Magazine
No Shortcuts, But Lots of Pitfalls
By Derek B. Lowe
I've long been sure that there is no one model for successful drug development. My confidence comes from history and statistics. There is, of course, a strong motivation to find a better way to discover and develop drugs, because there's an awful lot of money to be made in this industry if you can survive to make it. Think of the industry as an ecosystem, one that's under strong selection pressure. So many approaches have been tried, in so many variations, by so many research organizations, that if there were a general winning strategy out there, someone surely would have stumbled across it by now. They'd have made a big success out of it, and gone on to become a mighty force in the industry (and everyone else would be imitating them!).
But who are those mighty forces at the moment? Pfizer, perhaps? Does anyone really think that Pfizer has discovered the best way to do drug development? There's a lot of room to complain about Pfizer's own discovery efforts, which certainly aren't the reason that they're the largest drug company in the world. But it's hard to believe that the optimum strategy is to go out and buy huge-selling drugs, one after the other. It's especially hard to believe after one of those huge sellers (Celebrex) had its market potential shredded by the COX-2 troubles, and the biggest one (Lipitor, of course) is headed off patent with no replacement in sight. Pfizer increasingly reminds me of Sean Connery in Goldfinger, strapped down while a laser beam moves inexorably toward his haploids. But while the audience could be reasonably sure that 007 would escape (the movie still had some running time left, after all), Pfizer's escape looks increasingly unlikely. The best their current management team can do is to try to survive the coming lasering; avoiding it now seems impossible.
So much for #1. How about Merck? Perhaps there was a case to be made a few years ago, but then there was all that COX-2 unpleasantness. And while they've had some successes in the last few years, they've had some pretty nasty failures and missteps, too. I have to applaud their determination not to try to merge their troubles away, but troubles they do have. If theirs is the optimum strategy for drug research, then we're all in for a rough ride.
Novartis? I've long been interested to see how their attempt to remake their drug discovery efforts would turn out, but so far I'm not sure you can call it a clear success.
It's become a bit more rocky over there in recent months, that's for sure. AstraZeneca? GSK? I can't name a big company that's clearly outperforming everyone else. (I'm reluctant to name smaller organizations, because even the ones that look good might just be having a good run, or be pursuing a strategy that doesn't scale).
And even if I could name one, I'd worry that it would be like the leaders of those yearly lists of the best-performing mutual funds or the like. With hordes of investment managers trying to beat the market, it's inevitable that some of them will do it, but the problem is that it's mostly a different crowd every year. That same statistical argument I used above applies to Wall Street as well -- for example, the strongest evidence that no one knows how to predict interest rates is that no one is now doing so. The motivation is certainly there, just like the motivation is there to find a better way to discover drugs.
No, there is no one right way to do this work. There are, however, a fearsome variety of ways to do it wrong. A common feature of many of them, once you get past good old cluelessness, is something the ancient Greeks would have recognized: hubris, or overweening pride. One of the surest ways to make a costly mistake is to convince yourself that you've found the master formula for avoiding costly mistakes.
And if you accept that line of reasoning, it follows that there are several classes of people you should try to keep from helping you out. One, naturally, is the Single-Issue Fanatic. Someone with a new method to screen formulations, for example, will come in telling you that if you could just fix your formulation problems, your troubles would be over. And since everyone can think back to a program that had severe formulation issues, this claim might be easy to believe if you don't think about it for too long. But in reality, there doesn't seem to be one cause that accounts for anything like a majority of drug failures. Fixing one area in isolation might still be worthwhile, but you shouldn't expect your other problems to stop biting you on the ankle.
Another person to whom I wish more companies would show the door is the New Business Process Guru. As far as I can tell, drugs fail partly for institutional reasons, and partly for technical ones. I put all the business fads in the "non-technical fix" category -- six-sigma, continuous improvement, all that stuff. The compounds in the HPLC vials and the rats in the metabolic cages will not be impressed by the new slogans on the walls. Company culture is a very, very hard thing to change, and sometimes you end up wondering what the cure is for the cure.
Closely allied to the above voodoo practitioners is the Charismatic Boss. A new CEO or head of research could be just what your department needs, but if that's true, you must have some pretty bad problems. As I was pointing out above, even the best-functioning organizations have trouble performing in this industry, so if you've got one with extra issues, you're probably sunk but good. The new boss is presumably not coming in with any brand-new scientific insights, but is rather coming in to exhort the masses (and the institutional investors). Besides, the first thing your honcho will probably do is import fresh wisdom from some managerial guru's ashram, anyway.
So if these people aren't going to bail you out, what's to be done? Well, you could start by not looking for someone to bail you out at all. Give up the search for the big spectacular fix, because it's not out there to be found. That's not to say that you can't keep an eye out for improvements, especially with new technologies that might actually improve things across the board. But don't drive yourself crazy thinking that everywhere else in the industry must be smarter and more on the ball than where you work. Odds are that they worry about the same things over there. Remember, you're viewing everyone else from outside, from a place where every organization looks more powerful than it really is. Odds are, they're thinking the same thing about where you work.
