4 Tips for Managing Protocol Deviations in Cell Therapy Clinical Trials
The FDA recently released draft guidance to help sponsors, clinical investigators and Institutional Review Boards (IRBs) better define, identify and report protocol deviations in clinical trials. By establishing a standardized approach, the FDA aims to minimize risks associated with deviations and ensure trials remain trustworthy.
In cell therapy clinical trials, protocol deviations pose a significant concern due to the complexity of the treatments. Therapy is uniquely derived from participants’ cells or carefully matched donors, necessitating personalized treatment plans. This personalization increases the likelihood of protocol deviations, as any variation in collection, processing or administration can affect the therapy’s effectiveness and safety.
For example, in CAR T-cell therapy, patients are often assigned a specific premedication regimen before receiving treatment. Deviations can occur if the premedication is not ordered, skipped or taken out of sequence. In some cases, if study personnel do not receive clear instructions, the medication(s) can be given incorrectly, leading to a protocol deviation.
Although it may take some time for the draft guidance to go into effect, sponsors, CROs, investigators and research teams can be proactive and develop protocol deviation management plans in advance.
How to Manage Protocol Deviations
All stakeholders, including sponsors, CROs, investigators and research teams, must manage protocol deviations to ensure patient safety and study validity. Here are four actionable tips for minimizing the occurrence of protocol deviations.
- Develop Detailed Protocols
Sponsors should develop clear protocols with sufficient details about how research procedures will be carried out for the trial. Additionally, providing guidance documents, checklists or other tools to support investigators and their research teams fosters better communication and alignment. These resources should be easily accessible and serve as clear references for the investigator and the research team to foster strict adherence to the protocol.
Sponsors/CROs must also ensure that investigators and their research teams know the protocol’s nuances, particularly regarding the specifics of cell therapy treatments. A knowledgeable team is less likely to deviate from the study protocol, and ongoing training will help maintain consistency throughout the trial.
Additionally, a detailed protocol can streamline the IRB’s review process by minimizing the need for back-and-forth clarifications.
- Provide Training for All Stakeholders
Consistent training is key to preventing and handling deviations should they occur. Ongoing education keeps teams aligned and promptly communicates protocol updates or clarifications.
Sponsors must ensure investigators and research teams are well-trained in study specifics, including precise handling and timing requirements. During site initiation visits, the sponsor and CRO should work closely with investigators and research teams to clarify trial procedures. This is especially important for cell therapies with strict administration schedules, such as CAR T-cell therapy, where timing is critical to patient safety and efficacy.
During the IRB review process, the IRB will review the study protocol to confirm that the study plan is appropriate and contains clear details about:
- Eligibility criteria
- Investigational agent administration
- Study visits and procedures
- Reporting deviations, serious adverse events and exceptions
- Study monitoring plans
- Required investigator and research team training
- Foster Open Communication Across Stakeholders
Effective communication among sponsors, CROs, investigators and research teams minimizes deviations. Therefore, they should establish clear communication channels – video calls, phone calls and emails – to clarify protocol-related questions and ensure alignment.
From an IRB perspective, communication channels for timely reporting deviations should be established. It is important for sponsors, CROs, investigators and research teams to be familiar with the IRB’s specific reporting requirements. Prompt reporting of protocol deviations to the study sponsor, CRO and IRB is necessary to ensure that study participants’ safety is protected and demonstrates overall compliance with the research protocol.
- Establish Clear SOPs
The research protocol and the IRB standard operating procedure (SOP) detail how to document deviations, including what happened, when it was discovered and any immediate actions. Given the strict handling of cell therapies, investigators and research teams must be trained to promptly report major deviations to the sponsor, CRO, as applicable, and the IRB.
Establish clear definitions for what constitutes a major deviation versus minor deviation and the related processes for reporting such deviations.
The Path Forward
Managing protocol deviations in cell therapy clinical trials requires a proactive and structured approach to protect research participants and enhance trial data reliability. While the FDA’s guidance on deviations is still in draft form, forward-thinking stakeholders can take the initiative by prioritizing collaboration and rigorous oversight to manage deviations effectively.
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