NDA 21-576

1Dermatologic and Ophthalmic Drugs Advisory Committee Dermatologic and Ophthalmic Drugs Advisory Committee September 10, 2003September 10, 2003

NDA 21-576NDA 21-576

Methyl aminolevulinate Cream (MAL) with Curettage and

Photodynamic Therapy (PDT) for Basal Cell Carcinoma (BCC)


FDA Clinical and Statistical FDA Clinical and Statistical ReviewersReviewers

FDA Clinical and Statistical FDA Clinical and Statistical ReviewersReviewers

Brenda Vaughan, M.D., Medical Officer

Markham C. Luke, M.D., Ph.D., Dermatology Team Leader

Shiowjen Lee, Ph.D., Mathematical StatisticianMohamed Alosh, Ph.D., Mathematical Statistics Team

Leader


Treatment of Primary Nodular Treatment of Primary Nodular BCCBCC

Treatment of Primary Nodular Treatment of Primary Nodular BCCBCC

• Curette-MAL-PDT consists of:

– Lesion preparation (Curettage)– Methyl Aminolevulinate (MAL) Cream– Combined with Curelight Lamp (Drug/Device

Combination)

• Curette-MAL-PDT consists of:

– Lesion preparation (Curettage)– Methyl Aminolevulinate (MAL) Cream– Combined with Curelight Lamp (Drug/Device

Combination)


BackgroundBackgroundBackgroundBackground

• “Provided that efficacy and safety are established for nodular BCC: one independent, multi-center, randomized, active controlled study conducted in patients with primary superficial BCC might be acceptable if supported by strong evidence from a solid database.” Regulatory Guidance Meeting with PhotoCure - March 7, 2000

• “Provided that efficacy and safety are established for nodular BCC: one independent, multi-center, randomized, active controlled study conducted in patients with primary superficial BCC might be acceptable if supported by strong evidence from a solid database.” Regulatory Guidance Meeting with PhotoCure - March 7, 2000


Items for DiscussionItems for DiscussionItems for DiscussionItems for Discussion

•Efficacy– Adequacy of studies for estimating cure rate?

• Early histology and small numbers in pivotal studies• Minimal recurrence data for nodular BCC

– Adequacy of instructions for lesion preparation?• Apparent high VEH-PDT response rate• Center-to-center variability

– Estimate of cure rate for MAL-PDT vs. Surgery?•Safety

– Pain and minimal information regarding anesthesia/pain control

– Contact hypersensitization

•Efficacy– Adequacy of studies for estimating cure rate?

• Early histology and small numbers in pivotal studies• Minimal recurrence data for nodular BCC

– Adequacy of instructions for lesion preparation?• Apparent high VEH-PDT response rate• Center-to-center variability

– Estimate of cure rate for MAL-PDT vs. Surgery?•Safety

– Pain and minimal information regarding anesthesia/pain control

– Contact hypersensitization


Measurements of Efficacy for Treatment of Measurements of Efficacy for Treatment of Basal Cell CarcinomaBasal Cell Carcinoma

Measurements of Efficacy for Treatment of Measurements of Efficacy for Treatment of Basal Cell CarcinomaBasal Cell Carcinoma

• Agency Proposed:– Clinical Observation and Excision Histology– 5 year Recurrence Data (2 year data acceptable

for filing)• What was submitted:

– Excision Histology Alone– Clinical Observation Alone– Recurrence Rates Based on Clinical

Observation

• Agency Proposed:– Clinical Observation and Excision Histology– 5 year Recurrence Data (2 year data acceptable

for filing)• What was submitted:

– Excision Histology Alone– Clinical Observation Alone– Recurrence Rates Based on Clinical

Observation


Clinical StudiesClinical StudiesClinical StudiesClinical Studies

• Studies interpreted for efficacy for nodular BCC– 2 vehicle controlled randomized studies (307 &

308)– 1 open-label randomized MAL-PDT vs.

surgery for recurrence rates (303)– 1 open-label non-randomized MAL-PDT study

for recurrence rates (205) – also had superficial BCC

• Studies interpreted for efficacy for nodular BCC– 2 vehicle controlled randomized studies (307 &

308)– 1 open-label randomized MAL-PDT vs.

surgery for recurrence rates (303)– 1 open-label non-randomized MAL-PDT study

for recurrence rates (205) – also had superficial BCC


Pivotal StudiesPivotal StudiesPivotal StudiesPivotal Studies

• Study 307 - U.S. Study– 33 patients randomized to Curette-MAL-PDT– 32 patients randomized to Curette-VEH-PDT

