Contains Nonbinding Recommendations Revision History Date Version Summary of Changes 12/28/2017 1.0 Original Version 07/23/2020 2.0 1. Corrected footnote hyperlinks
Contains Nonbinding Recommendations BIORESEARCH MONITORING TECHNICAL CONFORMANCE GUIDE Technical Specifications Document This Document is Referenced by the Following Draft Guidance Document: Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions For questions regarding this technical specifications document, contact CDER-BIMONDA-BLA-request@fda.hhs.gov. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 27, 2020 Contains Nonbinding Recommendations BIORESEARCH MONITORING TECHNICAL CONFORMANCE GUIDE July 27, 2020 Date 12/28/2017 07/23/2020 Contains Nonbinding Recommendations Revision History Version 1.0 2.0 Summary of Changes Original Version 1. Corrected footnote hyperlinks 2. Edited variable names in examples and tables to maintain consistency across document 3. Clarified document, listings, and data requests 4. Deleted request for SITEFFE and SITEFFS variables in clinsite.xpt 5. Added COHORT variable 6. Revised PROTVIOL variable to IMPDEV and NOIMPDEV variables 7. Provided additional instructions for placement of files per eCTD format Contains Nonbinding Recommendations TABLE OF CONTENTS I. CLINICAL STUDY-LEVEL INFORMATION 1 A. COMPREHENSIVE AND READILY LOCATED LIST OF ALL CLINICAL SITES .........................................................1 B. TABLE LISTING ALL ENTITIES TO WHOM SPONSOR HAS CONTRACTED CLINICAL STUDY-RELATED ACTIVITIES .......................................................................................................................................................1 C. PROTOCOL, PROTOCOL AMENDMENTS, AND ANNOTATED CASE REPORT FORM...............................................2 II. SUBJECT-LEVEL DATA LINE LISTINGS BY CLINICAL SITE 2 A. ORGANIZATION OF THE SUBJECT-LEVEL DATA LINE LISTINGS ........................................................................2 B. SITE-SPECIFIC LISTINGS FORMAT .....................................................................................................................4 III. SUMMARY-LEVEL CLINICAL SITE DATASET 5 A. ORGANIZATION OF THE SITE-LEVEL DATASET .................................................................................................5 B. VARIABLES AND VARIABLE NAMES FOR SITE-SPECIFIC EFFICACY RESULTS....................................................5 C. CREATING THE DATA FILE (TEMPLATE AND STRUCTURE) ................................................................................6 IV. SUBMITTING BIMO CLINICAL DATA IN THE ECTD FORMAT 7 A. STUDY TAGGING FILE.......................................................................................................................................7 B. ECTD FOLDER STRUCTURE FOR CLINICAL STUDY-LEVEL INFORMATION AND SUBJECT-LEVEL LINE LISTINGS BY CLINICAL SITE .............................................................................................................................................7 C. ECTD FOLDER STRUCTURE FOR SUMMARY-LEVEL CLINICAL SITE DATASET ..................................................8 D. FILE FORMAT....................................................................................................................................................8 E. LEAF TITLES .....................................................................................................................................................9 F. SUBMISSION......................................................................................................................................................9 APPENDIX 1: CLINICAL STUDY-LEVEL INFORMATION 10 APPENDIX 2: FORMATTING SUBJECT-LEVEL DATA LINE LISTINGS BY CLINICAL SITE 11 APPENDIX 3: CLINICAL SITE DATA ELEMENTS SUMMARY LISTING 14 APPENDIX 4: EXAMPLES 17 Contains Nonbinding Recommendations 1 Bioresearch Monitoring Technical Conformance Guide 2 3 This technical conformance guide, when finalized, will represent the current thinking of the Food 4 and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any 5 person and is not binding on FDA or the public. You can use an alternative approach if it 6 satisfies the requirements of the applicable statutes and regulations. If you want to discuss an 7 alternative approach, contact the FDA staff responsible for this technical conformance guide. If 8 you cannot identify the appropriate FDA staff, send an email to cder-edata@fda.hhs.gov or 9 cber.cdisc@fda.hhs.gov. 10 11 This Bioresearch Monitoring Technical Conformance Guide (Guide) provides current FDA 12 specifications, recommendations, and general considerations for preparing and submitting 13 Clinical Study-Level Information, Subject-Level Data Line Listings by Clinical Site, and a 14 Summary-Level Clinical Site Dataset that are used by the Center for Drug Evaluation and 15 Research (CDER) for planning of Bioresearch Monitoring (BIMO) inspections in electronic 16 format for new drug applications (NDAs), biologics license applications (BLAs), and NDA or 17 BLA supplemental applications containing clinical data that are regulated by CDER.1 It also 18 applies when these data and information are submitted under certain investigational new drug 19 applications2 (INDs) in advance of a planned NDA, BLA, or supplemental submission. 20 21 22 I. CLINICAL STUDY-LEVEL INFORMATION 23 24 A. Comprehensive and Readily Located List of All Clinical Sites 25 26 The recommended format for the portable document format (PDF) of the comprehensive and 27 readily located list(s) of all clinical sites that participated in clinical studies for each major (i.e., 28 pivotal) study is provided in Appendix 1 of this Guide. 