1. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 1 How to Talk to Your Statistician… Reaching a Common Understanding George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222

2. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 2 Before we begin… Keeping Roles & Responsibilities in Perspective…

3. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 3 Before we begin… The Statistician’s Nightmare…

4. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 4 Before we begin… Every Non-Statistician’s Dream…?

5. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 5 UMC User Group Survey A recent survey of WHO Drug Dictionary Users provided some insight into the “state” of use within companies. As we go through this, please think about what is done at your company. Source: WHO Drug Dictionary - European User Group Presentation by Petra Barth

6. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 6 Preliminary result from survey Generally happy with the quality and quantity of the communication between coders analysis – but: –involve coders in meetings –Coders should be included in meetings –Coders and analysis team not always invited or present at all internal team meetings –The coders (dictionary experts) should be brought in more often for consultation. –An actual meeting with statistics discussing the analysis plan, dictionary version being used, conventions, –Additional training would be helpful so that we each understand one another's jobs. The industry tends to work in silos and not see the big picture.

7. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 7 The expert In your organization – who is the ‘dictionary expert’? Senior coder 57% Clinical Data Manager 24% Statistician 5% Other... 39%

8. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 8 The expert Is the dictionary expert and/or coder involved in: YesNo The development of the Study Protocol 18%70% The definition of Medications of Interest 47%40% The Statistical Analysis Plan 20%70% The definition of tables that include concomitant medication 40%47% The actual analysis of concomitant medication data at study end 28%62%

9. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 9 ATC assigment Does your company require the coders to select an ATC class that corresponds to the indication? Yes 86% No 9% Don't know 5%

10. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 10 ATC - process What is the process used for manual ATC coding? Select an ATC that best captures the indication for each time a medication is taken. (One per incidence.) 82% Select an ATC that best captures the "typical" indication for a medication in this trial. (One per medication per trial.) 5% Select an ATC that best captures the "typical" indication for a medication in all trials conducted by the company. (One per medication per company.) 5%

11. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 11 ATC – if it is not available ATC selection is sometimes difficult or impossible – for example if none of the available ATC classes fit the indication or if no indication is given. Does your organization have a principle for how to handle this? –Select an ATC that captures the "typical" indication –query the site for more specifics

12. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 12 ConMed lists When a list of concomitant medication is sorted by ATC class – how is it done? A programmatic merge is done with all applicable ATC codes based on a collected Drug Code 0% The table is based on an ATC class that is selected by a coder based on the indication -67% We don’t sort lists by ATC22% Don’t know11%

13. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 13 Presentation and Analysis of ConMeds There are important distinctions between: DRUG CLASSINDICATION Similar Anatomic Target / Action Similar Therapeutic Purposes Similar Pharmacologic Form Similar Chemical Structures Purpose for taking this particular instance of dosing

14. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 14 CM Coding to ATC… CRF CM WHO Drug (version) CMDECOD DrugCode CMCLAS ATC #2? ATC #1? ATC #3? Medications in a given Drug Class

15. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 15 CDISC SDTM: ATC codes Implementation Guide 3.1.1 –“CMDECOD with the drug’s generic name, and CMCLAS with the drug class only if the dictionary used codes drugs to a single class. When using WHODRUG, for example, CMCLAS would not be filled since a drug may have multiple classes.” –“Use only when the dictionary used codes to a single class. If using a dictionary that allows links to multiple classes, then omit CMCLAS from the dataset. For example, sponsors who use WHO Drug, which allows links from a medication to multiple ATC codes, would not include CMCLAS.” Implementation Guide 3.1.2 –“CMDECOD with the drug's generic name, and CMCLAS with the drug class used for the sponsor’s analysis and summary tables. If coding to multiple classes, follow assumption 4.1.2.8.1 or omit CMCLAS.” “By knowing the dictionary and version used, the reviewer will be able to obtain intermediate levels in a hierarchy (as in MedDRA), or a drug’s ATC codes (as in WHO Drug). The dictionary version should be listed in the Comments column of the Define data Definition document.”

16. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 16 CM Coding to ATC… CRF CM CRF MH CRF AE MedDRA (version) WHO Drug (version) Related Record CMDECOD DrugCode CMCLAS PT LLT SOC Meaningful Grouping Medications taken for… For more information, please refer to Oct 28, 2011 MedDRA User Group presentation

17. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 17 “An elephant is a mouse built to government specifications.” - Lazarus Long But what should we call it when we build something to “industry mythology” about government specifications??? Where do regulations specify coding indication to ATC?

18. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 18 Impediments to change… Some reluctance is due to Change (“We’ve always done it this way”) –Stakeholders, Pilot Studies, Timing/Planning Lack of tools for SAS programmers to import and relate relevant datasets within the dictionary Lack of tools for programmers to join the dictionary to the clinical datasets (CM, AE, MH) Lack of clarity on what analyses are needed by Regulatory Authority / Company

19. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 19 WHO Drug Dictionary (Version C)

20. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 20 WHO Drug Dictionary (Version B2) INA DDA DD

21. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 21 SAS: 1 - Configuration Program * SETUP DRIVE AND ROOT MAPPING; %let drive=c:; %let root=\data\WHOdd; %let SasData=\SAS\sd2; ***************************************************************; * UPDATE SOURCE; %let UMC=\UMC\2009-03; %let DictFiles=\9145_who_dd_mar_1_2009\B2; * UPDATE VERSION AND FORMAT; %let DictProduct=DD;* DD or DDE or DDE-HERBAL; %let DictVersion=2009-MAR;* YYYY-MMM; %let DictFormat=B2;* B2 or C; ***************************************************************; * INPUT FOLDER; filename UMC "&drive.&root.&UMC.&DictFiles."; * OUTPUT FOLDER; libname SASdata "&drive.&root.&UMC.&SasData."; %include “{Your File Location Here}\WHOdd_config.sas"/nosource2; DDINADDA

22. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 22 SAS: 2a – Import DD (drug names) data SASdata.dd; infile umc("dd.txt") missover; length WHOdrug $30. DrugName $45.; input DrugID 1 - 6 Seq1 7 - 8 Seq2 9 - 11 ChkDgt 12 Desig $ 13 SourceYr 14 - 15 SourceCd $ 16 - 19 CompnyCd $ 20 - 24 NoIngred 25 - 26 SaltEstr 27 CodeYr 28 - 29 CodeQtr 30 UMCName $ 31 – 75 ; label DrugID ="Drug Record Number" Seq1 ="Sequence #1" Seq2 ="Sequence #2" ChkDgt ="Check digit" Desig ="Designation" SourceYr ="Source Year" SourceCd ="Source Code" CompnyCd ="Company Code" NoIngred ="Number of ingredients" SaltEstr ="Salt/ester code" CodeYr ="Year Coded" CodeQtr ="Quarter Coded" DrugName ="Drug name" UMCName ="UMC Full Drug Name" WHOdrug ="Drug Dict Version" ; * STRIP OFF UMC SLASHED MODIFIERS; DrugName=UMCName; if ( substr(UMCName,36,1)="/" & substr(UMCName,45,1)="/" ) then DrugName=substr(UMCName,1,35); WHOdrug="&DictProduct."||" "||"&DictVersion."||" "||"&DictFormat."; run; 12 3 DDINADDA

23. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 23 SAS: 2b – Import DD (drug names) ** Create Indexes **; proc datasets library=SASdata; modify dd; index create DrugCode=(DrugID Seq1 Seq2) DrugName Compressed; quit; 4 DDINADDA

24. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 24 SAS: 3 – Import DDA (drug to ATC) data dda; infile umc("dda.txt") missover; input DrugID 1 - 6 Seq1 7 - 8 Seq2 9 - 11 ChkDgt 12 ATCcode $13 - 19 CodeYr 20 - 21 CodeQtr 22 ATCflag $ 23 ; label DrugID ="Drug Record Number" Seq1 ="Sequence #1" Seq2 ="Sequence #2" ChkDgt ="Check Digit" ATCcode ="ATC Code" CodeYr ="Year Coded" CodeQtr ="Quarter Coded" ATCflag ="Official ATC Code" ; run; 12 DDINADDA

25. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 25 SAS: 4 – Import INA data atc; length ATCcode $7 ATCLevel $1 ATCText $50; infile umc("ina.txt") missover; input @1 ATCcode $7. @8 ATCLevel $1. @9 ATCText $50.; run; ; 1 2 ** Create Indexes **; proc datasets library=Work; modify atc; index create ATCcode; quit; DDINADDA

26. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 26 SAS: 5 – Import / Join ATC Levels proc sql; ** Create the ATC_levels table **; create table atc_levels as select a.ATCcode as ATCcode, b.ATCcode as ATC1code, b.ATCtext as ATC1text, case when c.ATCcode = b.ATCcode then "" else c.ATCcode end as ATC2code, case when c.ATCcode = b.ATCcode then "" else c.ATCtext end as ATC2text, case when d.ATCcode = c.ATCcode then "" else d.ATCcode end as ATC3code, case when d.ATCcode = c.ATCcode then "" else d.ATCtext end as ATC3text, case when e.ATCcode = d.ATCcode then "" else e.ATCcode end as ATC4code, case when e.ATCcode = d.ATCcode then "" else e.ATCtext end as ATC4text 1 2 from (select * from atc) a left join atc b on substr(a.ATCcode,1,1) = b.ATCcode left join atc c on substr(a.ATCcode,1,3) = c.ATCcode left join atc d on substr(a.ATCcode,1,4) = d.ATCcode left join atc e on substr(a.ATCcode,1) = e.ATCcode; quit; 3 ** Create index on atc_levels **; proc datasets lib=work; modify atc_levels; index create ATCcode; quit; 4 DDINADDA

27. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 27 SAS: 6 – Import / Link Drug with ATC levels proc sql; create table SASdata.drug_atc as select a.DrugID, a.ATCcode, b.ATC1code, b.ATC1text, b.ATC2code, b.ATC2text, b.ATC3code, b.ATC3text, b.ATC4code, b.ATC4text from dda a left join atc_levels b on a.ATCcode=b.ATCcode where a.seq1<=001 and a.seq2<=001 order by a.drugid ; quit; 1 2 ** Create index **; proc datasets lib=SASdata; modify drug_atc; index create DrugID ATCcode; quit; DDINADDA

28. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 28 SAS: 7 – Analysis: Many to Many Merge libname whodd “{Your Drive Mapping Here – where WHOdd is}"; libname sasout “{Your Drive Mapping Here – where study data is}"; *** START SAS CODE - MANY TO MANY MERGE (CM & ATC) **********************************************************************************; proc sql; create table sasout.cm_ATC as select a.*, b.* from sasout.cm_coded_DrugID a LEFT JOIN whodd.drug_atc(rename=(drugid=who_drugid)) b on a.drugid=b.who_drugid; quit; run; *** END SAS CODE - MANY TO MANY MERGE **********************************************************************************; DDINADDA CM

29. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 29 The Result? Tables: Grouping by True (all) Drug Class Tables: Grouping by True (actual) Indication from MH/AE Analyses: Avoids missed “Drug Class” if taken for another indication or off-label Less work for Coders Less work for SAS Programmers Less work for Medical Writers

30. Annual US WHo Drug Dictionary user group meeting, October 27, 2011 Slide 30 How to Talk to Your Statistician… Reaching a Common Understanding George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222