Fatalities are an unfortunate reality of clinical trials. How can companies best protect themselves?
Over the past decade, an average of 177,798 clinical trial participants have died each year in the U.S. For deaths that could be expected because of the patient’s condition, drug developers report the event to the FDA and business continues as usual.
But sometimes, deaths are unexpected or are linked directly to the investigational therapy. In June alone, the FDA placed a partial clinical hold on a Phase I trial of BioNTech and MediLink’s BNT326, an antibody-drug conjugate being investigated for types of non-small cell lung cancer or breast cancer, following multiple patient deaths; and a Phase III clinical trial analysis linked Gilead’s magrolimab to an increased risk of death in myelodysplastic syndromes patients.
When these events occur, pharmaceutical developers must respond with both patients and stockholders in mind in an effort to create treatments that are ultimately safe and effective.
Anthony Japour, CEO of biopharma company iTolerance, has served as a clinical investigator, a member of an institutional review board and a medical monitor for clinical research studies with a CRO. He told BioSpace about a clinical trial that occurred early on in his career.
“I’ll never forget this,” Japour said, “because a healthy volunteer almost died—literally, almost died.” The trial assessed the safety of a combined therapy in which one of the products was already marketed and widely used.
The event was caused by “a rare, idiosyncratic response to the drug,” Japour explained. “We terminated the study immediately.”
In that case, the participant was treated in hospital and survived. “We had to pay all the hospital bills. There was a major lawsuit, which we settled out of court, and that was that,” Japour said.
Jesse Gelsinger’s Story Changed Gene Therapy
Outcomes aren’t always so antiseptic. One of the best-known cases occurred in 1999, when Jesse Gelsinger became the first publicly-identified person to die during a clinical trial for a gene therapy.
Twelve days after Jesse’s death, the FDA and the NIH Office for Protection from Research Risks reviewed the clinical trial protocol and noted that the investigators had failed to report side effects from two patients and that two monkeys had died in preclinical trials. Furthermore, Jesse should have been excluded from the trial because his liver wasn’t functioning at the minimal level required by the protocol when he received the treatment.
Gesinger’s family sued, and the University of Pennsylvania, which conducted the clinical trial, settled out of court. About four months after Jesse’s death, the FDA suspended human research at the university’s Institute for Human Gene Therapy and the program was closed. The FDA also charged the principal researcher with several violations, resulting in a fine of $514,000 and a five-year restriction on work involving human research. The university rebutted the findings and investigations continued until February 2005. The events chilled gene therapy development for years.
In the aftermath, the FDA and the NIH launched the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia to improve patient protection.
First Steps
Most trials involving unexpected deaths garner far less attention. Yet, as Drew Levinson, executive vice president at LifeSci Communications, acknowledged, “It’s heartbreaking for the families, and it also affects others in the trial who have to stop their treatment. And, if the drug fails, sometimes the company fails.”
Levinson recounted an early-stage, rare disease trial conducted by a small biotech company several years ago in which two patients died suddenly. The FDA suspended the trial until the cause of death was determined.
“The first thing we did was put together a holding statement.” That announcement confirmed there had been an incident, that the company didn’t yet know the cause, and that it was working to gather more information.
The company also reached out quickly to the affected families to express empathy and sympathy. “A lot of times, I think companies forget that,” Levinson commented.
“The initial statement gave the company time to plan its next steps and prepare a detailed press release,” which was issued about a week later. “Reporters need information fast, so our job was to help control the message,” he continued. In a more comprehensive, follow-up press release, “It was important to be as transparent as possible and to show that leadership was concerned, in control and committed. In the end, it turned out the deaths were not caused by the therapy, so the FDA lifted the hold.”
Craft a Plan Proactively
Before a crisis emerges, Ignacio Guerrero-Ros, vice president at RussoPartners LLC, strongly advised developing a crisis communications plan “that emphasizes transparency, empathy and proactive communications.
“In a crisis, strong emotions can fuel rumors and sensational media coverage,” he told BioSpace in an email. “Clinical trials inherently involve risks and uncertainties, making effective crisis communications essential.”
Therefore, Guerrero-Ros stressed, “Establishing and maintaining relationships with groups directly or indirectly involved in the study—such as patients, advocacy groups, sponsors and contract research organizations—is key.”
So is controlling the spread of misinformation. To do that, he advised developing approved messaging and monitoring media reporting and stakeholder concerns to ensure information is accurate.
“Never underestimate the power of emotional tone in communications. Respectful, transparent and courteous communication is critical in maintaining trust and credibility,” Guerrero-Ros said. Still, he noted, “Solving the problem is generally more effective than trying to manage its perception.”
Involve Regulators Immediately
Usually, deaths during clinical trials are made public only if a clinical hold or suspension of a trial occurred, David Dodd, chairman, president and CEO of GeoVax, told BioSpace.
Within seven days of a death, “(clinical trial) investigators usually are required to report any death or [severe adverse event] immediately to the clinical trial sponsor or the entity overseeing the research,” said Barbara Marusiak, senior director of the clinical research management and regulatory science program at Arizona State University.
Then, trial sponsors are “required to notify the FDA and all participating investigators in a clinical trial in a written safety report of any adverse experience associated with the use of a drug that is both serious and unexpected,” April Grant, an FDA spokesperson, told BioSpace in an email.
Before issuing a clinical hold or suspension, Grant added, “The FDA will attempt to discuss and satisfactorily resolve the matter with the sponsor by explaining the concerns identified by the review team . . . unless patients are exposed to immediate and serious risk.” Once identified, problems can be resolved. If a trial is placed on a clinical hold, only the FDA can allow it to resume.
“Depending on the severity and circumstances,” Marusiak added, “investigators also may need to report to ethics committees or institutional review boards. Detailed documentation of all aspects related to the death or severe adverse event (SAE) is crucial,” she said, “including records of all communications, reports submitted and any follow-up actions taken.”
If the trial is ultimately successful, deaths seem to become footnotes in the trial literature. If the therapeutic is the cause of death, however, those events can halt or delay the development of entire classes of medicines. Which it is depends largely on the details of the events.
