The document provides an overview of clinical data management (CDM) responsibilities and processes. It discusses the CDM mission of ensuring high quality, consistent, accurate and valid data collection. Key CDM responsibilities include protocol review, database design, data entry, verification, coding, query resolution and ensuring data quality. The CDM process involves multiple stages from database design to data transformation and locking. Medical coding systems like MedDRA are used to standardize adverse event and medical condition terms. Case report forms and logging procedures are also outlined.

1. Clinical Data Management

2. Overview Mission Responsibility Process Discrepancies Management Medical Coding and CTCAE CRF Filling Instructions Reminders

3. Mission of CDM Consistency Accuracy Validity Archiving High Quality Data is needed to perform statistical analysis CRF Entry Cleaning DM process Stat. Analysis Challenge Error rate 0%

4. Responsibilities of CDM Responsibilities Protocol Review CRF Design / Review Clinical DB Application Development Computer System Validation CRF tracking Data Entry / Verification Transformation to SAS data Medical Coding : AE, Medication, Medical condition

5. Responsibilities of CDM Responsibilities Audit trails - Transparency DB QA DB Security and Archiving Regular DB backup

6. CDM Process Database design Protocol Review & CRF Design/Review Development Stage Data validation program Data entry application Pre-entry review Double data entry Data Processing Stage Unmatched check Logical check Discrepancies mgt. Closing Stage Medical coding DB lock Validation of SAS data set Transformation to SAS data CRFs management

7. CDM Flowchart Data Entry Approved Blank CRF and Protocol Quality Control of Database and Database go live Batch Validation Medical Coding QA/QC of data CRF Annotation, Edit Specification Document Preparation Database Lock & Statistical report generation Database Design Setup Test Data Entry CRF’s completed at site. CRF Receipt and Tracking in Data Center Maintaining Missing & pending pages log Discrepancy Mgt. Pre-Data Entry Review

8. Discrepancy Management Why discrepancy Types of discrepancy Methods to resolve discrepancy

9. Why discrepancy? Data complete? Data consistent? Discrepancy Data correct? Data logical? Data legible?

10. Discrepancy Type Missing Illegible Range Date Logical

11. Discrepancy Resolve Methods Self Evident- discrepancies which are resolved by Data Coordinator. Ex: Details of concomitant medication are given but Yes/No field are not marked. CRA/Medical Monitor- discrepancies which are resolved by CRA or Medical Monitor.

12. Discrepancy Resolve Methods Query- Discrepancies which are resolved by Investigator. Ex: Start date of Adverse event not supply. Query has been send to investigator by Data Clarification Form (DCF)

13. Medical Coding Why Medical coding Different sites, Different culture, different time-zones, different physicians and various other factors leads to variation in the data entered in particular fields which cannot be effectively controlled. This varying fields require coding. Methods Auto-Coding Manually Combination of Both

14. MedDRA Med = Medical D = Dictionary for R = Regulatory A = Activities FDA and EU mandated for AE data coding

15. Objectives for MedDRA Development An international multi-lingual terminology Standardized communication between industry and regulators Support of electronic submissions Application through all phases of the development cycle

16. Objectives for MedDRA Development Classification for a wide range of clinical information Support for multiple medical product areas A terminology that saves time, resources, and money

17. MedDRA Is Designed For Coding: Signs (i.e. Redness) Symptoms (i.e. Dizzy) Diseases (i.e. AIDS) Diagnoses (i.e. Hepatic failure) Therapeutic indications (i.e. Congestive heart failure) Names and qualitative results of investigations (i.e. Increased SGOT) Surgical and medical procedures (i.e. Cholecystectomy) Medical, social, and family history (i.e. Alcoholism)

18. Not Code able Term A single event description contains multiple conditions. Ex: Leg red, swollen, and painful An event term contains a diagnosis and a symptom. Ex: Fever and Cold The event term can be interpreted more than one way. EX: Unable to focus The event term does not make sense. Ex: Left leg The event term is foreign Event term contains a question mark Improvement of a condition is implied, but the term does not state it is a benefit. Ex: Sleep improved

19. CTCAE Common Terminology Criteria for Adverse Events (CTCAE) They consist of the name of the area of interest and a grading which refer to the severity of the reaction: grade 1 (mild AE) to grade 5 (fatal) The actual medical condition may differ depending on the severity criteria More than one medical condition may be covered by the same CTCAE grade

20. CTCAE Codes for Abnormal Lab Results QTc >=501 or >60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Grade 4 Death QTc >=501 msec on at least two separate EKGs QTc 481 - 500 msec QTc 450 - 470 msec Prolonged QTc interval Grade 5 Grade 3 Grade 2 Grade 1 CTCAE v3.0 Term

21. CRF Filling Instructions Authorized individuals Block Letters and avoid over writing and writing out side the provided space Strike off all the blank pages with initial and date. Do not write in shaded area Sign and date CRF pages ,where requested

22. CRF Filling Instructions Subject Initials: Must be the same throughout the study. If the subject does not have a middle initial, ‘-’ should be used instead of ‘X’. e.g. Brian Jones should be recorded as: |B|-|J|

23. CRF Filling Instructions Errors: Error will be cross out with single horizontal line and write correction next to it. Initial and date the correction. e.g. |1|5| / |0|4| / |2|0|0|4| 2005 CJW 15/04/2005 Wrong practice which is not acceptable |1|5| / |0|4| / |2|0|0|4| Do not use correction fluid, pencil or red ink. Make Sure that the error, although crossed out, remains legible

24. CRF Filling Instructions Dates: Record the actual date of the visit. The order of entry in the date format is Day, Month, Year (07/01/2007). Day, month and year are to be expressed numerically. Correct entry for complete date: |0|7| / |0|1| / |2|0|0|7| DD MM Y Y Y Y In the absence of a precise date for events and therapies that precede the subject’s inclusion into the study, incomplete dates should be recorded as follows: Correct entry for incomplete date: |N|K| / |N|K| / |2|0|0|2| (NK: Not Known)

25. Reminders Adverse Event Log: Parasitological Assessment Log: Body Temperature log: Vital Signs Log: Prior and concomitant medication Log: PK Sampling Log: Physical Examination Log: Assessment of clinical Signs and Symptoms Log: 12 Lead ECG Log:

26. Reminders If ECG is CS or QTc is > 500 msec, Should be reported as AE. Any increase in grading of signs and Symptoms from previous day should be reported as AE. Please exclude the Subject, if axillary temperature is < 37.5 ºC or oral temperature is < 38° C.

27. Reminders In Clinical Signs and Symptoms, Please enter only One CTCAE Grade. Clinically significant (CS) abnormal laboratory tests must be followed up as described in the protocol. Did the subject develop any sign or symptom of severe malaria? If Yes, the subject withdrawn from trial. If Pregnancy test is “positive” complete ‘Notification of Pregnancy’ report

28. Reminders Exclude the subject if QTc interval >450msec. Use Fridericia’s formula to calculate QTc Please Exclude the Subject if weight is less than 35 kg.