5/21/2015 Non-Inferiority Assessment of Patch Adhesion Non-Inferiority Assessment of Patch Adhesion and and Dermatology Irritation of Post-Market Dermatology Irritation Evaluation Change and Generic Drug Evaluation • Presented by Mark Liu, Senior Director of Biostatistics » Mylan Pharmaceuticals • Coauthored by Russ Rackley, VP of Global PK » Mylan Pharmaceuticals 1 Non-Inferiority Assessment of Patch Adhesion and Dermatology Irritation Evaluation Disclaimer: This presentation reflects the views of the authors and not necessarily the Mylan’s official standing on the issues. 2 1
5/21/2015 Outlines • Overview of current Dermal Irritation Evaluation – Study Design and Irritation Scales – Current Statistical Method • Simulated Examples will show the problem of the current method • Our proposed Statistical method to overcome the problem. • Adhesion issues and an easy solution • Conclusions 3 Assessment of Irritation 2
5/21/2015 FDA Irritation Scales Dermal Response Scale Irritation 0 No evidence of irritation 1 Minimal erythema, barely perceptible 2 Definite erythema, readily visible; or minimal edema; or minimal papular response 3 Erythema and papules 4 Definite edema 5 Erythema, edema, and papules 6 Vesicular eruption 7 Strong reaction spreading beyond test (i.e., application) site Other Effects Scale Appearance A (0) Slighty glazed appearance B (1) Marked glazed appearance C (2) Glazing with peeling and cracking F (3) Glazing with fissures G (3) Film of dried serous exudates covering all or part of the patch site H (3) Small petechial erosions and/or scabs • Typically evaluated for multiple wear periods over 21 days. • Low scores associated with good performance. • Sum of the Dermal Response and Other Effects as final analysis value. 5 Current OGD Statistical Method • The analyses for cumulative irritation are intended to demonstrate that ’the upper bound of the one-sided 95% CI of the mean Test score minus 1.25 times the mean RLD score must be less than or equal to 0’. 95% ��� ����� ���� � 1.25 ∗ ���� ���� � 0 rearranged… ���� ������������ 95% ��� � 0 . 25 ������� • The rearrangement demonstrates that the result of this metric relative to acceptance criterion can become excessively stringent as the mean RLD score approaches zero. 6 3
5/21/2015 Hypersensitivity of the Current Assessment Criteria • In situations of low or minimal irritation response, the margins allowed are far lower than would be permitted relative to products with worse performance (i.e. scores >1). 2.5 2 Test - Mean Irritation 1.5 Line of Identity 1 FDA Limit 0.5 0 0 0.5 1 1.5 2 2.5 Reference - Mean Irritation 7 Hypersensitivity of the Current Assessment Criteria Absolute Margins with Different Levels of Mean Scores 2 1.5 1 0.5 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 Non ‐ Inferiority Margin 8 4
5/21/2015 Issues with current Method • For assessment of irritation of Transdermal product, issues exist with current recommended scoring system and statistical methodology such that a RLD with good clinical performance will predominately have low scores which creates a condition that is prohibitive to generic entry. • This situation flourishes at levels of irritation that are clinically negligible. And while infinitesimally small differences may exist between a Test and Reference product, they occur at levels for which clinical safety is self- evident. • The overly stringent nature of OGD’s method will be demonstrated via simulated examples. 9 Assessment of Irritation Simulated Examples – general rules • Five separate studies were used to generate five simulated examples. • Four of these five studies have more than 200 subjects completed the study, the other one has more than 100 subjects completed the study. • One Bootstrap simulation sample was selected from each study with desired mean values. 10 5
5/21/2015 Assessment of Irritation Simulated Example One Assessment of Irritation Simulated Example One • 21-day continuous cumulative irritation study • 3.5 days per patch application on same skin site , for total 6 patches per treatment • 200 subjects total with simultaneous wear of both Test and RLD patches. 12 6
