FDA Q&A on Risk-Based Approaches to monitoring in clinical trials

The FDA recently published Q&A guidance on risk-based approaches to the monitoring of clinical investigations. Just after the guidance came out, I was at the 3rd Risk-Based Quality Management (RBQM) Summit in Philadelphia, and I think it’s fair to say that the audience were more than a little disappointed. Many people were looking for more specificity on “how” to do things.

Now we all know that the FDA publish ‘guidance’ not ‘regulations’ in relation to risk-based approaches because one size doesn’t fit all. While we get that, publishing the ‘what to do’ doesn’t always help people with the ‘how to do it’.

In this post I’m going to quickly run through each of the questions and pick out key points from the answers rather than just copy them from the guidance.

The guidance was relatively short containing only 8 questions: 5 in Section A. the Monitoring Approach; 1 in Section B. The Monitoring Plan Content; and 2 in Section C. Follow-up and Communication of Monitoring results.

Section A. The Monitoring Approach

Q1. ??“What is the purpose of the risk assessment and should sponsors document their methodologies and activities for assessing risk?”

The first key point that I took out of the answer was that there needs to be a risk assessment conducted during the protocol design phase. That should be obvious to most people reading this, but we still hear of companies that don’t do a risk assessment on every study, so it bears reinforcement from the FDA.

Linked to that is the second key point that sponsors should document the risk assessment. Again, that sounds obvious (spoiler alert - lots of the information in the answers is obvious to be honest). What the FDA wants to see is documentation relating to the identification of the risks, evaluation of the potential causes, likelihood of detection, and the severity of consequences. In addition, you need to document methodologies for assessing risks, conclusions derived from the risk assessment, and how decisions were made as a result.

The third point is one that we often see overlooked by potential clients, and it’s that the risk assessment needs to inform the monitoring plan. That means making sure the monitoring plan monitors the right things. Again, obvious to anyone who delivers RBQM in the real world, but the FDA obviously felt the need to drive home the point.

As they did with the fourth point here, that risk management isn’t once and done. It’s an ongoing activity to review existing risks and identify new ones that arise as you go through your trial.

And the final point is that all the areas we just discussed need to be thoroughly documented because, to quote from the guidance, the “FDA may request, during inspection, documentation of the sponsor’s initial risk assessment, and any relevant updated risk assessments.

Q2.??“Should sponsors monitor only risks that are important and identified during their initial risk assessment as likely to occur?”

“No.” was the short answer. Everyone working in this space knows that of course you need to identify, monitor, and document new risks that occur after the initial risk assessment. The FDA also pointed out that risks detected during the trial but that weren’t anticipated or identified in the initial risk assessment also need to be added to your risk log.

The second key point I took out was interesting because it’s often overlooked, and that was that risks considered low likelihood of occurring, but that could have a significant impact on the quality of the trial need to be monitored.

And the final key point was that monitoring plans need to be revised as needed as new information becomes available.

Q3.??“What factors should sponsors consider when determining the timing, types, frequency, and extent of monitoring activities?

This is such an important question and we’re asked variants of it all the time. It was also the question with the longest answer from the FDA and there were five key points that I took out of it.

The first was that the monitoring plan needs to cover a range of factors that relate to both the overall trial and site-specific risks. It’s also important to recognise that some mitigation activities may not be relevant for all sites.

The second was that while electronic data capture systems can be used, sponsors need to carefully consider the quantity, extent, complexity, and criticality of data to be collected.

Linked to that, Sponsors also need to consider the types and intensity of monitoring activities and ensure they are best suited to addressing the identified key risks, while at the same time facilitating the identification of unanticipated risks. Monitoring activities must also be proportionate to the risks to participants’ rights, safety, and welfare, as well as to the data integrity and quality.

SDV is a very common topic of conversation when it comes to RBQM and risk-based approaches in general. The FDA guidance was that while SDV “may be part” of your risk-based monitoring approach, the extent to which SDV is used should be guided by the risk assessment and focused on critical data and processes. Importantly they say that this approach can help achieve the study objectives “without necessarily having to conduct frequent routine visits to all clinical sites and extensive SDV”.

And the final point that I took out was an important one that came up at the 3rd RBQM Summit, and that was that there are big potential benefits in conducting an early monitoring visit to ensure that everything is running smoothly and as expected. Much more effective to get things right from the start than try and fix things later.

Q4.??“How can a risk-based approach to monitoring that includes centralized monitoring help minimize missing data or protocol deviations?”

This is a great question, but I couldn’t help thinking it was not-so-subtle plant for the FDA to showcase the benefits of centralized monitoring, but that’s fine by me.

One of the clear and significant benefits of central monitoring is the potential impact on data quality. By that I mean it’s easy to identify missing data at both the study and at the site level, which is a big problem on many studies.

Other benefits include the ability to quickly and easily identify those sites that appear as outliers in your data visualizations. If they lie outside an expected range, for any number of indicators, that could be an important signal to scheduling an on-site visit and find out what’s happening on the ground.

And there was one other point that I thought was interesting and that was the use of metadata, the structured information that describes, explains, or makes it easier to retrieve, use, and manage data. This contextual data helps to understand the actual data and could be useful for ensuring data quality, so should be considered as part of your monitoring plan.

Q5.??“Should the risk-based monitoring approach include processes to ensure that appropriate blinding is maintained?”

For studies that include blinding, ensuring blinding of the investigation is maintained is a critical process and therefore should be considered in the risk assessment right at the start.

Obviously, any risks identified need to be mitigated, monitored, and managed, but the monitoring process needs to be flexible enough to identify new risks that occur and identify any tracking deviations that could result in unintentional unblinding.

Section B. Monitoring Plan Content

Q6.??“What elements should sponsors include in monitoring plans?”

Clearly, every monitoring plan should be specific to the individual study. But that doesn’t mean you can’t learn or re-use important information, and our critical variables and risk libraries demonstrate that.

We know that the monitoring plan should cover both study and site-specific risks because that was covered in some of the previous questions. However, the guidance made an interesting point about including in the monitoring plan descriptions of the types of issues that trigger immediate issue escalation.

And the final key point on this question was that the monitoring plan should describe your approach for determining whether an important issue discovered at a site may also be present at other sites, and identifying when there is a systemic problem such as a problem with the protocol.

Section C. Follow-Up and Communication of Monitoring Results

Q7.??“How should sponsors follow up on significant issues identified through monitoring, including communication of such issues?”

The first key point to note is the requirement for evaluating significant issues in a timely manner as set out in the monitoring plan. The next point is that Sponsors need to undertake a prompt root cause analysis, followed by appropriate corrective and preventative actions to reduce the impact of the identified issue on the rights, safety, and welfare of subjects, as well as the integrity and quality of the data.

And as covered in other questions, you need to review your risk assessment and monitoring plan, documenting decisions and actions, and making process changes where necessary.

Q8. ?“How should monitoring activities and the results of these activities be documented and shared with those involved in the investigation?”

This last question is briefly answered in the guidance but covers some important topics, including the need to capture basic details of the monitoring activities, including any areas of non-compliance, irregularities, or other deficiencies. Very importantly, the FDA are saying that there must be sufficient detail captured to clearly demonstrate adherence to the monitoring plan.

And finally, there obviously needs to be appropriate and timely reporting for both the conduct and oversight of the study.

Conclusion

As I said right at the beginning, many people were hoping for more detail, but the Q&A was guidance, not regulation. If you’re interested in learning more about how we help clients deliver these answers using our #RBQM??technology, OPRA, watch this space as we’ll be running a webinar on it very soon.

Thanks for reading and have a great day.