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Data Monitoring Committees for Phase 1 Clinical Trials

Written by David Kerr, Bill Coar, and Kent Koprowicz

 

Data monitoring committees (DMCs) review data from ongoing clinical trials to make recommendations regarding trial conduct based on risk-benefit and other criteria, and are an essential component to ensuring the integrity and safety of many clinical trials. While DMCs have most commonly been employed in the context of late-stage randomized clinical trials, we have also seen DMCs used for early-stage non-randomized clinical trials, including in Phase 1 studies.

Here we discuss unique aspects of DMC process for Phase 1 clinical trials.

Phase 1 clinical trials

Phase 1 studies are usually the first clinical trials in humans and are intended to learn about safety and identify the side effects resulting from a new treatment. There are many types of Phase 1 studies — some can include healthy participants, while others may include patients with a particular disease under investigation. Depending on the potential risk to patients, a Phase 1 trial may enroll small numbers of subjects and have extremely careful oversight of each person enrolled, when compared to the oversight in larger, later phases of clinical trials.

Studies that require such careful oversight may rely on a DMC to ensure the safety of patients is not compromised. For example, consider an oncology setting where the intent is to identify the maximum tolerated dose (MTD) of a new therapy. A common (but not universal) approach is that these MTD Phase 1 studies do not randomize subjects, whereas larger, later phases are likely to do so (e.g., employing randomization so that half the subjects are on the new treatment, and half receive established standard of care). Instead, these Phase 1 studies initially enroll a small cohort (perhaps 3 or 6 subjects) at a very low dose of the investigational treatment. These subjects are assessed for dose-limiting toxicities (DLTs). Based on specified criteria, another cohort might be enrolled at a lower dose, the same dose, or a higher dose. This process is repeated until the MTD is found that has acceptable toxicity while likely also being a therapeutic dose that will improve the condition under investigation. Other information is also obtained in Phase 1 studies that may not be collected in later studies, for example, more detailed data on drug-drug interactions (DDIs) and PK/PD (pharmacokinetics/pharmacodynamics) to see what the body does to the drug, and what the drug does to the body.

The decision on whether subjects have met the specific criteria for a DLT, and the decision on what dosing level to use for the subsequent cohort has traditionally been made by those working at the company sponsoring the clinical trial. However, there is growing awareness that bias might exist in this scenario. Cynics could suggest that the evaluations from those working at the company sponsoring the clinical trial might additionally consider corporate interests, such as timelines, at the expense of the safety of current and future people enrolled in the Phase 1 study. Therefore, there is value to an outside group to also review this data and give their independent opinion on the continuation of the clinical trial. This would be the role of a DMC.

 

FDA guidance on data monitoring committees

The most recent draft guidance from the FDA on DMCs states that “although all clinical trials have a plan for monitoring data and subject safety, not all trials call for involvement or monitoring by a DMC.”1 Traditionally, the value of the DMC is in a randomized study where the DMC is the only group that assesses risk-benefit by a randomized arm. So, it is natural to wonder if a DMC is needed or helpful for a non-randomized clinical trial, e.g., a Phase 1 study. A trial that enrolls quickly and has short follow-up period may be “impractical and of little value” if the DMC cannot have a “meaningful impact on the conduct of the trial.” However, the draft guidance also states that a DMC is of value where there is “limited experience in a therapeutic area,” which is generally the case for Phase 1 studies, and if the patients are “at risk of serious morbidity or mortality” or if the investigational treatment “may cause serious unexpected adverse events” — again, a common scenario in Phase 1 studies. (For more information on FDA guidance on DMCs, read our recent post.)

 

Use of data monitoring committees in Phase 1 studies

We have researched historical data at clinicaltrials.gov, the repository of information for clinical studies in the United States as well as globally. Among the data collected on each study is the phase and the use of a DMC. Our research shows that of studies started in 2023, over 25% of Phase 1 studies employ a DMC. That has increased from 15% of Phase 1 studies using a DMC for studies started in 2010.

 

Key differences of data monitoring committees in Phase 1 vs. later-stage studies

Listed below are some key differences between how a DMC might operate in a Phase 1 study compared to a larger, later-stage study, particularly one that is randomized.

  • Composition of the DMC

The DMC overseeing the Phase 1 study may not include a statistician as a voting member, as there likely will not be “by-arm” comparisons that require formal statistical interpretation. On the other hand, some Phase 1 studies have non-trivial algorithms for determining the dose level of a subsequent cohort, and there could be value to have a DMC member with technical knowledge of that algorithm. The DMC might also have a pharmacologist included to help interpret PK/PD data.

  • Flexibility of DMC meeting scheduling

DMCs for larger, later-phase studies generally have guidelines on frequency such as meeting bi-annually or after each 100 subjects are enrolled. This allows for reasonable predictability and meetings can be scheduled 2–3 months prior to the actual meeting date. However, Phase 1 studies might have an entire cohort enrolled on a single day or have the DMC meeting be triggered by the final subject in a cohort. The DMC would need to convene perhaps within weeks to assess the data from that cohort and have the DMC recommendation on the dosing of the next cohort to ensure that momentum of enrollment can continue. This requires the DMC members to prioritize these DMC meetings and have flexibility. An option would be to have a standing meeting monthly to use or not based on status of study. There may even need to be DMC meetings called on an emergency basis without any advance planning — for example, if the first two subjects in a cohort experience DLTs, the DMC may be needed for quick consultation on appropriate action going forward.