29 30 B. Table Listing All Entities To Whom Sponsor Has Contracted Clinical Study- 31 Related Activities 32 33 In the table(s) listing entities to whom the sponsor has contracted clinical study-related activities, 34 which are provided in a PDF for each pivotal study, the applicant should identify the location of 35 study-related documents for each study and whether they are sponsor- or Contract Research 36 Organization-generated. For example, these documents may include, but are not limited to, 37 monitoring plans and reports, training records, and data analysis plans (e.g., items that some 38 applicants organize in a Trial Master File). When the location of study-related documents has 39 not been finalized, the applicant should provide contact information (i.e., phone number and 1 We update technical conformance guides periodically. For the most recent version of this Guide, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 2 See FDA guidance for industry Providing Regulatory Submissions in Electronic Format Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 1 Contains Nonbinding Recommendations 40 email address) for the individual(s) who can provide updated location information upon request. 41 This information ensures that when CDER issues an inspection assignment for the application, 42 the inspection is of the most responsible entity for a given regulatory responsibility, and that the 43 inspection assignment is issued for the location where records are present for review. 44 45 C. Protocol, Protocol Amendments, and Annotated Case Report Form 46 47 The protocol and protocol amendments, with associated versions of the case report form, and the 48 final version of the annotated case report form (case report form containing Clinical Data 49 Interchange Standards Consortium and Study Data Tabulation Model (SDTM) annotations) are 50 generally included in Appendix 163 of the Clinical Study Report or in the datasets folder for each 51 study. When these items are included in an appendix to the Clinical Study Report or the dataset 52 folder for the study, there is no need to resubmit them. If the applicant is submitting a BIMO 53 Reviewer's Guide, the applicant should note that these items are present in an appendix of the 54 Clinical Study Report or the dataset folder and provide hyperlinks to their locations. 55 56 These items are included in the background materials provided to the Office of Regulatory 57 Affairs for BIMO inspections; it is important to provide all versions of these documents so that 58 the field investigator performing the inspection can reference the correct versions of protocols 59 and case report forms in place at the time of the conduct of specific study procedures. 60 61 62 II. SUBJECT-LEVEL DATA LINE LISTINGS BY CLINICAL SITE 63 64 A. Organization of the Subject-Level Data Line Listings 65 66 Examples of the formatting for the PDF of subject-level data line listings provided for each 67 major (i.e., pivotal) study used to support safety and efficacy in the application, including studies 68 with different treatment indications, are provided in Appendix 2 of this Guide. If the sponsor 69 believes alternative listings or formats are preferable for its submission, proposed alternatives 70 should be discussed with the Office of Scientific Investigations in advance of the application 71 submission--for example, before or during pre-NDA or pre-BLA meetings. 72 73 For clinical investigator sites involved in multiple studies in support of an application, the 74 subject listings should be provided independently for each study within the study-associated 75 PDF. 76 77 Subject-level data line listings, by clinical site, should include consented subjects, treatment 78 assignment, discontinuations, study population, inclusion and exclusion criteria, adverse events, 79 important protocol deviations, efficacy endpoints, concomitant medications, and safety 80 monitoring, as further described below. 81 82 1. Consented Subjects 83 3 See ICH guidance for industry E3 Structure and Content of Clinical Study Reports (July 1996). 2 Contains Nonbinding Recommendations 84 This by-subject, by-clinical site listing includes all subjects that consented to enroll in the study. 85 Consented subjects that were screen failures should also be included. For subjects that consented 86 but were not randomized to treatment or did not receive investigational product, the specific 87 reason they were not randomized or treated should be included in this listing. 88 89 2. Treatment Assignment 90 91 This by-subject, by-clinical site listing includes the treatment assignment to which the subject 92 was randomized. If a subject mistakenly received treatment different from the subject's assigned 93 treatment for any duration of time, the actual treatment received should also be included. 94 95 3. Discontinuations 96 97 This by-subject, by-clinical site listing includes: 98 99 · All subjects that discontinued during run-in period (if applicable) 100 · All subjects that discontinued from study treatment 101 · All subjects that discontinued from the study completely 102 103 For each subject, the date of and reason for discontinuation should be provided. 104 105 4. Study Population 106 107 This by-subject, by-clinical site listing identifies the protocol-defined study population in which 108 each subject was analyzed (e.g., intent-to-treat, safety, per protocol). For subjects that did not 109 meet criteria for inclusion in the per-protocol population, the reason they were excluded from the 110 per-protocol population should be provided. 111 112 5. Inclusion and Exclusion Criteria 113 114 This by-subject, by-clinical site listing should display whether each subject met each inclusion 115 and exclusion criterion defined in the protocol. 116 117 6. Adverse Events 118 119 This by-subject, by-clinical site listing should include all adverse events (i.e., nonserious adverse 120 events and serious adverse events, including deaths), date of occurrence and time if collected, 121 treatment(s) administered, severity, whether considered serious by the clinical investigator, 122 whether considered serious by the sponsor, action taken, whether the event led to discontinuation 123 of study therapy, and outcome/date of resolution. 