Authoritative report: Using risk-based monitoring to make clinical trial quality audits more efficient

The best way to monitor clinical trials is to focus on the key needs of the method, rather than all issues that may affect patient safety or data integrity The best way is to adopt risk-based monitoring (RBM), or a more comprehensive risk-based quality management (rbqm) The FDA requires the clinical trial sponsor to "provide surveillance to ensure the full protection of the rights, welfare and safety of the subjects, as well as the quality of the data submitted to the FDA." However, the industry has always believed that a comprehensive and resource intensive approach is the best way to obtain high-quality results, so traditionally, it has been taking on-site monitoring and 100% source data verification (SDV) to review the quality of clinical trials Such a method is not only expensive and time-consuming, but also can not guarantee the quality Regulators have realized that the best way is to adopt risk-based monitoring (RBM), or a more comprehensive risk-based quality management (rbqm) The FDA recommended RBM in 2013 and revised ICH-GCP e6-r2 guidelines in 2016, which identified RBM as a mandatory requirement for all clinical trials In this year's "Industry Guide: risk based clinical research audit Q & a" (Draft), FDA reiterated: "risk based audit is an important tool to enable the sponsor to identify and solve problems in the clinical research process." Recently, the association of clinical research organizations (acro) released a research report, which analyzed in detail the use of RBM by Arco members in clinical trials RBM and rbqm are the basis of quality control activities RBM is an adaptive clinical trial monitoring method, which can guide the focus and activities of the monitoring to the most needed aspects for the safety and data quality of the subjects The two main components of RBM are on-site and centralized monitoring On site audit includes the combination of source data verification (SDV) and source data review (SDR) SDV is the basic fact checking process of clinical trial supervision Through cross checking between the case report and the original source, the accuracy of the data is confirmed and the trial can be repeated SDR is different from SDV and does not involve the examination of case report form SDR involves the review of source document records and program compliance Relevant aspects must ensure that key processes and source document records are sufficient and meet the requirements of GCP With the continuous development of electronic data records, central monitoring (CM) has been applied more and more, which makes document review, data review and analysis can be carried out remotely, and it is not necessary to send inspectors to research sites FDA and EMA guidance documents now consider QBD and SDV, SDR, CM as part of the overall risk-based quality management (rbqm) approach At an FDA seminar held in July 2019, Dr David burrow, director of the scientific investigation office of the FDA drug review and Research Center, pointed out that in the current clinical trial environment, the FDA strongly encourages the use of clinical trial monitoring to keep the quality ahead and focus on the quality In this case, a more appropriate approach is to see RBM as an aspect of a quality based system that "will not produce significant errors." But some people believe that RBM is an end in itself, not a tool based on the quality system as a whole In some cases, the industry may just try to adopt RBM strategy on the basis of established agreements This approach is unlikely to succeed and will add unnecessary costs In order to fully implement rbqm, FDA has developed three necessary steps that need to be performed in sequence First, the cro must be conducted before and during the test Secondly, a clear research plan should be formulated according to the factors determined during the risk assessment Finally, RBM method is customized according to risk assessment and research plan Importantly, moving forward to rbqm is not only the regulatory focus of the United States, but also the global regulatory focus EMA has a deeper acceptance of the quality standards used to improve clinical trial monitoring In 2013, EMA released a risk-based quality management guideline for clinical trials In particular, in terms of rbqm sequential processes, EMA and FDA guidelines are highly consistent: "mitigation measures should be incorporated into the protocol and other test related documents (such as the audit plan) at the beginning of the protocol design." Based on the quality by design (QBD), a total quality management method is provided for clinical trial supervision QBD integrates quality into clinical trial protocols in the initial design phase to help ensure that audit strategies prioritize factors that are critical to patient safety and data integrity Photo source: reference [11] RBM is not a new concept in clinical trials RBM has been used in banking and aviation industry for a long time RBM was used in clinical trials for more than 10 years According to statistics, in 2016, the proportion of new clinical trials included in RBM was 18%, and in 2017 and 2018, the proportion rose to 41% and 61%, respectively However, due to different organizations and different definitions of RBM, it is difficult to accurately explain the prevalence of RBM in clinical trials, nor to answer the question whether the implementation of RBM method is appropriate in the quality-based system Nevertheless, a large number of evidences show that RBM plays an increasingly important role in clinical trials Results of acro research: members of the association of clinical research organizations (acro), which makes clinical trial quality verification more effective, include several well-known contract research organizations Recently, Arco released a research report on the use of RBM by member organizations in