About this Author
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: Twitter: Dereklowe

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November 30, 2011

The XMRV Story Is Not Getting Any Saner

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Posted by Derek

Dismissals, accusations, possible data theft, and now an arrest - when a scientific hypothesis (and a scientific career) unravels, it unravels all the way. . .

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

Lipitor Expiration Day

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Posted by Derek

As one of Garrison Keillor's characters says (in WLT), "I always knew the end would come. And here it is, the end". Lipitor (atorvastatin) goes off patent today, and I can recommend this overview by Matthew Herper at Forbes. Will there ever be another drug like it? The people developing the CETP inhibitors hope so. . .

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

Finding Even More New Reactions By Looking For them

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Posted by Derek

How do you find new reactions? I blogged here in September about a very direct way of doing it, from John Hartwig's lab: set up a bunch of things and see what happens. I liked it very much, but opinions in the comments were mixed. Some people found this approach refreshing, while others found it more simplistic than simple.

Well, get ready for some more, courtesy of the MacMillan group at Princeton. This paper has just come out in Science on reaction discovery, and it takes a very similar approach to "accelerated serendipity". They were looking at photoredox catalysts, which have been used for some interesting studies in the past few years. You mostly see iridium and ruthenium catalysts, with variations of tris-bipyridyl ligands on them, but the variety of reactions that they can initiate is extraordinary.

Clearly, there must be a lot of reactions in this area that haven't even been found, and that's what this latest paper sets out to do:

Assuming that serendipity is governed by probability (and thereafter manageable by statistics), performing a large number of random chemical reactions must increase the chances of realizing a serendipitous outcome. However, the volume of reactions required to achieve serendipity in a repetitive fashion is likely unsuitable for traditional laboratory protocols that use singular experiments. Indeed, several combinatorial strategies have previously been used to identify singular chemical reactions (2–11); however, the use of substrate-tagging methods or large collections of substrate mixtures does not emulate the representative constituents of a traditional chemical reaction. On this basis, we posited that an automated, high-throughput method of reaction setup and execution, along with a rapid gas chromatography–mass spectrometry (GC-MS) assay using National Institute of Standards and Technology (NIST) mass spectral library software, might allow about 1000 random transformations to be performed and analyzed on a daily basis (by one experimentalist). Although we recognized that it is presently impossible to calculate the minimum number of experiments that must be performed to achieve “chance discoveries” on a regular basis, we presumed that 1000 daily experiments would be a substantial starting point.

That it would, and by combining a broad selection of interesting starting materials with several plausible photoredox catalysts, and then basically just letting things rip, they found one. Dicyanobenzene, as it turns out, does a radical coupling with tertiary amines, giving you a direct C-C bond formation route that arylates next to the nitrogen. It's a perfectly believable reaction, but there are a lot of perfectly believable reactions that you could draw in this area that don't actually work.

Looking over the paper, it appears that the more time-consuming parts of the experimental setup were avoiding known chemistry in the starting combinations, and looking over the results to see what was worth following up on in more detail. Those are both human-brainpower intensive tasks; the rest was automated as far as possible. Interestingly, it appears that MacMillan had earlier been trying a very similar approach to that Hartwig paper I blogged about in September, doing reaction discovery with transition metals. But they then switched to photochemistry, thinking that this might be a more wide-open field.

It's not like the reaction dropped out of the robotics fully formed. They saw a new product form with an iridium catalyst, dicyanobenzene, and N,N-dimethylaniline, but further optimization gave better (and more general) conditions. That's as it should be; there's no way (yet) to run enough experiments to both find new reactions and the best ways to run them in one shot. But just getting a whiff of something new and useful is enough, and I don't see any reason not to engage in automated searches for such things.

But from the reaction in the comments here to that Hartwig paper, I gather that not everyone agrees. As far as I can tell, one objection is that famous talented organic chemistry professors shouldn't have to engage in such brute-force exercises. The more elegant way to come up with these things, by this opinion, is to use more brainpower up front, rather than just mixing up a bunch of stuff to see what works. I suppose - not being a famous talented organic chemistry professor, myself - that I'm not so proud. But then, John Hartwig and Dave MacMillan are FTOCPs, and they seem to have swallowed their pride enough to find something new. And good for them!

Comments (45) + TrackBacks (0) | Category: Chemical News

November 29, 2011

Podcast on Avastin

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Posted by Derek

As if hearing my voice on the page isn't enough, here's a podcast I did last week with Paul Howard of the Manhattan Institute on the FDA's Avastin decision. You might think that they'd be all worked up about this (a la the Wall Street Journal's editorial page), but you might be surprised. . .

Comments (4) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

The Burzynski Cancer Treatment

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Posted by Derek

There seems to have been a recent surge in interest in the Burzynski cancer therapy in the UK. A family publicly raised a good deal of money to have their daughter flown over to Texas for the treatment, and this seems to have raised the profile of the clinic quite a bit over there.

But Dr. Burzynski and his therapy have been around for decades, and not everyone has been pleased with their results. Orac over at Respectful Insolence has (as you'd expect!) taken up this topic before, and for background I definitely suggest reading his piece. Quackwatch also has background. Put together, it seems that no one has been able to replicate Burzynski's results, despite many attempts. This does not appear to have slowed down his acceptance of patients, nor his billing of them.

Perhaps the best single reference I can give for Burzynski and his associates, though, is this blog from Wales. Rhys Morgan, a high school student, wrote earlier this year about his misgivings about all the UK publicity and fund-raising to send patients to the clinic, and for his pains he was treated to some good old-fashioned legal scare tactics. I'm glad to see that he's standing up to these, and it appears to me as if he's been giving good legal advice in doing so. From his post, it seems that the same law firm is sending out such letters to other people who've written unfavorably about the Burzynski Clinic, and has this ever been a good sign?

It would appear that Dr. Burzynski has had a good deal of time, and numerous opportunities, to provide convincing data to back up his claims. Instead, he seems to have spent his efforts at expanding the definition of the phrase "clinical trial" in response to a court order - and in sending lawyers after people who point such things out. Personally, in my review of the literature, I have seen no reason to disagree with the American Cancer Society's opinion that the value, if any, of the Burzynski therapy has not been established, and I would add that this is still the state of affairs 35 years after his initial publications.

If anyone has anything that might change my mind about that - and I'd prefer data, not legal threats - I'd be glad to review it. But you'd think that the convincing evidence would already be out there by now. 1976!

Comments (16) + TrackBacks (0) | Category: Cancer | Snake Oil

A "Things I Won't Work With" Request

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Posted by Derek

I've been putting together a revised-and-expanded "Things I Won't Work With" collection, which I hope to release first as a Kindle e-book (with other platforms following close behind). Each entry in the series has been revisited, with more useful (or not so useful) information and raised-eyebrow opinions added, and I'm throwing in some bonus chapters that haven't appeared on the blog yet.

But I'd like to expand the list, both for the e-book and for future blog entries. So, what will you not work with? I'd be glad to take suggestions for the unpredictably explosive, alarmingly toxic, overwhelmingly stinky stuff that everyone with any sense avoids on sight. There have to be a lot of them that I've never come across, and I'd be glad to give them the full TIWWW treatment!

Comments (91) + TrackBacks (0) | Category: Blog Housekeeping

November 28, 2011

Amgen's New Patent: Explanations, Anyone?

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Posted by Derek

Perhaps someone with a better knowledge of the biomolecule patent world can answer this one for me: just how did Amgen suddenly carve out a whole new patent lifetime for Enbrel? This is US patent 8,063,182, and it's hard for me to unravel what the new parts are or how and why this got issued. Merck and others who have been eyeing biosimilars in this area have no doubt already formulated their legal challenges to it. But what's that line of attack going to be?

Update: explanation in the comments. This application was filed in 1995 and had a long, long history at the patent office before finally being granted. Now, of course, the thing runs for 17 years from date of issue. The law has since been changed to keep this exact sort of thing from happening, with a term of 20 years from the application date. But Amgen applied under the old rules, and gets to live by them. I'm still wondering what the difference is between this patent and the others on Enbrel, though. . .

Comments (21) + TrackBacks (0) | Category: Patents and IP

So What Did Lipitor Do for Pfizer? Or Its Shareholders?

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Posted by Derek

That's what this columnist at the Harvard Business Review would like to know. To the question "Was it worth it?", he answers "Probably not", and lists some things that other companies might learn from Pfizer's experience. I doubt that anyone will, though - the Big Acquisition looks so compelling when it comes along, and it's such a once-in-a-lifetime opportunity, and so different from all those other examples from the past, that gee, there's just no alternative. Right?

