Cohort management is part and parcel of conducting dose-escalation studies, but not all teams effectively manage it. Pharm-Olam is focused on expediting our sponsors’ early phase cycle time in Oncology to enable rapid delivery of a mean tolerated dose (MTD)/recommended Phase 2 dose (RP2D). Thus, tightly orchestrated cohort management strategies that both protect the safety of trial participants and support the capture of the quality data that sponsors need to move to the next stage of development are equally important.
At Pharm-Olam, we use a series of cohort management tactics as part of our best practices. Here is an outline of the methods that our operational and clinical teams utilize when conducting early-phase research.
Orchestrating Your Study Symphony
The prioritization of effective communication provides the critical foundation necessary for a well-run early phase oncology trial. In contrast to late phase studies that are often primarily focused on a reactive monitoring strategy driven by data cleaning and protocol deviation resolution, dose-escalation studies require a proactive approach consisting of tracking the individual patients' journey from pre-identification to screening to treatment. Notably, this also requires an awareness of the availability of enrollment slots, screen failures/dropouts, and safety events such as dose-limiting toxicities (DLT) that all pose a risk to data integrity, patient safety, and study delivery timelines. The coordination of each of these elements, like instruments in an orchestra, is the difference between chaos and harmony in obtaining the final MTD/RP2D. We look to our teams to conduct this process in partnership with sponsors, investigators, and vendors as a symphony marked by the maintenance of site relationships, the protection of patient safety, and the reduction of downtime. The sections below highlight the "instruments" we deploy to achieve this goal.
Checkpointed Patient Pathway
The recognition of the commitment and sacrifice of study participants in first-in-man oncology trials has led to the generation of our Checkpointed approach to cohort management. This site-facing process is designed to make the process of slot assignment transparent for the site and patient so that they can make informed decisions regarding when the study treatment may be available and any potential bridging therapies that may be taken in the interim. As a result, the transparency and commitment to the patient also has the added benefit of protecting the relationship of the sponsor with the investigator and providing a pathway for the identification of potential backup patients to mitigate screen failure delays and safety-driven cohort expansions.
In practice, the Checkpointed Patient Pathway is controlled at the following steps:
- Slot Assignment: Depending on the degree of competition anticipated for the indication, sponsors may wish to provide slots to patients based on a first come basis, medical need, or by rotating site assignments. We suggest checkpointing this process at the level of patient consent or post-screening depending on the overall morbidity of the patient population and the duration of the screening period. Patients not currently provided a slot are kept on a pre-identification log or screened with a forecast enrollment date to minimize downtime and facilitate quick enrollment of subsequent cohorts following completion of the previous cohorts’ safety review period.
- Patient Eligibility: To safeguard safety as well as data integrity it is paramount that only eligible patients are enrolled in a study and only when an assigned slot is available. We utilize a Patient Eligibility Checklist for each potential patient on a dose escalation study. This checklist is completed by the investigator and provided to the study Medical Monitor along with requested redacted source documentation. This form requires signed approval to grant the site permission to enroll, ensuring the study treatment is only provided to the correct patients and at the correct time.
- Patient Evaluability: Considering the overall health of participants in first-in-man oncology studies, it is important to be aware that dose interruptions or incomplete administration of study treatment over the review period can occur. Thus, it is critical that the study team communicates frequently with investigators to ensure each enrolled patient has completed the minimal dose requirements to be considered for the safety review period. The inability to checkpoint this process can lead to delays in replacing unevaluable patients as well as lead to the unnecessary further treatment of these patients that could instead be receiving an alternative therapy. The proactive monitoring of this process is essential to protecting data integrity required to make dose escalation decisions and reach MTD/RP2D.
As discussed above, orchestrating early phase oncology studies and deploying a checkpointed approach requires proactive communication with all parties. We suggest a two-prong approach in which daily individual communications combined with scheduled committee conferences captures details regarding each individuals patient pathway while also creating a collaborative venue for investigators to respond to potential safety issues, recruitment challenges, and to share early success critical for engagement when considering initial doses may be at subtherapeutic levels.
Below we provide further detail on our approach to communication:
- Day-to-Day Site-Level Communication: We train our clinical research associates (CRAs) to take proactive ownership of the Checkpointed Patient Pathway process as advocates for their investigators and patients. They oversee day-to-day communication with each site to gather intelligence regarding the current course of therapy for each potential patient and when they may be eligible for the trial. The project manager (PM) and clinical trial lead (CTL) in turn assimilate these findings to generate the pre-identification log to support in collaboration with the sponsor slot assignments. The CRAs are also the first line of responders in periodically checking with sites in real-time about possible safety issues, especially DLTs, that may have not been reported and significantly impact the patient and the overall outcome of the trial.
- Study-Level Investigator Teleconferences: Monthly or bi-weekly teleconferences with all investigators take these daily communications to the next level. They involve discussions at a higher level – how the cohorts are managed, trends that are emerging, sharing of study successes, discussion of best practices supporting protocol compliance, and especially treatment scheduling to ensure minimal delays or conflicts between cohorts in treatment.
- Safety/Cohort Review Committee Meetings: The conduct of dose escalation studies requires the establishment of a safety/cohort review committee (S/CRC) to review patient treatment data and to evaluate the decision to further escalate the dose or establish a RP2D. Often consisting of each site’s investigator, the study team, and the sponsor, the coordination of these meetings can be time consuming and therefore it is essential to minimize downtime by forecasting the meeting dates as soon as the last patient in a cohort is enrolled in treatment. Additionally, at the start of the study we recommend establishing and sharing with sites the key data points, lab results, and safety information that must be recorded in the database prior to each meeting as well as the deadline to ensure timely provision of results for evaluation of dose escalation.
Leveraging Cohort Management
Cohort management can be completed on an ad-hoc basis, but it is much more effective and impactful when it follows a procedure. Not only will consistent communication and planning help streamline dose determination, but it also enables a more effective staggering of patient treatments and minimizes downtime. This further ensures that data is regularly available for the cohort review committee and that dose determination for the next phase of research is simplified.
Outlining the steps we take and repeating those same efforts in every study allows us to better monitor the process and ultimately refine it so that our studies are as efficient as possible. These tactics allow us to produce quality data documentation and ensure patient safety while completing early phase research in oncology and ultimately helping to make the world a healthier place.
Conclusion: Benefits of our strategy:
- Proactive approach to communication the minimizes downtime within and between cohorts
- Ensuring patient safety and evaluability through a Checkpointed patient pathway
- Timely availability of key data points for stakeholders decision making and MTD/RP2D determination
- Increasing sponsor study value while minimizing study expenditure