The recent reports of adverse and near fatal reactions on a group of volunteers in a clinical trial in the UK has kicked up a string of issues, opinions and counter-opinions amongst the scientific circles. Now that the phase of accusations and counter accusations have died down, it is time to take stock of the situation and understand the lessons to be learnt.

Fundamentally, it is important to understand if this incident was really a 'fiasco', as has been suggested. It is of utmost importance to put in place the measures that nullify the chances of any bodily harm done to clinical trial volunteers. But equally important is the need to avoid the onset of this sort of 'blame-game' when such incidents occur in future. In this particular instance, voices were raised even questioning the very concept of clinical trials. Understanding the probable reasons behind the occurrence will stop us from trying to reinvent the wheel and rediscovering fire every time.

This particular instance was about the serious adverse reactions on 8 healthy volunteers who participated in a clinical trial for a drug designed to treat leukemia and chronic inflammation disorders. Within hours of being given the drug, the volunteers fell seriously ill. Presently, two of them are still critically ill, one is on organ support, while the other three are recovering. While the incident received tremendous media publicity, almost amounting to a frenzy, little was discussed about what might have really led to this happening.

TGN 1412, the drug under trial, belongs to a class of relatively modern biotech drugs called monoclonal antibodies. Monoclonal antibodies are molecules produced by the body against structurally defined regions of molecules that the body perceives as alien. In this case, TGN 1412 was designed against a protein molecule involved in cell defense and present on the surface of the cell, called the CD28 receptor. Receptors can be thought of as 'nodal junctions' in the flow of signals within and among cells. Therefore they represent convenient points of intervention in diseases like cancer, many of which take place due to aberrations in intercellular signaling.

While the idea of designing an antibody against an important receptor seems like a straightforward and elegant idea, the problems lie in the incredible complexity of cellular signaling pathways and our meager knowledge of receptor biology. The extracellular signals impinging on a receptor sitting on the cell surface, for example, generates chemical signals inside the cell that then determines events that might even change the cell into a cancerous one. To put it simplistically, permutations and combinations involving the number, type and distribution patterns of a receptor could determine the end result of signaling through the receptor. What makes this scenario even more complex is the fact that receptors are literally thousands in number and each one can have multiple subtypes that vary depending on age, sex, race, age, physical condition and even mood!! The serotonin receptor, which is involved in anxiety disorders, is an example of this.

TGN 1412 was different from many other monoclonal antibodies in that it was designed to activate the receptor that it bound to (CD28) rather than block it- as most other antibodies do. The drug had gone through multiple rounds of successful screening in the lab on animal populations. The clinical trial in this case was well designed and professionally executed by a firm that had a clean track record. The volunteers were carefully selected and were ensured to be healthy.

What, then went wrong?? The answer clearly, lies in the fact that our knowledge of cell signaling and receptor biology is inadequate. It is quite possible that that the type, number, or any other downstream signaling property of the CD28 receptor was differently affected in animals by the therapeutic antibody compared to it's effect in humans. The fact that not all the volunteers were affected to the same extent also underscores the truth about diversity of receptor subtypes even in human populations, and accentuates the importance for research in personalized medicines in the future.

So, what is the lesson that we have to learn from this incident? While the trauma caused to the volunteers is regrettable, no one is really at fault here in an obvious way. The honest truth is that there is every possibility that another incident like this may happen in the future. Only more research and in depth knowledge of cell signaling will alleviate the chances of another recurrence. It is also important for the Indian pharma and clinical research industry to take this opportunity to remove unsubstantiated fears from the mind of the public in the wake of this incident. India is now a hot spot for clinical research, and the industry is projected by some to touch the billion dollar mark soon. At the same time, the Indian pharma industry has woken up and is bracing up for the future in a big way. Since drug discovery and clinical research will have to go hand in hand, it is important that the public is well informed, and is not affected by this fear psychosis.


The author is regulatory CMC manager, Novartis, Basel.