Here, for reference, is Pfizer stock versus the S&P 500 since the merger was completed in June 2000. Not that the rest of Big Pharma looks much better - for example, Eli Lilly has been an even worse investment over that span (by a bit), and they're never merged with anyone. (Although there is that Imclone business. . .)

No, big drug companies have been horrendous, hair-curling investments over this span, and yes, I'm not fully taking dividends into account. But there are tax consequences to consider on those, too, versus buy-and-hold capital appreciation. The S&P 500 has been paying in the 2% dividend yield range over that span, while Pfizer's dividend payouts have fluctuated (and the yields, too, of course). But is any dividend yield worth taking a 60% principal hit? It's hard to imagine.

At the very least, then, Pfizer's strategy has not allowed it to stand out. Its stock is in the same nasty shape as its brethren - you have to think that nothing would have gotten much worse if they'd never Lipitored themselves, and things might well have been better. Some record!

Comments (17) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

November 24, 2011

Happy Thanksgiving

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Posted by Derek

My US readers will mostly be sitting around digesting turkey by now -that's about all I'm doing, although I hope to work up enough energy to take the telescope out into the back yard and show the relatives what's going on on Jupiter.

The menu here was pretty much our standard: an 18-pound kosher turkey (I like the brining), stuffed with my mother-in-law's proprietary mixture of bread cubes, apples, celery, onions, and pepperoni. (Not sure where she came up with that one, either, but it gets demolished by the entire table of guests every year). The big side dish is shirin pullo, also from the Iranian side of the family - that's basmati rice with slivered almonds, thin bits of orange peel, dried barberries, and saffron). Then mashed potatoes (only time I ever use the potato ricer gadget), gravy (from the turkey pan, with some added mushrooms and onions and thickened with roux), green beans with country ham (from my Arkansas side of things), brussel sprouts (caramelized in the pan a bit), sauteed mushrooms, my wife's homemade cranberry sauce, and some sweet potatoes with brown sugar. Add the two pies I made last night (pumpkin and chocolate pecan), and I'm not sure if I'm going to make it out to the yard or not. . .

Comments (10) + TrackBacks (0) | Category: Blog Housekeeping

November 23, 2011

Lab Preparation: Key Lime Pie

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Posted by Derek

Thanksgiving approaches for readers in the US, which means that I turn my attention around here to lab preparations that have already been through trials in my own kitchen. I've posted my procedure for chocolate pecan pie here in the past, and I plan to make it again this year (my kids will brook no change in this menu). And I should also note another reliable recipe from here at Pipeline HQ, chicken pot pie, which should adapt very easily to using up whatever leftover turkey you need to clear out. Personally, I can clear out quite a bit of it in the form of turkey sandwiches with mayonnaise-and-horseradish. My wife puts hoisin sauce on hers instead, in a wrap or flour torilla with fresh scallions to make a sort of turkey-for-duck Asian substitution, but you may need other options.

But I wanted to provide another well-tested prep, so for those of you looking for something a bit different, here's one for key lime pie, adapted from the Cooks Illustrated version. I've checked this procedure several times, and the only defect of the resulting pie is that it tends to have a short half-life, especially if left unwatched. It is, in theory, more of a summer dessert (being served cold), but no one's ever objected when I've made it at other times of the year.

First, the only tedious part of the whole recipe. You'll need to zest some limes - if you haven't done this before, it involves scraping the green peel off in small flakes or strips from the limes (wash 'em first), while not getting deep into the bitter white pith below. There's a lot of flavor in the volatile oils in that layer; this step really is important. Fellow blogger Megan McArdle has long recommended a Microplane Zesterfor this, and I may have to break down and buy one myself. There are other zesters, which are basically small, shallow grating tools. Judicious use of a standard grater, or even a peeler or sharp paring knife if you have a steady hand, will do the trick. You'll want to come up with four teaspoons of lime zest, and I have been unable to come up with a weight equivalent for that (I'll weigh it next time I do this recipe and amend this post!) But that's three limes worth if you're pretty efficient, but more likely four limes of zest, if that helps. Note: I'm talking about the amount from usual-sized "Persian" limes here, not the authentic Key limes, which are smaller. If you have the latter, feel free to use them, although zesting them is more of a pain and (to my palate, anyway) there's not too much difference in the finished product. Floridians disagree.

Take four eggs and separate out the yolks into a bowl (no use for the whites in this recipe, unfortunately). Mix the lime zest into the yolks - you'll notice that they'll extract some color, and they're doubtless doing the same with the flavor constituents as well. While that stands, take some of those ugly sheared limes you've created and squeeze out 1/2 cup (about 120 mL) of lime juice. If you're particular, you can run this through a strainer to remove pulp, which will give you a more homogeneous pie, but I sometimes don't bother. Stir the juice into the yolk mixture, and then mix in one 14 oz can of sweetened condensed milk. That's a standard can size here in North America, about 390 mL, but I have to confess that I'm less clear on the product's availability and packaging size in the rest of the world - clarifications welcome in the comments. Leave this mixture standing during the next part of the recipe; it'll set up a bit as the lime juice goes to work denaturing the casein protein in the milk (and probably albumin in the egg yolks). It will be an interesting yellow-green color.

Now, a crust. You'll need the oven heating to 325F (160 to 165C). The recipe calls for 11 full-sized Graham crackers to be put into a food processor (or crushed up in a bag) and thus turned into crumbs.That quantity is easy enough to round up in North America, but I'm not sure about the rest of the world. It comes to about 154g of Graham cracker, which might help. As for substitutions, I think that British wholemeal digestive biscuits (McVitie'sor equivalent) would work out fine, although they seem more open-textured than Graham crackers, so you might want to watch and not over-process them. The idea is to produce crumbs, not dust).

Combine these crumbs with 3 tablespoons (about 37g) granulated sugar. Melt 5 tablespoons (65 to 70 grams) of (unsalted) butter, and mix this into the crumb/sugar preparation. Press this into an even layer in a 9-inch round pie pan, up the edges as well. (I'm not sure about standard pan sizes in other parts of the world, but that's about 23 cm diameter and about 3 to 4 cm deep). Bake this for 15 minutes and let it cool to room temperature or a bit above. It's worth taking the time to make the crust, by the way - I think this pie is much better with a crumb crust than a standard pie crust, and the homemade one, although quite easy to make, will wipe out any store-bought version.

Pour the lime/milk/egg mixture into the crust, and bake the whole thing at the same temperature for about 17 minutes - the interior will still look a bit fluid, but it should be fine on cooling. Cool to room temperature, and then chill thoroughly before serving.

As mentioned above, these things don't last long around here - fresh limes (juice and zest) are sui generis, and if you like the flavor, you'll eat more of this than is good for you. Of course, there is the vitamin C content, which is no doubt substantial. Lemons for limes is an obvious substitution, although I haven't tried it - that's the equivalent of para-chloro for para-fluoro in a med-chem SAR (although I've seen that one fail, while lemon-for-lime is foolproof outside of the expected flavor change). I suspect that this would work with oranges as well, although you would probably want to add some extra lemon juice to take the acidity up in the first step. And for that matter, it would probably work with grapefruit, although you'd probably run into some bitterness problems that would require experimentation. Sugar won't cancel that out (consider the quinine-driven taste of bitter lemon, which you can hardly find in the US any more, and which I pounded down while in England the other month). I'd be glad to hear about any such research, naturally!

Comments (28) + TrackBacks (0) | Category: Blog Housekeeping

November 22, 2011

The Mouse Trap

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Posted by Derek

If you haven't seen it, this series by Daniel Engber at Slate, on the use of the mouse as a laboratory workhorse, is excellent. (And I'm not just saying that because he references some of my disparaging comments about xenograft models, although that did give me a chance to teach my kids what the word "acerbic" means).

He has a lot of good points, which will resonate with people who do research (and inform those who don't). For example, writing on the ubiquity of C57 black mice, he asks:

So one dark-brown lab mouse came to stand in for every other lab mouse, just as the inbred lab mouse came to stand in for every other rodent, and the rodent came to stand in for dogs and cats and rabbits and rhesus monkeys, the standard models that themselves stood in for all Animalia. But where is Black-6 taking us? How much can we learn from a single mouse?

A lot - but enough? That's always the background question with animal models. My take has long been that they're tricky, not always reliable, and still, infuriatingly, essential. The problem is that even things like xenograft models are terrible only on the absolute scale. On the relative scale - compared to all the other animal models for new oncology drugs - they're pretty good. And compared to not putting your drugs into an animal at all before going to humans, well. . .

