Е-MANAGEMENT AND ELECTRONIC CASE REPORT FORM AS AN ESSENTIAL TOOL OF CENTRALIZED CLINICAL TRIAL MONITORING

Abstract

Introduction. The results of clinical trials are the big data array formed during the study. The certain requirements are applied to these data regarding to their validity and accuracy. For this aim GCP requires the sponsor to provide "adequate" monitoring "on-site testing before, during and after the clinical trial." Such requirements stipulate the high cost of the procedure – on-site clinical monitoring costs 30% from the total cost of a separate study. However, FDA emphasizes that, unfortunately, high cost of on-site monitoring does not guarantee the achievement of good study quality. So, according to last recommendation of FDA, which were presented in «Guidance for Industry. Oversight of Clinical Investigations –A risk-based Approach to Monitoring», it is advisable to use the quality risk management approaches.

The development and improvement of centralized monitoring systems and the introduction of electronic management approaches (e-management) in the clinical trials of medicinal products is a reality of time and corresponds to the modern international requirements for quality management.

The aim of the work was to identify the most critical risks to the quality of the data by analyzing the discrepancies arising from the entry of data in the management of clinical trials, as well as providing scientific and practical substantiation of the risk control system and approaches to the implementation of these tasks in the development of e-CRF for bioequivalence studies.

Investigation methods.  In the current study 992 CRFs and the corresponding number of source documents were analyzed. The 968 CRFs of them were in the p-book version and match the design of bioequivalence studies, which have been held in healthy volunteers and 24 CRFs were in electronic format and have been held with the help of foreign electronic systems. ClinicalDiagnosticCenter of National University of Pharmacy (CDC NUPh) specialized on conducting of bioequivalence clinical trials, so in 2015 year the work on the creation of e-CRF for such studies began. For estimation of our research results we used methods of risk assessment, logical methods of system analysis and extrapolation.

Results and discussion. The data corrected during inputting and the queries made by monitor/ quality manager/ auditor regarding to the quality of data presented in CRF were assessed. For CRF in the p-book version the corrections were fixed in appropriate journals «Journal of CRFs correction registration», which is saved in master-file. For е-CRF information was proposed as unresolved, which are made by authority involved in data process, and the system, which checks data in centralized way.

The results of our assessment show that the general view of the risks have a technical nature because the reason of them is wrong calculation or estimation. For example during assessment of normal range and clinical significance of laboratory tests results the risk of laboratory parameters wrong assessment is happened in 25% cases. This is because the researcher can ignore parameters that go beyond the limit of normal, so he does not assess the significance of this indicator. The risks depended on calculations (calculations of body mass index, QTc interval, etc.) also are concerned mathematics aspects of analyze and although   they are almost twice less than the previous risk (10-15%), they still attracted the researchers attention.

Based on analysis of data from clinical studies of bioequivalence, Phase I and Phase II there were discovered the risks mostly in working process with CRF. It is proved that these risks are not critical, and bore a technical character arise. The results of the risk assessment indicate that the general view of the risks is of technical nature, as the reason for their appearance - it's wrong calculation or evaluation.

We consider it appropriate to reduce the risk of technical errors in subsequent trials to improve the quality of the research. Within the framework of e-management there were introduced control reference values (for laboratory parameters) and automatic calculators, which have been integrated in the developed e-CRF for the conduct of bioequivalence studies in CDC NUPh.

Conclusions. At the clinical trial site e-management implementation is the modern requirement to ensure the quality of the data obtained in the clinical trial and it is the key to the use of central monitoring in the framework of the simultaneous compliance with GCP standards and ISO 9001:2015. The practical implementation of such approaches can be realized through the development of e-CRF as tool for continuous quality control and the prevention of risks in the course of research.