1. 2 ND U.S. WHO Drug Dictionary User Group Meeting Boston, MA April 20, 2006

2. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 2 ATC Codes: Strategies for Adding Value Instead of Confusion George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222

4. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 4 Presentation Overview ATC classifications – quick primer What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Strategies for using the WHO Drug Dictionary to enhance value

5. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 5 ATC System - History 1969: Olso symposium “The Consumption of Drugs” –Drug Utilization Research Group (DURG) established. –European Pharmaceutical Market Research Association (EPhMRA) classification system modified = ATC classification 1975: Nordic Council on Medicines (NLN) published ATC/DDD 1981: WHO Regional Office for Europe recommends ATC for drug utilization studies. 1982: WHO Collaborating Centre for Drug Statistics Methodology established 1996: Oversight moved to WHO Headquarters in Geneva for international integration

6. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 6 ATC System - Currently Published annually by the WHO Collaborating Centre for Drug Statistics Methodology http://www.whocc.no/atcddd http://www.whocc.no/atcddd Becoming more commonly used in Canada, currently managed by Health Canada http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd- dpt/index_drugs_dpd_e.html http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd- dpt/index_drugs_dpd_e.html

7. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 7 ATC classification Anatomical –The organ or system on which a drug acts Therapeutic (& Pharmacological) –Indication for typical use(s) –Pharmacological Form Chemical –Compound structure and properties

8. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 8 ATC: 5 Class Levels ATC LevelATC CodeATC Text 1Anatomical Main Group AAlimentary tract and metabolism 2Therapeutic Subgroup A10Drugs used in diabetes 3Pharmacological Subgroup A10BOral blood glucose lowering drugs 4Chemical SubgroupA10B ABiguanides 5Chemical SubstanceA10B A02Metformin (DRecNo: 827)

9. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 9 *New Herbal ATC: 5 Class Levels ATC LevelATC CodeATC Text 1Anatomical Main Group AAlimentary tract and metabolism 2Therapeutic Subgroup A06Herbal laxatives 3Pharmacological Subgroup A06ALaxatives 4Chemical SubgroupA06A BContact laxatives 5Chemical SubstanceA06A B5001Aloe ferox extract (DRecNo: 16518)

10. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 10 Level 1 - Anatomical Groups (14) AALIMENTARY TRACT AND METABOLISM BBLOOD AND BLOOD FORMING ORGANS CCARDIOVASCULAR SYSTEM DDERMATOLOGICALS GGENITO URINARY SYSTEM AND SEX HORMONES HSYSTEMIC HORMONAL PREPARATIONS, EXCL. JANTIINFECTIVES FOR SYSTEMIC USE LANTINEOPLASTIC AND IMMUNOMODULATING AGENTS MMUSCULO-SKELETAL SYSTEM NNERVOUS SYSTEM PANTIPARASITIC PRODUCTS,INSECTICIDES AND REPELLENTS RRESPIRATORY SYSTEM SSENSORY ORGANS VVARIOUS

11. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 11 Level 2 – Therapeutic Groups ATC2Selected Examples A10 DRUGS USED IN DIABETES B05 BLOOD SUBSTITUTES AND PERFUSION SOLUTIONS C02 ANTIHYPERTENSIVES C07 BETA BLOCKING AGENTS H03 THYROID THERAPY L04 IMMUNOSUPPRESSIVE AGENTS M03 MUSCLE RELAXANTS N01 ANESTHETICS S01 OPHTHALMOLOGICALS S02 OTOLOGICALS

12. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 12 Level 3 - Pharmacological Groups ATC3Selected Examples A02A ANTACIDS A06A LAXATIVES A10A INSULINS AND ANALOGUES N05A ANTIPSYCHOTICS N06A ANTIDEPRESSANTS * S01 = OPHTHALMOLOGICALS (eye) ** S02 = OTOLOGICALS (ear) S01A ANTIINFECTIVES* S01C ANTIINFLAMMATORY AGENTS & ANTIINFECTIVES IN COMB* S02A ANTIINFECTIVES**

13. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 13 Presentation Overview ATC classifications – quick primer What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Strategies for using the WHO Drug Dictionary to enhance value

14. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 14 Clinical Trial Databases What should we capture in the CTDB? Options: –Drug Record Number –Drug Code (DRecNum + Seq1 + Seq2) –Medicinal Product ID –ATC code –Verbatim Text

15. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 15 Drug Record Number Example: Advil (DRecNum=1092) IbuprofenDoloflam AdvilHaltran Advil Liqui-gelsIbubufen ActiprofenIbuspray ZofenMotrin NuprinBoots fever and pain reliever DRecNum allows for grouping of all “synonyms” for the drug, including various companies, brands, generics, countries, preparations, etc.

16. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 16 Drug Code: DRecNum + Seq1 + Seq2 Seq1: Salt or Ester (Herbal: Plant part) Seq2: Trade Name or Synonym (generics) DRecNumSeq1Seq2Name 00000501001Ampicillin 00000501002Ampicin 00000501003Binotal 00000502001Ampicillin Sodium 00000502002Binotal 00000502003Polycillin-n 00000503001Ampicillin Trihydrate

17. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 17 Drug Code: DRecNum + Seq1 + Seq2 Seq1: Salt or Ester Seq2: Trade Name or Synonym (generics) DRecNumSeq1Seq2Name 00000501001Ampicillin 00000501002Ampicin 00000501003Binotal 00000502001Ampicillin Sodium 00000502002Binotal 00000502003Polycillin-n 00000503001Ampicillin Trihydrate

18. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 18 Medicinal Product ID The MP ID is new to version “C” of the WHO dd. It is unique to each entry in the dictionary. MP IDDRecNumSeq1Seq2Name 00014300000501001Ampicillin 08395000000501002Ampicin 08395100000501003Binotal 00022500000502001Ampicillin Sodium 08402200000502002Binotal 08402300000502003Polycillin-n 00025100000503001Ampicillin Trihydrate

19. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 19 ATC codes: comments Each product has at least one ATC code. The same product may have more than one ATC code, because it could be used for different indications. The drug code and MP ID are mapped to all ATCs in the dictionary hierarchy. ATC classifications can change over time with dictionary updates.

20. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 20 Verbatim Text From source (CRF, progress notes, DCF) –Drug name as reported by investigator or subject as clarified by data management (strength, etc.) –Start/Stop dates and times –Dosage, Route –Indication Taken for an Adverse Event (AE / SAE / ADR) Taken as a concomitant medication or supplement Previously ongoing therapy

21. Caution: Don’t lose sight of the purpose!

22. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 22 So, what should we capture in the CTDB? See discussion in “Guide” Determine needs/goals of: –Statisticians / Programmers –Medical Writers (for CSR) –Drug Safety Group / Surveillance Team –DSMB –Future Licensing Partners (ISS, ISE, etc.) Weigh benefits versus effort at data mgt level Plan for versioning through regulatory life cycle Capture the dictionary version in the CTDB!

23. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 23 Presentation Overview ATC classifications – quick primer What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Strategies for using the WHO Drug Dictionary to enhance value

24. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 24 Data Presentations: Listings Verbatim reported name “Preferred” name Seq1 = 01 Seq2 = 001 ATC Level (possibly)

25. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 25 Listing 14B: Concomitant Medications During Treatment Period SubjTx ----------------------- Medication Name --------------------StartStopFor IDcohortAgeSex ReportedPreferred* date AE 2103 5 mg37 M XYLOCAIN LIDOCAINE 07 JUL 2004 NO ULTRACAIN ARTICAINE 07 JUL 2004 NO RIZATRIPTAN 13 JUL 2004 YES 2104 5 mg35 M CITALOPRAM 20MG CITALOPRAM 01 JAN 2004 ONGOING NO BISOPROLOL 5MG O/D BISOPROLOL 01 JUN 2004 28 JUL 2004 TYLENOL EXTRA STR PARACETAMOL 06 JUL 2004 YES ACETAMINOPHEN PARACETAMOL 12 JUL 2004 YES PARACETAMOL 750 MG PARACETAMOL12 JUL 2004 19 JUL 2004 YES PARACETAMOL 1G PARACETAMOL 14 JUL 2004 YES 2107 5 mg46 M VALERON TILIDINE 01 MAR 2002 ONGOING NO VALORON 150/12MG TILIDINE 01 MAR 2002 ONGOING NEURONTIN GABAPENTIN 01 MAR 2002 ONGOING NO METOCLOPRAMID METOCLOPRAMIDE 12 JUL 2004 ONGOING YES NEURONTIN 600MG GABAPENTIN 01 MAR 2002 ONGOING (continues…)

26. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 26 Data Presentations: Tables Choose ATC level to group by: ATC1: Anatomical ATC2: Therapeutic Other

27. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 27 Table 13B: Concomitant Medications During Treatment Period by Treatment Cohort Safety Evaluable Population 5 mg10 mg20 mgAll Drug Class (ATC)(N = 8) (N = 24) Preferred Namen (%)n n n SUBJECTS WHO TOOK CONCOMITANT MEDS 4 (50.0)4 5 (62.5)13 (54.2) ANALGESICS 4 (50.0)2 (25.0)1 (12.5)7 (29.2) ANTIGRIPPINE 0 (0.0)1 (12.5)0 (0.0)1 (4.2) DOLORIN 0 (0.0)0 1 (12.5)1 (4.2) GABAPENTIN1 (12.5)0 (0.0)0 1 (4.2) PARACETAMOL2 (25.0)1 (12.5)1 4 (16.7) RIZATRIPTAN1 (12.5)0 (0.0)0 1 (4.2) SUMATRIPTAN0 (0.0)1 (12.5)0 (0.0)1 (4.2) TILIDINE1 (12.5)0 (0.0)0 1 (4.2) ANESTHETICS1 (12.5)0 (0.0)0 1 (4.2) ARTICAINE1 (12.5)0 (0.0)0 1 (4.2) LIDOCAINE1 (12.5)0 (0.0)0 1 (4.2) (continues…)

28. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 28 What about “double counting” ATCs? Since a drug may have more than one ATC, it will could show up in multiple sections of a table. The totals won’t sum correctly. Isn’t this a problem? –Only if it is not understood and explained (footnote) –The table’s purpose is to show how many subjects dosed with a med of a certain “type”. –Even if the med was taken for a different reason (indication/ATC) is still belongs to each “type”. –Only the totals across “types” become irrelevant

29. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 29 Presentation Overview ATC classifications – quick primer What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Strategies for using the WHO Drug Dictionary to enhance value

30. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 30 Analysis Techniques “Bottom Up” Prohibited Med; Over-represented in ATC “Top Down” eg: ATC group; multi-ingredients; responder analysis “Co-medication Profiles” –AE profiles within ATC levels, or –ATC profiles within AE groupings “Guide” discussion and example Precautions Demographics (age/sex), Disease/Treatment, Population

31. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 31 Analysis: ATC Co-Med Profile ATCATC Text4 th 3 rd 2 nd A01STOMATOLOGICAL PREPARATIONS21 A01ASTOMATOLOGICAL PREPARATIONS21 A01AACARIES PROPHYLACTIC AGENTS0 A01ABANTIINFECT. AND ANTISEPT. FOR LOCAL ORAL TREATMENT3 A01ACCORTICOSTEROIDS FOR LOCAL ORAL TREATMENT18 A01ADOTHER AGENTS FOR LOCAL ORAL TREATMENT0 A02DRUGS FOR ACID RELATED DISORDERS101 A02AANTACIDS60 A02AAMAGNESIUM COMPOUNDS21 A02ABALUMINIUM COMPOUNDS0 A02ACCALCIUM COMPOUNDS3 A02ADCOMB AND COMPL. OF ALUMIN., CALC. AND MAGNES. COMP6 A02AFANTACIDS WITH ANTIFLATULENTS9 A02AGANTACIDS WITH ANTISPASMODICS12 A02AHANTACIDS WITH SODIUM BICARBONATE0 A02AXANTACIDS, OTHER COMBINATIONS9

32. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 32 Analysis: AE vs ATC Profile ATC Total co-med profile (%) Reaction (%) A014.25 A01A4.25 A01AA01 A01AB0.61 A01AC3.63 A01AD00 A022025 A02A1213.6 A02AA4.23.8 A02AB00 A02AC0.60 ATC Total co-med profile (%) Reaction (%) A02AD1.20 A02AF1.82.4 A02AG2.45.4 A02AH00 A02AX1.82 A02B88.1 A02BA00 A02BB2.22.5 A02BC1.81.6 A02BD1.41 A02BX2.63 A02AG = ANTACIDS WITH ANTISPASMODICS

33. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 33 Presentation Overview ATC classifications – quick primer What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Strategies for using the WHO Drug Dictionary to enhance value

34. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 34 WHOdd: Value Enhancement Strategies Co-medication Investigations –Safety Profiles (risks / protections) –Efficacy (synergism / suppression) –Economics (drug sparing) DSMB / Surveillance / Vigilance Development Partnerships / Licenses Secondary Indications Residual Subject Recruitment

36. 2nd U.S. WHO Drug Dictionary User Group Meeting - Boston, MA - Apr 20, 2006Slide 36 ATC Codes: Strategies for Adding Value Instead of Confusion George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222

37. Boston, MA April 20, 2006 2 ND U.S. WHO Drug Dictionary User Group Meeting