Comments (18) + TrackBacks (0) | Category: Animal Testing | Cancer

Regeneron Finally Makes It to the Market

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Posted by Derek

I've been doing drug research since 1989 myself, which means that I'm fairly experienced. But Regeneron started in this business a year or two before I did, and they're just now getting their first major drug, Eylea (aflibercept) onto the market. To be fair, they did get approval for Araclyst (rilonacept) in 2008, but that one pays the electric bill and not much more - although that might be changing (see below).

As Andrew Pollack at the New York Times points out, the company has run through over two billion dollars over the years. I remember when they were working on nerve growth factors for ALS and other diseases, back in the early 1990s (I worked in the area briefly myself, to no good effect whatsoever). There are not a lot of nerve growth factor drugs on the market, although it seemed like a perfectly plausible mechanism for one back then.

That work shaded into another indication, ciliary neurotrophic factor for obesity. Regeneron spent a lot of time and money developing a modified form of that protein called Axokine, but in 2003 that project ran into the rocks. Some patients did lose weight on the drug (with daily injections), but too many of them developed antibodies to it, which raised the possibility of cross-reactivity with their own CNF, which would surely not have been a good thing. So much for Axokine.

But Eylea, a VEGF-based therapy for macular degeneration (entering the same space as Lucentis and Avastin), has now made it. And the company has another use for Arcalyst in preventative gout therapy coming along, and some interesting cholesterol work targeting PCSK9 in collaboration with Sanofi. So welcome, Regeneron, to the ranks of profitable biotech companies (well, pretty soon) who've developed their own products. It's taken a lot of time, a lot of patience - yours and your investors' - and a lot of cash. But you're still here, and how many other bioctech startups from the late 1980s can say that?

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Industry History | Regulatory Affairs | The Central Nervous System

November 21, 2011

Avastin Coverage, Amended

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Posted by Derek

In response to the press coverage on the FDA's Avastin decision on Friday, a reader forwarded a revised and extended version of the New York TImes article that appeared soon afterwards. Here are some excerpts, which I think get across the thinking of many medicinal chemists and drug researchers. His contributions are bolded for emphasis, although it's not all that hard to see where the original ends and his revisions start.

"The commissioner of the Food and Drug Administration on Friday revoked the approval of the drug Avastin as a treatment for breast cancer, ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials, two things that should never be compared, because that would be stupid.

The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.

. . .The F.D.A. “recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use.” Also, they shouldn’t take drugs that don’t work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.

. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.

Yet pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.’s own staff and the strong recommendations of the outside experts on its advisory committee.

. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don’t live as long and suffer more serious side effects from the control group.

. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."

Comments (23) + TrackBacks (0) | Category: Cancer | Press Coverage | Regulatory Affairs

Of Drug Research and Moneyball

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Posted by Derek

This piece on Michael Lewis and Billy Beane is nice to read, even if you haven't read Moneyball. (And if you haven't, consider doing so - it's not perfect, but it's well worth the time). Several thoughts occurred to me while revisiting all this, some of them actually relevant to drug discovery.

First off, a quick peaen to Bill James. I read his Baseball Abstract books every year back in the 1980s, and found them exhilarating. And that's not just because I was following baseball closely. I was in grad school, and was up to my earlobes in day-to-day scientific research for the first time, and here was someone who applied the same worldview to a sport. Baseball had long been full of slogans and sayings, folk wisdom and beliefs, and James was willing to dig through the numbers to see which of these things were true and which weren't. His willingness to point out those latter cases, and the level of evidence he brought to those takedowns, was wonderful to see. I still have a lot of James' thoughts in my head; his books may well have changed my life a bit. I was already inclined that way, but his example of fearlessly questioning Stuff That Everybody Knows really strengthened my resolve to try to do the same.

A lot of people feel that way, I've found - there are James fans all over the place, people were were influenced the same way, at the same time, by the same books. It took a while for that attitude to penetrate the sport that those books were written about, though, as that article linked to above details. And its success once it did was part of a broader trend:

Innovation hurts. After Beane began using numbers to find players, the A’s’ scouts lost their lifelong purpose. In the movie, one of them protests to Pitt: “You are discarding what scouts have done for 150 years.” That was exactly right. Similar fates had been befalling all sorts of lesser-educated American men for years, though the process is more noticeable now than it was in 2003 when Moneyball first appeared. The book, Lewis agrees, is partly “about the intellectualisation of a previously not intellectual job. This has happened in other spheres of American life. I think the reason I saw the story so quickly is, this is exactly what happened on Wall Street while I was there. . .”

(That would be during the time of Liar's Poker, which still a fun and interesting book to read, although it describes a time that's much longer ago than the calendar would indicate). And I think that the point is a good one. I'd add that the process has also been driven by the availability of computing power. When you had to bash the numbers by hand, with a pencil, there was only so much you could do. Spreadsheets and statistical software, graphing programs and databases - these have allowed people to extract meaning from numbers without having to haul up every shovelful by hand. And it's given power to those people who are adept at extracting that meaning (or at least, to the people willing to act on their conclusions).

The article quotes Beane as saying that Lewis understood what he was doing within minutes: "You’re arbitraging the mispricing of baseball players". And I don't think that it can be put in fewer words: that's exactly what someone with a Wall Street background would make of it, and it's exactly right. Now to our own business. Can you think of an industry whose assets are mispriced more grievously, and more routinely, than drug research?

Think about it. All those preclinical programs that never quite work out. All those targets that don't turn out to be the right target when you get to Phase II. All those compounds that blow up in Phase III because of unexpected toxicity. By working on them, by putting time and effort and money into them, we're pricing them. And too much of the time, we're getting that price wrong, terribly wrong.

That's what struck me when I read Moneyball several years ago. The problem is, drug research is not baseball, circa 1985. We're already full of statisticians, computational wizards, and sharp-eyed people who are used to challenging the evidence and weighing the facts. And even with that, this is the state we're in. The history of drug research is one attempt after another to find some edge, some understanding, that can be used to correct that constant mispricing of our assets. What to do? If the salt has lost its savour, wherewith shall it be salted?

Comments (17) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Who Discovers and Why

November 18, 2011

Avastin's Metastatic Breast Cancer Approval Revoked

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Posted by Derek

Here's the FDA's decision (70 page PDF). As I've said here many times, I think that this is the right decision. A key section:

. . .As noted, FDA may withdraw an accelerated approval when confirmatory trials fail to confirm clinical benefit, or when the evidence does not show that the drug is safe and effective. However, the agency also carefully considers the effect on current and future patients of such a decision, and there may be circumstances, in particular cases, that would lead the agency to conclude that it would be appropriate to exercise discretion and leave an approval in place pending further study. This is not such a case.

Accelerated approval was based on the results of E2100, which showed an effect on (progression-free survival) that would be large enough to constitute clinical benefit, despite the known risks of Avastin, which are serious. However, we now have five trials, and they have substantially changed our view of this drug. The current evidence no longer supports a determination that it has a strong effect in metastatic breast cancer, and it appears likely that its effects are very weak, while the risks associated with this drug remain serious and potentially life-threatening.

There's going to be a lot of commentary, not all of it very informed, to the effect that this decision is a price-driven attempt to bring down health care costs, an assault on medical progress, the opening salvo of Obamacare, and so on. Wrong.

Avastin doesn't work as well as we thought it did for this indication. If you're going to believe in medical progress at all, you have to believe in what multiple well-controlled clinical trials are telling you - trials carried out, keep in mind, by the drug company that has every interest in having them come out favorably. But they didn't. On medical grounds, on scientific grounds, this was the right decision.

Comments (12) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

Pushing Onwards with CETP: The Big Money and the Big Risks

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Posted by Derek

Remember torcetrapib? Pfizer always will. The late Phase III failure of that CETP inhibitor wiped out their chances for an even bigger HDL-raising follow-up to LDL-lowering Lipitor, the world's biggest drug, and changed the future of the company in ways that are still being played out.

But CETP inhibition still makes sense, biochemically. And the market for increasing HDL levels is just as huge as it ever was, since there's still no good way to do it. Merck is pressing ahead with anacetrapib, Roche with dalcetrapib, and Lilly is out with recent data on evacetrapib. All three companies have tried to learn as much as they could from Pfizer's disaster, and are keeping a close eye on the best guesses for why it happened (a small rise in blood pressure and changes in aldosterone levels). So far, so good - but that only takes you so far. Those toxicological changes are reasonable, but they're only hypotheses for why torcetrapib showed a higher death rate in the drug treatment group than it did in the controls. And even that only takes you up to the big questions.

