Informed Decisions

Informed Decisions

Rushika Fernandopulle, M.D., M.P.P.
Instructor, Harvard Medical School

Phase One Trial in England Raises Serious Questions

04/28/2006

The process to test and bring a drug to market involves a number of well-regulated steps. After rigorous laboratory and animal trials, drugs in both the US and Europe need to go through three phases of trials. Phase 1 trials are very small, conducted on a handful of often healthy volunteers to test toxicity in humans. When this proves successful, phase 2 and 3 trials are conducted, which are larger trials with people with the target condition to test efficacy (how well the drug works) and to determine the optimum dose.

In mid-March of this year, a small phase 1 trial conducted in London attracted a large amount of press attention when all six healthy volunteers who received a new drug called TGN1412 rapidly developed multi-system organ failure. Although such incidents where healthy volunteers develop serious life threatening complications in phase 1 trials are extremely rare (in the US the last notable example was Ellen Roche, a 24 year old who died of respiratory failure in 2001 while taking part in an asthma trial at Johns Hopkins), they necessarily raise serious questions about the way drugs are developed and tested.

TGN1412 is a humanized monoclonal antibody developed by a German pharmaceutical company TeGenero and is thought to act as an agonist (i.e activator) of the CD28 receptor found on human T cells. By activating regulatory T cells it was hoped to be effective against autoimmune conditions such as multiple sclerosis and rheumatoid arthritis. In laboratory trials and in doses up to 500x the human dose in mice, rabbits and monkeys it showed no signs of serious toxicity. Because of this, the British Medicines and Health Care Products Regulatory Agency (MHRA) – the equivalent of the US Food and Drug Agency (FDA) - gave approval for a phase 1 trial to be conducted by the contract research organization Parexel in their research unit in Northwick Park hospital, just outside of London. The protocol involved injecting a dose of TGN1412 to six of eight healthy volunteers, while the other two would be given a placebo. According to reports by the volunteers who received the placebo, all six of the subjects who received the drug soon developed severe symptoms including fever, nausea and vomiting, swelling, and headaches. All six rapidly developed multi-system organ failure that necessitated transfer to the intensive care unit.

These dramatic events in Northwick Park raise several serious questions about drug trials in general, and phase 1 trials in particular. The first is why such a catastrophic reaction was not foreseen. Currently the MHRA and other authorities are investigating all the possibilities- such as a manufacturing problem with the drug itself or a contaminant. But the more worrisome (and likely) scenario is simply that the animal models in this case failed to replicate the human physiology; indeed, particularly for immune therapies, there is good reason to suspect that this might be the case. While many anti-vivisectionists have taken this as an opportunity to argue against doing any animal testing at all, others feel it means we should actually require even more, and in higher organisms before allowing human trials.

A second issue concerns the use of healthy volunteers in phase 1 trials. Someone needs to be the first human to receive a new compound, and traditionally a small number of healthy volunteers are sought to test for safety before moving to larger phase 2 efficacy trials. In England volunteers receive sizable financial compensation (2000 British pounds, or roughly $3500 in this case), and there are arguments on both sides whether money ought to be involved in such trials. On the one hand it is felt to compensate people for the risk they take, on the other, it may unfairly induce people, particularly those with less financial means, to take on risk.

Finally there are issues with how the trial was conducted. Was it necessary to start with a full dose, or would it have been better to start with micro doses at first? While the approved protocol appeared to suggest spreading the injections over two hours, people who were present indicate all eight volunteers were injected every two minutes or so. Would it not have been better to wait for several hours or even days between subjects to minimize the possible downsides?

How public should the protocols be, both before and after the trial? The Lancet, a prominent British medical journal recently called for public disclosure of the protocol for this trial, but was rebuffed by both the drug company and the MHRA citing the need to protect their intellectual property.

By the end of March (two weeks later), two of the patients involved were discharged home, three were doing well and had left the ICU, and one remained in critical condition but was improving. All other human trials of TGN1412, including one already approved in Germany, have been indefinitely cancelled, and work on other immunomodulators will certainly fall under more scrutiny.

While the questions raised by this trial are good ones, they have no easy answers. The bottom line remains that as in all other cutting edge scientific endeavors such as human space flight, we will never be able to remove all risk without stopping progress; by definition, if we knew the outcome before we started there would not be innovation. What we can and must do, however, is make sure that there is adequate oversight and protection for those brave enough to participate, particularly for healthy volunteers such as the six in Northwick Park.

References

“Learning from the TGN1412 trial,” British Medical Journal, doi:10.1136, 22 Mar 2006, available at http://bmj.bmjjournals.com/cgi/rapidpdf/bmj.38797.635012.47v1?hrss=1