Reasons to be cheerful

The default setting for people in the pharmaceutical industry is a sort of enlightened pessimism. After all, the huge majority of our projects eat up time, effort, and money, but never deliver drugs.

Failure rates in the clinic run at about 85-95 per cent. Humans and other animals are so ridiculously complex that almost all of our best ideas turn out to have mysterious flaws in them that no one could have seen coming. In preclinical trials, our discovery compounds bounce off cells and do nothing, cause strange and unwanted changes in other organs, or just fail to make it out of the gut entirely. In most cases, we don’t have the first idea of how to fix any of those. Under those circumstances, it’s hard to have a truly sunny disposition. 

But if you’re doing this kind of work, you can’t let it get on top of you, either. People who take every research failure hard don’t last, because the failures are so relentless. You learn to take your triumphs where you can get them, and to realise that (for now) many of the really important issues are just out of your control. The rats, I remind younger colleagues frequently, are smarter than we are, and we shouldn’t be offended by their verdicts. They don’t mean it personally. 

There are even good reasons for widespread optimism, because those hair-tearing clinical failure rates conceal something rather interesting. Given the current state of affairs, we don’t have to string together a long series of breakthroughs to be in significantly better shape. Think about it: if 9 out of 10 clinical candidates are going down in flames, improving that to a mere 8 out of 10 will double the number of successful drugs. 

It wouldn’t take much. A slightly better understanding of how compounds are absorbed or distributed would go a long way. A more realistic animal model or two in a popular therapeutic area wouldn’t hurt. And the biggest potential impacts are for discoveries in predictive toxicology. Bad news from that direction comes as an ambush from nowhere, so any improvement at all will be a big event. 

We also have the structure of science on our side. We work in a system where failures, however numerous, are not thrown away and forgotten. They teach us something, whether we feel like learning the lessons or not. Every time a compound goes down in the clinic, we get smarter. Expensively, painfully smarter, but smarter nonetheless. At least no one is going to have to figure these things out again. 

I realize that the process is slow. I used to do Alzheimer’s drug research when I started out in the industry, and if you’d sent me a time-traveling message from 2007, I would have been taken aback. If I’d learned that by now people would still be arguing about whether beta-amyloid deposition was the main cause of the disease, I’m not sure what I would have done, but it might have been reckless. Yet the list of Alzheimer’s information that we have now and didn’t then is an impressive one, and it would have been well worth paying the fourth-dimensional e-mail fees to have it. 

So while it’s true that we’re in something of a hole right now, I don’t think that this is a permanent state of affairs. While we continue relentlessly to come up with better explanations for our compounds’ behaviours, the rest of the world continues to want what we’re trying to produce. The amount of unmet medical need in the world is staggering – it’s inconceivable that we won’t find ways to meet some of it. 

Derek Lowe is a medicinal chemist experienced in preclinical drug discovery.