Current State of Clinical Trials Impacted by the War in Ukraine
This Content is Part One of a Three-Part Series
The military conflict in Ukraine and Eastern Europe is a rapidly evolving humanitarian crisis with vast geopolitical implications and continuous accounts of human suffering. Beyond the immediate humanitarian and geopolitical concerns, areas impacted by the conflict are also seeing extreme disruption to the local health care ecosystem. Clinical trials throughout Ukraine and nearby parts of Eastern Europe are in peril.
There are roughly 2,500 public medical facilities in Ukraine that have previously run international clinical trials, and an average of 500 clinical trials are ongoing each year (Fierce Biotech, 2022). The FDA database indicates there are 251 drugs and devices currently undergoing trials in Ukraine, but the conflict in Ukraine and the sanctions placed on Russia have forced many drug manufacturers to pause patient recruitment efforts in existing trials and put the initiation of new trials on hold (US Food & Drug Administration, 2022).
The effects of war have made patient protection and trial risk mitigation efforts challenging for sponsors, Clinical Research Organizations (CROs), and clinical trial site staff. Unlike a natural disaster or a pandemic, which similarly places a great strain on human health and health care institutions, the current conflict in Ukraine unfolds under ever-worsening conditions with no predictable end in sight – a situation that has challenged sponsors and CROs to make difficult choices and forge unstable and uncharted paths forward.
As the situation continues, it is becoming crucial to analyze and understand the conflict’s impact on clinical trials so we can assess future trial design from a more resilient perspective. Here, in part one of a three-part article series, we discuss four main areas of difficulty encountered in the field based on our experience: patient communication and safety, regulatory hurdles, supply chain challenges, and ethical concerns.
Patient Communication and Safety
The widespread difficulty sponsors are experiencing supporting and tracking the health and well-being of their Ukrainian patients has hindered aspects of clinical trial progress. Ukrainian patients are dealing with far more immediate obstacles during this conflict, and efforts by sponsors to ensure patients remain informed about their treatment plan, have continued access to medical care, and receive vital medicine remain the leading priority.
We have seen examples of trial outreach that may serve as pathways to protect patients. Sponsors have worked to establish task forces that aim to deliver and track patient communication, and at times, their CROs are working collaboratively to assist in the buildout of these task forces. Tracking patient communication – which patients have been contacting their trial site and how often, and information about their travel – has been essential in developing insights around access to critical trial support.
An option examined in the attempt to continue treatment protocols has been to perform patient site transitions to safer neighboring countries. However, there are inherent dangers posed to Ukrainians who might seek to obtain treatment through relocation. In terms of patient mobility, these risks take the form of exposure to combat zones, inadequate shelter and life support during transit, and limited housing once they reach their destination. Without the guarantee of safety, it is difficult for sponsors to know how best to support Ukrainian patients and their families.
Hurdles to Patient and/or Site Transfers
Transferring a trial site or clinical trial participants to a neighboring country also presents a unique challenge for sponsors and competent approval bodies. Since the clinical trial monitoring and control requirements may differ from country to country, the procedures to ensure patient safety and data integrity are preserved with the transfer need to be carefully examined and accounted for. Because Ukrainian trial oversight has been severely reduced, there is a need to examine other nations’ ability to accept documentation for submissions and transfer agreements. Typical patient transfer agreement approvals state the patient’s country of origin in the clinical study and require notification of the transfer from the country of origin, but since patients cannot get approval through Ukrainian regulatory authorities that aren’t operating, Sponsors may opt to relocate willing trial participants under an urgent safety measure, with the understanding that a substantial protocol amendment would need to follow. We have heard examples of patient transfers from Ukraine into other nearby countries like Belarus, Poland, and Moldova.
Initiating the process for the patient and drug transfer may depend on how essential that investigational treatment is to its intended population. For trials that serve those with limited treatment options, some sponsors are taking the path of relocating Ukrainian patients because the investigational product may be their last hope.
The difficult reality, though, is that patient mobility – including the availability of their clinical trial documentation – across national lines is faulty. Attempts to transfer patients to trial sites in neighboring countries are met with delays and uncertainty, but we have observed a few common suggestions to navigate the complexity. Having cross-functional teams with solid communication and expertise to think through what’s feasible within the clinical trial protocol and within the regulatory bounds of this extreme situation can help sponsors understand ways to reimagine their trial without halting operations. Ensuring that these cross-functional teams have resources with extensive knowledge of cross-border regulations is imperative to developing a successful patient transition plan.
