Pharma Strategy Blog

This post is an update to an earlier one I posted 2 years ago relating to the sad events of TGN1412. Someone sent me an email asking what had happened to the volunteers in the clinical trial at Northwick Park in London?

Let’s recap.  TGN1412 was an experimental drug being investigated for the treatment of multiple sclerosis, leukemia and arthritis.  It was a monoclonal antibody that stimulated the immune system’s T-cells.  Tests on animals showed the drug to be ‘safe’.

However, in a fated phase I trial in humans, the men who received doses of TGN1412 suffered a massive inflammatory response (Cytokine Release Syndrome), and within 12 hours were admitted to hospital with multiple organ failure. The two patients receiving placebo were unaffected. TGN1412 was manufactured by the now insolvent German biotech company TeGenero.  Parexel, a contract research organisation, ran and administered the trials on behalf of the company.

The final investigation into the disastrous trial presented 22 recommendations to the UK Health Secretary, the main one being that an advisory body to assess high-risk clinical studies should be established. It also recommended that volunteers who are ill, as opposed to healthy candidates, should be considered for some drug trials. This is standard practice in trials involving cancer drugs, but not immunology.

It is still unclear why was the drug tested on healthy volunteers rather than immune compromised patients.  Phase I trials in healthy volunteers raise special ethical issues when the benefits are non-existent and the risks are high. This was important in this trial, in which an agonist targeting compromised immune systems was given to individuals with intact immune systems. The cytokine storm that followed is hardly surprising from a basic biochemistry standpoint.

The TGN1412 trial, which nearly killed six male volunteers, took place at London’s Northwick Park Hospital in March 2006.  One victim’s head swelled up like the “elephant man” and another has had fingers and toes amputated.  All six victims have been told their risk of contracting diseases due to impaired immune systems has gone up; this includes cancer and multiple sclerosis.

In addition to government action the pharmaceutical industry has revised its guidelines on clinical trial management and local and national bodies have agreed to improve communications.

The leader of the independent inquiry, Professor Duff, said he was confident the new recommendations, if adopted, would greatly reduce the likelihood of another disaster and ensure that the well being of volunteers is put first.

An editorial in the BMJ summed things up:

“Finally, what does this trial tell us about the degree of transparency throughout the process of developing new drugs? Many groups have called for mandatory registration and disclosure of clinical trials and their protocols.  Had this trial been available for public review, potential problems might have been identified and avoided.  Despite claims of the need to protect competitive advantage, public interest overwhelmingly requires that all information about this drug and this trial should now be made publicly available immediately. Lives are at stake and there can be no possible reason, save liability, for secrecy. 

We have been assured repeatedly that proper procedures were followed, when the real question is whether they were the right procedures.“

Sources:

BMJ