Victor Muts, PhD

	One of my former colleagues working in an emergency department once admitted that his job was reasonably good unless new patients were coming. For the study sponsor, however, the trouble starts when the patients do 

come in as planned. And this is quite a typical problem.

	Indeed, as much as 80 to 86% of clinical trials do not reach recruitment targets within their specified time period [1, 2], and about 19% of all trials are terminated altogether due to inability to reach the recruitment goal [3]. 

	The subject recruitment challenge is quite typical for clinical research industry and is not necessarily limited to a rare disease setting only. When the operational teams face this challenge, they quite often resort to solutions associated with casting an ever wider net. In this case the most obvious choices are advertisements, referrals, and additions of new sites or even new countries. All these solutions take time, effort, and inevitably make a considerable dent in study budget. If the patients cannot be found at the local sites, the teams may be tempted to consider the scenarios with international subjects being referred to the existing study centers, thus obviating the need to open additional sites. The latter sounds like a viable solution, but is it indeed the one?  

	There are several important factors which should be considered prior to resorting to international patient recruitment. Many of them apply not only to transatlantic travels, but should also be factored in when patients are moving within EU or across different states in USA.

. Some countries do share the same (or very similar) language as it is the case of Brazil and Portugal, or Spain and Peru, or Austria and Germany. Caution should be exercised regarding various questionnaires and scales, however. C-SSRS for instance, exists in 13 Spanish, 12 English, and 6 French versions, each of them applicable to a certain country. Depending on the specific country pair, adjustments may need to be made to the ICF wording (with appropriate customization, review and approval process) as well as to any other patient facing document… thus the process is not necessarily as straightforward as it sounds.

. Depending on the complexity of the travel, but even more so-on the age and medical condition of the potential subject-there may be the need for one or even two caregivers traveling along with the patient. This adds incremental costs to airfare, ground transportation, and subsistence. Having a whole family visiting the study center just to ascertain that the patient is a screening failure is an investment that everyone wants to avoid. In case of international travel and multiple patients being referred at roughly the same time, the impact will inevitably be more pronounced. Then a financial dilemma could occur if the subject does get randomized: traveling back and forth to the home country in-between the visits adds to travel budget, whereas staying close to the investigational site throughout the whole study offsets significant amounts in subsistence costs. One way or the other, the expenses will have to be reimbursed as otherwise the patient may well run out of money away from home and being in need of medical attention due to the underlying disease. An amendment to the site contract may be warranted, or as an alternative solution, a third-party vendor will need to be involved to process the receipts and issue reimbursements. Both scenarios take time to implement and should be considered and carefully evaluated from the very beginning. 

	Finally, as the patient will likely be reimbursed significant amounts of money, there is a question regarding potential coercion and undue incentive to join the study or stay in it. Local IRB/EC may well need to review the whole scenario and issue their opinion: what exactly can be billed and the maximum reimbursable amount is a bit of a gray area for ex-USA locations and the actual regulations can be very different depending on a specific country. The USA sites are in a better position because FDA has recently updated the guidance regarding payment to study subjects [4] where it is noted that “…in contrast to payment for participation, FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence”. Other countries should still implement a similar or alternative guidance to resolve patient reimbursement dilemma, as FDA guidance may not apply, especially in EU.

may well be impacted by the combined brunt of international travel with jet lag, climatem and dietary changes, all of which could exacerbate the disease or modify its signs and symptoms. Even subject eligibility for the study may be affected after extensive travel to the investigational site. While more subtle changes will still render the patient eligible, they may modify the baseline sufficiently to even question reliability of data received for this particular subject. As a result, it may be advisable to seek the opinion of the medical monitor and/or the treating physician in case international recruitment is on the agenda. The discussion with the treating physician should always be considered, even if the case seems to be very straightforward. A thorough review of the patient’s medical history, concomitant medications, and the current status prior to making travel arrangements may exclude a grossly inappropriate subject in the first place. Yet it may still be a challenge to have all relevant details reviewed and discussed between the physicians in different countries due to privacy laws and other considerations. The referring doctor should know enough about the study (which in itself is difficult to achieve without separate training) to ascertain subject eligibility and make sure that joining the study in a different country might indeed be in the best interest for the patient.

