Special Section: Clinical Research in Ukraine
Three Perspectives: Maintaining Good Clinical Practice (GCP) During War
Igor Bondarenko
Dnipro State Medical University
Evgeny Levenko
ARENSIA Exploratory Medicine GmbH
Olena Popova

aintaining quality and ensuring participant protection in clinical trials during wartime takes incredible effort and coordination. The ongoing war places unprecedented pressure on the healthcare system and clinical trials in Western Ukraine, and on patients, who need to find ways to continue treatment in their own country or find treatment in another country and then travel there. Investigators and sites coordinated activities to maintain good clinical practice (GCP) as the war in Ukraine began, ensuring continuity of research and care and providing lessons for future clinical trial and research conduct during disruptions such as war.

The Immediate Question: How to Stop?

“That very first day, it appeared that clinical research in Ukraine had fully collapsed. All local operations immediately stopped all activity. All international couriers immediately stopped. No airplane connections, no ground transportation, no public transportation. All borders blocked by millions of people evacuating from Ukraine. Pharmacies closed. We decided to be with our patients and to provide their medical services by staying at our main clinic in Kiev, although we were down to about 12 site staff. But all sponsors stopped enrollment, and some even stopped already randomized patients, immediately.

On the second day of the war, patients started to call us: Are you continuing? Will you be with us? We have no access to other hospitals. We have no pharmacy. We have nothing. After discussion with sponsors, we decided to continue to treat these patients. Twelve medics, here for 24 hours. We slept in our basement safely, on the ground. During the day, we climbed up to our third floor and continued with patient visits.” – Evgeny Levenko

To enable trials to continue, it was critical that local labs resumed operations. Patients were offered options for continued participation in their trials in Ukraine: Visit their clinic, home visits, a combination of home and office visits, or telephone visits only. Procedures for interacting with ethics committees were revised to allow for remote interactions. To support these approaches practically, the following should be considered in the design of trials and research studies in a time of disruption:

  • Options for telemedicine, electronic signatures for informed consent, remote monitoring, and related adaptations
  • Build flexibility into local ethics committee standard operating procedures
  • Timely communications with and flexibility from regulatory bodies
  • Build flexibility into protocols to allow for changes in approach and delivery
  • Build in flexibility to shift patients from one study site to another to reduce risk and enable continuity.

For many participants, no access to research meant no access to their study medication or routine care. Approvals from patients, sponsors, and regulatory authorities allowed patients to move to study sites in neighboring countries conducting the same study. To facilitate the transfer, the following was required:

  • Shifting of site- or study-specific equipment and accommodations and additional investigational medicinal product (IMP) to the receiving site
  • Adjustment of the Interactive Voice Response System (IVRS) to reflect the details (and the language, if necessary) of the new site
  • Reliance upon verbal approval for transfers since some patients were in urgent situations and needed their medications immediately
  • Submission of all documentation to regulatory authorities in both Ukraine and the receiving country following transfer

The receiving country must also make some regulatory adjustments before accepting these patients. Additionally, sites in Ukraine must now also consider how to accommodate patient cross-border travel because patients travel back and forth between countries.

Working Together to Overcome Risks and Challenges

“Immediately, martial law was introduced, and airspace was closed. This immediately affected travel of patients, physicians, CRO employees, within or coming in or out of Ukraine, which affected our international clinical trial supply chains, including the investigational medicinal product (IMP) supplies we receive from sponsors abroad. We also send and receive samples from international laboratories within protocol-specific timelines. This all became impossible after 24 February 2022.

During the first two weeks of the war, the main priority was employee and patient safety. We established a chain of action to bring our employees back from business trips because they met the war in different locations, sometimes far from their families. After supporting our employees to get to their homes or any safe location, we immediately started contacting study sites to collect information so we could translate what was happening on the ground and offer some solutions.” – Olena Popova

The war in Ukraine challenges clinical trial ethics, regulatory processes, data integrity, and patient safety. Each of these aspects is critical to maintaining GCP.

Protecting participants and ensuring safety is a top priority. At least six million people left Ukraine. Additionally, a great internal shift occurred as one-third of the population moved from their homes in the East to new places in the West. Investigators prepared lists of study sites within hospitals across different regions of Ukraine, which helped patients navigate to treatment at an alternate trial site at a hospital in a safer area. Information about trial sites in different countries was developed, and sponsors and project teams worked together to submit applications for cross-border travel so that patients in Ukraine could navigate to investigators at sites in surrounding countries.

