APPLICATION NUMBER€¦ · of the Federal Food, Drug, and Cosmetic Act for tazarotene lotion, 0.045%. We also refer to your October 11, 2018, correspondence, received October 11,

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER

211882Orig1s000

ADMINISTRATIVE and CORRESPONDENCE DOCUMENTS

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration Silver Spring MD 20993

IND 126277

MEETING PRELIMINARY COMMENTS

Dow Pharmaceutical Sciences Inc co Valeant Pharmaceuticals North America LLC Attention Sean Humphries Associate Director Regulatory Affairs 1330 Redwood Way Suite C Petaluma CA 94954

Dear Mr Humphries

Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food Drug and Cosmetic Act for tazarotene lotion 0045

We also refer to your October 11 2018 correspondence received October 11 2018 requesting a meeting to discuss the overall organization for submission of New Drug Application (NDA)

Our preliminary responses to your meeting questions are enclosed

You should provide to the Regulatory Project Manager a hardcopy or electronic version of any materials (ie slides or handouts) to be presented andor discussed at the meeting

In accordance with 21 CFR 1065(e) and FDA policy you may not electronically record the discussion at this meeting The official record of this meeting will be the FDA-generated minutes

If you have any questions call me at (301) 796-4224

Sincerely

See appended electronic signature page

Barbara Gould MBAHCM Chief Project Management Staff Division of Dermatology and Dental Products Office of Drug Evaluation III Center for Drug Evaluation and Research

ENCLOSURE Preliminary Meeting Comments

Reference ID 4347759

FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

PRELIMINARY MEETING COMMENTS

Meeting Type BMeeting Category PNDA

Meeting Date and Time November 13 2018 at 205 PMMeeting Location Teleconference

Application Number IND 126277Product Name tazarotene lotion 0045

Proposed Indication For the topical treatment of acne vulgaris in patients 9 years of age and older

Sponsor Name Dow Pharmaceutical Sciences Inc

1 Introduction2 This material consists of our preliminary responses to your questions and any additional 3 comments in preparation for the discussion at the teleconference scheduled for October 25 4 2018 at between Dow Pharmaceutical Sciences Inc and the Division of Dermatology and 5 Dental Product We are sharing this material to promote a collaborative and successful 6 discussion at the meeting The meeting minutes will reflect agreements important issues 7 and any action items discussed during the meeting and may not be identical to these 8 preliminary comments following substantive discussion at the meeting If you determine 9 that discussion is needed for only some of the original questions you have the option of 10 reducing the agenda andor changing the format of the meeting (eg from face to face to 11 teleconference) Contact the Regulatory Project Manager (RPM) if there are any major 12 changes to your development plan the purpose of the meeting or the questions based on 13 our preliminary responses as we may not be prepared to discuss or reach agreement on 14 such changes at the meeting 15 16 10 BACKGROUND 17 18 The purpose of this PNDA meeting is to discuss the format and content for future 19 marketing application to support the proposed indication of acne vulgaris in patients 9 20 years of age and older 21 22 20 DISCUSSION 23 24 Regulatory Correspondence History 25 26 We have had the following meetingsteleconferences with you

IND 126277Page 2

27 bull 12062016 End of Phase 2 Meeting 28 29 We have sent the following correspondences 30 bull 08092017 Advice Letter 31 bull 08022017 Pediatric Study Plan ndash Written Response 32 bull 10202015 Study May Proceed 33 34 21 Regulatory 35 36 Introductory Comment 37 If you intend to rely in part on information required for approval that comes from studies not 38 conducted by you or for you or for which you have not obtained a right of reference (eg 39 reliance on the FDArsquos finding of safety andor effectiveness for a listed drug or published 40 literature) then your marketing application will be a 505(b)(2) application 41 42 You are proposing to reference information from the Summary Basis of Approval (SBA) and 43 FDA reviewersrsquo public summaries for support of the safety of your product ldquoFull reports of 44 investigationsrdquo of safety and effectiveness are required to be submitted for approval of 505(b)(1) 45 and 505(b)(2) NDAs The SBA and FDA reviewersrsquo public summaries however do not 46 constitute full reports of investigations See 21 CFR 314430(e)(2) A 505(b)(2) applicant that 47 seeks to rely upon the Agencyrsquos finding of safety andor effectiveness for a listed drug may rely 48 on FDArsquos finding of safety and effectiveness as reflected in the FDA-approved labeling for the 49 listed drug 50 51 Within your background package you make reference to Clarify if you 52 intend to rely on our finding of safety for each of those listed drugs to support your marketing

(b) (4)

53 application The regulatory requirements for a 505(b)(2) application (including but not limited 54 to an appropriate patent certification or statement) apply to each listed drug upon which a 55 sponsor relies 56 57 You must establish that such reliance is scientifically appropriate and must submit data necessary 58 to support any aspects of the proposed drug product that represent modifications to the listed 59 drug(s) You should establish a ldquobridgerdquo (eg via comparative bioavailability data) between 60 your proposed drug product and each listed drug upon which you propose to rely to demonstrate 61 that such reliance is scientifically justified 62 63 You must establish that reliance on the studies described in the literature or on the other studies 64 is scientifically appropriate You should include a copy of such published literature in the 65 505(b)(2) application and identify any listed drug(s) described in the published literature (eg by 66 trade name(s)) 67 68 Refer to the 505(b)(2) REGULATORY PATHWAY section below for information about 69 submitting a 505(b)(2) NDA 70 71

IND 126277Page 3

72 Question 19 73 The Sponsor intends to request a partial waiver for the conduct of clinical studies with IDP-123 74 Lotion in pediatric subjects aged 0 to 8 years 11 months due to the very low prevalence of acne 75 in this age group The Sponsor included subjects 9 years of age and above in clinical studies 76 with IDP-123 Lotion The agreed to iPSP was submitted to IND 126277 on 15 August 2017 77 (Sequence 0017) 78 79 Does the Agency agree with the Sponsorrsquos request for partial waiver for pediatric subjects aged 0 80 to 8 years 11 months 81 82 FDA Response to Question 19 83 Your iPSP is currently pending internal consultation with the Pediatric Research Equity 84 Committee (PeRC) with a target date to provide you with final decision by November 22 2018 85 86 Question 20 87 The Sponsor proposes to submit the IDP-123 Lotion NDA in eCTD format with a complete 88 XML backbone The proposed content for Modules 1-5 is provided in Appendix 162137 89 90 Does the Agency concur with the content and format of the NDA as outlined in the briefing 91 package 92 93 FDA Response to Question 20 94 Your proposal appears reasonable 95 96 22 Chemistry Manufacturing and Controls (CMC)9798 Question 1 99 DPS is proposing specifications in accordance with the current International Council for 100 Harmonisation (ICH) guideline Q6A for drug substance and drug product

(b) (4)Tazarotene drug

101 substance is described in the manufacturerrsquos drug master file Details of the proposed 102 specifications are provided in the briefing package (Section 162131) We acknowledge that 103 the suitability of the acceptance criteria could be an NDA review issue and are subject to change 104 based on final stability data to be presented in the NDA 105 106 a Based on the specifications provided in the briefing package does the Agency have any 107 recommendations for the drug substance specifications proposed for tazarotene 108 109 b Based on the specifications provided in the briefing package does the Agency have any 110 recommendations for the drug product specifications proposed for use in commercial 111 drug product 112 113 FDA Response to Question 1 114 a The proposed drug substance specifications appear reasonable In addition to the drug 115 substance specifications submitted you should evaluate the need to control the 116 polymorphic form particle size distribution and the elemental impurities of the drug

IND 126277 Page4

117 substance in the specifications Since you have made reference to DMILj refer to 118 FDA DMF related comments dated on 02 December 2016 119

120 b The submitted diug product specifications appear reasonable However emulsion dimiddotoplet 121 size should be tested at release as well as on stability See further comments under the 122 FDA Response to Q3 123

124 We may have further comments for the test and acceptance criteria in the specifications for 125 both diu g substance and diu g product based on the totality of the overall data dming NDA 126 review 127

128 Ouestion 2 129 For other topical marketed products the physician s sample size has not been tested routinely per 130 United States Phannacopeia (USP)lt3gt unifo1mity in containers Given that the maximum daily 131 dose is approximately lt4jgday the physician sample size of 3 g can be considered for 1 time use 132 only and thus exempt from testing by USP lt3gt unifo1mity in containers 133

134 Does the Agency agree that the 3-g physician sample size is exempt from testing by USPlt3gt 135 unifo1mity in containers 136

137 FDA Response to Question 2 138 We agree However the content unifo1mity is one of the critical quality attributes of the lotion 139 dosage fo1m Even though 3-g physician sample is a single dose unit we still recommend you 140 test the container content unifo1mity per USP lt905gt The final recommendation will be made 141 based on the totality of the data submitted at the time ofNDA review 142

143 Ouestion 3 4

144 DPS has evaluated emulsion dimiddotoplet size for 9 bulk commercial scale batches ltbgtlt f filled in 4

145 various packaging configmations for (bJlt I and IDP-123 for a total ofGl packaged 146 lots As these diu g products contain the same Vehicle Lotion as described above the DlO D50 147 and D90 results are consistent across storage conditions time points and packa__~~--~mg148 confi uations It is proposed that the emulsion dimiddotoplet specification be tested (bJ

150 (b)(4J

151 Does the Agency agree that these studies suppo1i testing of this attribute for 152 (b)(4) ------shy

154 FDA Response to Ouestion 3 155 No we do not agree 156

(b)(4J 157 (b)(4J 158

159 (b)(4)

161 specification should be tested forthe proposed diu g product at release as well as on stability If 162 this NDA is approved for marketing we recommend you submit a post-approval supplement to

IND 126277Page 5

163 request removal of this test once adequate commercial scale batch stability data has been 164 generated with this specific formulation to justify the elimination of this test during shelf life 165 166 Question 4 167 DPS has conducted ICH registration stability studies in accordance with ICH Q1A guideline

using a (b) (4)168 kg batch size The 3 ICH stability batches consisted of a sample (3-g fill size) and 169 trade size (45-g fill size) stored at long term intermediate and accelerated conditions in the 170 inverted and horizontal orientation This design was accepted as per the EOP2 Meeting request 171 submitted on 14 October 2016 (IND 126277 sequence 0010) and in the FDA meeting 172 preliminary feedback dated 02 December 2016 173 174 The process validation lots and the routine commercial batches will be tested at the long term 175 condition in the horizontal orientation only The details of the stability studies and package for 176 the tube fill sizes are provided in Section 162131 177 178 a Does the Agency agree that the stability program described in the briefing package for 179 the ICH (registration) stability batches adequately meets the filing requirements for the 180 NDA 181 182 b Does the Agency agree that the stability programs described in the briefing package for 183 the process validation and routine commercial stability lots are acceptable 184 185 FDA Response to Question 4 186 Your stability program including the process validation and routine commercial lots appears 187 reasonable to support the NDA submission You should also refer to FDA End of Phase 2 188 preliminary comments for CMC question Q2 dated December 2 2018 189 190 Final recommendation regarding the drug product stability testing will be made during NDA 191 reviews based on the totality of the submitted data 192 193 Question 5 194 In addition to the ICH stability studies DPS conducted the following studies photostability 195 temperature cycling (both freezethaw and coldwarm) in-use testing and leachablesextractables 196 assessment in the proposed commercial container closure A brief description of these studies is 197 provided in Section 162131 The results of these studies will be summarized in Sections 198 32P24 Container Closure System and 32P81 Stability Summary and Conclusion of the 199 NDA 200 201 Does the Agency concur that these studies will adequately support filing and registration 202 203 FDA Response to Question 5 204 Your stability program appears reasonable to support the NDA submission We may have further 205 comments during NDA review based on the totality of data 206 207 208

IND 126277 Page 6

209 23 PharmacologyToxicology 210 211 Question 6 212 The IDP-123 Lotion nonclinical development program was discussed and agreed upon with the 213 Agency at the EOP2 meeting For the drug product IDP-123 Lotion DPS intends to provide 214 repeated dose toxicity and local tolerance data Additionally the Sponsor intends to rely on the 215 Agencyrsquos prior findings of safety for the LD Tazorac Cream 01 (NDA 021184) specifically 216 genotoxicity reproductive toxicity and carcinogenicity data 217 218 The results of the Phase 1 PK bridging study (V01-123A-501) used for relative bioavailability 219 assessment suggest that the systemic exposure of IDP-123 Lotion (all ages combined) is similar 220 to the LD 221 222 a Does the Agency agree that the Sponsorrsquos assessment of comparative bioavailability from 223 the PK bridging study data is sufficient to establish an adequate clinical bridge to the LD 224 225 b Assuming that a clinical bridge to the LD is established does the Agency agree in 226 principle that the nonclinical program is sufficient to support a 505(b)(2) NDA for IDP-227 123 Lotion and that no additional toxicity studies will be required 228 229 FDA Response to Question 6 230 a Refer to FDA responses for Questions 7 and 17 231 232 b Yes we agree that no additional nonclinical studies would be required to support a 233 505(b)(2) NDA for IDP-123 Lotion if it is determined that you have established an 234 adequate clinical bridge to the listed drug 235 236 24 Clinical Pharmacology 237 238 Question 17 239 In order to establish comparative bioavailability the Sponsor compared IDP-123 Lotion with 240 Tazorac Cream (LD) exposure in subjects aged 12 and above as part of the maximum use clinical 241 PK study (V01-123A-501) Relative bioavailability assessment was conducted by calculating the 242 ratio of the geometric means and the corresponding 90 CI for tazarotene Cmax and AUC from 243 IDP-123 Lotion over those for Tazorac Cream geometric mean ratios and corresponding 90 244 CIs were similarly calculated for tazarotenic acid Cmax and AUC The results of this analysis 245 as presented in the briefing package demonstrate comparable bioavailability for IDP-123 Lotion 246 versus the LD 247 248 Does the Agency agree that the data presented provide evidence of comparative bioavailability 249 between IDP-123 Lotion and Tazorac Cream 250 251 FDA Response to Question 17 252 The results from the study V01-123A-501 appear to demonstrate that the systemic exposures of 253 tazarotene and tazarotenic acid following application of IDP-123 Lotion are similar or less 254 compared to the exposures following application of Tazorac cream in subjects aged 12 and

