Site selection and patient recruitment go hand in hand, and, in many cases, are handled by CROs as part of their mandate. It is increasingly important, however, that sponsors remain involved in the process to ensure that the right sites are chosen and the right patient populations are involved in a clinical trial. With the help of Rodney Butt of Hamilton Medical Consultants Group, Clinical Trials Insight examines the challenges of site selection and how sponsors can put the right processes in place to overcome them.

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The pharmaceutical industry has had a long enough history of clinical trials to understand the importance of site selection in the success of a trial, not least because of its impact on levels of patient recruitment. Nevertheless, there are still questions that need to be answered when it comes to understanding that relationship fully. Many sites selected for clinical studies still do not yield the anticipated levels of patient accrual, which can generate significant costs in terms of time and money.

Sponsors of clinical trials have many elements to consider when choosing a site. They must, for example, look at the experience of the investigator, the site’s track record from previous trials, its location and its proximity to a suitable patient population. Understanding its ability to successfully recruit the required number of patients from that population, however, is often extremely difficult.

One option would be to hand the entire process of site selection to a CRO, but this may simply result in a postponement of the problem rather than a solution.

"The correct selection of sites for clinical trials is a big challenge for CROs and sponsors as it has a direct impact on patient recruitment," says Rodney Butt of Hamilton Medical Consultants Group. "Sites have the ability to channel patients into different studies – your study or a competitor’s study – and one challenge that has never been solved is identifying the key processes in site selection that affect patient accrual, study start-up times and the ultimate success of clinical trials."

Butt, who is also an adviser on clinical operations and regulations at Discover Clinical Trials, and director of project management and quality systems at Nutrasource Diagnostics, chaired a session at the Drug Information Association conference in June, where many issues around site selection and patient recruitment were discussed. A key issue that emerged was the need for better data to come out of feasibility studies.

"Sponsors and CROs tend to use sites that they are familiar with and they use historical data to gauge the success of those sites, but with new sites they have to put their faith in feasibility studies, and it has been found that the data does not translate well into patient accrual. Patient recruitment is the biggest challenge in getting a trial up and running, and in making it successful," explains Butt.

"What we find is that 50% of anticipated patient involvement data turns out to be false, and usually a third of sites don’t get enough patients. That has a big impact on time lines as many sites don’t get patients in quickly enough. The bulk of patients tend to come from relatively few sites."

Supporting the sites

To increase the rate of recruitment across a greater number of sites in a trial, it may be tempting to assume that more money is needed. To some extent, this may be true in that sites need the right support, and that will cost money. It is not true, however, that throwing more money at patients will prompt more to sign up to a trial.

"Sponsors and CROs tend to use sites that they are familiar with and they use historical data to gauge the success of those sites, but with new sites they have to put their faith in feasibility studies."

The question is whether we are supporting sites well enough," says Butt. "Sponsors need to ask themselves if their budgets are sufficient to give sites the tools they need to recruit enough patients. Interestingly, we have found that paying them more than the average does not have a very big impact on rates of patient recruitment, although it is certainly true that paying too little will reduce the number of patients in a trial.

"The industry is asking itself what increases rates of patient recruitment, and is trying different tactics. Increasingly it is using social media because current patient recruitment in clinical trials is neither sufficient nor reliable."

Choosing the right sites depends somewhat on the stage a clinical study has reached. In earlier stages, the selection of sites may be more dependent on the need to reach specific patient populations, so a narrower range of sites may be suitable. In such cases, it may be possible to fall back on tried and trusted sites that are known by the sponsor or the CRO to be appropriate, and which have a good track record of patient recruitment. In later stages, however, where the aim is to reach as large a patient population as possible, it becomes more critical to engage new sites.

When it is imperative that late-stage trials of a drug encompass new sites, it becomes essential to identify sites that are likely to engage a sufficient number of patients, so the effectiveness of feasibility studies becomes crucial to the ultimate outcome of the study.

"In phase IV trials, you are trying to influence the marketplace and make people familiar with a new drug," says Butt. "You want to put the drug in the hands of as many prescribing doctors as possible. Then you need
as many sites as possible, so the phase of development certainlyaffects site selection.

"From a sponsor’s perspective, choosing the right site means looking to those that have a proven track record, but it also means having a selection process that is based on a reliable feasibility study, which should take months to prepare. You cannot leave it to the last minute to assess sites properly."

Butt highlights many issues that sponsors and CROs must consider when supporting the sites they have chosen for a trial, including new technologies such as those that can assist with the use of electronic health records. This means providing sites with an adequate technology infrastructure to support the new era of clinical trials. Furthermore, an adequate budget must be provided, taking into account that paying too little will reduce rates of patient recruitment but paying too much will not be of additional benefit.

At the top of the list of considerations, however, is time. The more time that is put aside to bring new sites onboard and prepare them to be an active part of the investigation process, the better the outcome is likely to be.

A question of engagement

In Butt’s experience, there is a temptation in the pharmaceutical industry to underestimate the amount of time it takes to properly involve a new site in a clinical trial. Though this may be understandable, given the complexity of running a trial, it should be avoided at all costs.

"Not taking enough time is a big risk in the industry," says Butt. "Site selection is just one process that happens alongside many other processes. It is critical to the success of a trial that after sites are selected they are also engaged properly. This means doing the preparatory work so that at the investigator meeting the sites already understand important elements such as the inclusion and exclusion criteria.

"The industry is asking itself what increases rates of patient recruitment, and is trying different tactics."

"You need to take time to engage sites, although in some cases this may not be so crucial. For studies looking at acute conditions, such as when a patient comes in with a stroke, then different rules may apply, but for studies looking at chronic diseases, the engagement of sites is critical. Not only must you consider if the site is suitable for the drug being tested, you must also look at whether there are competing trials going on there."

Sites will often be host to a number of clinical trials simultaneously. For sponsors, therefore, it is vital to ensure that a sufficient number of patients is guided to their trial rather than that of a competitor. That is where the engagement process plays such an important role.

"A CRO may have a database of 27,000 sites, but only ten may be suitable," explains Butt. "In those ten, there may be competing trials, so you need to engage to get patients into your trial and you cannot achieve that overnight. The relationship between sponsors and sites is crucial."

In many cases, the engagement process may be handled completely by CROs, but Butt warns that this should not be assumed to be the ideal scenario.

"CROs can help the sponsor with engagement, but the process should not be left to them entirely," he says. "At the end of the day, the sites are groups of physicians who will be prescribing the drugs, so their relationship with the sponsor is essential. Also, the FDA said in 2012 that sponsors have an important role in managing the activity of CROs and clinical trials. So, sponsors must have adequate control over the work of CROs. The buck stops with them."

For sponsors and CROs alike, time is the essential ingredient in site selection, as a well-paced and considered approach to choosing the right site and engaging with investigators will ultimately avoid any waste of time and money at the end of the process.