• Study 308 - Australian Study– 33 patients randomized to Curette-MAL-PDT– 33 patients randomized to Curette-VEH-PDT

• Study 307 - U.S. Study– 33 patients randomized to Curette-MAL-PDT– 32 patients randomized to Curette-VEH-PDT

• Study 308 - Australian Study– 33 patients randomized to Curette-MAL-PDT– 33 patients randomized to Curette-VEH-PDT


Pivotal Studies: Study DesignPivotal Studies: Study DesignPivotal Studies: Study DesignPivotal Studies: Study Design

• First Treatment Cycle - two Curette-(MAL vs. VEH)-PDT treatments 7 days apart followed by clinical assessment at 3 months

• Second Treatment Cycle - if only partial response to First Treatment Cycle - two additional treatments 7 days apart

• First Treatment Cycle - two Curette-(MAL vs. VEH)-PDT treatments 7 days apart followed by clinical assessment at 3 months

• Second Treatment Cycle - if only partial response to First Treatment Cycle - two additional treatments 7 days apart


Pivotal Studies: Study DesignPivotal Studies: Study DesignPivotal Studies: Study DesignPivotal Studies: Study DesignClinical evaluation at 3-months to determine further

management:• Complete response (disappearance of lesions) >>

excision at 6-month for histology.• Partial response (lesion decreased by 50%) >> 2nd

PDT cycle >> excision at 9-month for histology.• No response (lesion decreased by 50%) or

Progression (lesion increased by 20%) >> excision at 3-month.

Complete response is not equal to “cure”.

Clinical evaluation at 3-months to determine further management:

• Complete response (disappearance of lesions) >> excision at 6-month for histology.

• Partial response (lesion decreased by 50%) >> 2nd PDT cycle >> excision at 9-month for histology.

• No response (lesion decreased by 50%) or Progression (lesion increased by 20%) >> excision at 3-month.



No ClinicalResponse Excise

1st Tx Cycle

3 MONTHS

CompleteClinicalResponse

Excise3 MONTHSLATER

IncompleteClinicalResponse

Excise

7 DAYSAPART

PartialClinicalResponse

2nd Tx Cycle

7 DAYSAPART

3 MONTHS

CompleteClinicalResponse

Excise3 MONTHSLATER

STUDIES307 and 308

RANDOMIZATION

MAL or VEH PDT


Biostatistical Analysis of Pivotal StudiesBiostatistical Analysis of Pivotal Studies

Dermatologic and Ophthalmic Drugs Advisory Committee Dermatologic and Ophthalmic Drugs Advisory Committee September 10, 2003September 10, 2003

Efficacy Evaluation in Pivotal Efficacy Evaluation in Pivotal StudiesStudies

Efficacy Evaluation in Pivotal Efficacy Evaluation in Pivotal StudiesStudies

Primary: Patient complete response rateSecondary: Lesion complete response rate

Criterion for assessing response: a. Clinical and histology - Agency recommendation to PhotoCure on March 7, 2000 b. Histology only – PhotoCure’s protocol (August, 2000)


Primary: Patient complete response rateSecondary: Lesion complete response rate

Criterion for assessing response: a. Clinical and histology - Agency recommendation to PhotoCure on March 7, 2000 b. Histology only – PhotoCure’s protocol (August, 2000)



Overview of Efficacy Findings in Overview of Efficacy Findings in Pivotal Studies Pivotal Studies


• Curette MAL-PDT is superior to Curette VEH-PDT

• Variability in the success rate estimate for MAL-PDT which might be attributed to:

a) Relatively small studies wide C.I. around these estimates

b) Uncertainty about lesion preparation description

• Curette MAL-PDT is superior to Curette VEH-PDT

• Variability in the success rate estimate for MAL-PDT which might be attributed to:

a) Relatively small studies wide C.I. around these estimates

b) Uncertainty about lesion preparation description




Clues:

• High vehicle response rate• Center-to-center variability:

Small studies with few patients per center

Clues:

• High vehicle response rate• Center-to-center variability:

Small studies with few patients per center


Apparent High Vehicle Response Rate Based Apparent High Vehicle Response Rate Based on Histological Evaluationon Histological Evaluation

Apparent High Vehicle Response Rate Based Apparent High Vehicle Response Rate Based on Histological Evaluationon Histological Evaluation

Table 1: Lesions and Patients with Complete Response (Histology– PhotoCure Analysis)Lesion response Patient responseAnalyses

