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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

« Merck, J&J, and Remicade: Waiting Nervously | Main | Noted, Through Massive Self-Restraint, With Almost No Comment Whatsoever »

February 14, 2011

New Cures! Faster! Faster!

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Posted by Derek

I wrote here the other day about the NIH's new translational medicine plans. The New York Times article that brought this to wide attention didn't go over well with director Francis Collins, who ended up trying to disabuse people of the idea that the NIH was going to set up its own drug company.

But there's been an overwhelming negative response from the academic research community, largely driven (it seems) by worries about funding. Given the state of the budget, flat funding would be seen as a victory by NIH, so this isn't the best environment to be talking about putting together a great new institute. The money for it will, after all, have to come out of someone else's pile. Collins spends most of that statement linked above denying this, but it's hard to see how there won't be problems.

I think, though, that there's an even more fundamental problem here. In the latest BioCentury, there's an interesting sidelight on all this:

In comments submitted to NIH, Joseph Zaia, associate director of the Center for Biomedical Mass Spectrometry at the Boston University School of Medicine, argued against setting timetables for research results. “I do not believe that running medical science on a short sighted business time schedule will produce more cures faster. It will, however, deplete NIH resources very rapidly and possibly tear down an infrastructure of knowledge that took decades to create.”

Zaia complained that the NCATS “process seems to be driven by the FasterCures movement sponsored by Michael Milken,” which he said has “been masterful in manipulating the political system for their purposes, and forcing NIH into this reorganization.”

FasterCures’ Margaret Anderson, executive director of the non-profit group that advocates for accelerating medical innovation, submitted a letter strongly endorsing NCATS, which she said “will provide a significant stimulus to moving ideas out of the lab and into the clinic.”

And that's the problem. Over the last few years, an idea has taken hold that there are all kinds of great ideas for all kinds of diseases that no one is doing anything with. Now, I'm not going to claim that everyone is trying every single thing that could possibly be tried, but I really don't see how there's this treasure chest of great discoveries that aren't being followed up on. Drug companies of all sizes are always watching for such opportunities - I've been a part of many such efforts to jump on these as they show up.

My guess is that many of these advocates have a different definition of what a "great discovery" is than I do. There are all kinds of things that come out in the literature, often with breathless press releases from the university PR office, that make it sound like the latest JBC paper has the cure for cancer in it. But the huge majority of these things don't pan out, generally because they're just part of a much, much larger (and more complicated) story. And that's why things tend to fail on the way to (and through) the clinic.

Am I exaggerating? Well, many advocates in this area have taken to using the phrase "valley of death" to describe the gap between basic research and success in the clinic. Here's Amy Rick of the Parkinson's Action Network:

Rick said patient groups are concerned that the valley of
death is growing, and they want government to help bridge it. The prospect that there are “good discoveries that are basically collecting dust” is “terrifying to patients,” she said.

“What we are finding from a patient perspective is that discoveries that are being made in very exciting basic research are not being acted upon,” Rick told BioCentury This Week. “They are not moving through the pipeline. So the patient community is pushing very hard — if private money isn’t filling that space, the government should be moving some of its funding into that space.”

I have a great deal of sympathy for the patient population - they're our customers in this business, after all, and any one of us could join their ranks at any time. (Drug company researchers come down with all the maladies that everyone else does). But the patient population is not the group of people discovering and developing drugs. What looks like agonizingly slow progress from outside is often just the best that can be done. It can be hard to imagine how crazy, complex, and frustrating medical research can be unless you've tried doing it. Nothing else quite compares.

I worry that some of these people have an unrealistic view of how things work (or should work). This all reminds me of Andrew Grove, ex-Intel, and his complaints that the drug research business wasn't moving as fast as the semiconductor industry. It sure isn't. That's because it's a lot harder.

