Special Section: Clinical Research in Ukraine
Maintaining Safety and Continuity While Relocating Ukrainian Clinical Trial Participants
Agata Bloswick
Labcorp Drug Development, Poland
Bettina Ryll
Lindsay McNair
Equipoise Consulting
Stefan Strasser
Austrian Agency for Health and Food Safety
Serhiy Mykhaylov
Kateryna Orlovska

MSD, Ukraine
Anna Titkova
Pratia/Pratia Clinic, Ukraine

nsuring the safety of research participants during times of war is unique to the situation of each individual participant and must consider multiple aspects of each individual and the situation they are in.

A UNHRC agency estimated that 6 million Ukrainians left Ukraine and about 7.7 million were displaced internally (about a third of the population) by June of 2022. During peaceful times, thousands of Ukrainian patients participate in clinical trials, and many continued to participate despite the conflict. Protecting participant safety took on new meaning and consequences in these circumstances, and actions that allowed for continuity when the participant desired should be considered to inform safe trial access in similar future circumstances. Many of these considerations are partly dependent upon how the participant chose to continue participating, or not.

Many Participants Continue Trial Participation During War

Several important elements of clinical research ensure fulfillment of the ethical mandate to protect participants. These include but are not limited to the informed consent process, evidence-based inclusion and exclusion criteria, ongoing ethics and data monitoring reviews, adherence to a research protocol, participant monitoring, and regulatory oversight.

Although participants may be relocated to protect them from conflict and improve their physical safety and security during their trial participation, there are other important considerations. For example, some participants may not have access to healthcare if not for the clinical trial. This may compel some to continue participating in the trial at the original site despite the potential risks to their safety and compel others to relocate to remain in the trial despite uncertainty about the resources required to move to a different country.

Three different scenarios emerged for Ukrainian participants when the war started in 2022: internal displacement and continuity of participation; international displacement and continuity of participation; and discontinuation of trial access (regardless of location). Unique considerations emerged for each group.

Internal Displacement: Minimizing Burden with Safety and Continuity

Many participants were internally displaced and opted to move from one part of Ukraine to another but remained in their trial. For these participants, making the choice to continue trial participation was less complex for many reasons than for those in the other scenarios. The language for care delivery and/or source documents remained unchanged, with minimal to no modifications needed. A consistent regulatory umbrella, principles of work for local ethics committees, and informed consent could be applied. And due to the principle of universality and inclusion of clinical trials in Ukraine’s care continuum, the participant’s health insurance could also apply. For these trial participants, several aspects of safety were also facilitated by the ease with which study files and participant information were transferred from one site to another.

The investigator at the new study site receives the new participant by:

  • Receiving and confirming notice of patient relocation with the investigator at previous (former) study site
  • Contacting participant in advance for verbal consent to retrieve their medical records to determine eligibility for the study
  • Contacting eligible participants for verbal consent to participate in the study at new site
  • Completing written informed consent during the first visit or initial medical examination at new site
  • Enrolling the participant to continue in the clinical study at the new site.

To minimize the burden on the participant, it is recommended to not require separate visits to complete these steps. One approach is to obtain consent from participants verbally (via telephone) as noted above before the first visit, so you can document that verbal consent when they come into the site.

In some cases, the receiving principal investigator may accept a relocating trial participant without the benefit of access to the participant’s medical history because source documents from the original site were destroyed or not available for other reasons. In this case, the receiving principal investigator is accepting responsibility for the participant without the benefit of history. This risk can be mitigated if the accepting principal investigator completes a comprehensive medical history upon accepting the new patient.

International Displacement: Confirm, Coordinate, and Consider

Other participants chose to move to a different country where their trial was ongoing to continue their participation. When these participants desired to continue, investigators in Ukraine worked within Ukraine as well as with investigators at trial sites in other countries to ensure these participants’ safety and continuity of care. However, these participants faced complexities that were not an issue for internally displaced participants.

Investigators ensured continuity by providing information about international sites conducting the study or by determining if the receiving country (selected by the participant) was conducting the study. In these cases, the Ukraine investigator could initiate or accept contact with investigators in the receiving country. The new regulatory umbrella and ethics committees for these participants were critical points of consideration and compliance. This may require a translator to enable communication with the participant. In some cases, participant materials in the receiving country had to be translated into Ukrainian not only to inform the participant but also to comply with regulations or guidelines.

