In a multipart series, ICE Global Consulting’s Head of Site Readiness, Maria P. Ladd, explores factors leading to Site Start-up delays.
Part 1: Factors for Delays
During 18 years of working with study start-up activities, much of that involving the site start-up process of countless sites, I have had many occasions to wonder how it is that the best of intentions can be lost in the final product when it comes to activating sites on a clinical research study. It’s quite a lot of work to activate sites – often taking a herculean effort of large teams just to get to to the Site Initiation Visit (SIV). Why hasn’t much of a dent been made over time to get sites ready for activation more quickly?
Delays in site start-up are a historical issue in progressing clinical research studies. As an industry, there have been strides in technology to address some basics such as electronic documents and signature versus courier and wet ink, site binder systems on a shared electronic platform, etc. Overall, however, these individual solutions have not helped timelines. Little effort has been made to improve the basic process and address some of the core issues that are not fixed with standalone technology products. Despite years of bright minds and thought leaders observing the issues, the challenges persist.
A Well-Known Problem
Delays in the overarching study start-up will occur in most studies with the most common reasons noted below. Each study delay creates a downstream impact on the site work and adds to the myriad of opportunities for site-centric delays. With so many activities happening at once, issues as a by-product are inherently here to stay. How those are predicted, handled, and managed are the keys to smoother activations; although these are not the whole problem, they add to the site challenges.
- Site ID and Feasibility
- Protocol finalization delays – amendments and clarification documentation
- Delays with study templates such as manuals, CRFs, ICFs, etc.
- Regulatory submission and review delays
A large factor for site delays is based around resourcing challenges at the site, an issue made worse during the pandemic and not fully recovered. If resourcing is a primary issue, the problem can be exacerbated from the very beginning during Site ID and Feasibility, a laborious process by nature. While that should trigger conversations on the front-end of how to better support the site from the beginning, it many times does not – or if it does, there is rationale applied that does not address the underlying resourcing problem.
Even when resourcing is not a direct factor, it impacts as a secondary issue when there are not enough people available to do what is needed in real-time; study work is cyclical, requiring a
heavier effort up-front. Staffing could be a scalable aspect if the size of an organization and how much research is done there does not warrant a dedicated role(s) for time-intensive tasks. In these cases, the tasks are taken on by the clinical staff – juggling both the clinical and the administrative work of getting a study off the ground at the site.
Indications of when this may be presented as a longer-term challenge can be seen as early as the feasibility process. Care has to be taken to identify the best site fit for the study needs. However, what has developed over time is a process that has gained more and more steps for the site to complete. In an effort to get better information up front, the questionnaire can be very lengthy requiring multiple levels of expertise at the site to answer accurately. Sites may receive countless questionnaires, and time is needed for them to confirm a study is feasible to participate in. The questionnaires may be delayed for long periods or may not be accurate or complete when there is a push. Seasoned sites may be vague from the beginning, anticipating the changes that can come along in the middle of the process; during this period, changing and revised protocols can result in initial information provided by the site becoming obsolete or incorrect. Site staff can be overwhelmed early on, feeling rushed for information. Unless a site is selected, going through this process is unpaid work and can take a back seat to the work required for ongoing studies. The nature of feasibility is frustrating and if choices need to be made on where best to spend time, this work does not win the amount of time a site staff member has to give in the moment. Ultimately, a site isn’t selected until they complete the process, but the process can be so labor intensive that it takes an inordinate amount of time to get through; it’s a catch-22.
Study delays such as waiting for core documents for the ethics submission creates a vacuum that will be filled by the next most pressing tasks, bumping the newest award to the back of the line as often as a delay occurs. Sites operating at risk by moving ahead with submissions ahead of regulatory approval will have an advantage of conditional ethics approval when regulatory approval is received, but other work may have been pushed back while waiting. Delays that are not site centric to begin with manifest as if they were.
‘Study fatigue’ is a phenomenon that happens when sites have been involved in a study for a while, sometimes for years. The start-stop nature of studies getting off the ground so that sites can enroll can create an atmosphere of ‘start-up fatigue’ early on when multiple obstacles are encountered. Care should be taken with the number of changes made and communicated, ensuring that site staff don’t feel pulled back and forth. Many standard industry practices wind up resulting in re-work by the site, time not factored into the overall process.
Once past feasibility and site selection, sites are typically provided with a large file of documents to complete; robust instructions are provided with guidance of exacting criteria for the documents and a requested deadline for completion. The typical industry standard is to collect the documents, review, and return a long list of revisions needed to meet the criteria for completeness – the loop can feel endless and daunting. Even when there is a dedicated resource to complete the work, it takes a lot of time to complete and provide exactly what was requested. Various Sponsors and CROs have differing criteria and those change over time. It’s a time-consuming process to undertake amid activities such as ethics submissions, study training and the logistics of readying the site for enrollment and an influx of subject visits to conduct.
Getting From the Why to the How
From the outset of any clinical research project, there are risks of losing momentum before it’s even begun to take shape; the first step to decrease site impact is to make the larger issues invisible to the site. Underestimation of site resourcing, a lengthy feasibility process, delays on the study level that prevent site work – all of these can wreak havoc on site timelines. Many times, this is countered by adding more sites into the mix for selection with a race to see which ones can make it to the finish line and begin enrolling first. Multiply this scenario times the number of sites that are targeted for selection and the impact is not only protracted timelines but rising costs for Sponsors to
conduct the trial.
The issues are not insurmountable but are often not dealt with as a total package. These factors can apply to most clinical research studies but getting to the specifics when a site is selected is where the rubber meets the road. Baseline information can be predicted and accounted for but the real-time site factors on any given study make for understanding the unique challenges in the moment – we’ll dissect those and how they play into site activation in Part 2, Reasons for Delays.