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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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October 30, 2009

Fifty Years of Scientific History For You

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Posted by Derek

Here's a most interesting graph from the latest issue of Nature Reviews Drug Discovery. It's from an article on trying to discern trends from broad-scale literature analysis, and it's worth a separate blog post of its own (coming shortly). But after yesterday's discussion of whether there are too many graduates in science and engineering, this looked useful.
big%20graph.jpg
Note, for example, the ramp up in NIH funding in the late 1950s/ early 1960s (a very large change in percentage terms), which was followed by a similar surge in doctorates granted. The late-1990s funding increases seem to be having a similar effect near the end of the chart.

Note also the well-publicized drug drought - but the historical perspective is interesting. We've clearly fallen off the 1970-2000 trend line of increasing drug approvals, but we seem to be stabilizing at roughly a 1980s level. The argument is whether that's where we should be or not. We have all these new tools, but all these new worries. Lots of new targets, but fewer good ones like the old days. Many new tools, but plenty of difficult-to-interpret data generated from them. And so on. But 1985 is apparently about where the balance of all these things is putting us.

Comments (34) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Who Discovers and Why


COMMENTS

1. anon on October 30, 2009 9:12 AM writes...

One might argue the FDA has become too CYA. I mean, they've pulled some REALLY safe drugs in recent years-- Vioxx. It gives one pause.

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2. Chemjobber on October 30, 2009 9:17 AM writes...

I think the mistake many people made is assuming that the late-90's spike was "the way it's gonna be." I know that's what I was thinking when I got into the field as an undergrad; 10 years later, of course, I'm thinking it was a one-time artifact. Who knows what I'll think 10 years from now.

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3. anon also on October 30, 2009 9:49 AM writes...

Of course, there are several other potential data points missing. What were the average patent terms? What was private R&D funding? What was the average ROI from NMEs? What happened in 1995 to dirert the NME slope?

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4. Reyn on October 30, 2009 10:08 AM writes...

Perhaps there is also a lag as we go from the "old way" of one target, inhibit with a small molecule and get a blockbuster to the "new way." The new way being combination therapies, proteins, cell based therapies with small biotechs and startups being the source of most of these products.

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5. Hap on October 30, 2009 10:15 AM writes...

Drug approvals at a 1985 level would help if costs stayed at a 1985 level - but they don't. The costs of doing trials seem larger, as well as the financial pressures on drugs (which make it harder to recoup those costs) and the likely pay of all the people involved.

It doesn't really seem all that hopeful to me. I hope I'm missing something.

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6. gyges on October 30, 2009 10:17 AM writes...

It says to me that the copyright of any paper published, based upon this source of funding, does not belong to the journal where it is published.

The claim on that copyright by the publishing journal is void ab initio; it belongs to the funding source, ie, the government, hence, us.

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7. GWR on October 30, 2009 11:10 AM writes...

Interesting data. I haven't read the article but using the 2000 data above, it's seems that it's costing around $2.8 million per doctorate, and $42,000 per publication. Looks like a lot of very expensive infrastructure for the training and probably a lot of inappropriate research and publication. That's the peer pressure system unfortunately, and it does not seem to be generating new drugs. NIH funding tripled over the period 1950-1970, FDA approvals peaked in 1995. If this is to be taken seriously, the burst in NIH funding in 1995-2005 will result in more approvals in 2025-2030. A lead time of +25 years is ridiculous - that's actually longer than most careers in the industry.

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8. Anonymous on October 30, 2009 11:32 AM writes...

It's interesting that FDA approvals follow such a cyclical boom/bust pattern.

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9. Philip on October 30, 2009 12:40 PM writes...

It's now pretty obvious to me just what happened. The explosion of publications in 1996 led to everyone sitting around reading journals and no one working in the lab.

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10. mad on October 30, 2009 12:58 PM writes...

Keep in mind with FDA apprivals that many big pharma time there submissions in reaction to the market and/or their current patant time remainig. Number of sumbission to the FDA would be required to better understand the approval trend

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11. Anon^2 on October 30, 2009 1:11 PM writes...

Obviously if the NIH has money to employ people via academia it will. So academia produces 10X scientists using that money, but there is only a job market for 3X.

This asymmetry must come to an end. Even a crude AMA style limitation on the number of scientists produced or permitted into the country would help out the starving masses.

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12. MTK on October 30, 2009 1:27 PM writes...

Honestly, I have no clue how to interpret this data.

a) I'm not sure what relationship, beyond coincidental, NIH funding has with # of FDA approvals.

and

b) Should not NIH funding be expressed in terms of real dollars, not nominal dollars, to have any significance?

Maybe I ought to read the article. :)

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13. Tok on October 30, 2009 1:29 PM writes...

When did the mega-merger mania (e.g. Pfizerization) start? Does that have any impact on the results of this graph?

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14. hypnos on October 30, 2009 1:35 PM writes...

Yes, we're back on the level of the 1980s. The bad thing is that pharma world looks different now: generic competition is tougher and reimbursement hurdles are much higher nowadays. Thus, we can no longer afford the approval rates we were happy with 30 years ago.

