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Blog: Site Selection

How do you find the right sites for your clinical study?

The world has changed a lot in the last 18 or so months. The COVID pandemic caused us to rethink the way we do a lot of things. How we shop, travel, even visit with family and friends had to be reimagined and re-engineered. It is no surprise that the healthcare world, and clinical research along with it, had to make adaptions as well. The use of technology skyrocketed with the number of telemedicine visits reaching higher levels than ever before. Physicians who had sworn they would never interact with patients over a computer did so to ensure patient care. Clinical trials quickly shifted gears to find ways to keep going when patients could not come in for study assessments. The focus truly shifted to ‘what do we need to do to take care of the patient’, with this focus remaining even as the effects of COVID wane.

As clinical trials are getting back to “normal” and new trials are beginning, many are re-examining the way sites and investigators are selected for study participation. Given all we learned during COVID, should we change the way we choose the sites who work on our clinical trials? Are we looking for the right things at the right sites?

Choosing the “right” sites is critical as 80% of trials fail to meet enrollment goals and 30% of phase III trials terminate early due to enrollment difficulties.1  Why does this happen? Is it solely because of the site’s ability to enroll? Or could it be because the sites weren’t the appropriate ones to select?

Traditionally, Sponsors look for sites that “can do” the study. What does this mean? Per ICH regulations, Section 4, the investigator(s) must be qualified by education, training, and experience to conduct the trial. An investigator also needs to have the appropriate resources and facilities to conduct the trial, as well as sufficient time to provide oversight of the study’s conduct. ICH Section 5.6 states that it is the Sponsor’s responsibility to confirm this of the investigator(s) that they choose to participate in the trial. However, being qualified and having the resources and facilities are only part of what is needed to successfully participate in a clinical trial.

Identifying appropriate sites for a given clinical trial can be based on many different factors. Typically, Sponsors like to use sites with they are familiar with or have used in previous trials. While this may have some advantages, such as experience with a site’s start-up timelines, contracting templates, study staff, etc., performance on a prior study is not necessarily a good predictor of performance in a current study. Each protocol and study are unique. There may be different eligibility criteria, testing requirements, study durations, dosing requirements, etc., all of which will affect a site’s ability to enroll the study.

Another important way to identify sites is through contact with patient advocacy groups, especially when the trial focus is a rare disease. These groups are well placed to provide information about the doctors who work in the field,  who the patients see for current treatments, other trials the patients have participated in, their experiences, and the type of trials they would be willing to part of in the future. This information can be invaluable not only for identifying sites, but also when designing a protocol.

Other resources for site identification are websites such as clinicaltrials.gov, Clinical Trials GPS (clinicaltrialsgps.com), and canadatrials.com.  Searching by therapeutic area and/or indication can help find the sites that are working on, or have worked on, similar studies. Also looking at the eligibility criteria and/or the sites’ enrollment for a particular study can identify additional possible sites.  This information can produce an initial list of sites, which can then be further analyzed to determine if the sites have the qualifications for the study you wish to run.

Typically, a feasibility questionnaire is sent to prospective sites to gauge their interest in a new study.  Depending on whether a confidential disclosure agreement (CDA)) is in place with the site, a copy of the protocol (draft or final) may or may not be shared with the site at this point. Providing sites with the most information possible, so they can make an informed decision about their ability to find and enroll appropriate patients, is the best way to help identify appropriate sites for the study.

Once the initial feasibility questionnaire is returned, the responses should be evaluated and ranked or compared with the other sites’ responses to determine which sites are most appropriately positioned to participate. It is important to identify the key criteria in advance that are vitally important for the sites to have to ensure their success. For example:

  • Does the site need to have previous clinical trial experience in this indication?
  • Does the site need to have multiple sub-investigators?
  • Does the site need to have a certain number of eligible patients in their database?
  • Is it acceptable for the site to be working on a competing trial?

There are many criteria that can be considered, but it is helpful to make a list ranked in order of importance to help determine which sites are best equipped to participate.

Once the initial assessment is complete, more information will likely need to be obtained from the sites via additional questionnaires, phone calls, e-mails, etc.  It is best to speak with different members of the site staff when compiling the information to gain a variety of insights. Members of the Sponsor and CRO team should also collect this information as each person will potentially ask the questions in different ways. All perspectives and information gathered should be evaluated and used when determining whether a site is appropriate for a study. Remember, it is not only the site that needs to be considered, but also the protocol and the subject population to be recruited. Can the site effectively execute the protocol?  Does the site have access to the right patients? Does the site have the means to successfully recruit for the study? Some of these answers cannot be found just by checking boxes. They can only be found by speaking with the site staff, gauging their interest and enthusiasm about the study, and often physically assessing the site to ensure all required aspects are present.                                                                                                                  

Being able to accurately determine if a site has access to the target patient population for the study is one of the key components of site selection. Estimates of the total patients in the practice and how many of the patients have the target clinical condition may be included in the questionnaire. Also determining an investigator’s usual treatment practices may help determine if the site’s patients will qualify for the study.

Next, an estimate of how many patients may be eligible for the study and, of those, how many the site thinks they could enroll in a given enrollment timeframe, is calculated. Sites often will estimate these numbers based on their current patient volumes. However, is this the best method to use? Sites provide more accurate estimates when given the actual protocol with which to evaluate the inclusion/exclusion criteria, rather than with just a general description of the study.

