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Trialling abroad: How sponsors, ethics committees and regulators can improve patient outcomes in cross-border trials

Patients’ need for novel investigational treatments for life-impacting diseases in the absence of available treatment options drives an ongoing debate on how sponsors, ethics committees and regulatory bodies can work together to overcome both logistical and regulatory barriers and open the doors to cross-border clinical trials more widely to those in need.

If you or a loved one were to suffer from a life-impacting disease without available standard care treatment options, you might be prepared to travel or relocate in the short-term to other countries to gain access to an investigational treatment in a clinical study. Whilst participation in a cross-border clinical trial is an obvious choice, gaining access can be a huge challenge.

Any pharmaceutical or biotech company will be aware of the complexities that cross-border patient enrolment can pose and it extends far beyond the obvious geographic and language differences. So, are sponsors, ethics committees and regulatory authorities, with their efforts combined, ready to accommodate this patient need?

Considerations for cross-border trials

There are two considerations where cross-border enrolment is likely to be considered by clinical trial sponsors: rare diseases and geography. Rare disease studies often have a small patient pool which may limit the rationale of investment for opening a fully operational investigational site in a specific country. These investigational sites would also be required to have experienced staff with specialised rare disease experience, this is often limited and may not be available in a country where the patient need for investigational treatment options may exist. 

Scarcity of treatment opportunities in rare disease motivates patients to look for options that do not exist in the standard healthcare. Low geographic patient density drives establishment of expansive virtual communities where information on clinical trials in other countries is commonly discussed. Patients are ready to be more mobile in their journey in search of treatment options. Cross-border clinical trial sites may extend access to eligible patients without requiring a site in each potential country. Geography might dictate possibilities for cross-border patient enrolment and present opportunities for positioning of investigational sites for patient groups living near a border region between two countries. 

Difficulties to overcome

Not surprisingly, the challenge starts with identifying and selecting the right clinical study site that could accommodate a cross-border patient. Besides the adequate qualification, clinical research experience and relevant site facilities, the sites need to be willing and able to welcome foreign study subjects and have the patient-centred infrastructure and language capabilities to accommodate the travelling patient. 

Cross-border ethics committee and regulatory authority approvals 

Cross-border patient enrolment introduces complexity in obtaining relevant ethics committee and regulatory authority approvals. Unfortunately, there is currently no overall EU legal framework defining the conditions for accessing clinical trials in another EU country. Although the EU Directive on the application of patients’ rights in cross-border healthcare (2011/24/EU) aims to facilitate access to safe, high-quality cross-border healthcare and to promote healthcare-related cooperation between EU and EEA (Iceland, Liechtenstein, and Norway) member states, it does not mention the access conditions for clinical trials. Approval requirements vary based on the country and the ethics committee. The need to create a more robust and straight-forward process for cross-border clinical trial approvals remains unaddressed and the burden for sponsors, patients, caregivers and regulatory bodies remains complex.

Outside of the EU regional regulatory context as well as within, ethics committee review requirements vary widely. Though most ethics committees display compassion to cross-border patient participation in clinical trials on ethical grounds, some ethics committees as well as regulatory authorities object to the cross-border clinical trial enrolment practice. For example, Ireland’s regulatory authority forbids patients from participating in clinical research abroad.

Sponsor’s burden of thoughtful planning

Besides site identification/selection and ethical/regulatory considerations, sponsors should design a clinical trial where cross-border recruitment is expected and the following areas thoroughly addressed:

  • Justification for enrolling patients from another country
  • Recruitment process
  • Pre-screening and consent
  • Confidentiality
  • Insurance
  • Logistics and patient liaison / support
  • Patient-facing documentation
  • Planned post-study support

A cross-border recruitment plan developed by the sponsor should thoughtfully detail eligibility checks to be performed before travel by any prospective patient, instances that constitute ‘exigent circumstances’, and the mitigating factors. Moreover, cross-border patient enrolment requires that the following are addressed: the long-term strategy for treatment of patients, use of mobile nursing or home-country healthcare for patient treatment follow-up, adverse event reporting by all treating physicians, whether in the trial country or in the home country, and appropriate patient status tracking and oversight. Development of a well-established cross-border recruitment plan during study start up is a way sponsors can maximise patient enrolment and retention, and minimise any patient safety and data quality risks. 

Success in cross-border trials

Despite the complexities outlined, ICON has success stories to share. In our recent experience, patients from the UK and Germany had a chance to participate in a rare disease clinical study at a cross-border site in Belgium. With the experience of smooth ethics committee and regulatory authority approvals in this case, the timely delivery of investigational product (IP) to patients was possible. Home visits not being an option, study IP delivery within EU countries did not cause issues allowing shipments to be arranged directly to the patients in Germany at specific time points between visits. Meanwhile, the UK patients needed to travel to onsite visits in Belgium each time due to customs regulations preventing direct-to-patient shipments.

Source document management challenges were overcome by patients bringing certified copies of their medical notes from their treating physicians and family doctors to ensure eligibility checks. Having investigators with the necessary language skills to read the notes in the patient’s local language at the cross-border site was particularly helpful. Finally, in the oversight process, resources with the appropriate language skills were brought in to assist the clinical research associates with the translations of source documents in the source document verification activities.

Moving forward

The EU Cross-Border Clinical Trials initiative (EU-X-CT) was established in November 2022 to help enable cross-border access to trials for patients in the absence of options for them to join a clinical trial in their own country. To support this, EFGCP and EFPIA have set up a multi-stakeholder collaboration platform of patient organisations, academic researchers and institutions, research networks, CROs and pharmaceutical companies. Based on systematic analysis on the requirements for cross-border patient enrolment in clinical research, obstacles and options in all European countries both within and outside of the European Union, EU-X-CT aims to develop multi-stakeholder recommendations for cross-border access to clinical trials and to provide information for each country on a publicly available platform. This initiative can potentially facilitate cross-border clinical trial access to patients and help sponsors to overcome the existing complexity of ethical and regulatory considerations through more streamlined pathways.

Despite these challenges, success stories exist. Instances where patients from different countries participated in a rare disease study across borders illuminate the possibilities. Overcoming document management hurdles, navigating regulatory nuances, and ensuring timely delivery of investigational products to patients demonstrate the potential for success in these ventures. In the pursuit of opening doors to cross-border clinical trials, the convergence of sponsors, ethics committees, and regulatory bodies remains pivotal. As these entities navigate the intricate landscape, the promise of innovative treatments and improved patient outcomes stands as a beacon, urging a concerted effort to overcome barriers and extend the reach of life-changing therapies to those in need, regardless of borders.

This blog is based on the whitepaper "Cross-border enrollment of rare disease patients".

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