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15. Some Dude on October 30, 2009 2:42 PM writes...

My concern is that it looks like for the same number of FDA approvals in 1985 we now have almost twice the number of PHDs. Where will all these people work if the income has fallen?

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16. Jose on October 30, 2009 3:07 PM writes...

The use of ratio value (x) to value (x) in 2000 seems spurious, and makes analysis difficult. Why not normalize it? I'll have to read the paper now.

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17. Tok on October 30, 2009 3:53 PM writes...

That is normalizing it. This way you have a unitless measure of amount so they can all be on the same graph and easily compared.

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18. Kismet on October 30, 2009 4:09 PM writes...

Does anyone know if anon @1 is serious? Vioxx a safe drug? Isn't it just an extremely boring me too with an abhorrent safety profile?

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19. researchfella on October 30, 2009 4:31 PM writes...

You might conclude from this graph that
(a) NIH funding was substantially increased during 1999-2003 in response to the marked drop in FDA approvals observed from 1996 to 1997, and
(b) the NIH funding increase during 1999-2003 resulted in the observed increase in publications (with a 2-year lagtime), and
(c) the NIH funding increase during 1999-2003 resulted in the observed increase in doctorates (with a 4- to 5-year lagtime).
And maybe we could therefore expect to see, as a result of the increase in NIH funding during 1999-2003, an increase in FDA approvals, but with a 10- to 20-year lagtime.

...but I doubt it.

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20. anon the II on October 30, 2009 7:15 PM writes...

to # 18

Here's the deal with Vioxx. Historically, NSAID (COX inhibitors) pharmacology had been rather complex. There's the clear anti-inflammatory component and the stomach rotting piece. But there is also that platelet aggregation part and the analgesic component. When the COX-1/COX-2 story was told, everyone focused on the first 2 effects and ignored the latter 2. So they dosed the hell out of the COX-2 inhibitors and got great relief and no stomach irritation. Unfortunately, the SAR for the 4 components isn't as simple as the COX-1/COX-2 ratio and at higher doses those funny cardiovascular effects start showing up in bad ways. At lower doses those cardiovascular effects seem to be good, hence the 80 mg aspirin a day thing. In the old days, dose was limited by stomach irritation. With the COX-2 inhibitors, you started to get much rarer side effects which were less dosed limiting and more likely, merely lethal. If the COX-2 inhibitors had been dosed at a level where they were only twice as potent as the NSAIDs of old, I suspect that the lethality would have never shown up. So Vioxx is probably safer than a lot of similar drugs still on the market when dosed at comparable effect. It just doesn't warn you to limit the dose by tearing up your stomach before getting to the dose that kills you.

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21. Melody: Aseptic Filling on October 30, 2009 8:41 PM writes...

Fascinating comparison. I agree with Hap above. The costs of conducting trials continue to increase while approvals take a step back. This does not bode well for the direction of the industry, or for those awaiting new therapies.

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22. AlchemX on October 30, 2009 9:41 PM writes...

Government money seems to destroy a lot of things. Government healthcare programs seem to just increase the price of care. Student loans subsidized by the government have increased the cost of education. Government backed money destroyed the housing market. Government money has created disastors overseas. Welfare has been a disastor for the poor. The war on drugs has created bigger drug lords, criminals and has decreased the price of drugs. When are we going to stop government money from ruining our profession?

Permalink to Comment

23. Anders on October 31, 2009 6:55 AM writes...

Like #5 and #21 I think a graph of cost of trials would be interesting.

But even more interesting would be a graph of total spending on drugs. As a society, are we getting more or less for our money?

Permalink to Comment

24. Tok on October 31, 2009 10:27 AM writes...

#22 -
Greedy speculators destroyed the housing market. The next time you start regularly meeting people who "flip" houses (or anything else for that matter), brace for impact.
I personally like government help for the poor to get an education, without it I would not have gone to college. I also like welfare and food programs, without it I would not have survived childhood to get my PhD, and my sisters would not be a geologiest and neurologist. So rest assured, the welfare program does help sometimes.
Now, disasters overseas I can agree with, but I'm afraid the smaller government party we currently have to choose from tends to greatly exacerbate the problem.

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25. AlchemX on October 31, 2009 5:11 PM writes...

The smaller government party (republicans) have never made good on their promise to reduce government. If there was not so much government funding in the sciences we wouldn't have this excessive amount of unemployed scientists and post-docs. What good is government funding if it just goes to waste like this?

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26. Mercury on October 31, 2009 6:40 PM writes...

Do not forget that people themselves, not the government, choose what they want to study. (Fortunately.) And they tend not to be very bright about it, often choosing to study what is fashionable at the moment, without seriously considering their own expectations and skills, and without realizing that when they all graduate the market will be flooded. A popular television series can suddenly boost the number of students in a science nobody knew of the year before: It is a bit harsh to blame that on government.

But an excess of highly educated people is a luxury problem. The solution is not to educate less of them, but to find other roles for them: There often is a lack of flexibility in matching jobs and job seekers -- especially, these days, on the part of employers, who all want cheap but highly experienced 25-year olds, a perfect match for the scientific role they had in mind, with management skills and the ability to play the bagpipes while they think of cheaper ways to synthesize DNA. In reality, a good scientist can be useful in a great many roles, including some his or her educators probably never thought of.

