When volunteers offer to help test the safety of a new drug in a clinical trial, they anticipate nothing 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 that identify all known risks. And that is usually correct. However, what happens when a novel drug has effects that have not been encountered before? This was the case in a clinical trial carried out at Northwick Park Hospital in March 2006.
Six volunteers offered to help in the testing of a new drug, called TGN1412, to treat leukaemia and also diseases like rheumatoid arthritis. However, within 90 minutes of receiving the experimental drug they were writhing in agony as the drug had caused reactions never seen in a clinical trial before, nor in any of the pre-clinical safety tests. The reaction, dubbed by scientists “a cytokine storm”, was life threatening. Within 12 hours all were in intensive care which lasted up to 16 days as doctors fought to control the symptoms. In the end, all six volunteers survived. However, one of them lost his toes and fingers and all of them may face health complications in the future as a consequence of life threatening "cytokine storm" they experienced.
So 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? As the organisation that had given permission for the trial to take place, the MHRA were involved immediately, along with the police. One of the first actions that the MHRA undertook was to seize the remainder of the drugs used in the patients and send them to scientists at NIBSC. Very quickly, tests showed that the TGN1412 used in the study had not been tampered 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?
The dramatic symptoms observed in the volunteers, the “cytokine storm” can be reproduced in human blood cells in the laboratory by adding potent stimulatory chemicals, called mitogens. However, when the drug 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, then 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 closely related monkeys spotted the problem? Further research, applying the modified tissue culture test to blood cells from monkeys did not result in the massive response that were now seen in human cells treated in the same way. This result 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 that mean, for this drug, monkey studies would never predict the catastrophic reactions suffered by the volunteers. In addition, it also found that the way scientists predict safe doses for humans based upon the pre-clinical studies were flawed for this class of drug.
The information gathered by the NIBSC team to try and understand what went wrong with the TGN1412 clinical trial was central in the development of new European regulations that govern clinical trials which are the first time that a new drug is given to volunteers. In addition, the practical experience identified a raft of new in vitro assays that may predict better the likelihood that new drugs and vaccines will cause white blood cells to initiate the “cytokine storm” that almost killed the volunteers at Northwick Park Hospital. These tests, that are designed to detect the so-called Immuno-toxicological reactions, are now being used to ensure that new drugs cannot cause these terrible reactions. These tests are very difficult to set up and so the team at NIBSC are preparing key control materials that help to ensure that the tests work with the same sensitivity and precision wherever they are carried out.