Laboratory samples are a regular practice in oncology protocols because we always need fresh white cell counts to determine whether the next infusion is allowed, and ambient samples require meeting very precise timelines we were unable to keep without air transportation. A shift to using centralized local laboratories helped with more timely and comprehensive assessment of safety parameters according to protocol.

Understanding the best use of investigational medicinal product (IMP) as well as finding new supply routes to ensure availability also required tremendous coordination. Sponsors, medical advisors, and project teams worked together to gather and provide advice about the use of IMP in clinical trials during wartime; for example, whether it’s possible (based on protocol design) to allow for an interruption (and if so, for how long or which period), titration schemes, washout, and how to return to the IMP per the protocol. In some cases, enough IMP could be stored at the study site to provide for a patient two or three visits in advance. Although direct delivery of IMP into Ukraine was disrupted, alternatives such as delivery to a neighboring country and delivery by global courier services enabled compliance with storage and other requirements and customs clearance directly into Ukraine.

Data collection and trust in data that is collected regardless of the circumstances is critical for ensuring decisions that protect patient safety are made during the approval process. Although use of eSource, remote source verification, and remote source data review can enable continuity and trust in the data that is collected, eSource is not well-developed in Ukraine and remote verification and review were more difficult due to the war and the strain on resources to prepare documentation for remote activities.

Remote services and telemedicine also contributed to the ability to maintain GCP by keeping a mechanism of continued oversight for principal investigators, who are responsible for supervising clinical trials and may have moved away from a site for safety reasons.

Digital Site Management Enables Continuity

“The perception of the war is different when you are somewhere else in Europe and when you are here in Ukraine. Ten times per day, air threat and sirens and rocket explosions in many cities, almost every day. The challenge for clinical trials is that they continue in war.” – Igor Bondarenko

Maintaining GCP compliance—ensuring patient protection and clinical trial quality—during wartime requires careful planning and is made possible by using modern site management systems that can maintain medical records, ensure remote monitoring, and streamline invoicing and payments. Each of these elements are critical clinical trial touchpoints.

Site management with technological tools not only allows for research continuity but can also improve overall efficiency, reduce the resource burden, and allow for flexibility in delivery, increasing the site’s ability to conduct trials during disruptions. Critical elements of a digital trial and site management system include:

  • Train all personnel: This ensures that technologies will work as intended, which bolsters staff motivation and retention and supports study continuity.
  • Ensure digital planning and control: This improves performance and efficiency of all site activities.
  • Enable remote monitoring: This reduces the need for participant travel and/or staff presence near areas of combat.
  • Integrate artificial intelligence: This supports the creation and analysis of medical records, which supports the formulation of medical conclusions by physicians.
  • Implement automatic invoicing: This reduces staff burden and invoicing errors, enables the invoice to more accurately reflect the work that was done, and increases payment success.

Many of these elements are also beneficial during normal times but are crucial during times of war and other disruptive events.

Support and Solidarity for Future Patients, Research, and Trials

“We can keep our researchers funded and our patients cared for in this most difficult time for Ukraine, if we work study to study, site to site, researcher to researcher, in solidarity and support.” – Igor Bondarenko

The needs for clinical research and care do not stop despite the logistical challenges and service disruptions of war. Ukraine teaches us that it is possible to deliver GCP-compliant research despite such devastation, while also demonstrating what is needed to build more resilient global clinical trials and research programs. These lessons suggest some practical solutions for peacetime consideration:

  • Build harmonized international patient transfer procedures.
  • Develop recommendations and platforms to enable access to care upon relocation.
  • Continue to improve remote practices and approaches to care delivery, research, and continuity.
  • Refine informed consent to allow for potential protocol deviations or extra measures, such as off-cycle IMP distribution or telemedicine visits, when these deviations or measures are implemented to protect the patient.

Ultimately, research continuity during wartime is important for all of Ukraine: for individual health, psychological well-being, economic prosperity, and scientific advancement. Implementing new systems and technology advancements that allow for research connectivity and continuity are crucial for improving clinical research in Ukraine and around the world. Working together as a global enterprise is crucial to support maintaining workflow during disruption and for the development of processes and frameworks that enable flexibility and reliability and ensure the scientific integrity of studies, and the safety of their participants, during future challenges.