Drug trial disaster prompts call for changed procedures
and World Science staff
A U.K. medical journal has called for changing the approval processes for early-phase drug trials in that country in the wake of a disaster that put six British men in intensive care last month.
Researchers found that an experimental drug, TGN1412, had caused the effect in the previously healthy men at London’s Northwick Park Hospital. But the reason for it was puzzling, as the problem didn’t show up when the drug was tested in monkeys.
Scientists announced last week that there is no evidence of contamination in the treatments.
“Urgent change is needed in the approval processes and regulation of phase I trials of biological agents,” stated an editorial in this week’s issue of the London-based medical journal The Lancet.
In Phase I clinical trials, researchers test a new drug or treatment in a small group of people, usually between 20 and 80, for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
The U.K. government’s Medicines and Healthcare products Regulatory Agency authorised the TGN1412 trial, and in a later interim report concluded that “it was run according to the agreed protocol.”
The drug is a type of superantibody, an experimental treatment in which patients are treated with laboratory-enhanced versions of substances produced naturally by the immune system to fight malignant or foreign cells.
TGN1412 had been an “an enticing candidate for treating autoimmune diseases such as rheumatoid arthritis and type-1 diabetes,” according to the April 13 issue of the research journal Nature.
One recognized risk of the treatment, the Lancet commented, was that it could trigger massive release of proteins called cytokines, which serve to regulate the immune system. This could lead to an imbalance in cytokines, with serious adverse effects.
But the published documents relating to the trial make no mention of any “precautionary dosing interval between volunteers” to protect against this, the Lancet added. “As the Academy of Medical Sciences suggests: ‘it would be usual practice to administer a single dose in a single patient, who would then be observed for an appropriate period of time.’”
How clinical trials are regulated is now under review following the release of the MHRA’s interim report.
Nature, in a news report in its April 13 issue, described a new theory about what could have gone wrong.
TGN1412 was designed to switch on immune cells by attaching itself to a molecule called CD28 on the surface of the cells. This molecule, also called a receptor, is identical in humans and monkeys, so researchers thought that the drug would have similar effects in both species.
The Nature news report speculated that the natural antibody that binds to this receptor is slightly different in humans and monkeys. The human version of the antibody molecule may have a “tail” that boosts an immune response through a process of cross-linking with other tails. This could have caused a runaway boosting effect leading to the “cytokine storm” that researchers were concerned about.
The monkey version of the molecule might have a different type of “tail” without this property, so that the problem wouldn’t show up during monkey testing, according to the article, by Nature reporter Michael Hopkin.
He also wrote that Thomas Hünig—an immunologist at the University of Würzburg in Germany and co-founder of TeGenero, developer of the drug—agreed that this idea might be correct.
Send us a comment
on this story, or send
it to a friend