Investigator’s Meeting Boehringer Ingelheim 1230.14 POLO-AML-2 RDC Onsite and eCRF Toronto 23 February 2013 Investigator’s Meeting confidential information 23 February 2013

Contents of the Presentation General Information about RDC Onsite Data Entry Discrepancy Management eCRFs: Changes in CTCAE Grade Coding of AE Eligibility for Further Course Trial Termination confidential information 23 February 2013

confidential information 1. General Information about RDC Onsite confidential information 23 February 2013

confidential information What is RDC? Remote Data Capture is a web-based application that enables the user to enter the clinical data into the electronic Case Report Form (eCRF). Data is entered directly in the clinical database of Boehringer Ingelheim. Several user roles available: Investigator role　(Only PI has page approval privilege) Site role CRA role Data Manager role confidential information 23 February 2013

RDC Data Flow day 1 day 2 day 3 Data entered Query resolution Example: Data should be entered within 2 days of the patient visit Resolve queries promptly Investigator approves entered data on an ongoing basis, not just  “at the end of the trial” (visit by visit) Data changes need to be re-approved by investigator Electronic signature for approval of eCRFs is implemented by use of username and password (Keep your password private!) day 1 day 2 day 3 Data entered Query resolution query Example: confidential information 23 February 2013

What Does Approval Mean within RDC? Approval within RDC documents that the investigator agrees that the data as given represent the patients‘ conditions in the course of the trial. Approval gives the investigator the control over the contents of the data. BI will lock the database based on the approved data. For this reason, all data that has been entered including blank pages, MUST be approved at the end of the trial. Investigator can approve per visit, and on page basis each time a change was made. confidential information 23 February 2013

Login name and job function Logout Tabs RDC Onsite Homepage Login name and job function Logout Tabs Patient search Study and site drop-down lists Instruction for CRF completion links Patient icon confidential information 23 February 2013

confidential information eCRF Page Structure Patient number CRF header Blank page status box CRF body Patient status Casebook Page number Removed “visit date” feild CRF footer confidential information 23 February 2013

confidential information 2. Data Entry confidential information 23 February 2013

confidential information General Rules Use English only Do not use special characters like ®, µ, β blocker Do not enter any information other than expected in the data fields (e.g. “Not done” (ND) should NEVER be written in any entry fields) Issue: If an examination was not performed. Solution: Please leave the field blank. If a query appears, please enter "ND" in the comment field of the query and forward this response back to Data Management. confidential information 23 February 2013

confidential information Blank Pages Any individual pages that will not be completed should be ticked as blank You should also log a complete visit as blank if it was skipped and will not be done at all, but patient continues in the trial (i.e. optional V2 & V4 from Cycle 2) If a patient discontinues the trial, pages for visits that will not be done should NOT be logged as blank Example: 20 cycles are set up in the database. If a patient stops treatment at the end of Cycle 5, visits of Cycles 6 to 20 should remain as not entered. Please note that End of treatment visit should be completed. confidential information 23 February 2013

confidential information 3. Discrepancy Management confidential information 23 February 2013

confidential information Discrepancies Discrepancies are inconsistencies in the information that has been entered in RDC. This lead to Queries, which are created : immediately, after a CRF has been saved or after batch validation session (normally automated overnight process). In these cases, RDC detects discrepancies automatically based on pre-defined screening rules. In other cases, CRAs or TDMs add discrepancies manually. confidential information 23 February 2013

The person/ system who creates the query Discrepancies The person/ system who creates the query is the only one able to close it. confidential information 23 February 2013

confidential information 4. eCRFs: Coding of AE Changes in CTCAE Grade Eligibility for Further Course Trial Termination confidential information 23 February 2013

Only one AE is recorded per eCRF. Adverse Events Form Only one AE is recorded per eCRF. confidential information 23 February 2013

Cross check AE end date with AE outcome. AE Outcome and End Date Cross check AE end date with AE outcome. If the outcome of the AE is „Recovered“ or „Fatal“, the end date should be present confidential information 23 February 2013

Serious Adverse Events Entries on the SAE form need to be consistent with entries on the eCRF Please check when entering or updating SAE data Follow SAE reporting procedures For TDM, this is for <RAPID trial> Select all criteria that apply confidential information 23 February 2013

confidential information Coding of AE Record each medical term on a separate AE page in the CRF Give the diagnosis if known If a diagnosis has not been established, report symptoms (one per AE page) that describe the untoward medical occurrences. The diagnosis can be added later. In this case, please replace the symptom with the diagnosis and delete all remaining symptoms related. Signs and symptoms, which are part of the normal pattern of the diagnosis, should not be recorded as adverse events. In such a case, the diagnosis only is sufficient. However, symptoms, which are not part of the normal pattern of the diagnosis, should be recorded as appropriate. 　 =>Cytopenias that are symptoms of AML should not be recorded as AE confidential information 23 February 2013

Changes in CTCAE grade of events Each time the CTCAE grade of an adverse event or a baseline condition changes, i.e. worsens or improves, it should be entered in a new AE page in the eCRF End date of the original entry = Start date of the new entry = date of the CTCAE grade change Outcome of the original entry = 2 (Not yet recovered) Example: The CTCAE grade changes several times, outcome is always assessed as ‘Not yet recovered’, only in the last entry – when “Febrile Neutropenia” is really resolved – outcome should be assessed with ‘recovered’. AE Name Start Date End Date CTCAE Outcome Febrile Neutropenia 23Nov2012 24Nov2012 3 Not yet recovered 25Nov2012 4 26Nov2012 recovered confidential information 20 23 February 2013

Laboratory Tests – Data Entry Not all abnormal laboratory values are adverse events. An abnormal laboratory value is recorded as an adverse event if it is judged clinically relevant by the investigator And it is not a symptom of an already recorded AE When abnormal laboratory value is recorded as an adverse event, please consider the AE name with following example: Not enough information as AE name for it to be coded　(e.g.) Information , sufficient for coding　(e.g.) “Glucose” “Hyperglycemia” OR “High Glucose” confidential information 23 February 2013

Laboratory Reference Ranges Laboratory reference ranges and units for all parameters will be entered ONCE directly into RDC: Thus it is highly recommended to use same local laboratory (primary) for all patients Secondary (non-primary) lab reference ranges are captured on a separate eCRFs and all data fields MUST be completed confidential information 23 February 2013

Eligibility for Further Course Based on protocol, a patient is eligible to continue treatment, if the following criteria are met: Absence of disease progression or relapse. Recovery from any drug-related non-haematological AE to CTCAE grade less than 2, or baseline, whichever is higher. The patient is eligible to continue treatment based on investigator’s medical assessment (e.g. Blood count, bone marrow smear, physical examination etc.) confidential information 23 February 2013

Eligibility for Further Course – eCRF Completion If patient is NOT eligible to immediately starting the next cycle: Complete all eCRF pages at Visit 5 Repeat Visit 5 until the patient meets all of the criteria to continue to the next course (Additional visits recommended on weekly basis at investigator’s discretion ) Data for the initial Visit 5 Data for the second Visit 5 confidential information 23 February 2013

Termination of Trial Medication The date of last drug administration should be known and entered for each patient When the patient discontinued study medication , select the primary reason for discontinuation. Indicate if the medication code has been broken. If yes, please enter the date. confidential information 23 February 2013

confidential information Questions confidential information 23 February 2013 Confidential © Almac Group 2012