involved in international recruitment scenarios can be extensive, sometimes rendering the whole endeavor not practical. In particular, the insurance company providing coverage for study subjects may approach the case differently depending on whether the patients in question are local or international. The terms and conditions will have to be verified and an add-on insurance may need to be arranged for, depending on a specific situation. Another typical challenge for patients traveling overseas can be visa regimen and bilateral migration agreementsbetween referral country and destination country. In many cases, the patients may still need to secure the paperwork necessary to enter and/or stay in a given country. The responsibilities of all parties involved (study sponsor, CRO, PI, referring physician, patient) will have to be outlined clearly from the very beginning as the penalties associated with overstaying the visa can be harsh, up to and including imprisonment. Even if the consequences are relatively minor for the first offense, the subject will likely face significant difficulties entering the destination country next time if a follow-up visit, or indeed an open label extension, are considered. 

can be complex enough in a conventional clinical trial setting, but in case of international recruitment the associated considerations may be even more convoluted. E.g. if the patients do travel back to their home country in-between the visits, separate provisions may need to be made in order to bring the study drug along. For instance, the latter may turn out to be a scheduled medication in patient’s home country (or might require specific import license and/or prescription). Thus associated homework should be made in each individual case. If the IMP exists in a liquid form and the bottle volume exceeds 100ml, the IATA letter may have to be arranged for before the patient boards the flight; if it is temperature controlled, some unconventional logistical solutions might also be warranted. 

	It is hardly possible to anticipate all potential roadblocks in case international subjects are considered for a study, so it is always a good idea to brainstorm and review all aspects, including local regulations, timelines, cost, and alternative solutions. Even though it is a complicated endeavor, having referrals from other countries may work with careful planning and on a limited scale. 

	When the patient recruitment lags behind, it typically means issues with the study itself, and there may be multiple reasons in the background, some of them being inappropriate study design, poor investigator selection, insufficient number of sites or inadequate geographical coverage, overly complicated procedures, competitive trials, suboptimal grant amount, or site relationship issues. Casting a wider net is always tempting as a universal solution, but it may be more productive to try and see what can be done at the existing sites instead to bring the study back on track. In other words, if one takes the time to water their own grass, it would be just as green as the grass on the other side.

	1. Grant D. Huang et al. Clinical trials recruitment planning: a proposed framework from the Clinical Trials Transformation initiative. Contemporary Clinical Trials, Volume 66, March 2018, pages 74-79
	Available at: 

https://www.sciencedirect.com/science/article/pii/S155171441730753X

	2. Daniel Garrun. Clinical trial delays: America’s patient recruitment dilemma. 18 July 2012. 

https://www.drugdevelopment-technology.com/features/featureclinical-trial-patient-recruitment/

	3. Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: An empirical analysis of recently closed trials. 

	4. Payment to research subjects – information sheet. Guidance for institutional review boards and clinical investigators. FDA, office of Good Clinical Practice, Updated Jan. 25, 2018. 

https://www.fda.gov/RegulatoryInformation/Guidances/ucm126429.htm

Associate Project Director, CNS, Syneos Health

Articles

There are several important factors which should be considered prior to resorting to international patient recruitment.

International Patient Recruitment: The Grass is Not Always Greener Abroad

	Whenever a new clinical study is in planning stage, the operational teams are busy trying to locate recruitment data from similar previous studies to project the number of sites needed, forecast study timelines, and make other seminal decisions. It goes without saying that having the reference data always helps and this is definitely a good benchmark; however, there are several considerations suggesting that the historical figures should be taken with a grain of salt.

	The problem is, trials are never identical. Apart from well documented differences (inclusion/exclusion criteria, study design, study footprint, etc.) there are less tangible, but no less important, considerations.

	One of the most crucial factors in achieving rapid subject recruitment is having motivated sites. It is easier said than done to achieve this goal. The ops team must secure a beneficial combination of agreeable study design, appropriate grant amounts, low competition for time and resources from rival projects, as well as a host of other factors. Site CRAs can also have a tremendous impact on overall site enrollment.