Curette-MAL-PDT

Curette-VEH-PDT

Curette-MAL-PDT

Curette-VEH-PDT

Study 307 ITT, n/N (%) PP, n/N (%)

32/41 (78%)31/39 (79%)

13/39 (33%)13/37 (35%)

25/33 (76%)24/31 (77%)

11/32 (34%)11/32 (34%)

Study 308 ITT, n/N (%) PP, n/N (%)

23/34 (68%)22/30 (73%)

7/36 (19%)7/33 (21%)

22/33 (67%)21/29 (72%)

6/33 (18%)6/32 (19%)


Summary of Response rates along with 95% Summary of Response rates along with 95% Confidence Intervals Confidence Intervals

Summary of Response rates along with 95% Summary of Response rates along with 95% Confidence Intervals Confidence Intervals

Table 2: Patient and Lesion Complete Response Based on Clinical and Histological Evaluations, ITT 1

Patient Response Lesion Response

Study # Curette MAL-PDT Curette VEH-PDT Curette MAL-PDT Curette VEH-PDT

Study 307 n/N ( % ) (95% C.I.)

24/33 (73%) (54%, 87%)

8/32 (25%) (11%, 43%)

28/41 (68%) (52%, 82%)

10/39 (26%) (13%, 42%)

Study 308 n/N ( % ) (95% C.I.)

21/33 (64%)(45%, 80%)

5/33 (15%) (5%, 32%)

22/34 (65%)(46%, 80%)

6/36 (17%)(6%, 33%)

1 Agency Analysis


Estimates of Response for 1Estimates of Response for 1stst Treatment Treatment CycleCycle

Estimates of Response for 1Estimates of Response for 1stst Treatment Treatment CycleCycle

Table 5: PhotoCure and Agency Response Rates for 1 st Treatment Cycle ( Pivotal Studies, ITT )Histological Evaluation Clinical and Histological

EvaluationsStudy/ Analyses

Cur. MAL PDTn/N (%)

Cur. VEH PDTn/N (%)

Cur. MAL PDTn/N (%)

Cur. VEH PDTn/N (%)

Study 307PhotoCure’s Analysis 1

Agency Analysis23/28 (82%)23/41 (56%)

9/30 (30%)9/39 (23%) 19/41 (46%) 7/39 (18%)

Study 308 PhotoCure’s Analysis 1

Agency Analysis18/29 (62%)18/34 (53%)

5/32 (16%)5/36 (14%) 17/34 (50%) 4/36 (11%)

1 Photocure’s Briefing Document for FDA Advisory Committee Meeting, dated 6 August 2003, Table 41, p.94

PhotoCure excluded from the denominator those lesions which had partial response and were treated with a 2nd treatment cycle in post-hoc analysis.

rate is inflated because not all lesions treated with 1st PDT cycle are included in the denominator, as shown in the following table

PhotoCure excluded from the denominator those lesions which had partial response and were treated with a 2nd treatment cycle in post-hoc analysis.

rate is inflated because not all lesions treated with 1st PDT cycle are included in the denominator, as shown in the following table


Treatment Cycle ResponseTreatment Cycle ResponseTreatment Cycle ResponseTreatment Cycle Response

• Study design precludes estimating response rates for only one treatment cycle:– Second treatment cycle is based on

clinical decision regarding first treatment cycle outcome, i.e. “partial response”

– Outcome measure was done at 3 months– No randomization before second cycle

• Study design precludes estimating response rates for only one treatment cycle:– Second treatment cycle is based on

clinical decision regarding first treatment cycle outcome, i.e. “partial response”

– Outcome measure was done at 3 months– No randomization before second cycle


Study 307: Lesion Response Inter-Study 307: Lesion Response Inter-Center VariabilityCenter Variability


Table 3: Lesion Response Rate by Center for 1 st treatment cycle and overall , Study 307 1 st PDT Cycle

Clinical & Histological 1 st & 2 nd Cycles

Clinical & Histological 1 st & 2 nd Cycles

HistologicalCenter Cur-MAL-

PDTCur-VEH-PDT

Cur-MAL-PDT

Cur-VEH-PDT

Cur-MAL-PDT

Cur-VEH-PDT

30702 2/7 1/8 4/7 2/8 4/7 2/830703 2/4 0/2 4/4 0/2 4/4 0/230704 0/7 1/7 3/7 1/7 4/7 2/730705 1/2 1/3 2/2 1/3 2/2 2/330706 6/13 4/10 7/13 4/10 10/13 4/1030707 5/5 0/5 5/5 0/5 5/5 0/530709 3/3 0/4 3/3 2/4 3/3 3/4