IND 126277 Page 7

255 above The final determination will be made at the time of NDA submission following detailed 256 review of your study report and associated bioanalytical method validation and bioanalysis 257 reports 258 259 Question 18 260 The PK profile for IDP-123 Lotion has been established in subjects 9 years of age and older 261 (V01-123A-501) Systemic exposure in subjects aged 9 to lt 12 years of age were found to be 262 higher than for subjects aged ge 12 years of age The adverse event profiles in these two age 263 groups were similar Furthermore there are adequate exposure safety margins to nonclinical 264 toxicity studies in subjects 9 to lt 12 years of age Additionally the safety of IDP-123 Lotion in 265 ages 9 and above was established in the two Phase 3 studies 266 267 Does the Agency agree that the available data as summarized in this briefing package supports 268 the safety of IDP-123 Lotion at the observed maximal use PK exposures in the target population 269 of 9 years of age and older 270 271 FDA Response to Question 18 272 It is premature to agree whether the available data would support the safety of IDP-123 Lotion in 273 the target population down to 9 years of age without reviewing your study reports and associated 274 bioanalytical method validation and bioanalysis reports This determination will be made during 275 the review of your NDA submission 276 277 In your NDA submission provide a justification to support higher systemic exposure of IDP-123 278 Lotion in subjects 9 to lt12 years of age compared to subjects 12 years of age and older 279 280 25 ClinicalBiostatistics 281 282 Question 7 283 The bridging strategy to Tazorac Cream 01 was agreed upon with the FDA at the pre-IND 284 meeting held 17 June 2015 and again at the EOP2 meeting The program includes a PK bridging 285 study V01-123A-501 and a safety and efficacy bridging study V01-123A-201 The results 286 from these studies as summarized in this briefing package suggest an adequate clinical bridge 287 has been established 288 289 Does the Agency agree that the results from the bridging studies are adequate to establish a 290 clinical bridge to Tazorac Cream 01 and allow for a successful 505(b)(2) NDA pathway for 291 IDP-123 Lotion 292 293 FDA Response to Question 7 294 Yes pending review of the final study reports under the NDA 295 296 Question 8 297 Based on the completion of the clinical program as detailed in the briefing package does the 298 Agency agree that the clinical program is adequate to support approval of IDP-123 Lotion with 299 an indication for the topical treatment of acne 300

IND 126277Page 8

301 FDA Response to Question 8 302 The clinical program appears adequate for filing and review under the NDA Determination of 303 specific labeling will be discussed during the second half of the NDA review 304 305 Question 9 306 A total of approximately 1174 human subjects will have been exposed to at least 1 dose of IDP-307 123 Lotion and will be included in the NDA submission as part of the safety database Of these 308 approximately 897 are subjects with acne and treated with the to-be-marketed formulation of 309 IDP-123 Lotion 310 311 Does the Agency agree that the total subject exposure is adequate to support approval of the 312 NDA 313 314 FDA Response to Question 9 315 Yes unless some new safety issue is identified following review of the clinical study reports 316 317 Question 10 318 The Sponsor plans to provide Bioresearch Monitoring (BIMO) Clinical Data in the eCTD 319 format For each pivotal Phase 3 study the following will be provided in Module 5 Section 320 5354 321 322 bull BIMO STF containing general study related information and specific clinical investigator 323 information (if specific items are provided elsewhere in the submission a location or link 324 will be provided) 325 326 o General study related information and specific clinical investigator information in 327 tabular format (submitted in portable document format [PDF]) 328 329 o Data listing by site in tabular format (submitted in PDF) 330 331 o Data listings by Study in tabular format (submitted in PDF) 332 333 bull Site level data sets across studies (clinsitexpt) 334 335 For each pivotal Phase 3 study the following will be provided in Module 5 Section 5351 (data 336 listing datasets) 337 338 bull Subject level data listings by site (PDF) 339 340 bull Define file (PDF) 341 342 Does the FDA agree to the eCTD location of the BIMO information that will be included in the 343 original NDA 344 345

IND 126277 Page 9

346 FDA Response to Question 10 347 Yes we agree with the location and the approach appears acceptable Please refer to the 348 February 2018 draft guidance for industry ldquoStandardized Format for Electronic Submission of 349 NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for 350 CDER Submissions When final this guidance will represent FDArsquos current thinking on the 351 topic The guidance is available at the following link 352 httpswwwfdagovdownloadsdrugsdevelopmentapprovalprocessformssubmissionrequiremen 353 tsucm332466pdf 354 355 Question 11 356 For the 2 pivotal Phase 3 studies (V01-123A-301 and V01-123A-302) the Sponsor plans to 357 submit case report forms in Appendix 163 of the CSR by study center and subject identifier 358 Case report forms for the following subjects will be submitted in the NDA 359 360 bull Deaths during the study(s) 361 362 bull Other SAEs during the study(s) 363 364 bull Discontinuations due to an AE during the study(s) 365 366 Does the Agency agree with the case report forms the Sponsor proposes to submit in the NDA 367 for the pivotal Phase 3 studies 368 369 FDA Response to Question 11 370 With your NDA submit electronic case report forms (eCRFs) for deaths SAEs AEs leading to 371 discontinuations and withdrawals and adverse events of special interest eCRFs for subjects 372 who were exposed to investigational product should be available upon request and for inspection 373 during the review period For the principal record keeping requirements for clinical investigators 374 and sponsors developing drugs see Guidance for Industry Electronic Source Data in Clinical 375 Investigations 376 377 Question 12 378 At the pre-IND meeting held 17 June 2015 and EOP2 meeting a long term study waiver was 379 discussed and FDA stated that a long term safety study may not be required if an adequate 380 clinical bridge is established The safety and efficacy results from the Phase 2 bridging study and 381 the PK results from the Phase 1 PK bridging study provide evidence that the safety profile and 382 systemic exposure of IDP-123 Lotion is similar for all ages combined to Tazorac Cream 01 383 and consequently would not require a separate long term safety study to support registration of 384 IDP-123 Lotion 385 386 Does the Agency agree that based upon the available data an adequate clinical bridge will be 387 established and an additional long term safety study with IDP-123 Lotion is not needed for a 388 505(b)(2) NDA approval 389 390 391

IND 126277Page 10

392 FDA Response to Question 12 393 A long-term safety study does not appear necessary unless a new safety issue is identified 394 following review of the clinical study reports 395 396 Question 13 397 Tazarotene formulated in Tazorac Cream and Gel 005 and 01 has been approved and 398 commercialized for use since June 1997 (Tazorac Gel) with no associated reported cardiac 399 events of interest (eg torsades de pointes and cardiac arrhythmia) 400 401 In the pre-IND meeting minutes and EOP2 meeting (Section 162132) the FDA stated a TQT 402 waiver is reasonable provided that the systemic exposure from IDP-123 Lotion is similar to the 403 systemic exposure from Tazorac Cream 01 The similar bioavailability of IDP-123 Lotion to 404 Tazorac Cream 01 based on the PK results from the Phase 1 bridging study coupled with the 405 lack of association between postmarketing tazarotene use and cardiac arrhythmiasadverse 406 effects indicate that a pro-arrhythmia risk is not anticipated with the use of IDP-123 Lotion In 407 addition nonclinical data including in vitro hERG and ECGs in minipigs did not reveal any 408 safety concerns Therefore DPS intends to request a waiver for conducting a clinical study with 409 IDP-123 Lotion to evaluate the potential for QTQTc interval prolongation 410 411 Does the Agency agree that a TQT study to assess the potential of QT prolongation with the use 412 of IDP-123 Lotion is not needed for NDA filing and approval 413 414 FDA Response to Question 13 415 Yes 416 417 Question 14 418 The complete list of clinical studies is presented in Table 9 The datasets for the following 419 clinical studies will be included in the NDA in CDISC format 420 421 bull V01-123A-301 (Phase 3 safety and efficacy) 422 bull V01-123A-302 (Phase 3 safety and efficacy) 423 bull V01-123A-201 (Phase 2 safety and efficacy bridge to Tazorac Cream) 424 bull V01-123A-501 (Phase 1 maximal use PK bridge to Tazorac Cream) 425 bull V01-123A-101 (21-day cumulative irritation) 426 bull V01-123A-102 (RIPT) 427 428 Does the Agency agree with the provision of the files in this format 429 430 FDA Response to Question 14 431 We agree that the datasets for your clinical studies should be submitted in CDISC format We 432 recommend submitting the raw data in SDTM format and the analysis datasets in ADaM format 433 Submit the datasets in SAS transport format (xpt) Ensure that the analysis datasets include all 434 variables needed for conducting all primary secondary and sensitivity analyses included in the 435 study reports 436

IND 126277 Page 11

437 Include dataset documentation (definexml) for tabulation and analysis datasets The analysis 438 dataset documentation should include sufficient detail such as definitions or descriptions of each 439 variable in the dataset algorithms for derived variables (including source variables used) and 440 descriptions of the codes used in factor variables 441 442 Because the protocols specified handling missing data using multiple imputation clarify how 443 you intend to submit the datasets We recommend submitting the observed-case datasets along 444 with complete statistical programs for conducting the multiple imputation through all stages of 445 the analyses so that the full analyses can be conducted from the observed-case datasets Also 446 include any additional statistical programs for non-standard or model-based analyses 447 448 Include the study protocol all protocol amendments the statistical analysis plan and an 449 annotated copy of the case report form as well as the other required elements for the clinical 450 trials 451 452 Question 15 453 Statistical analysis of the safety data for the Phase 3 studies V01-123A-301 and V01-123A-302 454 conducted with the to-be-marketed formulation will be pooled and presented in the Integrated 455 Summary of Safety (ISS) A copy of the ISS statistical analysis plan is included in Appendix 456 162134 The ISS text document will be placed into Module 2 Section 274 with the 457 appendices and datasets provided in Module 5 As per Option D in the Guidance for 458 Industry Integrated Summaries of Effectiveness and Safety Location Within the Common 459 Technical Document each section of the ISS will refer the reader to the appropriate section 460 where the remainder of the ISS is located within the NDA 461 462 a Does the Agency agree with the statistical analysis plan for pooling of safety data for the 463 Phase 3 clinical studies 464 465 b Does the Agency agree with the plan to provide the ISS text document in Module 2 466 Section 274 and datasets in Module 5 Section 5351 467 468 FDA Response to Question 15 469 a Your proposal to provide descriptive safety summaries for the pooled Phase 3 studies 470 appears reasonable 471 472 b If you meet the size and complexity parameters described under lsquoOption Drsquo of the 473 guidance then it is acceptable to include the narrative portion of the ISS in Section 274 474 and the appendices and datasets in Module 5 Note however that the appendices and 475 datasets for the ISS should be included in Section 5353 rather than 5351 476 477 Question 16 478 Statistical analysis of the efficacy data for the Phase 3 studies V01-123A-301 and V01-123A-479 302 conducted with the to-be-marketed formulation will be pooled and presented in the 480 Integrated Summary of Efficacy (ISE) A copy of the ISE statistical analysis plan is included in 481 the appendix 162133 The ISE text document will be placed into Module 2 Section 273 482 with the appendices and datasets provided in Module 5 As per Option D in the Guidance for

