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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

« Pfizer Loses, So Far | Main | Getting To Lyrica »

March 24, 2008

That's Never Gonna Work

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Posted by Derek

A colleague and I were talking the other day about the (long) list of drugs that have been left for dead at some point during their development. There are some famous cases – Lipitor, for example, which wasn’t thought by many at Warner-Lambert to have a business case worth even taking into the clinic. But these things are all over the place.

One that I know about was Claritin (loratadine). Schering-Plough worked on nonsedating antihistamines for a while, without too much success, and the whole program was eventually killed. The head of research at the time stated flatly: “There are no nonsedating antihistamines”. Of course, when the first one (Seldane) came on the market, that made everyone rethink a bit. In the interim, one of the chemists had continued making compounds, despite several (increasingly testy) warnings to stop.

As it turned out, he (Frank Villani) and one of his associates (Charlie Magatti) had made loratadine itself, the nonsedating antihistamine which helped to pay everyone’s salary at Schering-Plough through the 1990s. But by the time that was worked out, Villani himself had been eased out the door (or not eased while on his way out, depending on who you talk to), in good part due to his continued work on the compounds. That head of research, to his credit, actually referred ruefully later on to his own “no nonsedating antihistamines” comment – there are plenty of other people who would have just Never Said Such a Thing At All in that position.

You can find a lot of other examples, going back a long way. Many of these are medical and marketing arguments: ACE inhibitors weren’t necessarily going to be of that much use for hypertension (how many people had high blood pressure because of problems with their renin-angiotensin system anyway?) And the K/H ATPase compounds weren’t going to be of much use for acid reflux, because the H2 antagonists had the market covered (Prilosec and its progeny managed to carve out a little market share for themselves, though). The Lipitor-won’t-make-any-money mistake falls squarely into this category.

My theory is that it’s always possible to find a list of plausible reasons why a given project, or a given drug candidate, won’t work. Finding those things is (comparatively speaking) the easy part. The hard part is working out which of those things you’re wrong about, because you’re sure to be wrong about some of them. (Of course, thinking about this stuff makes you start to wonder about the drugs that never quite made it, but would have done well if they had. Most experienced development people have a list of might-have-beens that they still wonder about, but some of those would surely have also blown up disastrously even later in the process, taking even more money with them).

Further that’ll-never-work examples are welcome in the comments. I know there must be plenty of them out there. . .

Comments (24) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. sroy on March 24, 2008 10:28 AM writes...

And that is why uninformed business people or other assorted twits removed from reality (ex-researchers) who do not understand the science behind a compound should not have the ultimate say in drug development.

A good understanding of the disease in humans, appropriate animal models etc help- but ultimately it boils down to one simple question.

Can the pharmacological effect of a compound be translated into a therapeutic effect in humans? It certainly helps if it is better than the existing drugs or has fewer side effects, though that can be developed further if a target is promising.

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2. sroy on March 24, 2008 10:51 AM writes...

A quick clarification-

Though I am one of the naysayers when it comes to many new drugs, my positions are based on an objective look at the science behind the drugs.

Good objective science can predict the potential pitfalls of an approach. It is however necesary to find out if those predictions are real. Facts matter more than the best theories I can conjure up. In many cases (COX-2 Inhibitors, CETP inhibitors etc ) I would have been happier if I was wrong.

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3. Lowly_Modeler on March 24, 2008 11:19 AM writes...

Everybody's a genius in hindsight...

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4. Clark Kent on March 24, 2008 12:26 PM writes...

Glaxo returned all the rights to Cialis to ICOS because there was no market, then turned around a few years later and bought the right to Levitra because there was a huge market. They were wrong both times.

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5. MTK on March 24, 2008 12:52 PM writes...

Clark,

Correct me if I'm wrong, but when Glaxo gave back the rights to Cialis it was pre-Viagra and ED indication and when they brought in Levitra it was for ED. Now maybe you can argue they should have had the imagination for the ED indication. I'll be generous and give them a 1-1 on that one, not a 0-2.

One medication that people tried to kill several times at GSK but somehow made it was Coreg. The rumor was that it was only through the efforts of Bob Ruffalo, now head of R&D at Wyeth, that Coreg ever made it to market.

Modeler,

I agree 100%.

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6. emjeff on March 24, 2008 1:44 PM writes...

It was before I got there, but when I was at DuPont Pharma (the former DuPont/Merck), I heard stories about how efavirenz was almost killed numerous times. Makes you wonder...