Total 19/41(46%)

7/39(18%)

28/41(68%)

10/39(26%)

32/41(78%)

13/39(33%)

B-D Test 1 0.025 * 0.134 0.3181 Breslow-Day test for homogeneity of responses across centers as directed sensitivity analysis.* p-value for Zelen’s exact test = 0.072




Table 4: Lesion Complete Response Rate after the 1st PDT Cycle and Overall by Center, Study 308

1 st PDT CycleClinical & Histological

1 st & 2 nd PDT CyclesClinical & Histological

1 st & 2 nd CyclesHistological

Center Cur-MAL-PDT

Cur-VEH-PDT

Cur-MAL-PDT

Cur-VEH-PDT

Cur-MAL-PDT

Cur-VEH-PDT

30801 1/2 0/3 1 /2 1/3 1/2 1/330802 8/13 3/12 9/13 3/12 9/13 4/12

30803 0/0 0/1 0/0 0/1 0/0 0/130804 2/2 0/3 2/2 0/3 2/2 0/330805 3/4 1/5 3/4 1/5 3 /4 1/530806 3/8 0/7 3/8 0/7 4/8 0/730807 0/5 0/5 3/5 1/5 4/5 1/5

Total 17/34(50%)

4/36(11%)

21/34(62%)

6/36(17%)

23/34(68%)

7/36(19%)

B-D test1 0.56 0.703 0.5681 Breslow-Day (B-D) test for homogeneity of responses across centers.


Pivotal Studies: Pivotal Studies: Summary of Statistical AnalysisSummary of Statistical Analysis

Pivotal Studies: Pivotal Studies: Summary of Statistical AnalysisSummary of Statistical Analysis

• Curette-MAL-PDT is statistically superior to Curette-VEH-PDT for the treatment method used in the protocol of nodular BCC.

• For each pivotal study there is relatively high Curette-VEH-PDT response rate. There is also center-to-center variability in Study 307. This might be attributable to:– Small study size– Lesion preparation for treatment– Accuracy of clinical and histological evaluations

• The center-to-center variability in the efficacy results reduces the reliability in the overall point estimates of Curette-MAL-PDT.

• Curette-MAL-PDT is statistically superior to Curette-VEH-PDT for the treatment method used in the protocol of nodular BCC.

• For each pivotal study there is relatively high Curette-VEH-PDT response rate. There is also center-to-center variability in Study 307. This might be attributable to:– Small study size– Lesion preparation for treatment– Accuracy of clinical and histological evaluations

• The center-to-center variability in the efficacy results reduces the reliability in the overall point estimates of Curette-MAL-PDT.


Efficacy Conclusions from Pivotal StudiesEfficacy Conclusions from Pivotal StudiesEfficacy Conclusions from Pivotal StudiesEfficacy Conclusions from Pivotal Studies

• Curette-MAL-PDT is statistically superior to Curette-VEH-PDT using the protocol guided outcome assessment

• High response rates with Curette-VEH-PDT– Effect of curette– Short follow-up– Low ability to detect residual nodular

BCC by histological methods used

• Curette-MAL-PDT is statistically superior to Curette-VEH-PDT using the protocol guided outcome assessment

• High response rates with Curette-VEH-PDT– Effect of curette– Short follow-up– Low ability to detect residual nodular

BCC by histological methods used


PhotoCure Video – Lesion Preparation


Effect of CurettageEffect of CurettageEffect of CurettageEffect of Curettage

• Response may depend on extent and depth of curettage– Efficacy shows center dependence– High Curette-VEH-PDT response

• Other factors– Lamp exposure appears to have been

applied in a consistent manner for each pivotal study

• Response may depend on extent and depth of curettage– Efficacy shows center dependence– High Curette-VEH-PDT response

• Other factors– Lamp exposure appears to have been

applied in a consistent manner for each pivotal study


CurettageCurettageCurettageCurettage

Page 124 of PhotoCure AC Briefing, Figure 20


Recurrence Data: RegulatoryRecurrence Data: RegulatoryRecurrence Data: RegulatoryRecurrence Data: Regulatory• Agency and PhotoCure discussed in the context of

nodular BCC recurrence data, that a minimum of 250 subjects were to be submitted. Pre-NDA meeting minutes with PhotoCure - June 20, 2002

• A two-year follow-up was recommended for NDA submission. Regulatory Guidance Meeting with PhotoCure - March 2000

• It was recommended that patients be followed up to five years post treatment. Regulatory Guidance Meeting with PhotoCure - March 2000

