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Quality in clinical trials may be defined by the absence of errors that matter.”– Meeker-O’Connell A., Ball L., Current Trends in FDA Inspections March/April 2011

Risk-based monitoring is a process which identifies, assesses, monitors and mitigates the risks that may make a difference in the quality or safety of a trial. It is often misunderstood that it increases the operational risks. This is the opposite of what RBM approach is. It is a process to ensure that the quality of clinical trials is upheld throughout the study. Ideally, clinical trial sites will have different levels of quality and experience. The already used approach of on-site monitoring did not take into account these differences at various sites. RBM however, understands that such differences could arise all through the course of the trial and that based on these differences resources such as time and money should be allocated efficiently.

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What is driving the adoption of a risk based approach ?

Over the last 19-20 years, clinical trials have grown in their complexity. This has led to difficulties in conducting clinical trials and their oversight, with variability in clinical investigator experience, site infrastructure, standards of care and treatment choices. The advances being made in technology was also not taken advantage of in clinical trials. The ideal method for clinical site monitoring was to conduct routine site visits every 4-10 weeks. It was also seen to it that 100% source data verification was obtained in most cases. As a result, clinical monitors had to review all the details listed in subjects’ charts to confirm that the investigators report gave the correct efficacy and safety.(Myshko, January 2014)

According to Kyle Given, principal at Medidata solutions, “This practice assumes that all sites have an inherent quality issue and that every data point must be verified. Basically, the practice subscribes to the one-bad-apple-spoils-the-bunch philosophy.” This process was slow, ineffective and costly. It also leads to a lot of time of the Clinical Research Associates being spent on sites doing activities that could have been done from a remote location. Almost 34 % of phase 3 study budget goes into Source Data Verification(Gupta, 2013). However, there is evidence which shows that 100% SDV has a minimum impact on the quality of data(Myshko, January 2014). Various regulatory agencies such as FDA, MHRA and EMEA have agreed that the traditional approach to clinical trials monitoring leads to an increase in demand and cost of resources and have suggested that risk based monitoring could prove to be an efficient and cost effective endeavour.

The main reasons why a risk based approach is being considered can be summarised as follows:

FEWER ERRORS: on-site monitoring methods have to be conducted manually. This means that although there is 100% SDV, its accuracy will only be 85%. When a centralised approach is adopted, automated reviews are used which leads to a reduction in the errors.

 LOWER COST: Even though the main aim of adopting this new technique is data quality improvement and increase in efficiency, less on-site monitoring leads to reduction in costs which is an added benefit of risk-based monitoring.

BETTER ANALYSIS: Since all the data is input into a RBM system, statistical checks can be performed with ease. This helps in better identification of unusual patterns in the data.

CROSS-SITE COMPARISON: Centralised monitoring helps to compare data between two or more different sites. This helps to identify if a particular site has input any fraudulent data or if there is a miscalibrated equipment in a site.

TIMELY RESULTS: Since all the data is recorded timely and input regularly into the system, it is possible to identify and rectify the issues even before the trial is over.

what do sponsors have to have in place to meet the requirements ?

Although there are a lot of benefits associated with risk-based monitoring, most organisations involved in clinical research have been slow in implementing this process. The main concerns usually revolve around perceived deterioration in site and data quality. However, due to the strong regulatory endorsements and the success of companies already implementing it, more and more companies are beginning to follow suit and adopt this approach.(Young, July 2014).

In order to meet the requirements mentioned in the ICH GCP E6 guidelines, the RBM system of sponsors should have the following key characteristics:

1. Clinical Process and Data Identification: Within the RBM system, it is possible to identify the important data and processes that were marked during protocol development. The RBM system should however also include risk mitigation strategies for the identified data and processes.

2. Risk Identification: Risks should be identified both at the system level and clinical trial level

3. Risk Evaluation: The identified risks should be evaluated by the sponsor. For both identification and evaluation tools such as TransCelerate Risk Assessment and Categorisation Tool can be used.

4. Risk Control: After deciding, which risks require mitigation, the RBM system should be able to fully configure risk control features and also send alerts when the risk thresholds have passed.

5. Risk Communication: The sponsors should have role-based workflows in the system so that timely communication with team members and stakeholders is possible. There should also be an audit trail of these decisions and communication so that it can be provided as evidence to inspectors.

6. Risk Review: The RBM system should allow for review and update of identified risks, Key Risk Indicators, triggers, site scoring etc to ensure that they are working as intended.

7. Risk Reporting: It is imperative that the sponsor summarise the deviations for predetermined tolerance limits and the actions taken to improve it.(Mauri, March 2017)

At the root of it, RBM focuses on data, document and processes which are important. This technique ensures that sponsors or other personnel who are carrying out the trial can conduct the evaluation at a site different from where the study is being conducted. According to FDA, RBM will help to improve the sponsor oversight in clinical trials. It is up to the sponsor to design a monitoring plan that is specific to their company and trials. Such a plan should be specific to the data integrity risks of the trial and should be a mix of centralised monitoring and on-site monitoring.eg. PAREXEL uses a data driven approach to risk based monitoring which also involves adaptive monitoring and centralised monitoring as part of the process.(Parexel, 2017)

 

The central monitoring team may not necessarily take action on the data, but rather provide this to the study teams. From there on either the study teams, the data managers or a combination of both help with the risk assessment. Risk assessment deals with identifying, analysing and determining which of the risks should be modified. This modification could involve a change in policies or practices. It is imperative that the sponsor identify and understand the nature, source and potential of risks that could possibly affect collection of data or performance of critical processes. The risks that are identified should then be assessed based on: 1.The possibility of errors occurring 2. Effect of these errors on subject protection and trial integrity 3. The extent to which such errors would be detected.

