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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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May 21, 2009

The NIH Takes the Plunge

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Posted by Derek

The NIH has announced that they're going to start up a preclinical drug discovery effort to address rare diseases. I find this interesting for several reasons. For one thing, it's worth a try for conditions where no company has seen a way to fund research, and there are quite a few of them. Treating rare diseases can be quite profitable in the industrialized world (ask Genzyme, among other companies), but if the conditions are localized in poorer areas no one's likely to take a crack at them. So my first reaction is "Good, and the best of luck to you". The NIH has been getting closer to doing preclinical drug discovery in recent years, so this is a logical next step.

The second thought I have is that this will be an interesting experience for the researchers involved. There's nothing quite like drug discovery, and if they do it right, everyone will come away with an appreciation of just how complicated a process it is. The only way to make it simple and reasonable is to cut corners. I notice that the press release says:

Typically, drug development begins when academic researchers studying the underlying cause of a disease discover a new molecular target or a chemical that may have a therapeutic effect. Too often, the process gets stuck at the point of discovery because few academic researchers can conduct all the types of studies needed to develop a new drug. If a pharmaceutical company with the resources to further the research does get involved, substantial preclinical work begins with efforts to optimize the chemistry of the potential drug. This involves an iterative series of chemical modifications and tests in progressively more complex systems — from cell cultures to animal tests — to refine the potential medicine for use in people. Only if these stages are successful can a potential treatment move to clinical trials in patients.

Unfortunately, the success rate in this preclinical process is low, with 80 to 90 percent of projects failing in the preclinical phase and never making it to clinical trials. And the costs are high: it takes two to four years of work and $10 million, on average, to move a potential medicine though this preclinical process. Drug developers colloquially call this the "Valley of Death."

. . .If a compound does survive this preclinical stage, TRND will work to find a company willing to test the therapy in patients. There are several stages to the clinical trials process that can take several years before the safety and efficacy of a new drug is determined. FDA will only approve a drug for general use after it passes these trials. The clinical trials process is also expensive, but the failure rate is lower at this stage.

Well, a tiny bit lower. I think that the general clinic-to-market failure rate is still somewhere around 90%, but it varies by therapeutic area. And that 80 to 90% failure rate that they quote for preclinical is a bit lowballed, I'd say, because you'd want to subtract that things that get recommended to the clinic (but really should never have been). But overall, this is a reasonably clear-eyed look at the difficulties involved. If they can get some things to the point that a company or foundation is willing to take on the (now somewhat reduced) risks, that'll be great.

The last thought I have (for now) is that I feel like writing a bunch of people and asking them why the NIH is doing this, since they've been telling me for years that this is what the NIH already does, anyway. The "Big Pharma does nothing but rip off NIH" meme hasn't surfaced for a little while, but it's always out there.

Comments (15) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. AnoII on May 21, 2009 9:10 AM writes...

Decidedly curious. A few years back, a friend and colleague at the UCSF Cancer Center told me about the Center's semi-annual meeting with its external advisors--folks like Andy Grove, movers and shakers of Silicon Valley and the SF banking scene (such as it was). After a number of presentations about exciting new anti-cancer drugs, one of the advisors asked when these new drugs would make it to market. The response was that no one knew. To which the advsior replied, "You have GLP in your labs, you do GCP research in your clinics, all you need is someone to manufacture the drugs, a CMO, under GMP and you've got a drug company. You should do it." I was asked for my opinion as someone in the industry. I had heard of similar conversations when I was in Big Pharma back in NJ. My thoughts haven't changed much over the years on this topic. The process of drug development is simply too foreign to academia to have any chance of success. Look, you've got Department Chairs and Deans who have major angst about providing for 3 years of a professor's salary in recruiting some star to a department. If there were a commitment of a million dollars to that star, you'd have an investigation by the faculty senate over favoritism or some other "reason" for outrage. Now you're asking that Dean or Department Chair to make a wager of $50-100 million on a product which may never get to market, never mind all the research needed to maximize the commercial label, all the pharmacoeconomics reports needed for EU reimbursement, all the regulatory hurdles (yes, academics walk on water in the FDA's eyes, but how long do you think that view lasts if academics--including the NIH--go into the pharmaceutical business), etc. I don't think so. It's extremely counter-cultural for academia to handle such a task well. It isn't the creation and communication of knowledge as such. Better for the NIH to stay out of something it doesn't know or understand. If someone submitted an R01 with such a theme, it would be lucky to fetch lower than a 450 on the reviews.