clinical trials The figure below is a summary of the results of this survey The sponsor reported that the RBM method accelerated the quality audit process, made the clinical trial quality verification more effective, helped to submit the data to FDA more quickly, and could provide patients with the required treatment more quickly According to the report, when the company checks the data through RBM model, the contract research organization and the sponsor are more likely to detect the quality problem earlier and make quick rectification in the clinical trial site For the safety of patients in clinical trials, this monitoring method is the most important Compared with 100% SDV and field verification, RBM consumes less time and resources and can provide better quality, which seems to be the opposite of intuition Contract research organizations are increasingly incorporating RBM into clinical trial monitoring, not only to respond to regulatory requirements, but also to properly integrate RBM and QBD strategies into the system-based path, which can bring direct benefits to the sponsor and improve the quality of clinical trial data With more and more clinical trials and more complicated situations, it is expected that the importance of RBM will continue to increase Acro said it will continue to work with FDA to encourage wider adoption of RBM across the industry Photo source: reference [2] insufficient application of RBM in clinical trials can improve the clinical monitoring process, while reducing costs and resource occupation However, RBM has not been fully used in clinical trials The research report lists a number of challenges These challenges may limit the application of RBM centered on perception management and expectation management Some companies mistakenly believe that the risk of the traditional audit method is low, the data inspection strategy is more secure, and the complete SDV is the best way to ensure the data quality In 2017, Hurley et al Published a survey of 132 academic led clinical trials on trial, found that many obstacles to the implementation of RBM were caused by inadequate understanding of the process, including misunderstanding of cost-benefit and lack of understanding of RBM Arco's research report shows that the industry faces many major challenges in promoting the use of RBM "Change management" is one of the challenges facing the industry Because the RBM method requires the participation of multiple stakeholders, including contract research organizations, sponsors and research sites, if the RBM method is adopted, it must promise to give up the old clinical trial monitoring method In addition, these stakeholders are only part of the mechanism needed for the effective operation of RBM Other components that need to be seamlessly integrated and run smoothly include initial risk identification and components of a broader quality management system, such as data science and clinical operations In addition, all of these components must operate in a cost-effective manner For example, although the introduction of central monitoring (CM) in clinical trials can improve the safety of patients, if we continue to maintain 100% SDV while introducing cm, the actual cost will definitely increase In addition, RBM needs to be operated in order, first with appropriate risk assessment, and then with clear research plan Another challenge is that the industry not only needs to integrate all RBM steps within a quality based system, but also needs to establish a chain of customer between different stakeholders In some cases, the sponsor is responsible for electronic data collection, the contract research organization is responsible for data management, and the other party is responsible for centralized monitoring, which results in the failure of centralized maintenance of data and data sources and the difficulty of access by all parties Because of these difficulties objectively, some companies are reluctant to give up the traditional clinical trial monitoring methods Fully promote the implementation of RBM although RBM has become a more common element in clinical trials in the past few years, acro still believes that RBM has not been fully utilized Previous research shows that many respondents adopt RBM to meet regulatory requirements, indicating that if the industry emphasizes that adopting RBM is a guideline recognized by regulators, the acceptance scope of RBM may be expanded Therefore, to encourage wider implementation of RBM, acro recommends that FDA grant RBM best practice status Other potential drivers include additional training for researchers to better understand the benefits of implementing RBM However, for companies and researchers who lack the time and resources to deal with the complexity of clinical trial monitoring, it is not enough to only strengthen RBM training RBM itself is a risk reduction mechanism, which needs to be integrated into the clinical trial monitoring method based on the overall system The cro can help the sponsor integrate the concept of "data knowledge" (or all relevant drug knowledge owned by the company) into a system based approach rather than focusing on specific parts of RBM that meet the strategic objectives of the sponsor, such as reducing SDV and on-site monitoring The contract research organization with rich clinical trial supervision experience is very suitable for guiding the sponsor to complete this process, helping to fine tune multiple components of RBM to meet the requirements of optimizing data integrity and patient safety For some clinical trials, on the face of it, trying to select a few of these components may seem useful, but this piecemeal approach carries the risk of increasing costs (without removing unnecessary steps) or reducing quality (without adding key steps) The contract research organization can work with the sponsor to prepare a list of RBM elements and incorporate them into the base without difference