In recent years sponsors invest greater efforts than ever to cut monitoring expenses using the emergence of new technological solutions and by designing different monitoring modalities to perform monitoring activities in the most cost effective way but with no damage to quality.
It is estimated that on-site monitoring activities make up 25-30% of clinical trial expenses. As opposed to a standard monitoring plan, which usually suggests on-site complete source data verification and frequency-based practice, the focus now is to create a tailor-made monitoring plan which includes a more adaptive and flexible approach.
As we all know, clinical trial data needs to be of sufficient quality and quantity to support trial outcome and decision making. According to the FDA’s 2013 guidance document on risk-based monitoring, “ICH E6 and ISO 14155:2011 advise sponsors to consider the objective, design, complexity, size and endpoints of a trial to determining the extent and nature of monitoring for a given trial.” This risk-based monitoring approach is approved and encouraged by the regulatory authorities (including FDA and EMA). The main goal of risk-based monitoring is to monitor the site primarily when efficacy and safety milestones are reached and when remote monitoring suggests arising site and safety issues. A risk-based monitoring plan requires the development of quality risk management that focuses on factors that are at high risk for generating errors and applying an efficient monitoring approach to rapidly detect and correct issues while the study is ongoing.
The traditional intense on-site monitoring does not guarantee identification of all subject safety and data issues, and the associated high cost is disproportionate with the value gained. In contrast, risk-based monitoring eliminates waste of valuable time and resources which can be applied to other activities where they are needed.
No matter what monitoring modality is chosen, the following main quality objectives must be monitored:
- Ensuring the protection of human subjects
- Training and qualifying site teams
- Adhering to the protocol and procedures
- Ensuring scientific integrity to minimize missing data and maximizing “clean” data to protect statistical power
- Detecting frauds
- Ensuring compliance with regulatory requirements (GCP, FDA etc.)
- Ensuring compliance with Adverse Events reporting
- Ensuring IP accountability and storage
Adaptive and flexible monitoring modalities often categorize clinical data into one of two types: Critical and Non-Critical.
The critical data, such as subject eligibility, must be fully monitored while non-critical data, such as routine laboratory tests that do not address protocol-specified safety or efficacy endpoints, may be monitored less intensively.
Adaptive and flexible monitoring modalities require a thoroughly instructive monitoring plan, well-designed protocols and case report forms – these are the foundational influencers on quality and efficient monitoring.
There are electronic solutions which will “calculate” for the CRA the time points at which a monitoring visit is expected to be performed but in the absence of such tools, and due to the complexity of such designs, a well written manual and rigorous CRA training is required.
We are increasingly using electronic-based documents and tools. These tools definitely make the remote monitoring more accurate and efficient. Prior to study start it is recommended to create well-designed source documents or worksheets as well as to utilize Electronic Data Capture (EDC) systems which allow optimal verification of all the required elements of the study. The literature suggests that in the future we will see the increased use of electronic informed consent, electronic source documents and many other tools which will most probably reduce furthermore the frequency of on-site monitoring.
The FDA encourages greater use of remote monitoring practices, where appropriate, than has been encouraged in the past. Creativity and advance planning will save the sponsors time and money in the long run!