	Furthermore, the sites are becoming increasingly sensitive to any logistical/administrative hiccups in clinical studies and this may severely impact team motivation as well as subject recruitment rates. As a real life example, in a recent oncology study a central histology lab had been utilizing very low threshold values according to instructions from the study sponsor, so that even minute receptor expression could be flagged. This increased sensitivity resulted in multiple discrepancies with local lab reports and since the PIs had no reason to distrust their local colleagues, study teams were having heated discussions about the credibility of reports generated by the central lab. During the study close out meetings, many KOLs commented that they wouldn’t bother screening in any future study utilizing the same central laboratory, so the recruitment rates from this recent study can’t be taken at face value. Long story short, if a given site was motivated yesterday and recruited well, it does not automatically mean that the same will apply tomorrow, even for a sister study.

	Indeed it is of utmost importance to have the right mix of study sites to ensure that the trial is successful, thus both the study sponsors and CROs are working hard to attract and retain top recruiters, utilizing various strategies. For obvious reasons, top recruiting sites will gravitate more towards successful companies, oftentimes entering into preferred provider relationships. The data obtained as part of this collaboration may prove to be difficult to be extrapolated to prospective trials utilizing a different site relationship model. Also, as a side note, the site which is more motivated than the others will tend to encourage prospective subjects to classify their symptoms as more pronounced in order to become eligible and join the trial, so high recruitment rates in this relationship model might be associated with questionable data.

	Study start up times can also impact a site’s ability to enroll patients in clinical trials. If there are delays in the time it take for that site to be initiated and ready to start enrolling patients then any patients lined up for that protocol may/will be enrolled in whatever else is ongoing at that site.

	The other consideration which is becoming more and more important nowadays is neuromarketing and creation of high expectations for the study drug. In an increasingly competitive market, pharmaceutical companies frequently go out of their way to promote a potential blockbuster as early as during Phase I. This boils down to more aggressively marketed trials being more successful in recruiting subjects, all other assumptions being equal. The flip side of aggressive neuromarketing is having a more pronounced placebo response as it was shown in several recent studies, but that is a different story.

	Route and frequency of drug administration will be another key factor in predicting recruitment rates. Indeed, even for a very promising molecule, being injectable is undesirable for many prospective patients who might opt to stay on moderately effective oral therapy instead and never join the study. In a similar vein, it has been shown earlier that placebo administered twice daily will turn out to provide a more significant relief than the same placebo administered just once. Thus more frequent drug administrations during a clinical trial may inflate response rate, create too optimistic expectations towards the study drug after a few early subjects have shared their experience, and indirectly promote recruitment rates in the second half of the study. These days, the study subjects do share their study experiences as soon as they leave the hospital, and there are multiple online platforms available to host this kind of feedback and keep the community well informed. With that in mind, the trials with more frequent drug administration (up to a point) may recruit more patients for this sole reason.  

	Seasonal factors may prove to be crucial for a clinical study to recruit well, too. For example, in any given trial spanning across European sites, screening rates in September-October will almost inevitably be higher than in July-August due to vacation schedules and even summer hospital closures in some southern countries. End of the year is quite often a dead season for majority of “classic” study countries, and similar seasonal patterns may be found pretty much everywhere on the globe. In other words, the same EU study being open for recruitment in September may well have shorter screening period than the study open in July.

		Overall, if the study teams have the access to more historical data for a given indication (or country), all above considerations are more balanced out and future projections will be more reliable. In the recent few years however we see an increased number of trials targeting rare diseases, and by definition the historical data in this setting is quite limited. The question is, how much attention should be paid to historical recruitment figures if the team only reviews the data from one (or two) similar studies? Any decisions based on this limited information may turn out to be very costly at the end of the day so it may be advisable to treat reference data as is – a reference, but not a guidance and by no means a predictor of future performance.   

, Associate Project Director, Project Management, Syneos Health

The question is, how much attention should be paid to historical recruitment figures if the team only reviews the data from one (or two) similar studies?

How Helpful are Historical Subject Recruitment Rates?

	Large lab ABC sends you its $1M proposal for a Phase III study. However you know that the actual sample analysis is performed by three referral labs-A, B, and C. Upon reaching out to them directly, you learn that the sum total of their individual proposals for the same test panels turns out to be 30 percent lower as compared to the previous scenario. The ultimate decision “ABC vs A+B+C” is a no-brainer, right?