Based on the risk assessment evaluations, sponsors should develop the monitoring plan. The type, frequency and extent of monitoring plan will change depending on a range of factors considered during risk assessment such as study design, safety of the product under investigation, electronic data capture, study population, stage of study etc.  (Gupta, 2013)

The parts of a monitoring plan include: Description of monitoring approaches, communication of monitoring results, management of noncompliance, ensuring quality monitoring and monitoring plan amendments.(FDA, August 2013)

Although the ICH GCP document does not mention to what extent onsite monitoring and centralised monitoring can be combined, it does state that it is the sponsor’s responsibility to determine the best approach to a risk based monitoring and does not mention any particular strategy. However, the FDA guidance describes that in some cases a higher or lower proportion of onsite and centralised monitoring maybe required. (FDA, August 2013) Along with the rationale, outcome of verification should be reported in terms of its nature and impact as also the corrective and preventive steps taken. The findings, decisions and actions should be saved throughout the trial. The assessment of the monitoring reports should be based on objective decision-making criteria. It should not be left for interpretation of an individual as this will mean that a particular risk that he/she does not deem important will not be recorded. This will compromise the monitoring process as the decisions will have been taken in a haphazard manner.(Andrianov, Widler et al., Oct 20, 2015)

Use of technology has optimised the processes in risk-based monitoring by making them more efficient. Technology based solutions integrate data, analysis and visualization needs into a single tool. The RBM plan should include the technology and applications used to assess risks and create reports. The sponsors should decide if they want to improve the already used technology or if a new one should be put in place for effective risk-based approach. Some examples of technology and techniques include EDC and Clinical Trial Management Systems.(Ghone, April 2015)

To sum it up, implementation of RBM requires the following steps:

·         Identify critical data and processes

·         Recognising areas or risks based on experience with previous similar trials i.e. risk assessment

·         Allocating roles for staff with operational instructions

·         Making decision trees in case of failure events

·         Devising a monitoring plan to ensure coordination between members of the project

·         Ensuring training on RBM strategies is carried out for all the members(King, July 2015)

what do you think the impact is likely to be on the industry as a whole?

The goal of the new addendum remains precise: “To encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity.”With less time and resources available at the disposal of clinical trials, a risk based methodology will help to focus on the important aspects of it and stay with it throughout the trial. The update in the addendum will affect the sponsors and pharmaceutical industry globally in many ways including: Adaptive onsite monitoring based on data from centralised monitoring, Use of Electronic Data Capture for review of site and data, Data management and shift in monitoring quantity to quality (Gupta, 2013). The scenario in clinical trial always demands that pharmaceutical companies find ways to reduce complexity in clinical trial, developmental costs of drugs and obtain more value from limited research and budgets. Adopting a risk-based approach could have the following impacts on the industry as a whole:

Evolution of role of CRA:

CRAs will be able to focus better on patient safety and data quality because of risk based monitoring technology like Xcellerate Monitoring. The CRAs will not need to look into non critical monitoring targets and will be able to focus on high-value compliance checks. They will be able to conduct off-site monitoring thereby enabling site staff to take control of the compliance process and data reporting onsite. Since the trial’s performance at site and subject level can be better understood with the help of technologies, the CRAs will be able to make a better informed decision regarding the trial.

Impact on On-site visits:

In the traditional approach, on-site monitoring visits would  be conducted at all sites at fixed intervals i.e. every four weeks, two months etc. This approach did not consider that some sites may be performing poorly and may need extra visits or that sites which showed smooth performance would require less oversight. In risk based monitoring, tools have been created to collect data from different sites. Monitors can identify the high-risk sites from these data and regulate site visits to these places. Thus, risk based approach would help with making strategic decisions.(Stone, 2016)

Less emphasis on Source Data Verification:

The traditional approach focussed on 100% source data verification. Based on the new guidelines by FDA, SDV is not entirely removed from the plan, but if the analysis favours, it can be reduced to a certain extent. Also by reducing source data verification, monitors will be able to focus on other strategies that improve data quality.(Tantsyura, Grimes et al., 2010)

Impact on time and money:

Since there are fewer onsite visits, the resources and time needed for these visits is saved. Since SDV contributes to 30% of costs of a typical trial, reducing it will result in considerable benefits. Overall the sponsors and companies will benefit from implementing RBM in terms of reduction in costs and other resources used. However, this should not be the driving factor in implementing RBM because the main aim should be to improve data quality and efficiency of trials.(Myshko, January 2014)

Cultural shift:

Since monitoring and quality management will be conducted from a risk-based approach, it is possible that those who have been applying the conventional method of monitoring will approach it with caution or be uncomfortable. It is necessary that extra educational efforts be undertaken for such people to bring about a change in the way risks are identified, assessed and mitigated.(Sawant, Shukla et al., 2016)

RBM has become the new standard of the industry. It isn’t a one step process where the benefits of implementing it will be seen in the first go itself. It is a journey and at the beginning it will require extra time, resources and money. However, after a few trials the impact and benefit of RBM will become evident and high-quality data, patient safety and effective use of resources will be seen.

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