The international conference on harmonization’s (ICH) guideline for good clinical practice (GCP, document E6) has been officially revised. There has been much commentary about this as of late and I recently interviewed an executive from Bioclinica. You can watch that video in its entirety here.
Much has been said about the GCP revisions, this blog post will focus on the practical implications for research clinics, sponsors, and CRO's and CRA's.
Some of the enhancements to the guidelines include the obvious technological innovations such as electronic source documents, electronic record retention, virtual workspaces and the like that have occurred since the last GCP revision, but most notably, the greater role of centralized monitoring has finally come to the forefront of the conversation from the FDA’s perspective. The meaning of monitoring itself, according to the FDA, has been widened to include the monitoring plan. While updated guidelines do not require a separate document for a monitoring plan, regulators do expect that sponsors have a formal plan. In addition, centralized monitoring which has been a strategy used by sponsors and CRO's heavily these past few years, will need to show sufficient documentation just as a traditional monitoring visit would necessitate. As is currently the case when the monitor goes onsite they have to submit a report to their project manager or team lead after the site visit. This report will then be sent to the trial master file, most of which are electronically stored. Sponsors will need to have access to these monitoring reports in order to maintain sufficient oversight. With centralized monitoring, similar reports will be necessary and a similar process will need to be followed and documented as per sponsor’s standard operating procedures (SOP) and monitoring plan. The fact that this is included in the updated guidelines would suggest that these monitoring reports and monitoring plans are subject to FDA audit when deemed necessary.
As far as principal investigators are concerned, the FDA has now made more revisions to the GCP guidelines which state that the investigator is responsible for supervising any individual or party to whom the investigator delegates tasks. Furthermore, any third-party that the investigator delegate duties to, must be fully trained by the investigator on all procedures that they will undertake. Sponsors have always kept investigators responsible for following these standards, however now it is formally documented in this new guidance from the FDA. In short this means investigators must document training to any staff members or third-party vendors that they delegate tasks to and this could come under FDA scrutiny in the event of an audit. Needless to say, investigator oversight is now front and center on the FDA's agenda. The changes to the guidelines finally include the acronym ALCOA (attributable, legible, contemporaneous, original and accurate). While this has always been proper source data documentation practice, the FDA decided to once and for all include this in GCP formally.
In addition to more responsibilities being given to the investigators, sponsors and CRO's are not off the hook themselves. In fact, the GCP revisions have substantial changes and additions that deeply impact the way sponsors and CRO’s will have to manage a clinical trial going forward. There is a much greater emphasis on risk management and the adoption of risk based monitoring to manage the clinical trial at hand. Sponsors will need to take a more active role in overseeing their CRO’s just as investigators are required to take a more active role in overseeing and documenting any third-party vendors that they outsource tasks to. Gone are the days that a sponsor can simply outsource a clinical trial to a CRO and move onto other tasks. New guidelines suggest that the sponsor will need to have appropriate oversight over the conduct of the trial that are overseen by CRO’s. Risk based monitoring will eventually become standard for every clinical trial, and every site will have a separate monitoring plan which will be adapted as necessary based on that site's particular risk profile. To quote the guidance, “the sponsor should develop a systematic prioritized risk-based approach to monitoring clinical trials. A combination of on-site and centralize monitoring activities may be appropriate for sponsorship document the rationale for the chosen monitoring strategy.” The emphasis here is to proactively combat protocol deviations and inconsistent data, missing data, or just outright fraud. Furthermore, site performance metrics will need to be analyzed, and this will determine the monitoring plan for that particular site going forward. Monitoring reports, whether through traditional monitoring visits or centralized monitoring oversight, will need to be submitted to the sponsor in a timely manner. In practical terms, clinical research associates (CRA’s) will be required to document even more extensively than they have done in the past. These reports will then be stored in a trial master file available for sponsor review, and ultimately FDA inspection. Since every study and every site poses unique risks, the monitoring strategy should properly document rationale for the tools and strategies being utilized. Gone are the days of the cookie-cutter monitoring plans, new monitoring plans will need to focus on aspects of clinical trials that are not routine and that may pose future problems. The goal is that these future problems will be avoided by adopting a risk-based approach.