*(Contents within this section have been edited for accuracy and clarity and supported by research in the references section below)
Supply Chain Turmoil
The complications of clinical supply chain management are interwoven with slow regulatory submissions. When clinical trials don’t have adequate supplies the impact if two-fold: patients fail to receive potentially lifesaving treatment, and the trial runs the risk of not having enough clinical data to move an important product forward towards general use. Many of the ongoing clinical trials in Ukraine are supplied through a central depot located near the airport in Kyiv. With teams of Ukrainian workers unable to safely operate these facilities, sponsors are running into the supply chain and transport issues for both experimental drugs and biospecimens. Whether these issues stem from attempts at rerouting to a new destination, shipping delays, or the lack of product availability at medical sites, they have placed added strain on trials in progress.
In the case of Russian sites, supply has been permissible into the Russian trial sites, but the flow of medical information out of the country presents the core challenge. Sponsors have been unsuccessful in reliably engaging with investigation sites without running the risk of subjecting local investigators to serious repercussions from the Russian government.
No matter the location, the supply chain has struggled to accommodate trial needs. But where there is some product available, sponsors may need to adjust their strategy by taking a deep dive into the data around supply chain logistics, determining how critical the delivery of certain drugs and samples are to the primary endpoints of their trial, and applying risk mitigation strategies to the loss of data to serve patients amidst a broken supply chain.
While companies and research groups holding clinical trials in Ukraine and Russia are grappling with how to safely carry out their mission – both medically and financially – they must also closely examine the ethical and legal ramifications of any response. Although it is unclear whether remaining in Ukraine or Russia is advisable for each sponsor who has an ongoing clinical trial, the decision to pull away from the region poses an ethically complex challenge worthy of careful deliberation. There may be potential legal ramifications of altering or ending a trial of a potentially vital medicine that must be examined. Every decision in response to the conflict returns another challenging, yet different, dynamic. Redirecting resources and removing clinical trial presence from war-impacted Ukrainian territory might mean solving immediate enrollment challenges, but it does not necessarily offer safety to patients and site staff.
Even if sponsors work to maintain payments and operations as planned, they may be running into issues seeing these finances through. Often the sanctions placed on Russia have dismantled systems for paying site staff and investigators, and for providing compensation to patients. With the burden on continued financing of clinical operations in the region, drug developers may turn to other geographies. Particularly for smaller drug developers who may have limited resources, we have seen a geographical pivot in their clinical trial enrollment strategy. Patient enrollment demands and clinical data gaps for trials that were formerly based in Ukraine and Russia are now planned (or being considered) with patient populations in other parts of the world to meet study timelines.
The Future State of Clinical Trials
These challenges pose the question ‘where do we go from here?’ as sponsors work hard to protect patients and trial operations in the midst of conflict while adhering to regulations. As an industry, we must learn from the conflict’s impact on trials so we can assess future trial design.
The conflict in Ukraine has already given way to certain operational changes in the clinical trial landscape that was both unavoidable and inevitable. Between disrupting the scheduled study visits and adjustments made for trial participants fleeing Ukraine to transfer to other sites, clinical trial protocol deviations have become a necessary path forward to ensuring patients’ rights and safety, wherever possible.
It is essential that the continuation of ongoing trial treatment and the preservation of the quality of data should be undertaken with urgency. But how do we inform and equip leaders with the best information to respond ethically and within the bounds of trial protocol? Is it better to ask for permission or apologize later under this extreme circumstance? The answers to these questions are complex. As regulatory agencies pointed to experience gained during the COVID-19 pandemic to help inform sponsors, we anticipate more lessons learned from this conflict to be shared with the industry.
As additional recommendations for this specific situation are being developed across the industry, we also anticipate new changes to come. With the topic of decentralization already at the forefront of clinical trial study design, the added benefits of telemedicine with respect to trial agility and patient mobility are part of the discussion. We aim, in part two of this article series, to examine key components that may offer conflict-resilient strategies to clinical trial design.