Special Section: Clinical Research in Ukraine

Cancer Trial Continuity in Ukraine Is a Shared Responsibility and a Global Imperative

Oleksandr Stakhovskyi
National Cancer Institute (NCI), Ukraine

Ukrainian Society of Clinical Oncology (USCO)

Leonid Shylovskyi
Clinical Trials Assistance LLC, Ukraine
Richard Sullivan
King’s College London
Igor Bondarenko
Dnipro State Medical University, Ukraine

eople living with cancer often participate in clinical trials because that is their only, or the best, available care option. Participation in oncological trials gives them access to verified diagnosis, novel treatment approaches, and qualified and trained physicians mostly inaccessible compared to the average patient. The invasion of Ukraine poses a serious risk and threat to clinical research continuity that also constitutes patient care.

We note that clinical trials are not a “luxury add-on” when patients require specialist treatment. Clinical trials are an integral part of delivering accessible, affordable, equitable cancer prevention and treatment strategies and plans in public health. Patients with cancer participate in different kinds of research studies. In Ukraine, in particular, patients approach their participation through the lens of the care continuum.

Ukrainian Cancer Research in a Global Context

Ukraine is second (to India) as a low- and middle-income country (LMIC) conducting international, multicenter clinical trials, and one of the largest recruiters to major randomized control trials. In this context, the martial law status in Ukraine has negatively impacted not only patients and clinicians in Ukraine but the entire global oncology research enterprise.

At the end of 2020, there were approximately 1.1 million oncology patients in Ukraine; that corresponds to approximately 2,600 patients per 100,000 inhabitants. Annually, nearly 100,000 (new) patients are diagnosed with cancer in Ukraine, from a total population of approximately 44 million. (To compare: In 2022, approximately 1.9 million people from the total population of more than 332 million were diagnosed with cancer in the US.)

This partly explains why oncological patients make up the most significant portion of patients who have chosen to relocate from Ukraine after the outbreak of hostilities. It also demonstrates the importance and relevance of national cancer care, especially concerning the future of cancer clinical research in Ukraine, to ensure the continuity of cancer treatment and of biomedical research and innovation. Minimizing and mitigating situations that expose cancer trials in Ukraine to the risk of suspension and discontinuation on the one hand, while facilitating the generation of evidence-based knowledge and understanding of how to conduct oncology trials in wartime on the other hand, is in the interest of patients, communities, and economies. It is a shared responsibility of all stakeholders and a global issue.

The resilience and growth potential of clinical research and healthcare systems in a context of active warfare is an under-researched subject. However, some researchers have already begun to document and analyze the challenges of conducting clinical research under martial law. Many major cancer centers of the National Cancer Institute (NCI) of Ukraine reported that they are able to continue delivering treatment to patients. Their lived experiences and insights should inform and be applied to future thinking and planning of trial conduct under adverse conditions, and also inform deliberations on a national cancer plan for Ukraine.

Importance of Cancer Clinical Trial Continuity in Ukraine

Importance of Cancer Clinical Trial Continuity in Ukraine

Cancer Research in Ukraine

Oncology research and care in Ukraine is commonly performed by regional cancer centers. Oncology care in general hospitals is rather rare. Because of this distribution pattern, treatments resumed quickly for patients receiving standard of care or who had already been enrolled in a trial. However, for newly diagnosed patients and for patients awaiting enrollment, the disruption of the war has had a direct impact on each patient’s life.

Chemotherapy was the initial treatment option most quickly restarted or renewed by the NCI after the war began. Many patients were relocated within Ukraine to provide continuity of care. Patients in the NCI pediatric oncology department were evacuated through a charitable foundation (Tabletochki) in cooperation with the Ministry of Health (MoH), first to Western Ukraine, and later to Poland and other countries in the West.

War is considered generally a high-risk factor, and therefore inevitably impinges on paradigms considered necessary and essential for supporting life. Even so, clinical studies continue despite the armed conflict. The NCI has begun to rebuild and restructure the clinical trials and treatment programs which had 60 simultaneous ongoing trials by the second and third weeks of the war. It is noteworthy that patients were not jeopardizing their immediate safety by returning to NCI centers for provision of their medication, blood and other lab tests, etc.

Challenges to Ukraine’s Cancer Patients and the NCI

In Ukraine, cancer care and oncology research are unevenly distributed among the different regions. Patients who live in the rural areas or in small cities without access to adequate healthcare often arrive at the NCI in end-stage disease. At the beginning of the war, many patients, physicians, and therapies were temporary relocated from NCI’s two regional centers to Western Ukraine, which offered treatment opportunities for patients in remote areas.