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7. Chrispy on March 24, 2008 2:18 PM writes...


My understanding is that Gleevec was nearly killed a few times at Novartis because it was thought that there were not enough patients to be profitable. Now we understand that all you need to do is charge them enough (currently >$30k/yr.).

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8. CMC guy on March 24, 2008 2:39 PM writes...

In most every program worked on in about 20 years there has been "recovery from near death" instances (plus no recoveries) and for many various reasons thus somewhat inherent to what we do. Far too often it has appeared to be driven by dollars more than science but my perception is admittedly biased.

Maybe not a good example but Renin inhibitors could illustrate a diverted pathway. Although Novartis last year gained first approval for Aliskerin to treat hypertension there was extensive activity at many companies in late 80s early 90s in this area. I believe a big reason Renin programs where scaled back was because market projections at the time could not justify the complexity/expense of the compounds being developed so interest soured. The fortuitous fact is that these molecules became leads as HIV protease inhibitors and thus spawned many successful drugs (where the cost considerations only came later) so timing/luck is an uncontrolled variable in discovery and development.

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9. milkshake on March 24, 2008 3:05 PM writes...

People working on norepinefrine reuptake inhibitors at Pfizer were told repeatedly to stop but they continued it as a submarine project. One of their late compounds, a trans-disubstituted tetraline, was eventually re-screened for SSRI activity and was found promising. It turned out even more promising when it became clear that the activity resided with 5% of the cis isomer, present after reductive amination of tetralone. That compound got name Zoloft.

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10. qetzal on March 24, 2008 3:18 PM writes...

sroy said:

A good understanding of the disease in humans, appropriate animal models etc help- but ultimately it boils down to one simple question.

Can the pharmacological effect of a compound be translated into a therapeutic effect in humans? It certainly helps if it is better than the existing drugs or has fewer side effects, though that can be developed further if a target is promising.

Sorry, I don't agree with that at all. A drug can easily have a clear therapeutic effect and still be an utter failure in the market. Especially if you don't even require increased efficacy or safety. Exubera, anyone?

There's no point in developing a drug if there no market. (Not in a for-profit enterprise, anyway.) The problem is that it's hard to predict in advance what the market for a drug will be. Sort of like it's hard to predict in advance if the drug will work.

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11. MTK on March 24, 2008 4:18 PM writes...

Good point, CMC. I guess every compound has it's story to tell.

As for why compounds get killed. You can't ignore business aspects in a business. If you did, it would be called academics.(Those same academics that most of us scorned a couple of posts ago.) At the same time, of course, sound science should play a role also. As in most things in life, the trick is to strike the right balance.

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12. sroy on March 24, 2008 4:52 PM writes...

Hi qetzal,

While a drug that has therapeutic activity might still fail to become a successful drug, no drug without a therapeutic activity can succeed (unless marketed by fraudulent means).

Pharmacological activity -> Therapeutic activity -> some chance of success.

Pharmacological activity -> No therapeutic activity -> No chance of success.

Permalink to Comment

13. qetzal on March 24, 2008 5:24 PM writes...

sroy,

sorry, perhaps I misunderstood your original point. I agree the business/marketing types should decide whether a drug is likely to work from a scientific/therapeutic perspective. At the same time, the science-types are rarely in the best position to decide whether there's an adequate business case for the proposed drug.

In the end, you have to answer two questions: will it work, and will it sell? One is science, the other marketing. Both are important, and unfortunately, both are highly uncertain until after you've sunk $millions into the project.

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14. sroy on March 24, 2008 5:40 PM writes...

Hi qetzal,

I agree and it comes down to one basic question for pharma management- Are you willing to take a well calculated risk?

Unfortunately the twits in charge of the money (often with no drug discovery background) want to make more money with minimum risk. Running a company that discovers innovative drugs requires a firm understanding of the peculiar and risky nature of this business. It takes a different skill set from running a company that makes hamburgers, donuts, cars etc.

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15. milkshake on March 24, 2008 5:43 PM writes...

much bigger problem is that since failures are costly and no-one in top management wants to have one on his resume, and is unwilling so sign on a developing drug candidate until someone provides him with enough alibi to go ahead...

Permalink to Comment

16. sroy on March 24, 2008 5:51 PM writes...

Why not reduce development costs by outsourcing clinical trials (much more than is currently done). There are many places from E.Europe to India, where you find well run private hospitals + well trained medical professionals that could do all the stuff for a fraction of what we spend here. And don't give me the ethics line - business as such is devoid of ethics.

