Elke Sennewald Berlin, 28 September 2010

1. CDASH Tutorial Elke Sennewald Berlin, 28 September 2010

2. Learning Objectives • Learn more about CDASH V1.0 • Identify the domains addressed • Understand the content of domains • Get insight into design decisions • Understand CDASH team recommendations

3. General Remarks • CDASH: A set of ‘content standards’ • Initial scope: 16 core safety domains • The term “CRF” used throughout this document refers to both paper and electronic formats, unless otherwise specified • Not CRF layouts • “Fields” refers to fields that are commonly seen on the CRF. • “Variables” refers to what is seen in a clinical database. • “Study treatment” has been used in order to include all types of study designs and products. • Different data collection mechanisms can be used to control how data are collected, e.g., tick boxes, check boxes, radio buttons, drop-down lists, etc. These terms will be used interchangeably.

4. Contents Sections1 to 4 • Section 1: Orientation • purpose and goals of the CDASH project as well as • organization of CDASH Standard Version 1.0. • Section 2: CDASH Alignment with Other Standards • relationship of CDASH Standard Version 1.0 to the Study Data Tabulation Model Implementation Guide (SDTMIG), controlled terminology and other non-CDISC standards. • Section 3: Best Practice Recommendations • for creating data collection instruments • Frequently Asked Questions (FAQs) section • Section 4: Overview of CDASH Domain Tables • new ideas and approaches recommended by the CDASH Domain Teams • data collection fields noted not necessary to collect • core designations used throughout CDASH Standard Version 1.0 • explains the table headers used in the domain tables.

5. Contents Section5: CDASH Domain Tables • Approach taken regarding common identifier and timing variables • Metadata tables and/or recommendations for the following domains: - Adverse Events (AE) - Inclusion and Exclusion Criteria (IE) - Comments (CO) - Laboratory Test Results (LB) - Prior and Conc. Med. (CM) - Medical History (MH) - Demographics (DM) - Physical Examination (PE) - Disposition (DS) - Protocol Deviations (DV) - Drug Accountability (DA) - Subject Characteristics (SC) - ECG Test Results (EG) - Substance Use (SU) - Exposure (EX) - Vital Signs (VS)

6. Contents Sections 6 and 7 • Section 6: Change Control and the Process for Creating New CDASH Domains • describes the procedure for change control and maintenance of CDASH Standard Version 1.0 as well as the • procedure for creating new CDASH domains. • Section 7: Appendices • provides additional background material regarding the CDASH project as well as • references and supplemental information relevant to implementation of CDASH Standard Version 1.0

7. Core Designations for Basic Data Collection Fields • Highly Recommended: A data collection field that should be on the CRF (e.g., a regulatory requirement). • Recommended/Conditional: A data collection field that should be collected on the CRF for specific cases or to address TA requirements (may be recorded elsewhere in the CRF or from other data collection sources). • Optional: A data collection field that is available for use if needed.

8. CDASH Delivers ContentNOT CRF Layout Basic data to be collected.. How to implement the CRF data collection variable Describes the purpose of the data collection field SDTM-IG based variable name(CDASH)(Variable name shaded) CRF Completion Instructions for Sites CDASH Core Designations

9. Example Question or data being collected

10. Example EDC or database variable name Unshaded = SDTM name Shaded = CDASH specific

11. Example Purpose of the field May or may not mirror the text in the SDTMIG CRF text examples are presented in italics

12. Example Reference to the code list:{code list name}

13. Example Suggested instructions to give to the sites for completing the CRF These will vary depending upon the protocol

14. Example More information that explains the field, helps with implementation or clarifies intent Not only for sponsors but for anyone who is using the standard

15. Example • Degree of ‘required-ness’ • Highly recommended • Recommended / Conditional • Optional

16. Core Domains • Common Identifier Variables • Common Timing Variables • Adverse Events (AE) • Comments (CO) • Prior and Conc. Med. (CM) • Demographics (DM) • Disposition (DS) • Drug Accountability (DA) • ECG Test Results (EG) • Exposure (EX) • Inclusion and Exclusion Criteria (IE) • Laboratory Test Results (LB) • Medical History (MH) • Physical Examination (PE) • Protocol Deviations (DV) • Vital signs (VS) • Subject Characteristics (SC) • Substance Use (SU)

17. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation

18. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Disposition (DS) • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation The intent/purpose is to help with data cleaning and monitoring. It provides verification that all other fields on the CRF were deliberately left blank. Note: AEYN will not be included as part of the SDTMIG AE Domain for submission.

19. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Disposition (DS) • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation Sponsor-defined reference number. Perhaps pre-printed on the CRF as an explicit line identifier or defined in the sponsor’s operational database (derived)

20. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Disposition (DS) • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation The date of data collection in conjunction with End Date and the Ongoing CDASH fields would determine how the SDTMIG variable AEENRF will be populated.

21. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Disposition (DS) • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation If the details regarding a Serious AE need to be collected in the clinical database, then it is recommended that a separate Yes/No variable be defined for each Serious AE type, e.g.: Congenital Anomaly or Birth Defect Initial or Prolonged Hospitalization Life Threatening Death

22. Domain Review: AE • Where any AEs experienced? • Line # • Adverse Events Text • Start Date / Start Time • End Date / End Time • Ongoing • Disposition (DS) • Severity • Serious Event • Serious Event Type • Relationship to Study Treatment • Action Taken with Study Treatment • Other Action Taken • Outcome • Adverse Event that Caused Study Discontinuation CDISC controlled terminology should be used to indicate the action taken with the study treatment in response to the AE. Other Action: Free text field. Example: Treatment Unblinded, Primary Care Physician Notified.

23. Domain Review: Comment Just say no ICH E3 & E6: no requirement that indicate unsolicited comments should be included in a submission dataset. Recommendation: only the parameters captured in appropriate CRF data collection fields are considered clinical study data that is submitted to regulatory parties in datasets; all other comments are considered unsolicited comments.

24. Domain Review: Prior & Conc. Med. • Where any medications taken? • Line # • Medication Name • Active Ingredient(s) • Indication • AE Line # • MH Line # • Dose • Total Daily Dose • Unit • Dose Form • Frequency • Route • Start Date / Start Time • Mark if taken prior to study • End Date • Mark if Ongoing

25. Domain Review: Prior & Conc. Med. • Where any medications taken? • Line # • Medication Name • Active Ingredient(s) • Indication • AE Line # • MH Line # • Dose • Total Daily Dose • Unit • Dose Form • Frequency • Route • Start Date / Start Time • Mark if taken prior to study • End Date • Mark if Ongoing Intent is to establish a link between the adverse event / medical history condition and the medication taken for the adverse event. May result in unnecessary data cleaning work. Note: will not be included in the SDTMIG CM domain in submissions.

26. Domain Review: Prior & Conc. Med. • Where any medications taken? • Line # • Medication Name • Active Ingredient(s) • Indication • AE Line # • MH Line # • Dose • Total Daily Dose • Unit • Dose Form • Frequency • Route • Start Date / Start Time • Mark if taken prior to study • End Date • Mark if Ongoing

27. Domain Review: Prior & Conc. Med. • Where any medications taken? • Line # • Medication Name • Active Ingredient(s) • Indication • AE Line # • MH Line # • Dose • Total Daily Dose • Unit • Dose Form • Frequency • Route • Start Date / Start Time • Mark if taken prior to study • End Date • Mark if Ongoing

28. Domain Review: Prior & Conc. Med. • Where any medications taken? • Line # • Medication Name • Active Ingredient(s) • Indication • AE Line # • MH Line # • Dose • Total Daily Dose • Unit • Dose Form • Frequency • Route • Start Date / Start Time • Mark if taken prior to study • End Date • Mark if Ongoing

29. Domain Review: Demographics • Date of Birth (and time) • Year of Birth • Month of Birth • Day of Birth • Time of Birth • Age • Age Units • Today’s date • Sex • Ethnicity • Race

30. Domain Review: Demographics • Date of Birth (and time) • Year of Birth • Month of Birth • Day of Birth • Time of Birth • Age • Age Units • Today’s date • Sex • Ethnicity • Race Subjects in countries where privacy rules preclude the collection of personal data containing more detail than the year of birth might only provide date of birth data to the year level. Note: It is recommended that the CRF should be modified for sites in these counties to prevent the clinician from entering the data that would violate the privacy rule (i.e., gray out the month and day fields on paper or make them inaccessible for entry in an EDC system).

31. Domain Review: Disposition • Trial Epoch • Subject Status • Date of Completion or Discontinuation • Time of Completion or Discontinuation • Was treatment unblinded by the site • Will the subject continue? • Next trial epoch or new trial subject will be entering

32. Domain Review: Disposition . Subject Status data collection field should be presented on the CRF as a check box linked to an item from the approved controlled terminology list (DSDECOD). Only collect the date of completion or discontinuation on the disposition CRF module if the same information is not being collected on another CRF module. • Trial Epoch • Subject Status • Date of Completion or Discontinuation • Time of Completion or Discontinuation • Was treatment unblinded by the site • Will the subject continue? • Next trial epoch or new trial subject will be entering

33. Domain Review: Drug Accountability • Date Study Treatment Dispensed • Study Treatment Dispensed or Returned • Results of Study Treatment Dispensed or Returned • Units of Study Treatment Dispensed or Returned • Date Study Treatment Returned • Study Treatment Category • Study Treatment Subcategory

