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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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May 21, 2008

Lurching Around For Fun and Profit

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Posted by Derek

I’ve been in this business for almost 19 years now. That means that the drugs that were discovered during my first few years of work are now either on the market or expected to be there soon. Fine, I spent my first eight years at Schering-Plough, so what do I see when I look back? There’s ezetimibe, discovered by sheer chance (but developed by sheer determination, though) and the thrombin receptor antagonist, squirrelly chemical matter from a failed Alzheimer’s program, a compound that a lot of medicinal chemists wouldn’t have even made in the first place. Well, now.

This is not a whack at Schering-Plough. Far from it. These are compounds that any organization would have been glad to find, but they weren’t exactly found by direct routes. This is a general phenomenon. You’d think, surveying the industry, that a lot of drugs are discovered, at least partly, by outright luck. And as far as I can tell, you’d be right. Realizing that tends to bring on several different reactions, depending on your world view:

That can’t be right. I’ve seen this one mostly from people outside the immediate realm of drug discovery, well-meaning people who just can’t believe that this is how it works. The harm comes when these well-meaning folks decide that the problem is that the industry is just behind the times, and that we wouldn’t have to do it this way if we’d just adopt some modern management techniques – ISO whatever-thousand, umpteem-sigma, Quality Assurance Tiger Team Circle Continuous Improvement Metrics, or what have you. Harm generally ensues.

That shouldn’t be right. Some of the people in this category are actually offended by the sight of luck calling so many of the shots, while others are just hoping for a more productive way of doing things. A lot of computational approaches have come from this attitude: “We wouldn’t have to run around stumbling over stuff if we’d just turn on this great new flashlight that’s just been invented” Nothing’s quite illuminated the landscape in the way that people have hoped, though, although efforts continue, as they should.

OK, if we’re stumbling around, let’s stumble faster. This is the basic idea behind the improvements in high-throughput screening and combichem in the late 1980s and the 1990s. For a while, the more optimistic folks thought that this would be enough: just crank out millions of compounds, and the drugs would come – they’d have to. It didn’t work that way, partly because the space of usable chemical structures is much, much larger than we can usefully deal with. But that’s not to say that cranking out more compounds and screening them more quickly isn’t a good idea – it’s just not the good idea.

Well, stumble more purposefully, then. I think that this is where most drug discovery organizations are (or should be). You admit that luck has a big role to play, but you go for the “Fortune favors the prepared mind” approach. Don’t rely just on random runs of odd structures to fill your screening banks – but be sure to put some in, because you never know. Turn over every rock – but recognize that you can’t turn over every rock everywhere, so try to pick the most likely place to start.

The problem with this approach is that it doesn’t promise much, at least compared to the various You’re Doing It Wrong approaches, and it doesn’t make a very compelling PowerPoint slide. But although it’s the blood-toil-tears-and-sweat option, I think that for now it’s the right one. Until something better comes along, that is, and the fascinating problem is that something better is always coming along. Given this state of affairs, why shouldn’t it?

I have no room to talk, of course. I can be as much of a sucker as the next medicinal chemist for some new approach that’s going to change everything – mainly because I look around and realize that a lot of what we do would be better off changing. All the wasted effort. . .you can get downright melancholy if you look at the business from the saddest angles. For all my self-proclaimed realism, I probably have more of that second response in me than I like to admit. The idea is to keep trying for something dramatically better, while realizing that even a smaller improvement would still be worth a lot. . .

Comments (26) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. anonagain on May 21, 2008 8:05 AM writes...

NASSIM NICHOLAS TALEB
Epistemologist of Randomness and Applied Statistician; Author, Fooled By Randomness

The Birth of Stochastic Science

....

The world is giving us more "cheap options", and options benefit principally from uncertainty. So I am particularly optimistic about medical cures. To the dismay of many planners, there is an acceleration of the random element in medicine putting the impact of discoveries in a class of Mandelbrotian power-law style payoffs. It is compounded by another effect: exposure to serendipity. People are starting to realize that a considerable component of the gravy in medical discoveries is coming from the "fringes", people finding what they are not exactly looking for. It is not just that hypertension drugs lead to Viagra, angiogenesis drugs lead to the treatment of macular degeneration, tuberculosis drugs treat depression and Parkinson's disease, etc., but that even discoveries that we claim to come from research are themselves highly accidental, the result of tinkering narrated ex post and dressed up as design. The high rate of failure should be sufficiently convincing of the lack of effectiveness of design.

But if the success rate is very low, the more we search, the more likely we are to find things "by accident", outside the original plan — or the more an unspecified original "plan" is likely to succeed. Looking at the swelling pipeline, something tells me that the discovery of cures, or near-cures for unspecified diseases is about to happen — except that I do not know which one, nor do I know where it is coming from. More technically, I see the sign of fractal randomness in these payoffs from the fact that results are more linear to the number of investments than they are to quantities invested — thus favoring the multiplication of small bets.

