# Presentation: 369681

## NDA 21-576

**Methyl aminolevulinate Cream (MAL) with Curettage and Photodynamic Therapy (PDT) for Basal Cell Carcinoma (BCC)**** **

## FDA Clinical and Statistical Reviewers

- Brenda Vaughan, M.D., Medical Officer
- Markham C. Luke, M.D., Ph.D., Dermatology Team Leader
- Shiowjen Lee, Ph.D., Mathematical Statistician
- Mohamed Alosh, Ph.D., Mathematical Statistics Team Leader

## Treatment of Primary Nodular BCC

**Curette-MAL-PDT consists of:**
- Lesion preparation (Curettage)
- Methyl Aminolevulinate (MAL) Cream
- Combined with Curelight Lamp (Drug/Device Combination)
**	****	****	****	**

## Background

- “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 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

## Measurements of Efficacy for Treatment of Basal 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

## Clinical 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

## Pivotal 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

## Pivotal 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

## Pivotal Studies: Study Design

- 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.
- Complete response is not equal to “cure”.

## STUDIES

- 1st Tx Cycle

- 7 DAYS
- APART

- 307 and 308

- RANDOMIZATION

- MAL or VEH PDT

## Biostatistical Analysis of Pivotal Studies

## Efficacy Evaluation in Pivotal Studies

**Primary:      Patient complete response rate**
**Secondary:  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)
**Complete response is not equal to “cure”.**

## Overview of Efficacy Findings in 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**

## Overview of Efficacy Findings in Pivotal Studies 

**Clues:**
**High vehicle response rate**
**Center-to-center variability: **
**	****	****Small studies with few patients per center**
**	****	****	****	**

## Apparent High Vehicle Response Rate Based on Histological Evaluation

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

## Estimates of Response for 1st Treatment Cycle

- 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 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 307: Lesion Response Inter-Center Variability

## Study 308: Lesion Response Inter-Center Variability

## Pivotal Studies: Summary 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.

## Efficacy 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

## PhotoCure Video – Lesion Preparation

**PhotoCure Video – Lesion Preparation**

## Effect 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

## Curettage

**Page 124 of PhotoCure AC Briefing, Figure 20**

## Recurrence 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*

## Recurrence 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.

## Assessment 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.

## Study 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

## Example of Complete Response?

**Page 100 of PhotoCure AC Briefing, Figure 19**

## Lesion Recurrence Data: Study 303

## Failure to Cure Analysis: Study 303

## Phase 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

## Factors Affecting Applicability of 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

## Recurrence: Study 205

- Lesion recurrence (at 24 months)

- *Early failures are not included

## Recurrence: 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.

## Cosmetic 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.

## Cosmetic 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.*

## Pivotal Studies: Cosmetic Outcome

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

## Safety: Risks Identified

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

## Local Adverse Events 

## Local AEs with MAL-PDT

## Local 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

## Summary of Local AEs with MAL-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.”

## Sensitization

**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 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

## Dermal Safety: Sensitization Study 

- Dermal Safety: Sensitization Study

- Enrollment stopped due to skin reactions

- 52% of the 58 Subjects Who Continued and Did Not Refuse MAL
- Were Sensitized to MAL Cream

##  ALA  48 hour Cross Sensitization/Challenge         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

## 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

## NDA 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

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

**Safety**
- Pain and minimal information regarding anesthesia/pain control
- Contact hypersensitization

## PhotoCure Video