Medical Management Series
The medical monitor’s role in the close-out phase: data review and cleaning
Over the course of the next few short articles we will cover the key medical management activities required during the study close-out phase. We shall also provide advice based on our extensive experience of medical monitoring to make these activities as efficient as possible in order to achieve a successful end to the study.
For these articles, the close-out phase refers to the period from last patient out to issuing the final Clinical Study Report (CSR). As the study conduct operations conclude, the routine medical monitoring activities give way to intense data cleaning and data review. This same set of activities are also performed whenever interim analyses are performed at predefined timepoints of the study.
Data review and cleaning
After data entry cut-off for all subjects in the study, the medical monitor holds the responsibility of reviewing the study data that are being presented for accuracy and logic. The medical monitor plays a vital role in ensuring that all raised medical queries have been addressed adequately and satisfactorily answered by study sites, and that clarifications have been provided where needed.
The timelines for data cleaning and review are agreed between data management and the medical and project management teams. This plan should include agreed dates, from the last patient last visit (LPLV) onwards, thereby bringing into line scheduled dates for last data entry in the Case Report Form (CRF), last query answered, database lock (DBL), production of data outputs and, when applicable, closure of sites.
The data review activities are intensified to meet the timelines and the methodology of data cleaning and review is followed per the Data Management Plan (DMP) and the Medical Management Plan (MMP) established during the study set-up phase. The clinical operations members play an important role in supporting the sites to provide all required data within the CRF, conducting site visits to perform Source Data Verification (SDV) and ensuring that data entry obligations are kept up by the sites. The agreed data listings and patient profiles are generated by data management at the planned data cut-off for clinical database output, generally after the last data entry.
The medical review cycle is then started, marked by medical monitor review and query generation by the use of a designated Medical Query Tracker (MQT) that can be circulated within the study team. The number of review cycles depends on the volume and quality of data available at the cut-off date. Besides the patient profiles used for the in-depth review of individual subject data, aggregate data listings are also utilized.
The review can also be performed using smart listings designed and programmed to capture critical parameters. The smart listing is a customized tool to review specific data sets representing information usually entered in various locations within the CRF such as relevant efficacy, safety or eligibility parameters. This can also be a useful tool to assess consistency and identify any discrepancies between data entered in different electronic platforms. A good example of this would be the randomization/ enrolment data or study drug assignment information entered both in various CRF pages and in the Interactive Web Response System (IWRS). Additionally, the reconciliation between safety and clinical databases is performed, usually by the data manager and the pharmacovigilance (PV) officer, with any needed medical support provided by the medical monitor.
Medical coding of the events and medications are also reviewed by the medical monitor, with reference to the applicable coding conventions. The Medical Dictionary for Regulatory Activities (MedDRA) is commonly used for the coding of adverse events and medical history conditions, while the World Health Organization–Anatomical Therapeutic Chemical (WHO-ATC) classification is used for coding medications. Ambiguous reporting of events or medications is queried and resolved at this point to ensure that correct coding terms are assigned before the safety analyses.
Wherever local laboratories are used for the study assessments, the medical monitor provides input to harmonize the results across sites during the generation of conversion tables to aid the review. The finalized list of protocol deviations is also reviewed by the medical monitor to determine the effect of major deviations on data analysis based on the pre-defined study population. When applicable, the major deviations are also classified accordingly in order to foresee the impact on planned intention-to-treat or per protocol analysis.
Mohamed El Malt MD, PhD, Vijayanand Rajendran, MD, Kelechi K. Olu MD, MSc (2016) Medical management in clinical trials: A roadmap to operational excellence (Part 4 – Close-out Phase). Journal for Clinical Studies 8(6): 22-25.
Medical Management in Clinical Trials:
A Roadmap to Operational Excellence
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