Related Articles
1. An Improved Trial Model
2. Measures of Success
3. The Clinical Investigative Site Network

Historically, the selection of countries and investigators for clinical trials has been based on a combination of unsubstantiated feasibility questionnaires and legacy familiarity with a core group of investigators. In this vein, the determination of the number of countries/sites and subject recruitment forecasting traditionally has been based on assumptions that all sites start at the same time and perform similarly. This leads to overpromising to deliver within timelines, as the variability in initiation and performance among the sites has not been accounted for. The result is familiar to everyone: Most trials are running behind schedule in terms of enrollment targets and other milestones.

This article introduces a more informative approach to site selection based on the analysis of past performance and how the review of epidemiological and demographic data can help identify the "golden site profile." The prestudy phase is a great opportunity to use current information and past experiences with similar studies to objectively pressure test site selection and performance assumptions. Furthermore, the article showcases how this data can be used to forecast subject recruitment timelines and measures, such as CRF page volume and CRA/monitoring and data management resource requirements, to predict and prevent overstaffing and waste as well as understaffing and delays. Indeed, it's not enough to be smart at the start. There is a clear need for continuous proactive mitigation of project-related risks across the entire lifespan of the trial.

Generally, disease indication and study design drive the degree of variability in observed recruitment rates. Less complex designs in more common therapeutic indications with fewer treatment options increase the investigator's familiarity with trial procedures and increase the pool of potential subjects.

The distribution of recruitment rates across sites is likely to be asymmetric. This may result in the minority of sites recruiting the majority of subjects, leading to deviations from the planned subject demographic profile in the final analysis population. If sites that recruit higher numbers of subjects per month can be identified (golden site profile), then potentially the recruitment rate of chosen sites can be made more symmetric and subject recruitment can be more evenly distributed across sites. High recruitment by each site is beneficial in terms of the number of sites required (and hence the budget) to meet recruitment timelines. However, it is important to ensure adequate site resources to cope with the increased volume of work and the need for early monitoring to capture subject evaluability issues early so that data quality remains high.

The development of this golden site profile begins, where possible, with the evaluation of historic data, preferably from protocols with similar inclusion/exclusion criteria. The objective is to look at aspects of sites that would appear to predict higher recruitment rates. If historic data from similar trials are not available, then trials from within the same therapeutic area or similar diseases may provide indicators. Even when historic data come from very similar trials, it is important to recognize the limited applicability of the data and the need for a study-specific feasibility assessment using the initial assessment of the golden site profile as a sampling frame.

The primary aim of the feasibility assessment should concentrate on confirming/refining the golden site profile against which potential sites can be compared during the subsequent site identification process. This is achieved through provision of a detailed protocol synopsis (under a confidentiality agreement) together with a series of questions relating to:

• site location and subject referral networks.
• site makeup (e.g., site resources, necessary equipment).
• anticipated subject recruitment and screen failure/drop-out rates.
• competitive environment (e.g., the number of other studies being concurrently conducted in the therapeutic area).
• reimbursement rates (it is sometimes useful to ask the investigator to specify the level of reimbursement that he or she would expect to recruit a subject into the trial. Although budgets should not be set based primarily on investigator feedback, the information is useful in assessing likely site interest moving forward).