The Biocentury article is right in line with my thinking here:

FASEB’s Talman argues that patient groups and the public are overly optimistic about the breakthroughs that could be made by shifting resources to translational science. He believes basic scientists are partly to blame because “there is too much of a tendency for basic or clinical scientists to sell our work.” In the process, he said, “we can come across as saying that the newest discovery can lead to a cure.”

Senior NIH officials have contributed to the belief that cures are around the corner by dangling the prospect of quick payoffs in front of congressional appropriators. For example, in 1999, Gerald Fischbach, then director of the National Institute of Neurological Diseases and Stroke, told a Senate committee that with sufficient funding it was reasonable to expect a cure for Parkinson’s disease within five years. The NINDS budget has increased from $902 million in FY99 to $1.6 billion in FY10, but PD hasn’t been cured.

Starting in 2004, National Cancer Institute Director Andrew von Eschenbach claimed in numerous public speeches that it would be possible to “end suffering and death from cancer by 2015,” a claim that current NCI Director Harold Varmus has repudiated.

When he led the human genome sequencing effort, NIH Director Collins himself made comments that the press, public and politicians interpreted as promising that it would directly and quickly lead to new medicines for common diseases.

“There is a real danger of over-promising,” Keith Yamamoto, executive vice dean of the University of California San Francisco School of Medicine, told BioCentury. “Scientists too often take an intellectual short cut. They think they will not be able to explain the nuances of why basic discovery takes so long, so they just say if you give me the money we are about to cure the disease.”

He added: “That’s thin ice — it is our responsibility to explain why things are as difficult as they are.”

It sure is. I know that patients and the general public get tired of hearing about how it's hard, how discoveries take time, all that sort of thing, while the diseases just keep marching on and on. But it's all true. I honestly don't think that most people realize, despite that huge amounts of knowledge we've managed to accumulate, just how little we know about what we're doing.

Comments (39) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Drug Development | The Central Nervous System


COMMENTS

1. MTK on February 14, 2011 11:10 AM writes...

I realize it's a small portion of the NIH budget overall, but the money that is for the most part wasted on NCCAM annoys me to no end.

Whenever I hear about NIH's budget crunch, I can't help but think of the $127M going to this center that could be better spent.

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2. Gil Roth on February 14, 2011 11:17 AM writes...

I think you need a Tura Satana tribute picture in this post.

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3. bad wolf on February 14, 2011 12:01 PM writes...

You could also add a picture of Scott "Where's the Passion?" E. Kern.

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4. virgil on February 14, 2011 12:07 PM writes...

You're missing a close-italics HTML tag after "JBC", so everything below that on the page appears in italics.

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5. Jonathan on February 14, 2011 12:20 PM writes...

@MTK - when the head of the relevant Senate Appropriations subcommittee (ie the person who has a very large say over how much NIH gets) says NIH has to create NCCAM and here's the money for it, NIH has to say "yes sir, thank you Senator."

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6. FundMyMedicalResearch on February 14, 2011 12:44 PM writes...

Derek,

You're right that no-one should delude themselves not thinking this is an extremely complex problem to solve. But the core of the discussion is not the complexity of the problem, but the way we address it. If we start believing in the status quo, it's then our own limits in thinking that stall any progress. You can't believe we've reached the ultimate organization to move medical research forward. Can you?

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7. RM on February 14, 2011 1:14 PM writes...

I think it is correct to state that many academics don't have any clue on how to move their discovery through the pipeline toward a successful clinical treatment. So in that sense, there's a number of discoveries which are either flailing around undirected, or are stagnating. Although there are many drug companies which search out academic discoveries, I think it's optimistic to say you're getting 100% coverage - you're just getting those discoveries and academics who are already industry inclined.

That said, I also think it's foolish to think that simply introducing the academics and the industry people to each other is going to suddenly result in a rush of new treatments. As you said, medical research is hard, and the discoveries which are languishing are doing so precisely because they're the ones with the unclearest future. Industry involvement may help them along more so than academia-only work, but it's not a magic wand.

More academic/industry collaboration will help, but it's not a panacea, nor even the limiting factor.

