Friday, September 29, 2006

Were the "Elephant Men" Given TGN 1412 Infusions Too Fast?

We have posted frequently, here, here, here, and here, about the disastrous trial, now colloquially known as the "elephant men" trial after the bizarre clinical effects it produced, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG, which is now bankrupt. Last week, the Times (UK) found new information suggesting another hypothesis about what went wrong.
A "reckless” mistake apparently overlooked by government regulators lay behind the drug trial disaster that saw six young volunteers badly injured by an experimental medicine.

Confidential documents obtained by The Sunday Times and Channel 4’s Dispatches programme reveal the drug was administered on average 15 times more quickly to the volunteers than to monkeys in earlier safety studies. The possibility that such a crude error led to the disaster is likely to raise questions over whether the government’s Medicines and Healthcare products Regulatory Agency (MHRA) scrutinises trials adequately and protects the public from the risks of new medicines.

Experts say the drug, TGN1412 — one of a new generation of “magic bullet” treatments targeting the immune system — was infused so quickly into the volunteers that the potential for life-threatening problems was foreseeable.

'When you give an antibody . . . the quicker you put it in, the more likely you are to get an infusion reaction,' said Professor Terry Hamblin of Southampton University, a leading authority on monoclonal antibodies, the family of drugs to which the trial medicine belonged.

The volunteers were given TGN1412 in only three to six minutes. 'To quickly infuse it over three to six minutes in six individuals I think is . . . reckless,' said Hamblin.

Hamblin’s judgment is backed by other experts, including Dr David Glover, formerly chief medical officer of Cambridge Antibody Technology. He concludes: 'The drug was given too quickly.'

The speed at which the monkeys received TGN1412 was set out in the application to the MHRA for permission to carry out the trial. This was submitted by Parexel International, a contract research company, on behalf of TeGenero, a tiny German drug developer. But the paperwork did not explicitly detail how quickly the volunteers would be given the drug, although this could be calculated from the information given.

Parexel declined to comment.
And TeGenero is now bankrupt.

Obviously, whether an excessively rapid infusion of TGN 1412 lead to the terrible results of this trial is unproven. Hopefully, some sort of more detailed official inquiry might come to more definitive conclusions. Yet, as we said in a previous posting, "clearly, this article raises concerns about whether Parexel could have done a better job protecting its research subjects. Minimizing the risks to human research subjects should be the highest priority for those who do clinical research."

Parexel's web-site page on clinical research services states,
Your success depends on your ability to move your product concept from early research through clinical trials and regulatory review to the market in the shortest possible time. The bottlenecks and hurdles in your path, both known and unknown, must be identified and eliminated. Over the past two decades, PAREXEL has helped nearly a thousand clients find success.
Maybe the company's focus on speed hindered its ability to protect its research subjects.

In my humble opinion, it is time to re-think whether clinical trials of drugs and devices should be designed by the companies that make the products, implemented by for-profit contract research organizations, and supervised by for-profit "institutional review boards," as they are called in the US. If we continue these practices, we clearly need to think how to regulate them. Better yet would be to have these trials done by independent organizations who are not beholden to the manufacturers and whose missions include a priority on protecting their human research subjects, and then who are supervised by reviewers with similar independence and similar commitment to patient welfare.

WHAT YOU CAN DO: In the US, write your Representative or Senator, in the UK, contact your MP, and ask for a legislative review of how clinical trials of drugs and devices are designed, implemented, and supervised, with emphasis on scrutinizing the influence of the manufacturer (who want their products t0 look good), and the contract research organizations and for-profit review boards that serve the manufacturers.

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