WHO Drug Dictionary North American User Group Meeting Chicago (Deerfield), IL October 1, 2009

ATC Coding Revisited George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222 WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Presentation Overview WHO Drug Dictionary – quick review What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Change Management WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Drug Record Number DRecNum allows for grouping of all “synonyms” for the drug, including various companies, brands, generics, countries, preparations, etc. Example: Advil (DRecNum=1092) Ibuprofen Doloflam Advil Haltran Advil Liqui-gels Ibubufen Actiprofen Ibuspray Zofen Motrin Nuprin Boots fever and pain reliever At the most basic level, the Drug Record Number captures the essential active ingredient. This allows for consistent terminology across various trade names, generic names, country-specific differences, strengths, routes, etc. For most clinical trial purposes, this is the most commonly reference field for analyses, presentations. It is the most simple to capture and (using the dictionary hierarchy) may be all that is necessary. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Drug Code: DRecNum + Seq1 + Seq2 Seq1: Salt or Ester (Herbal: Plant part) Seq2: Trade Name or Synonym (generics) DRecNum Seq1 Seq2 Name 000005 01 001 Ampicillin 002 Ampicin 003 Binotal 02 Ampicillin Sodium Polycillin-n 03 Ampicillin Trihydrate The Drug Code is a concatenation of the Drug Record Number plus the sequence fields SEQ1 and SEQ2. SEQ1 distinguishes between the salt or ester presentations of the active ingredient. In the Herbal ATC, SEQ1 differentiates the parts of the plant from which the herb is extracted. (ADVANCE) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Drug Code: DRecNum + Seq1 + Seq2 Seq1: Salt or Ester Seq2: Trade Name or Synonym (generics) DRecNum Seq1 Seq2 Name 000005 01 001 Ampicillin 002 Ampicin 003 Binotal 02 Ampicillin Sodium Polycillin-n 03 Ampicillin Trihydrate SEQ2 segregates the various trade names and generic synonyms of the product. In the Herbal ATC SEQ2 represents the accepted scientific name of the plant. Note that entries where SEQ1=01 and SEQ2=001 are generally considered the “preferred name” of the product and may be used in listings and/or tables. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Medicinal Product ID The MP ID: version “C” of the WHO dd. It is unique to each entry in the dictionary. MP ID DRecNum Seq1 Seq2 Name 000143 000005 01 001 Ampicillin 083950 002 Ampicin 083951 003 Binotal 000225 02 Ampicillin Sodium 084022 084023 Polycillin-n 000251 03 Ampicillin Trihydrate WHO drug dictionary version C contains a new identifier called the medicinal product ID. This field has no intrinsic meaning, but represents a unique identifier for each entry in the dictionary. Version C also maps the MP-ID to the Drug Code field(s) contained in version B-2. However, keep in mind that these mappings may change over time across dictionary updates, so version control strategies may need to be anticipated. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

ATC classification Anatomical Therapeutic (& Pharmacological) Chemical The organ or system on which a drug acts Therapeutic (& Pharmacological) Indication for typical use(s) Pharmacological Form Chemical Compound structure and properties The ATC system for classifying drugs is widely used in European countries. ATC classifications are updated and published once a year by the World Health Organization Collaborating Centre for Drug Statistics Methodology (http://www.whocc.no/atcddd ). The ATC system is now becoming more commonly used in Canada, and is currently managed by Health Canada (http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_drugs_dpd_e.html). There are 3 components: Anatomical, Therapeutic, Chemical groupings. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

ATC: 5 Class Levels ATC Level ATC Code ATC Text 1 Anatomical Main Group A Alimentary tract and metabolism 2 Therapeutic Subgroup A10 Drugs used in diabetes 3 Pharmacological Subgroup A10B Oral blood glucose lowering drugs 4 Chemical Subgroup A10B A Biguanides 5 Chemical Substance A10B A02 Metformin (DRecNo: 827) There are 5 levels of the ATC hierarchy WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