Which are: will raising HDL really make a difference in cardiovascular morbidity and mortality? And if so, is inhibiting CETP the right way to do it? Human lipidology is not nearly as well worked out as some people might think it is, and these are both still very open questions. But such drugs, and such trials, are the only way that we're going to find out the answers. All three companies are risking hundreds of millions of dollars (in an area that's already had one catastrophe) in an effort to find out, and (to be sure) in the hope of making billions of dollars if they're correct.

Will anyone make it through? Will they fail for tox like Pfizer did, telling us that we don't understand CETP inhibitors? Or will they make it past that problem, but not help patients as much as expected, telling us that we don't understand CETP itself, or HDL? Or will all three work as hoped, and arrive in time to split up the market ferociously, making none of them as profitable as the companies might have wanted? If you want to see what big-time drug development is like, I can't think of a better field to illustrate it.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Toxicology

Two From Glaxo's Old Days

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Posted by Derek

Two of the scientists behind Glaxo's rise have passed away recently, within a couple of weeks of each other. There's John Bradshaw, who joined Allen and Hanburys in 1971. He was the chemist who discovered Zantac (ranitidine) in 1976. Later, he moved into computational chemistry and made a key insight that led to the discovery of Salmeterol, one of the two drugs that make up Advair. Not many people have ever put their fingerprints on two bigger compounds in one medicinal chemistry career.

And closely intertwined with these projects, and with at least five others that made it to market, was pharmacologist Sir David Jack, who'd joined Allen and Hanburys ten years earlier. Remarkably, he kept up his research in the field after retirement, and a compound he championed (RPL554) is even now in clinical trials from Verona Pharma.

Discoveries, never forget, don't make themselves. They're made by people, and it's well worth paying attention to people who've made several. Odds are that they are (or were) doing something right. . .

Comments (7) + TrackBacks (0) | Category: Drug Industry History

November 17, 2011

Business Note: Random Promotion, Anyone?

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Posted by Derek

Since it's end-of-the-year performance review time at many workplaces, I thought it might be an appropriate time to link to this article. It points to some recent research that suggests that traditional promotion strategies in large organizations are, in fact, counterproductive. The null hypothesis - random promotion - would actually be more effective. (Although it's not easy to see how you'd implement that!)

There seem to be several reasons for this. Difficulty in judging the criteria for promotion and picking the wrong criteria in the first place are certainly factors. And you certainly can't ignore Peter-Principle effects, where someone gets promoted to a position where they're less effective than they were before. Here's one of the papers talking about its results:

Notwithstanding the previous discussion on performance, the current study raises the uncomfortable suggestion that all the time and effort put into promotion and selection by HR practitioners doesn’t really matter that much. After all, even though performance went up and down in response to contingency factors, the average difference between promotion systems at a given level could be measured in single digits on a hundred point scale (even random promotion wasn’t that much different from the rest). Could it be that the particular method used for job assignment really has little effect on an organization’s bottom line? This is directly relevant to HR practitioners because they typically spend a lot of time on the job assignment task and such time might be allocated elsewhere if the effort in unproductive or inefficient.

But then, the people evaluating such systems and such ideas are generally HR practitioners themselves. . .

Comments (21) + TrackBacks (0) | Category: Business and Markets

Brain Cells: Different From Each Other, But Similar to Something Else?

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Posted by Derek

Just how different is one brain cell from another? I mean, every cell in our body has the same genome, so the differences in type (various neurons, glial cells) must be due to expression during development. And the differences between individual members of a class must be all due to local environment and growth - right?

Maybe not. I wasn't aware of this myself, but there's a growing body of evidence that suggests that neurons might actually differ more at the genomic level than you'd imagine. A lot of this work has come from the McConnell lab at the Salk Institute, where they've been showing that mouse precursor cells can develop into neurons with various chromosomal changes along the way. And instead of a defect (or an experimental artifact), he's hypothesized that this is a normal feature that helps to form the huge neuronal diversity seen in brain tissue.

His latest work used induced pluripotent cells transformed into neurons. Taking these cells from two different people, he found that the resulting neurons had highly variable sequences, with all sorts of insertions, deletions, and transpositions. (The precursor cells had some, too, but different ones, suggesting that the neural cell changes happened along the way). And this recent paper suggests that neurons have an unusual number of transposons in their DNA, which fits right in with McConnell's results.

The implication is that human brains are mosaics of mosaics, at the cell and sequence levels. And that immediately makes you wonder if these processes are involved in disease states (hard to imagine how they wouldn't be). The problem is, it's not too easy to get ahold of well-matched and well-controlled human brain tissue samples to check these ideas. But that's the obvious next step - take several similar-looking neurons and sequence them all the way. Obvious, but very difficult: single-cell sequencing is not so easy, to start with, and how exactly do you grab those single neurons out of the tangle of nerve tissue to sequence them? Someone's going to do this, but it's going to be a chore. (Note: McConnell's group was able to do the pluripotent-cell-derived stuff a bit more easily, since those come out clonal and give you more to work with).

Now, the idea that neurons are taking advantage of chromosomal instability to this degree is a little unnerving. That's because when you think of chromosomal instability, you think of cancer cells (See also the link in that last paragraph. It's interesting, as an aside, to see that those last two are to posts from this blog in 2002 - next year will mark ten years of this stuff! And I also enjoy seeing my remark from back then about "With headlines like this, I can't think why I'm not pulling in thousands of hits a day", since these days I'm running close to 20K/day as it is).

So, on some level, are our brains akin to tumor tissue? You really wonder why brain cancer isn't more common than it is, if these theories are correct. There may well be ways to get "controlled chromosomal instability", though, as opposed to the wild-and-woolly kind, but even the controlled kind is a bit scary. And all this makes me think of a passage from an old science fiction story by James Blish, "This Earth of Hours". The Earthmen have encountered a bizarre civilization that seems to involve many of the star systems toward the interior of the galaxy, and a captured human has informed them that these aliens apparently have no brains per se:

"No brains," the man from the Assam Dragon insisted. "Just lots of ganglia. I gather that's the way all of the races of the Central Empire are organized, regardless of other physical differences. That's what they mean when they say we're all sick - hadn't you realized that?"

"No," 12-Upjohn said in slowly dawning horror. "You had better spell it out."

"Why, they say that's why we get cancer. They say that the brain is the ultimate source of all tumors, and is itself a tumor. They call it 'hostile symbiosis.' "


"In the long run. Races that develop them kill themselves off. Something to do with solar radiation; animals on planets of Population II stars develop them, Population I planets don't."

The things you pick up reading 1950s science fiction. Blish, by the way, was an odd sort. He had a biology degree, and a liking for James Joyce, Oswald Spengler, and Richard Strauss. All of these things worked their ways into his stories, which were often much better and more complex than they strictly needed to be. Here's a PDF of "This Earth of Hours", if you're interested - it's not a perfect transcription, though; you'll have to take my word for it that the original has no grammatical errors. It's a good illustration of Blish's style - what appears at first to be a pulpy space-war story turns out to have a lot of odd background dropped into it, along with speculations like the above. And for someone who didn't always write a lot of descriptive prose, preferring to let philosophical points drive his plots, I find Blish's stories strangely vivid, particularly the relatively actionless ones like "Beep" or "Common Time". He's pretty thoroughly out of print these days, but you can find the paperbacks used, and in many cases as e-books. Now if you're looking for someone who always lets philosophical points drive his stores, then you'll be wanting some Borges. (As it happens, I've had occasion to discuss that particular translation with an Argentine co-worker. But this is not a literary blog, not for the most part, so I'll stop there!)

Comments (28) + TrackBacks (0) | Category: Biological News | Book Recommendations | Cancer | The Central Nervous System

November 16, 2011

Ray Firestone's Take On Pharma's Plight

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Posted by Derek

And while I'm linking out to other opinion pieces, Ray Firestone has a cri du couer in Nature Reviews Drug Discovery, looking back over his decades in the business. Regular readers of this blog (or of Ray Firestone!) will recognize all the factors he talks about, for sure. He talks about creativity (and its reception at some large companies), the size of an organization and its relation to productivity, and what's been driving a lot of decisions over the last ten or twenty years. To give you a sample:

if size is detrimental to an innovative research culture, mergers between large companies should make things worse — and they do. They have a strong negative personal impact on researchers and, consequently, the innovative research environment. For example, the merger of Bristol-Myers with Squibb in 1989, which I witnessed, was a scene of power grabs and disintegrating morale. Researchers who could get a good offer left the company, and the positions of those who remained were often decided by favouritism rather than talent. Productivity fell so low that an outside firm was hired to find out why. Of course, everyone knew what was wrong but few — if any — had the nerve to say it.