  • DMC meeting

DMCs for larger, later-phase studies generally begin with a short open session with personnel to review “total” data, but the majority of their time in a longer closed session with just the DMC in attendance to review “by-arm” data. That is not typically the case for DMCs reviewing Phase 1 studies. If the study is not randomized, all involved likely have full information on the dosing data and safety data. The open session is likely longer where the sponsor gives their thoughts on the data, particularly on subjects who may have had DLTs. There is still value to having a closed session for the DMC to talk amongst themselves about the cases and create a recommendation on the continuation of the study. But that closed session could be relatively brief, especially if there have not been any DLTs in a cohort.

On the other hand, the DMC might have other questions the sponsor wishes them to answer. They might be asked if they approve of moving to the next cohort/dose. They may be asked if they feel the PK profile is acceptable. They may be asked if they feel it is appropriate to begin a Phase 2 study at a dose proposed by the sponsor. There likely will be more direct communication between the DMC and the sponsor personnel, instead of a carefully controlled firewall between the two groups that would be in place for a randomized study. If the DMC recommends a course of action different than what the sponsor team had in mind, there can be direct communication.

One aspect not changed between a DMC for a Phase 1 study and other DMCs is that the DMC is generating recommendations, not mandates. The sponsor team can proceed as they wish, but there is still value in learning the opinions of this independent DMC as they view the study focused on the perspective of patient safety. The DMC would not typically be the group that formally adjudicates if a patient has met the specific criteria for a DLT, but the DMC might have their own interpretation of the event that impacts how they interpret that patient and that dose cohort.

  • Outputs created for DMC review

DMCs for larger, later-phase studies generally focus on tables and figures that help to identify by-arm differences. However, outputs for Phase 1 review will be more “patient focused.” Listings will be more common. These might be more sophisticated “patient profile” listings, which show multiple domains (baseline characteristics, AEs, key lab results) for a single patient on 1–3 pages / patient. Figures that show specific patients’ information could be employed, for example, a figure displaying patient-level hepatoxicity lab data over time for a patient who has met Hy’s Law criteria. There may still be tables summarizing baseline data and adverse events, which have columns split by dose cohort. But these tables likely will be less of a focus for the DMC than the subset of patients meeting specific criteria of interest. Narratives on patients with particularly concerning events (such as those who have had a DLT, a serious adverse event, cytokine release syndrome, or neurotoxicity) could be important to the DMC.

Some data such as PK data might be more commonly shown to DMCs as well for Phase 1 study to link up cases of DLT to the actual levels of investigational product in the person. In immune-oncology studies, there could be specific information about the dosing/manufacturing, such as leukapheresis, lymphodepletion, or successful infusion with the expected dose.

  • Flexibility of Statistical Data Analysis Center (SDAC)

DMCs are usually supported by an external SDAC, typically a CRO that has experience with supporting DMCs. The processes and standard timelines for receiving data, generation of reports, and distribution of materials for DMC review that work well for Phase 2 or 3 studies may not be suitable for Phase 1 DMCs. For example, consider where enrollment of a subsequent cohort will be on hold until the DMC’s review of the data. The duration from the last participant’s assessment to data extract and subsequent generation of the reports likely needs to be expedited, as would be the DMC’s review time prior to the meeting. This is particularly important to consider for the first review, where the underlying data might represent just three patients and there would be extremely limited time for the SDAC to prepare programming using live data in advance of receiving the data transfer representing those three patients.

Planning and resourcing of Phase 1 studies may therefore deviate from the SDAC’s typical standards. Therefore, it is important to have the SDAC that is involved understand this and have the flexibility to accommodate these expedited timelines for the success of these Phase 1 studies.

 

Final takeaways

Data monitoring committees play a crucial role in ensuring the integrity and safety of clinical trials. While traditionally associated with later-stage randomized trials, their use in Phase 1 studies is becoming increasingly common and new FDA guidance has highlighted their value in these settings. However, there are important differences to consider in how DMCs operate in Phase 1 studies vs. other trials. As clinical research continues to evolve, the adaptation of DMC practices to suit the unique demands of Phase 1 studies remains essential.

 

 

David Kerr new_crop

 

About David Kerr

David Kerr is Director, DMC Services, at Axio, a Cytel company. He has worked at Axio for 28 years and specifically for DMC activities on over 250 studies and attended over 1,000 DMC meetings in disease areas such as oncology, cardiology, infectious disease, respiratory disease, and rheumatology. His goal is to make sure the DMC has the best information available to help them make educated recommendations for the success of the trial and the protection of the study patients.

 

Bill Coar_cropAbout Bill Coar

Bill Coar is a Senior Director of Biostatistics for Axio Research, a Cytel company, in a biostatistics department primarily focused on supporting data monitoring committees (DMC) in clinical trials. For more than 14 years, he has served as either the (non-voting) independent statistician or the voting DMC member in clinical trials primarily for indications in oncology and rare diseases. He also has extensive experience in SAS programming to support data management and statistics for over 25 years. He regularly attends and presents at professional conferences such as the Joint Statistical Meetings, SAS Global Forum, and PharmSUG.

 

Kent Koprowicz_cropAbout Kent Koprowicz

Kent Koprowicz is Vice President, DMC, at Axio, a Cytel company. Kent has been a practicing biostatistician for over 25 years. Since joining Cytel, Kent has served as the DMC independent statistician on over 150 clinical trials across a broad spectrum of therapeutic areas. As the DMC independent statistician, he has implemented numerous adaptive designs for interim efficacy and futility analyses including group sequential, sample size re-estimation, conditional power, Bayesian posterior probability of success, dose selection, and population enrichment.

 

 

Notes

1 U.S. Food and Drug Administration. (2024). Use of data monitoring committees in clinical trials.

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