All the while institutional science is largely driven by causal certainties, or the illusion of the ability to grasp these certainties; stochastic tinkering does not have easy acceptance. Yet we are increasingly learning to practice it without knowing — thanks to overconfident entrepreneurs, naive investors, greedy investment bankers, and aggressive venture capitalists brought together by the free-market system. I am also optimistic that the academy is losing its power and ability to put knowledge in straightjackets and more out-of-the-box knowledge will be generated Wiki-style. But what I am saying is not totally new. Accepting that technological improvement is an undirected (and unpredictable) stochastic process was the agenda of an almost unknown branch of Hellenic medicine in the second century Mediterranean Near East called the "empirics". Its best known practitioners were Menodotus of Nicomedia and my hero of heroes Sextus Empiricus. They advocated theory-free opinion-free trial-and-error, literally stochastic medicine. Their voices were drowned by the theoretically driven Galenic, and later Arab-Aristotelian medicine that prevailed until recently.

This idea applies to so many other technological domains. The only bad news is that we can't really tell where the good news are going to be about, except that we can locate it in specific locations, those with a high number of trials. More tinkering equals more Black Swans. Go look for the tinkerers.

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2. Nick K on May 21, 2008 11:17 AM writes...

The comment about the futility of management fads is only too true. I've seen their effects at close range, and it isn't pretty. You just cannot run drug discovery like a Toyota factory.

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3. Eric J on May 21, 2008 11:45 AM writes...

Someone once said that the sound of scientific discovery is rarely "Eureka!" It's usually "Huh, that's weird."

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4. RKN on May 21, 2008 12:04 PM writes...

Finding something favorable by chance while looking for something else requires a ready mind, yes, but doesn't it equally feel like a slap upside the head, like why wasn't I looking for that in the first place? It seems to me that serendipity always comes with a big slice of humble pie.

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5. Peter Madrid on May 21, 2008 12:47 PM writes...

I think most medicinal chemists would agree that this is often how some of the best discoveries get made, but we are forced to describe our medicinal chemistry programs as a series of very logical and rational progressions. I always enjoy a good med chem journal article or talk where the scientist actually describes how the research actually took place.

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6. Rich Apodaca on May 21, 2008 12:57 PM writes...

Dogma is always something that needs to be guarded against in fields, like drug discovery, with few first principles.

The same approach, successfully used in a previous program, can be disastrous when applied in the next.

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7. Petros on May 21, 2008 1:55 PM writes...

Deerek

Blinkered management has always been around. You joined the WDF too late to see 1,4-dihydropyridines being pursued for virtually every therapeutic indication!

We had to battle to pursue a rational drug design approach for our approach, following along Black's pioneering approach

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8. CMC guy on May 21, 2008 2:15 PM writes...

Although a well expressed analysis perhaps have over distilled the complexities involved with all the interdependencies of drug discovery. This blog regularly addresses the many various other aspects but here if predominately focus on med chem discovery where the portrait is seemingly a somewhat bleak tone. A fuller picture is before major med chem contributions can start there are the Disease Target, then (good?) models/assays required and (hopefully) an active lead molecule/class. Then one has to generate a compound that has the high potency but still is well behaved for clinical development (PK/ADME, Formulation, Process) and then cross fingers as it travels forward (Reg & Marketing hurdles).

SCH530348 was from an unexpected lead but appears to have been solid effort to get to the final compound that is progressing. We are net yet smart enough to do everything de novo so if can take advantage of serendipidy useful drugs can result. Med Chem can be frustrating, humbling and a stretch beyond initial educational background and that's why not everyone can do it and individuals that do typically have to find their own measures of satisfaction.

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9. Retread on May 21, 2008 5:27 PM writes...

Not to toot my own horn, but have a look at the latest Chemiotics post on the Skeptical Chymist.

Here we have a drug (a tricyclic antidepressant) whose mechanism of action we supposedly 'know' (inhibiting a neurotransmitter reuptake protein) having a completely different effect in a complex system. Tricylics weren't designed to hit the reuptake protein (they were found long ago), but there is convincing evidence that they do, and yet their effects on intracellular ceramide levels is almost certainly coming from somewhere else. Since ceramide is a second messenger, this may explain why reuptake inhibition is instantaneous but why therapeutic effects on depression take a few weeks to appear (true pretty much for all antidepressants).

A major problem in drug discovery is that we don't know all the players in the system and even when we do, we have just scratched the surface of how they interact. Have a look at Proc. Natl. Acad. Sci. vol. 105 pp. 6795 - 6796, 6959 - 6964 '08 for a guess of how many protein protein interactions humans have. Proteins certainly aren't the whole story, and drug design to target RNA (particularly microRNAs) is just starting.