Comments (26) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Who Discovers and Why

Virtual Pharma, Revisited

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Posted by Derek

John LaMattina takes on the perennial question of "Should a big drug company ditch R&D and just inlicense everything?". That one comes up regularly, and I've never been able to quite see how it works. (You'd also figure that since it's not exactly a new idea, that various people at said companies have run the numbers and can't see how it works, either). But as a former Pfizer honcho, LaMattina's opinion on this topic carries more weight than most.

Comments (11) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

Proteins in a Living Cell

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Posted by Derek

It's messy inside a cell. The closer we look, the more seems to be going on. And now there's a closer look than ever at the state of proteins inside a common human cell line, and it does nothing but increase your appreciation for the whole process.

The authors have run one of these experiments that (in the days before automated mass spec techniques and huge computational power) would have been written off as a proposal from an unbalanced mind. They took cultured human U2OS cells, lysed them to release their contents, and digested those with trypsin. This gave, naturally, an extremely complex mass of smaller peptides, but these, the lot of them, were fractionated out and run through the mass spec machines, with use of ion-trapping techniques and mass-label spiking to get quantification. The whole process is reminiscent of solving a huge jigsaw puzzle by first running it through a food processor. The techniques for dealing with such massive piles of mass spec/protein sequence data, though, have improved to the point where this sort of experiment can now be carried out, although that's not to say that it isn't still a ferocious amount of work.

What did they find? These cells are expressing on the order of at least ten thousand different proteins (well above the numbers found in previous attempts at such quantification). Even with that, the authors have surely undercounted membrane-bound proteins, which weren't as available to their experimental technique, but they believe that they've gotten a pretty good read of the soluble parts. And these proteins turn out to expressed over a huge dynamic range, from a few dozen copies (or less) per cell up to tens of millions of copies.

As you'd figure, those copy numbers represent very different sorts of proteins. It appears, broadly, that signaling and regulatory functions are carried out by a host of low-expression proteins, while the basic machinery of the cell is made of hugely well-populated classes. Transcription, translation, metabolism, and transport are where most of the effort seems to be going - in fact, the most abundant proteins are there to deal with the synthesis and processing of proteins. There's a lot of overhead, in other words - it's like a rocket, in which a good part of the fuel has to be there in order to lift the fuel.

So that means that most of our favored drug targets are actually of quite low abundance - kinases, proteases, hydrolases of all sorts, receptors (most likely), and so on. We like to aim for regulatory choke points and bottlenecks, and these are just not common proteins - they don't need to be. In general (and this also makes sense) the proteins that have a large number of homologs and family members tend to show low copy numbers per variant. Ribosomal machinery, on the other hand - boy, is there a lot of ribosomal stuff. But unless it's bacterial ribosomes, that's not exactly a productive drug target, is it?

It's hard to picture what it's like inside a cell, and these numbers just make it look even stranger. What's strangest of all, perhaps, is that we can get small-molecule drugs to work under these conditions. . .

Comments (22) + TrackBacks (0) | Category: Analytical Chemistry | Biological News

November 15, 2011

Managing For Motivation, The Simple Way

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Posted by Derek

I thought I'd pass on a little motivational managerial story, adapted from the version told in Kingsley Amis' Memoirs. Many of you may have experienced this advanced management technique yourselves, although perhaps in not such a refined form.

There was, the story goes, a pork-pie company over in England that was producing huge numbers of the things. Huge, that is, compared to their number of employees. In fact, on closer inspection, they were cranking out more pork pies than even seemed possible. This began to attract attention, and soon a team of managerial consultants had flown over from the US, eager to learn the secret.

"Do you have Pareto chart analysis?", they asked the owner of the firm. "No, no, nothing like that, he said. "Six-sigma black belt tiger teams?" asked another. "Speak English," said the owner, squinting at the consultant. "Multifactor quality control analysis, then?" came the next question, but that just got another impatient "No, no, never heard of it".

"Look now", said the factory owner, waving them all off, "I'll tell how things work here. Every so often, I just go over to that window there, the one that looks out over the floor, and I stick my head through, and I have a look around, and then I scream FASTER, YOU BASTAAAAARDS! And that's all there is to it."

Comments (19) + TrackBacks (0) | Category: Business and Markets

Exit Icahn, Enter Denner?

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Posted by Derek

Well, Carl Icahn may well be through messing with the biotech industry, as speculated earlier this year. His chief biotech strategist has now left his employ - but looks to be starting his own hedge fund. So look out for Alex Denner, folks, because he might just be ready to continue the tradition.

Comments (2) + TrackBacks (0) | Category: Business and Markets

Geron, Stem-Cell Pioneers, Drop Stem Cells

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Posted by Derek

Are stem cells overhyped? That topic has come up around here several times. But there have been headlines and more headlines, and breathless reports of advances, some of which might be working out, and many of which are never heard from again. (This review, just out today, attempts to separate reality from hype).

Today brings a bit of disturbing news. Geron, a company long associated with stem cell research, the company that started the first US trial of embryonic stem cell therapy, has announced that they're exiting the field. Now, a lot of of this is sheer finances. They have a couple of oncology drugs in the clinic, and they need all the cash they have to try to get them through. But still, you wonder - if their stem cell trial had been going really well, wouldn't the company have gotten a lot more favorable publicity and opportunities for financing by announcing that? As things stand, we don't know anything about the results at all; Geron is looking for someone to take over the whole program.

As it happens, there's another stem-cell report today, from a study in the Lancet of work that was just presented at the AHA. This one involves injecting heart attack patients with cultured doses of their own cardiac stem cells, and it does seem to have helped. It's a good result, done in a well-controlled study, and could lead to something very useful. But we still have to see if the gains continue, what the side effects might be, whether there's any advantage to doing this over other cell-based therapies, and so on. That'll take a while, although this looks to be on the right track. But the headlines, as usual, are way out in front of what's really happening.

No, I continue to think that stem cells are a very worthy subject of research. But years, quite a few years, are going to be needed before treatments using them can become a reality. Oh, and billions of dollars, too - let's not forget that. . .

Comments (12) + TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage

November 14, 2011

Translation Needed from Execulinga

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Posted by Derek

And Google Translate is no help at all for this sort of thing. A reader who attended the recent TEDMED conference sent along a quote transcribed from one of the speakers, a high-ranking Pfizer executive:

"We’ve moved from a [two-dimensional] to a [three-dimensional] approach. [Now,] we need to work all dimensions of the problems that face us, including the fourth dimension … time. Let’s call it “metacollaboration” — an approach that links knowledge and assets in a productive way to problem solve in every dimension."

Let's call it something else, shall we?

Comments (68) + TrackBacks (0) | Category: Snake Oil

Anticoagulants, One After Another

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Posted by Derek

Back earlier this year, when some bad results had come out about Merck's thrombin receptor antagonist, I wrote ". . .another result like this one, and vorapaxar could be completely sunk". Well, perhaps it is. Merck has unveiled the results of a large Phase III trial in 13,000 at-risk patients, and the drug failed completely to beat a placebo control. Moreover, there were higher bleeding risks in the treatment group, and theh follow-up phase of the trial was terminated early for safety reasons. There are a lot of potential markets for an anticoagulant, and a lot of trials that can potentially be run, but this compound is in a great deal of trouble at the very least.

Meanwhile, at the same AHA meeting, Pfizer and BMS had the unpleasant job of announcing that their anticoagulant hope, apixaban, did not beat heparin (in the form of enoxaparin, Lovenox) for protection against cardiovascular events. About 5,000 patient participated in that study.

You can see from this sort of news how much fun it is to work in the anticoagulant field. Great big expensive trials await you, and the standard of care is surprisingly hard to beat. That's not to say that the standard is so wonderful - physicians would be glad to ditch things like warfarin and heparin. But they're still out there, and with Plavix going generic, the cost/benefit bar isn't going down any, either.

One big drug that actually did provide some good news was the Bayer Factor Xa inhibitor rivaroxaban (Xarelto). That one did manage to beat placebo in post-heart-attack patients (a mere 15,500 of them), albeit with, again, an increased risk of bleeding. Overall, though, it was a grim weekend for a lot of big clinical programs.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease

November 11, 2011

Things I Won't Work With: Hexanitrohexaazaisowurtzitane

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Posted by Derek

Let's start with the name. Quite a mouthful, isn't it? Believe me, that one's pretty chewy even for experienced organic chemists. We see lots of more complicated nomenclature, of course, but this one some features some speed bumps, that make you go back to make sure that you're reading it correctly. I'll take you through my own thoughts as an example.