5/21/2015 Assessment of Irritation Example One – simulated dataset Test formulation Irritation Patch number Values 1 2 3 4 5 6 194 194 188 181 177 152 0 6 3 10 16 16 39 1 2 0 1 0 1 5 7 0 2 2 2 2 2 3 200 200 200 200 200 200 Total RLD formulation Irritation Patch number Values 1 2 3 4 5 6 0 192 192 192 178 171 159 8 8 6 20 15 32 1 0 0 2 2 14 4 2 3 0 0 0 0 0 5 200 200 200 200 200 200 Total 13 Assessment of Irritation Example One – Summary Statistics Summary Statistics on cumulative Means Treatment N Mean Std Dev CV Range 200 0.123 0.325 264% 0 - 2.67 Test 200 0.123 0.227 225% 0 - 1.67 RLD 14 7
5/21/2015 Assessment of Irritation Example One - results • Statistical results using OGD’s method – Upper one-sided 95% confidence interval of cumulative adhesion for the mean Test adhesion score minus 1.25 times the mean Reference adhesion score should not exceed zero. Test Reference Parameter Upper Criteria Pass/Fail 95% CI 0.123 Test – 1.25*Ref 0.0016 ≤ 0 0.123 Fail 15 Assessment of Irritation Example One – Bootstrap simulation RLD mean irritation ~ 0.125 Number of Subjects Passing Rate 13% 36 18% 60 30% 120 44% 200 72% 400 All based on 2000 simulation samples 16 8
5/21/2015 Assessment of Irritation Simulated Example Two Assessment of Irritation Simulated Example Two • 21-day continuous cumulative irritation study • 3.5 days per patch application on the same skin site, total 6 patches per treatment • 200 subjects total with simultaneous ware of both Test and RLD 18 9
5/21/2015 Assessment of Irritation Example Two – simulated dataset Test formulation Irritation Patch number Values 1 2 3 4 5 6 0 167 176 171 165 162 158 27 14 20 24 24 29 1 6 10 9 9 9 5 2 0 0 0 0 3 6 3 0 0 0 0 0 0 4 0 0 0 0 0 0 5 0 0 0 1 1 1 6 0 0 0 1 1 1 7 200 200 200 200 200 200 RLD formulation Irritation Patch number 1 2 3 4 5 6 Values 163 177 174 159 163 146 0 28 16 18 32 26 41 1 9 7 7 8 6 6 2 0 0 0 0 4 6 3 0 0 1 0 0 0 4 0 0 0 1 0 0 5 0 0 0 0 1 0 6 0 0 0 0 0 1 7 200 200 200 200 200 200 19 Assessment of Irritation Example Two - summary Summary Statistics on cumulative Means Treatment N Mean Std Dev CV Range 200 0.25 0.552 220% 0 - 4.167 Test 200 0.25 0.469 188% 0 - 4.000 RLD 20 10
5/21/2015 Assessment of Irritation Example Two – Bootstrap Simulation RLD mean irritation ~ 0.25 Number of Subjects Passing Rate 32% 36 35% 60 41% 120 50% 200 74% 400 All based on 2000 simulation samples 21 Assessment of Irritation Simulated Example Three 11
5/21/2015 Assessment of Irritation Simulated Example Three • 21-day continuous cumulative irritation study • 2-days, 2-days, and 3-days per week patch application on same site, total 9 patches per treatment • 200 subjects total with simultaneous wear of both Test and RLD 23 Assessment of Irritation Example Three – simulated dataset Test formulation Irritation Patch number 1 2 3 4 5 6 7 8 9 Values 110 14 4 0 0 0 0 0 0 0 86 183 188 170 135 3 0 18 9 1 4 3 8 16 30 131 106 63 56 2 0 0 0 0 0 17 39 55 67 3 0 0 0 12 30 14 6 5 4 4 0 0 0 0 0 30 43 53 51 5 0 0 0 0 0 0 1 0 7 6 0 0 0 2 5 0 0 1 1 7 0 0 0 0 0 5 5 5 5 8 200 200 200 200 200 200 200 200 200 RLD formulation Irritation Patch number 1 2 3 4 5 6 7 8 9 Values 103 5 9 2 0 0 2 2 0 0 85 166 162 129 92 63 22 14 26 1 12 29 29 54 61 68 85 70 58 2 0 0 0 9 8 12 2 9 0 3 0 0 0 6 37 51 79 81 81 4 0 0 0 0 0 0 0 14 25 5 0 0 0 0 0 1 3 3 3 6 0 0 0 0 2 5 7 7 7 7 0 0 0 0 0 0 0 0 0 8 200 200 200 200 200 200 200 200 200 24 12
5/21/2015 Assessment of Irritation Example Three – Statistical summary Summary Statistics on cumulative Means Treatment N Mean Std Dev CV Range 200 2.00 0.841 42% 0 – 5.444 Test 200 2.00 0.773 39% 0 – 4.667 RLD 25 Assessment of Irritation Example Three – Statistical results • Statistical results using OGD’s method – Upper one-sided 95% confidence interval of cumulative adhesion for the mean Test adhesion score minus 1.25 times the mean Reference adhesion score should not exceed zero. Test Reference Parameter Upper Criteria Pass/Fail 95% CI 2.000 Test – 1.25*Ref -0.4402 ≤ 0 2.001 Pass 26 13
5/21/2015 Assessment of Irritation Example Three – Bootstrap simulative RLD mean irritation ~ 2.0 Number of Subjects Passing Rate 100% 36 100% 60 All based on 2000 simulation samples 27 Assessment of Irritation Summary results of all Examples Boot-strap simulation summary of power, depending on mean RLD score Number of RLD Means and Test mean Subjects 0.123 0.25 0.50 1.00 2.00 13% 32% 60% 77% 100% 36 18% 35% 79% 93% 60 30% 41% 96% 100% 120 44% 50% >99% 200 72% 74% 100% 400 All estimates based on 2000 simulation samples each 28 14
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