• Agency and PhotoCure discussed in the context of nodular BCC recurrence data, that a minimum of 250 subjects were to be submitted. Pre-NDA meeting minutes with PhotoCure - June 20, 2002

• A two-year follow-up was recommended for NDA submission. Regulatory Guidance Meeting with PhotoCure - March 2000

• It was recommended that patients be followed up to five years post treatment. Regulatory Guidance Meeting with PhotoCure - March 2000


Recurrence Rate DatabaseRecurrence Rate DatabaseRecurrence Rate DatabaseRecurrence Rate Database

• PhotoCure provided 2 year recurrence data for 46 patients (47 lesions) with nodular BCC treated with Curette-MAL-PDT (clinical observation for recurrence): Study 303/99 (Phase 3, randomized open-label).

• Additional data for 30 patients with nodular BCC: Study 205/98 - Phase 2, non-randomized open-label, included both nodular (38 lesions) and superficial (39 lesions) BCC. Focus would be primarily on nodular.

• PhotoCure provided 2 year recurrence data for 46 patients (47 lesions) with nodular BCC treated with Curette-MAL-PDT (clinical observation for recurrence): Study 303/99 (Phase 3, randomized open-label).

• Additional data for 30 patients with nodular BCC: Study 205/98 - Phase 2, non-randomized open-label, included both nodular (38 lesions) and superficial (39 lesions) BCC. Focus would be primarily on nodular.


Assessment of RecurrenceAssessment of RecurrenceAssessment of RecurrenceAssessment of Recurrence

• “Recurrence of lesions is based on clinical assessment (inspection and palpation) confirmed by punch biopsy [when positive clinically].”

• Treated areas that were apparently clinically clear were not biopsied and followed.

• “Recurrence of lesions is based on clinical assessment (inspection and palpation) confirmed by punch biopsy [when positive clinically].”

• Treated areas that were apparently clinically clear were not biopsied and followed.


Study 303Study 303Study 303Study 303

• European randomized, open-label, multicenter study in 101 subjects

• Curette-MAL-PDT (n=52) • Surgical Excision (n=49)• Initial post-treatment assessment at 3

months • Followed by 12 and 24 month clinical

assessments for recurrence

• European randomized, open-label, multicenter study in 101 subjects

• Curette-MAL-PDT (n=52) • Surgical Excision (n=49)• Initial post-treatment assessment at 3

months • Followed by 12 and 24 month clinical

assessments for recurrence


Example of Complete Response?Example of Complete Response?Example of Complete Response?Example of Complete Response?

Page 100 of PhotoCure AC Briefing, Figure 19


Lesion Recurrence Data: Study 303Lesion Recurrence Data: Study 303Lesion Recurrence Data: Study 303Lesion Recurrence Data: Study 303

ARM

Analysis

6 month

12 month

24 month (95% CI)

MAL-PDT

Recurrent Lesions/Lesions with “Complete Response” at 3 or 6 months

1/47 (2%)

3/47 (6%)

4/47 (9%)

(2%, 20%)

to 16/47 (34%)*

(21%, 49%)

Surgery

Recurrent Lesions/Lesions with “Complete Response”

0/51

0/51 to

1/51 (2%)**

1/51 (2%)

(0%, 11%)

to 8/51 (16%)***

(7%, 29%)

* 12 additional lesions missing at 24 months from MAL-PDT arm. ** One lesion missing at 12 months from Surgery arm. *** 7 additional lesions missing at 24 months from Surgery arm


Failure to Cure Analysis: Study 303Failure to Cure Analysis: Study 303Failure to Cure Analysis: Study 303Failure to Cure Analysis: Study 303

ARM

Analysis

6 month

12 month

24 month (95% CI)

MAL-PDT

Failure to Cure*/Total MITT Lesions

9/56 (16%)

12/56 (21%)

25/56 (45%)**

(31%, 59%)

Surgery

Failure to Cure/Total MITT Lesions

0/51

1/51 (2%)

8/51 (16%) (7%, 29%)

* Failure to Cure = Treatment Failures + Recurrences + Missing ** 12 additional lesions missing at 24 months from MAL-PDT arm.


