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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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April 2, 2007

Failure: Not Your Friend, But Definitely Your Companion

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Posted by Derek

Here's something that you don't see discussed very often, but it's worth some thought: what kind of personality do you need to have to do drug discovery research? Clearly, any conclusions are going to carry over well to other fields, but drug work has some peculiarities that can't be ignored.

The most obvious one is that the huge, horrible, overwhelming majority of projects never lead to a marketed drug. Many readers will have seen the sobering statistics of 85 to 95% failure rates in the clinic, but (bad as that is) it doesn't get across the number of times that projects get nowhere near the clinic at all. Take it from the top: the majority of targets that are screened for chemical matter don't turn up anything useful (it's not even close). The majority of the ones that do still die on their way to clinical trials. And then a solid 90% of those don't make it to market.

So, if you define yourself as a success by whether or not you've put something on a pharmacy shelf, you've set a very high bar, one that many people in basic research don't reach. It's different for people further down the line, where the field has already narrowed. But if you're working on early med-chem, for example, you're likely to go years between realistic shots at a drug you can claim part of the credit for.

That'll vary by your company's culture, too. Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence). But you'll certainly have more shots on goal at the first type of company, which might keep your spirits up. Of course, the fact that you're largely going to be getting more chances to fail in the clinic might just depress them again, so you have to take that into account.

It'll also vary by therapeutic area. Central nervous system projects are going to run slower than oncology ones, by and large. In cancer, the clinical goals are comparatively clear, and where the disease is often (and most terribly) progressing at such a pace to give you solid numbers in a reasonably short period. Contrast that to Alzheimer's disease, for example, whose ruinous clinical trials could take years to tell you anything useful. Cancer will also give you more shots per compound, since a drug that does zilch for pancreatic cancer (and most do just that) might be useful in the lung or liver. While what we call cancer is several hundred diseases, what we call Alzheimer's might only be one. Depression and schizophrenia are clearly more complicated and split up, but (as opposed to cancer), there's no easy way to tell how many types there are or what particular one a patient might be presenting with, so the clinical work is correspondingly more difficult.

So, this is the pharmaceutical world you're going to have to live in. If you take each drug project personally, as an indicator of your own worth, you're probably not going to make it. You'll be beaten down by the numbers. As an antidote, a bit of realistic fatalism is helpful, although too much of it will shade into ah-that'll-never-work cynicism, which is the ditch on the other side of the road from prideful optimism. I'd recommend learning to enjoy the upside surprises, and to not be surprised by the failures (while still looking them over to see if there's something you can avoid next time around). You really have to draw a line between the things you can affect through your own talent and hard work, and the things you can't. Most of the crucial stuff is in the second category. A sense of humor about your own abilities and limitations will serve you well. But that goes for a lot of other jobs besides the drug business, doesn't it?

Comments (15) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | The Central Nervous System | Who Discovers and Why


COMMENTS

1. Anonymous on April 2, 2007 9:21 PM writes...

Derek

You missed the absolutely necessary mental makeup to be prepared for unemployment any time...which I could be soon. Of course this is just a practical side, nothing scientific.

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2. milkshake on April 2, 2007 10:37 PM writes...

Looking back at maybe 12 or 15 medchem projects I was working on I am resigned about the prospect of making it to the clinc. Sure, it would be nice if it ever happens - but if the boss runs around saying: "What are we gonna do to increase cell potency? or What should we do about the tox problem, with our compound making mice drowsy in PK?" my take is "It is too early, we have been working on this molecule only for 3 months so I would maybe start worrying next year if we won't make a progress - but we will probably find something by then"

I refuse to lose my sleep over the latest turn of my project because most projects I was on died for completely non-scientific reasons and remembering the past "urgent" projects has very calming effect.

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3. GeekSpawn on April 2, 2007 11:21 PM writes...

I think the answer to the personality question also depends what area and phase of the research process you are in. You definitely need thick skin if you are in any of the areas classified as "discovery support" or "infrastructure" (i.e., informatics, automation, analytical chemistry, DMPK, HTS) - researchers, analysts, and engineers in these areas are very often taken for granted. Once in awhile, researchers in analytical chemistry and DMPK become the scapegoats for problems having roots in other research areas. Informatics analysts and automation engineers need to put up with endless last-minute changes and/or suggestions (some of which can be completely ludicrous). Depending on the kind of culture a company fosters, HTS resarchers will often get treated as if their work doesn't "really" count and that they're not "true" researchers (whatever that means).

