Six healthy volunteers who took TGN1412 for the first human trial in London on 13 March 2006 showed serious toxic reactions with collapse and loss of consciousness with multiple organ failure (MOF) and were admitted to ICU [1-3]. Three of them still need ventilator and two of the three remain unconscious and seriously ill with MOF . As of 31 March 2006, four of the six patients had returned to their homes. One of the other two has been transferred out of Critical Care, and the worst-affected patient "is now fully conscious and we are encouraged by his progress," according to a press release on the North West London Hospitals NHS Trust website [11,22].
For more details, see March 2006 issue of "The Informed Prescriber"
The clinical trial in question is conducted by PAREXEL, a U.S. clinical research organization (CRO) at Northwick Park Hospital in London, and involved TG1412, an agent tested on human for the first time. Eight healthy volunteers took part in the trial (six on TGN1412 and two on placebo). Right after the six volunteers took the agent, they all started to complaine of body ache and difficulty in breathing and fell unconscious. Within an hour they were admitted to ICU for multiple organ failure (MOF) and needed to be on ventilator. The news as of 19th March reports that four out of the six came back conscious and three came off ventilator. However, remaining three are still on ventilator and two of them continued to be unconscious and critically ill . As of 31 March 2006, four of the six patients had returned to their homes. One of the other two has been transferred out of Critical Care, and the worst-affected patient "is now fully conscious and we are encouraged by his progress," according to a press release on the North West London Hospitals NHS Trust website [11,22].
Raste Khan who was given a placebo said in the Times Online report :
"They took blood samples from everybody. Then they dosed people at two-minute intervals. Routinely five minutes after everyone had been given the drug, the first person who was given the drug started to shake. He took his top off, he looked like he was burning up, and rubbed his head. Several minutes later, it missed me and went to the third person. He started doing similar things but he vomited on several occasions. He came back to consciousness but was hyperventilating. He looked like he was in the worst pain. Then No. 4 went through similar symptoms. He took several steps and collapsed. He said 'I can't control myself. I need to use the toilet' ...Nurses had a big black liner for them to vomit in. People were fainting and coming back to consciousness. The gentleman on my left was screaming, saying his back was hurting. It was horrible. I feel guilty that I had the placebo. It was like Russian roulette. I was doing it for the money. But £2,000 is not worth your life."
One of the victims, Ryan Wilson, 21, begged doctors to put him to sleep because he was in such searing agony. To sum up what his family said, his head swelled to nearly three times its normal size. His neck was the same and was wider than his head, and his skin had turned dark purple. He was likely to die after his heart, lung and kidney had failed. 
The trial was immediately discontinued and MHRA withdrew authorisation for the trial . PAREXEL, a CRO that conducted the trial, and TeGenero (Germany) that developed the agent say that dose administered was one five hundredth of that proved safe in animal test, and they strictly followed the procedures, so it was not possible to predict the event.
However, Kusuri-no-Check’s analysis reveals the following problems: PAREXEL and TeGenero might have ignored information about toxicity. And it was also possible that MHRA’s regulation was not sufficient.
The agent used in the trial was aiming at now a popular "molecule targeting agent". The target is CD28, a molecule on the surface of lymphocytes that is deeply related to immunity and inflammatory reaction. The agent is a monoclonal antibody that combines with CD28. Conventional antibodies of the same class do not activate lymphocytes without additional stimulation. In contrast, it is said that this agent alone can characteristically activate lymphocytes without additional stimulation because it combines with different part of the CD28 molecule as the conventional anti-CD28 antibody. Therefore, it is called "CD28 superagonist"  or CD28-SuperMAB .
The agent was expected to stimulate lymphocytes and to induce a substance that suppresses inflammation for treating intractable rheumatism and chronic leukemia. However, it induced extreme inflammation in healthy human instead of improving inflammation.
Another Superagonist "JJ316" is a similar substance to TG1412, but was developed for animal (superagonistic anti-rat CD28 monoclonal antibody). In an animal test, it improved inflammation of rheumatism-model animal . Contrarily, in healthy animals, lymph nodes and spleen have swollen to several times their normal size . Also, a trial in which another substance of the same class was first tested on cancer patients showed half the patients experienced severe adverse reactions . Much data are now coming up to question whether the toxicity was really unpredictable.
TGN1412 is a superagonistic humanized anti-CD28 monoclonal antibody. However, lymph nodes and spleen of healthy rats administered superagonistic anti-rat CD28 antibody (JJ316) swelled severely .
The fact that the trial was approved by the regulatory authority in UK may be a problem to be reconsidered in its own. If the event was an accident as a result of the trial conducted in a way the regulator authorized, the current standard needs to be reviewed. Conventionally, drugs are mainly chemical, but now the trend is shifting to development of biological substances. Reflecting such trend, we need to reexamine the current safety measures in which human safety is assumed based on animal test results.
Moreover, it is necessary to thoroughly investigate, referring to common sense, whether current measures are appropriately followed.
In Japan, streamlining of clinical trial, including phase I trial, is urged without any established legal system to protect research subjects [17-19]. We, NPOJIP (Kusuri-no-Check) and The Informed Prescriber (TIP) submitted an opinion report in July 2005, demanding the establishment of legal system to publicly manage and monitor all trials involving human and to protect subjects for clinical trials . Also we criticized the revised proposal that allowed examination of clinical trial to be inconsiderately entrusted to external body, in our opinion report (March 2006) about "proposal of partial revision of ministerial ordinance concerning the implementation standard for clinical trial of medicines that involves examination committee" .
This event in the UK is a strict warning against easy streamlining and promotion of clinical trial. We believe that the similar incident can also happen in Japan. We continue to monitor the conduct and regulation of clinical trials to ensure the safety of research participants. Please keep an eye on our upcoming information.
The MHRA has today (5th April) released its interim report into the adverse incidents which occurred on 13th March 2006 during the clinical trials of TGN1412 (see report below) .