Phase 2 Recurrence StudyPhase 2 Recurrence StudyPhase 2 Recurrence StudyPhase 2 Recurrence Study

• Study 205 – Non-randomized, open-label study with both nodular and superficial BCC

• 57 patients (79 lesions) were evaluated for recurrence at 24 months

• 30 patients with 38 nodular BCC lesions*• 6, 12, and 24 month data available

• * 3 patients with 1 superficial/nodular lesion each were in the study

• Study 205 – Non-randomized, open-label study with both nodular and superficial BCC

• 57 patients (79 lesions) were evaluated for recurrence at 24 months

• 30 patients with 38 nodular BCC lesions*• 6, 12, and 24 month data available

• * 3 patients with 1 superficial/nodular lesion each were in the study


Factors Affecting Applicability of Factors Affecting Applicability of Recurrence Data (Study 205)Recurrence Data (Study 205)

Factors Affecting Applicability of Factors Affecting Applicability of Recurrence Data (Study 205)Recurrence Data (Study 205)

• Different patient population (high risk)• Difference in written instructions for lesion

preparation (curetting below epidermis)• Difference in MAL application border• Different lamps used - Some patients had a

lamp other than that used in the pivotal studies

• Different patient population (high risk)• Difference in written instructions for lesion

preparation (curetting below epidermis)• Difference in MAL application border• Different lamps used - Some patients had a

lamp other than that used in the pivotal studies


Recurrence: Study 205Recurrence: Study 205Recurrence: Study 205Recurrence: Study 205

BCC N*(Lesions) Missing

PhotoCureAnalysis

ofRecurrence

Agency Analysis ofRecurrence

-missing lesions added to numerator(95% CI)

Superficial 39 3 (8%) 8 (21%) 11/39 (28%)(15%, 45%)

Nodular 38 10 (28%) 4 (11%) 14/38 (37%)(22%, 54%)

Superficial &Nodular

3 0 0/2 1/3 (33%)(0%, 91%)

Total 80 13 (16%) 12 (15%) 26/80 (33%)(22%, 43%)

BCC N*(Lesions) Missing

PhotoCureAnalysis

ofRecurrence

Agency Analysis ofRecurrence

-missing lesions added to numerator(95% CI)

Superficial 39 3 (8%) 8 (21%) 11/39 (28%)(15%, 45%)

Nodular 38 10 (28%) 4 (11%) 14/38 (37%)(22%, 54%)

Superficial &Nodular

3 0 0/2 1/3 (33%)(0%, 91%)

Total 80 13 (16%) 12 (15%) 26/80 (33%)(22%, 43%)

Lesion recurrence (at 24 months)

*Early failures are not included


Recurrence: ConclusionsRecurrence: ConclusionsRecurrence: ConclusionsRecurrence: Conclusions

• A database of 46 patients with 2 year recurrence data for primary nodular BCC was submitted by PhotoCure in Study 303.

• The 2 year recurrence rate for MAL-PDT treated patients ranged from 9% to 34% depending on how missing data were accounted for.

• Failure to treat adequately rate was 45% at 2 years.

• A larger database was requested.

• A database of 46 patients with 2 year recurrence data for primary nodular BCC was submitted by PhotoCure in Study 303.

• The 2 year recurrence rate for MAL-PDT treated patients ranged from 9% to 34% depending on how missing data were accounted for.

• Failure to treat adequately rate was 45% at 2 years.

• A larger database was requested.


Cosmetic OutcomeCosmetic OutcomeCosmetic OutcomeCosmetic Outcome• In the pivotal studies, vehicle treated patients had as

good as or better cosmetic outcome than MAL treatment, but poorer response with regard to BCC treatment outcome.

• Cosmetic outcome is considered by Agency to be secondary to non-recurrence of the basal cell carcinoma skin cancer. Recurrence may ultimately result in a worse cosmetic outcome due to need for further treatment.

• The assessment of cosmetic outcomes across treatments were not pre-agreed upon between PhotoCure and FDA.

• In the pivotal studies, vehicle treated patients had as good as or better cosmetic outcome than MAL treatment, but poorer response with regard to BCC treatment outcome.

• Cosmetic outcome is considered by Agency to be secondary to non-recurrence of the basal cell carcinoma skin cancer. Recurrence may ultimately result in a worse cosmetic outcome due to need for further treatment.

• The assessment of cosmetic outcomes across treatments were not pre-agreed upon between PhotoCure and FDA.


Cosmetic OutcomeCosmetic OutcomeCosmetic OutcomeCosmetic Outcome

• Data from the pivotal studies are presented (next slide)

• Limited numbers of patients in each study arm• Photographic basis for assessment was not

provided by PhotoCure to confirm the data• “Cosmetic assessments could be made prior to

surgical excision and supported by blinded independent [review] of photographs.” March, 2000 Regulatory Guidance Meeting Minutes.