IND 126277Page 12

483 Industry Integrated Summaries of Effectiveness and Safety Location Within the Common 484 Technical Document each section of the ISE will refer the reader to the appropriate section 485 where the remainder of the ISE is located within the NDA 486 487 a Does the Agency agree with the statistical analysis plan for pooling of efficacy data for the 488 Phase 3 clinical studies 489 490 b Does the Agency agree with the plan to provide the ISE text document in Module 2 491 Section 273 and datasets in Module 5 Section 5351 492 493 FDA Response to Question 16 494 a Your proposal to provide descriptive efficacy summaries for the pooled Phase 3 studies 495 appears reasonable Refer also to the Guidance for Industry Integrated Summary of 496 Effectiveness for information on content and format of the ISE 497 498 b If you meet the size and complexity parameters described under lsquoOption Drsquo of the 499 guidance then it is acceptable to include the narrative portion of the ISE in Section 273 500 and the appendices and datasets in Module 5 Note however that the appendices and 501 datasets for the ISE should be included in Section 5353 rather than 5351 502 503 30 ADMINISTRATIVE COMMENTS 504 505 PREA REQUIREMENTS 506 507 Under the Pediatric Research Equity Act (PREA) (21 USC 355c) all applications for new 508 active ingredients (which includes new salts and new fixed combinations) new indications new 509 dosage forms new dosing regimens or new routes of administration are required to contain an 510 assessment of the safety and effectiveness of the product for the claimed indication(s) in 511 pediatric patients unless this requirement is waived deferred or inapplicable 512 513 Please be advised that under the Food and Drug Administration Safety and Innovation Act 514 (FDASIA) you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-of-515 Phase-2 (EOP2) meeting In the absence of an EOP2 meeting refer to the draft guidance below 516 The iPSP must contain an outline of the pediatric study or studies that you plan to conduct 517 (including to the extent practicable study objectives and design age groups relevant endpoints 518 and statistical approach) any request for a deferral partial waiver or waiver if applicable along 519 with any supporting documentation and any previously negotiated pediatric plans with other 520 regulatory authorities The iPSP should be submitted in PDF and Word format Failure to 521 include an Agreed iPSP with a marketing application could result in a refuse to file action 522

IND 126277 Page 13

523 For additional guidance on the timing content and submission of the iPSP including an iPSP 524 Template please refer to the draft guidance for industry Pediatric Study Plans Content of and 525 Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at 526 httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidancesU 527 CM360507pdf In addition you may contact the Division of Pediatric and Maternal Health at 528 301-796-2200 or email Pedsdrugsfdahhsgov For further guidance on pediatric product 529 development please refer to 530 httpwwwfdagovDrugsDevelopmentApprovalProcessDevelopmentResourcesucm049867ht 531 m 532 533 PRESCRIBING INFORMATION 534 535 In your application you must submit proposed prescribing information (PI) that conforms to the 536 content and format regulations found at 21 CFR 20156(a) and (d) and 20157 including the 537 Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30 538 2015) As you develop your proposed PI we encourage you to review the labeling review 539 resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation 540 Labeling Final Rule websites which include 541 542 bull The Final Rule (Physician Labeling Rule) on the content and format of the PI for human 543 drug and biological products 544 bull The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of 545 information related to pregnancy lactation and females and males of reproductive 546 potential 547 bull Regulations and related guidance documents 548 bull A sample tool illustrating the format for Highlights and Contents and 549 bull The Selected Requirements for Prescribing Information (SRPI) minus a checklist of 550 important format items from labeling regulations and guidances 551 bull FDArsquos established pharmacologic class (EPC) text phrases for inclusion in the 552 Highlights Indications and Usage heading 553

IND 126277Page 14

554 Pursuant to the PLLR you should include the following information with your application to 555 support the changes in the Pregnancy Lactation and Females and Males of Reproductive 556 Potential subsections of labeling The application should include a review and summary of the 557 available published literature regarding the drugrsquos use in pregnant and lactating women and the 558 effects of the drug on male and female fertility (include search parameters and a copy of each 559 reference publication) a cumulative review and summary of relevant cases reported in your 560 pharmacovigilance database (from the time of product development to present) a summary of 561 drug utilization rates amongst females of reproductive potential (eg aged 15 to 44 years) 562 calculated cumulatively since initial approval and an interim report of an ongoing pregnancy 563 registry or a final report on a closed pregnancy registry If you believe the information is not 564 applicable provide justification Otherwise this information should be located in Module 565 1 Refer to the draft guidance for industry ndash Pregnancy Lactation and Reproductive Potential 566 Labeling for Human Prescription Drug and Biological Products ndash Content and Format 567 (httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidances 568 UCM425398pdf) 569 570 Prior to submission of your proposed PI use the SRPI checklist to ensure conformance with the 571 format items in regulations and guidances 572 573 DISCUSSION OF SAFETY ANALYSIS STRATEGY FOR THE ISS 574 575 After initiation of all trials planned for the phase 3 program you should consider requesting a Type 576 C meeting to gain agreement on the safety analysis strategy for the Integrated Summary of Safety 577 (ISS) and related data requirements Topics of discussion at this meeting would include pooling 578 strategy (ie specific studies to be pooled and analytic methodology intended to manage between-579 study design differences if applicable) specific queries including use of specific standardized 580 MedDRA queries (SMQs) and other important analyses intended to support safety The meeting 581 should be held after you have drafted an analytic plan for the ISS and prior to programming work 582 for pooled or other safety analyses planned for inclusion in the ISS This meeting if held would 583 precede the Pre-NDA meeting Note that this meeting is optional the issues can instead be 584 addressed at the pre-NDA meeting 585 586 To optimize the output of this meeting submit the following documents for review as part of the 587 briefing package 588 589 bull Description of all trials to be included in the ISS Please provide a tabular listing of clinical 590 trials including appropriate details 591 bull ISS statistical analysis plan including proposed pooling strategy rationale for inclusion or 592 exclusion of trials from the pooled population(s) and planned analytic strategies to manage 593 differences in trial designs (eg in length randomization ratio imbalances study 594 populations etc) 595 bull For a phase 3 program that includes trial(s) with multiple periods (eg double-blind 596 randomized period long-term extension period etc) submit planned criteria for analyses 597 across the program for determination of start end of trial period (ie method of 598 assignment of study events to a specific study period)

IND 126277Page 15

599 Prioritized list of previously observed and anticipated safety issues to be evaluated and planned 600 analytic strategy including any SMQs modifications to specific SMQs or sponsor-created 601 groupings of Preferred Terms A rationale supporting any proposed modifications to an SMQ or 602 sponsor-created groupings should be provided 603 604 When requesting this meeting clearly mark your submission ldquoDISCUSS SAFETY ANALYSIS 605 STRATEGY FOR THE ISSrdquo in large font bolded type at the beginning of the cover letter for 606 the Type C meeting request 607 608 SUBMISSION FORMAT REQUIREMENTS 609 610 The Electronic Common Technical Document (eCTD) is CDER and CBERrsquos standard format for 611 electronic regulatory submissions The following submission types NDA ANDA BLA 612 Master File (except Type III) and Commercial INDs must be submitted in eCTD format 613 Submissions that do not adhere to the requirements stated in the eCTD Guidance will be subject 614 to rejection For more information please visit httpwwwfdagovectd 615 616 The FDA Electronic Submissions Gateway (ESG) is the central transmission point for sending 617 information electronically to the FDA and enables the secure submission of regulatory 618 information for review Submissions less than 10 GB must be submitted via the ESG For 619 submissions that are greater than 10 GB refer to the FDA technical specification Specification 620 for Transmitting Electronic Submissions using eCTD Specifications For additional information 621 see httpwwwfdagovForIndustryElectronicSubmissionsGateway 622 623 MANUFACTURING FACILITIES 624 625 To facilitate our inspectional process we request that you clearly identify in a single location 626 either on the Form FDA 356h or an attachment to the form all manufacturing facilities 627 associated with your application Include the full corporate name of the facility and address 628 where the manufacturing function is performed with the FEI number and specific 629 manufacturing responsibilities for each facility 630 631 Also provide the name and title of an onsite contact person including their phone number fax 632 number and email address Provide a brief description of the manufacturing operation 633 conducted at each facility including the type of testing and DMF number (if applicable) Each 634 facility should be ready for GMP inspection at the time of submission 635 636 Consider using a table similar to the one below as an attachment to Form FDA 356h Indicate 637 under Establishment Information on page 1 of Form FDA 356h that the information is provided 638 in the attachment titled ldquoProduct name NDABLA 012345 Establishment Information for Form 639 356hrdquo

IND 126277 Page 16

640 641

Site Name Site Address

Federal Establishment Indicator (FEI) or Registration Number (CFN)

Drug Master File Number (if

applicable)

Manufacturing Step(s) or Type of Testing [Establishment function]

642 643 Corresponding names and titles of onsite contact 644

Site Name Site Address Onsite Contact (Person Title)

Phone and Fax number

Email address

645 646 505(b)(2) REGULATORY PATHWAY 647 648 The Division recommends that sponsors considering the submission of an application through 649 the 505(b)(2) pathway consult the Agencyrsquos regulations at 21 CFR 31454 and the draft 650 guidance for industry Applications Covered by Section 505(b)(2) (October 1999) available at 651 httpwwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesdefaulthtm 652 In addition FDA has explained the background and applicability of section 505(b)(2) in its 653 October 14 2003 response to a number of citizen petitions that had challenged the Agencyrsquos 654 interpretation of this statutory provision (see Docket FDA-2003-P-0274-0015 available at 655 httpwwwregulationsgov) 656 657 If you intend to submit a 505(b)(2) application that relies for approval on FDArsquos finding of 658 safety andor effectiveness for one or more listed drugs you must establish that such reliance is 659 scientifically appropriate and must submit data necessary to support any aspects of the proposed 660 drug product that represent modifications to the listed drug(s) You should establish a ldquobridgerdquo 661 (eg via comparative bioavailability data) between your proposed drug product and each listed 662 drug upon which you propose to rely to demonstrate that such reliance is scientifically justified 663 664 If you intend to rely on literature or other studies for which you have no right of reference but 665 that are necessary for approval you also must establish that reliance on the studies described in 666 the literature or on the other studies is scientifically appropriate You should include a copy of 667 such published literature in the 505(b)(2) application and identify any listed drug(s) described in 668 the published literature (eg by trade name(s)) 669

IND 126277Page 17

670 If you intend to rely on the Agencyrsquos finding of safety andor effectiveness for a listed drug(s) or 671 published literature describing a listed drug(s) (which is considered to be reliance on FDArsquos 672 finding of safety andor effectiveness for the listed drug(s)) you should identify the listed drug(s) 673 in accordance with the Agencyrsquos regulations at 21 CFR 31454 It should be noted that 21 CFR 674 31454 requires identification of the ldquolisted drug for which FDA has made a finding of safety and 675 effectivenessrdquo and thus an applicant may only rely upon a listed drug that was approved in an 676 NDA under section 505(c) of the FDampC Act The regulatory requirements for a 505(b)(2) 677 application (including but not limited to an appropriate patent certification or statement) apply 678 to each listed drug upon which a sponsor relies 679 680 If FDA has approved one or more pharmaceutically equivalent products in one or more NDA(s) 681 before the date of submission of the original 505(b)(2) application you must identify one such 682 pharmaceutically equivalent product as a listed drug (or an additional listed drug) relied upon 683 (see 21 CFR 31450(i)(1)(i)(C) 31454 and 314125(b)(19) see also 21 CFR 314101(d)(9)) If 684 you identify a listed drug solely to comply with this regulatory requirement you must provide an 685 appropriate patent certification or statement for any patents that are listed in the Orange Book for 686 the pharmaceutically equivalent product but you are not required to establish a ldquobridgerdquo to 687 justify the scientific appropriateness of reliance on the pharmaceutically equivalent product if it 688 is scientifically unnecessary to support approval 689 690 If you propose to rely on FDArsquos finding of safety andor effectiveness for a listed drug that has 691 been discontinued from marketing the acceptability of this approach will be contingent on 692 FDArsquos consideration of whether the drug was discontinued for reasons of safety or effectiveness 693 694 We encourage you to identify each section of your proposed 505(b)(2) application that is 695 supported by reliance on FDArsquos finding of safety andor effectiveness for a listed drug(s) or on 696 published literature (see table below) In your 505(b)(2) application we encourage you to 697 clearly identify (for each section of the application including the labeling) (1) the information 698 for the proposed drug product that is provided by reliance on FDArsquos finding of safety andor 699 effectiveness for the listed drug or by reliance on published literature (2) the ldquobridgerdquo that 700 supports the scientific appropriateness of such reliance and (3) the specific name (eg 701 proprietary name) of each listed drug named in any published literature on which your marketing 702 application relies for approval If you are proposing to rely on published literature include 703 copies of the article(s) in your submission 704 705 In addition to identifying the source of supporting information in your annotated labeling we 706 encourage you to include in your marketing application a summary of the information that 707 supports the application in a table similar to the one below 708 709

List the information essential to the approval of the proposed drug that is provided by reliance on the FDArsquos previous finding of safety and effectiveness for

a listed drug or by reliance on published literature

IND 126277 Page 18

Source of information (eg published literature name of

listed drug)

Information Provided (eg specific sections of the 505(b)(2)

application or labeling)