124 125 7. Important Protocol Deviations 126 3 Contains Nonbinding Recommendations 127 This by-subject, by-clinical site listing should include all protocol deviations. The listing should 128 include a description of the deviation and identify whether the sponsor considered the deviation 129 to be an important or non-important protocol deviation.4 130 131 8. Efficacy Endpoints 132 133 This by-subject, by-clinical site listing(s) should contain primary and key secondary efficacy 134 parameters or events. For derived or calculated endpoints, the raw data points used to generate 135 the derived or calculated endpoint should be provided. When efficacy endpoints are collected as 136 clinical events, a by-subject, by-clinical site listing should be provided that includes clinical 137 event date of event, and when adjudicated, the date of adjudication and the outcome of the 138 adjudication process. 139 140 9. Concomitant Medications 141 142 This by-subject, by-clinical site listing should contain all concomitant medications as specified 143 by the protocol. The date started, date stopped, dose, route of administration, and reason for 144 administration should be included. 145 146 10. Safety Monitoring 147 148 This by-subject, by-clinical site listing(s) should contain results of tests (e.g., laboratory, 149 electrocardiogram) performed for safety monitoring as defined in the protocol. When safety 150 endpoints are collected as clinical events, a by-subject, by-clinical site listing should be provided 151 that includes clinical event, date of event, and when adjudicated, the outcome of the adjudication 152 process. 153 154 B. Site-Specific Listings Format 155 156 The specified data line listings are anticipated to fit reporting requirements for most applications. 157 If a sponsor believes additional listings are needed to permit FDA to verify key study data during 158 inspections, additional listings should be included. If the size of the PDF file exceeds 500 159 megabytes, it should be split into smaller components.5 160 161 Although listings are currently requested in PDF format, CDER is in the process of developing 162 tools to extract site-specific listings, needed for inspectional purposes, from submitted Clinical 163 Data Interchange Standards Consortium, SDTM, and Analysis Data Model (ADaM) datasets and 164 intends to make those tools available in the future. FDA intends to update these technical 165 specifications to include details for the submission of SDTM and ADaM datasets, including 166 controlled terminology standards. In anticipation of the development of CDER tools for 4 See ICH guidance for industry E3 Structure and Content of Clinical Study Reports -- Questions and Answers (R1) (January 2013). 5 See ICH guideline Specification for Submission Formats for eCTD v1.2 (June 2018) at http://estri.ich.org/ssf/Specification_for_Submission_Formats_for_eCTD_v1_2.pdf. 4 Contains Nonbinding Recommendations 167 extraction of by-site, by-subject data listings, sponsors should ensure that they are prepared to 168 submit clinical study data using standards specified in the Data Standards Catalog.6 169 170 171 III. SUMMARY-LEVEL CLINICAL SITE DATASET 172 173 A. Organization of the Site-Level Dataset 174 175 A single summary-level clinical site dataset that contains data from all major (i.e., pivotal) 176 studies used to support safety and efficacy in the application, including studies with different 177 treatment indications, should be provided. 178 179 For each major (i.e., pivotal) study used to support safety and efficacy, data by clinical site and 180 treatment arm for the safety population (SAFPOP) should be provided. 181 182 For clinical investigator sites involved in multiple studies in support of an application, the site 183 data should be reported independently for each study within the dataset. 184 185 B. Variables and Variable Names for Site-Specific Efficacy Results 186 187 For each study and investigator site, it is critical to submit the following variables associated 188 with efficacy and their variable names: 189 · Treatment Efficacy Result (TRTEFFR) -- The summary statistic for each primary efficacy 190 endpoint, by treatment arm at a site. Values reported in TRTEFFR generally reflect simple 191 summary statistics for the primary efficacy endpoint(s). The method used for deriving the 192 TRTEFFR, including a description of which analysis datasets and associated variables are 193 used to derive the TRTEFFR, should be described in the data define table provided with the 194 clinsite.xpt file. (See discussion below for examples of summary statistics according to 195 different types of efficacy endpoints.) 196 · Treatment Efficacy Result Standard Deviation (TRTEFFS) -- The standard deviation (STD) 197 of the summary statistic (TRTEFFR) for each primary endpoint, by treatment arm. The 198 method used to calculate STD should be included in the data define table. 199 · Endpoint (ENDPOINT) -- A plain-text label that describes the primary endpoint as 200 described in the data definition file data dictionary included with each application. 201 · Treatment Arm (ARM) -- A plain-text label for the treatment arm that is used in the Clinical 202 Study Report. 203 In addition, for studies whose primary endpoint is a time-to-event endpoint, it is critical to 204 include the following data element: 6 Available at http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm. 5 Contains Nonbinding Recommendations 205 · Censored Observations (CENSOR) -- The number of censored observations for the given 206 site and treatment. 