• Data from the pivotal studies are presented (next slide)

• Limited numbers of patients in each study arm• Photographic basis for assessment was not

provided by PhotoCure to confirm the data• “Cosmetic assessments could be made prior to

surgical excision and supported by blinded independent [review] of photographs.” March, 2000 Regulatory Guidance Meeting Minutes.

Dermatologic and Ophthalmic Drugs Advisory Committee Dermatologic and Ophthalmic Drugs Advisory Committee September 10, 2003September 10, 2003

Pivotal Studies: Cosmetic Pivotal Studies: Cosmetic OutcomeOutcome

Pivotal Studies: Cosmetic Pivotal Studies: Cosmetic OutcomeOutcome

Cosmetic Outcome for Lesions Having Histological Complete Response -- PhotoCure’s results

Cosmetic Outcome for Lesions Having Histological Complete Response -- PhotoCure’s results

Assessment Excellent Good Fair MissingStudy 307MAL-PDT(N=28)

InvestigatorPatient

17 (61%)18 (64%)

9 (32%)8 (29%)

2 (7%)2 (7%)

44

VEH-PDT(N=10)

InvestigatorPatient

6 (60%)8 (80%)

3 (30%)2 (20%)

1 (10%)0

33

Study 308MAL-PDT(N=22)

InvestigatorPatient

13 (59%)14 (64%)

8 (36%)8 (36%)

1 (5%)0

11

VEH-PDT(N=6)

InvestigatorPatient

2 (33%)5 (83%)

3 (50%)1 (17%)

1 (17%)0

11

Source: PhotoCure’s NDA submission (page 125, Volume 39; page 119, Volume 42).


Safety: Risks IdentifiedSafety: Risks IdentifiedSafety: Risks IdentifiedSafety: Risks Identified

• Local• Pain, Burning & Stinging• Phototoxic Reactions• Contact Sensitization

• Local• Pain, Burning & Stinging• Phototoxic Reactions• Contact Sensitization


Local Adverse Events Local Adverse Events Local Adverse Events Local Adverse Events

Number of Subjects in Pivotal Studies(%)

Curette-MAL-PDT(n=66)

Curette-VEH-PDT(n=65)

Pain skin 12 (18%) 3 (4.5%)

Burning skin 19 (29%) 8 (12%)

Stinging skin 10 (15%) 5 (8%)

Number of Subjects in Pivotal Studies(%)

Curette-MAL-PDT(n=66)

Curette-VEH-PDT(n=65)

Pain skin 12 (18%) 3 (4.5%)

Burning skin 19 (29%) 8 (12%)

Stinging skin 10 (15%) 5 (8%)


Local AEs with MAL-PDTLocal AEs with MAL-PDTLocal AEs with MAL-PDTLocal AEs with MAL-PDTITT Population for Open Label Studies

N=196

Any (% of N)

Mild Moderate Severe

Pain skin 63 (32%) 30 22 11

Burning skin 72 (37%) 22 44 6

Stinging skin 54 (28%) 26 24 4

ITT Population for Open Label Studies N=196

Any (% of N)

Mild Moderate Severe

Pain skin 63 (32%) 30 22 11

Burning skin 72 (37%) 22 44 6

Stinging skin 54 (28%) 26 24 4


Local AE: PhototoxicityLocal AE: PhototoxicityLocal AE: PhototoxicityLocal AE: Phototoxicity

• Patients treated with Curette-MAL-PDT could have skin ulceration, and blisters that last 1 to 2 weeks after treatment and in two cases erythema lasted more than a year.*

• No separate analysis for rates of such occurrence.

*PhotoCure summary of non-U.S. labeling and Summary of Safety

• Patients treated with Curette-MAL-PDT could have skin ulceration, and blisters that last 1 to 2 weeks after treatment and in two cases erythema lasted more than a year.*

• No separate analysis for rates of such occurrence.

*PhotoCure summary of non-U.S. labeling and Summary of Safety


Summary of Local AEs with Summary of Local AEs with MAL-PDTMAL-PDT

Summary of Local AEs with Summary of Local AEs with MAL-PDTMAL-PDT

• Curette-MAL-PDT was associated with higher incidence rates of Pain, Burning, or Stinging than Curette-VEH-PDT.

• The use of local anesthesia with MAL-PDT treatment was not studied in a systematic fashion.

• Minimal instructions for use of anesthesia –“Tumor fragments from most lesions may be removed without damaging normal skin and without use of anaesthetics.”

• Curette-MAL-PDT was associated with higher incidence rates of Pain, Burning, or Stinging than Curette-VEH-PDT.