Conflict alters the landscape of cancer care in many other ways. Patients will seek care at a later stage of the disease due to these delays in diagnosis and treatment. These access-related factors have an impact on the patient and also on the research community and their international partners: Because of the likelihood that locally advanced metastatic disease will rise in frequency, earlier phase clinical trials may see increased enrollment, while fewer patients may go into adjuvant or neoadjuvant trials.

The problem of timely therapy (dosing) and the effectiveness of therapy is inextricably intertwined with diagnostic tests. As an example, paraffin blocks with biopsy biomaterial were sent for analysis outside Ukraine (e.g., for histology) before enforcement of martial law. But logistics were complicated in the first months of the war, leading to delays in patient screening (per the trial protocol). Intermittent power supplies for operating imaging diagnostic instruments (CT, MRI, PET scanners, etc.) were bridged with alternative energy sources (e.g., generators). These initial logistics-related restrictions had been overcome by September 2022.

Relocated patients (particularly women leaving their homes and going elsewhere) have created fragmented and heterogenous caseloads for clinicians and challenges for retaining and recruiting patients in cancer clinical trials.

War affects health in ways that create additional comorbidities and greater vulnerability (including mental health issues) in cancer patients. As these patients become more comorbid and frailer, they increasingly fail to meet the inclusion and exclusion criteria of clinical trial protocols. This is a highly complex issue seen in other conflict ecosystems as well and warrants closer scrutiny.

The impact of the war is particularly felt within the cancer trial industry, and substantively in early phase trials. Ukraine’s ability to apply precision medicine in clinical trials, in terms of expertise and infrastructure, has grown exponentially over the last two decades. These significant and remarkable advances in technology, and specifically the increase in hematology-oncology expertise, are now at risk of plateauing without additional support from outside Ukraine. It is important to note that most cancer centers are able to open new trials while continuing active clinical investigations. These research and treatment centers are critical for plans to rebuild and strengthen the country’s clinical trial infrastructure. In what ways the international health community may support the investigators and the patient communities in Ukraine is our urgent question.

A second challenge relates to the shifting therapeutic geographies of cancer research and care, especially the retention of the specialized human resources and the fundamental physical infrastructure required to conduct oncology trials: Building and rebuilding imaging resources, CT scans, PET, nuclear medicine, more advanced precision centralized pathology, and the pathways on which those happen, will present a significant challenge to address.

A third challenge is the concerns of sponsors regarding the integrity of clinical research data and specifically the safety of the primary documentation. Reducing such risks has been a priority on the agenda of the State Expert Center (SEC), MoH, Ukraine’s national competent authority (NCA). Prompt SEC interventions to adapt national regulatory policy to these historically unprecedented circumstances, and their concerted effort in supporting the clinical trials industry, must be acknowledged. As a risk-mitigation strategy to ensure clinical research data integrity, the SEC adapted its guidance to allow for the possibility of remote data monitoring and the use of cloud services for encrypted data storage. Another paradigmatic example of a feasible adaptive solution is the clinical trial data management system developed and used by one of the authors (Professor Igor Bondarenko, an internationally renowned oncologist and clinical investigator in Ukraine). Despite the uncertainty and instability in Dnipro, the Center for Clinical Research in Cancer Therapy that he leads was able to maintain the required level of management of cancer patients outlined in the study protocols. The noteworthy proactive initiatives and resilience of their research team can also be credited to their own customized clinical trial management system (CT site management system) and this new remote-monitoring approach, which allow sponsors and site management organizations to continue their observations, monitor protocol adherence in real time, and avoid protocol deviations to the largest extent possible under the present circumstances.

One major challenge to patient relocation is that the transfer requires additional clinical data management and monitoring resources. The primary documentation cannot be transferred from the study site due to the regulatory requirement to store the data on site. The investigator, as a rule, provides the patient with an epicrisis certificate which documents and summarizes their medical history and therefore facilitates and simplifies the process of retaining the patient in the study at study sites abroad. However, this individual approach comes at a manual cost. It requires translation of medical records into the language of the researcher, data analysis of the patient’s participation eligibility for the study, and the transition of the patient to a new treating physician. These clarifying, refining activities show the significance of data management services for the sponsor and contract research organizations.

2021 USCO – Ukrainian Society of Clinical Oncology
2021 USCO – Ukrainian Society of Clinical Oncology

National Cancer Research Strategies and Plans

The above observations indicate that fortifying and recapacitating Ukraine’s healthcare system requires the inclusion of clinical research support as an integral part of the national public health policy. Clinical trials are a constitutive element of cancer care provision and innovation in Ukraine, as the MoH nationwide cancer care strategy plan will attest. (This policy draft has not yet been approved, due to the war.) To take this reform strategy to the next level, more than political will is needed. Raising the level of professional education in oncology trial capacity requires substantive investment in the educational and training infrastructure for new medics, nurses, paramedics, interns, and fellows. This large-scale project requires a multistakeholder approach.