	Let’s assume that the scenario with three separate labs was selected for the study. This means that your sites will receive three separate sets of lab kits, manuals, and requisition forms-from all three providers. Worse, there will likely be three separate courier companies involved in sample shipment. Any experienced site should be able to handle this set up; however it can be expected that the study budget will grow due to investigator grant increase to offset the increased complexity. For less experienced sites, potential errors and re-sampling should also be factored in. In either scenario, courier cost will automatically increase and these are hundreds, or even thousands, of samples for any moderately sized study.

	There will also be additional cost involved on CRO’s end. Having three separate labs (versus 1) would mean three times as many electronic transfers and reconciliation campaigns. Plus, there’s vendor management cost involved, which will also grow proportionately.

	What happens if a lab undergoes a merger or acquisition? This typically means updates to FDA 1572 form for all sites, update on CAP/CLIA certificates and lab director CVs (with associated potential gaps in the TMF), release of one more set of lab supplies/courier instructions to the sites-all which mean extra cost. Going with three separate labs triplicates the chance of these events happening in the study.

	Same applies to another very likely scenario-when a protocol amendment comes up, it is quite often associated with changes to lab procedures or visit schedule adjustments (or both). This entails three separate change orders with the labs-each one having its unique complexities and study teams to work with. Likewise, here we are speaking about three new potential bulk shipments to the sites to update their kit stock.

	Chances are, this is an international study, and the smaller labs might not well have the required experience with various local customs and regulations. When the project team learns about lab kits held by any various customs agency one week prior to SIVs, the small lab in Michigan (or Singapore) originally shipping these kits may well throw their hands up in the air and concede that their experience with ROW specifics may have been limited and they don’t have a clear plan B. The associated issues may be benign enough (e.g. kits may just need to be returned to the shipper for CE marking), or they may take some time to be resolved (e.g. communication about importer of records with the local customs) or they may take months (e.g. application for import/export licenses and work with the local authorities). If you’re lucky enough, the CRO will provide its helping hand for a fee, but if the labs were selected and contracted by the study sponsor, the actual mileage and experience may vary and you may have to find someone local to rectify customs issues quickly.  

	Before and throughout the study, due diligence and oversight for all vendors involved will need to be performed. During study closeout, there will be document transfer from the vendors for the TMF. With increased number of study labs this will inevitably add to time, effort, and budget expenditures.

	Finally, very unfortunate scenarios do happen and you are likely to have a case or two when a subject’s sample is sent accidentally to lab B in lab C tubes… via courier company contracted by lab A. This opens up a few additional questions about sample viability, associated safety and ethical considerations, or even privacy issues (e.g. when the case in question is about a genetic sample), and any scenario will mean long hours invested to investigate and resolve the case, as well as prevent it from happening in the future.

	There are less tangible considerations in the mix, such as patient and site satisfaction with sample-related procedures. This aspect will have an impact on subject recruitment rates, patient compliance, and protocol adherence so any complex set-up will prove to be detrimental to the overall study success. More complicated laboratory procedures are also oftentimes associated with longer review times by the local ECs, as well as potential discrepancies between study protocol, IM/SIV presentations, and laboratory manuals.

	Still think about saving 30 percent in lab fees during study start up?

	In many cases, going with just one central lab will be a straightforward, clean, and efficient decision. In the long run, it can also save you money, even if this might not be so evident during the bidding stage. Having a secondary lab might make sense if there is the need for a very special test panel, something that the big lab may not necessarily be able to arrange for; however, the likelihood of this scenario is quite small. In vast majority of cases, it might be better, even if somewhat counter-intuitive, to keep all eggs in one basket and have just one single central laboratory in the clinical trial. Chances are, a larger lab is more experienced in clinical trials, too and it is impossible to quantify this benefit.

When less is more. Using three referral labs vs. one central lab.

Victor Muts, PhD

Articles

International Patient Recruitment: The Grass is Not Always Greener Abroad

How Helpful are Historical Subject Recruitment Rates?

Setting up a Central Lab for a Clinical Trial