You skip to the end in chemical names - Mark Twain would have felt about them the same way he felt about the German language. But this brings me up short, because very few chemists could walk up to the board and draw an isowurtzitane. And I am not among their number. I have a vague picture of these "wurtz" compounds being funky three-dimensional cage structures, and that much only from having probably read too many photochemistry papers over the years. So the only thing that "isowurtzitane" calls to mind is some complicated framework of fused rings, looking like one of those wire sculptures that unexpectedly fold up flat when you pull on them.

Moving on out, as you do in a systematic name, I see that this is a hexaaza variation, which makes the picture a bit fuzzier. That's a lot of nitrogens substituted for carbons, and the first thought is that this must be some weirdo condensation product of ammonia, some aldehyde, and who knows what. You can get some pretty funny-looking structures that way, like hexamethylenetetramine (which I've actually used a couple of times). I don't know where those nitrogens are, I think to myself, but I'll bet that's how they got there, because any other pattern would be a synthetic nightmare. So far, so good. But now comes the unexpected habanero.

Hexanitro? Say what? I'd call for all the chemists who've ever worked with a hexanitro compound to raise their hands, but that might be assuming too much about the limb-to-chemist ratio. Nitro groups, as even people who've never taken a chemistry class know, can lead to firey booms, and putting six of them on one molecule can only lead to such. And since there are six nitrogens and six nitro groups, the first assumption must be that these are all bonded to each other. I mean, come on, leaving the nitro groups attached to the carbons is for wimps. So that means that someone, somewhere, has perversely made a poly-N-nitro cage compound, as if they'd been dared to cram the most bond energy into the smallest space.
That, as it happens, is exactly the case. Hexanitrohexaazaisowurtzitane, or CL-20, was developed as a highly energetic, compact, and efficient explosive. What makes it unusual is not that it blows up - go find me a small hexa-N-nitro compound that doesn't - but that it doesn't actually blow up immediately, early, and often. No, making things that go off when someone down the hall curses at the coffee machine, that's no problem. Making something like this that can actually be handled and stored is a real accomplishment.

Not that it's what you'd call a perfect compound in that regard - despite a lot of effort, it's still not quite ready to be hauled around in trucks. There's a recent report of a method to make a more stable form of it, by mixing it with TNT. Yes, this is an example of something that becomes less explosive as a one-to-one cocrystal with TNT. Although, as the authors point out, if you heat those crystals up the two components separate out, and you're left with crystals of pure CL-20 soaking in liquid TNT, a situation that will heighten your awareness of the fleeting nature of life.

Stabilized or not, I still won't get near it. For one thing, I'm a drug discovery chemist, and if you think a structure like this is going to be a drug, then you must be on some strong ones yourself. No, the thing about these compounds is that they can be handled as long as they're very pure and formulated just right. The side products from their synthesis, well, those might not be so nice. And if a batch gets contaminated, or doesn't come out so clean, well, that might not be so nice, either. Synthesizing polynitro compounds is no chocolate fondue party, either: if you picture a bunch of guys wheeling around drums of fuming nitric acid while singing the Anvil Chorus from Il Trovatore, you're not that far off the mark. You really have to beat the crap out of a molecule to get that many nitro groups on it, which means prolonged heating of things that you'd really rather not heat up at all.

No, I'll leave the can-you-top-this nitration chemistry to those that love it. You guys just go ahead and stuff as many energetic bonds as you can into the smallest tangles; I'll be over here in the bunker cheering you on, and jumping a foot in the air every time someone sneezes. I'm not cut out for hexanitro anything.

Addendum: it's an odd thing, but when you search for information on this compound, a significant number of the Google hits are for its environmental effects. This is an explosive, meant for munitions and destruction, but there are all kinds of studies on its effects on earthworms, fish, soil microorganisms, and so on. Steven Pinker must be right when he says that violence is getting tamer all the time.

Comments (67) + TrackBacks (0) | Category: Things I Won't Work With

November 10, 2011

Makena's Market. Or Lack of One.

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Posted by Derek

I put up a note here yesterday about KV Pharmaceuticals and their complaint to the FDA about compounding pharmacies selling a version of their Makena progesterone ester drug. The conclusion was that the combination of Makena's high price and the FDA's we-won't-enforce attitude towards the compounders was hurting sales.

And that it is. The people at BioCentury have more. Basically, the estimate is that about 140,000 women per year fall into the potential treatment class of high-risk pregnancies. How much Makena has been sold since its launch last March? The company says that about 2,400 patients have started treatment or are enrolled to start. Now, we don't have figures on how many patients have filled prescriptions from compounding pharmacies, and I don't know how many people took this therapy before KV got involved.

But still. . .that's what, a 2 or 3% market penetration? I'll bet KV's sales projections weren't at that level.

Comments (4) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs

Resveratrol in Humans: Results of a Controlled Trial

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Posted by Derek

The effects of resveratrol have been controversial, to say the least. Arguments rage about whether (and how) it affects the various sirtuin pathways, what those various sirtuin pathways are and what they do, and what the compound does in animal models at all (whether you care about the mechanism or not). That last topic recently boiled over once more. I've spoken about the compound and these issues many, many times around here, as long-time readers will know - go here and just keep scrolling back if you're interested. GSK halted its development of resveratrol itself (as opposed to follow-up ligands) last year, it appears.

Get ready for more head-scratching. There's a new paper out from researchers in the Netherlands and Switizerland looking at the effects of resveratrol in obese human subjects. They ran a small (11-subject) double-blind crossover trial vs. placebo of 150mg of resveratrol per day, and found. . .well, let me quote the summary, because I can't put it in fewer words myself. If you're not a technical kind of person, that last line (emphasis added) tells the story:

Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Well, that is interesting. What this (and some of the earlier data) seems to be telling us is that resveratrol may well be beneficial - but particularly so under conditions of metabolic stress, such as in obesity. As for the mechanism, when they looked at muscle tissue samples, they found over 400 genes with altered expression (some up, some down). These seem to have particularly concentrated in metabolic and inflammation pathways, particularly mitochondrial oxidative phosphorylation. These are quite similar results to those seen in obese rodents.

On the other hand, some things were very different indeed in the two species. Mice actually showed an increase in energy expenditure during reservatrol treatment - these humans showed a decrease. The plasma concentration reached in both experiments were similar, but mice needed a 200-fold higher dose of resveratrol to reach that, which has to be one confounding factor. (Another is the duration of treatment; the mice got the compound for several months, which is longer by the calendar but also a much higher percentage of their entire lives).

Still, the effects in the human subjects were quite impressive. Not all the changes were huge, but they all seem to point in the same direction: mimicking the effects of caloric restriction and exercise. This is exactly the sort of thorough, well-controlled study this field has been needing, and it makes all the questions in it take on that much more urgency. What does resveratrol do in humans, on a molecular level? Are sirtuins involved, and to what extent? Can other compounds do the same thing, or even more? What are the long-term effects of such compounds on human morbidity and mortality? Do these effects only manifest themselves in obese subjects? How much would happen in people who are under less metabolic stress to start with? And so on. . .

Comments (43) + TrackBacks (0) | Category: Aging and Lifespan

November 9, 2011

KV Pharmaceutical's Latest Makena Move

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Posted by Derek

Remember the Makena story from earlier this year? That's the progesterone ester whose price was raised (and how) after FDA approval by its manufacturer, KV Pharmaceuticals. (Here's the whole history). When last heard from, the FDA had sent out a letter to compounding pharmacies who were providing the drug at lower cost, saying that they were not intending to take action against them (an unusual move, to be sure).

Now KV has made their next move. According to this FDA statement, the company has provided the agency with data on a number of samples of the drug, claiming variable purity and potency in the compounded products. The FDA is looking over KV's data, and is conducting their own investigation into this as well. For now, they're reminding people that "greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product". But they're not taking any more action, for now. We'll probably be hearing more about this. . .

Comments (14) + TrackBacks (0) | Category: Regulatory Affairs

November 8, 2011

In-Sourcing Chemistry: Lilly and AMRI

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Posted by Derek

Here's an interesting release from Albany Molecular: they're announcing that they're hiring "more than 40" chemists to work at Eli Lilly's facilities in Indianapolis. They plan to hire them from the surrounding area - that is, I assume, that they plan to hire from the pool of people that Lilly has already let go.

This is interesting on several levels. I assume that AMRI's salaries and benefits are such that it's cheaper for Lilly to hire people this way than it is to hire them as Lilly employees. This is a technique (one could use the word "ploy", depending on one's vantage point) to get the work done without having to actually shell out for it. But then again, that's what outsourcing is, exactly, and this is outsourcing without going to China or India. Instead, the invoices are routed through exotic Albany, NY, while you get to have the chemists right there in front of you, with the corresponding improvements in communication and turnaround.