1 Example Published literature Nonclinical toxicology

2 Example NDA XXXXXX ldquoTRADENAMErdquo

Previous finding of effectiveness for indication A

3 Example NDA YYYYYY ldquoTRADENAMErdquo

Previous finding of safety for Carcinogenicity labeling section B

710 711 Please be advised that circumstances could change that would render a 505(b)(2) application for 712 this product no longer appropriate For example if a pharmaceutically equivalent product were 713 approved before your application is submitted such that your proposed product would be a 714 ldquoduplicaterdquo of a listed drug and eligible for approval under section 505(j) of the FDampC Act then 715 it is FDArsquos policy to refuse to file your application as a 505(b)(2) application (21 CFR 716 314101(d)(9)) In such a case the appropriate submission would be an Abbreviated New Drug 717 Application (ANDA) that cites the duplicate product as the reference listed drug 718 719 OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS 720 721 The Office of Scientific Investigations (OSI) requests that the items described in the draft 722 Guidance for Industry Standardized Format for Electronic Submission of NDA and BLA Content 723 for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions 724 (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide 725 Containing Technical Specifications be provided to facilitate development of clinical investigator 726 and sponsormonitorCRO inspection assignments and the background packages that are sent 727 with those assignments to the FDA ORA investigators who conduct those inspections This 728 information is requested for all major trials used to support safety and efficacy in the application 729 (ie phase 23 pivotal trials) Please note that if the requested items are provided elsewhere in 730 submission in the format described the Applicant can describe location or provide a link to the 731 requested information 732 733 Please refer to the draft Guidance for Industry Standardized Format for Electronic Submission of 734 NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for 735 CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical 736 Conformance Guide Containing Technical Specifications 737 738 httpswwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire 739 mentsUCM332466pdf 740

IND 126277 Page 19

741 httpswwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire 742 mentsUCM332468pdf 743 744

--------------------------------------------------------------------------------------------

------------------------------------------------------------

Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically Following this are manifestations of any and all electronic signatures for this electronic record

BARBARA J GOULD 11082018

IND 126277

Dow Pharmaceuticals Sciences Inc co Valeant Pharmaceuticals North America LLC Attention Sean Humphrey Senior Manager Regulatory Affairs 1330 Redwood Way Suite C Petaluma CA 94954

Dear Mr Humphrey

We also refer to your October 14 2016 correspondence received October 14 2016 requesting a meeting to discuss the development program for tazarotene lotion 0045

Sincerely

Omolara Laiyemo PharmD Regulatory Health Project Manager Division of Dermatology and Dental Products Office of Drug Evaluation III Center for Drug Evaluation and Research

ENCLOSURE

Reference ID 4022011 Reference ID 4586083

IND 126277

Preliminary Meeting Comments

Meeting Type Type B Meeting Category End of Phase 2

Meeting Date and Time December 6 2016 at 1100 am ET Meeting Format Teleconference

Application Number IND 126277 Product Name Tazarotene lotion 0045 Proposed Indication Treatment of acne vulgaris Sponsor Name Dow Pharmaceuticals Sciences Inc

1 Introduction 2 This material consists of our preliminary responses to your questions and any additional 3 comments in preparation for the discussion at the meeting scheduled for December 6 2016 4 at 1100 am ET between Dow Pharmaceuticals Sciences Inc and the Division of 5 Dermatology and Dental Products We are sharing this material to promote a collaborative 6 and successful discussion at the meeting The meeting minutes will reflect agreements 7 important issues and any action items discussed during the meeting and may not be 8 identical to these preliminary comments following substantive discussion at the meeting 9 However if these answers and comments are clear to you and you determine that further

10 discussion is not required you have the option of cancelling the meeting (contact the 11 regulatory project manager (RPM)) If you choose to cancel the meeting this document 12 will represent the official record of the meeting If you determine that discussion is needed 13 for only some of the original questions you have the option of reducing the agenda It is 14 important to remember that some meetings particularly milestone meetings can be 15 valuable even if the pre-meeting communications are considered sufficient to answer the 16 questions Contact the RPM if there are any major changes to your development plan the 17 purpose of the meeting or the questions based on our preliminary responses as we may not 18 be prepared to discuss or reach agreement on such changes at the meeting 19 20 Purpose of the Meeting To discuss the development program for tazarotene lotion 0045 21 22 Regulatory 23 Question 8 24 The Sponsor intends to request a partial waiver for the conduct of clinical studies with IDP-123 25 Lotion in pediatric subjects aged 0-8 years 11 months due to the very low prevalence of acne in 26 this age group The Sponsor intends to include subjects 9 YOA and above in clinical studies with

IND 126277 Page 2

27 IDP-123 Lotion The initial Pediatric Study Plan will be submitted to IND 126277 within 60 28 days from the date of the End-of-Phase 2 meeting date 29 30 Does the Agency agree with the Sponsorrsquos request for partial waiver for pediatric subjects aged 31 0-8 years 11 months 32 33 FDA Response 34 As discussed at the pre-IND meeting this is reasonable Incidence and prevalence data for 35 various pediatric age groups should be provided in the PSP to support the waiver request 36 37 Chemistry Manufacturing and Controls (CMC) 38 Question 1 39 DPS is proposing specifications in accordance with the current International Council for 40 Harmonisation (ICH) guideline Q6A for drug substance and drug product Tazarotene drug 41 substance is not described in a US Pharmacopoeia monograph Details of the proposed 42 specifications are provided in the briefing book (Section 162131) We acknowledge that the 43 suitability of the acceptance criteria could be an NDA review issue 44 45 Based on the specifications provided in the briefing book does the Agency have any 46 recommendations regarding 47 a the drug substance specifications 48 49 FDA Response 50 In general the submitted drug substance specifications appear reasonable In addition to the drug 51 substance specifications submitted evaluate the need to control the polymorphic form of the 52 drug substance in the specifications Since the information for the control of starting materials 53 intermediates manufacturing process potential impurities and degradation products is all

(b) (4)54 referenced to DMF we cannot provide detailed input on whether additional controls are 55 necessary for other potential impurities or if additional tests will be needed in the drug substance 56 specifications These specific requests will be communicated to the DMF holder during review 57 of the marketing application and you will be notified that a request has been made to the DMF 58 holder at that time 59 60 b the drug product specifications proposed for use in phase 3 clinical studies (to be 61 conducted with the to-be-marketed formulations) 62 63 FDA Response 64 Besides the tests proposed in the drug product specification we recommend you add a test for 65 globule size of the lotion to the drug product specification The test methods and acceptance 66 criteria of the drug product specification will be evaluated during IND and NDA reviews

67 c the ability to obtain reasonable assurance of filing and approvability of the NDA 68 submission 69 70 FDA Response

IND 126277 Page 3

71 See responses to a and b in Question 1 72 73 Question 2 74 For Phase 3 and registration stability stability studies will be conducted in accordance with the 75 current ICH guideline Q1A For the registration stability batches a physicianrsquos sample (3 g) and 76 1 trade size (45 g) will be filled into tubes The details of the proposed stability studies and 77 package types for the tube fill sizes are provided in the briefing book (Section 162131) Note 78 2 of the 3 registration stability batches have been manufactured and placed on stability 79 Does the Agency agree that the stability program described in the briefing document for the ICH 80 (registration) stability batches adequately meets the filing requirements for the NDA 81 82 FDA Response 83 Your stability program appears reasonable to support the NDA submission You should update 84 your drug product specification to include the recommended globule size test when conducting 85 stability studies Additionally the results of extractable and leachable studies should be included 86 in your NDA submission 87 88 Nonclinical

89 Question 3 90 The Sponsor intends to establish a clinical bridge to rely on the Agencyrsquos prior findings of safety 91 for the RLD TAZORAC Cream 01 (NDA 021184) this specifically includes genotoxicity 92 reproductive toxicity and carcinogenicity The preliminary results from the Phase 2 clinical 93 bridging study (V01-123A-201 Section 1627423) suggest that the safety profile of IDP-123 94 Lotion in subjects with acne is comparable to that of TAZORAC Cream 01 The preliminary 95 results of the Phase 1 PK bridging study (V01-123A-501 Section 1627422) suggest that the 96 systemic exposure of IDP-123 Lotion is similar to the RLD 97 For the drug product IDP-123 Lotion DPS intends to rely on repeat dose toxicity and local 98 tolerance data from the nonclinical studies conducted in support of the development of IDP-118 99 Lotion

100 101 Does the Agency agree that no additional nonclinical studies would be required and that the 102 studies for IDP-123 Lotion coupled with the existing body of nonclinical data for TAZORAC 103 Cream are sufficient to support filing and registration of IDP-123 Lotion considering that 104 TAZORAC will be the RLD selected for a 505(b)(2) NDA 105 106 FDA Response 107 Yes we agree that no additional nonclinical studies would be required to support a 505(b)(2) 108 NDA for your product IDP-123 Lotion if it is determined that you have established an adequate 109 clinical bridge to the listed drug 110 111 Clinical 112 113 Question 4 114 The bridging strategy to TAZORAC Cream 01 was agreed upon with the FDA at the pre-IND 115 meeting held 17 June 2015 (meeting minutes provided in Section 162132) The program

IND 126277 Page 4

116 includes a PK bridging study V01-123A-501 (preliminary results are provided in Section 117 1627422) and a safety and efficacy bridging study V01-123A-201 (preliminary results are 118 provided in Section 1627423) The results submitted in the briefing document suggest an 119 adequate clinical bridge will be established 120 121 Does the Agency agree that the results from the bridging studies are adequate to establish a 122 clinical bridge to TAZORAC Cream 01 and allow for a successful 505(b)(2) NDA pathway 123 for IDP-123 Lotion 124 125 FDA Response 126 You note in the briefing document (page 28) that while the clinical visit portion of the phase 2 127 bridging study is complete ldquodata analysis and interpretation are ongoingrdquo Based on interim 128 results we cannot comment on the adequacy of the clinical bridge at this time Final agreement 129 will be made following review of the final study report and bioanalytical method validation 130 reports at the time of NDA review 131 132 Question 5 133 The Sponsor proposes to conduct two 12-week vehicle-controlled Phase 3 adequate and 134 well-controlled studies to confirm the efficacy and safety of IDP-123 Lotion to obtain reasonable 135 assurance of approvability from the treatment of acne in patients 9 YOA and older 136 137 a Does the Agency agree that the design endpoints subject population inclusion and 138 exclusion criteria for the Phase 3 clinical studies described within the protocol are 139 adequate to produce substantial evidence of efficacy and safety for the treatment of acne 140 141 FDA Response 142 You propose to conduct a Phase 3 Multi-Center randomized double-blind vehicle-controlled 143 study to compare the safety and efficacy of IDP-123 Lotion 144 in the treatment of acne vulgaris 145 Approximately subjects will be randomized in a ratio to the following treatment 146 groups 147 148 149 150 151

(b) (4)

152 Co-Primary efficacy endpoints 153 IDP-123 Lotion will be compared to (b) (4) and Vehicle Cream 154 Co-primary endpoints are 155 Absolute change from Baseline to Week 12 in mean inflammatory lesion counts 156 Absolute change from Baseline to Week 12 in mean non-inflammatory lesion counts 157 Percent of subjects who achieve at least a two-grade reduction from baseline and are Clear or 158 Almost Clear at Week 12 in the Evaluatorrsquos Global Severity Score 159

IND 126277 Page 5

160 The controlled clinical studies as proposed in your briefing document would appear to be 161 adequate to support filing of 505(b)(2) NDA for the treatment of acne vulgaris As you are 162 aware approvability of such an application would be a review issue 163 164 b Does the Agency agree that the planned statistical analyses for the Phase 3 clinical 165 studies described within the protocol are adequate to produce substantial evidence of efficacy 166 and safety for the treatment of acne 167 168 FDA Response 169 Your planned statistical analyses appear reasonable You should ensure that all the details of the 170 statistical analysis plan are adequately pre-specified Additional comments may be provided 171 when completed protocols are submitted to the IND 172 173 Question 6 174 At the pre-IND meeting held 17 June 2015 (meeting minutes provided in Section 162132) a 175 long-term study waiver was discussed and FDA stated that a long term safety study may not be 176 required if an adequate clinical bridge is established The preliminary safety and efficacy results 177 from the Phase 2 bridging study (Section 1627423) and the preliminary PK results from the 178 Phase 1 PK bridging study (Section 1627422) provide evidence that the safety profile and 179 systemic exposure of IDP-123 Lotion is similar to TAZORAC Cream 01 and consequently 180 would not require a separate long term safety study to support registration of IDP-123 Lotion 181 182 Does the Agency agree that based upon the available data an adequate clinical bridge will be 183 established and an additional long-term safety study with IDP-123 Lotion is not needed for a 184 505(b)(2) NDA approval 185 186 FDA Response 187 You are referred to the response to this question in the pre-IND meeting minutes ldquoA long-term 188 safety study with IDP-123 lotion 0045 may not be required if you construct an adequate 189 clinical bridge to Tazorac cream 01rdquo This proposal is still reasonable assuming your study 190 demonstrate comparable systemic exposure to Tazorac cream 01 191 192 Regarding the clinical bridge see the Agency response to Question 4 above 193 194 Question 7 195 Tazarotene formulated in TAZORAC Cream and Gel 005 and 01 has been approved and 196 commercialized for use since June 1997 (TAZORAC Gel) with no associated reported cardiac 197 events of interest (eg torsades de pointes and cardiac arrhythmia) (Section 1627442) 198 The bioavailability of IDP-123 Lotion has been shown to be similar to that of TAZORAC Cream 199 01 based on the preliminary PK results (Section 1627422) from the Phase 1 bridging 200 study that when coupled with the lack of reported cardiac arrhythmias associated with tazarotene 201 use indicate a pro-arrhythmia risk is not anticipated with the use of IDP-123 Lotion In addition 202 in vitro hERG and ECGs in minipigs did not reveal any safety concerns (Section 1627442) 203 In the pre-IND meeting minutes (meeting minutes provided in Section 162132) the FDA 204 stated a TQT waiver is reasonable provided that the systemic exposure from IDP-123 Lotion is 205 similar to the systemic exposure from TAZORAC Cream 01 Therefore DPS intends to

