Monday, March 20, 2006

An Update on the Tragic TGN 1412 Trial

Our most recent post on the lack of transparency in the trial run by Parexel of TGN 1412, a drug developed by TeGenero, which left all six participants in intensive care with multi-organ system failure, was here.

This trial has generated tremendous media attention. Thus, we now know a bit more about it, but still not much.

According to TeGenero's website, the drug TGN 1412 is a monoclonal antibody that targeted the CD28 receptor on T-lymphocytes. The drug is not meant to destroy T-lymphocytes, but rather to activate the CD28 receptor. According to TeGenero, the TGN 1412 leads to "pronounced T-cell activation and expansion." Thus, unlike some other monoclonal antibodies used to treat cancer, this drug was meant to change the settings, as it were, of the patient's immune system. This was thus a novel therapy, and hence one whose results might have been unpredictable.

Furthermore, the Times (UK) reported that before the trial was carried out, there may have been reasons to be concerned that this drug might have had adverse effects. The Times article quoted Angus Dalgleish, (who holds the Foundation Chair of Oncology at St. George's Medical School in London, but is also the Research Director for Onyvax, a company that also is developing cancer treatments based on immunology), "I would have told the people doing this trial [on TGN 1412] not to do it because the dangers were so great." He cited studies of a "similar drug," "They should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways." (I have not yet been able to figure out precisely which studies he meant.) Furthermore, the Times quoted Jorg Schaaber, "a member of the German drug industry monitoring group Buko Pharma" (whose web-site is here, but appears to only be in German), that monoclonal antibodies like TGN 1412 carry "considerable risks." Finally, it quoted Michael Seed, a Senior Research Fellow at the William Harvey Institute at Barts and the London Hospital and the Queen Mary's School of Medicine and Dentistry, "The danger is that they are messing around with T regulator cells and we don't know what all the T regulator subsets do. Some will switch things on and some will switch things off."

Furthermore, newspaper reports hint at irregularities in how the trial was conducted. The Times (UK) article suggested that the fees paid volunteers were sufficient to be inducements, rather than just payments for time and expenses. It also alleged that in other trials, Parexel, the contract research organization conducting the TGN 1412 trial, used consent forms so long as to be unreadable, and "pressured" volunteers to sign the form with reading it, "because I felt like I was slowing everyone down." Also, it noted that some trial participants may have been professional research subjects, e.g., one, referred to as a "serial human guinea pig," had reportedly made 60,000 pounds sterling in four previous years from participating in drug trials.

An article in the Telegraph (UK) cited a review article on the effects of monoclonal antibodies to CD28 (Hunig T, Dennehy K. CD28 superagonists: Mode of action and therapeutic potential. Immunol Letters 2005; 100: 21-28 )which noted "massive expansion and functional activation of regulatory T-cells by in vivo treatment with CD28 superagonists," but also revealed gaps in current knowledge about what CD28 activation does, and then asked "does it even make sense to talk of informed consent when the experts themselves admit to sugh gaps in their knowledge?"

Thus, there are reasons to suspect that this trial had not been fully thought through, and that it it was not optimally implemented.

Once again, while hoping that six participants in this trial get better, I also hope this tragedy prompts a re-evaluation of our drug testing procedures, and particularly more transparency in all phases of the process.


Anonymous said...'injected+too+quickly'/

The victims of the catastrophic 'Elephant Man' clinical trial were given the test drug at a 'reckless' rate, according to experts.

The drug TGN 1412, designed to fight leukaemia, rheumatoid arthritis and multiple sclerosis, was injected 15 times more quickly than when given to monkeys in animal studies, confidential documents have revealed.

Leading scientists believe this 'reckless' mistake could explain the horrendous reaction to the drug which left volunteers fighting for their lives.

The six young men - all fit and healthy before signing up for the March trial at Northwick Park Hospital in North-West London - suffered a host of side-effects, including pain, vomiting and organ failure.

Bar manager Mohamed 'Nino' Abdelhady, 28, was described as 'the Elephant Man' by his partner Myfanwy Marshall after his head swelled up.

Trainee plumber Ryan Wilson, 20, suffered heart, kidney and liver failure, pneumonia and blood poisoning and was in a coma for three weeks.

While in the coma, he suffered a frostbite-like reaction and has since lost parts of his fingers and had his toes amputated.

The volunteers, who are launching a multimillion pound damages claim against Parexel, the private research firm that ran the trial, face contracting cancer and other chronic and incurable diseases such as multiple sclerosis.

An investigation by the Government's drugs watchdog, the Medicines and Healthcare products Regulatory Agency, concluded no mistakes had been made in either making or testing the drug.

Instead, the horrific side-effects were down to an effect of the drug in the human body that could not have been predicted.

Now, documents obtained by the Channel 4 programme Dispatches reveal that the speed at which the drug was given could be to blame.

They show that Mr Wilson was given the drug - a cutting-edge medicine known as a monoclonal antibody - in just four minutes. The others were injected or infused with the solution over periods ranging from three to six minutes.

In contrast, monkeys used in earlier experiments were slowly infused with the drug over an hour.

Professor Terry Hamblin, a Southampton University expert on monoclonal antibodies, said: 'When you give an antibody, the quicker you put it in, the more likely you are to get a reaction.

'I usually give it over about six hours. If you give it in less than an hour you get horrific reactions.

'To quickly infuse it over three to six minutes in six individuals I think is reckless.'

Dr David Glover, former chief medical officer of drug developer Cambridge Antibody Technology, said: 'The drug was given too quickly.'

Parexel refused to comment on the Dispatches findings, while TeGenero, the German company which made the drug, said the trial was 'the right thing to do'.

The MHRA, which gave the human trial the go-ahead after looking at the results of animal experiments, said the men were given doses 500 times lower than those used in animals.

A spokesman said similar drugs have been given to people in the past at a faster rate without any problems.

He added: 'There was no reason to believe the administration rate proposed would present as a foreseeable hazard to the subjects.

* Watch Dispatches: The Drug Trial That Went Wrong on Channel 4 on Thursday at 9pm.

Anonymous said...

It was an absolutely educative and analytical article.