There are non-profits, like the Institute for One World Health which do focus on neglected diseases, and do so from within the industry. Wouldn't it be better if NIH simply gave such organizations block grants? It would sure be more efficient. Then again, efficiency hasn't been in evidence at the NIH since the 1980s, so perhaps my expectations are simply too high. After all, didn't the NIH try to do this sort of thing in sequencing the genome, and didn't it lose that race (but for the face-saving of HGS)? Now it will play out the same themes with neglected diseases--giving false hope and little more.

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2. CMCguy on May 21, 2009 9:45 AM writes...

I agree that the quoted success rate is skewed as too optisimtic and that getting academia and NIH involved would be interesting shift in those environments (might help them appreciate what companies have been doing/contribute).

I do believe this is laudable effort in targeting under served diseases and should be a mission of NIH (as Derek suggested thought this was going on for years). I am not against this program yet not sure $24M per year (less than $1/person targeted) will go far in looking at 6600 untreated rare diseases so still few likely will get significant attention ($3600/year/disease seem more for show than substance).

Another reality though is that most the expense for drug development is after the “preclinical” phase in turning that Research Knowledge and Ideas in to actual Medicines/Treatments with Development and Clinical Trials being highly expensive so it is unclear how willing any companies (that wishes to stay in business) will be to take on such ventures. Because of the inherent rare nature of the targets the trials can be slower and more costly to run then once is approved do not have a large patient population to recoup the costs, particularly if short Patent life and/or NIH Royalties burdensome (long term likely not profitable so almost have to act as charity). Perhaps there is room for collaborations between academia/government/industry/patent advocacy groups to deal with the issues.

If nothing else NIH should hire some of the people laid off from pharmaceutical companies to provide expertise that it currently lacks (although for most would mean significant salary reductions).

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3. barry on May 21, 2009 10:32 AM writes...

The contribution to the failure-rate in the clinic for potential drugs that should never have gone that far is one of the most jealously guarded secrets in the industry. Four times a year, VP's in big pharma are asked to justify their activities for the last quarter. Four times a year therefore there is pressure to put another compound or two into the clinic, despite the merits. This can contribute directly to delaying good candidates (although they would get priority going forward, they can get sidelined if there's another which advanced on other criteria is in the same therapeutic area). More importantly, it adds to the average cost of each success.

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4. partial agonist on May 21, 2009 11:44 AM writes...

I think the blanket statements such as "drug development is something that the NIH will never understand" and "the process of drug development is simply too foreign to academia to have any chance of success" are a bit off the mark, though they were once true.

There has for a long time been a brain drain from big pharma. In the aftermath of mergers and shutdowns often some of the very brightest hit the pavement. Academia has seen an influx of people that understand the process and have a shot at making translational research a success, people that know that everyone can't just do their own thing on their own grants, people that set up interdiscipliary chemistry/cell bio/tox/DMPK/pharmacology teams that are in marked contrast to the past academic model of everyone doing their own thing and maybe "throwing it over the wall" at the end to find some use.

I don't know much about the inner workings of the NIH and how they plan to run this, but I have a feeling that they have some practical sensibilities derived from managerial experience in successful big pharma operations. I may be wrong, but it seems likely to me.

Having been in big pharma, I recall many good ideas shot down for marketing reasons. Some of those marketing reasons were even wrong- there was a market, but nobody knew it because there were no drugs for it. If this is done well, then a lot of people could benefit who wouldn't otherwise simply because they lack big wallets or they are few in number.

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5. Canuck Chemist on May 21, 2009 4:19 PM writes...

I would think that perhaps a big "X-Prize" type reward might be good for such rare diseases. Which begs another question-- given the immense costs of drug discovery/development, is it really worth it?

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6. CMCguy on May 21, 2009 4:58 PM writes...

Although as #4 partial agonist suggests marketing can play a negative role in determining programs that get worked on I still have difficulty accepting that expanding drug development functions of academics and NIH is going to work all that well. There is a different mindset involved, from the basic wide open exploratory research to a more directed applications orientation, which often is not trivial transition for individuals/organizations.

A link in the NIH press release provided following Q&A:

"Where will TRND be located and who will manage it?

The location of TRND's laboratories has not yet been determined. TRND will have state-of-the-art equipment for medicinal chemistry, biological assays, bioinformatics, pharmacology and toxicology testing.

