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With 20 treatment-related deaths in U.S. clinical drug trials, watchdog group files amendment to FDA citizen petition.

With at least 20 treatment-related deaths in clinical drug trials between May 2016 and April 2017, Center for Responsible Science (CRS) has updated its July 2015 citizen petition, also adding a declaration from the father of a 24-year-old patient who died two days after receiving an experimental cancer therapy developed by Juno Therapeutics.

The amendment, filed before the latest death was reported, urges the Food and Drug Administration (FDA) to amend 29 regulations to allow the preclinical test method most predictive of human response to be used during drug testing. Current regulations mandate the use of animal models, even if there are human-relevant tests that could predict toxicity that animal tests may miss.

Treatment-Related Clinical Trial Deaths

  • Juno Therapeutics – On May 24, 2016, 24-year-old clinical trial participant Max Vokhgelt died from cerebral edema, likely brought on by a cytokine storm in a phase II trial for a chimeric antigen receptor T-Cell (CAR-T) therapy (which uses a patient's T cells that are changed in the laboratory so they will attack cancer cells). After review of that event, Juno and FDA concluded that a change in trial protocol was not warranted at that time. Max’s death was not reported until July 13, 2016, after two more participants died from cerebral edema. FDA issued a clinical hold of the trial on July 7, 2016, but lifted the hold just five days later based on Juno’s assertion that the chemotherapy preconditioning agent (fludarabine) in combination with the CAR-T therapy had caused the deaths. Juno resumed the trial without fludarabine, and two more clinical trial participants died from cerebral edema in November 2016. 

“My son was the first to die of cerebral edema in the Juno trial,” said Max’s father, Michael Vokhgelt. “I believe in the promise of CAR-T therapy, but if traditional tests don’t always predict deadly toxicities, drug sponsors must be allowed to use more predictive tests that better predict what happens to clinical trial participants. It is FDA’s responsibility to protect human health and safeguard the public from dangerous drugs. Shouldn’t all available tests to predict safety be used? I don’t want another family to go through what my family went through.”

  • Ziopharm – On July 14, 2016, three deaths were reported that occurred in a phase I trial for a gene therapy for brain tumors.
  • Seattle Genetics – In late December 2016, four more deaths from hepatoxicity in a cancer drug trial prompted FDA to issue a clinical hold.
  • Stemline Therapeutics – In February 2017, Stemline Therapeutics announced the death of one patient in a phase II trial for blastic plasmacytoid dendritic cell neoplasm (BPDCN). This was the third death from capillary leak syndrome in this trial. In March, a fourth death was announced.
  • Kite Pharma – In December 2016, Kite Pharma announced there had been three treatment-related deaths in their ZUMA-1 CAR-T trial. On May 8, 2017, Kite reported another death in its ZUMA trial, this time from cerebral edema.

Despite their potential as a breakthrough cancer cure, there are serious safety concerns related to CAR-T cell therapies. Lack of relevant animal models for safety testing has been exemplified by numerous serious adverse events in studies using CAR-T engineered cells. It is essential that this promising cancer therapy be tested in human-relevant test methods to more specifically determine the safety risks before it is tested in humans.

There are human-relevant test methods that can predict cytokine release syndrome and inflammation-related adverse events, including cerebral edema. CAR-T therapies could be tested in this platform in combination with any preconditioning drugs. However, due to current FDA regulations, the animal tests are required. It’s clear that traditional animal tests could not predict the deadly cerebral edema that killed five in the Juno ROCKET trial. Given what is known, CRS strongly encourages FDA to allow the test that most reliably predicts what will happen in humans, instead of insisting only on long-standing animal models. 

Lives at Stake

“With the recent documented failure of animal-based preclinical test methods to predict safety in humans, and the tragedy of at least 20 treatment-related deaths in clinical trials, it is more urgent than ever that FDA update regulations to broaden drug sponsors’ options to use the most predictive tests available,” said CRS President Dr. Neil Wilcox. “FDA’s adoption of these conservative amendments to Investigational New Drug (IND) and Investigational Device Exemption (IDE) regulations should happen now. The lives of clinical trial participants are at stake.”

The 20 deaths reflect what has been reported in the media and some Securities and Exchange Commission (SEC) filings. Because most of what the public can learn about clinical trial deaths and FDA clinical holds comes from press releases issued by drug sponsors, the actual number is likely higher. 

The Center for Responsible Science is a nonpartisan, nonprofit organization advocating for more modern and predictive test methods in drug development.

(Source: Center for Responsible Science)

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