No wonder drug discovery is hard (but it's a fascinating and important game to be in).

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10. milkshake on May 21, 2008 6:12 PM writes...

The enlightened way to manage research is the hands-off zoo keeper approach: you hire good people and let them do their thing and you keep them happy by making sure they have what they need, by disouraging interpesonal rivalries and bureaucracy while calming down the neurotics and encouraging the cynics and gently pressing the disorganised types. If you get lucky you end up with a good drug candidate somewhat related to the original research proposal. Switching the project to another class of compound, a different selectivity profile or for a different therapeutic application is quite normal turn of events.

I prefer pragmatic manager types who have the actual understanding of research, best aquired by having done research by themself.

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11. SRC on May 21, 2008 6:29 PM writes...

Great post on how humility is in order in chemistry in general, and medchem in particular.

But chemistry is a mature field, and amenable to relatively rigorously controlled experiments.

Now consider climatology, for which neither is true...

Of course they can predict the climate a years from now. And while they're at it, they should predict the binding constant of given compounds for given receptors too.

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12. Anonymous BMS Researcher on May 21, 2008 10:13 PM writes...

"Umpteen Sigma" -- nice term! During Thanksgiving 2006 at the home of my mother-in-law I saw a Dilbert strip lampooning this. The following Tuesday, I heard the first of MANY MANY MANY presentations on such at BMS.

The main catchphrase being tossed around BMS these days is "Next-generation Biopharma Model," whose meaning is summarized below.

"Bless me, it seems the Next-generation
Biopharma Model
Is very like a wall"

"This wonder of a Next-generation
Biopharma Model
Is very like a spear".

"I see," quoth he, "the Next-generation
Biopharma Model
Is very like a snake."

[Etcetera]

http://en.wikipedia.org/wiki/Blind_Men_and_an_Elephant

Permalink to Comment

13. Brooks Moses on May 21, 2008 11:55 PM writes...

There's also the "But we've nearly got computers powerful enough to model the whole human body, and then we can just design the drugs we want using computer modeling!" reaction I've come across a few times.

I have yet to come up with an appropriate response that truly conveys the heights of absurdity of this while remaining reasonably polite in ways that blatantly laughing in someone's face do not. Perhaps you have suggestions?

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14. jeepster on May 22, 2008 7:23 AM writes...

Do you think that the Folding@Home effort is useful?

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15. Paul Hsieh on May 22, 2008 7:24 AM writes...

How much of the long delay from discovery-to-market is attributable to government regulations, such as onerous FDA testing requirements?

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16. rosignol on May 22, 2008 7:40 AM writes...

"We have to know how something works in order to build a computer model of it."

It might be useful to use computer modeling of global warming to illustrate the difficulties. Then again, it might not.

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17. Stella Daily on May 22, 2008 8:38 AM writes...

To answer Paul's question: an awful lot. Once a compound is discovered, the estimate of time to bringing the drug to market is about eleven years. That's eleven years in which no one but patients lucky enough to make it into a clinical trial can benefit from a drug, and the process of clinical trials is drawn out while government regulators grant or deny their approval at every step of the way. An FDA-free market would not cut this time to zero years, but I bet it wouldn't be even close to eleven.

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18. CMC guy on May 22, 2008 10:43 AM writes...

I do not totally agree with #17 Stella as even though substantial impact eliminating Reg Agencies I think would reduce cycle time only at most 2-4 years which is mostly the static Review Periods. Believe surveys along these lines indicate most Pharma would be doing much the same studies in drug development even if not required. Perhaps this reflects an inherent conservative nature or possible desire to deflect litigation but generating the data from preclinical & clinical trials is lengthy exercise.

What might change is the size and types of studies as rather than emphasis on statistical absolutes could pursue other markers of safety & efficacy and/or other disease targets. Most current trials need to be bigger (meaning more costly) and narrowly focused to gain approval so effort becomes iterative. Having more target opportunities increases chances a drug will work although would also require less blockbuster mindset and willingness to pursue smaller/multiple markets.

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19. Shannon Love on May 22, 2008 11:26 AM writes...

I think that technological innovation is a darwinian process that follows the rules of natural selection.

A quick look at historical patents shows that for every technological idea that becomes a successful and widely used product, hundreds of failed variations exist. That count does not even include those that failed before their inventor reached the point of filing for a patent. Drug research no doubt follows the same pattern.

One speeds up biological evolution by increasing diversity. Unfortunately, in human institutions we tend to focus on the winnowing process. We might find some benefit in looking far abroad from the classes of compounds we usually explore.

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20. Anonymous on May 24, 2008 8:06 AM writes...

