Sponsors should build risk-based quality management (RBQM) into their trials as if they were constructing a house from the basement up, advises the director of the FDA’s Office of Bioresearch Monitoring Operations.

When developing an RBQM strategy, it’s critical to begin with a strong foundation — a risk assessment — Chrissy Cochran told attendees at the 2023 Avoca Quality Consortium (AQC) Summit last week.

“You wouldn’t start building a house with the second floor,” Cochran said. “You should start with the basement, and that should start with your risk assessment. That is what we really should be basing the foundation of all our clinical trials on.”

The construction crew should include more than just clinical operations personnel, she said. Cochran strongly advises including people that offer valuable perspectives, such as thought leaders, clinical investigators and monitors. It’s important, for instance, to learn how those managing data will be looking at a protocol and the data generated and how those in charge of monitoring safety consider risks.

Before building the protocol, the ground floor in Cochran’s house analogy, get everyone involved in the trial together to identify potential risks and mitigations. And keep them involved afterward, she stressed. This will significantly help inform the protocol design and eliminate inconsistency, one of the most prominent problems the FDA encounters when inspecting protocols, she said. Inconsistency can lead to failing to follow the protocol, the FDA’s top investigator finding.

“Generally, when you think about when a protocol is built, there’s a table with the list of all of the assessments that need to be done, the timeframes, the dates, all of that information, and then you have the narrative part of the protocol. Sometimes those two are in conflict,” she said. “For clinical investigators, our number-one finding is failure to follow the protocol and it’s easy to see how that can happen if our protocols are not internally consistent.”

The top and final floor in Cochran’s clinical trial quality house is the monitoring/quality assurance (QA) plan. Here, too, it’s important to involve monitoring and QA staff in protocol development so there’s a strong framework when the time comes to create the monitoring/QA strategy. Building this floor can be done in a number of ways, she said:

• Ensure there are appropriate checks and balances established to limit the opportunities for errors (such as checking internal protocols for consistency);
• Simplify protocol outcomes and assessments by contrasting what you’d like to know with what you absolutely need to know about the product’s safety and efficacy, which can reduce potential for error;
• Use technology to track, trend and increase the visibility of errors so they can be dealt with in real time, such as case report forms (CRF) with built-in edit and logic checks;
• Standardize systems and formats where you can and use standard definitions and validated instruments when possible;
• Aim to keep protocol amendments to a minimum and check CRFs and consent forms against each amendment; and
• Push for training on the protocol and assess the training to ensure understanding.

Training is particularly important in Cochran’s view, and sponsors should cover all the bases to make sure staff are trained and fully qualified. In some states, certain nursing licenses do not allow the holder to conduct physical exams, for example; this could impact sites carrying out a protocol requiring nurses to do these assessments. Be aware of differing state requirements to ensure sites are able to follow your protocol.

When selecting investigators, ensure they have sufficient experience, training and skills in the disease state relevant to the trial and indication, Cochran said. A cardiologist would probably not be the best pick for a trial of a gastrointestinal (GI) condition treatment, for example, and could lead to certain GI patient-specific issues being missed.

Similarly, when conducting site selection visits, sponsors should consider whether they have the adequate equipment, time and resources to perform the trial adequately. Think about how many staff members the site has, how many trials they’re already doing and how strong their commitment is to research vs. regular care. For example, FDA investigators occasionally see a conflicting “clinician vs. clinical investigator” attitude during inspections, and this can spell failure to follow the protocol, among other problems.

In these situations, “the protocol isn’t written in a way they would normally treat their patients, so they try to do it in a way that flows with their clinical practice,” she explained. “Now they’re not following the protocol. Then we see issues with failure to follow the protocol — perhaps procedures aren’t being done in the right timeframe — and that could cause issues with data collection.”

Having an audit trail for the electronic systems in a trial that keeps track of changes made, who made them and why they were made is also critical to risk management. But there’s one thing Cochran says she cannot stress enough: ensure the audit trail can be exported in a format investigators can easily make sense of.

“Please make sure you’re checking that when you’re developing your systems or implementing a system. We will ask for audit trails. We do look at those,” she said. “We want to be able to go through them without having to refer back to a huge chart because everything is coded or in symbols. Having a clear audit trail that is human-readable will really go a long way to making your inspection go faster.”