207 If a study does not contain a time-to-event endpoint, this data element should be recorded as a 208 missing value (if not applicable, leave blank in clinsite.xpt). 209 210 To accommodate the variety of endpoint types that can be used in analyses, it is critical that the 211 following endpoint type definitions be referenced, and summaries be provided when tabulating 212 the site-specific summary statistic by treatment arm (TRTEFFR): 213 · Discrete Endpoints -- Endpoints based on efficacy observations that can take on a discrete 214 number of values (e.g., binary, categorical). Summarize discrete endpoints by an event 215 frequency (i.e., number of events), proportion of patients with an event, proportion of 216 patients responding to treatment, or similar method at the site for the given treatment. 217 · Continuous Endpoints -- Endpoints based on efficacy observations that can take on an 218 infinite number of values. Summarize continuous endpoints by the mean, median, or other 219 distributional quantile of the observations at the site for the given treatment. 220 · Time-to-Event Endpoints -- Endpoints where the time to occurrence of an event is the 221 primary efficacy measurement. Summarize time-to-event endpoints by two data elements: 222 the number of events that occurred (TRTEFFR) and the number of censored observations 223 (CENSOR). 224 · Other -- If the primary efficacy endpoint cannot be summarized in terms of the previous 225 guidelines, a single value or multiple values with precisely defined variable interpretations 226 should be submitted as part of the dataset. 227 In all cases, the endpoint description provided in the ENDPOINT plain-text label should be 228 expressed clearly to interpret the value provided in the TRTEFFR variable. 229 230 When more than one primary efficacy endpoint exists, additional rows should be added to the 231 dataset to report additional ENDPOINT, Primary Endpoint Type (ENDPTYPE), TRTEFFR, and 232 TRTEFFS values by arm for each site. 233 234 It is anticipated that efficacy data for all subjects included in the SAFPOP variable will be 235 included in TRTEFFR and TRTEFFS variables reported. If efficacy data is not available for all 236 subjects reported in the SAFPOP variable, then efficacy data for these subjects should be 237 reported as specified in the study Data Analysis Plan, and the method used for calculation of 238 efficacy variables should be described in the data define table provided with the clinsite.xpt file. 239 240 The summary-level clinical site dataset should be accompanied by a data definition file. The 241 contents of the define file for a dataset and fictional examples are presented in Appendix 3 and 242 Appendix 4 of this Guide. 243 244 C. Creating the Data File (Template and Structure) 245 6 Contains Nonbinding Recommendations 246 A sample summary-level clinical site data submission using the variables identified in Appendix 247 3 of this Guide is provided in Appendix 4. 248 249 250 IV. SUBMITTING BIMO CLINICAL DATA IN THE eCTD FORMAT 251 252 Clinical study-level information, subject-level data line listings by clinical site, and the 253 summary-level clinical site dataset submitted with an application, in Electronic Common 254 Document (eCTD) format, should be placed in eCTD Module 5 (M5) -- Clinical Study Reports, 255 using the following conventions: 256 A. Study Tagging File 257 258 Construct a BIMO study tagging file (STF) and place it in eCTD Module 5.3.5.4, "Other Study 259 reports and related information." The study identifier (ID) for this STF is "BIMO." Files 260 described in section III (e.g., Description of Clinical Study-Level Information, Subject-Level 261 Data Line Listings by Clinical Site, and Summary-Level Clinical Site Dataset) of the draft 262 guidance Standardized Format for Electronic Submission of NDA and BLA Content for the 263 Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 264 2018) are linked to this BIMO STF using file tags as indicated below.7 Leaf titles for these data 265 are named "BIMO [list study ID, followed by brief description of file being submitted]." 266 267 Table 1: STF File Tags Requested Item STF File Tag Used For Required File Formats III.A.1-2 data-listing-dataset General clinical studylevel information .pdf III.A.3 Protocol-or-amendment Protocol and Protocol Amendments, by study .pdf III.A.3 annotated-crf Sample annotated case report form, by study .pdf III.B data-listing-dataset Data listings, by study (Line listings, by site) .pdf III.C data-listing-dataset Site-level dataset, across studies .xpt III.C data-listing-datadefinition Define file .xml Optional data-listing-dataset BIMO Reviewer's Guide .pdf 268 269 B. eCTD Folder Structure for Clinical Study-Level Information and Subject- 270 Level Line Listings by Clinical Site 271 7 When final, this guidance will represent the FDA's current thinking on this topic. 7 Contains Nonbinding Recommendations 272 Clinical study-level information and subject-level line listings by clinical site are submitted for 273 each major (i.e., pivotal) study used to support safety and efficacy in the application. 274 275 Within the eCTD folder structure, place clinical study-level information and subject-level line 276 listings by clinical site in the M5 folder as follows: 277 278 Figure 2: Place Clinical Study-Level Information and Subject-Level Line Listings by 279 Clinical Site in the M5 Folder 280 281 282 283 C. eCTD Folder Structure for Summary-Level Clinical Site Dataset 284 285 For the site-level dataset, use the filename "clinsite.xpt." A single file containing data from all 286 major (i.e., pivotal) studies used to support safety and efficacy in the application should be 287 provided. 