The scientists who will manage and coordinate TRND activities will be experienced, high-level experts from pharmaceutical and biotechnology organizations. These scientists will not perform their own independent research, but will work together with researchers from outside of NIH to translate their basic research findings into candidate drugs for patients with rare and neglected diseases.

TRND will initially model its infrastructure and staffing on best practices in the pharmaceutical and biotechnology industries, pulling together experience from many different companies to develop its own innovative paradigm. The program will also capitalize upon the many human, intellectual and technological resources available at NIH that are not easily accessed by industry."

Again elements of promise there (bringing experienced resources to bear on specific rare targets) however sounds more and more expensive model and perhaps less effective and duplicative of current system with greater industry, even with the faults. We really need both Industry and NIH to work together and the earlier the better because things done "incorrectly" early may not become evident till much later.

One theoretical advantage in this scheme is that maybe if someone from the NIH goes to the FDA and questions "why certain things are done without any real scientific basis" perhaps they actually might eliminate a few "check box" activities of no/limited value.

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7. qetzal on May 21, 2009 5:46 PM writes...

CMCguy wrote:

One theoretical advantage in this scheme is that maybe if someone from the NIH goes to the FDA and questions "why certain things are done without any real scientific basis" perhaps they actually might eliminate a few "check box" activities of no/limited value.

Now who's being overly optimistic about NIH's ability to make a difference in drug development?

;-)

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8. Anonymous BMS Researcher on May 21, 2009 8:23 PM writes...

Unless academia is VERY different from what it was when I was among its denizens, the vast majority of academic researchers know zilch about what industrial R&D is like -- and I have enough contacts with academics today that I think academia is basically what it was when I was there.

I am reminded daily of how much I *still* need to learn, though I hope I know a *little* more than I did when I left the Ivy League for the Pharma League over ten years ago...

Permalink to Comment

9. Pfizerite on May 22, 2009 12:47 AM writes...

Maybe NIH will use Pfizer's screening library to generate its initial hits then follow up by hiring Pfizer med chem and other research assets as needed.

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10. cantabchem on May 22, 2009 3:30 AM writes...

Is translational research the flavour of the decade?
This is being tried elsewhere too: A few years ago in the UK the Medical Research Council and Cancer Research UK each set up their own stand-alone translational drug discovery units, MRCT and Cancer Research Technology respectively. These are staffed by industry veterans rather than academics and modelled on biotechs, with the explicit idea of taking the academic research funded by them to the point of in vivo proof of concept and licensing the target to pharma for development. More recently the Max Planck Institute in Germany has set up something similar with the Lead Discovery Centre.
Perhaps too early too know how successful this model is - but it does look like a good way of bridging the gap between basic research and drug development.

Permalink to Comment

11. medicamenta vera on May 22, 2009 9:16 AM writes...

An obvious choice for the TRND site is the Pfizer Ann Arbor laboratories (formerly Warner-Lambert Parke-Davis) which the University of Michigan is acquiring. The area still has a deep resevoir of expertise. It would be interesting to see what an experienced group of scientists could accomplish without HR nonsense and upper management prevarication plus dog and pony shows.

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12. Anonymous on May 22, 2009 9:54 AM writes...

#11 yeah because goodness knows there's no HR nonsense or upper management prevarication in the government. Sorry, couldn't resist.

I'd be more interested in knowing who the leadership is. The right champion can make it work, but if it's a conglomeration of NIH researchers and professors who are each responsible for 1 of 3600 diseases - with all due respect, because NIH does great things and basic research is every bit as important as clinical and translational research - no chance. Regardless, they're going to need a lot more than $24 million.

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13. Alaster on May 22, 2009 10:49 AM writes...

This program has about a 12% chance of resulting in one effective treatment in 2020 for one out of the 6600 untreated rare diseases.

It is a step in the right direction, but let's not get carried away.

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14. AnoII on May 22, 2009 11:38 AM writes...

Anon

Yes, one person could do it, and there was a time when the NIH had a number of such persons in different areas who were doing such things. That happens to have coincided with a period when the NIH showed major leadership in biomedical research. Unfortunately, that was at least two decades past, arguably longer. I hold little hope of such a person newly emerging. Many Fauci, but even he hasn't been leading much during the past decade or so.

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15. Anonymous on May 22, 2009 2:37 PM writes...

qetzal one can hold on to dreams of better worlds can't they?

thanks for the laugh

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