> You just cannot run drug discovery
> like a Toyota factory.

I somehow doubt if most of the listed management fads offer much real benefit for automobile manufacturers, either.

milkshake: why by themselves? Wouldn't having done actual research be just as valuable if it were done as part of a group?

SRC:
> But chemistry is a mature field,

Is it? I tend to think that pretty much everything we know about chemistry is based on models that are extremely rough approximations with significant deviation from real-world behavior. Consider the Bohr model for instance: electrons don't actually behave that way. We know they don't. But we like to pretend they do, because it simplifies everything.

Certainly in *organic* chemistry at least there's a great deal more that we don't know than there is that we do understand. Perhaps I'm just reading too much into the phrase "mature field".

> and amenable to relatively rigorously
> controlled experiments. Now consider
> climatology, for which neither is true...

Okay, compared to climatology, even artificial intelligence is a mature field. At least in AI we have rejected some incorrect ideas. In climatology, we really haven't been able to do that yet, not for sure. (We've got, what, fifty years of decent data? A hundred? It's going to be a *while* before we know anything. And I'm not sure I'd call any field that doesn't do controlled experiments a "science" anyhow.) If your standard for what constitutes a mature field is "more mature than climatology", I'm not sure it's really meaningful to call a field mature.

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21. Derek on May 24, 2008 8:26 AM writes...

Most management techniques are 'if I did it again, this is how I would do it'. What if what you are doing hasn't been done, which is the definition of new science.

RKN, yes. When you are working on the outer limits of your knowledge, humility comes with the territory.

The problem, if there is one, is the interface between the scientists working away, and the guy who writes a cheque for $1/2 billion. Maybe after 20 years something will come of this, maybe we'll have to throw it all away, or worse pay out another $1/2 billion when the drug kills 3 people. How can you control risk in an undefinable system? How can you reward failure which probably advances the art more than drop from heaven successes?

Derek

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22. Skeptic on May 24, 2008 5:40 PM writes...

Theoretical chemistry is a disgrace. See the texts by Jan Boeyens for elaboration.

The comment by Milkshake is especially humorous. Leave us [medicinal chemists] alone and everything will be fine. Haha. Don't need management at all for that brilliant strategy.

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23. Nick K on May 25, 2008 11:54 AM writes...

Anonymous: Point taken about management fads and auto manufacture. In fact, Toyota's only management "fad" is to promote steady, incremental improvement over the years. This has made the company the most efficient and profitable car manufacturer in the world. However, I stand by my assertion that making cars cannot be used as a model for discovering drugs.
Skeptic: Milkshake is correct. Overbearing, heavy-handed management is disastrous for originality and risk-taking.

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24. RTW on May 26, 2008 9:46 AM writes...

Overbearing, heavy-handed management is disastrous for originality and risk-taking.

Yes one only needs to look at Pfizer's current situation to see that heavy-handed management is the kiss of death. When a 20 year veteran senior scientist without a PHD is told that they are obsolete, by their director because they didn't automatically adopt the latest technologies in their work. When in fact said non PHD often evaluated those same technologies earlier and found them wanting and of little use... Pressures to leave the department become pretty great. More important (prestigious) to have wet behind the ears PHDs working for you I guess than steady experienced producers.

I was always a very good problem solver. But in the end all management wanted was a pair of monkey hands.... Sadly I no longer do bench chemistry, and miss it a great deal. But there is a glass ceiling barrier to promotion and rewards in organizations when one has a lesser degree quite separate from actual ability to get the job done. In your late 40s with a BS you will probably never go any further in your career than you currently are if you want to stick to working at the bench or actual do what you were trained to do. You will never have people reporting to you. How would that look?

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25. CMC guy on May 26, 2008 11:05 AM writes...

Skeptic is either way off base or just being provocative. At the same time Milkshake's view may be great for the working scientist and can be productive but there is a risk of such environments getting caught up in a research mode that does not focus to the end goals. There must be strong leadership providing direction and making strategic decisions (including when to move on) otherwise it can be more akin to another academic exercise. Ideally the company has individual/team at the top and/or effective translators in the middle who can connect and invigorate all the pieces to contribute to success. Unfortunate as seems majority of companies these days are run by marketing/business/legal types who do not know how to build, maintain and utilize the potential and mandate unrealistic objectives.

Nick K is correct about Toyota and continuous improvement philosophy plus they also promote responsive teamwork. Although autos may not be a good model and the various management fads generally poor fit for R&D in an overall sense, there are a few applicable lessons that can extracted if desired but the programs are either force feed or blown off so nothing good results.

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26. Nick K on May 27, 2008 10:38 AM writes...

RTW: You read my mind! Pfizer was the company I had in mind when I made that remark about incompentent management in Pharma. Pfizer's share price collapse tells its own story.

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