The biggest historical proponent of clinical trial quality conducted his first one during a war. In 1941, in Salonika, Greece, Archibald Cochrane, a soldier for the British army, was taken prisoner by the Germans. The only doctor amongst 20,000 prisoners, Cochrane observed many cases of swollen legs, his own included. He became so desperate that he decided to run his own experiment. He obtained yeast from the prison's black market and split 40 prisoners into two groups: One received two spoons of yeast every day, and the other a vitamin C tablet. By the fourth day, he determined that the yeast group had improved more than their vitamin-treated counterparts. Today we know him today as the father of evidence-based medicine; Cochrane called this his “first, worst, and most successful clinical trial.”
But make no mistake: War is a huge obstacle to medical research. Russia's invasion of Ukraine—which has forced more than 2.3 million people to flee to nearby countries—is no exception. According to the US Food and Drug Administration’s clinical trials database, there are over 250 active trials with research sites in Ukraine. Of those, 117 involve interventions related to cancer. Others are for conditions like multiple sclerosis, schizophrenia, and Covid-19 infection.
Now the war threatens to cut off the supply of medications and scatter the participants, making their health records harder or impossible to track. In the clinical world, consistency is king; gaps in data can blight the reliability of any takeaways, or beleaguer analysis. And any investigator who tries to restart their trial will be doing so in a totally different Ukraine from when they started, says Mike Clarke, a clinical trial design expert at Queen’s University Belfast. The health and research infrastructure will still be recovering, millions will have fled, resources might be scarce. “The environment that they will be restarting in will be so different that they might have to view it as two trials,” he says: the trial before the invasion, and the one after it. And that’s imagining a scenario in which the previously collected data hasn’t been destroyed. Clarke points to trials that may have almost finished “but are never ever going to report their findings now—a complete waste.”
And not only does suspending and restarting trials potentially produce bad data, it can be devastating for the patients—especially those with end-stage diseases for whom participating in a trial is their last hope. “For oncology patients, this is also a matter of survival,” says Ivan Vyshnyvetskyy, president of the Ukrainian Association for Clinical Research.
Ukraine has a reputation as a hub for clinical trials. It has a sizable, capable medical and research workforce with a reputation for delivering reliable data. And for many years, its health care system was underfunded. This meant that participating in clinical trials became an alternate—often speedier—pathway to receiving care, so patient recruitment was easy. Plus, that wobbly health care system meant that much of the population is made up of “treatment-naïve patients,” or individuals who haven’t yet received any treatment, a trial investigator’s dream. Over the past few years, Ukraine has overhauled its medical system and made digital records the norm, which in turn made participant recruitment a snap. But, as Putin’s invasion wreaks devastation across the country, all of these trials are now in grave jeopardy.
“The main problem is logistics,” says Vyshnyvetskyy. “It is almost impossible to ship biosamples from Ukraine and investigational medical products into Ukraine from the sponsors.” Many of the materials required for clinical trials are located in Kyiv, he says, which is a combat zone. “So it is almost impossible to get those materials, even though they are in Ukraine now.”
In western and some central parts of Ukraine, trial runners are continuing to make patient visits where they can, or to at least check in by phone. Vyshnyvetskyy’s organization is trying to relocate patients from the most vulnerable research sites to other regions of Ukraine where the research is able to continue, for now. The group is also figuring out how to support people who are escaping to Poland or Hungary so that they can continue their treatment and participation, either remotely or at trial sites in those countries.
Clinical research in Russia may be under threat, too: There are 557 active trials ongoing there, but flight bans may affect the transportation and analysis of samples. Moscow State Medical University, one of the biggest universities in Russia, said it has paused recruiting of new patients for its 120 ongoing trials, citing the university’s inability to receive samples from other parts of the world, as Russia has closed its airspace to airlines from dozens of countries.
