Multiple pharma failures increasingly coming to light demonstrate that the basic understanding of these disorders is the problem. The targets of drug discovery were wrong, not the technology to hit at the targets. (i) Anti-amyloid antibodies have failed to prevent dementia/AD (ii) anti-IL-6 antibody and other anti-inflammatory drugs could effectively reduce inflammatory markers but could not prevent atherosclerosis or any other disorders believed to be caused by chronic inflammation (iii) so called diabetes remission defined by sustained glucose normalization by drugs or by diet failed to prevent complications and mortality. In most of these examples the “causes” hypothesized to be responsible for the pathology could be controlled quite well but the incidence of any of the adverse events caused by them did not come down.
This is not a failure of technology. The target that the treatment was supposed to hit were actually hit accurately. But the targets were simply wrong. They were not the causes of the pathological changes. So, hitting them was not going to help. Our understanding of the pathophysiology of the disease was wrong. How would anyone prevent or cure a disorder by aiming the wrong target even when the hit was perfect? And this was actually quite evident much before the clinical trials failed. A series of experiments had already indicated that the targets were wrong, but nobody listened to the kid’s naked emperor laugh.
I am convinced that the problem is in the way we perceive cause effect relationship in bio-medicine. Scientists seem to hold on to a causal narrative and ignore all evidence when it goes against the narrative. This is natural to the human mind – system 1 of Daniel Kahneman. But we also have the ability of careful conscious thinking, deliberately overcome the biases of the human mind, what Kahneman calls system 2. But scientists don’t seem to do that.
Added to it are the money-making goals of the pharma industry and individuals working within the system. There is a conflict of interest within these two levels too. So everyone is in a hurry to announce success beating drums without waiting for enough evidence to accumulate. Further on, others can potentially raise queries or cross question, but there are effective mechanisms to suppress questioning. So the wrong narrative gets pursued to its limits when it ultimately fails. The industry will make all attempts to hide the failure and claim that the drug worked using a series of tricks. All of them need to fail in order to admit failure. A failure at an advanced stage is a huge loss for the company. But by this time individuals may blame someone and get away having made money in the meanwhile and shifting to something more lucrative.
The insulin resistance theory of type 2 diabetes was falsified by experiments 20 years ago. The hypertension theory was always very ambiguous and did not have clear cut mechanisms through which it would lead to stroke, CVD and other complications. The origin of the amyloid theory started with in a paper that was shown to be fraudulent much later. Inflammation was always an ill-defined, ambiguous and hazy concept. But pharm R and D needs a strawman to hit. They make the strawman quickly and keep on targeting it until it fails so badly that no effort can hide the failure. They do not give up wrong theories until someone could make money with them. That’s how applied science works.
Would outright failure change the picture? It should, but it doesn’t. “I was wrong” is almost impossible to admit, as Max Plank said over a century ago. In the era of peer reviewed publications, alternative theories are actively destroyed before they can get published. They can never get published in mainstream journals. If they get published in the non-elite journals, the mainstream will not even read them. The culture of debate, questions and challenges has simply vanished from academia. This deficiency is sufficient to kill all alternative ways of thinking. In the absence of better alternatives, the wrong theories continue even when everyone knows that they are wrong.
In effect, the fault lies with basic science, not with drug discovery. If the wrong target is given to the R and D units, they are bound to make something wrong. They might end up hitting the target effectively but that does nothing to prevent or cure any disease, because the target is not causally related to the disease.
The only solution I can see is that science needs to be done outside both the castles of the day. Neither academia not industry would do good science of complex systems. Science needs to come out of academia as well as industry. Citizens, students and teachers need to ask questions, think independently, cross question prevalent dogmas, try to come up with alternative ways of thinking. They need to strengthen themselves and make their voice heard. If this happens, it will set both the academia and industry on the right path in no time.
My science, My way 