Permalink to Comment

17. Polymer Bound on March 24, 2008 11:44 PM writes...

re: outsourcing trials -- that goes on to the degree that the developing nations are sophisticated enough to hold the trials. You can't sidestep ethical issues. If you try to go too cheap, you might not be getting good science and you might even hurt people. My understanding is that many HIV prevention trials take place in developing nations (easy to find populations at high risk).

re: the topic at hand -- if you don't have someone trying to kill every compound on its way up, you're working at the wrong company. The price of late failure is too high.

Permalink to Comment

18. sroy on March 25, 2008 1:58 AM writes...

Hi Polymer Bound,

You might have realized that some of your colleagues are from such countries. I do not think they got a brain transplant when they came to the "first world". The reality is that there are many excellent hospitals/ physicians in these countries, it just happens that most people there cannot afford them. But they are still cheaper than their counterparts in the US.

Permalink to Comment

19. Keith Robison on March 25, 2008 7:55 AM writes...

A PBS documentary on heart transplants a while back covered the case of cyclosporine, which was nearly killed in the cradle -- in the end Sandoz carried it forward as a charity project as the marketing department pointed out that there was no market for transplant drugs because there were so few transplants. Good example of successful compound bootstrapping the conditions necessary to be successful.

Permalink to Comment

20. eugene on March 25, 2008 9:34 AM writes...

"But they are still cheaper than their counterparts in the US."

Don't kid yourself kid. Like Polymer Bound said, it's not ethical. If you think the healthy volunteers are doing it for anything other than money, then you're very, very wrong.

When I was really poor and desperate for rent money, I volunteered for medical trials too. The NIH (or at least that particular trial) didn't care if you had a SSN but they did want a bank account of some sort, if I remember correctly. Would I do it now? Hell no! Health is one of the most important things in your life and once it's gone, it's gone. 99% of the healthy researchers on this site would not choose to volunteer for clinical trials no matter what the glossy broshures and ads say. The pitiful money is not worth the risk for us chemists. It is to a college kid or someone from the ghetto.

Outsourcing to China and Ukraine is all about getting desperate people for cheaper. That's inevitably what the issue is, not only the doctors' salary. You need safeguards. It's not a simple outsourcing issue since our society has placed a high price on human rights. Unlike some places where the outsourcing goes. It doesn't matter how many excellent hospitals they have and poorly paid doctors who are not willing to cook outcomes for an extra study opportunity.

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21. CMC guy on March 25, 2008 11:11 AM writes...

MTK- I agree can not ignore business side however I have observed very little balance with the marketing drivers dominate even though their basis are usually much fuzzier and likewise these seem to be only aspects that grab investor attention no matter how good science is. I also concur with Polymer Bound in need for critical evaluations and willingness to kill something early- typically at small companies that comes from outside consultants or others (partner diligence) since is very easy to get caught up in the positives and deemphasize the negatives.

I do not know about India/China situation yet are good clinical sites in E.Europe/former Soviet Union however unless you already have infrastructure in place to appropriately monitor and collect data the cost differential is not dramatic- the value comes from the saving time on the study as can be faster start up, stronger recruitment and just having more sites. I trust majority of pharma people/companies do act ethically and that those that don't will be eliminated quickly without too much damage.

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22. MTK on March 25, 2008 4:34 PM writes...

Interesting. Honestly, I never really felt that business factors intruded that much. Of course, I only worked at one big pharma. Or maybe the projects I worked on had so many other problems that the business stuff seemed pretty far down the list.

As for ethics, a couple of things. First, CMC is right. In fact, I was involved in a project where we could have saved a lot of money and headache by just turning our heads when in-licensing a compound. Instead, we told this company we would not go forward with the deal until they brought the worker safety conditions up to US standards. Second, GCP, unlike GLP and GMP, includes ethical standards and quality standards, so even if you wanted to screw ethics, you can't. Not in the clinic.

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23. processchemist on March 26, 2008 5:32 AM writes...

MTK, good to know that some big company ask the outsourcing partners to raise the safety standards (it would be great if they start to ask about environmental ones too). Some others don't ask about anything at all. Cheaper it's always better, anyway: this is the most common politics in most of places.

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24. drug_hunter on March 29, 2008 6:56 AM writes...

C'mon guys, there must be more examples out there that we all know about!

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