288 289 Within the eCTD folder structure, place the site-level dataset define file and BIMO Reviewer's 290 Guide, if it is being submitted, in the M5 folder as follows: 291 292 Figure 2: Place the Site-Level Dataset Define File and BIMO Reviewer's Guide in the M5 293 Folder 294 295 296 297 D. File Format 298 299 The Clinical Study-Level Information and Subject-Level Data Line Listings by Clinical Site 300 should be submitted in PDF (*.pdf). When submitting a BIMO Reviewer's Guide, it should also 301 be submitted in PDF (*.pdf). The summary-level clinical site data should be submitted in SAS 8 Contains Nonbinding Recommendations 302 transport file format (*.xpt). The define file for the summary-level clinical site data should be 303 submitted in Extensible Markup Language (define.xml) format. For more information, see the 304 Study Data Technical Conformance Guide.8 305 E. Leaf Titles 306 307 Leaf titles for study-level information and study-level, subject-level data line listings by clinical 308 site are named "BIMO [list study ID, followed by brief description of file being submitted]." For 309 the leaf representing the clinsite.xpt dataset, please clearly identify it with the leaf title "BIMO 310 summary-level clinical site data." 311 312 F. Submission 313 314 See the technical specifications in Transmitting Electronic Submissions Using eCTD 315 Specifications for details on electronic transmission or physical media submissions.9 316 317 The following are helpful references for eCTD submission: 318 · ICH eCTD STF Specification V 2.6.1, The eCTD Backbone File Specification for Study 319 Tagging Files (June 2008) (available at 320 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequ 321 irements/ElectronicSubmissions/UCM163560.pdf). 322 · FDA guidance for industry Providing Regulatory Submissions in Electronic Format 323 Certain Human Pharmaceutical Product Applications and Related Submissions Using the 324 eCTD Specifications (February 2020) (available at https://www.fda.gov/regulatory- 325 information/search-fda-guidance-documents). 326 · FDA eCTD web page 327 (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/E 328 lectronicSubmissions/ucm153574.htm ). 329 · For general help with eCTD submissions, submit your questions to the following email 330 address: ESUB@fda.hhs.gov. 331 332 8 Available at https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources. 9 Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSub missions/UCM163567.pdf. 9 Contains Nonbinding Recommendations 333 APPENDIX 1: CLINICAL STUDY-LEVEL INFORMATION 334 335 Format for comprehensive and readily located list of all clinical sites that participated in each 336 clinical study. A separate table should be provided for each clinical study. 337 Table A: Format for Clinical Site Lists Protocol Number: Protocol Title Site Identifier Investigator Name (Prior Clinical Investigator(s)) Site Address at Time of Clinical Study (Updated Site Address when exists and available) SITEID LASTNAME, FRSTNAME, MINITIAL FACILITY NAME STREET CITY, STATE, POSTAL COUNTRY Site Contact Information at Time of Clinical Study (Updated Contact Information when exists and available) PHONE FAX EMAIL 0001* Doe, John M. Doe University Department of Medicine 1 Main St., Suite 100 Silver Spring, MD 20850 USA Phone: 1-555-555-5555 Fax: 1-555-555-5555 Email: john.doe@mail.com 0002 003 Doe, Jean (Smith, John) Dietric-Fischer, Inge Doe University Department of Medicine 1 Main St., Suite 100 Silver Spring, MD 20850 USA Hartmannstrasse 7 5300 Bonn 1 Germany Phone: 1-555-555-5555 Fax: 1-555-555-5555 Email: john.smith@mail.com (Phone: 1-555-555-5554 Email: jean.doe@mail.com ) Phone:49-555-555-5555 Fax: 49-555-555-5555 Email: Dietric.Fischer@web.de * Site terminated, or clinical investigator changed, at request of sponsor before study completion. 338 339 10 Contains Nonbinding Recommendations 340 APPENDIX 2: FORMATTING SUBJECT-LEVEL DATA LINE LISTINGS BY 341 CLINICAL SITE 342 343 By Site, by Listing Option A: 344 345 Figure A: By Site, by Listing Option A Protocol Number - Site Number Listing "1" Listing "2" Listing "3" Listing "4" Etc. Etc. Etc. + Next Site Number 346 + Next Site Number 347 348 By Site, by Subject Profile Option B: 349 11 Contains Nonbinding Recommendations 350 Figure B: By Site, by Subject Profile Option B Protocol Number - Site Number - Subject Number Subject Profile That Containing All Elements of Requested Line Listings for this Subject + Next Subject Number + Next Subject Number + Next Site Number + Next Site Number 351 352 12 Contains Nonbinding Recommendations 353 Example of By Site, by Listing Option A: 354 355 Figure C: Example of By Site, by Listing Option A Protocol #1234 - Site #0001 Consented Subjects Treatment Assignment Discontinuations Study Population Etc. Etc. Etc. + Site #0002 356 + Site #0003 357 358 Example of By Site, by Listing Option B: 359 360 Figure D: Example of By Site, by Listing Option B Protocol #1234 - Site #0001 - Subject Number #0001-001 Subject Profile Containing All Elements of Requested Line Listings for this Subject + Subject Number #0001-064 + Subject Number #0001-101 + Site #0002 + Site #0003 361 13 Contains Nonbinding Recommendations APPENDIX 3: CLINICAL SITE DATA ELEMENTS SUMMARY LISTING Table B: Clinical Site Data Elements Summary Listing Variable Index Variable Name Variable Label Type Controlled Terms or Format 1 STUDYID Study Identifier Char String 2 TITLE Study Title Char String 3 SPONCNT Sponsor Count Num Integer 4 SPONSOR Sponsor Name Char String 5 IND IND Number Num 6 digit identifier 6 UNDERIND Under IND Char String 7 NDA NDA Number Num 6 digit identifier 8 BLA BLA Number Num 6 digit identifier 9 SUPPNUM Supplement Num Integer Number 10 SITEID Study Site Char String Identifier 11 ARM Description of Char String Planned Treatment Arm 12 COHORT Description of Char String Planned Cohort Notes or Description Study or trial identification number. Title of the study as listed in the clinical study report (limit 200 characters). If the title exceeds 200 characters, provide shortened title and define (e.g., use the abbreviated title from clinicaltrial.gov). Total count of sponsors throughout the study. If there was a change in the sponsor while the study was ongoing, with sponsors as defined in § 312.3 (21 CFR 312.3), enter an integer indicating the total count of sponsors. If there was no change in the sponsor while the study was ongoing, enter "1." Full name of the sponsor organization conducting the study at the time of study completion, as sponsor is defined in § 312.3. If the sponsor name exceeds 200 characters, provide short-form sponsor name and define. IND number. If study not performed under IND, leave blank. Value should equal "Y" if study at the site was conducted under an IND (i.e., a Form FDA 1572 was signed by the investigator) and "N" if study was not conducted under an IND at the site (i.e., a Form FDA 1572 was not signed by the investigator). FDA NDA number, if available/applicable. If not applicable, leave blank. FDA identification number for BLA, if available/applicable. If not applicable, leave blank. Serial number for supplemental application, if applicable. If no information is available, leave blank. Investigator site identifier assigned by the sponsor. Plain-text label for the name given to an arm or treatment group as referenced in the clinical study report (limit 200 characters). When no arm or treatment group is available due to only screen failure subjects at site, use label "Screen Failure." For cohort studies, the plain-text label given to a cohort as referenced in the clinical study report (limit 200 characters). When not a cohort study, leave blank. Sample Value ABC-123 Double blind, randomized, placebocontrolled clinical study on the influence of drug X on indication Y 1 DrugCo, Inc. 010010 Y 021212 123456 4 50 Active name and dose (e.g., "Active 25mg"), Comparator product name (e.g., "Drug x"), Placebo, Screen Failure A 14 Contains Nonbinding Recommendations Variable Index 13 14 15 16 17 18 19 20 21 22 Variable Name SAFPOP SCREEN DISCSTUD DISCTRT ENDPOINT ENDPTYPE TRTEFFR TRTEFFS CENSOR NSAE Variable Label Number of Subjects in Safety Population Number of Subjects Screened Number Subjects Discont. Study Number Subjects Discont. Study Treatment Primary Endpoint Primary Endpoint Type Treatment Efficacy Result Treatment Efficacy Result STD Number of Censored Observations Number of Non-Serious Adverse Events Type Num Num Num Num Char Char Num Num Num Num Controlled Terms or Format Integer Integer Integer Integer String String Floating Point Floating Point Integer Integer Notes or Description Total number of subjects in safety population at a given site by treatment arm. When a subject has transferred from one site to another, the applicant should handle reporting of such subjects consistently across sites and include in the define file the reporting convention used. The applicant may opt to further explain the reasons subjects transferred between sites in the BIMO Reviewer's Guide, if a guide will be provided. Total number of subjects screened (and consented) at a given site (overall number per site as subjects have not yet been assigned to treatment arm). When a subject has transferred from one site to another, the applicant should handle reporting of such subjects consistently across sites and include the reporting convention used in the define file or the BIMO Reviewer's Guide (if provided). The applicant may opt to further explain the reasons subjects transferred between sites in the BIMO Reviewer's Guide, if provided. Number of subjects in the safety population who discontinued from the study by treatment arm at a given site. Number of subjects in the safety population who discontinued from the study treatment by treatment arm at a given site. Plain-text label used to describe the primary endpoint as described in the define file included with each application (limit 200 characters). Variable type of the primary endpoint (i.e., "continuous," "discrete," "time to event," or "other"). Summary statistic for each primary efficacy endpoint by treatment arm at a given site for subjects in SAFPOP. Standard deviation (STD) of the efficacy result (TRTEFFR) for each primary efficacy endpoint by treatment arm at a given site for subjects in SAFPOP. If N=1, set to "0." Total number of censored observations at a given site by treatment arm for primary endpoint (e.g., applicable to timeto-event). If not applicable, leave blank. Total number of nonserious adverse events at a given site by treatment arm for subjects in the SAFPOP. This value should include multiple events per subject and all event types (i.e., not limited to only those that are deemed related to study drug or that are treatment emergent events). When events with the same preferred term have occurred on different dates for a subject, each event should be counted separately in event count. Sample Value 20 100 5 10 Average increase in blood pressure Continuous 1.00 0.065 5 10 15 Contains Nonbinding Recommendations Variable Index 23 24 25 26 27 28 29 30 31 Variable Name SAE DEATH IMPDEV NOIMPDEV FINLDISC LASTNAME FRSTNAME MINITIAL PHONE Variable Label Number of Serious Adverse Events Number of Deaths Number of Important Protocol Deviations Number of Non-Important Protocol Deviations Financial Disclosure Amount Investigator Last Name Investigator First Name Investigator Middle Initial Investigator Phone Number Type Num Num Num Num Char Char Char Char Char Controlled Terms or Format Integer Integer Integer Integer String String String String String Notes or Description Total number of serious adverse events, excluding deaths, at a given site by treatment arm for subjects in the SAFPOP. This value should include multiple events per subject. When events with the same preferred term have occurred on different dates for a subject, each event should be counted separately in event count. Total number of deaths at a given