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Some pharmaceutical industry sponsors had procedures in place to cope with a possible escalation of the war. But, Vyshnyvetskyy says, “some sponsors appeared absolutely not ready for this.” Most of the companies contacted by WIRED said they will try to run ongoing trials as best they can, even if the participants have left Ukraine, and pause recruitment for new ones. A spokesperson for Swiss biotech company Roche said that there are 33 Roche-led global investigational studies with sites in Ukraine and that “the situation for those patients is currently very challenging.” The spokesperson said “we are actively working on solutions to ensure continued access to treatment for these patients, including if they have left Ukraine and moved to other countries. With regards to displaced persons or refugees, a number of neighboring countries have confirmed they will be eligible for the same access to health care as local citizens. We are working with health care providers in these countries to ensure sufficient supply is available.”
A spokesperson for pharma giant Merck told WIRED that Ukraine and Russia represent about 7 percent of their active test sites and that they would try to transfer some of this work to other regions. “Screening and enrollment in ongoing clinical trials and planning for new studies in these regions have been paused until further notice,” the spokesperson wrote, as the company determined it cannot safely conduct clinical trials in Ukraine or Russia.
Likewise, Pfizer issued a statement saying that the recruitment of new participants has been paused, and a spokesperson for British-Swedish drugmaker AstraZeneca told WIRED: “In order to continue serving patients around the world, we are working to maintain existing clinical trials. We have, however, decided to pause recruitment of new patients to some trials in Ukraine and Russia while we analyze the impact sanctions have on supply chains.”
French health care company Sanofi and French drugmaker Servier Group both confirmed they have trials in Ukraine that remain ongoing. But as a Servier spokesperson wrote of the company’s two oncology trials there, “due to the situation and communication difficulties, it is very difficult to date to obtain precise information on the progress of these studies.”
If trials in Ukraine are paused or disrupted, the ramifications for medicine could be felt for a long time. Clinical trials are a lengthy, complicated, and singular pathway to getting new treatments approved, and the war could stall the progress of drugs that are approaching the end of the development pipeline—Phase 3, in which the safety and effectiveness of a new treatment is tested against the current standard treatment. Karuna Therapeutics, a biotech company based in the US, wrote in a February SEC filing that the timeline for the third phase of its trial of a “blockbuster” drug for the treatment of schizophrenia is delayed, as 10 of the 19 trial sites are in Ukraine. Similarly, Tricida, a Californian biotech company, has delayed the expected date for reporting results from its Phase 3 of Veverimer, for chronic kidney disease. Around 15 percent of the trial’s subjects are from Ukraine.
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Ukraine is also home to very early-stage research, the lab research that precedes human clinical trials. The invasion will “disrupt the supply chain of intermediates for people doing discovery work,” Ed Griffen, a medicinal chemist, told The Medicine Maker, a magazine covering the pharmaceutical industry. In particular, Enamine, a company based in Kyiv, is a global supplier of chemical compounds and reagents necessary for drug discovery, including the Moonshot project, which is developing antiviral treatments for Covid to be made freely available to the world. On February 24, the company announced via social media that its services were being temporarily postponed as its employees escape the country or stay to fight.
If a clinical trial’s ultimate goal is to improve the lives of patients, then their safety is paramount—endangering them in the research process would be antithetical to the cause. That’s the purgatory medical investigators in Ukraine currently find themselves in: What’s more dangerous, pulling experimental drugs from people who might desperately need them or forcing patients to continue with trials in a country where today’s trial sites could be tomorrow’s bomb targets? Medical facilities, where trials are often carried out, are already under siege. On March 8, the World Health Organization confirmed 16 attacks on medical facilities in Ukraine—including a maternity ward—and said these attacks were increasing rapidly. Getting to research sites in a war-torn country is treacherous for even the healthiest individual. What if your patient has Stage IV cancer?
The crisis in Ukraine parallels the dilemmas faced by researchers during the early days of Covid-19, when thousands of trials were halted, disrupted, or delayed. Trial investigators were forced to weigh the risks: Did the danger of a Covid infection outweigh the benefit of the trial?
Vyshnyvetskyy says that unless the current conflict is resolved, clinical trials in Ukraine could stop completely. But for now, because the situation is changing by the day, Ukrainian authorities haven’t ordered any shutdown, he says—“just because nobody knows when this madness will stop.”
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