Drug Trial Tragedy Traced to Animal Test Failure
By John J. Pippin, M.D., F.A.C.C.
On March 13, 2006, six participants in a London drug trial were sent to the hospital within hours of receiving the first dose of a trial medication. All had multiple organ failure and nearly died, and all may have permanent immune system damage. The most critically injured man was still hospitalized more than 10 weeks later, and gangrene has caused sloughing of some of his fingers and toes.
A subsequent inquiry by the United Kingdom’s Medicines and Healthcare Products Regulatory Authority (MHRA) concluded that these disastrous results from the monoclonal antibody TGN1412 were caused by “[a] previously unknown biological effect on humans that did not arise in any of the animal testing phases.” TGN1412 is directed against a specific class of immune cell receptors, and animal studies convinced the German drug manufacturer TeGenero AG that TGN1412 was likely to be an effective treatment for human inflammatory disorders such as rheumatoid arthritis and certain inflammation-mediated cancers such as B-cell chronic lymphocytic leukemia.
Preliminary studies in mice and rats demonstrated a consistent anti-inflammatory benefit from TGN1412. Subsequent efficacy and safety studies in rabbits and monkeys confirmed the mechanism of action, anti-inflammatory effects, and safety of the drug. An MHRA spokeswoman later reported: “The trials on animals did not give any grounds to say the clinical trial could not go ahead.”
|An MHRA spokeswoman later reported: “The trials on animals did not give any grounds to say the clinical trial could not go ahead.”
Yet the drug triggered lethal immune system attacks on the participants’ own bodies, because it produced an inflammatory cascade of killer T-cell activity rather than the anti-inflammatory suppressor T-cell response seen in all tested animal species. MHRA Executive Director Prof. Kent Woods explained after the inquiry: “There was a powerful pharmacological action of this drug in man that was not detectable in tests on non-human primates at far higher [500x] doses.”
What a Difference a Species Makes
This incident underscores a critical problem with the way both the United Kingdom and the United States evaluate the safety of new drugs. At issue is the dangerous reliance by drug companies and government regulators on misleading animal testing. While progress has been made in replacing animal drug tests with computer-based, in vitro, and human tissue methods, all drugs are still safety tested in animals to select those that will advance to human testing.
This approach has frequently proved unreliable, not only creating disasters like TGN1412 and Vioxx (see sidebar), but also likely preventing the discovery of beneficial drugs because of failed animal safety tests.
Some non-animal testing methods for early stage human drug testing are available. Microdosing allows evaluation of drug activity in the human body using sensitive imaging techniques and miniscule drug doses that are only 1/100th of the dose that could cause drug effects in the body. It is unknown whether microdosing would have prevented the TGN1412 disaster.
Drug testing is a difficult process, and no current testing methods are foolproof. But microdosing is one of several techniques, including tissue engineering and microfluidics methods using human tissues, that hold particular promise. When combined with computer-derived dosing information or sequential drug dosing studies, microdosing allows for what may prove to be less risky and more accurate safety testing in humans. Microdosing’s accuracy has been validated in numerous studies, and it is endorsed by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products.
The recent events in London should prod drug companies and regulatory agencies worldwide to move quickly to consider microdosing as an alternative to animal testing and a substitute for phase 1 trials as first-in-man testing. Refocusing efforts toward developing and implementing this and other human-based testing methods may greatly improve drug testing accuracy and human safety.