Organizations from outside the political-economic realm can also have a stake in formulating and proposing strategies for developing and strengthening Ukraine’s cancer research and innovation capacity and growth potential, analogous to The Cancer Mission, a component of Horizon Europe that aims to reduce the cancer burden and improve the quality of life of cancer patients in the European Union (EU). The NCI is already engaged in various collaborative projects through Horizon2020 (a research grant program in Europe) and is conducting numerous noncommercial clinical trials to strengthen Ukraine’s position in the global cancer research and care ecosystem.

Further examples are the collaboration between the European Cancer Organisation (ECO) and the American Society of Clinical Oncology (ASCO) that includes a Special Network providing the support that Ukraine needs to keep clinical trials open and to invest in the future of the clinical trial industry. In the US, the Cancer Moonshot program has articulated a global vision for cancer research and care. Ensuring cancer clinical trials continuity in Ukraine must remain high on their agendas and those of other health initiatives that seek to ease the global burden of cancer.

The Ukrainian Society of Clinical Oncology (established in 2021) focuses specifically on offering education and training opportunities abroad, including conducting and presenting oncology research, to the younger generation of English-speaking Ukrainian medical and primary care professionals. This international knowledge exchange and transfer furthers curriculum innovation and also how medicine is taught and how research findings are used and disseminated. This inter-institutional flow of knowledge and expertise is vital for developing and strengthening the medical and healthcare professions in Ukraine. Despite its comparatively recent establishment, the society has engaged with over 400 new members (before the war).

Some of these transformational developments are already felt on the ground. The National Health Service Office is rebuilding its system of patient-doctor-hospital interactions to be similar to the organization of the National Health Service (NHS) in Great Britain or Canada. In addition, oncology centers and other hospitals can buy chemotherapy and medication according to their needs. (Previously, only oncology centers could receive these supplies from the government.) Another innovation is that cancer patients can find information about clinical trial participation at a general hospital. This patient-centered strategy is expected to increase preclinical, clinical, and academic (i.e., noncommercial) research in prophylaxis diagnostics and treatment for cancer care and control, and reduce recruitment costs.

Opportunities for Investors

Ukraine’s legislative and regulatory reform project (aligned with the EU Clinical Trial Regulation) creates opportunities for financial and intangible investment opportunities in state-of-the-art clinical research infrastructures at specialized cancer clinics and for research methodology innovation, particularly in the fields of childhood cancer, adult solid cancers, precision medicine, and other newer research areas in Ukraine. Ukraine’s recent legislative changes regarding the tightly regulated and restricted use of investigational medicinal products that came into force after the enactment of martial law, and after being granted EU candidacy status (including two Compassionate Use Programs), may be of particular interest to private and public funders and private-public partnerships.

Several funders support the European cancer community. The public sector has spent €16B over the past 10 years on cancer research in Europe. In pediatrics, St. Jude’s is among the major hematology funders through the European Hematology Association. Both ASCO and the Cancer Mission in Europe support infrastructure and clinical trials funding. The UK, alongside EU countries, has specific research infrastructure strengthening funds that come directly from government budgets.

By analogy, an official cancer research and care policy and plan that outlines the key clinical research and treatment priorities will be useful in infrastructure and related negotiations with Ukraine’s national and international stakeholders in oncology treatment, research, and innovation. As with most large-scale health projects, funders are concerned about the implementation practicalities: How many staff are going to need funding, broadly over what time period, and in what research domains, to support clinical researchers and “bridge” the cancer community of Ukraine into the future? One way forward may be to channel the energies arising from adopting hybrid and adaptive pathways for accelerating the innovation process to deliver innovative diagnostic methods and treatments to cancer trial continuation and patient recruitment. The success of programs that search for and recruit patients for clinical trials in Ukraine, including a hybrid approach which combines on-site with remote patient safety and data verification, may serve as a model for introducing innovative diagnostic methods to patients in future conflict situations.

Opportunities for Oncology Patients

Patients enrolled in chemotherapy clinical trials, as mentioned above, tend to enter at the end stage of the disease. A commonly held view among cancer patients in Ukraine is that without treatment, the disease will prevail. While seeking care even at an advanced stage is a psychological aspect of a cancer diagnosis, it also helps explain why patients keep traveling to the clinical study site even when the route is unsafe. From the patient’s vantage point, the benefit of treatment continuity outweighs the risk of travel.

The continuation of clinical trial conduct, the resumption of patient recruitment, the introduction of two official Compassionate Use Program mechanisms, and the prospect of a national cancer research and care policy and plan, combined with the sustained international support and solidarity of the international oncology community, are all encouraging signs for expanding affordable and equitable patient access to innovative oncology therapies and care in Ukraine.