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NDA 21-576

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

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NDA 21-576

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  1. NDA 21-576 Methyl aminolevulinate Cream (MAL) with Curettage and Photodynamic Therapy (PDT) for Basal Cell Carcinoma (BCC)

  2. 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

  3. Treatment of Primary Nodular BCC • Curette-MAL-PDT consists of: • Lesion preparation (Curettage) • Methyl Aminolevulinate (MAL) Cream • Combined with Curelight Lamp (Drug/Device Combination)

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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”.

  11. Excise 3 MONTHS LATER Complete Clinical Response Excise 3 MONTHS LATER Complete Clinical Response 2nd Tx Cycle Partial Clinical Response 7 DAYS APART 3 MONTHS 3 MONTHS Incomplete Clinical Response No Clinical Response Excise Excise STUDIES 307 and 308 RANDOMIZATION 1st Tx Cycle 7 DAYS APART MAL or VEH PDT

  12. Biostatistical Analysis of Pivotal Studies

  13. 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”.

  14. 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

  15. Clues: High vehicle response rate Center-to-center variability: Small studies with few patients per center Overview of Efficacy Findings in Pivotal Studies

  16. Apparent High Vehicle Response Rate Based on Histological Evaluation

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

  18. 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

  19. 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

  20. Study 307: Lesion Response Inter-Center Variability

  21. Study 308: Lesion Response Inter-Center Variability

  22. 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.

  23. 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

  24. PhotoCure Video – Lesion Preparation

  25. 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

  26. Curettage Page 124 of PhotoCure AC Briefing, Figure 20

  27. 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

  28. 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.

  29. 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.

  30. 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

  31. Example of Complete Response? Page 100 of PhotoCure AC Briefing, Figure 19

  32. Lesion Recurrence Data: Study 303

  33. Failure to Cure Analysis: Study 303

  34. 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

  35. 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

  36. Recurrence: Study 205 Lesion recurrence (at 24 months) *Early failures are not included

  37. 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.

  38. 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.

  39. 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.

  40. Pivotal Studies: Cosmetic Outcome Cosmetic Outcome for Lesions Having Histological Complete Response -- PhotoCure’s results

  41. Safety: Risks Identified • Local • Pain, Burning & Stinging • Phototoxic Reactions • Contact Sensitization

  42. Local Adverse Events

  43. Local AEs with MAL-PDT

  44. 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

  45. 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.”

  46. Sensitization • Dermal Safety – Sensitization Studies • Subjects during clinical trials • 2 patients with urticaria/hypersensitivity reaction • Post-Marketing (Europe) • 2 patients with 1 positive rechallenge

  47. 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

  48. 215 planned 156 Included 58 Drop-outs 98 Continued to Challenge 58 Challenged with MAL 30 Positive 3 Equivocal 25 Negative 40 Refused MAL 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

  49. 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

  50. 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

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