site by treatment arm for subjects in the SAFPOP. Total number of important protocol deviations at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change. This value should include multiple deviations per subject and all major deviation types. Important deviations are those deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, or well-being. Total number of protocol deviations, excluding important protocol deviations, at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change. Total financial disclosure amount (US$) by site calculated as the sum of disclosures for the clinical investigator and all sub-investigators, to include all required parities under the applicable regulations (21 CFR 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860). Enter ">=$25,000," "< $25,000," "unknown" if a proper value is applicable but is not known (i.e., unable to obtain information from investigator at site), or "masked" if information on this item is available but it has not been provided by the sender due to security, privacy, or other reasons. Last name of the clinical investigator as it appears on the Form FDA 1572 or the signed investigator agreement. At sites where the clinical investigator has changed during the course of the study, the most recent clinical investigator should be listed. First name of the clinical investigator as it appears on the Form FDA 1572 or the signed investigator agreement. Middle initial of the clinical investigator, if any, as it appears on the Form FDA 1572 or the signed investigator agreement. Phone number of the clinical investigator. Include country code for non-U.S. numbers. Sample Value 5 1 2 98 >= $25,000 Doe John M 44-555-555-5555 16 Contains Nonbinding Recommendations Variable Index 32 33 34 Variable Name FAX EMAIL COUNTRY Variable Label Investigator Fax Number Investigator Email Address Country 36 STATE State 37 CITY City 38 POSTAL Postal Code 39 STREET Street Address 40 STREET1 Street Address Continued Type Controlled Terms or Format Char String Char String Char ISO 3166-1-alpha-3 Char String Char String Char String Char String Char String Notes or Description Fax number of the clinical investigator. Include country code for non-U.S. numbers. If not available, leave blank. Email address of the clinical investigator. Three-letter International Organization for Standardization (ISO) 3166 country code for the country in which the site is located. Unabbreviated state or province in which the site is located. If not applicable, enter "NA." Unabbreviated city, county, or village in which the site is located. Postal code in which the site is located. If not applicable, enter "NA." Street address and office number at which the site is located (limit 200 characters). Street address and office number at which the site is located. Use this field when the STREET variable does not permit sufficient space to fully describe street address and office number at which the site is located. Sample Value 44-555-555-5555 John.doe@mail.com USA Maryland Silver Spring 20850 2005 John Fitzgerald Kennedy Boulevard Northwest, International Technology Center, Department of Medicine and Pharmacokinetics, National Institute of Clinical Research Twin Towers Building, The Executive Wing, Suite # 209 APPENDIX 4: EXAMPLES The following is a fictional example of a dataset for a placebo-controlled trial. Four international sites enrolled a total of 205 subjects who were randomized in a 1:1 ratio to active or placebo. In the first example there is a single primary endpoint (percent of responders). In the second example there are co-primary endpoints (percent of responders and change from baseline). Note that since there were two treatment arms, in the first example, each site contains two rows and there are a total of eight rows for the entire dataset. In the second example, each site contains a total of 4 rows, and there are a total of 16 rows for the entire dataset. Table C: Example for Clinical Site Data Elements Summary Listing with One Endpoint STUDYID TITLE SPONCNT SPONSOR IND UNDERIND NDA BLA SUPPNUM SITEID ARM COHORT ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 001 Active - SAFPOP 26 SCREEN 61 DISCSTUD 3 DISCTRT 2 17 Contains Nonbinding Recommendations ABC-123 Double blind... 1 ABC-123 Double blind... 1 ABC-123 Double blind... 1 ABC-123 Double blind... 1 ABC-123 Double blind... 1 ABC-123 Double blind... 1 ABC-123 Double blind... 1 ENDPOINT Percent Responders Percent Responders Percent Responders Percent Responders Percent Responders Percent Responders Percent Responders Percent Responders ENDPTYPE Binary Binary Binary Binary Binary Binary Binary Binary MINITIAL M M PHONE 555-123-4567 555-123-4567 020-3456-7891 020-3456-7891 01-89-12-34-56 01-89-12-34-56 555-987-6543 555-987-6543 DrugCo, Inc. 000001 Y 200001 001 DrugCo, Inc. 000001 Y 200001 002 DrugCo, Inc. 000001 Y 200001 002 DrugCo, Inc. 000001 Y 200001 003 DrugCo, Inc. 000001 Y 200001 003 DrugCo, Inc. 000001 Y 200001 004 DrugCo, Inc. 000001 Y 200001 004 TRTEFFR 0.48 0.14 0.48 0.14 0.54 0.19 0.46 0.12 TRTEFFS 0.0980 0.0694 0.1042 0.0694 0.0959 0.0769 0.0977 0.0625 CENSOR NSAE 0 2 3 0 2 3 4 1 SAE 2 2 2 2 2 6 1 2 DEATH 0 0 1 0 0 0 0 0 IMPDEV 1 1 0 3 1 0 0 1 FAX 555-123-4560 555-123-4560 020-3456-7890 020-3456-7890 01-89-12-34-51 01-89-12-34-51 EMAIL John@mail.com John@mail.com george@mail.com george@mail.com tom@mail.com tom@mail.com COUNTRY RUS RUS GBR GBR FRA FRA STATE Moscow Moscow Westminster Westminster N/A N/A 555-987-6540 abe@mail.com USA Maryland 555-987-6540 abe@mail.com USA Maryland Placebo - 25 61 4 1 Active - 23 54 2 1 Placebo - 25 54 4 3 Active - 27 62 3 0 Placebo - 26 62 5 3 Active - 26 60 2 2 Placebo - 27 60 1 0 NOIMPDEV 4 6 9 11 4 7 8 13 FINLDISC < $25,000 < $25,000 >= $25,000 >= $25,000 >= $25,000 >= $25,000 unknown unknown LASTNAME Doe FRSTNAME John Doe John Washington George Washington George Jefferson