• The use of local anesthesia with MAL-PDT treatment was not studied in a systematic fashion.

• Minimal instructions for use of anesthesia –“Tumor fragments from most lesions may be removed without damaging normal skin and without use of anaesthetics.”


SensitizationSensitizationSensitizationSensitization

• Dermal Safety – Sensitization Studies• Subjects during clinical trials

– 2 patients with urticaria/hypersensitivity reaction

• Post-Marketing (Europe) – 2 patients with 1 positive rechallenge

• Dermal Safety – Sensitization Studies• Subjects during clinical trials

– 2 patients with urticaria/hypersensitivity reaction

• Post-Marketing (Europe) – 2 patients with 1 positive rechallenge


Sensitization Study DesignSensitization Study Design Sensitization Study DesignSensitization Study Design

• Induction Phase – MAL and MAL-vehicle applied for 3 weeks

• 2 Week Rest Period• Challenge Phase

– 3 hour MAL/VEH application– 48 hour Aminolevulinate 0.1% in soft

paraffin (ALA) vehicle cross-sensitization challenge

• Induction Phase – MAL and MAL-vehicle applied for 3 weeks

• 2 Week Rest Period• Challenge Phase

– 3 hour MAL/VEH application– 48 hour Aminolevulinate 0.1% in soft

paraffin (ALA) vehicle cross-sensitization challenge


215 planned

156 Included

58 Drop-outs 98 Continued to Challenge

58 Challenged with MAL

40 Refused MAL

30 Positive

3 Equivocal

25 Negative

Dermal Safety: Sensitization Study

Enrollment stopped due to skin reactions

52% of the 58 Subjects Who Continued and Did

Not Refuse MALWere Sensitized to MAL

Cream


ALA 48 hour Cross ALA 48 hour Cross Sensitization/Challenge Sensitization/Challenge

Results (N=98)Results (N=98)

ALA 48 hour Cross ALA 48 hour Cross Sensitization/Challenge Sensitization/Challenge

Results (N=98)Results (N=98)

• None judged positive to 0.1% ALA

• 2% (2) were judged equivocal to ALA

• 2% (2) were judged positive to soft yellow paraffin vehicle for ALA

• None judged positive to 0.1% ALA

• 2% (2) were judged equivocal to ALA

• 2% (2) were judged positive to soft yellow paraffin vehicle for ALA


Safety Conclusions Safety Conclusions Safety Conclusions Safety Conclusions

• MAL has a high sensitization potential (at least 52% sensitization rate in a provocative study)

• Cross sensitization to ALA (an endogenous substance) cannot be ruled out

• Sensitization to MAL of healthcare providers and patients are of concern

• MAL has a high sensitization potential (at least 52% sensitization rate in a provocative study)

• Cross sensitization to ALA (an endogenous substance) cannot be ruled out

• Sensitization to MAL of healthcare providers and patients are of concern


NDA 21-576: Risk/BenefitNDA 21-576: Risk/BenefitNDA 21-576: Risk/BenefitNDA 21-576: Risk/Benefit•Efficacy

– Curette-MAL-PDT was shown to be statistically superior to Curette-VEH-PDT for the chosen outcome assessment in the pivotal studies.

– Adequacy of studies for estimating treatment effect?• Early histology and small numbers in pivotal studies• Minimal recurrence rate data for nodular BCC

– Adequacy of Instructions for Lesion Preparation?• Apparent high VEH-PDT response rate• Center-to-center variability

– Numerically higher recurrence rate with MAL-PDT vs. Surgery in one small open-label study - exact point estimate is uncertain

•Efficacy– Curette-MAL-PDT was shown to be statistically

superior to Curette-VEH-PDT for the chosen outcome assessment in the pivotal studies.

– Adequacy of studies for estimating treatment effect?• Early histology and small numbers in pivotal studies• Minimal recurrence rate data for nodular BCC

– Adequacy of Instructions for Lesion Preparation?• Apparent high VEH-PDT response rate• Center-to-center variability

– Numerically higher recurrence rate with MAL-PDT vs. Surgery in one small open-label study - exact point estimate is uncertain


NDA 21-576: Risk/Benefit NDA 21-576: Risk/Benefit (continued)(continued)

NDA 21-576: Risk/Benefit NDA 21-576: Risk/Benefit (continued)(continued)

• Safety– Pain and minimal information regarding

anesthesia/pain control– Contact hypersensitization

• Safety– Pain and minimal information regarding

anesthesia/pain control– Contact hypersensitization


PhotoCure Video

NDA 21-576

Documents

Transcript of NDA 21-576