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There are several important factors which should be considered prior to resorting to international patient recruitment.
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 not 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 .
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.
Language. 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.
Travel expenses. 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  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.
Underlying patient’s condition 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.
The paperwork 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.
Logistical challenges 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.
3. Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: An empirical analysis of recently closed trials. Clin Trials. 2015;12(1):77-83.
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
Victor Muts, MD, PhD, Associate Project Director, CNS, Syneos Health