IND 126277 Page 6

206 request a waiver for conducting a clinical study with IDP-123 Lotion to evaluate the potential for 207 QTQTc interval prolongation 208 209 Does the Agency agree that a TQT study to assess the potential of QT prolongation with the use 210 of IDP-123 Lotion is not needed for NDA filing and approval 211 212 FDA Response 213 The proposed plan is reasonable provided review of the final Phase 2 study report demonstrates 214 that the systemic exposure from IDP-123 is similar to or lower than the systemic exposure from 215 Tazorac cream 01 216 217 See Agency response to Question 4 above 218 219 ADMINISTRATIVE COMMENTS 220 221 PREA REQUIREMENTS 222 223 Under the Pediatric Research Equity Act (PREA) (21 USC 355c) all applications for new 224 active ingredients (which includes new salts and new fixed combinations) new indications new 225 dosage forms new dosing regimens or new routes of administration are required to contain an 226 assessment of the safety and effectiveness of the product for the claimed indication(s) in 227 pediatric patients unless this requirement is waived deferred or inapplicable 228 229 Please be advised that under the Food and Drug Administration Safety and Innovation Act 230 (FDASIA) you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End of 231 Phase (EOP2) meeting In the absence of an End-of-Phase 2 meeting refer to the draft guidance 232 below The PSP must contain an outline of the pediatric study or studies that you plan to 233 conduct (including to the extent practicable study objectives and design age groups relevant 234 endpoints and statistical approach) any request for a deferral partial waiver or waiver if 235 applicable along with any supporting documentation and any previously negotiated pediatric 236 plans with other regulatory authorities The PSP should be submitted in PDF and Word format 237 Failure to include an agreed iPSP with a marketing application could result in a refuse to file 238 action 239 240 For additional guidance on the timing content and submission of the PSP including a PSP 241 Template please refer to the draft guidance for industry Pediatric Study Plans Content of and 242 Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at 243 httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidancesU 244 CM360507pdf In addition you may contact the Division of Pediatric and Maternal Health at 245 301-796-2200 or email pditfdahhsgov For further guidance on pediatric product 246 development please refer to 247 httpwwwfdagovDrugsDevelopmentApprovalProcessDevelopmentResourcesucm049867ht 248 m 249 250 DATA STANDARDS FOR STUDIES 251

IND 126277 Page 7

252 Under section 745A(a) of the FDampC Act electronic submissions ldquoshall be submitted in such 253 electronic format as specified by [FDA]rdquo FDA has determined that study data contained in 254 electronic submissions (ie NDAs BLAs ANDAs and INDs) must be in a format that the 255 Agency can process review and archive Currently the Agency can process review and 256 archive electronic submissions of clinical and nonclinical study data that use the standards 257 specified in the Data Standards Catalog (Catalog) (See 258 httpwwwfdagovforindustrydatastandardsstudydatastandardsdefaulthtm) 259 260 On December 17 2014 FDA issued final guidance Providing Electronic Submissions in 261 Electronic Format--- Standardized Study Data 262 (httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidances 263 UCM292334pdf) This guidance describes the submission types the standardized study data 264 requirements and when standardized study data will be required Further it describes the 265 availability of implementation support in the form of a technical specifications document Study 266 Data Technical Conformance Guide (Conformance Guide) (See 267 httpwwwfdagovdownloadsForIndustryDataStandardsStudyDataStandardsUCM384744pd 268 f) as well as email access to the eData Team (cder-edatafdahhsgov) for specific questions 269 related to study data standards Standardized study data will be required in marketing 270 application submissions for clinical and nonclinical studies that start on or after December 17 271 2016 Standardized study data will be required in commercial IND application submissions for 272 clinical and nonclinical studies that start on or after December 17 2017 CDER has produced a 273 Study Data Standards Resources web page that provides specifications for sponsors regarding 274 implementation and submission of clinical and nonclinical study data in a standardized format 275 This web page will be updated regularly to reflect CDERs growing experience in order to meet 276 the needs of its reviewers 277 278 Although the submission of study data in conformance to the standards listed in the FDA Data 279 Standards Catalog will not be required in studies that start before December 17 2016 CDER 280 strongly encourages IND sponsors to use the FDA supported data standards for the submission of 281 IND applications and marketing applications The implementation of data standards should 282 occur as early as possible in the product development lifecycle so that data standards are 283 accounted for in the design conduct and analysis of clinical and nonclinical studies For clinical 284 and nonclinical studies IND sponsors should include a plan (eg in the IND) describing the 285 submission of standardized study data to FDA This study data standardization plan (see the 286 Conformance Guide) will assist FDA in identifying potential data standardization issues early in 287 the development program 288 289 Additional information can be found at 290 httpwwwfdagovDrugsDevelopmentApprovalProcessFormsSubmissionRequirementsElectr 291 onicSubmissionsucm248635htm 292 293 For general toxicology supporting nonclinical toxicokinetic and carcinogenicity studies 294 CDER encourages sponsors to use Standards for the Exchange of Nonclinical Data (SEND) and 295 submit sample or test data sets before implementation becomes required CDER will provide 296 feedback to sponsors on the suitability of these test data sets Information about submitting a test 297 submission can be found here

IND 126277 Page 8

298 httpwwwfdagovDrugsDevelopmentApprovalProcessFormsSubmissionRequirementsElectr 299 onicSubmissionsucm174459htm 300 301 LABORATORY TEST UNITS FOR CLINICAL TRIALS 302 303 CDER strongly encourages IND sponsors to identify the laboratory test units that will be 304 reported in clinical trials that support applications for investigational new drugs and product 305 registration Although Systegraveme International (SI) units may be the standard reporting 306 mechanism globally dual reporting of a reasonable subset of laboratory tests in US 307 conventional units and SI units might be necessary to minimize conversion needs during review 308 Identification of units to be used for laboratory tests in clinical trials and solicitation of input 309 from the review divisions should occur as early as possible in the development process For 310 more information please see the FDA website entitled Study Data Standards Resources and the 311 CDERCBER Position on Use of SI Units for Lab Tests website found at 312 httpwwwfdagovForIndustryDataStandardsStudyDataStandardsucm372553htm 313 314 SUBMISSION FORMAT REQUIREMENTS 315 316 The Electronic Common Technical Document (eCTD) is CDER and CBERrsquos standard format for 317 electronic regulatory submissions Beginning May 5 2017 the following submission types 318 NDA ANDA BLA and Master Files must be submitted in eCTD format Commercial IND 319 submissions must be submitted in eCTD format beginning May 5 2018 Submissions that do 320 not adhere to the requirements stated in the eCTD Guidance will be subject to rejection For 321 more information please visit httpwwwfdagovectd 322 323 505(b)(2) REGULATORY PATHWAY 324 325 The Division recommends that sponsors considering the submission of an application through 326 the 505(b)(2) pathway consult the Agencyrsquos regulations at 21 CFR 31454 and the draft 327 guidance for industry Applications Covered by Section 505(b)(2) (October 1999) available at 328 httpwwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesdefaulthtm 329 In addition FDA has explained the background and applicability of section 505(b)(2) in its 330 October 14 2003 response to a number of citizen petitions that had challenged the Agencyrsquos 331 interpretation of this statutory provision (see Docket FDA-2003-P-0274-0015 available at 332 httpwwwregulationsgov) 333 334 If you intend to submit a 505(b)(2) application that relies for approval in part on FDArsquos finding 335 of safety andor effectiveness for one or more listed drugs you must establish that such reliance 336 is scientifically appropriate and must submit data necessary to support any aspects of the 337 proposed drug product that represent modifications to the listed drug(s) You should establish a 338 ldquobridgerdquo (eg via comparative bioavailability data) between your proposed drug product and 339 each listed drug upon which you propose to rely to demonstrate that such reliance is 340 scientifically justified 341 342 If you intend to rely in part on literature or other studies for which you have no right of 343 reference but that are necessary for approval you also must establish that reliance on the studies

IND 126277 Page 9

344 described in the literature or on the other studies is scientifically appropriate You should 345 include a copy of such published literature in the 505(b)(2) application and identify any listed 346 drug(s) described in the published literature (eg trade name(s)) 347 348 If you intend to rely in part on the Agencyrsquos finding of safety andor effectiveness for a listed 349 drug(s) or published literature describing a listed drug(s) (which is considered to be reliance on 350 FDArsquos finding of safety andor effectiveness for the listed drug(s)) you should identify the listed 351 drug(s) in accordance with the Agencyrsquos regulations at 21 CFR 31454 It should be noted that 352 21 CFR 31454 requires identification of the ldquolisted drug for which FDA has made a finding of 353 safety and effectivenessrdquo and thus an applicant may only rely upon a listed drug that was 354 approved in an NDA under section 505(c) of the FDampC Act The regulatory requirements for a 355 505(b)(2) application (including but not limited to an appropriate patent certification or 356 statement) apply to each listed drug upon which a sponsor relies 357 358 If you propose to rely on FDArsquos finding of safety andor effectiveness for a listed drug that has 359 been discontinued from marketing the acceptability of this approach will be contingent on 360 FDArsquos consideration of whether the drug was discontinued for reasons of safety or effectiveness 361 362 We encourage you to identify each section of your proposed 505(b)(2) application that relies on 363 FDArsquos finding of safety andor effectiveness for a listed drug(s) or on published literature In 364 your 505(b)(2) application we encourage you to clearly identify (for each section of the 365 application including the labeling) (1) the information for the proposed drug product that is 366 provided by reliance on FDArsquos finding of safety andor effectiveness for the listed drug or by 367 reliance on published literature (2) the ldquobridgerdquo that supports the scientific appropriateness of 368 such reliance and (3) the specific name (eg proprietary name) of each listed drug named in any 369 published literature on which your marketing application relies for approval If you are 370 proposing to rely on published literature include copies of the article(s) in your submission 371 372 In addition to identifying in your annotated labeling the source(s) of information essential to the 373 approval of your proposed drug that is provided by reliance on FDArsquos previous finding of safety 374 and efficacy for a listed drug or by reliance on published literature we encourage you to also 375 include that information in the cover letter for your marketing application in a table similar to the 376 one below 377

List the information essential to the approval of the proposed drug that is provided by reliance on the FDArsquos previous finding of safety and efficacy for a

listed drug or by reliance on published literature

listed drug)

Previous finding of effectiveness for indication X

IND 126277 Page 10

Previous finding of safety for Carcinogenicity labeling section XXX

378 379 Please be advised that circumstances could change that would render a 505(b)(2) application for 380 this product no longer appropriate For example if a pharmaceutically equivalent product were 381 approved before your application is submitted such that your proposed product would be a 382 ldquoduplicaterdquo of a listed drug and eligible for approval under section 505(j) of the FDampC Act then 383 it is FDArsquos policy to refuse to file your application as a 505(b)(2) application (21 CFR 384 314101(d)(9)) In such a case the appropriate submission would be an Abbreviated New Drug 385 Application (ANDA) that cites the duplicate product as the reference listed drug 386 Office of Scientific Investigations (OSI) Requests 387

388 The Office of Scientific Investigations (OSI) requests that the following items be provided to 389 facilitate development of clinical investigator and sponsormonitorCRO inspection assignments 390 and the background packages that are sent with those assignments to the FDA field investigators 391 who conduct those inspections (Item I and II) This information is requested for all major trials 392 used to support safety and efficacy in the application (ie phase 23 pivotal trials) Please note 393 that if the requested items are provided elsewhere in submission in the format described the 394 Applicant can describe location or provide a link to the requested information 395

396 The dataset that is requested in Item III below is for use in a clinical site selection model that is 397 being piloted in CDER Electronic submission of the site level dataset is voluntary and is 398 intended to facilitate the timely selection of appropriate clinical sites for FDA inspection as part 399 of the application andor supplement review process 400 This request also provides instructions for where OSI requested items should be placed within an 401 eCTD submission (Attachment 1 Technical Instructions Submitting Bioresearch Monitoring 402 (BIMO) Clinical Data in eCTD Format) 403

404 I Request for general study related information and comprehensive clinical investigator 405 information (if items are provided elsewhere in submission describe location or provide 406 link to requested information) 407 408 1 Please include the following information in a tabular format in the original NDA for each 409 of the completed pivotal clinical trials 410 a Site number 411 b Principal investigator 412 c Site Location Address (eg Street City State Country) and contact information 413 (ie phone fax email) 414 d Location of Principal Investigator Address (eg Street City State and Country) and 415 contact information (ie phone fax email) If the Applicant is aware of changes to a 416 clinical investigatorrsquos site address or contact information since the time of the clinical