Thoughts? Is this the beginning of the on-shoring of chemical jobs - albeit at a lower level of compensation? Or is this just a desperate move by a company that's facing a hideous, hair-pulling patent cliff? Or both?

Comments (92) + TrackBacks (0) | Category: Business and Markets

Targacept's Antidepressant Fails, And How

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Posted by Derek

Bad news yesterday from Targacept, a small company that's been developing an antidepressant with AstraZeneca. TC-5214 (the S enantiomer of the nicotinic ligand mecamylamine) missed its endpoints in a trial of 295 patients in Europe who had not responded to standard drug therapy - the trial started with more like 700 patients, who received open-label therapy with one of the usual agents, and then they picked out the tough cases for the real trial, adding this compound to the standard regimens.

Seeing results in such a population is a very tall order, but that's why AZ and others were excited about the earlier Targacept data. The Phase II numbers were extraordinary. A compound that followed through on that promise would be huge. This piece by Adam Feuerstein gets across the excitement - people really couldn't believe what they were seeing.

And maybe they shouldn't have. The grumbling today, though, is taking an interesting turn. What you might not realize from reading about those Phase II results is that they were the result of a clinical trial in India. That's added an extra layer of can-we-trust-this-stuff to the usual despairing comments about Phase II/Phase III disconnects. This is an unusually brutal disconnect, because the earlier data were unusually good. So the muttering is not going to go away any time soon.

AstraZeneca says that they're committed to further studies of TC-5214, so we'll see what happens then. Depression is a tricky illness, and getting solid clinical data isn't easy. It's possible that this latest study just had some confounding variable that messed up the numbers - but then, it's possible that the earlier one did, too, and that, sad to say, is probably the way to bet. This is bad news for AZ, a company that needs all the help it can get, and downright catastrophic news for Targacept, as I'm sure their stock price will reflect. And it might even be bad news for India, and Indian clinical research.

Update: to drive the point home, Adam Feuerstein has posted this under the heading of "My punishment for getting TRGT wrong".

Comments (26) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

November 7, 2011

Where's the Best Place to Apply Modeling to Drug Discovery?

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Posted by Derek

An e-mail correspondent and I were discussing this question, and I thought it would be an interesting one for everyone. He's a computational guy, and he's been wondering where the best use of computation/modeling effort in drug research might be. The obvious place to apply it is in lead generation and SAR development - but is that the best place? Is it the rate-limiting step enough of the time?

Problem is, the things that are often limiting steps are not as amenable to modeling. These are things like toxicology, target selection, and the like, and I'm not sure what they're susceptible to, except that simulation is probably not the answer. Or not yet, anyway. So what's the sweet spot, the place that maximizes importance and feasibility?

Update: an early vote for clinical trial design, which is a strong contender. Can't say that that doesn't get right to the hard part. . .

Comments (38) + TrackBacks (0) | Category: In Silico

Rating A Massive Pile of Compounds

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Posted by Derek

Here's an interesting exercise carried out in the medicinal chemistry departments at J&J. The computational folks took all the molecules in the company's files, and then all the commercially available ones (over five million compounds), minus natural products, which were saved for another effort, and minus the obviously-nondruglike stuff (multiple nitro groups, solid hydrocarbons with no functionality, acid chlorides, etc.) They then clustered things down into (merely!) about 20,000 similarity clusters, and asked the chemists to rate them with up, down, or neutral votes.

What they found was that the opinions of the med-chem staff seemed to match known drug-like properties very closely. Molecular weights in the 300 to 400 range were most favorably received, while the likelihood of a downvote increased below 250 or above 425 or so. Similar trends held for rotatable bonds, hydrogen bond donors and acceptors, clogP, and other classic physical property descriptors. Even the ones that are hard to eyeball, like polar surface area, fell into line.

It's worth asking if that's a good thing, a bad thing, or nothing surprising at all. The authors themselves waffle a bit on that point:

The results of our experiment are fully consistent with prior literature on what confers drug- or lead-like characteristics to a chemical substance. Whether the strategy will yield the desired results in the long term with respect to quality, novelty, and number of hits/leads remains to be seen. It is also unclear whether this strategy can lead to sufficient differentiation from a competitive stand-point. In the meantime, the only undeniable benefits we can point to is that we harnessed our chemists’ opinions to select lead-like molecules that are totally within reasonable property ranges, that fill diversity holes, and that have been purchased for screening, and that we did so in a way that promoted greater transparency, greater awareness, greater collaboration, and a renewed sense of involvement and engagement of our employees.

I'll certainly give them the diversity-of-the-screening-deck point. But I'm not so sure about that renewed sense of involvement stuff. Apparently 145 chemists participated in total (this effort was open to everyone), but no mention is made of what fraction of the total staff that might be. People were advised to try to vote on at least 2,000 clusters (!), but fewer than half the participants even made it that far. Ten people made it halfway through the lot, and 6 lunatics actually voted on every single one of the 22,015 clusters, which makes me think that they had way too much time on their hands and/or have interesting and unusual personality features. A colleague's reaction to that figure was "Wow, they'll have to track those people down", to which my uncharitable reply was "Yeah, with a net".

So while this paper is interesting to read, I can't say that I would have been all that happy participating in it (although I've certainly had smaller-scale experiences of this type). And I'd like to know what the authors thought when they finally assembled all the votes and realized that they'd recapitulated a set of filters that they could have run in a few seconds, since they're surely already built into their software. And we all should reflect on how thoroughly we seem to have incorporated Lipinski's rules into our own software, between our ears. On balance, it's probably a good thing, but it's not without a price.

Comments (16) + TrackBacks (0) | Category: Drug Assays | Life in the Drug Labs

November 4, 2011

Table Of Content Graphics, Mocked

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Posted by Derek

Someone has to make fun of lousy graphical abstracts in science journals. And apparently this is that person. I've no idea who this is, but they're helping, in their way, to make the world a better place.

Comments (19) + TrackBacks (0) | Category: The Scientific Literature

What's the Hardest Thing?

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Posted by Derek

Here's a quick question for the crowd: when you're talking with people outside your field, or outside of science completely, what's the hardest thing in your area to explain? I end up doing a lot of explaining myself, and I find that a lot of key drug discovery concepts can be communicated pretty quickly.

But not all of them, and perhaps not all at the same time. I can talk about PK and absorption, metabolism, etc., and I can talk about molecular properties and selectivity, and toxicology. Keeping all of those in mind at the same time, though, seems to be difficult if you're not used to doing it, thus the trouble with explaining Paracelsus' remark that "the dose makes the poison". Selenium is a good place to experience that: try getting across to someone that there's an essential nutritional element that's also poisonous. It's like trying to say that cyanide is a vitamin - but then again, if carbon monoxide is a neurotransmitter, maybe it is.

I think that the other broad issue that's hard to communicate is the amount that we don't know. That specifically comes up in discussions of toxicology - people want to know if this drug, this compound, is toxic or not. And if it is, how do we know that the next one isn't like that? Those are all questions that do a sort of reverse origami trick: they start off in a neat, comprehensible shape, but unfold to heaps of crumpled paper as soon as you really start pulling on them. How can we know so much, yet know so little? Why have we been studying some of these systems for decades and still not understand them? That probably gets back to the repeated point that living biological systems are simply more complex - much more complex - than anything that anyone has ever dealt with in everyday life. And what's more, they're complex in different ways than we're ever used to dealing with; it's not just differences in degree (although those certainly apply) but differences in kind.

But don't confine yourself to the big meta-issues. There are plenty of smaller concepts and ideas that don't lend themselves to fast explanations. A meaningful one-paragraph (or one-sentence!) explanation of NMR imaging for someone with no background, for example, is no small undertaking. (My attempt: "We're all full of water molecules, in all sorts of environments in the body. And they behave differently when you put them in a strong magnetic field, which lets us pick up different signals from them and turn them into images.") How about hydrogen bonding? Or chirality? What are your sticking points when you try to explain what you do?

Comments (66) + TrackBacks (0) | Category: General Scientific News

November 3, 2011

Verastem Goes Public: Why Not?

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Posted by Derek

Doesn't this seem just a bit. . .early. . .for an IPO? In this climate?

Chris Westphal, a founder of Sirtris and a fixture of Cambridge/Boston biotech startup culture, helped to launch a company called Verastem in the middle of 2010. They're concentrating on the role of stem cells in cancer, a very interesting field (and one that a lot of other oncology players are interested in as well). And rather to everyone's surprise, they've now announced that they're going public. No, there's no compound, nothing heading for the clinic in the foreseeable future. They're just going public, presumably because the equity markets are in such a placid, welcoming mood or something.