Thomas Jefferson Thomas Lincoln Abraham Lincoln Abraham CITY Moscow Moscow London London Paris Paris Rockville Rockville POSTAL 103009 103009 SW1A 2 SW1A 2 75002 75002 20852 20852 STREET Kremlin Road 1 Kremlin Road 1 10 Downing St 10 Downing St 1, Rue Road 1, Rue Road 10903 New Hampshire Avenue, Office of Medical Products and Tobacco, Center for Drug Evaluation and Research 10903 New Hampshire Avenue, Office of Medical Products and Tobacco, Center for Drug Evaluation and Research STREET1 Building 4, Room 1375 Building 4, Room 1375 18 Contains Nonbinding Recommendations Table D: Example for Clinical Site Data Elements Summary Listing with Multiple Primary Endpoints STUDYID TITLE SPONCNT SPONSOR IND UNDERIND NDA BLA SUPPNUM SITEID ARM COHORT SAFPOP SCREEN ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 001 Active A ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 001 Active B ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 001 Placebo A 26 61 26 61 25 61 ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 001 Placebo B ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 002 Active A ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 002 Active B 25 61 23 54 23 54 ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 002 Placebo A ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 002 Placebo B ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 003 Active A 25 54 25 54 27 62 ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 003 Active B 27 62 ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 003 Placebo A ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 003 Placebo B ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 004 Active A 26 62 26 62 26 60 ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 004 Active B ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 004 Placebo A ABC-123 Double blind... 1 DrugCo, Inc. 000001 Y 200001 004 Placebo B 26 60 27 60 27 60 DISCSTUD 3 3 4 4 2 2 4 4 3 3 5 5 2 2 1 1 DISCTRT 2 2 1 1 1 1 3 3 0 0 3 3 2 2 0 0 ENDPOINT Percent Responders Change from Baseline Percent Responders Change from Baseline Percent Responders Change from Baseline Percent Responders ENDPTYPE Binary Continuous Binary Continuous Binary Continuous Binary TRTEFFR 0.48 0.74 0.14 0.14 0.48 0.67 0.14 TRTEFFS 0.0980 0.0861 0.0694 0.0699 0.1042 0.0983 0.0694 CENSOR NSAE 0 0 2 2 3 3 0 SAE 2 2 2 2 2 2 2 DEATH 0 0 0 0 1 1 0 IMPDEV 1 1 1 1 0 0 3 NOIMPDEV 5 8 5 8 11 13 11 FINLDISC < $25,000 < $25,000 < $25,000 < $25,000 >= $25,0000 >= $25,0000 >= $25,0000 LASTNAME Doe Doe Doe Doe Washington Washington Washington FRSTNAME John John John John George George George 19 Contains Nonbinding Recommendations ENDPOINT Change from Baseline Percent Responders Change from Baseline Percent Responders Change from Baseline Percent Responders Change from Baseline Percent Responders Change from Baseline ENDPTYPE Continuous Binary Continuous Binary Continuous Binary Continuous Binary Continuous TRTEFFR 0.14 0.54 0.65 0.19 0.19 0.46 0.71 0.12 0.15 TRTEFFS 0.0700 0.0959 0.0931 0.0769 0.0769 0.0977 0.0891 0.0625 0.0694 CENSOR NSAE 0 2 2 3 3 4 4 1 1 SAE 2 2 2 6 6 1 1 2 2 DEATH 0 0 0 0 0 0 0 0 0 IMPDEV 3 1 1 0 0 0 0 0 1 NOIMPDEV 13 9 5 9 5 0 3 0 3 FINLDISC >= $25,0000 >= $25,0000 >= $25,0000 >= $25,0000 >= $25,0000 unknown unknown unknown unknown LASTNAME Washington Jefferson Jefferson Jefferson Jefferson Lincoln Lincoln Lincoln Lincoln FRSTNAME George Thomas Thomas Thomas Thomas Abraham Abraham Abraham Abraham MINITIAL M M M M PHONE 555-123-4567 555-123-4567 555-123-4567 555-123-4567 020-3456-7891 020-3456-7891 020-3456-7891 020-3456-7891 01-89-12-34-56 01-89-12-34-56 01-89-12-34-56 01-89-12-34-56 FAX 555-123-4560 555-123-4560 555-123-4560 555-123-4560 020-3456-7890 020-3456-7890 020-3456-7890 020-3456-7890 01-89-12-34-51 01-89-12-34-51 01-89-12-34-51 01-89-12-34-51 EMAIL John@mail.com John@mail.com John@mail.com John@mail.com george@mail.com george@mail.com george@mail.com george@mail.com tom@mail.com tom@mail.com tom@mail.com tom@mail.com COUNTRY RUS RUS RUS RUS GBR GBR GBR GBR FRA FRA FRA FRA STATE Moscow Moscow Moscow Moscow Westminster Westminster Westminster Westminster N/A N/A N/A N/A CITY Moscow Moscow Moscow Moscow London London London London Paris Paris Paris Paris 555-987-6543 555-987-6540 abe@mail.com USA Maryland Rockville POSTAL 103009 103009 103009 103009 SW1A 2 SW1A 2 SW1A 2 SW1A 2 75002 75002 75002 75002 20852 555-987-6543 555-987-6540 abe@mail.com USA Maryland Rockville 20852 STREET Kremlin Road 1 Kremlin Road 1 Kremlin Road 1 Kremlin Road 1 10 Downing St Suite 2058 10 Downing St Suite 2058 10 Downing St Suite 2058 10 Downing St Suite 2058 1, Rue Road 1, Rue Road 1, Rue Road 1, Rue Road 2005 John Fitzgerald Kennedy Boulevard Northwest, International Technology Center, Department of Medicine and Pharmacokinetics, National Institute of Clinical Research Twin Towers Building, 2005 John Fitzgerald Kennedy Boulevard Northwest, International Technology Center, Department of Medicine and Pharmacokinetics, National Institute of Clinical Research Twin Towers Building, STREET1 The Executive Wing, Suite # 209 The Executive Wing, Suite # 209 20 Contains Nonbinding Recommendations MINITIAL PHONE 555-987-6543 FAX 555-987-6540 EMAIL COUNTRY abe@mail.com USA STATE Maryland CITY Rockville 555-987-6543 555-987-6540 abe@mail.com USA Maryland Rockville POSTAL 20852 20852 STREET 2005 John Fitzgerald Kennedy Boulevard Northwest, International Technology Center, Department of Medicine and Pharmacokinetics, National Institute of Clinical Research Twin Towers Building, 2005 John Fitzgerald Kennedy Boulevard Northwest, International Technology Center, Department of Medicine and Pharmacokinetics, National Institute of Clinical Research Twin Towers Building, STREET1 The Executive Wing, Suite # 209 The Executive Wing, Suite # 209 21Microsoft Word for Office 365 Microsoft Word for Office 365