IND 126277 Page 11

417 investigatorrsquos participation in the study we request that this updated information also 418 be provided 419 420 2 Please include the following information in a tabular format by site in the original NDA 421 for each of the completed pivotal clinical trials 422 a Number of subjects screened at each site 423 b Number of subjects randomized at each site 424 c Number of subjects treated who prematurely discontinued for each site by site 425 426 3 Please include the following information in a tabular format in the NDA for each of the 427 completed pivotal clinical trials 428 a Location at which sponsor trial documentation is maintained (eg monitoring plans 429 and reports training records data management plans drug accountability records 430 IND safety reports or other sponsor records as described ICH E6 Section 8) This is 431 the actual physical site(s) where documents are maintained and would be available for 432 inspection 433 b Name address and contact information of all Contract Research Organization (CROs) 434 used in the conduct of the clinical trials and brief statement of trial related functions 435 transferred to them If this information has been submitted in eCTD format 436 previously (eg as an addendum to a Form FDA 1571 you may identify the 437 location(s) andor provide link(s) to information previously provided 438 c The location at which trial documentation and records generated by the CROs with 439 respect to their roles and responsibilities in conduct of respective studies is 440 maintained As above this is the actual physical site where documents would be 441 available for inspection 442 443 4 For each pivotal trial provide a sample annotated Case Report Form (or identify the 444 location andor provide a link if provided elsewhere in the submission) 445 5 For each pivotal trial provide original protocol and all amendments ((or identify the 446 location andor provide a link if provided elsewhere in the submission) 447 448 II Request for Subject Level Data Listings by Site 449 450 1 For each pivotal trial Site-specific individual subject data listings (hereafter referred to as 451 ldquoline listingsrdquo) For each site provide line listings for 452 a Listing for each subject consentedenrolled for subjects who were not randomized to 453 treatment andor treated with study therapy include reason not randomized andor 454 treated 455 b Subject listing for treatment assignment (randomization) 456 c Listing of subjects that discontinued from study treatment and subjects that 457 discontinued from the study completely (ie withdrew consent) with date and reason 458 discontinued 459 d Listing of per protocol subjects non-per protocol subjects and reason not per protocol 460 e By subject listing of eligibility determination (ie inclusion and exclusion criteria) 461 f By subject listing of AEs SAEs deaths and dates

IND 126277 Page 12

462 g By subject listing of protocol violations andor deviations reported in the NDA 463 including a description of the deviationviolation 464 h By subject listing of the primary and secondary endpoint efficacy parameters or 465 events For derived or calculated endpoints provide the raw data listings used to 466 generate the derivedcalculated endpoint 467 i By subject listing of concomitant medications (as appropriate to the pivotal clinical 468 trials) 469 j By subject listing of testing (eg laboratory ECG) performed for safety monitoring 470 471 2 We request that one PDF file be created for each pivotal Phase 2 and Phase 3 study using 472 the following format

473 474 475 476 477 478 III Request for Site Level Dataset 479 480 OSI is piloting a risk based model for site selection Voluntary electronic submission of site 481 level datasets is intended to facilitate the timely selection of appropriate clinical sites for FDA 482 inspection as part of the application andor supplement review process If you wish to 483 voluntarily provide a dataset please refer to the draft Guidance for Industry Providing 484 Submissions in Electronic Format ndash Summary Level Clinical Site Data for CDERrsquos Inspection 485 Planningrdquo (available at the following link 486 httpwwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire 487 mentsUCM332468pdf ) for the structure and format of this data set

IND 126277 Page 13

489 Attachment 1 490 Technical Instructions 491 Submitting Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format 492 493 494 A Data submitted for OSI review belongs in Module 5 of the eCTD For items I and II in 495 the chart below the files should be linked into the Study Tagging File (STF) for each 496 study Leaf titles for this data should be named ldquoBIMO [list study ID followed by brief 497 description of file being submitted]rdquo In addition a BIMO STF should be constructed 498 and placed in Module 5354 Other Study reports and related information The study ID 499 for this STF should be ldquobimordquo Files for items I II and III below should be linked into 500 this BIMO STF using file tags indicated below The item III site-level dataset filename 501 should be ldquoclinsitexptrdquo 502

DSI Pre-NDA

Request Item1

STF File Tag Used For Allowable File

Formats

I data-listing-dataset Data listings by study pdf I annotated-crf Sample annotated case

report form by study pdf

II data-listing-dataset Data listings by study (Line listings by site)

III data-listing-dataset Site-level datasets across studies

III data-listing-data-definition Define file pdf 503 504 B In addition within the directory structure the item III site-level dataset should be placed 505 in the M5 folder as follows 506

507 508 509 C It is recommended but not required that a Reviewerrsquos Guide in PDF format be included 510 If this Guide is included it should be included in the BIMO STF The leaf title should be 511 ldquoBIMO Reviewer Guiderdquo The guide should contain a description of the BIMO elements 512 being submitted with hyperlinks to those elements in Module 5 513

1 Please see the OSI Pre-NDABLA Request document for a full description of requested data files

IND 126277 Page 14

515 References 516 517 eCTD Backbone Specification for Study Tagging Files v 261 518 (httpwwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire 519 mentsElectronicSubmissionsUCM163560pdf) 520 521 FDA eCTD web page 522 (httpwwwfdagovDrugsDevelopmentApprovalProcessFormsSubmissionRequirementsElect 523 ronicSubmissionsucm153574htm) 524 525 For general help with eCTD submissions ESUBfdahhsgov

526 NEW PROTOCOLS AND CHANGES TO PROTOCOLS 527 528 To ensure that the Division is aware of your continued drug development plans and to facilitate 529 successful interactions with the Division including provision of advice and timely responses to 530 your questions we request that the cover letter for all new phase 2 or phase 3 protocol 531 submissions to your IND or changes to these protocols include the following information 532 533 1 Study phase 534 2 Statement of whether the study is intended to support marketing andor labeling changes 535 3 Study objectives (eg dose finding) 536 4 Population 537 5 A brief description of the study design (eg placebo or active controlled) 538 6 Specific concerns for which you anticipate the Division will have comments 539 7 For changes to protocols only also include the following information 540 A brief summary of the substantive change(s) to the protocol (eg changes to 541 endpoint measures dose andor population) 542 Other significant changes 543 Proposed implementation date 544 545 We recommend you consider requesting a meeting to facilitate discussion of multiple andor 546 complex issues

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature

OMOLARA R LAIYEMO 12022016

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure

FOOD AND DRUG ADMINISTRATION








Proposed Indication For the topical treatment of acne vulgaris in patients 9 years of age and older Sponsor Name Dow Pharmaceutical Sciences Inc

1 Introduction2 This material consists of our preliminary responses to your questions and any additional 3 comments in preparation for the discussion at the teleconference scheduled for October 25 4 2018 at between Dow Pharmaceutical Sciences Inc and the Division of Dermatology and 5 Dental Product We are sharing this material to promote a collaborative and successful 6 discussion at the meeting The meeting minutes will reflect agreements important issues 7 and any action items discussed duri

10 reducing the agenda andor changing the format of the meeting (eg from face to face to 11 teleconference) Contact the Regulatory Project Manager (RPM) if there are any major 12 changes to your development plan the purpose of the meeting or the questions based on 13 our preliminary responses as we may not be prepared to discuss or reach agreement on 14 such changes at the meeting 15

16 10 BACKGROUND 17 18 The purpose of this PNDA meeting is to discuss the format and content for future 19 marketing application to support the proposed indication of acne vulgaris in patients 9 20 years of age and older 21



22 20 DISCUSSION 23 24 Regulatory Correspondence History 25 26 We have had the following meetingsteleconferences with you



27 bull 12062016 End of Phase 2 Meeting 28 29 We have sent the following correspondences 30 bull 08092017 Advice Letter 31 bull 08022017 Pediatric Study Plan ndash Written Response 32 bull 10202015 Study May Proceed 33

34 21 Regulatory 35 36 Introductory Comment 37 If you intend to rely in part on information required for approval that comes from studies not 38 conducted by you or for you or for which you have not obtained a right of reference (eg 39 reliance on the FDArsquos finding of safety andor effectiveness for a listed drug or published 40 literature) then your marketing application will be a 505(b)(2) application 41 42 You are proposing to reference information from the Summary Basis of Approval (SBA) and 4


51 Within your background package you make reference to

Clarify if you 52 intend to rely on our finding of safety for each of those listed drugs to support your marketing 53 application The regulatory requirements for a 505(b)(2) application (including but not limited 54 to an appropriate patent certification or statement) apply to each listed drug upon which a 55 sponsor relies 56 57 You must establish that such reliance is scientifically appropriate and must submit data necessary 58 to support any aspects of the proposed drug product that represent modif


Figure

72 73 The Sponsor intends to request a partial waiver for the conduct of clinical studies with IDP-123 74 Lotion in pediatric subjects aged 0 to 8 years 11 months due to the very low prevalence of acne 75 in this age group The Sponsor included subjects 9 years of age and above in clinical studies 76 with IDP-123 Lotion The agreed to iPSP was submitted to IND 126277 on 15 August 2017 77 (Sequence 0017) 78 79 Does the Agency agree with the Sponsorrsquos request for partial waiver for pediatric subjects aged 0

Question 19

FDA Response to Question 19

Question 20


96 22 Chemistry Manufacturing and Controls (CMC)9798 99 DPS is proposing specifications in accordance with the current International Council for

Question 1

100 Harmonisation (ICH) guideline Q6A for drug substance and drug product Tazarotene drug 101 substance is described in the manufacturerrsquos drug master file

Figure

Details of the proposed 102 specifications are provided in the briefing package (Section 162131) We acknowledge that 103 the suitability of the acceptance criteria could be an NDA review issue and are subject to change 104 based on final stability data to be presented in the NDA 105 106 a Based on the specifications provided in the briefing package does the Agency have any 107 recommendations for the drug substance specifications proposed for tazarotene 108 109 b Based on the specifications provi



120 b The submitted diug product specifications appear reasonable However emulsion dimiddotoplet 121 size should be tested at release as well as on stability See further comments under the 122 FDA Response to Q3 123 124 We may have further comments for the test and acceptance criteria in the specifications for 125 both diug substance and diug product based on the totality of the overall data dming NDA 126 review 127 128 Ouestion 2 129 For other topical marketed products the physician s sample size has n

4

144 DPS has evaluated emulsion dimiddotoplet size for 9 bulk commercial scale batches ltbgtltf filled in

4

145 various packaging configmations for (bJltI and IDP-123 for a total ofGl packaged 146 lots As these diu g products contain the same Vehicle Lotion as described above the DlO D50 147 and D90 results are consistent across storage conditions time points and packa__~~--~

mg

148 confi uations It is proposed that the emulsion dimiddotoplet specification be tested (bJ

4

VJ-t

149

150 (b)(4J

151 Does the Agency agree that these studies suppo1i testing ofthis attribute for

152 (b)(4) ------shy

153 154 FDA Response to Ouestion 3 155 No we do not agree

(b)(4J (b)(4J

156

157

158 159

(b)(4)

160 161 icatihould be tested fort dlease as well as on stability If 162 this NDA is approved for marketing we recommend you submit a post-approval supplement to

specif

on s

he proposed

iu g product at re

163 request removal of this test once adequate commercial scale batch stability data has been 164 generated with this specific formulation to justify the elimination of this test during shelf life 165 166 167 DPS has conducted ICH registration stability studies in accordance with ICH Q1A guideline 168 kg batch size The 3 ICH stability batches consisted of a sample (3-g fill size) and 169 trade size (45-g fill size) stored at long term intermediate and accelerated conditions in the 170 inverted and horizo










Question 4

using a


Question 5


209 23 PharmacologyToxicology 210 211 212 The IDP-123 Lotion nonclinical development program was discussed and agreed upon with the 213 Agency at the EOP2 meeting For the drug product IDP-123 Lotion DPS intends to provide 214 repeated dose toxicity and local tolerance data Additionally the Sponsor intends to rely on the 215 Agencyrsquos prior findings of safety for the LD Tazorac Cream 01 (NDA 021184) specifically 216 genotoxicity reproductive toxicity and carcinogenicity data 217 218 The results

Question 6

-


Question 17


255 above The final determination will be made at the time of NDA submission following detailed 256 review of your study report and associated bioanalytical method validation and bioanalysis 257 reports 258 259 260 The PK profile for IDP-123 Lotion has been established in subjects 9 years of age and older 261 (V01-123A-501) Systemic exposure in subjects aged 9 to lt 12 years of age were found to be 262 higher than for subjects aged ge 12 years of age The adverse event profiles in these two age 263 groups

Question 18


Question 7


Question 8

301 302 The clinical program appears adequate for filing and review under the NDA Determination of 303 specific labeling will be discussed during the second half of the NDA review 304 305 306 A total of approximately 1174 human subjects will have been exposed to at least 1 dose of IDP307 123 Lotion and will be included in the NDA submission as part of the safety database Of these 308 approximately 897 are subjects with acne and treated with the to-be-marketed formulation of 309 IDP-123 Lotion 310 311


Question 9

-


Question 10

346 347 Yes we agree with the location and the approach appears acceptable Please refer to the 348 February 2018 draft guidance for industry ldquoStandardized Format for Electronic Submission of 349 NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for 350 CDER Submissions When final this guidance will represent FDArsquos current thinking on the 351 topic The guidance is available at the following link 352 353 354 355 356 For the 2 pivotal Phase 3 studies (V01-123A-301 and V0


httpswwwfdagovdownloadsdrugsdevelopmentapprovalprocessformssubmissionrequiremen


tsucm332466pdf

Question 11


Question 12

392 393 A long-term safety study does not appear necessary unless a new safety issue is identified 394 following review of the clinical study reports 395 396 397 Tazarotene formulated in Tazorac Cream and Gel 005 and 01 has been approved and 398 commercialized for use since June 1997 (Tazorac Gel) with no associated reported cardiac 399 events of interest (eg torsades de pointes and cardiac arrhythmia) 400 401 In the pre-IND meeting minutes and EOP2 meeting (Section 162132) the FDA stated a T