Questions for how sites will identify and recruit patients, as well as on any anticipated barriers, are also valuable. For example:

  • Do the patients live close to the site, or will there be travel considerations?
  • Is there competition for the patients from local or regional medical practices?
  • Are there competing clinical trials?
  • Are there requirements for specific or limited prior therapies that may impact eligibility?

The answers provide important pieces of information when sites are evaluated for participation. Of note, if the site and proposed principal investigator are key leaders in the clinical realm for the given indication, even limited enrollment may be acceptable. This is because the expertise they can provide to the trial may be more valuable than the patient enrollment.

Study design may also impact a site’s ability to participate. Trial requirements such as managing and maintain blinding, detailed medication preparation, extensive pharmacokinetic sampling, or other study procedures that are time or resource intensive may make a study impractical or challenging for a site to implement. These specialized requirements should be clearly outlined to the site in the questionnaire so that sites can factor this into their responses.

The protocol requirements may also impact the resources required for the site to participate. For example:

  • Who is the proposed principal investigator (PI) for the trial?
  • Does the PI have the time and expertise to oversee the study conduct?
  • Does the PI have active involvement in the target clinical area?
  • Which staff members can the site dedicate to the trial?
  • Do the staff members have research experience?
  • How many sub-investigators will be involved?
  • How does the site manage the study coordinator, regulatory, and data management tasks required for the trial?
  • Does the site have a proven track record for timely date entry and regulatory document management?

Determining if the study will have sufficient staff and time to manage the trial is critical, especially if the accrual will be fast or labor intensive.

Finally, the start-up process and timeline are critical to site evaluation. Determining if additional internal protocol reviews are required by a site in addition to IRB review is extremely importance. Academic centers may have multiple internal committees that must review the study, which can add weeks to months to start up timelines. The use of a central IRB, versus a local IRB, may shorten timelines for IRB approvals. General timelines for clinical trial agreement execution, including the study budget, must also be considered. Contracts often take many months to execute, and this time must be considered when evaluating sites. Some sites can work on contract and budget execution in tandem with committee/IRB review, while others must work on one after the other. It is also helpful to know historically the average time from site initiation to first patient enrolled for the site.

Unless the Sponsor/CRO has recent experience with the site in the same or similar indication, the next step will be a Pre-Study or Qualification Visit. A clinical research associate (CRA) on behalf of the Sponsor will visit the site to perform a more in-depth evaluation of the site capabilities and fit for the study. During the visit the CRA will meet with the proposed principal investigator and study team to review the protocol requirements and discuss the feasibility, recruitment plans and goals, and study team responsibilities. The CRA will assess the facilities and their fit for the study. This information, combined with the information from the feasibility questionnaire, provides the data for the Sponsor to determine the final sites best suited to participate in the trial.

In determining the selected sites, the top factors are the availability of the relevant patient population; the ability of the site to recruit the patients in a timely manner; and rapid, or at a minimum reasonable, start-up timelines. If it is determined that a site can meet all the basic requirements, it is also important that they demonstrate enthusiasm, interest, and commitment to the trial, often shown by timely and open communication.

Despite diligent efforts by the site, CRO, and Sponsor to determine if a study and site are a good fit, sites often do not deliver on their projected enrollment. Timelines are not met, the trial is delayed, costs are increased, and, most importantly, evaluation of the safety and effectiveness of a treatment is delayed. According to an article by Johns Hopkins University (2015), 70% of clinical trials experience start-up delays. This contributes directly to the 45% of clinical trials that are completed late.2

 Site selection is not a simple process. There is no magic formula, one-size-fits-all, or even one-size-fits-most, equation that can be applied. Even reuse of sites that have performed well for the Sponsor in prior studies may not guarantee the desired results. A systematic review of each site’s qualifications, limitations, resources, and capabilities pertinent to each study protocol needs to be carefully conducted to determine if the site will be successful with trial participation. Site selection involves a lot of hard work and communication with prospective sites to ensure the ones who best fit the protocol and requirements of the study have been selected.

Sources:

1  https://www.pharmoutsourcing.com/Featured-Articles/333830-Clinical-Trials-A-Data-Driven-Feasibility-Approach/

2 Johns Hopkins University.  (2015).  Successful Pharmaceutical Study Start-Up:  Key Steps for Investigators. 

Dombernowsky, T., Haedersdal, M., Lassen, U. et al. Criteria for site selection in industry-sponsored clinical trials: a survey among decision-makers in biopharmaceutical companies and clinical research organizations. Trials 20, 708 (2019). https://doi.org/10.1186/s13063-019-3790-9

A Review of Patient Recruitment and Retention Practice Benchmarks Impact Report, Tufts Center for the Study of Drug Development, Vol. 15, No. 1, Tufts University, 2013

Critical Success Factors for Planning for Site Selection and Patient Recruitment Planning by Beth D. Harper and David Zuckerman; BioExecutive International – 2006 Supplement Series – June

Selecting Study-Appropriate Clinical Sites in 3 Steps; Anais Silva, 11 April 2018.  Applied Clinical Trials.

Site selection – identifying high performing clinical sites: An Insider’s Insight;  Karen Chalk  Copyright 2017 Niche Science & Technology Ltd., UK; Medical Document Templates | Niche Science & Technology

https://www.fdareview.org/issues/the-drug-development-and-approval-process/

https://www.appliedclinicaltrialsonline.com/view/selecting-study-appropriate-clinical-sites-3-steps

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3790-9

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