Their plan seems to be to develop assays based on stable populations of cancer stem cells, and then to find compounds that selectively target them and develop these into drug candidates. Each step of that process is very much an open question, and is most definitely not trivial. It's a very worthy area of research, don't get me wrong - but it does seem odd to be going public at this stage with it, when there's so little for potential investors to evaluate. And it's worth noting that Verastem raised $32 million in financing just back in July. Are they already plowing through that? The IPO looks to raise about another $50 million - is that a sum that just couldn't be brought in via private investors?

Those are other questions will get aired out extensively in the weeks to come. We'll see how smoothly this all goes - and a lot of other small companies will be watching as well. One first reaction hasn't been too favorable: over on Twitter, biotech watcher Adam Feuerstein says "Christoph Westphal is why the clubby, VC-back scratching world of private biotech is derided by public investors". They'll soon get their chance to deride in person!

Comments (21) + TrackBacks (0) | Category: Business and Markets | Cancer

Medivation Comes Through With MDV3100

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Posted by Derek

Remember Medivation? That's the small biotech that was trying to develop a Russian compound as an Alzheimer's drug, an effort which blew up completely in early 2010. The company did have one other compound in development, targeting prostate cancer, a ligand for the androgen receptor called MDV3100.

You'll note from that link that it's a rather odd-looking compound, a thiohydantoin, which is a heterocycle that you don't see very often. The discovery of the compound is detailed here, in a collaboration between Michael Jung's group at UCLA and Charles Sawyers' at Sloan-Kettering (here's an interview with him). It's been a long road. The starting point was another known ligand, RU 59063, which comes out of research in France in the early 1990s. The whole left-hand side of MDV3100 (including the thiohydantoin) comes from that scaffold, but it behaves differently on the androgen receptor. Taking advantage of the wild and often intractable complexity of nuclear receptor signaling, it binds in a different mode than other AR ligands, and in a way that the receptor loses its ability to further bind DNA in the nucleus.

Here's the J. Med. Chem. paper (in open-access form) on the development of the series. The compounds were pushed through relatively quickly in cellular assays and in an in vivo model in mice, which allowed MDV3100 and its close analogs to stand out not only for their superior activity on the androgen receptor (which many compounds in the series had), but for their pharmacokinetics. Interestingly, the lead compound for some time seems to have been a spiro-cyclobutyl analog (RD162), but the corresponding gem-dimethyl compound was just as active and a lot easier to make, so that one became the clinical candidate.

Medivation's Phase III trial of the compound came in with data yesterday, and it was startlingly good, so much so that the trial was stopped early and the placebo group switched to the drug. The company's stock is going through the top of the chart in pre-market trading as I write, which shows that the expectations weren't all that high. But MDV3100 certainly seems to have come through, and considering how much failure we live with in drug discovery, it's nice to see something actually outperform. Congratulations to the company, and to Jung and Sawyers as well - they've added another straight-out-of-academia drug to the list, and helped to considerably advance the standard of care in prostate cancer. Good news all around.

Oh, and by the way. . .you have to wonder if this guy stuck around for this result. It all depends on what price he was in at - after today's trading, Medivation's stock might even make it up past where it was back when everyone was hoping that they had an Alzheimer's drug. Expectations!

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials

November 2, 2011

Sanofi Announces Layoffs

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Posted by Derek

Sanofi seems to have told employees this morning that layoffs are on the way. These will be in both the sales and the R&D organizations, and will be part of some rearranging of the later between the Boston/Cambridge and New Jersey sites. Details aren't very clear at the moment; anyone with more info is welcome to add it to the comments. . .

Comments (50) + TrackBacks (0) | Category: Business and Markets

Tiny, Tiny Molecules for MS

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Posted by Derek

What is the deal with multiple sclerosis and small off-the-shelf molecules? Last year I wrote about Ampyra, which is 4-aminopyridine. Now Biogen is showing what looks like good results with BG-12, which is. . .dimethyl fumarate. See the Haystack blog for more. The same comments I made earlier about Ampyra's intellectual property situation apply here - it's just interesting to see that Biogen has a hand in both of these. What's next? Toluene?

Comments (38) + TrackBacks (0) | Category: The Central Nervous System

Faking Two Papers A Month. For Seven Years.

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Posted by Derek

There's a big research scandal that's been coming on for a while in the Netherlands. I haven't covered it, since it's in academic psychology, and thus pretty far out of my field, but some of the behavior in it is well worth noting. Here's a rundown from Science on Diederik Stapel, who appears to have forged scores of studies over the years. It seems that he rarely bothered to collect actual data, preferring to just condense it out of thin air to save time and effort:

Many of Stapel's students graduated without having ever run an experiment, the report says. Stapel told them that their time was better spent analyzing data and writing. The commission writes that Stapel was "lord of the data" in his collaborations. It says colleagues or students who asked to see raw data were given excuses or even threatened and insulted.

Here's more from Nature, via Scientific American. At least two earlier groups of whistleblowers had raised questions about Stapel's work, the commission found. No one followed up on their concerns, however. . .His colleagues, when they failed to replicate the results, tended to blame themselves, the report says. Among Stapel's colleagues, the description of data as too good to be true "was a heartfelt compliment to his skill and creativity," the report says.

Well, he did have skill and creativity - I mean, we're talking about someone who's published over 150 papers in the last seven years. And that means that he wasn't lazy, either, because keeping that many balls in the air is no small job. No, what we have here is an industrious, committed, fraud with a real talent for his chosen line of work: fakery. I'd like to think that it's somewhat easier to get away with this (for this long) in a social science field, but then, there's Jan-Hendrik Schön to think about. So I'm not sure that my high ground is all that high.

The same old lessons apply (". . .And the Gods of the Copybook Headings / limped up to explain it once more"): if something looks too good to be true, it probably is. If multiple people can't reproduce what's supposed to be a scientific result, then there may well be something wrong with it. And if someone that you're working for or with won't show you raw data, then head for the door, because nothing but trouble can ensue. The alarm bells have at that point gone off, whether you can hear them or not.

Comments (19) + TrackBacks (0) | Category: The Dark Side

November 1, 2011

Exelixis Fights City Hall, and City Hall Looks Like Winning

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Posted by Derek

So what happens when you and the FDA disagree on the clinical trials needed to show efficacy for your new drug? Well, this happens: your stock opens down 40%. That's what's going on with Exelixis today - here are the details. Basically, the company had a fast clinical path in mind, taking their prostate cancer candidate cabozantinib into late-stage patients and using pain reduction as an endpoint. But the FDA wasn't (and isn't) buying that as a marker.

I see their point. Survival is really what you're looking for, and there doesn't seem to be enough evidence that pain reduction is going to translate to that. As that Adam Feuerstein piece notes, all the other prostate drugs have had to show survival benefits. EXEL was planning to follow up with a second trial to show that, but hoped to jump-start things by getting approval just on the pain data. It appears that they're going to stick with their strategy and hope that the numbers are so dramatic that the agency will reverse course. But is that realistic - both for the chances of getting great data and the chances of persuading the FDA? The market doesn't think so. Neither do I.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

President Obama Orders the FDA to. . .Do What, Exactly?

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Posted by Derek

Headlines of the "Obama Orders FDA to Take Action on Drug Shortages" were all over the news yesterday. But anyone who actually knows the industry could be forgiven for wondering what was going on.

That's because the drug shortage problem is not something that can be solved by fiat. There are a number of factors that got us all into this fix: two big ones are changes in Medicare billing for generic cancer drugs, and manufacturing problems with overseas suppliers. (A low-margin business gives you even more incentive to source the bargain-basement options). None of these things can be fixed overnight.

And when you look at the executive order itself, you find that there's not much there. It directs FDA to expedite reviews of new suppliers and new manufacturing sites, but aren't they doing that already? And it also tells the agency to send out letters to all the companies, reminding them to remind the FDA about potential shortages, which is clearly the kind of decisive step this crisis has been waiting for. Oh, and it also calls for determining whether any of the shortages have led to "price gouging". Can't have the price of something going up just because there's a shortage - that's just basic economics, right?

So call me cynical, or call me someone who just hasn't been that impressed with Obama. (Note: the Republicans have not been covering themselves in glory, either, as far as I can see). But this whole announcement seems to be just a public relations game, made to provide a line for a speech. "Congress wouldn't take action, so I issued an Executive Order for the FDA to. . ." But during the campaign, that sentence won't end the way it should: ". . .for the FDA to do what it's already doing! Yes! And send out some letters, too!"

Comments (33) + TrackBacks (0) | Category: Regulatory Affairs