Question 13


Question 14


437 Include dataset documentation (definexml) for tabulation and analysis datasets The analysis 438 dataset documentation should include sufficient detail such as definitions or descriptions of each 439 variable in the dataset algorithms for derived variables (including source variables used) and 440 descriptions of the codes used in factor variables 441 442 Because the protocols specified handling missing data using multiple imputation clarify how 443 you intend to submit the datasets We recommend s

Question 15


Question 16

-

483 Industry Integrated Summaries of Effectiveness and Safety Location Within the Common 484 Technical Document each section of the ISE will refer the reader to the appropriate section 485 where the remainder of the ISE is located within the NDA 486 487 a Does the Agency agree with the statistical analysis plan for pooling of efficacy data for the 488 Phase 3 clinical studies 489 490 b Does the Agency agree with the plan to provide the ISE text document in Module 2 491 Section 273 and datasets in


PREA REQUIREMENTS

-

523 For additional guidance on the timing content and submission of the iPSP including an iPSP 524 Template please refer to the draft guidance for industry Pediatric Study Plans Content of and 525 Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at 526 527 In addition you may contact the Division of Pediatric and Maternal Health at 528 301-796-2200 or email For further guidance on pediatric product 529 development please refer to 530 531 532 533 534 535

httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidancesU


CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov

httpwwwfdagovDrugsDevelopmentApprovalProcessDevelopmentResourcesucm049867ht


m

PRESCRIBING INFORMATION

CFR 20156(a) and (d)

20157

PLR Requirements for Prescribing Information

Pregnancy and Lactation

Labeling Final Rule

554 Pursuant to the PLLR you should include the following information with your application to 555 support the changes in the Pregnancy Lactation and Females and Males of Reproductive 556 Potential subsections of labeling The application should include a review and summary of the 557 available published literature regarding the drugrsquos use in pregnant and lactating women and the 558 effects of the drug on male and female fertility (include search parameters and a copy of each 559 reference publication)

httpwwwfdagovdownloadsDrugsGuidanceComplianceRegulatoryInformationGuidances

UCM425398pdf

DISCUSSION OF SAFETY ANALYSIS STRATEGY FOR THE ISS

-

599 Prioritized list of previously observed and anticipated safety issues to be evaluated and planned 600 analytic strategy including any SMQs modifications to specific SMQs or sponsor-created 601 groupings of Preferred Terms A rationale supporting any proposed modifications to an SMQ or 602 sponsor-created groupings should be provided 603 604 When requesting this meeting clearly mark your submission ldquoDISCUSS SAFETY ANALYSIS 605 STRATEGY FOR THE ISSrdquo in large font bolded type at the beginning of the

SUBMISSION FORMAT REQUIREMENTS

must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must

httpwwwfdagovForIndustryElectronicSubmissionsGateway


MANUFACTURING FACILITIES

Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address


Drug Master File Number (if applicable)


1

1

2

2


Site Name

Site Name

Site Name

Site Address

Onsite Contact (Person Title)


Email address

1

1

2

2

645 646 647 648 The Division recommends that sponsors considering the submission of an application through 649 the 505(b)(2) pathway consult the Agencyrsquos regulations at 21 CFR 31454 and the draft 650 guidance for industry Applications Covered by Section 505(b)(2) (October 1999) available at 651 652 In addition FDA has explained the background and applicability of section 505(b)(2) in its 653 October 14 2003 response to a number of citizen petitions that had challenged the Agencyrsquos 654 interpretatio


505(b)(2) REGULATORY PATHWAY

httpwwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesdefaulthtm


)

httpwwwregulationsgov

670 If you intend to rely on the Agencyrsquos finding of safety andor effectiveness for a listed drug(s) or 671 published literature describing a listed drug(s) (which is considered to be reliance on FDArsquos 672 finding of safety andor effectiveness for the listed drug(s)) you should identify the listed drug(s) 673 in accordance with the Agencyrsquos regulations at 21 CFR 31454 It should be noted that 21 CFR 674 31454 requires identification of the ldquolisted drug for which FDA has made a finding of safety and 675

List the information essential to the approval of the proposed drug that is provided by reliance on the FDArsquos previous finding of safety and effectiveness for a listed drug or by reliance on published literature


Source of information (eg published literature name of listed drug)



Information Provided (eg specific sections of the 505(b)(2) application or labeling)

1 Example Published literature


Nonclinical toxicology







4

4

710 711 Please be advised that circumstances could change that would render a 505(b)(2) application for 712 this product no longer appropriate For example if a pharmaceutically equivalent product were 713 approved before your application is submitted such that your proposed product would be a 714 ldquoduplicaterdquo of a listed drug and eligible for approval under section 505(j) of the FDampC Act then 715 it is FDArsquos policy to refuse to file your application as a 505(b)(2) application (21 CFR 716 314101(d)(9))

OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS

httpswwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire


mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure









1 Introduction 2 This material consists of our preliminary responses to your questions and any additional 3 comments in preparation for the discussion at the meeting scheduled for December 6 2016 4 at 1100 am ET between Dow Pharmaceuticals Sciences Inc and the Division of 5 Dermatology and Dental Products We are sharing this material to promote a collaborative 6 and successful discussion at the meeting The meeting minutes will reflect agreements 7 important issues and any action items disc

10 discussion is not required you have the option of cancelling the meeting (contact the 11 regulatory project manager (RPM)) If you choose to cancel the meeting this document 12 will represent the official record of the meeting If you determine that discussion is needed 13 for only some of the original questions you have the option of reducing the agenda It is 14 important to remember that some meetings particularly milestone meetings can be 15 valuable even if the pre-meeting communications are

Regulatory

23 Question 8 24 The Sponsor intends to request a partial waiver for the conduct of clinical studies with IDP-123 25 Lotion in pediatric subjects aged 0-8 years 11 months due to the very low prevalence of acne in 26 this age group The Sponsor intends to include subjects 9 YOA and above in clinical studies with


27 IDP-123 Lotion The initial Pediatric Study Plan will be submitted to IND 126277 within 60 28 days from the date of the End-of-Phase 2 meeting date 29 30 Does the Agency agree with the Sponsorrsquos request for partial waiver for pediatric subjects aged 31 0-8 years 11 months 32 33 FDA Response 34 As discussed at the pre-IND meeting this is reasonable Incidence and prevalence data for 35 various pediatric age groups should be provided in the PSP to support the waiver request 36 37

Chemistry Manufacturing and Controls (CMC)

38 Question 1 39 DPS is proposing specifications in accordance with the current International Council for 40 Harmonisation (ICH) guideline Q6A for drug substance and drug product Tazarotene drug 41 substance is not described in a US Pharmacopoeia monograph Details of the proposed 42 specifications are provided in the briefing book (Section 162131) We acknowledge that the 43 suitability of the acceptance criteria could be an NDA review issue 44 45 Based on the specifications provided in the briefing

Figure

we cannot provide detailed input on whether additional controls are 55 necessary for other potential impurities or if additional tests will be needed in the drug substance 56 specifications These specific requests will be communicated to the DMF holder during review 57 of the marketing application and you will be notified that a request has been made to the DMF 58 holder at that time 59 60 b the drug product specifications proposed for use in phase 3 clinical studies (to be 61 conducted with the to-be-m


71 See responses to a and b in Question 1 72 73 Question 2 74 For Phase 3 and registration stability stability studies will be conducted in accordance with the 75 current ICH guideline Q1A For the registration stability batches a physicianrsquos sample (3 g) and 76 1 trade size (45 g) will be filled into tubes The details of the proposed stability studies and 77 package types for the tube fill sizes are provided in the briefing book (Section 162131) Note 78 2 of the 3 registration stability batches

Nonclinical

89 Question 3 90 The Sponsor intends to establish a clinical bridge to rely on the Agencyrsquos prior findings of safety 91 for the RLD TAZORAC Cream 01 (NDA 021184) this specifically includes genotoxicity 92 reproductive toxicity and carcinogenicity The preliminary results from the Phase 2 clinical 93 bridging study (V01-123A-201 Section 1627423) suggest that the safety profile of IDP-123 94 Lotion in subjects with acne is comparable to that of TAZORAC Cream 01 The preliminary 95 results of t

100 101 Does the Agency agree that no additional nonclinical studies would be required and that the 102 studies for IDP-123 Lotion coupled with the existing body of nonclinical data for TAZORAC 103 Cream are sufficient to support filing and registration of IDP-123 Lotion considering that 104 TAZORAC will be the RLD selected for a 505(b)(2) NDA 105 106 FDA Response 107 Yes we agree that no additional nonclinical studies would be required to support a 505(b)(2) 108 NDA for your product IDP-123 Lotion i


Clinical

116 includes a PK bridging study V01-123A-501 (preliminary results are provided in Section 117 1627422) and a safety and efficacy bridging study V01-123A-201 (preliminary results are 118 provided in Section 1627423) The results submitted in the briefing document suggest an 119 adequate clinical bridge will be established 120 121 Does the Agency agree that the results from the bridging studies are adequate to establish a 122 clinical bridge to TAZORAC Cream 01 and allow for a successful 50

142 You propose to conduct a Phase 3 Multi-Center randomized double-blind vehicle-controlled 143 study to compare the safety and efficacy of IDP-123 Lotion 144 in the treatment of acne vulgaris 145 Approximately subjects will be randomized in a ratio to the following treatment 146 groups 147 148 149 150 151

152 Co-Primary efficacy endpoints 153 IDP-123 Lotion will be compared to

and Vehicle Cream 154 Co-primary endpoints are 155 Absolute change from Baseline to Week 12 in mean inflammatory lesion counts 156 Absolute change from Baseline to Week 12 in mean non-inflammatory lesion counts 157 Percent of subjects who achieve at least a two-grade reduction from baseline and are Clear or 158 Almost Clear at Week 12 in the Evaluatorrsquos Global Severity Score 159







Figure

160 The controlled clinical studies as proposed in your briefing document would appear to be 161 adequate to support filing of 505(b)(2) NDA for the treatment of acne vulgaris As you are 162 aware approvability of such an application would be a review issue 163 164 b Does the Agency agree that the planned statistical analyses for the Phase 3 clinical 165 studies described within the protocol are adequate to produce substantial evidence of efficacy 166 and safety for the treatment of acne 167 168 FDA Re

206 request a waiver for conducting a clinical study with IDP-123 Lotion to evaluate the potential for 207 QTQTc interval prolongation 208 209 Does the Agency agree that a TQT study to assess the potential of QT prolongation with the use 210 of IDP-123 Lotion is not needed for NDA filing and approval 211 212 FDA Response 213 The proposed plan is reasonable provided review of the final Phase 2 study report demonstrates 214 that the systemic exposure from IDP-123 is similar to or lower than the systemic e

ADMINISTRATIVE COMMENTS

PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m

DATA STANDARDS FOR STUDIES

252 Under section 745A(a) of the FDampC Act electronic submissions ldquoshall be submitted in such 253 electronic format as specified by [FDA]rdquo FDA has determined that study data contained in 254 electronic submissions (ie NDAs BLAs ANDAs and INDs) must be in a format that the 255 Agency can process review and archive Currently the Agency can process review and 256 archive electronic submissions of clinical and nonclinical study data that use the standards 257 specified in the Data Standards Catalog

httpwwwfdagovforindustrydatastandardsstudydatastandardsdefaulthtm



UCM292334pdf

httpwwwfdagovdownloadsForIndustryDataStandardsStudyDataStandardsUCM384744pd


f

cder-edatafdahhsgov

cder-edatafdahhsgov

Study Data Standards Resources

httpwwwfdagovDrugsDevelopmentApprovalProcessFormsSubmissionRequirementsElectr


onicSubmissionsucm248635htm

298 299 300 301 302 303 CDER strongly encourages IND sponsors to identify the laboratory test units that will be 304 reported in clinical trials that support applications for investigational new drugs and product 305 registration Although Systegraveme International (SI) units may be the standard reporting 306 mechanism globally dual reporting of a reasonable subset of laboratory tests in US 307 conventional units and SI units might be necessary to minimize conversion needs during review 308 Identification




LABORATORY TEST UNITS FOR CLINICAL TRIALS


httpwwwfdagovForIndustryDataStandardsStudyDataStandardsucm372553htm



must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)


344 described in the literature or on the other studies is scientifically appropriate You should 345 include a copy of such published literature in the 505(b)(2) application and identify any listed 346 drug(s) described in the published literature (eg trade name(s)) 347 348 If you intend to rely in part on the Agencyrsquos finding of safety andor effectiveness for a listed 349 drug(s) or published literature describing a listed drug(s) (which is considered to be reliance on 350 FDArsquos finding of safety