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8. MoMo on February 14, 2011 1:16 PM writes...

Same Old, Same old! But you might as well throw money at it like they do other drug discovery programs dancing around the NIH. Maybe something will stick.

BUT, It beats giving it to the academic biologists who spend their lives eating our hard-earned taxpayer money while they build their fragile egos and careers.

Now if you gave that 127M$ to chemists that weren't imbeciles and it to generate newer and better scaffolds and synthetic methodology then WE BE TALKIN'!

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9. Derek Lowe on February 14, 2011 1:36 PM writes...

Gil (#2), I won't pretend that that idea didn't cross my mind! My wife does read the blog, though, so I might have some explaining to do when I got home. Then again, she knows me pretty well. . .

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10. Anonymous on February 14, 2011 1:51 PM writes...

@5:

I realize that. It still annoys me, especially when Harkin says that he's disappointed with NCCAM's performance because they've disproven things, but not proven anything.

Imagine that.

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11. DrSnowboard on February 14, 2011 2:02 PM writes...

Hey but everyone knows:

“It’s a wonderful idea,” said Prof Pepys. “We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else. "

http://www.ft.com/cms/s/0/d1e31184-37a5-11e0-b91a-00144feabdc0.html#ixzz1DxgpBnPe

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12. HelicalZz on February 14, 2011 2:05 PM writes...

These gentlemen weren't being misleading, but Its a lot like the fortune cookie game. When you hear something is going to be 'cured' be sure to add 'in rats'.

Zz

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13. RB Woodweird on February 14, 2011 2:37 PM writes...

Gil Roth -
You mean the Faster, Pussycat! Cure! Cure! In The Pipeline tribute?

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14. victorypilsner on February 14, 2011 2:38 PM writes...

I agree very much with most of your sentiments; I've been at both big and small pharma all my career, and know that pharma researchers are dedicated to pursuing any and all targets that emerge as possibly relevant to disease. However, there is one growing issue that is going to be increasingly problematic. Drug development is so expensive, and more and more, it is concentrated in the hands of fewer and fewer, thanks to continued big pharma M&A. Problem is that many of the top management in big pharma (case in point the Pfizer guy) seem woefully focused on short term results and frankly incompetent. So when you have this scenario setting up, it is not difficult to see why the public sentiment is the way it is, and this is an issue that needs to be addressed somehow for the long term benefit of both science and patients?

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15. MIMD on February 14, 2011 2:52 PM writes...

Derek wrote:

This all reminds me of Andrew Grove, ex-Intel, and his complaints that the drug research business wasn't moving as fast as the semiconductor industry. It sure isn't. That's because it's a lot harder.

Don't forget the similar incantations of the Google leadership. Medicine's just a "database platform problem."

By the way, my response to Mr. Grove is that their 8086/8088 processors (of the original IBM PC and successors) wasted tens of millions of person-hours and billions of dollars. Programmers and end users had to deal with the effects of the segmented memory architecture, with resultant fritter, workarounds and bugs, extended/expanded memory settings, etc. as opposed to other linear-addressing processors (such as used in the early Macs).

The segmented architecture should have become passe after the 1970's PDP-8 era. I think Windows 7 is finally free of this caveman artifact, but I'm not entirely sure.

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16. anchor on February 14, 2011 2:54 PM writes...


Derek: Mr. Kevin Trudeau knows the faster way to cure just about anything and everything! Lot of people subscribes to his philosophy which is "they don't want you to know", but he has panacea for your problems

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17. SMF on February 14, 2011 3:39 PM writes...

There is a death valley in drug discovery in academia. NIH grants will only get one so far and that distance is short of what people in industry would like to see. For example, we have a compound with good antibacterial activity in animals, but industry types want more toxicology, long studies and some have even suggested Phase I trials before they would get interested. I understand the desire of those in industry to minimize risk, but unless there is a mechanism to take interesting compounds and move them forward, a lot of stuff will eventually die; especially once someone publishes a paper instead of a patent. There needs to be some mechanism to address this problem. I don't know if a new center is the cure, but we need to try something.

