (20%)
`24 (20.5%)
`Glazer
`6 (21%)
`
`
`
`
`
`
`13 (15%)
`18 (15.4%)
`Goodman
`5 (17%)
`
`
`
`
`18 (20%)
`24 (20.5%)
`Ling
`6 (21%)
`
`
`
`
`
`9 (10%)
`11 (9.4%)
`Piacquadio + Scher
`2 (7%)
`
`
`
`
`
`15 (17%)
`20 (17.1%)
`5 (17%)
`Taylor
`
`
`
`
`
`
`10 8.5% 8 9%
`Whitmore
`
`
`
`
`
`
`
`
`
`
`
`
`
`As it is shown in Table II, no statistical differences were found between the two treatment arms
`in regards to the demographics and baseline characteristics of the subjects (p202).
`
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`

`[null-n Kemtlck (Aminolevnllnlc Add 3CD, NDA 20-965
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`Page 5 of 10
`
`Clinical Efficacy Analysis & Resulgs;
`
`Table III summarizes the results ofthe analysis for the primary endpoint variable:
`
`__
`Table 111
`Rate of Complete Clearance of the ActinicT‘K‘Eratosis Lesions
`Intent-To-Treat Population
`Stud ALA-018
`
`
`
`Levulan n=88 W- [Mll-
`
`
`54/88=61%
`
`28l29=97%
`
`59/88=67%
`29l88=33%
`
`’
`
`4/29=14%
`25/29=86%
`
`Week-4
`
`Not-Cure
`Week-8
`
`
`
` Week- 12
`
`Cure
`Not-Cure
`
`Cure
`3/29=10%
`70l88=80%
`
`Not-Cure
`
`
` l 8/88=20%
`26/29=90%
`
`As it is seen in Table 1]], highly significant results (p=0.001) were observed when Levulan was
`____kgcomparedtmtheyehicleann relativetea-ateefeomplete clearance at Week-8.
`
`7:
`
`Analysis controlling for center effect, age category (younger than 60, 60 and older), sex, skin
`type and the location of the lesions (face or scalp) showed the same highly significant results
`(p=0.001).
`
`Study ALA-019:
`
`Demographics:
`A total of 126 subjects from eight centers were enrolled into this study, where 93 subjects were
`randomized into the Levulan and ‘33 into theVehicle arm.
`
`Four (4%) subjects in the Levulan arm dropped out and two (6%) in the vehicle group.
`
`Table IV summarizes the demographics of these subjects.
`4
`
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`lien-In Kenniek (Aminolewllnlc Add 3C1), NDA 20-965
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`,
`
`..
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`*
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`‘ l -
`Page 6 of 10
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`BEST POSSIBLE COPY
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`
`
`
`
`Gender.
`
`Female
`Male
`
`P-Value
`
`
`
`
`Table IV
`Demographics & Baseline Characteristics
`All Randomized Subjects
`Stud ALA-019
`
`Levulan
`Vehicle
`n=93
`n-33
`
`Whole Population
`=126
`
`
`
`21 (17%)
`105 83%
`
`19 (20%)
`74 80%
`
`2 (6%)
`31 94%
`
`0.7
`
`"W"
`
`
`
`
`
`W—
`
`m_—EM__
`
`Wmm1-___
`
`Location of Lesions:
`02
`Face
`87 (69%)
`67 (72%)
`20 (61%)
`
`39 31%
`Seal-
`26 28%
`13 39%
`
`
`SkinTy‘pe:
`
`
`
`
`11 (33%)
`33 (35%)
`44 (35%)
`
`
`
`
`57 (45%)
`44 (47%)
`13 (39%)
`
`
`
`
`23 (18%)
`15 (16%)
`8 (24%)
`
`
`
`
`2 2%
`
` Total # of Lesions per
`Subject:
`
`
`9 (7%)
`
`
`6 (6%)
`3 (9%)
`
`
`13 (10%)
`ll (12%)
`2 (6%)
`
`
`
`22(f7%)“
`”(18%)
`5(15%)
`
`
`
`
`l 1 (9%)
`9 (10%)
`2 (6%)
`
`
`
`
`17(13%)
`13 (14%)
`402%)
`
`
`
`
`
`7 (6%)
`5 (5%)
`2 (6%)
`
`
`ll (9%)
`9 (10%)
`2 (6%)
`
`
`
`
`6 (5%)
`4 (4%)
`2 (6%)
`
`
`
`
`10 (8%)
`6 (6%)
`4 (12%)
`
`
`
`
`5 (4%)
`2 (2%)
`3 (9%)
`
`
`
`
`
`2 (2%)
`I4
`4 (3%)
`2 (6%)
`
`
`15
`
`
`
`mI
`
`
`
`nvestigator:
`Chen
`Fowler
`Hmza
`
`Phillips
`Rallis
`Tashjian
`
`Taylor
`
`Weinstein
`
`
`
`
`
`
`12 (9.5%)
`4 (12%)
`
`
`16 (12.7%)
`12 (13%)
`4 (12%)
`
`
`
`
`20 (15.9%)
`15 (16%)
`5 (15%)
`
`
`
`
`16(12.7%)
`12 (13%)
`4 (12%)
`
`
`
`
`
`16(12.7%)
`12 (13%)
`4 (12%)
`
`
`
`
`l4(ll.l%)
`10 (11%)
`4(12%)
`
`
`
`
`16 (12.7%)
`12 (13%)
`4 ( 12%)
`
`
`
`
`
` 12 13%
`16 12.7%
`
