Comparison of Non-Commercial Risk Based Monitoring Tools by Their Application on Clinical Trial Protocols

Clinical trial monitoring involves intensive on-site monitoring visits at clinical trial sites and exhaustive source data verification (monitoring) of clinical trial data [1]. Clinical researchers have questioned the validity and necessity for traditional monitoring methods [2], which have been under investigation due to their ineffectiveness in improving the quality of clinical trial data or in protecting trial participants [3]. Implementing a risk based monitoring (RBM) system is suggested by the ICH’s newly adapted guidelines to improve overall quality management [3]. The RBM involves the identification of any risk that might have an effect on areas routinely subject during monitoring activities. Risks should be identified by a RBM system followed by an evaluation of their likelihood of occurring and the extent to detect these errors and their impact on human subject protection, trial data reliability, and GCP- and protocol compliance [4].


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request improved and more effective methods to protect the rights of clinical trial participants, and to ensure data reliability as well as GCP and trial protocol compliance. The existing ICH guideline has been modified with respect to points such as principles of GCP, investigator responsibilities, sponsor responsibilities, and the essential documents [6]. The amended ICH (GCP) guideline suggests different recommendations to the sponsor to improve overall quality management in a clinical trial. One of the recommendations is to implement a risk based approach monitoring system. Identification should be followed by risk evaluation instead, risk likelihood, the extent to detect these errors and their impact on human subject protection, trial data reliability, GCP, and protocol compliance [7].
To date various tools for risk identification have been developed as either paper based or in electronic format [8,9]. These tools have been compared regarding their characteristics and their employed strategies in identification and classification of potential risks.
Additionally it has been stated that the lack of evidence to show superiority of RBM over traditional onsite monitoring has held back their utilization [10]. Recent research using ADAMON negates the inferiority of risk adapted monitoring to extensive monitoring [10]. We aim to evaluate the effectiveness of RBM as a tool for onsite risk based monitoring, given the lack of investigation into such a method so far [9]. pages of results of which 10 were suitable. We did not use any additional restrictions for the advance search option in Google Scholar. Additionally "clinicaltrial.gov" has been used with the terms clinical trial protocols. An advanced search was used to specify available study protocols.

Assessment of Clinical Trial Protocols: The first objective was to find out whether non-commercial
RBM tools give similar overall risk assessment for the selected protocols. Noncommercial RBM tools (ADAMON [10], NORM [11], MHRA [12], Yee [13], Transcelerate [14], OPTIMON [15] and SWISS [16]) were applied to perform risk assessment of 18 clinical trial protocols from different phases with different indications. Based on the outcome the risk was categorized into high, medium, low for the respective clinical trial.

Comparison of RBM Tools Risk Covered
The second objective was to investigate whether the tools cover different risk aspects. Transcelerate RBM tool has been used as a standard by six commercial RBM tools [9]. For this reason it was used for the second investigation as a base for risk category to be compared to each RBM tool by its risk category structure: safety, study phase, complexity, technology, subject population, data collection, endpoints, staff experience, Investigational medicinal drug (IMP), laogistics, blinding, operation complexity, geography in order to investigate the different risks covered between the RBM tools. Evaluation of the different risk statements was done by the following rating scale that we developed to identify whether the risk is also investigated by the other RBM tools and to which level as shown in Table 1.

Search Strategy
In total 24 RBM tools were identified based on a systematic review article [9], of which 7 were publicly available ( Figure 1).

Assessment of Clinical Trial Protocols (Figure 2)
For the overall risk assessment of each protocol by different     The assessment of protocols by the non-commercial RBM tools has shown that they result in different risk outcomes regardless of the clinical trial phase. Hence the mitigation plan to manage these risks will differ as well. The mitigation plan of an assessed risk should be implemented with either onsite monitoring or centralized monitoring [3]. The observed differences in the assessment clearly show that there is not yet an ideal non-commercial RBM. Each RBM tool focuses on specific risk aspects. Our findings highlight differential risk considerations between RBM tools. Of the latter that fail to cover risk categories, their comparison revealed a significant difference. Moreover the weight age of a certain risk and its importance is usually assessed by the individual risk assessor implementing the RBM tool. The risks covered by each RBM tool should guarantee the safety and rights of the human subjects nevertheless the accuracy and reliability of data3. Our research points to apparent heterogeneity in the different risks being covered by each RBM tool.

Conclusion
An ideal RBM tool should cover risks related to a clinical trial.
Further classification and scoring system should be included for the RBM tool user. Furthermore, a detailed monitoring strategy equipped with a proper plan to prevent detected risk should be readily available for the user.
A key quality feature of an RBM tool is the identification and classification of potential risks associated with a planned study.
As described, the requirements are very different and sometimes only partially fulfilled by selected software tools as investigated.
The development of such software requires a well-structured illustration of a clinical trial as it should be in the study protocol.
In addition to this structural mapping, potential risks have to be defined in advance in order to enable a systematic screening by the software. Ideally, the potential risks should be weighted to allow for an internal assessment of a risk characteristic and thus to enable

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Copy@ Firas Fneish the generation of a study risk score. A corresponding preparatory work on this is still missing and is therefore, in the opinion of the authors, the next step in the further development of RBM systems whose developmental approach then no longer decides which risk level a clinical study has.

Limitations
The quality of the protocols was not taken into consideration, as our aim was to assess the protocols that follow ICH GCP guidelines and have already been reviewed, approved and accepted by the institutional review board (IRB). The author has solely done the assessment of the protocols with RBM tools, critical questions have been discussed within the author's group before the decision making process.

Conflict of Interest
None to declare