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18. Lester Freamon on February 14, 2011 4:01 PM writes...

If it gets more compounds going at novel targets into animals and humans, it'll be worth it. Honestly sometimes I think the industry would do better just by taking a dartboard with every (targetable) human protein on it, throwing 10 darts, getting a decent inhibitor of anything that sticks (and switching to a different target if it looks intractable), and then randomly testing each new compound in every good disease model we have.

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19. CMCguy on February 14, 2011 4:17 PM writes...

There are a bunch of tough issues to deal with and unfortunately there is never a clear single pathway to follow.

I understand academicians concerns that the efforts could impact funding of NIH grants as a shift away from basic scientific learning to "application driven" research. As noted there can be significant over-promising of early bench level data (primarily to secure more funding), particularly with real sense for time and effort subsequently required. Facts are that majority of discovery research retrospectively proves to be no more than blind alleys or added only minimal new understanding. Rarely is the path straight or does not require multiple pieces of the puzzles to come together. With out support for the earliest type of work in uncovering science, which I view as the primary mission of NIH, then there will be nothing to build on later.

On the other hand the "translation" stage between biology or even chemical leads to actual medicines is where most the complexity lies, and that is what the NIH center is reportedly aiming at. There is a gap in many diseases that are undeserved and again suggestion is proportionately where NIH will focus. Big Pharma, due to M&As, does not seems to have much willingness to devote to anything without a high bar market size. While Biotech may be somewhat more willing to take on smaller projects they have great difficultly in attaching funding for anything today that has gone well beyond concept translation. I do not necessarily feel that conducting this in government institutions are best solution however if the choice is there are nowhere then if it can be additive rather than substitution to NIH mission the benefits would outweigh the negatives.

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20. MTK on February 14, 2011 4:22 PM writes...

@17.

SMF,

That mechanism is called venture capital. If your compound is that good, then you should be able to build a convincing business plan and find investors willing to back it.

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21. Jumbo on February 14, 2011 4:36 PM writes...

@MTK: The VC model is broken if not at an end. They spent most of the last 10 yr investing in compounds that big pharma didn't want, on the premise that BP is too stupid to recognize a good compound and hoping that, by just completing the Ph2 trial, they would get their money back with a big, Ph3-style deal. Ask the people at Jazz (to pick on just one of many) how that model is working out!

Having criticized VC's, it is worth also noting that academics have a fairly over-blown view of what consititutes a legitimate clinical candidate. I have worked in pharma licensing for almost 15 years, specifically looking for early stage opportunities and talking a lot to academic groups. They are good at identifying interesting targets (though not, in my experience, better than the able pharma researchers with whom I have worked!). But they and the grant system are not oriented toward validating pharmacological agents. They are satisfied with using some off-the-shelf compound that happens to hit their kinase (amongst 4 others) and saying that inhibiting this new kinase will cure plantar warts. And then they wonder why it takes so long to get pharma to follow up. Is it perhaps that their dirty compound didn't prove anything?

I am not saying that the valley of death doesn't exist. It does and it is getting worse since VC's have given up on investing in preclinical programs. But it is ridiculous to say "Let's give NIH $1B and they will fix what pharma broke."

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22. MTK on February 14, 2011 4:51 PM writes...

Jumbo,

The VC model you describe may be broke, but I don't think the VC model as a whole is broke. What it will take is some lowered expectations on ROI. So instead of taking something to Phase II looking for that big payout, how about getting something through pre-clinical, which is a lot less investment, and then selling to Big Pharma, which will pay a lot less at that point also.

Big Pharma is always looking for promising things as you know. Just like Big Pharma may need to look for singles and doubles instead of home runs, the VC's should be doing the same. Actually, any VC worth their salt would be looking to have a mix of companies with different strategies in order to manage risk.