`As it is shown in Table N, no statistical differences were found between the two treatment
`arms in regards to the demographics and baseline characteristics of the subjects (p20.06).
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`Levulan Kuutick (Amlnolevullnlc Acid HCI). NDA 20-965
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`V .
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`Page 1 of m
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`glinical Efficacy Analysis & Results:
`
`Table V summarizes the results of the analysis for the primary endpoint variable, rate of
`complete clearance of lesions:
`
`Week-4
`
`Cure
`
`Not-Cure
`
`Week-8
`
`Levulan n=93
`
`Vehicle n=33
`
`52/93=56%
`
`3/33=9%
`
`Table V
`Rate of Complete Clearance of the Actinic Keratosis Lesions
`Intent-To-Treat Population
`Stud ALA-019
`
`
`
`
`41/93#4%
`30/33=91% _
`
`
`
`
`
`
`
`
`
`
`4/33=12% _
`Not—Cure
`39/93=42%
`29/33=88%
`
`
`
`
`Cure
`Not-Cure
`Week-12
`
`Cure
`
`58/93=62%
`35/93=38%
`
`54/93=58%
`
`4/33=12%
`29/33=88%
`
`As it issegn in Table V,,highlysignificant results (p=0.001) were observed when Levulan was»
`compared to the Vehicle arm.
`
`Analysis controlling for center effect, age category (younger than 60, 60 and older), sex, skin
`type and the location of the lesions (face or scalp) showed the same highly significant results
`(p=0.001).
`
`Subset Analysis:
`
`The two data sets were merged and subset analysis was done based on gender, age category
`(younger than 60, 60 and older), skin type and the location of the lesions (face or scalp). The
`highly significant results was observed in each sub-category (p=0.001).
`
`Among all the subjects in the two studies, twenty subjects who were completely cured on
`Week-8 had recurrence by Week-12. Of these, 17 had been treated by Levulan and three
`subjects with the Vehicle.
`
`,
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`Levulan Kerutick (Aminolevulinle Add HCI), NDA 20-965
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`Page 8 of lo
`
`Per-Lesion Analysis:
`
`Study ALA-018:
`
`A total of 803 lesions were under the study. Of these, the data was available for only 784 at Week-8.
`Table VI gives the cure rate for these lesions.
`
`,
`Table VI
`Rate of Complete Clearance of the Actinic Keratosis Lesions
`Per-Lesion Analysis
`Stud ALA-018
`
`.mm-
`
`Week-8
`
`H
`
`”“43“"
`
`
`
`
`Cure
`
`Not-Cure
`Week-12
`Cure
`
`
`54sx5so=94%
`- 47—,“ 35/58026%'""‘
`
`438/574=76%
`
`'
`
`I H
`
`49sxsss=35%
`s7/sss=15%
`
`43/203=24%
`
`69/199=35%
`l30/l99=65%
`
`155/203=76% “
`
`
`
`,
`68/199=34%
`
`131/199=66%
`
`
`0.001
`
`As it is seen in Table VI, highly significant results (p=0.001) were observed when Levulan was
`compared to the Vehicle arm, relative to rate of complete clearance at Week-8
`
`All investigators followed the same pattern of significance, except the investigator “Taylor”.
`The success and failure rates for this center were different from the rest of the centers.
`
`Cure Rate for Investi - ator Ta lor
`
`
`
`——_—
`Week-8
`
`
`
`44/57=77%
`104/136=76%
`Cure
`13/57=23%~
`32/136=24%
`Not-Cure
`
`
`
`Removing this center fi-orn the analysis did not change the statistically significant results.
`
`Analysis controlling for center effect, age category (younger than 60, 60 and older), sex, skin
`type, grade and the location of the lesions (face or scalp) showed the same highly significant
`results (p=0.001). _
`
`Subset Analysis:
`
`Subset analysis was done for gender, age category (younger than 60, 60 and older), skin type
`grade and the location of the lesions (face or scalp). The highly significant results were
`observed in each sub-category (p=0.001).
`
`

