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Protocol deviations can be extremely costly to clinical trials – both financially and with patient safety. In some cases, they can be so severe that they lead to patients being removed from a trial and cause a trial to be terminated.
A protocol violation is a significant occurrence or event which may affect participant safety or the integrity of the research, or a consistent variation in practice from the defined protocol.
The US Food and Drug Administration (FDA) released draft guidance in December 2024, with the agency urging sponsors, investigators, clinical research organisations (CROs) and others involved in clinical trials to provide feedback on the guidance by 28 February 2025.
There has been some guidance in documents by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), however, there has been no guidance until now from regulatory agencies as to how they view protocol deviations.
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Speaking exclusively to the Clinical Trials Arena, Vera Pomerantseva, Director of Product Management, Risk Based Quality Management (RBQM) at software provider eClinical Solutions, said that the agency could go further and set out examples to assist sponsors in implementing this guidance.
Abigail Beaney (AB): Can you talk about the guidance itself and how important and helpful it will be for the industry?
Vera Pomerantseva (VP): Protocol deviation management is not a new process in the industry – it’s rather complex. There is a lot of variability in how protocol deviations are managed by sponsors. Previously, it has been touched on in other regulatory documents, including the ICH E6 among others but there has never been dedicated guidance from health regulators.
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By GlobalDataIn 2015, TransCelerate had an initiative to create a paper on key, common industry practices. In the published white paper, there are several process diagrams and recommendations which many companies have been following. But that is an industry consortium, so it does not have the same authority power as the FDA. The FDA’s Protocol Deviation draft guidance is very much in line with the TransCelerate recommendations.
My recommendation for the sponsors is to read through the document and provide comments to the FDA. I would highly encourage everyone to do that. This is the first draft and the first time we have received specific industry guidance in this space, so it is in our best interest to make it as robust as possible.
When I reviewed it, I was concerned that the FDA was not directly referencing serious breaches or an escalation process – this should be part of the guidance. Some, not all, but some of the important protocol deviations should be assessed from the perspective of whether they could become serious breaches. The EMA issued guidance on reporting serious breaches in 2023 so I would expect that to be referenced in the FDA guidance, but I cannot find anything.
Another recommendation that concerned me – but it will be interesting to hear thoughts from peers – is the recommendation to include protocol deviations in the trial protocol, and to what extent should it be included? In ICH M11 there is a section which recommends this. My concern however is the approach to protocol deviation may slightly change through the course of the trial. If it’s part of the protocol, it could cause unnecessary amendments to the protocol that are not discovered until later. There should be a certain level of detail of what should be included versus what should not be. It would be great to hear from industry peers and companies that do not have robust protocol deviation processes in place.
I would recommend sponsors look at the consistency of the terminology in the FDA regulation and pay attention to the difference between GCP non-compliance issues and protocol deviations. There has always been confusion between these and this guidance touches upon that. It also touches on decentralised clinical trial elements such as at-home visits or visits conducted by local health providers. For companies with DCT elements, I would highly recommend looking at how they oversee that and include that in their protocol deviation management process.
Another consideration is the system’s capabilities. It’s all good and well having these regulations and frameworks in place, but do we have systems and technology to support the end-to-end process? For example, duplications, with your approach, can you confidently assess the number of patients impacted? It comes a lot from the way you capture data, obviously oversight and continuous improvement, as well as the escalation process with a protocol deviation. That is something I would have in mind when I’m revisiting my processes.
AB: How would you say that the FDA’s guidance aligns with guidance by the EMA?
VP: Serious breaches are the next step. It’s not included in the overall protocol deviation management process but if a sponsor has important protocol deviations which have a significant impact on the patient’s well-being and the scientific outcome, it might be assessed from the perspective of whether it is a serious breach. Some companies have a governance committee or an escalation committee, which will review if a serious breach occurs. I wouldn’t expect all those details to be included in the protocol deviation guidance, but I feel like the FDA should mention that important protocol deviations, depending on the volume and the scope, should be assessed for potentially being a serious breach. There is a reference in EMA guidance, but I have not seen FDA guidance on that.
AB: You mentioned it was nearly a decade ago that TransCelerate worked on the protocol deviation white paper. Why do you think it’s taken the FDA this long to bring official guidance out?
VP: That is a good question and I wish I had an answer. I think the FDA took quite some time to recognise the need. The general definition was included in ICH 3 and ICH 6, but that is, as I mentioned more of a definition. The trigger may have been that when the FDA received submissions from the sponsors, they realised how differently it’s handled by everyone. This puts a burden on the FDA because it has to process and oversee how sponsors are conducting clinical trials. In trials, patient protection is very important, and I believe that health authorities in general move very slowly. I’m sure they have had this guidance in mind for quite a while, but finally, we have something from them. It’s exciting.
AB: As sponsors are utilising more adaptive trial designs, how does this guidance help understand deviations in these trial designs?
VP: That’s a very challenging question because adaptive trial designs in their nature are very challenging because they change over the course of the trial. I think the key is thorough documentation and communication within cross-functional teams and documenting inspection readiness. Sponsors should have that storyboard, of what was changed when it was changed in the trial and what the impact of that will be and how it will be handled moving forward.
AB: What next steps would you recommend for companies that are looking over this guidance and are planning new clinical trials?
VP: I think the typical challenge for adopting a new guidance is there will still be a certain level of ambiguity. Typically, the guidance we receive from the health authorities provides the framework, but they don’t give all the details of how it should be applied. When I reviewed this draft guidance from the FDA, I had hoped there would be an annexe or more examples to provide consistency to sponsors, but I still feel it’s a huge step by the FDA to provide us with this guidance.
The agency touched a lot on the integration of risk-based quality management so for some companies that still have low expertise in this space, that might still be a potential challenge for them in the adoption of this guidance. The important thing in my opinion with risk-based quality management is quality by design. It’s an intelligent way of preparing for issues in advance. A sponsor can look at the design and try to assess what the unnecessary risks and complexities are and whether they can be avoided which will reduce any future ambiguity while adding flexibility. The trial design is the chance to derisk the protocol and remove elements which are not necessary to reduce the workload. Because it’s part of the protocol, the clearer and less complex it is, the fewer unnecessary protocol deviations will occur.
With systems and metrics to measure these deviations, I question how a sponsor will oversee that. A sponsor’s capabilities and approach can vary. The current way protocol deviations are captured in the industry varies from Excel spreadsheets to robust outsourced systems, or in-house developed systems. A sponsor must make sure this guidance aligns with that process, so it supports the trial, and a sponsor can oversee the whole process, whether that process is outsourced or internal, or maybe hybrid. Ensuring that alignment is the responsibility of a sponsor.