Research During Wartime–Ethical Challenges Faced by Oncology Researchers in Ukraine

In low- and middle-income countries, the best chance for quality care for many patients with cancer is in clinical trials. In Ukraine, clinical research has grown significantly during the last decade, with over 2500 clinical trials conducted between 2011 and 2021¹ and 549 oncology trials currently registered on ClinicalTrials.gov.² (There are 119 trials listed as actively recruiting patients and 149 active but not recruiting. We assume that these data reflect the situation prior to the Russian invasion but are not entirely accurate even as to that, as some clinical trials identified are listed as being conducted in territory that has been occupied since 2014, eg, Donetsk.) Russian military aggression has endangered research participants and researchers, destroyed research sites and infrastructure, and disrupted logistics. This war not only demonstrates the vulnerability of the clinical research process,³ it introduces unique ethical challenges. Physician researchers must determine how to best continue treatment for patients with cancer enrolled in clinical trials in the face of disrupted supply, threats of mortal harm, and the potential need for evacuation.

Limited guidance exists to direct decisions about continuing clinical research during war. It seems obvious that scientific goals become a lower priority, and thus clinical research should generally pause to prioritize patient safety. However, it is not clear what to do to provide the greatest possibility of benefit to individual patient participants already enrolled in a trial, given limited treatment options even before the war and disruptions to the supply of basic necessities. International Ethical Guidelines for Health-Related Research Involving Humans of the Council on International Organizations of Medical Sciences (CIOMS)⁴ provides international consensus on ethical principles and their application in specific circumstances. Guideline 20 covers research in disasters, including military conflicts, but only addresses implementation of new research studies relevant to the emergent situation, positing that in such cases, research should be done only if it is responsive to community needs and not able to be conducted outside the “disaster situation.”⁴ This advice is not relevant to questions of clinical research during the acute phase of war; in such conditions, although community-level benefits diminish and become less relevant, there may be potential benefits of continuing for patient-participants. CIOMS issued more recent guidance on Clinical Research in Resource-Limited Settings,⁵ but this, too, does not address wartime concerns. Neither CIOMS document addresses how to weigh the risks and benefits of continuing an individual patient in a phase 2, 3, or 4 cancer trial protocol or of altering a protocol (eg, unblinding participants and/or switching those in the placebo arm to active medication) while they and their communities, including health care facilities, are at risk of bombing. In deciding whether and how to proceed with treatment, physician-researchers must balance patient-participants’ immediate and longer-term health needs with personal safety considerations for both clinical staff and participants. Physician-researchers should have authority to decide what is in the best interest of patient-participants (eg, unblinding, protocol alterations) and in some cases without sponsor approval.

Due to the unpredictability of Russian hostilities, soon after invasion, most study sponsors prioritized the safety of Ukrainian study participants and research staff, stopped randomization and initiation of new sites/studies, and allowed physician-researchers to make decisions independently on a case-by-case basis. On April 5, the State Expert Center of Ukraine formally recommended stopping new trials, endorsed remote communication and suspension of audits, and provided instructions for relocating patients to other approved research sites in safer areas if necessary and possible.⁶

Initially, logistics across Ukraine were so disrupted that patient-participants had no options except to continue in their clinical trial or pause treatment entirely as they sheltered in place or evacuated. Some patients in western Ukraine have been able to continue on-trial treatment with some alterations to protocols, but in the east the situation is more challenging. In simple terms: The same rules cannot apply to the whole country. Decisions must be based on local conditions and what is best for each individual patient–continue potentially beneficial experimental treatment that might be interrupted due to migration, destruction of facilities, limited transportation, or death/injury of research team, or shift to focusing on symptom management and simple treatments that can be administered with less burden, possibly in the home. Beyond prioritizing patient safety, potential benefits to each patient must be considered, particularly given that provision of treatment outside the study is not likely given the conditions of war. If experimental treatment will continue, the physician-researcher must decide what modifications might be necessary and permissible given limited resources, difficulties of monitoring, and a heightened duty to minimize participant burden. These changes and the ways in which they alter risks and benefits must be communicated to the patient, and researchers and sponsors have a duty to ensure equitable access of all research participants to continued treatment.

Currently in Ukraine there have been 3 situations, each with different considerations and recommendations for clinical trials: active war zones (such as Kyiv, Kharkiv, Chernihiv, and Sumy), frontline zones (such as Zaporozhye, Mykolaiv, and Dnipro), and areas where direct aggression is, for now, unlikely (Lviv and Transcarpathian regions). The war in Ukraine, taking into account its geographical location and stretch from east to west, is unique in that all 3 scenarios are present simultaneously and dynamically. (There is also a fourth scenario of occupation, as in Kherson and part of the Zaporozhye region; given the lack of state jurisdiction over such territory, it is not possible to continue or conduct research.)

In active war zones, patients’ physical safety must be top priority. Trials should stop, and researchers should shift focus to provide necessary supportive care, basic protection, and support evacuation when possible. Physician-researcher duties may include monitoring conditions locally and on evacuation routes, communicating with the patient-participant and their family during evacuation, and transferring care to another clinician and/or research team after relocation. Physicians benefit personally from participating in commercially sponsored research, and the desperate situation of war may exacerbate tendencies to prioritize personal gain over patient welfare. Those who prioritize patient benefit will support relocation, but unfortunately those who prioritize their own financial benefit may decide to continue a patient in a trial even if it is not in the patient’s best interest.

Frontline zones are likely to become war zones. Here, researchers must balance the patient-participant’s health, which may directly benefit from continuing the research protocol with the patient’s immediate safety from the threats of war. In some cases, it is impossible to obtain alternative medical treatment, so continuing trial medication (and perhaps with some alteration to the protocol) may be the only way to help patients. Under these circumstances, concerns about protocol deviations should not prevent continuing treatment using clinical research resources for the patient-participant’s benefit.

In western Ukraine, increased hostilities are, for now, unlikely. With necessary logistics, infrastructure, and personnel, clinical trials could be continued, with some restrictions regarding the launch of new trials and new patient recruitment. Traditional Belmont principles are useful here. Physician-researchers should outline risks to safety as well as potential benefits to health, provide patient-participants with the information necessary to support their right to decide if, where and how to continue participation, and provide equal access for all patient-participants to each possible option.⁷

In conclusion, the primary goal of research is the generation of new knowledge, and thus ethical decision-making generally prioritizes strict adherence to a protocol in the name of scientific integrity over individual benefit. In conditions of war, priorities must shift, and patient safety and beneficence take priority. This may require protocol deviations and continued use of research resources. While individual physician-researchers should have final authority regarding what is best for each patient, formal guidance is needed not only to guide decision-making but to hold researchers and sponsors accountable when research goals must change due to war.