Office of Scientific Investigations (OSI) Requests

List the information essential to the approval of the proposed drug that is provided by reliance on the FDArsquos previous finding of safety and efficacy for a listed drug or by reliance on published literature
















4

4

388 The Office of Scientific Investigations (OSI) requests that the following items be provided to 389 facilitate development of clinical investigator and sponsormonitorCRO inspection assignments 390 and the background packages that are sent with those assignments to the FDA field investigators 391 who conduct those inspections (Item I and II) This information is requested for all major trials 392 used to support safety and efficacy in the application (ie phase 23 pivotal trials) Please note 393

395

396 The dataset that is requested in Item III below is for use in a clinical site selection model that is 397 being piloted in CDER Electronic submission of the site level dataset is voluntary and is 398 intended to facilitate the timely selection of appropriate clinical sites for FDA inspection as part 399 of the application andor supplement review process

400 This request also provides instructions for where OSI requested items should be placed within an 401 eCTD submission (Attachment 1 Technical Instructions Submitting Bioresearch Monitoring 402 (BIMO) Clinical Data in eCTD Format)

403

404 I Request for general study related information and comprehensive clinical investigator 405 information (if items are provided elsewhere in submission describe location or provide 406 link to requested information) 407 408 1 Please include the following information in a tabular format in the original NDA for each 409 of the completed pivotal clinical trials 410 a Site number 411 b Principal investigator 412 c Site Location Address (eg Street City State Country) and contact information 413



417 investigatorrsquos participation in the study we request that this updated information also 418 be provided 419 420 2 Please include the following information in a tabular format by site in the original NDA 421 for each of the completed pivotal clinical trials 422 a Number of subjects screened at each site 423 b Number of subjects randomized at each site 424 c Number of subjects treated who prematurely discontinued for each site by site 425 426 3 Please include the following information in a tabul

462 g By subject listing of protocol violations andor deviations reported in the NDA 463 including a description of the deviationviolation 464 h By subject listing of the primary and secondary endpoint efficacy parameters or 465 events For derived or calculated endpoints provide the raw data listings used to 466 generate the derivedcalculated endpoint 467 i By subject listing of concomitant medications (as appropriate to the pivotal clinical 468 trials) 469 j By subject listing of testing (eg

472 the following format 473 474

475 476 477 478 III Request for Site Level Dataset 479 480 OSI is piloting a risk based model for site selection Voluntary electronic submission of site 481 level datasets is intended to facilitate the timely selection of appropriate clinical sites for FDA 482 inspection as part of the application andor supplement review process If you wish to 483 voluntarily provide a dataset please refer to the draft Guidance for Industry Providing 484 Submissions in Electronic Format ndash Summary Level Clinical Site

httpwwwfdagovdownloadsDrugsDevelopmentApprovalProcessFormsSubmissionRequire


mentsUCM332468pdf

489 Attachment 1 490 Technical Instructions 491 Submitting Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format 492 493 494 A Data submitted for OSI review belongs in Module 5 of the eCTD For items I and II in 495 the chart below the files should be linked into the Study Tagging File (STF) for each 496 study Leaf titles for this data should be named ldquoBIMO [list study ID followed by brief 497 description of file being submitted]rdquo In addition a BIMO STF should be constructed 498 and placed in

DSI Pre-NDA Request Item1



STF File Tag

Used For

Allowable File Formats

I

I

data-listing-dataset

Data listings by study

pdf

I

I

annotated-crf

Sample annotated case report form by study

pdf

II

II


Data listings by study (Line listings by site)

pdf

III

III


Site-level datasets across studies

xpt

III

III

data-listing-data-definition

Define file

pdf

503 504 B In addition within the directory structure the item III site-level dataset should be placed 505 in the M5 folder as follows 506

Figure


Please see the OSI Pre-NDABLA Request document for a full description of requested data files


1

515 References 516 517 eCTD Backbone Specification for Study Tagging Files v 261 518 (519 ) 520 521 FDA eCTD web page 522 (523 ) 524 525 For general help with eCTD submissions



mentsElectronicSubmissionsUCM163560pdf

httpwwwfdagovDrugsDevelopmentApprovalProcessFormsSubmissionRequirementsElect


ronicSubmissionsucm153574htm

ESUBfdahhsgov

ESUBfdahhsgov

526 527 528 To ensure that the Division is aware of your continued drug development plans and to facilitate 529 successful interactions with the Division including provision of advice and timely responses to 530 your questions we request that the cover letter for all new phase 2 or phase 3 protocol 531 submissions to your IND or changes to these protocols include the following information 532 533 1 Study phase 534 2 Statement of whether the study is intended to support marketing andor labeling changes

NEW PROTOCOLS AND CHANGES TO PROTOCOLS



s


IND 126277

Dear Mr Humphries

Sincerely

IND 126277Page 2

(b) (4)

IND 126277Page 3

IND 126277 Page4

143 Ouestion 3 4

150 (b)(4J

(b)(4J 157 (b)(4J 158

159 (b)(4)

IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

annotated-crf


pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277Page 2

(b) (4)

IND 126277Page 3

IND 126277 Page4

143 Ouestion 3 4

150 (b)(4J

(b)(4J 157 (b)(4J 158

159 (b)(4)

IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

annotated-crf


pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277Page 2

(b) (4)

IND 126277Page 3

IND 126277 Page4

143 Ouestion 3 4

150 (b)(4J

(b)(4J 157 (b)(4J 158

159 (b)(4)

IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

annotated-crf


pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277Page 3

IND 126277 Page4

143 Ouestion 3 4

150 (b)(4J

(b)(4J 157 (b)(4J 158

159 (b)(4)

IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

annotated-crf


pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277 Page4

143 Ouestion 3 4

150 (b)(4J

(b)(4J 157 (b)(4J 158

159 (b)(4)

IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

annotated-crf


pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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Email address

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1

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

744

744




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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277 Page 7

IND 126277Page 8

IND 126277 Page 9

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IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


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Question 6

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Question 18


Question 7


Question 8



Question 9

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tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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Site Name

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1

2

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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pditfdahhsgov



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UCM292334pdf



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IND 126277Page 8

IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


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VJ-t

149

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157

158 159

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using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

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UCM292334pdf



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IND 126277 Page 9

IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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(b)(4J (b)(4J

156

157

158 159

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specif

on s

he proposed

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



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UCM292334pdf



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4


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IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














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)





















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4


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IND 126277Page 10

IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














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do

not adhere

rejection

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httpwwwfdagovectd




)





















4

4


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IND 126277 Page 11

IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


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I



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I

I

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pdf

II

II



pdf

III

III



xpt

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III


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1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277Page 12

IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

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pdf

II

II



pdf

III

III



xpt

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pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277 Page 13

IND 126277Page 14

IND 126277Page 15

IND 126277 Page 16

640 641

applicable)

Email address

IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


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using a


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Question 6

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Question 18


Question 7


Question 8



Question 9

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Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

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Site Name

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1

2

2


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4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


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742

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743

743

744

744




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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277Page 15

IND 126277 Page 16

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IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


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Question 5



Question 6

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Question 17



Question 18


Question 7


Question 8



Question 9

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Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

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Site Address




1

1

2

2


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4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



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UCM292334pdf



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IND 126277Page 15

IND 126277 Page 16

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IND 126277Page 17

IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

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157

158 159

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

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1

2

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



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IND 126277 Page 16

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IND 126277Page 17

IND 126277 Page 18

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IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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Site Name

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Site Address



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1

1

2

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



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IND 126277Page 17

IND 126277 Page 18

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IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

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1

1

2

2






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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

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4

4


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IND 126277 Page 18

listed drug)

IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














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do

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rejection

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httpwwwfdagovectd




)





















4

4


395



403










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Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277 Page 19

--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










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STF File Tag

Used For


I

I



pdf

I

I

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pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


--------------------------------------------------------------------------------------------

------------------------------------------------------------

IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










mentsUCM332468pdf





STF File Tag

Used For


I

I



pdf

I

I

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pdf

II

II



pdf

III

III



xpt

III

III


Define file

pdf


Figure




1








ESUBfdahhsgov

ESUBfdahhsgov





s


IND 126277

Dear Mr Humphrey

Sincerely

ENCLOSURE

IND 126277

IND 126277 Page 2

IND 126277 Page 3

IND 126277 Page 4

(b) (4)

IND 126277 Page 5

IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

iu g product at re











Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277 Page 4

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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


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Question 20



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Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

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20157



Labeling Final Rule



UCM425398pdf


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must be

do not adhere

rejection

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httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

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1

2

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4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



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UCM292334pdf



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IND 126277 Page 4

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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


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4


4


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Question 18


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Question 8



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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

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Site Address




1

1

2

2


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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

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UCM292334pdf



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IND 126277 Page 4

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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


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4


4


mg


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150 (b)(4J


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Question 18


Question 7


Question 8



Question 9

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tsucm332466pdf

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Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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Site Name

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1

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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UCM292334pdf



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IND 126277 Page 4

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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

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149

150 (b)(4J


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157

158 159

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Question 6

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Question 18


Question 7


Question 8



Question 9

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tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



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UCM292334pdf



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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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156

157

158 159

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specif

on s

he proposed

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using a


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Question 18


Question 7


Question 8



Question 9

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Question 10





tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


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1

1

2

2






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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



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UCM292334pdf



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IND 126277 Page 6

IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

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IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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157

158 159

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he proposed

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Question 6

-


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Question 18


Question 7


Question 8



Question 9

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tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

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IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

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IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

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specif

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he proposed

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using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

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4

4


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IND 126277 Page 7

IND 126277 Page 8

IND 126277 Page 9

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IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

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specif

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he proposed

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using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



f

cder-edatafdahhsgov

cder-edatafdahhsgov














must be

do

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rejection

httpwwwfdagovectd

httpwwwfdagovectd




)





















4

4


395



403










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ESUBfdahhsgov





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IND 126277 Page 8

IND 126277 Page 9

listed drug)

IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


152 (b)(4) ------shy


(b)(4J (b)(4J

156

157

158 159

(b)(4)


specif

on s

he proposed

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Question 4

using a


Question 5



Question 6

-


Question 17



Question 18


Question 7


Question 8



Question 9

-


Question 10





tsucm332466pdf

Question 11


Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



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IND 126277 Page 12

IND 126277 Page 13

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APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




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IND 126277

TR

Page 16

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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




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PREA REQUIREMENTS



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IND 126277 Page 10

IND 126277 Page 11

IND 126277 Page 12

IND 126277 Page 13

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Request Item1

Formats

IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



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4


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PREA REQUIREMENTS

-




CM360507pdf

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must be

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TR

IND 126277

TR

Page 16

640

640

641

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mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

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742

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743

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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277 Page 12

IND 126277 Page 13

DSI Pre-NDA

Request Item1

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IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



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4


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PREA REQUIREMENTS

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CM360507pdf

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20157



Labeling Final Rule



UCM425398pdf


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must be

do not adhere

rejection

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httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

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mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



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IND 126277 Page 12

IND 126277 Page 13

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Request Item1

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IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



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4


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20157



Labeling Final Rule



UCM425398pdf


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must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

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IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

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744




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IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277 Page 13

DSI Pre-NDA

Request Item1

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IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


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Question 18


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Question 13


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Question 15


Question 16

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PREA REQUIREMENTS

-




CM360507pdf

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m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

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Site Name

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4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

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743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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IND 126277 Page 14

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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-


Question 17



Question 18


Question 7


Question 8



Question 9

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tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

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1

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4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

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pditfdahhsgov



m






UCM292334pdf



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---------------------------------------------------------------------------------------------------------

----------------------------------------------------

Structure Bookmarks



APPLICATION NUMBER

211882Orig1s000

211882Orig1s000






IND 126277




Dear Mr Humphries







Sincerely




Figure
























Figure


Question 19


Question 20



Question 1


Figure





4


4


mg


4

VJ-t

149

150 (b)(4J


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157

158 159

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using a


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Question 6

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Question 17



Question 18


Question 7


Question 8



Question 9

-


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tsucm332466pdf

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Question 12



Question 13


Question 14



Question 15


Question 16

-



PREA REQUIREMENTS

-




CM360507pdf

Pedsdrugsfdahhsgov

Pedsdrugsfdahhsgov



m



20157



Labeling Final Rule



UCM425398pdf


-



must be

do not adhere

rejection

httpwwwfdagovectd

httpwwwfdagovectd

must




Table

TR

IND 126277

TR

Page 16

640

640

641

641

Site Name

Site Name

Site Name

Site Address




1

1

2

2


Site Name

Site Name

Site Name

Site Address



Email address

1

1

2

2






)


















4

4





mentsUCM332466pdf

IND 126277

IND 126277

IND 126277

Page 19

Page 19

741

741


742

742

mentsUCM332468pdf

743

743

744

744




s





IND 126277




Dear Mr Humphrey







Sincerely



ENCLOSURE




Figure











Regulatory






Figure




Nonclinical




Clinical











Figure




PREA REQUIREMENTS



CM360507pdf

pditfdahhsgov

pditfdahhsgov



m






UCM292334pdf



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4

4


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s


Documents

APPLICATION NUMBER€¦ · of the Federal Food, Drug, and Cosmetic Act for tazarotene lotion, 0.045%. We also refer to your October 11, 2018, correspondence, received October 11,