Thick skin is a "must-have".

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4. NJBiologist on April 3, 2007 6:19 AM writes...

"Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence)."

Are there really companies that do one or the other over the period of years it takes to move a drug to approval? You might be giving pharma management too much credit for consistency here, Derek.

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5. biohombre on April 3, 2007 8:37 AM writes...

As one who has just seen a company go down due to adverse outcomes in a clinical trial (apparently adverse, it appears more a problem of inappropriate design- but that is a different issue and story), I am acutely attune to this issue. And one of my colleagues, not having experienced this before, has a sense they bear some fault- feeling they should have done more!

Statistically speaking, I must question my sanity at staying in this business when one knows the likelihood the 'product' makes it to market is insignificant! The question of sanity is particularly relevant in small biotech, here you usually are a one-shot pony. Then you not only live with failure, but also (as, Derek you may be experiencing) you deal with lack of steady income.

I am well seasoned in this area, having seen 'my' small company fail due to 1) withdrawn funding, 2) in part, the death of the president (and major shareholder), 3) stumbles in clinical trials, 4) loss of confidence (and thus funding), as a result of failure of a similar therapy, 5) a company with an efficacious product that mismanages into bankruptcy. So am I an "up-side surprise" junkie? As I try to live with that close companion- failure, the sanity question nags, at least until a new source of "up-side surprise" (and cash-flow) arises. Then I tend to let the latter question recede into the shadow of my shadow companion- failure...

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6. datadriven on April 3, 2007 11:08 AM writes...

I agree with milkshake. Any compound that makes it into development is a success in my book. If a compound makes it to phase II, then Woohoo! Unfortunately, in a large company, we have no control over how clinical trials are designed, and it's unbelievable how many compounds I have been associated with have gone down because of poor study design in humans.

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7. Don B on April 3, 2007 12:50 PM writes...

Derek:

I think you need to be an unending optimist.

On a small point:
I think that what people call "Alzheimer's" these days covers a lot more than the disease that took the name of the discoverer of "plaques & tangles" at autopsy.

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8. Eric Johnson on April 3, 2007 1:46 PM writes...

^

Why so? Isn't the disease still officially defined by abnormal excess of those very microscopic histologic changes (at autopsy)? Or do you mean diagnoses not confirmed by autopsy?

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9. Daniel on April 4, 2007 5:49 PM writes...

You seem to be describing the chemist as a mere blue collar worker that should be unconcerned about their failures. And perhaps that's why pharma management treats chemists in a similar fashion to circuit city employees. I'm not sure why you think a failure of PK/PD should rest on the shoulder's of the average lab chemist. But you paint a fine picture of the chemist as a worker drone. Because it appears that is what the profession had degraded to.

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10. Derek Lowe on April 4, 2007 7:39 PM writes...

Not at all, Daniel. You seem to have my polarities reversed. The most exalted chemists you can think of - Nobel winners, etc. - all have to come to terms with the fact that most of their ideas don't work. Drug research, being a fairly structured activity, can really rub a person's nose in that fact.

And I'm not saying (at all!) that a PK failure is necessarily the fault of the chemist. But I've seen chemists who take it that way, as a personal affront, and it ends up wearing them down and driving them out of the business.

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11. milkshake on April 4, 2007 7:48 PM writes...

Chemists are very concerned about what they do, the chemistry. It is the other things in the project that they cannot control.

If you farm, you don't control weather, and you have to deal with pests, diseases and the price fluctuations. To stretch the analogy, medicinal chemist is like an exotic fruit farmer whose stuff takes couple ears to harvest and his crop fails in 9 out of 10 cases.

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12. superman on April 4, 2007 8:35 PM writes...

While cancer trials made read out faster, they also have a higher failure rate. The last numbers I saw, 95% of cancer drugs that enter Phase I, fail.

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13. Kay on April 5, 2007 7:25 AM writes...

PK failures don't occur these days. Our tools have improved; simple yet effective. Wall Street loves us.

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14. Anonymous on April 12, 2007 3:58 PM writes...

Excuse my ignorance but what is "PK/PD"?

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15. Derek Lowe on April 12, 2007 4:21 PM writes...

Anon, those are abbreviations for pharmacokinetics and pharmacodynamics. (You can see why we shorten them). Both refer to the way that compounds are taken up and distributed once in the body. It's a complex business with a lot of variables, many of which we don't understand worth a hoot. Thus the failures and surprises. . .

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