`

`Levulan Ker-stick (Aminolevnllllc Add 3C1). NDA 20-965
`
`Page 9 of 10
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`l ' ‘
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`Among all the lesions in the study, twenty-eight lesions that were completely cured on Week-8
`had recurrence by Week-12. Of these, 19 had been treated with Levulan and nine lesions with
`the Vehicle.
`
`Study ALA-019:
`
`A total of 1086 lesions were under the study. Of these, the data was available for 1066 at Week-8;-
`Table VII gives the cure rate for these lesions.
`
`646/780=83%
`
`134/730=17%
`
`77/298=26%
`
`Cure
`
`Not-Cure
`—
`
`Table VII
`Rate of Complete Clearance of the Actinic Keratosis Lesions
`Per-Lesion Analysis
`Stud ALA-019
`
`
`_———
`
`
`Week-4
`221/298=74% _
`
`
`
`
`
`
`m
`
`
`
`7 Cure”
`7 i , masesz‘x.
`105/29s=35%
`Not-Cure
`l38/768=18%
`l93/298=65%
`
`
`
`
`664/760=87% 85/284=30% u96/760=13%
`
`
` l99/284=70%
`
`
`
`
`
`
`As it is seen in Table VII, highly significant results (p=0.001) were observed when Levulan
`was compared to the Vehicle arm relative to the rate of complete clearance at Week-8.
`
`All investigators followed the same pattern of significance, except the investigator “Tashjian”.
`The success and failure rates for this center were different from the rest of the centers.
`
`Cure Rate for Investi ; ator Tash ian
`
`
`————
`
`
`Week-8
`0.5
`
`
`12/38=32%
`35/9l=38%
`Cure
`
`26/38=68%
`"
`56/9l=62%
`Not-Cure
`
`Removing investigator Tashjian hour the analysis did not change the statistically significant
`results.
`-
`~
`
`Analysis controlling for center effect, age category (younger than 60, 60 and older), sex, skin
`type, grade and the location of the lesion: (face or scalp) showed the same highly significant
`results (p=0.001).
`
`

`

`Levulan Rennie]: (Aminolevullnlc Add ucn. NBA 20-965
`
`Page lo oflo
`
`Subset Analysis:
`Subset analysis was done for gender, age category (younger than 60, 60 and older), skin type,
`grade and the location ofthe lesions (face or scalp). Highly significant results were observed
`in each sub-category (p=0.001).
`
`Among all the lesions in the study, one hundred and one lesions that were completely cured on Week-8
`had recurrence by Week—12. Of these, sixty-four had been treated with
`Levulan and thirty-seven lesions
`with the Vehicle.
`
`III. Conclusions;
`
`The results of the analyses of efficacy of the two studies (Study ALA-018 & ALA-019) demonstrate
`that Levulan Kerastick Topical Solution 20% is statistically significantly better than Vehicle in the
`treatment oil
`’Actinic Keratoses ofthe face & scalp.
`
`The subset analyses relative to gender, age category (<60, .260), skin type and location of lesions also
`demonstrated similar statistically significantly results favoring Levulan over Vehicle.
`
`According to the reviewing medical officer, the data presented by the sponsor did not raise any
`safety issues to be analyzed and addressed by the statistical reviewer.
`
`3/32/99
`
`Shahla S. Farr, M.S.
`Mathematical Statistician, Biometrics III
`
`Concur: R. Srinivasan, PhD.
`Team Leader, Biometrics III
`
`cc:
`
`Archival NDA 20-965
`HFD-54O
`
`HFD-540/Dr. Okun
`
`I-IFD-540/Dr. Walker
`
`HFD-540/Dr. Wilkin
`
`HFD-540/Ms. Cintron
`
`HFDJZS/Ms. Farr
`HFD-725/Dr. Srinivasan
`
`HFD-725/Dr. Huquc
`Chron.
`
`This review contains 10 pages.
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