|An auditor's goal is to confirm the trial runs |
in a way that ensures the safety of the subjects,
protects their rights and generates reliable data.
by Jessica Masarek
Quality Assurance Consultant | Independent Auditor
Director, Muse Clinical
Audits and inspections seem to be wrapped in a shroud of mystery, making folks stressed and unsure of exactly what is going to happen. What if I say the wrong thing? What if I don’t know the answer? What if I can’t provide what they are asking for? Realistically, all of these things will probably happen! That said, as long as you are honest, all will be well. Mistakes happen and no auditor or inspector is expecting perfection. We are expecting transparency. As an auditor, my goal is to confirm that the trial is run in a way that ensures the safety of subjects, protects their rights, and generates reliable data. Sponsors want to continue working with sites in which so much effort has been invested and will work to identify areas for improvement if deficiencies are noted. An inspector has a similar goal with respect to the assessment of trial conduct. So, how do we ensure that trials are run at the level of quality that regulators are looking for and that are truly inspection ready?
First, what does it mean to be inspection ready? Simply put, if one is inspection ready, one has documented all aspects of a clinical trial in a way that provides a clear, accurate and complete picture of how a trial was run to an outside observer. The key here is that it is ongoing, real-time and involves operating at a level of quality in which a successful inspection could happen at any moment. What it’s not is last-minute preparation for an inspection.
With that in mind, I want to talk about how we can take what we know, namely public information about inspection focus areas and methods, and apply it to what we do. How can we use this information to make better decisions about how we run and document clinical trials? By educating both investigator site and sponsor staff, we can turn small shifts in awareness and understanding into impactful changes in operations and documentation. Monitors and sponsor staff can use this information to identify areas of greatest risk and understand what aspects of trial conduct are considered most vulnerable to error or poor documentation. Investigators can incorporate this information into their processes so they may focus on the areas that matter most.
This article is related to the Whitepaper: FDA Inspections of Clinical Investigators - Are You Ready? To get the full details, please download your free copy.
Regional inspection documents contain a wealth of information about which areas inspectors think are most important. In the United States, the Bioresarch Monitoring (BIMO) guidance document tells us exactly how an inspection is conducted, from start to finish. This document is guidance for inspectors but we can benefit from the fact that it is available to the public. Other regions have inspection-related documents, and some are aimed at the investigator site. While the BIMO guidance appears to be the most detailed, the EU has a high level guidance on common provisions for member states, and Health Canada offers a detailed Pre-inspection Package. All of these guidance documents can be valuable, regardless of your region, as they are rooted in the same principles. It’s like having a copy of the test before you take it.
A great plan of attack is to first gain familiarity with your regional inspection document(s) and even those of other regions. Select one of your studies and, for each of the focus areas/questions, think about how you would answer them for your trial. How would the documentation support the answers? Is there information that is not documented and is retained only in the memories of your staff? Would an outside observer be able to follow your documentation and answer all the pertinent questions? Does your documentation follow ALCOA principles? Completing this exercise for even a single trial is likely to reveal gaps in process, documentation and training which can be addressed across other trials within your institution.
I’d like to take a closer look at just one of the inspection focus areas, investigator oversight. As an auditor, I see this as a common challenge of investigator sites. How do you demonstrate that the Principal Investigator (PI) is both adequately involved and has oversight of the trial? Considering the diversity of clinical trials, the level of involvement may vary, but there are numerous ways that oversight can be documented. The key is transparency. Investigator oversight should be woven into the various aspects of the trial and visible to an outside observer. Documentation should answer questions about how study tasks were delegated and whether it was to appropriately qualified individuals, whether the PI is informed about the trial (e.g., study status, safety updates, subject care, protocol deviations, trends), and it should demonstrate involvement in key decisions about trial conduct. To illustrate this, I’d like to share an example of poor oversight documentation and some options to address.
Example: Documentation of Oversight
Source documentation was insufficient to demonstrate adequate investigator oversight. There was a lack of progress notes showing regular interaction with subjects, adverse events (AE) captured in an AE log were reviewed and signed off months after site awareness, and there was no documentation in the source that potential issues were discussed with the investigator. There was no documentation of discussion of study status or subjects between study coordinators or sub investigators. The informed consent form did not require an investigator signature, so it wasn’t clear that the PI was available or present during the consent process.
In this particular case, based on interviews, it appeared to be primarily an issue of documenting oversight. There were frequent phone discussions about subject care, adverse events and safety updates. Regular meetings were held with site staff to debrief on the current status of studies and provide an opportunity to discuss any important or difficult cases. The PI was always either present or available during the consent process and always went over the study with the patient for a second time prior to the physical exam. However, none of this was documented.
To address this moving forward, the site could ensure that the PI was writing detailed progress notes and including information about any consent discussions. If an AE log was employed it should show review and sign-off in a timely manner, but the source should also include mention of any verbal discussions between the PI and Study Coordinator that are pertinent to the medical care, study decisions or to simply demonstrate PI awareness. Regular staff meetings could have documented minutes.There are many ways in which investigator oversight might be documented; the list below notes just a few of these. Please keep in mind that examples should be tailored to the trial type and PI qualifications, as not all principal investigators are physicians.
- Documentation of protocol deviations, demonstration of PI awareness/review, and decision whether reportable to Institutional Review Board (IRB)
- Progress notes that demonstrate interaction with subjects, appropriate follow-up to potential medical issues and overall medical care
- Using notes to file to document issues that are not documented elsewhere more appropriately and include complete corrective and preventive action(s), demonstrate understanding of the issue, ownership by the site and principal investigator (PI), and appropriate steps to prevent recurrence
- Meeting minutes demonstrating sharing of important trial and safety information with site staff
- Decision logs may demonstrate important decisions and transmission of process information to site staff
- Timely signed reviews of labs and other medical reports that demonstrate an awareness of trends and abnormal values
- Training of site staff in policies, procedures, ad-hoc issues/CAPA, protocol, including the PI
- Documented delegation that is accurate and appropriate, and includes documented supervision of staff, as needed, to perform tasks. Awareness of qualifications required by local law for various medical professionals, and relevant documentation.
- Monitoring reports show the PI meeting with the monitor on a regular basis
- Any application of investigator or physician discretion, as allowed by the protocol, thoroughly documented at the time it occurs and, if required, accompanied by Sponsor acknowledgment
- Adverse events acknowledged and assessed for both causality and severity by the investigator, in the source, and in a timely manner
Inspection readiness takes work, but everyone can get there, often with just a small shift in mindset and a few changes to how we work. The first step is awareness and the next is applying the resources that are available to assess our current state and making small, but meaningful, changes to improve quality.
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Jessica Masarek is director at Muse Clinical, a small consulting group that works with sponsors, investigators and CROs to provide or supplement quality assurance activities. She has worked in a number of industry management roles and her expertise spans the full spectrum of quality assurance activities, with a particular focus on independent auditing, risk mitigation strategies and trial master file system and process development. She believes in a cooperative approach to compliance, offering balanced, proactive solutions to ensure inspection readiness. Jessica may be reached at Jessica.firstname.lastname@example.org.