To protect participants during international trial transfers:

  1. Confirm compliance with the receiving country’s specific rules and regulations. Many agencies updated guidelines and issued recommendations specifically for receiving participants from Ukraine. Clinical trial oversight is regulated at the national level, and detailed requirements are available on agency websites.
  2. Confirm trial site capabilities, expectations (including payments or other financial considerations), and requirements in the receiving country trial site. Before transferring a participant to a new site, it is important to understand if the site is recruiting new participants and, if so, if they can handle additional participants.
  3. Additional items to confirm at the new trial site include, but may not be limited to, availability of drug supply, someone who speaks the participant’s language, ability to send/receive medical information about a participant, or other things that could be unique in the receiving country.
  4. Translate (and adapt, if necessary) patient-focused materials into the language, and according to the legislation, of the receiving country. This may include resubmission and reapproval.
  5. Complete national insurance paperwork for the receiving country to provide standard of care treatment for the transferred participant.
  6. Confirm and coordinate the transfer with each participant and the trial sites in both Ukraine and the receiving country, plus the Ukraine Ministry of Health, with support from the study sponsor. Throughout this transfer process, maintain the privacy and confidentiality of each participant and site staff.
  7. Sponsors inform the ethics committees and the national competent authority in the receiving country to which the participant has moved.

Discontinued Trial Participation

The last group is participants who voluntarily discontinued their participation or whose circumstances prevented them from continuing their participation in the trial. Some of these participants could not physically continue the trial or decided that they didn’t want to continue and dropped out without notification or follow-up. In these situations, investigators often went out of their way to locate participants, enabled by regulatory flexibility which allowed investigators to utilize telephone or remote visits to help identify necessary actions, to ensure the safety of these participants. Telephone or remote visits, and optimizing other communications via technology, also helped ensure investigator safety by removing the need for them to be in dangerous areas near combat.

Frameworks, Networks, and Guidelines Facilitate Transfers

Not every country has issued guidance for relocating trial participants, in time of war or in other circumstances. Not every ethics committee has issued guidance. There are no established frameworks to dictate when or where participants should relocate, domestically or internationally. This means sponsors and participants take on risk with each decision.

The Clinical Trials Coordination Group, currently chaired by Austria and Belgium, rapidly issued its recommendation paper at the European level with harmonized recommendations from Member States on how this should be best accomplished. This group’s key message to sponsors: If you have a multinational clinical trial running in Ukraine, you are allowed and are encouraged to transfer participants. However, sponsors must be mindful of the risk of assuming responsibility for any humanitarian response beyond those obligations required to ensure the safety of participants in their clinical trials.

Many organizations responded rapidly by establishing participant mobility teams, business continuity plans, and agency partnerships to meet ad hoc participant triage needs and ensure safety. Such plans were guided by experts from different functional areas including regulatory, ethics, quality, clinical operations, and decentralized trial delivery, among others, who would meet regularly to address current and anticipated issues.

Clear guidelines for assuring trial participant safety under different sets of circumstances that would help guide research teams through unexpected events, including whether participants choose to relocate or not and where, remains a noticeable gap. Such guidelines would also include considerations for supporting study sites and investigator teams as well as frameworks for maintaining data integrity.

Additionally, sponsors would benefit from guidance for how to protect participant safety without taking on humanitarian response obligations that extend beyond the trial. For example, while finding a safer trial site in a different country may at first seem the best course, sustaining the participant’s basic needs (shelter, food, work, etc.) must also be considered. Relocation can also present the risk of stranding participants. Participants must not be encouraged to leave their home country solely to continue in their trial without other support for their basic needs.

Planning for major disruptive events can become an integral part of planning new clinical trials. For example, trial risk management plans should include emergency provisions designed to ensure trial stability and continuity despite unexpected difficulty if the participant prefers to continue. Establishing networks for communication between sites in the same region and more global networks for multinational trials before times of disruption would help ensure trial continuity during any future disruption. Sponsors can also refine existing or build new online resources that help trial participants maintain communication with their investigators or study sites during an emergency. Such networks and the research continuity they provide will ultimately benefit study participants, researchers and scientists, and the public health at large.

Learning from Past Experience

“When we realized we couldn’t continue studies in east Ukraine … in 2014 because it was just too dangerous, it was right to say: we are not able to safely bring participants back to the site for their visits, we are not able to continuously deliver medication and have samples taken for the safety and efficacy of the trial. It was just too dangerous. We reached out to several participants and told them: Here’s a list of sites in Ukraine where you can continue participation. If you are holding onto this location just because that’s where your trial is, you don’t have to. We can’t help you with the relocation financially. But if you want to continue participation, here’s what you can do. Here are the phone numbers. Here’s where you can go.

“About eight of those 12 or 14 participants decided to go [back in 2014]. This suggested they were almost held back by the clinical trial: They knew that the drug was working for them, there was no placebo arm, the drug was very close to registration, it was really working. That’s what was making them stay behind.

“It is worth considering: Are participants staying behind because of that treatment? We offer information on where the trial is conducted, but we are not encouraging relocation. We say: If you want to relocate, tell us where you’re going, and we’re going to find a way to make it happen. Even if there isn’t a trial in that specific place, we look at the area. If they relocate to Germany but very close to Austria, or vice versa, maybe there is some transborder short commute we can offer if they decide to continue. So, participants don’t choose their location based on where the trial is, but after they choose a location, we can offer help in continuing their participation.” – Agata Bloswick

The authors thank the DIA Bioethics Community and Chair Karla Childers for their critical input into the preparation of these webinars and of this article.