SAE Reconciliation process Barbara Inversini Data Manager Biostatistics, Data Management and Clinical Systems Department Rottapharm - Monza Definition of SAEs Reconciliation 1. Serious adverse events data Reconciliation is the comparison of key safety data between two database (a clinical database defined as a closed system and a safety database defined as an open system) 2. A clinical database is defined as closed since it can receive data only for a very short period of time that is the lasting of the trial. 3. A safety database is defined as an open system since it continues to receive new SAEs or updates of pre-exiting SAEs concerning any clinical trials even when they are locked. p. 2 1
Definition of SAEs Reconciliation SAEs reconciliation is done to assure consistency 1. between the two databases (clinical db and safety db) for the numerousity of SAEs recorded for the same clinical trial 2. among the key safety data defined in the DMP*/SOP** SAEs Reconciliation occurs several times during the whole study period and it depends on 1. the frequency of data receipt and 2. the management of safety updates from the Pharmacovigilance to the regulatory agencies * DMP = data management plan ** SOP = standard operating procedure p. 3 SAEs Reconciliation management SAEs Reconciliation is ruled by an appropriate SOP that describes the general workflow and that 1. lists all the responsibilities 2. all the tasks to be performed SAEs Reconciliation is detailed in the DMP where in the proper section what follows will be listed: 1. key safety data to be reconciled, 2. the differences that may be acceptable in the key safety data, 3. the cut-off* time *Cut-off time is defined as the last point after which no new SAEs or update will be added or done even if the Safety database continues to be updated. p. 4 2
Key safety data Key safety data to be reconciled could be but not limited to: 1. Subject ID and randomisation number if applicable 2. SAE verbatim 3. LLT term 4. PT term 5. SOC 6. Onset date 7. Stop date 8. Outcome 9. Severity 10.Seriousness criteria 11.Causal relationship with study drug/ medical device 12.Action taken with study drug/medical device p. 5 Key safety data When comparing key safety data it is necessary that 1. key safety data fields are in the same (both in manual and electronic comparison) 2. they are in the same format (electronic comparison) 3. they share the same values codelist for the same field when applicable (both in manual and electronic comparison) p. 6 3
Key safety data Some other additional data can be taken into consideration during the process to complete the case and if they are considered relevant could be object of reconciliation and as such described in the DMP. 1. From the demographic panel data such as: age, date of birth, weight, height, gender and race can be selected 2. From physical examination and medical/surgical history sections such as all the abnormalities can be selected p. 7 Key safety data 3. From the concomitant medication sections all information concerning therapies such as: patient ID, medication, indication, start date and stop date or if ongoing can be selected 4. From the study drug administration panel data such as: study drug administration dates, batch number if applicable can be selected p. 8 4
Acceptable differences between key safety data SAEs Reconciliation detailed in the DMP foresees also a short list of all differences that both DM Dept and Pharmacovigilance Dept judge not to decrease consistency between data such as 1. a slight difference in the verbatim not affecting the medical coding 2. structural difference between the two databases that obliges to record data in a different manner p. 9 Acceptable differences between key safety data Examples: 1. clinical database verbatim reported EAR PAIN, safety database verbatim reported EARACHE if the two are the same also when considering the medical coding of the terms (LLT, PT,SOC) the two stay different. 2. clinical database field Worsening of pre-study condition?, safety database has no such a field so this information is captured by adding a new record such as CONDITION AGGRAVETED p. 10 5
Cut-off point Often SAEs continues to be reported after a clinical trial has ended, therefore it is important to define a cut-off point after which no new SAEs or updates will be added to the clinical database so that the process will be considered as closed for the clinical database even if the safety database continue to receive new SAEs or updates concerning that specific clinical trial. p. 11 Procedure Before starting with SAEs Reconciliation the DM Dept. must ensure that all data to be included in the process have been entered, coded (if needed), and validated with no data clarification form pending, data must be final for that/those patient(s) at the time of reconciliation* * (note that if the process is at its first run some SAEs will be not in the clinical database since those pages have not been received yet) p. 12 6
Procedure The procedure is organized as it follows: Retrieving data from the two database Check between information Actions to be taken Process Tracking p. 13 Retrieving data from the two database First step is to retrieve data from the database and to create two hardcopy listings/two electronic listings and the two source will be reconciled through direct comparison by adding each difference or with a pen or electronically. This step can be done by DM Dept when receiving data from Pharmacovigilance Dept or viceversa. It is not important the direction but the operation in itself. p. 14 7
Check between information Checks to be done by DM before starting comparing the key safety data: 1. Verify that number of patients that experienced SAEs in both databases is the same at the time of reconciliation* 2. Verify that all SAEs recorded in the safety database are recorded in the clinical database as well and viceversa at the time of reconciliation* 3. Verify all the key safety data defined as mandatory in the DMP * (note that if the process is at its first run some SAEs will be not in the clinical database since those pages have not been received yet) p. 15 Actions to be taken 1. SAEs that are in the clinical database but not in the Safety. Those can be potentially unreported events so copies of the appropriate pages of CRF must be forwarded to Pharmacovigilance 2. SAEs that are in the safety database but not in the clinical database. If the visit has been monitored, collected and processed the site can be queried and a data clarification form is issued since the DM has no right to add a new SAE without any data clarification form signed by the investigator. No SAEs can be added to the clinical database without the data for that visit having been monitored against source documents. p. 16 8
Action taken on Key Safety data discrepancies acceptable Differences in the key safety data: depending on the nature of discrepancies the DM can decide to issue a data clarification form to the site or to accept those discrepancies since defined as acceptable in the DMP and so there is no need to query the investigator. p. 17 Action taken on Key Safety data discrepancies unacceptable The review of all the unacceptable discrepancies is made by comparing the information reported in the clinical database and SAE Form that is attached to the CRF. Before issuing a data clarification form an agreement with the Pharmacovigilance Dept is taken since the nature of the data clarification form can change a SAE from no-expedited to expedited and because it is necessary a homogenous vision of the case to limit the number of data clarification form that can be distracting for the investigator and time consuming for the DM p. 18 9
Actions to be taken The data clarification form are signed by the investigator will be used to update either or both databases by their respective staff p. 19 Process Tracking All actions taken by one of the two Dept to solve the corresponding discrepancies must be tracked in a form such as the sample SAE Data Reconciliation Form to be signed for approval by the responsibles for the task SAE Reconciliation as detailed in the pertaining SOP p. 20 10
Last task Prior to data lock the DM must verify that all data clarification done for SAEs Reconciliation have been received and entered. A quality control should take place to ensure that 1. the process has been done accurately and consistently, 2. reconciliation has been done for all SAEs 3. All expected SAE information has been received At the end a written communication should be made when the entire process has been successfully completed to point out that the Safety database must be held open for updates after study closure. p. 21 Electronic SAE Reconciliation The process described just right now is a process based on a manual activity of reconciliation but SAEs reconciliation can also be done automatically. A programmatic reconciliation can take place (as in the manual reconciliation) when 1. key safety data fields are in the same, 2. if they are in the same format 3. if the share the same values codelist for the same field when applicable. p. 22 11
Electronic SAE Reconciliation A program that creates a output table of all discrepancies between the two databases is an effective mean to perform this activity that frequently is time consuming so when an application is designed for the purpose it is necessary to validate and to verify that the new software fulfill all the user and regulatory requirements. p. 23 12