34. Domain Review: ECG • Scenario 1: Central reading • Scenario 2: Local reading • Scenario 3: Central reading with Clinical Significance Assessment and/or Overall Interpretation

35. Domain Review: ECG (Central Reading) • Indicate if ECG was performed • ECG Reference ID • Method of ECG • Position of the Subject • Date of ECG • Planned Time Point • Time of ECG

36. Domain Review: ECG (Local Reading) • Indicate if ECG was performed • Method of ECG • Position of the Subject • Date of ECG • Planned Time Point • Time of ECG • Test Name • Test Result • Units • Clinical Significance

37. Domain Review: ECGCentral processing but CRF includes site assessment of clinical significance and/or overall interpretation • Indicate if ECG was performed • ECG Reference ID • Method of ECG • Position of the Subject • Date of ECG • Planned Time Point • Time of ECG • Test Name • Test Result • Units • Clinical Significance

38. Domain Review: Exposure • Start Date / Start Time • End Date / End Time • Dose Amount • Dose Unit • Study Treatment Identification Number • Study Treatment Name • Dose Adjusted? • Reason for Dose Adjustment • Frequency • Route • Formulation • Duration of Optional Interruption (including units) • Body Location • Total Volume Administered • Total Volume Administered Unit • Flow Rate • Flow Rate Unit • Planned Time Point • Did subject complete full course of study med • Planned Dose • Planned Dose Units

39. Domain Review: Inclusion/Exclusion • Met All Eligibility Criteria? • Criterion Identifier * • Criterion • Inclusion or Exclusion? * This variable is only populated in SDTM for those criteria that are not met, and it will only be recorded on the CRF for those criteria that are not met.

40. Domain Review: Lab Test Results • Scenario 1: Central processing • Scenario 2: Local processing • Scenario 3: Central processing with Clinical Significance Assessment for abnormal values

41. Domain Review: LB – Central • Lab Status • Date of Collection • Time of Collection • Panel Name • Planned Time Point • Protocol-defined testing conditions met • Accession Number

42. Domain Review: LB – Local Processing • Lab Status • Date of Collection • Time of Collection • Panel Name • Planned Time Point • Protocol-defined testing conditions met • Sample Status • Test Name • Test Result • Units • Reference Range Lower Limit Numeric Value • Reference Range Upper Limit Numeric Value • Reference Range for Character Results in Standard Units • Abnormal Flag • Clinical Significance • Lab Name • Accession Number

43. Domain Review: LB – Central Processing & CRF with Site Assessment • Lab Status • Date of Collection • Time of Collection • Panel Name • Planned Time Point • Protocol-defined testing conditions met • Sample Status • Test Name • Test Result • Clinical Significance • Accession Number

44. Domain Review: Medical History • Has the subject experienced any past and / or concomitant diseases or past surgeries? • Pre-printed row number (e.g., 1, 2, 3) • Type of Medical History being collected • Category of Medical History being collected • Reported Term • Ongoing? • Disease controlled? • Pre-printed prompt for a specific condition/surgery (e.g., Does the subject have high blood pressure?) • Onset Date • End Date • Completion Date

45. Domain Review: Physical Examination • Traditional:Use PE form at baseline and post-baseline visits. Record abnormalities for each listed body system. • Intermediate:Use PE form at baseline but not post-baseline visits. Record any post-baseline abnormalities or conditions that worsened post baseline on the AE page. • Best Practice:Use PE CRF only to record whether PE was performed, and if so, the date of the examination. Record any baseline abnormalities on Medical History CRF and any post-baseline abnormalities or conditions that worsened post baseline on the AE page.

46. Domain Review: Physical ExaminationTraditional Approach • Was the Physical Examination Performed? • Date of Examination • Time of Examination • Sponsor-Defined Identifier • Body System Examined • Examination Result • Abnormal Findings • Clinical Significance • Evaluator

47. Domain Review: Physical ExaminationBest Practice Approach • Was the Physical Examination Performed? • Date of Examination • Time of Examination • Sponsor-Defined Identifier • Body System Examined • Examination Result • Abnormal Findings • Clinical Significance • Evaluator

48. Domain Review: Protocol Deviations Generally form is discouraged • Were there any protocol deviations? • Protocol Deviation Term (text) and or Protocol Deviation Coded Term • Start Date • Start Time • End Date • End Time • Sponsor-Defined Identifier

49. Domain Review: Subject Characteristics • Subject Characteristic Question • Subject Characteristic Answer/Result • Examples of Subject Characteristics Questions • Gestational Age at Birth • Childbearing Potential • Education • Sub-study Participation

50. Domain Review: Substance Use • Type of substance used? • Substance use? • Category of substance used • Amount • Unit • Frequency • Start Date • End Date • Duration • Unit for Duration