*New Herbal ATC: 5 Class Levels ATC Level ATC Code ATC Text 1 Anatomical Main Group A Alimentary tract and metabolism 2 Therapeutic Subgroup A06 Herbal laxatives 3 Pharmacological Subgroup A06A Laxatives 4 Chemical Subgroup A06A B Contact laxatives 5 Chemical Substance A06A B5001 Aloe ferox extract (DRecNo: 16518) UMC introduced a new herbal ATC classification system (H-ATC) to facilitate analyses of the increasing presence of supplemental and alternative therapies in domestic and international clinical trials. (Note: Seq1 = Part of the plant) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Level 1 - Anatomical Groups (14) ALIMENTARY TRACT AND METABOLISM B BLOOD AND BLOOD FORMING ORGANS C CARDIOVASCULAR SYSTEM D DERMATOLOGICALS G GENITO URINARY SYSTEM AND SEX HORMONES H SYSTEMIC HORMONAL PREPARATIONS, EXCL. J ANTIINFECTIVES FOR SYSTEMIC USE L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS M MUSCULO-SKELETAL SYSTEM N NERVOUS SYSTEM P ANTIPARASITIC PRODUCTS,INSECTICIDES AND REPELLENTS R RESPIRATORY SYSTEM S SENSORY ORGANS V VARIOUS When reducing medication data for presentations (listings, tables, analyses) you can group by different hierarchical levels. The highest level (Level 1 – Anatomical Groups) has 14 groups. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Level 2 – Therapeutic Groups ATC2 Selected 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 These are select examples of some ATC level 2 “Therapeutic” Groups. This is a common ATC level for reduction in data presentations. A deeper level may be necessary for analyses and investigations. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Level 3 - Pharmacological Groups S01A ANTIINFECTIVES* S01C ANTIINFLAMMATORY AGENTS & ANTIINFECTIVES IN COMB* S02A ANTIINFECTIVES** ATC3 Selected Examples A02A ANTACIDS A06A LAXATIVES A10A INSULINS AND ANALOGUES N05A ANTIPSYCHOTICS N06A ANTIDEPRESSANTS Some companies prefer to focus on a lower level of the hierarchy – either for presentations, or for selecting classes of drugs of interest, perhaps to identify prohibited medications as protocol violations, or for special sub-group analyses to investigate the interactions between medications and the study drug. For example – to identify all subjects who were administered an opiod (N02A) like morphine in a post-operative setting. Here are some examples from Level 3 – the Pharmacological Groups. (ADVANCE) Caution should be taken to be sure all relevant ATC classifications are selected. Some may be represented in solo as well as combinations, or across different therapeutic (Level 2) groups. For example, AntiInfectives are in S01 (OPHTHALMOLOGICALS) as well as S02 (OTOLOGICALS), and in combination with AntiInflammatory Agents. * S01 = OPHTHALMOLOGICALS (eye) ** S02 = OTOLOGICALS (ear) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

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, formulations, etc. The drug code and MP ID are mapped to all ATCs in the dictionary hierarchy. ATC classifications can change over time with dictionary updates. The most useful feature of the dictionary are the ATC codes – though users often have the most questions about how to capture and implement this hierarchy. WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Presentation Overview WHO Drug Dictionary – quick review What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Change Management WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Do we see clearly what is really needed? The building, completed in 2006, is part of Melbourne's Digital Harbour Port 1010 and houses the Australian Customs Service. The horizontal lines of these floors are actually perfectly parallel.  But so much other information has clouded our perception, so that we fail to see clearly.  Sometimes our practices can be similar - so many competing demands and additional assumptions about what might be required obscure our ability to discern what is really needed... Melbourne's Digital Harbour Port 1010, Australian Customs Service (2006)

Clinical Trial Databases What should we capture in the CTDB? Options: Verbatim Text + CRF fields Drug Record Number Drug Code (DRecNum + Seq1 + Seq2) Medicinal Product ID Generic (Preferred) Name / Decode ATC code ??? There are multiple possibilities for what dictionary fields would be coded directly into the Clinical Trial Database, and which would rely upon the hierarchy/mapping intrinsic to the WHOdd. These options include: (ADVANCE through each) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

CDISC: SDTM - SDTM 3.1 Implementation Guide, Section 4.1.3.5 …fill CMDECOD with the drug’s generic name and fill 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. … No other intermediate levels or relationships should be stored in the dataset. By knowing the dictionary and version used, the reviewer will be able to obtain intermediate levels ... a drug’s ATC codes (as in WHO Drug). Clinical Data Interchange Standards Consortium Submission Data Tabulation Model Reference: Julie Evans, CDISC Submission Data Standards (SDS) Team WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