I guess my whole point is that if there's return to be had for a compound, target, etc. then someone will pay for it. It's a matter of how much someone is willing to spend and how much someone is willing to give up.

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23. milkshake on February 14, 2011 5:08 PM writes...

@jumbo: it would be great if off-the-shelf kinase inhibitor hit only other 4 kinase targets. More often its like another 80.

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24. don't tell anyone! on February 14, 2011 5:55 PM writes...

Re: #7: I think it is correct to state that many academics don't have any clue on how to move their discovery through the pipeline toward a successful clinical treatment.

Not only do they not have a clue, they do not want to know. They cured cancer in mice. That's easy. That gets you Nature papers and piles of grant dollars. Victory! What a pity it would be to actually try it in humans and discover that it doesn't work. Much better to just stick with "model" systems, which of course, aren't models for anything useful the vast majority of the time.

Collins is right. The NIH needs very desperately to get studies translated into humans, because the NIH isn't curing anybody and the taxpayers will take their money elsewhere.

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25. Unix Ronin on February 14, 2011 6:49 PM writes...

Michael Milken...?  Wait, Milken the junk bond king?  In what universe does he have any credibility about medicine?  Is this his Next Big Scam?

This sounds like a bad case of crash-program-itis à la Wernher von Braun, who observed that most crash programs fail because they're based on the reasoning that with nine women pregnant, you can get a baby a month.

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26. SP on February 14, 2011 8:00 PM writes...

Why is the assumption that all the research at the new center will just be doing what pharma is doing, only with different targets/hits? Isn't there room for innovation in lead optimization & preclinical- better predictive markers, phase 0 studies, etc.? Do people think there's no innovation to be funded beyond basic research?

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27. hibob on February 14, 2011 8:20 PM writes...

In a related development:
"What we are finding from a soldier's perspective is that discoveries that are being made in very exciting basic research on invisibility cloaks are not being acted upon", Rick told Stars and Stripes this week.

The main difference between the two interviews was the two additional digits between the "$" and the "." in the DOD funding proposal.

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28. Watch this unfold on February 14, 2011 9:23 PM writes...

NIH meets FDA what a reality check for academia.
Innovation meets risk aversion. these people really think the best brains went back to school for less money? It really insults Pharmas intelligence that we don't filter the best bets and try every trick from within, biotech and academia. It will all be down the pan before they realize their naievity.

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29. Sheesh on February 14, 2011 10:33 PM writes...

#28 - So you're smarter because you took more money to go to industry? Check out the big brain on Brett!

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30. Anonymous on February 15, 2011 3:07 AM writes...

"What looks like agonizingly slow progress from outside is often just the best that can be done."

Your industry is not alone. Just look at alternative energy supoply. The only new technology to have a significant impact on energy product is nuclear poower. Wind, solar, batteries and biomass (either for fuel or power) still constitute a very small share of the market. This is primarily due to costand their inability to compete with natural gas or coal.
Research is hard full stop. It does not matter aht industry you are in; failure is always a possibility.

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31. anon on February 15, 2011 7:45 AM writes...

#28

A good portion of the FDA staff came from NIH.

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32. MoMo on February 15, 2011 9:33 AM writes...

I know numerous academics who have invented and had developed drugs, myself included, and know both sides with industry equally well, so don't you Industry Only types get self-righteous about your abilities to bring drug to the clinic.

Newer discoveries IN CHEMISTRY are coming from academia in the form of start-ups and we laugh everytime the royalty checks get cashed!

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33. RM on February 15, 2011 12:05 PM writes...

MTK @ 20 If your compound is that good, then you should be able to build a convincing business plan and find investors willing to back it.

Wait ... so not only are they supposed to be cutting edge researchers and superb grantsmen, they're supposed to be able to churn our business plans that'll delight VC's in a tough economy too?

