More Than Document Collection: The eTMF As the Conductor of Study Start-Up Part 1 – Site ID and Selection
Study start-up (SSU) is all about speed, because in the costly world of clinical trials, time is literally money. A recent study places the cost of the median Phase III clinical trial at nineteen million dollars[1], and a typical Phase III trial may take between one and four years to complete. A study conducted by the Tufts Center for the Study of Drug Development found that start-up for an individual site (pre-visit to site initiation) takes about eight months, a significant portion of the overall time and expense of a clinical trial[2]. Clinical trial delays can cost a sponsor between six hundred thousand and eight million dollars per day[3], but despite the high stakes and costs, 11% of selected sites are not activated[4], and in a given trial, 30 to 70% of sites will fail to deliver a single enrolled patient[5].
Based on the available research, SSU is a resource-intensive non-optimized process that is ripe for improvement. As TMF professionals, we play an outsized role in SSU, especially during essential document collection. The essential documents required by GCP are collected from sites to lay the foundation of the story of a clinical trial in the TMF. These are the documents that “permit evaluation of the conduct of a trial and the quality of the data produced”[6], and approximately 50% of artifacts from the TMF Reference Model are collected (at least in their first iteration) during SSU.
SSU, however, is not just difficult because of the number of documents collected but because of what those documents represent—many critical and interdependent events occurring simultaneously. These events include site ID and selection, site activation, clinical supply set-up, vendor and logistics set-up, CTA and budget negotiation, regulatory/ethics approval, and the aforementioned essential document collection. Each individual event is like an instrument in an orchestra. There are individual sites, stakeholders, regulatory requirements, and documents. Each has their own location, identity, and score, but all must move in harmony to produce a symphony.
What SSU needs is a conductor, and the eTMF is capable of filling this role. In this blog series we’ll examine some key events of SSU, and show how an eTMF, when used to its full potential, can play a central role in mitigating the drivers of delay by helping the many stakeholders of a clinical trial work together. In this post, we’ll discuss how the eTMF can mitigate the main drivers of delay in the site ID and Selection process.
Site ID and Selection
Site ID and selection is the process of discovering and identifying qualified investigators and sites, conducting feasibility activities to determine the characteristics and abilities of those sites, and then selecting the investigators and sites that best fit the requirements of a clinical trial. Common SSU delays related to site ID and selection include:
Site Scarcity: There is a shortage of qualified investigators and clinical research sites. Due to many factors, including growing regulatory expectations, increasing clinical trial complexity, and diminishing financial incentives to conduct clinical research, more than 50% of clinical investigators are considered ‘one and done,’ meaning the site’s investigator decided not to pursue clinical research after their first clinical trial. As a result of the scarcity of qualified sites, many sites have inexperienced staff, high investigator turnover, and/or are already committed to similar studies. In niche or popular areas of clinical research, investigator availability can indefinitely delay a development program.
eTMF Solution: Leveraging the potential of the eTMF can help alleviate this challenge in several ways. eTMF technology can help reduce the number of staff needed to manage the regulatory expectations of clinical research, especially the administrative burden surrounding essential documentation. Reducing administrative burden decreases staff turnover and should also lower the high turnover rate of investigators by increasing the profitability of site participation in clinical research. eTMF technology also allows the sponsor and CRO to provide greater administrative support to clinical trial sites, further incentivizing investigator participation. Finally, the overall increase in site efficiency from eTMF and eReg Binder technology allows experienced sites to execute more protocols with the same number of resources, which has the potential to reduce the severity of the site scarcity problem.
Poor Feasibility Assessment: Assessing principal investigator and clinical trial site feasibility (the ability of the site to meet trial performance goals) is central to the role of the sponsor and a main component of the sponsor’s duty to select and oversee qualified investigators. As discussed above, 11% of selected sites go on to enroll zero patients, a massive squandering of clinical trial resources. Feasibility is the sponsor’s main opportunity to eliminate this waste and supercharge trial performance with the right portfolio of qualified sites that can fully enroll a clinical trial.
eTMF Solution: eTMF technology can greatly reduce the cost and improve the effectiveness of the feasibility assessment process by preserving valuable information about historical site performance and patient population. Of course, the information collected by a feasibility assessment, like a questionnaire, will only be valuable if the questionnaire collects useful information in the first place. The eTMF can greatly aid the development of a well-designed feasibility questionnaire through its reporting capabilities by generating quantitative metrics that are easily probed by the feasibility questionnaire format. Additionally, the eTMF, by allowing easy access to a record of past site performance, ensures poor or non-enrolling sites can be excluded from future trials, high performers can be continually presented with new opportunities, and concerning metrics, like high staff turnover or unusual screen pass/fail ratio, can easily be identified and investigated.
Inefficient Selection Process: Once a feasibility questionnaire is returned by a site, the real work of a clinical trial begins. In many cases, a CRA will need to tour the site as part of a selection visit. It’s not always possible to send a CRA familiar with the disease area, site, or protocol, so the usefulness of the site selection visit can vary. Despite the potential inefficiencies, site selection activities are an important part of verifying the information collected during the feasibility assessment.
eTMF Solution: The eTMF can greatly improve the efficiency of the site selection process in two primary ways. First, the eTMF is an invaluable source of site performance information that, when used to its full potential, produces reports that allow a largely qualitative and subjective selection process to become quantitative and evidence-based. Second, the eTMF can be used to standardize the process of conducting selection visits and to ensure the expected information is collected during those visits, regardless of the CRA conducting the visit. The eTMF also has the potential to eliminate an in-person site selection visit, especially for repeat sites, through remote monitoring capabilities. Eliminating the need for an in-person site selection visit could potentially reduce the time between selection and activation by weeks or months.
Site ID and selection may have more responsibility for the success or failure of both SSU and an entire clinical trial than any other part of clinical research. Poor site selection leads to low enrollment, extended timelines, compliance issues, and can even jeopardize patient safety. Selecting appropriate sites, with the right patient population, the right expertise to successfully collect data, and the right culture is a steep initial investment in the long-term success of a clinical trial, but it is a necessary one. Even short delays to SSU cost hundreds of thousands of dollars. The eTMF is your best tool for building a portfolio of quality investigators, producing evidence-based actionable insights from historical data, and streamlining the activation process for your most experienced and accomplished investigators.
[1] https://bmjopen.bmj.com/content/10/6/e038863.full#F1
[2] START Study Tufts CSDD, 2012. Ken Getz’s presentation entitled: Uncovering the drivers of R&D costs.
[3] https://acrpnet.org/2017/02/01/accelerating-study-start-up-the-key-to-avoiding-trial-delays/
[4] https://www.statnews.com/2018/03/28/clinical-trials-startup-speed/
[5] https://www.pharmexec.com/view/site-activation-key-more-efficient-clinical-trials
[6] https://www.fda.gov/files/drugs/published/E6%28R2%29-Good-Clinical-Practice–Integrated-Addendum-to-ICH-E6%28R1%29.pdf