In part one of “Uncommon Patient Recruitment Strategies in Alzheimer’s Disease Clinical Trials”, Talking Trials discussed the recent clinical trial enrollment challenges for early phase Alzheimer’s disease clinical trials. Though not traditionally considered, the exhaustion level and recruitment fatigue of clinical trial site staff due to fast moving and unpredictable patient enrollment scenarios has become a potential barrier to efficient management of these early phase, or “cohort” studies, which are characterized by a relatively small number of patients being enrolled at each dose or cohort across one or more clinical sites. Too often the result is sluggish recruitment and randomization which leads to missed timelines, potentially putting funding or other critical milestones at risk.
Cohort Study Optimization Can Increase Predictability, Decrease Recruitment Fatigue
In part two of the series, we examine Worldwide Clinical Trials’ uncommon cohort optimization strategy in early phase Alzheimer’s disease clinical trials that initially promised to:
- – increase the predictability of timelines,
- – stabilize patient enrollment fluctuations,
- – master the timing and unpredictability of complex cohort study designs,
- – fight recruitment fatigue and
- – ensure that all eligible patients who can be randomized actually are randomized.
At the foundation of this clinical trial recruitment strategy is a “virtual waiting room” using sophisticated interactive response technology (IRT) which enables proactive management of patient enrollment/randomization, dosing/drug dispensation, clinical supply logistics, drug inventory management, unblinding, etc.
This virtual waiting room was designed to permit clinical trial investigators to recruit patients on an ongoing, rolling basis in a “next in line” approach that would permit multiple sites to simultaneously enroll patients into a single cohort, while continuing to recruit for the upcoming cohorts. In this design, patients recruited who meet eligibility criteria when randomization is closed for a specific cohort are simply placed in the virtual waiting room while screening activities continue for the subsequent cohorts. This patient recruitment solution is intended to stabilize recruitment efforts and patterns in early phase Alzheimer’s disease clinical trials such that sites do not have to be shut down and started back up multiple times.
Forecasting Metrics Such as Last Patient Visit in Each Cohort Can Be More Easily Achieved
By utilizing a virtual waiting room, the appropriate patient enrollment of each individual cohort can be more easily managed simply by proper programming of the IRT to ensure that all eligible patients are randomized, that there is no over-enrollment within the cohort, and that the time between cohorts is minimized. Importantly, forecasting important metrics such as last patient visit in each cohort can be more easily achieved. As many sites requiring local investigational review board or ethics committee approvals take longer to start up, they are at a disadvantage in patient enrollment compared to sites that use central review. Worldwide’s uncommon IRT-assisted clinical trial recruitment strategy permits an equal opportunity for all sites to enroll in a particular cohort despite regulatory clinical trial enrollment challenges.
In addition, IRT can be utilized to successfully manage the appropriate dosing and often complex timing/tracking requirements mandated per protocol in early phase Alzheimer’s disease clinical trials. For instance, in a classic cohort study design which requires sentinel dosing, in which the first one to three patients dosed within each cohort are more strictly monitored to determine tolerability for a given time period prior to administration of the next dose. In this situation, the IRT can be designed to effectively halt patient enrollment not just within a site but across sites, to ensure that there is no additional enrollment until the requisite time period is met1. Additional “breaks” may be implemented to ensure that all safety parameters are observed, i.e. no further dosing proceeds until a one-week period has occurred following the dose of the “nth” patient in each cohort, depending upon study specifications. The IRT can simply restrict further randomization until this or any time parameter is met.
Technology Enables Modeling of Enrollment Curves to Reflect a Specific Cohort
Importantly, information that is typically used to generate patient enrollment curves across an entire study can also be modelled to reflect a specific cohort, and this model can vary from cohort to cohort. For example, enrollment rates may be very low in the first cohort but peak by cohort number three or four as the “virtual waiting room” fills with appropriate patients.
Screen failure rates also vary with cohort succession, with the highest rates usually evidenced in the first cohorts and then continually declining over successive cohorts or until the investigators’ patient database is depleted. These cohort metrics can be used to estimate the number of early phase Alzheimer’s disease clinical trial sites needed to enroll at any one time period, noting that not all sites need to be actively recruiting at the same time. For example, in a common single ascending dose/multiple ascending dose (SAD/MAD) study of 10 cohorts enrolling eight patients per cohort (six drug and two placebo) it may be necessary to launch at least 12-16 sites overall, although only six to eight would be active at one time with three to four utilized for the last two cohorts only, especially if the last cohort is expanded in terms of sample size or treatment duration.
Unique Approach to Managing Screen Failure Saves Weeks per Cohort
It is important to note, however, that those sites activated last should not be viewed as “back-up” sites as it is imperative that they are initiated and fully ready to screen early on in the timeline. Also note that Worldwide’s uncommon cohort optimization strategy and patient recruitment solutions requires adding screen time for patients currently in the virtual waiting room, with an average screen time of 42-49 days recommended. The benefit of this increased screen time is that it allows patients to be in the virtual waiting room for longer periods of time and not be screen failed simply due to the screening time elapsing.
Even though this recommendation of 42-49 days may be two to three times longer than the screen times in typical SAD/MAD studies, this time is more than recompensed over the length of the entire cohort study conduct. In fact, Worldwide’s experience in a recent set of early phase Alzheimer’s disease clinical trials suggests that the use of IRT-assisted cohort optimization saves an average of 2.9 weeks per cohort. In a 10 cohort SAD/MAD study, the overall timelines were reduced by over six months compared to studies conducted using a standard approach to recruitment.
More Accurate and Timely Review of Safety Data is Achieved
In addition to promoting continuous recruitment efforts across clinical trial sites, IRT also permits increased data vigilance enabling more accurate and timely review of safety data. In cohort studies, a review of safety data is typically required prior to escalating to the next cohort and the parameters for the advancement to successive cohorts can be incorporated into the IRT specifications. For example, once the nth patient in a cohort completes a certain visit (nominally week four or six visit), the site is required to enter all data into the electronic data capture (EDC) system within 24 hours of the patient completing that visit.
Hematology and chemistry lab results should be returned to the site minimally two days after being drawn and therefore would be available for monitoring by the designated site monitor and/or physician. The regional monitor could then plan their visit to the site two days after the patient completes the week four or six visit.
This would ensure that all relevant data is monitored, cleaned and available prior to the cohort safety review meeting. Once analysis of any pharmacokinetic, pharmacodynamics or biomarker variables have been completed, data management can run the appropriate patient profiles or listings required for the cohort safety review meeting.
Continue on to the final installment of this three-part series concludes the discussion of technology-assisted cohort optimization as part of our uncommon clinical trial recruitment strategy.
Reference
- Byrom B. Using IVRS in clinical trial management. Applied Clinical Trials. 2002; 10: 36-42
