Ph USE Pooling WHODrug B 3 Format Marlo

Ph. USE: Pooling WHODrug B 3 Format Marlo Searcy, RPh September, 2017

Agenda • Project Overview • Working Group Introductions • Timelines & Meeting Structure • Review of B 2 vs. B 3 Key Differences • Start discussing/identifying options for pooling strategy 2

Project Overview In a March 2015 Federal Register Notice, the FDA encouraged sponsors to provide WHODrug Dictionary codes for concomitant medication data in investigational studies provided in regulatory submissions. The request indicated that codes should include the drug product trade name (where available), the active ingredient(s) and the Anatomical Therapeutic Chemical (ATC) Class. As indicated in the May 2015 Data Standards Catalog, the expectation for it's requirement begins March 2018. Additional information was provided in the October 2015 Study Data Technical Conformance Guide. Other regulatory agencies have communicated similar notices. In order to facilitate the population of active ingredients, the Uppsala Monitoring Centre, who maintains the WHODrug Dictionary, updated the dictionary (B 3 and C 3 formats) to improve the structure for multi-ingredient drugs. While this change will greatly improve the efficiency of reviewing, analysing and reporting medication data, it introduces several challenges when creating an integrated database. 3

Project Deliverables This project team will create a white paper outlining best practices for creating an integrated database with medication data collected in different formats (B 3 format and whatever format was applied previously). 4

WG Introductions • Introduce yourself … • Does your organization plan to implement WHODrug B 3? If so, when? • What systems do you currently use to code medication data? • What clinical data sources are coded at your organization (EDC systems, Drug Safety systems, other)? • What do you see as the biggest challenge to B 3 implementation and pooled submission? 5

Standard Medication Table Display • Ph. USE Standard Scripts Analysis Whitepapers WG is developing recommendation for standard WHODrug medication table display • Leading proposal is an individual ingredient-based display (ATC not included) • Preferable to have recommendation for standard table prior to tackling pooled table 6

Proposed Standard Medication Table 7

WG Timelines and Meeting Structure • Meeting schedule: 3 rd Wednesday of the month? • Other housekeeping? December meeting? • Project Timelines: § Draft White Paper December 2017? § Final White Paper March 2018? 8

Ph. USE Resources • Pooling WHODrug B 3 Format Wiki Page: http: //www. phusewiki. org/wiki/index. php? title=Poo ling_WHODrug_B 3_Format 9

B 2 vs. B 3 Format – Key Differences • Field Length: § B 3 generic names increased to 1500 CHAR, ATC to 110 CHAR § B 2 generic names truncated at 45 CHAR, C truncated at 80 CHAR • Combination products: § B 2/C preferred generic name is the first entered trade name of their respective ingredients § B 3/C 3 preferred generic name represent the substance or substance combination (separated by semi-colon, not w/). 10

B 3 Combination Product 11

B 2 vs. B 3 Format – Key Differences Cont. • Salt/Base relationships: § B 2/C salt variations of a combination product are located on separate Drug Record Numbers. § B 3/C 3 salt variations of a substance (including combination products) are connected to the Preferred Base Name. • Non-unique names: § Non-unique names are made unique in the B 2 -format by the addition of /DRECNOSEQ 1/ after the trade name. § Non-unique names are made unique in the B 3 -format by the addition of [INGREDIENTS] after the trade name. 12

B 3 Non-Unique Names 13

FDA Guidance • Federal Register § § “Although use of WHO Drug Dictionary codes are not required at this time, FDA now supports and encourages the use of WHO Drug Dictionary coded concomitant medications used in clinical trials. ” “The codes should include the drug product trade name where available, the active ingredient(s) and the ATC class. ” • Data Standards Catalog • Study Data Technical Conformance Guide § Typically, WHO Drug is used to code concomitant medications. --DECOD should be populated with the generic name from the WHO dictionary, and --CLAS populated with the drug class, if the utilized dictionary codes drugs to a single class. When using WHODRUG, generally, --CLAS would not be filled because a drug may have multiple classes. However, one Anatomic Therapeutic Code (ATC) level 4 code could be mapped to --CLAS and the remainder of the ATC codes could be placed in SUPPCM. 14

SDTM Regulatory Submission & WHODrug 15

CDISC SDTM Implementation Guide (Version 3. 2) • CDISC SDTM Implementation Guide (Version 3. 2) § For concomitant medications, populate CMDECOD with the drug's generic name and populate CMCLAS with the drug class used for the sponsor’s analysis and summary tables. If coding to multiple classes, follow Section 4. 1. 2. 8. 1, Multiple Values for an Intervention or Event Topic Variable or omit CMCLAS. § For concomitant medications, supplemental qualifiers (see Section 8: 8. 4, Relating Non-Standard Variables Values to a Parent Domain and Appendix C 2 - Supplemental Qualifier Name Codes for more information) may be used to represent additional coding dictionary information, e. g. a drug’s ATC codes from the WHO Drug dictionary. However, by knowing the dictionary and version used, the reviewer will be able to obtain additional coding dictionary information. § Note: The sponsor is expected to provide the dictionary name and version used to map the terms by utilizing the define. xml external codelist attributes. 16

