When volunteers offer to help test the safety of a new drug in a clinical trial, they don’t expect anything much to happen. Perhaps the injection of the drug and the “scratch in the arm” as they provide a blood sample. They feel safe in the knowledge that exhaustive pre-clinical safety checks have been carried out and that all known risks have been identified. And that is usually the case.
But what happens when a novel drug has catastrophic effects that have not been encountered before? This is what happened in a clinical trial carried out at Northwick Park Hospital in 2006. On the 10th anniversary of this event, we look back at the important role NIBSC played in uncovering what went wrong, and in making clinical trials safer for the hundreds of volunteers who take part in them every year. A cytokine storm
Back in 2006, six volunteers offered to help test a new drug called TGN1412, intended as a treatment for leukaemia and diseases such as rheumatoid arthritis. But things did not go according to plan. Within 90 minutes of receiving the experimental drug the volunteers were writhing in agony. The drug had caused reactions never seen before in a clinical trial or in any of the pre-clinical safety tests. The reaction, dubbed by scientists “a cytokine storm”, was life threatening. Within 12 hours, all six volunteers were in intensive care, some for as long as 16 days, while doctors fought to control the symptoms. Fortunately, all six volunteers survived. One of the volunteers lost toes and fingers, and all were told they could face health complications in the future as a consequence of experiencing a life threatening "cytokine storm".
What went wrong?
Was the drug the same as the material that appeared perfectly safe in preclinical trials? Or had the drug been tainted in some way? MHRA - as the organisation that had given permission for the trial to take place - was involved immediately. The first action was to remove the remainder of the drugs used in the patients and send them to scientists at NIBSC. Very quickly, tests at NIBSC showed that the TGN1412 used in the study had not been tampered with and was identical to the materials used in the pre-clinical safety tests performed in tissue culture and in animals. So why hadn’t these tests spotted any problems?
NIBSC unearths the answer
The dramatic symptoms observed in the volunteers can be reproduced in human blood cells in the laboratory by adding potent stimulatory chemicals, called mitogens. But when TGN1412 was added to the cells, nothing happened. In a serendipitous observation, the team at NIBSC found that coating the TGN1412 onto a solid surface, in this case by drying the drug onto the wells of a plastic plate with a hair dryer, a very different result occurred. This drug was more potent than the best mitogen used in the lab as a positive control.
If an answer had been found for why tissue culture tests had not identified the problem with TGN1412, why hadn’t studies in animals (including in monkeys closely related to humans) spotted the problem? Further research, involving applying the modified tissue culture test to blood cells from monkeys, did not result in the massive response that had been seen in the volunteers. This suggested that there was a difference between the way human and monkey blood cells processed the drug.
Detailed studies of the way that white blood cells respond to signals delivered by the drug identified a subtle difference between monkeys and humans. There were two key findings. The first was that for this drug, monkey studies would never predict the catastrophic reactions suffered by the human volunteers. Secondly, the way scientists predict safe doses for humans based upon the pre-clinical studies was flawed for this class of drug.
New clinical trials regulations
The information gathered by the NIBSC team to try and understand what went wrong with the TGN1412 clinical trial was pivotal in the development of new European regulations that govern the first time a new drug is given to volunteers in a clinical trial.
NIBSC research into what went wrong also identified a raft of new in vitro assays that may predict better the likelihood of new drugs and vaccines causing a “cytokine storm”. These tests are now being used to ensure that new drugs cannot cause the terrible reactions seen with TGN1412. The challenge is this these tests are difficult to set up, so the team at NIBSC are preparing key control materials to help ensure that the tests work with the same sensitivity and precision wherever they are carried out.
Ten years on from Northwick Park event , the work undertaken by NIBSC continues to ensure that new powerful drugs designed to improve patient health don’t hide unwelcome and possibly fatal side effects that otherwise would not surface until they are tested in clinical trial volunteers.