CDISC: CDASH CDASH (Clinical Data Acquisition Standards Harmonization) Section 5.5 CMTRT Medication Name CMINDC Indication for taking this medication CMAENO Identifier for the Adverse Event that is the indication CMMHNO Identifier for the Medical History that is the indication WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Difficulties using ATC for consolidation CRF CM WHO Drug (version) DrugCode CMDECOD CMCLAS ATC #1? ATC #2? ATC #3? WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Instead: WHOdrug + MedDRA CRF CM WHO Drug (version) DrugCode CMDECOD CMCLAS CRF MH CMMHNO Meaningful Grouping MedDRA (version) SOC CRF AE PT CMAENO Kudos to… Standardized Drug Queries (SDQs) working group. This group is an initiative by the World Health Organization (WHO) on the development of standard drug queries requested by Pharma/Biotech industries. LLT Medications taken for… WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Presentation Overview WHO Drug Dictionary – quick review What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Change Management WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Data Presentations: Listings Verbatim reported name “Preferred” name Seq1 = 01 Seq2 = 001 ATC Level(s) ? CRF fields (dose, route, dates, etc) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Listing 16.2.4.6: Concomitant Medications During Treatment Period  Subj Tx   ----------------------- Medication Name -------------------- Start Stop For ID cohort Age Sex Reported Preferred* date AE 2103 5 mg 37 M XYLOCAIN LIDOCAINE 07 JUL 2004 NO ULTRACAIN ARTICAINE RIZATRIPTAN 13 JUL 2004 YES 2104 35 CITALOPRAM 20MG CITALOPRAM 01 JAN 2004 ONGOING BISOPROLOL 5MG O/D BISOPROLOL 01 JUN 2004 28 JUL 2004 TYLENOL EXTRA STR PARACETAMOL 06 JUL 2004 ACETAMINOPHEN 12 JUL 2004 PARACETAMOL 750 MG 19 JUL 2004 PARACETAMOL 1G 14 JUL 2004 2107 46 VALERON TILIDINE 01 MAR 2002 VALORON 150/12MG NEURONTIN GABAPENTIN METOCLOPRAMID METOCLOPRAMIDE NEURONTIN 600MG (continues…) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Tables – if grouping by ATC… Choose ATC level to group by: ATC1: Anatomical ATC2: Therapeutic Other WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Tables – if grouping by ATC… Choose an ATC strategy Select a “primary ATC” based on the indication for each individual report Select a “primary ATC” once per drug within the study or program Select a “primary ATC” once per drug within the company “Let the dictionary do the walking…” WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Safety Evaluable Population Table 14.1.4.4: Concomitant Medications During Treatment Period by Treatment Cohort Safety Evaluable Population   5 mg 10 mg 20 mg All Drug Class (ATC) (N = 8) (N = 24) Preferred Name n (%) SUBJECTS WHO TOOK CONCOMITANT MEDS 4 (50.0) 5 (62.5) 13 (54.2) ANALGESICS 2 (25.0) 1 (12.5) 7 (29.2) ANTIGRIPPINE (0.0) (4.2) DOLORIN GABAPENTIN PARACETAMOL (16.7) RIZATRIPTAN SUMATRIPTAN TILIDINE ANESTHETICS ARTICAINE LIDOCAINE (continues…) WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Challenges when using ATC for grouping 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 Discuss term: “signal detection”. Comes from analysis techniques developed during radio waves – isolating meaningful transmissions from background noise/static. We want to reflect all meaningful actions of a medication, not just the action that the subject intended to employ. The medication will act in the body based on presence (chemistry), not intention. Acetylsalicylic Acid (aspirin) 27 B01AC: Platelet Aggregation: cardiovascular/thrombosis prophylaxis; Especially in hemodialysis patients [10049908] Or precaution for knee replacement surgery N02BA: Analgesics and Antipyretics Gabapentin (Neurontin) 10030 N03AX: AntiEpileptic (post traumatic epilepsy) [10036312] N02BG: Other Analgesics and Antipyretics: Post-Laminectomy Syndrome (“nerve entrapment”/Sciatica) [MedDRA 10057239] Off-label: Diabetic Peripheral Polyneuropathy [10012683] WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Presentation Overview WHO Drug Dictionary – quick review What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Change Management Participation Groups ?: Companies: Large Pharma; Mid/Small Pharma; Biotech; CRO; Consultant; Sites; Other Responsibilities: Clinical; Data Mgt; Coding Group; Safety / Pharmacovigilance; Statistics; Medical Writing; Regulatory; Executive; Other Systems: Oracle/Clinical; ClinTrials; EDC (PhaseForward; E-Trials; DataTrack); Other Dictionary, Subscription, Version, Format WHOdd, WHOdd-E, Herbal? Annual; Semi-Annual; Quarterly March; June; Sept; Dec B-1; B-2; C WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Analysis Techniques Safety Signals / Pharmacovigilance Prohibited Meds “Co-medication Profiles” AE profiles within ATC Secondary Indications Residual Subject Recruitment Prohibited Meds Eligibility Criteria Efficacy Suppression Efficacy Synergism Drug Sparing Comparative Effectiveness WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Presentation Overview WHO Drug Dictionary – quick review What should we capture in a Clinical Trial Database? Data Reduction / Presentation Techniques Analysis Techniques Change Management WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

Change Management Highlighting the problem / “Feel the Pain” Budget, Staffing, Timelines Identify stakeholders CDM, Statistics, Safety, Regulatory, Licensing Early preparation / meetings Anticipate resistance / Bring solutions Pilot (concurrent study) Plan for implementation Feedback Loop  ROI WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

ATC Coding Revisited George B. Stoms Vital Systems, Inc. George.Stoms@VTLsys.com (847) 458-2900 x222 WHO Drug Dictionary User Group Meeting - Chicago/Deerfield, IL - Oct 1, 2009

WHO Drug Dictionary North American User Group Meeting Chicago (Deerfield), IL October 1, 2009

Do we see clearly what is really needed? The building, completed in 2006, is part of Melbourne's Digital Harbour Port 1010 and houses the Australian Customs Service. The horizontal lines of these floors are actually perfectly parallel.  But so much other information has clouded our perception, so that we fail to see clearly.  Sometimes our practices can be similar - so many competing demands and additional assumptions about what might be required obscure our ability to discern what is really needed... Melbourne's Digital Harbour Port 1010, Australian Customs Service (2006)

Caution: Don’t lose sight of the purpose!