Continuing with our series on What's New in E6 R3, we look at the Monitoring section, which has been moved into the Quality Assurance and Quality Control section. The term "risk-based" no longer appears in the monitoring section, but centralized monitoring is featured. It's not just about the frequent flyer miles anymore!
The Monitoring section starts with a pre-amble that establishes the purpose (to ensure participants' rights, safety, and well-being, with "safety" newly added) and a statement that monitoring encompasses a broad range of activities, including those we would associate with site start-up activities, on-site monitoring, centralized monitoring, and oversight of decentralized activities.
The guideline proceeds to two new sections, "Investigator Site Monitoring" and "Centralized Monitoring," to emphasize this point. Investigator Site Monitoring is defined as a single-site-focused activity, but one that includes both remote and on-site activities. R3 includes this new statement: "Monitoring may include secure, remote, direct read-only access to source records, other data acquisition tools and essential record retention systems." The guideline does not specify "where permitted by law," but we can assume.
Centralized monitoring is defined, in contrast, as monitoring of aggregate data, which may be performed by a "medical monitor, data scientist/data manager, biostatistician." Thus, all the requirements that follow must be considered in context of the entire quality control system, encompassing on-site visits, remote visits, and all data review activities.
The Monitoring Plan is considered next (in R2, it has been appended at the end of the Monitoring section). New details here:
- The risk-based approach to the monitoring plan should include critical-to-quality factors.
- Particular attention should be given to procedures relevant to participant safety and to trial endpoints.
- The monitoring strategy should take the site's capabilities and the burden on the site into account.
- The monitoring plan should describe centralized monitoring activities, particularly those related to primary endpoints, key secondary endpoints, and critical data and processes.
The Monitoring Activities section has been re-organized into four sections: communication; investigator site selection, initiation, management, and closeout; monitoring of investigational medicinal product; and monitoring clinical trial data. Below are new and changed responsibilities. Keep in mind that they apply not just to on-site monitoring, but to monitoring as a whole:
- Communication includes informing site staff of protocol and GCP deviations and taking appropriate action to prevent recurrence. Note this was also listed as an investigator responsibility.
- Site selection and confirmation that site staff have adequate qualifications and resources is listed as a monitoring responsibility.
- Site management responsibilities now include verifying that blinding is being maintained and that investigational product is adequate and within expiry (somewhat unusually worded as "within their shelf-life").
- Site closeout responsibilities now include verification of "arrangements" for record retention and final IMP accountability, a nod to the process of reminding sites of their continued obligations at closeout.
- Data monitoring responsibilities include identification of missing and inconsistent data, outliers, "unexpected lack of variability," protocol deviations, trends, and significant errors at individual sites and across sites.
- R3 now specifies that monitoring report requirements should be described in the "sponsor's procedures" (note that SOPs are not specified; the monitoring plan would suffice)
- Monitoring reports should describe findings that require escalation.
- The sponsor should determine and document actions in response to escalations.