When people talk of the "valley of death" that's sort of what they're indicating. Academics are good at what they need to do to succeed in academics. The skills, efforts, and experiments needed to successfully publish papers and get grants don't really overlap with the skills, efforts, and experiments that are needed to secure VC funding and bring the discovery to the clinic.

There are some that work well in both worlds (those are the ones you hear about), but there are others who either don't have the overlap, or, as don't tell anyone!@24 indicates, don't *want* to have the overlap. Not that they don't want their discovery to make it to the clinic, but they're already dealing with NIH review panels and the university regents - they don't have time to learn the vagaries of what another group of demanding, judgmental people want. (Every minute you're securing VC funding is a minute you're not getting grants or publishing papers.)

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34. KC Spingos on February 15, 2011 1:40 PM writes...

Meidcal research is very hard largely because of the limitations of ethics. If semiconductors researcsh had to secure possible hazards in all areas involved with ethics as rigorous as in medicine (actually, where is any concern that plasma TV screens, for instance, do not cause serious "side effects" on global warming?) would not have gone any essentially longer distance than clinical medicine.
It is really surprising that pharma industry is able just to survive nowadays and I suppose that this is mainl the result of rigorous -ethically controversial- marketing efforts.

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35. KC Spingos on February 15, 2011 1:42 PM writes...

Meidcal research is very hard largely because of the limitations of ethics. If semiconductors researcsh had to secure possible hazards in all areas involved with ethics as rigorous as in medicine (actually, where is any concern that plasma TV screens, for instance, do not cause serious "side effects" on global warming?) would not have gone any essentially longer distance than clinical medicine.
It is really surprising that pharma industry is able just to survive nowadays and I suppose that this is mainl the result of rigorous -ethically controversial- marketing efforts.

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36. NeonCortex on February 15, 2011 1:58 PM writes...

I think tour last sentence sums it up pretty well.

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37. metaphysician on February 15, 2011 6:20 PM writes...

#20-

*cough* That has little if anything to do with insufficient money and man-hours spent on "green energy", and a hell of a lot to do with most of the mentioned methods being intrinsically problematic ( useless ). No amount of money spent will make the wind blow or 24/7, and short of putting it in space, the same applies to getting the sun to shine.

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38. Dr. Bob on February 23, 2011 5:26 PM writes...

There is quite a debate going on about why the drug industry is failing to discover new drugs. While there is plenty of blame to go around, I see a few specific problems. Almost none of them relate to not being able to find good early stage candidates. After many years of working in pharma, I have seen very few projects where a good lead or more could not be found, and most projects produced preclinical candidates that meet all or most criteria, even when they were quite conservative.

The challenge is that many projects that got that far were eventually canned due to "commercial issues", "risk aversion", "poor return on investment", and many other excuses to not develop medicines. And that is due to the bar being raised so high by the FDA and others that almost no drug can meet the current expectations for a new medicine.

Also, the ability to test compounds in humans has become so difficult, that it is hard to pick the best compound to go forward with. Years ago, (1950-1960's especially) when the first drugs were being developed, it was not uncommon to take several candidates into development, then move the best ones forward. Look at the path to Benedyl and other antihistamines for example. They went into humans within weeks of synthesis. Now, it is nearly 5 years from conception to man, and that is only the first stage of trials.

So due to the inability to test compounds in man quickly, and the fear of developing the ones that do look good due to the costs, I would guess that 90% or more of the drugs that exist already in big pharma which look promising will never be tested in man, even though many may be great drugs. So if the NIH wants to do something, they could ask researchers for the drugs that big pharma was afraid to test and run the phase 1 trials. There is no shortage of early leads, however, so creating more leads won't help.

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39. Karin on October 21, 2011 7:50 AM writes...

#37 metaphysician - actually, the problem is that fossils are subsidised. If the price for environmental clean-up, carbon storage, flooding and storm damages, wars, etc, was paid by the users of fossil fuels then renewabels would be more than competitive. A proper market without externalised costs is what is needed.
And as to the nature of wind and solar - storage of energy is hardly impossible.

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