CDISC SDTM Implementation Guide (Version 3. 2) cont. § 4. 1. 2. 8. 1 Multiple Values for an Intervention or Event Topic Variable § If multiple values are reported for a topic variable (i. e. , --TRT in an Interventions general-observation-class dataset or --TERM in an Events general-observation-class dataset), it is assumed that the sponsor will split the values into multiple records or otherwise resolve the multiplicity as per the sponsor’s standard data management procedures. For example, if an adverse event term of “Headache and Nausea” or a concomitant medication of “Tylenol and Benadryl” is reported, sponsors will often split the original report into separate records and/or query the site for clarification. By the time of submission, the datasets should be in conformance with the record structures described in the SDTMIG. Note that the Disposition dataset (DS) is an exception to the general rule of splitting multiple topic values into separate records. For DS, one record for each disposition or protocol milestone is permitted according to the domain structure. For cases of multiple reasons for discontinuation see Section 6. 2 - DS Domain: Assumption 5, DS Assumptions for DISPOSITION Domain Model for additional information. 17

Class submission requirements • There are currently 3 options for submitting WHODrug ATC Class information based on the SDTM Implementation Guide v 3. 2: § One single class selected § Multiple Classes § No Classification 18

UMC SDTM CMDECOD • CMDECOD may be up to 1500 CHAR • Supplemental dataset should be utilized when CMDECOD is longer than 200 CHAR • Text should be truncated between words, after the semicolon closest to 200 CHAR 19

UMC CMCLAS Example 20

Pooling Option 1 • Medication data for studies coded in B 2 (or other proprietary dictionary) and studies coded in B 3 are summarized separately. This approach may be acceptable when no specific medication analysis is done for the study, and standard concomitant medication table is simply appended to the submission. Approach would require approval by FDA reviewer. 21

Pooling Option 2 • Aggregate medication table contains mixed data summarized by Generic text from both B 2 (or other proprietary dictionary) and B 3. This approach may be acceptable when no specific medication analysis is done for the study, and the standard concomitant medication table is simply appended to the submission. Same combination product may be listed twice (e. g. B 2 trade and B 3 ingredients) Approach would require approval by FDA reviewer. 22

Pooling Option 3 • Studies coded in B 2 (or other proprietary dictionary) are recoded in WHODrug B 3 from Generic level up (creation of a filing-specific B 2/Other-B 3 Generic Bridge). This approach would be reserved for submissions where specific medication analyses are included or where B 3 is required by the FDA reviewer. 23

Pooling Option 4 • For studies coded in B 2, B 2 drug codes are submitted to the UMC CAT (Change Analysis Tool). UMC CAT suggestions are used to upversion the B 2 data to B 3. UMC suggestions for deleted terms may require review and modification. This approach would be reserved for submissions where specific medication analyses are included or where B 3 is required by the FDA reviewer. 24

Pooling Option 5 • Studies coded in B 2 (or other proprietary dictionary) are recoded in WHODrug B 3 from verbatim medication term. This approach requires significant resources and would be reserved for submissions where specific medication analyses are included or where B 3 is required by the FDA reviewer. 25

Other Pooling Options? 26

Questions? Doing now what patients need next 27

Backup Slides 28

CDASH User Guide 29

ADa. M CDISC ADa. M Occurrence Data Structure (OCCDS) (Version 1. 0) 30

ADa. M CDISC ADa. M Occurrence Data Structure (OCCDS) (Version 1. 0) 31

ADa. M Table 32

ATC Codes • ATC = Anatomical Therapeutic Chemical classification • Official hierarchical classification system maintained by the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway. Unofficial classifications added to WHODrug by the UMC. • Allows for grouping of active substances based on the organ or system on which they act, and/or their therapeutic, pharmacological and chemical properties (Drug Class). • Each preferred drug name can be associated with one or multiple ATC codes (WHODrug does not have the concept of ‘primary path’) 33

ATC Levels • The official ATC hierarchy consists of five levels. • The first level in the ATC system is represented by 14 anatomical main groups. • The second level further classifies active substances according to pharmacological/therapeutic properties (therapeutic main group). • The third and the fourth ATC levels are chemical/pharmacological/therapeutic subgroups. • The fifth levels represent active substances, and is not included in WHODrug (equivalent to Drecno Concept) 34

ATC Level 1 35

ATC Hierarchy Example • Official ATC Classification for Morphine (5 th level not included in WHODrug) 36

ATC Considerations • ATC codes are not always complete to the 4 th level. There a significant number of Preferred Names that have only the ATC 3 level, some with only the ATC 2 level assigned and a few with only the ATC 1 level. • WHODrug does not specify a primary ATC code for each generic preferred name. Some sponsor companies select a single ATC code for each record based on indication or dosage form information. Many companies do not. In the current version of B 3, drugs can have up to 26 ATC classes assigned. • ATC Code text field 110 CHAR in B 3 37

UMC US User Group Poll October 2016 38

UMC US User Group Poll October 2016 39

Ibuprofen example 40