Education in itself, as far as I know, has been proven to contribute positively to people's health. (Although the benefit from a PhD is probably marginal.) As do clean drinking water, waste and sewage removal, laws banning or restriction dangerous chemicals, the infrastructure to move around large quantities of food, and other steps for which some form of government is clearly necessary.

One can question the benefits of NIH spending, and I know some people in industry who are very sceptic about at least some of the NIH's programmes, which they see as naive attempts to emulate the pharma industry without possessing the required know-how... One the other hand, having seen the callous attitude of some industry managers to basic science, it is obvious to me that at least some government spending on research is absolutely essential. And while it is very likely that some it is misguided and a waste of money, we cannot pretend that we in industry are always smarter about how we spent on our money. My bet is that we are not.

The big problem with government spending on research is that so much is in the form of short-term grants. One result is a ridiculously high administrative overhead, for little evident improvement of the efficiency of spending: On the contrary, a growing number of highly intelligent people spends their time generating soul-destroying paperwork. It discourages people from seeking a long-term career on science; in that it probably hurts women more than men. And it contributes to a diarrhoea of publications that are of no use to anybody except the authors, which probably harms science itself.


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27. Kismet on October 31, 2009 9:40 PM writes...

AlchemX, the 'sciences' are actually quite underfunded in the US thanks to Bush et al - IIRC.
I think you are confusing cause, effect and some other things.

OTOH, it is true that what is being spent, often is being spent inefficiently.

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28. Chelsea on October 31, 2009 10:51 PM writes...

I'm not a scientist, but interesting discussion everyone. Thanks. To the vioxx comments - a single dose made my mother's blood pressure jump from well controlled to 200. Fortunately she was at a SNF and being monitored so no more doses were given.

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29. Malcolm on November 1, 2009 6:18 PM writes...

#20 interesting speculation but apart from the lack of hard evidence I see two flies in the ointment.

Firstly, rofecoxib (Vioxx) dosing was presumably chosen based on analgesic efficacy (along with PK and general safety considerations of course). At the approved dose it was no more efficacious than traditional (non-COX-selective) NSAIDs, and there is no guarantee it would be sufficiently efficacious at a significantly lower dose (feel free to find something in the FDA approval package to prove me wrong).

Secondly, while rofecoxib caused fewer serious gastrointestinal problems than, say, naproxen, AFAIK the dose-response of GI effects was never part of the dosing considerations. The differences in clinical outcomes are just too small (e.g. some fraction of 1 event per 100-patient-years). Add to that that the rate of dyspepsia and other GI adverse effects that the patient actually notices day to day ("stomach irritation") is no better for the COX-2s compared with the older drugs.

Of course, it is true that the remaining COX-2 selective drugs on the market (celecoxib and etoricoxib) have had their approved doses reduced since they were originally filed. In 2002 Merck submitted etoricoxib for registration in Australia with 60mg as the weakest strength tablet. It's now approved at 30mg/day for osteoarthritis.

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30. Alchenist on November 1, 2009 9:01 PM writes...

#7:

This seems to be an effect of "Parkinson's Law in Researh" which goes something like this:
"Big success in research creates such a huge increase in subsidies, that it renders any continuation of research impossible"
New Scientist, 13, No271, (1962)

(I apologize for the frivolous translation, since the only ref I could find was a Russian translation ...perhaps some kind soul could dig out the original?)

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31. Zippy on November 2, 2009 7:20 PM writes...

I believe that any serious analysis of drivers of FDA NME numbers would need to consider consolidation in the pharmaceutical industry.

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32. cliffintokyo on November 4, 2009 9:48 PM writes...

Apologies for my late comment post (to anyone who is still following this item that is).
As I think was already mentioned, the only clear correlation I can see in this (overgeneralized) figure is the one between increases in NIH funding and increases in number of Doctorates.
It is tempting to speculate that the fall-off in NIH funding since 2002 is a conscious response to the realization that this correlation exists.
It has become obvious that there are too many PhDs, so if the correlation holds and the number of Doctorates awarded levels off or even falls, this is probably a welcome and wise (if intended) budgetary move.
It would be interesting to see a breakdown across disciplines; it has been commented on this blog that MS chemists in big pharma are (probably deservedly) as well paid as PhDs these days, which also suggests that 'average' PhD Chemists (i.e. without academic ambitions, including myself incidentally) are in oversupply at present.
One point: I can see no rhyme or reason for including NME approvals in this figure, except to show that there is no correlation to funding, etc. A further confounding factor is that many (if not most?) NDAs are submitted (at least jointly) by foreign companies these days.

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33. Anonymous on November 8, 2009 8:26 PM writes...

Globalization is to blame! It deprives natural resources and creates more junk (electronic and steel) for the world and wealth for a few. Poor becomes poorer in both the US and China.

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34. cristine on November 12, 2009 2:31 AM writes...

generic competition is tougher and reimbursement scale are much higher these days.

Generic is much better for me, its cheaper and almost the same.

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