BioProcess International

‘Patients Sought for Lung-Cancer Drug Trials’ was the headline of a recent article in one small city newspaper. It appeared a week after headlines from the United Kingdom about six men enrolled in a phase 1 study who became seriously ill. The article stated that the medical facility conducting the lung cancer trial is one of three in the United States and noted that this is only the second time this facility has been involved in a phase 1 trial. Would you be interested in volunteering? The end of the article mentioned that currently there are no patients in the program, but the first two patients enrolled in the worldwide study were from the same city where this study will be conducted; those two patients have since died from their illness. Still interested?

Making headlines: On 16 March 2006 the British media reported that six healthy male volunteers in a phase 1 study required intensive care after taking an investigational drug. The drug, TGN1412, a monoclonal antibody (MAb) manufactured by the German biopharmaceutical company TeGenero AG to treat autoimmune diseases, set off an immune response in all six volunteers resulting in loss of consciousness, multiple organ failure, and other unexpected adverse reactions.

The BBC interviewed a university student scheduled to receive the investigational drug, who said that although he was concerned about a friend who was one of those volunteers, he still planned to participate in future clinical trials. He is not alone. Many volunteers, admittedly motivated by financial compensation, enroll in trial after trial, believing that there are adequate safety precautions and they receive careful health screening and professional treatment. He went on to say that without clinical trials, pharmaceutical companies would be unable to find new medical treatments for devastating illnesses.

Indeed, researchers regard clinical trials as essential in the development of safe and effective new drugs. They argue that sufficient safeguards are in place to protect volunteers from undue risk. Published studies show that it is highly unusual to see adverse drug reactions such as those associated with TGN1412.

Tough questions: Was this phase 1 trial appropriate for healthy volunteers? In the development of anticancer drugs, phase 1 volunteers usually have advanced or refractory disease and have exhausted conventional treatment options. Would it not have been more reasonable to test this compound in subjects already facing life-threatening illness from leukemia?

The preclinical evidence from studies in rabbits and monkeys suggested that TGN1412 was safe. But two out of 20 monkeys tested with TGN1412 had swollen lymph glands. This side-effect was included in data sent to regulators and addressed in the consent forms signed by the phase 1 volunteers. But MAbs are genetically engineered proteins primarily derived from human products; animal testing cannot entirely stand in for human testing, and thus the toxic dose for humans in phase 1 trials is hard to predict.

One explanation for what went wrong in this phase 1 trial is that TGN1412 binds to an immune system protein, CD28, differently in animals than it does in humans. In fact, the drug may target different proteins in different species.

Lessons learned: There may be some positive outcomes from this unfortunate event. This trial could influence the way the phase 1 studies are currently designed. Hopefully, the biopharmaceutical industry will be encouraged to explore innovative phase 1 clinical trial designs.

With so many new agents in clinical development that target specific molecules, Chen and Tannock (1) suggested that study "endpoints based on changes in target expression, pharmacokinetics, and function imaging should be incorporated in phase 1 studies." For instance, there should be assays to evaluate cellular signals from receptors. The relationship between molecular target activation, drug dosing, and toxicity can be extremely useful in designing clinical trials.

Another positive result of this failed trial is that the media have raised the public's consciousness about the role of clinical trials in drug development. The risks have been highlighted, and investigators will need to redouble their efforts to ensure that all volunteers give truly informed consent. There is data suggesting that explaining research risks may improve clinical trial participation. In a 2001 Harris Interactive/BBK Healthcare poll of 5348 health consumers (2), 66% indicated they would be likely to participate in a clinical trial if they were well informed of the protective measures taken. Furthermore, a 1999-2000 Centerwatch survey of 1050 study volunteers found that 77% would definitely participate in another clinical trial (2).

Additionally, there will be increased pressure for pharmaceutical companies to register their clinical trials and publish reports of failed preliminary studies such as this aborted phase 1 trial. This is exactly what GlaxoSmithKline agreed to do in the settlement of a lawsuit that charged it had suppressed important information on the antidepressant drug, Paxil. Increased transparency within the scientific and medical communities will allow researchers to learn from such experiences. Overall, open and honest communication will improve trust between research scientists, health professionals, regulatory agencies, patients, and other healthcare consumers.

References

1 Chen EX, Tannock IF. Risks and Benefits of Phase 1 Clinical Trials Evaluating Anticancer Agents: A Case for More Innovation.[Editorial].JAMA, 292 (17) 2004: 2150–2151.

2 Borfitz D. Quantifying Risk in Clinical Trials. CenterWatch, 8(10) October 2001:1, 4–9.

Tamara D. Norman MS, is a freelance medical writer and adjunct assistant professor for George Washington University's School of Medicine and Health Sciences Clinical Research and Education Programs

To make any comments on this article, or to ask a question of the author, please contact the publisher. If you would like to submit an article please subscribe to our PL Intelligence service.

The opinions expressed in the articles published in this section do not necessarily reflect those of Pharmalicensing or UTEK Corporation. No actions including proposals to or agreements with other companies should be taken by any reader without obtaining specific business or legal advice. Neither the publisher nor the authors accept any liability for any actions or activities undertaken by any reader or other third party as a consequence of these articles or for any errors or omissions therein.