About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
December 28, 2006
One of the main things I'm going to have to do when I get back to my lab is clean it up. That's not something that I spend much time on, under ordinary conditions. For one thing, I don't run as many reactions as I used to, so it doesn't get dirty as fast. But I'm not someone who makes a clean lab bench my goal at the end of each working day, that's for sure. There are messier people at the Wonder Drug Factory, but there are neater, too.
In fact, I distrust lab benches that look as if you could safely make a sandwich on them. Those, as far as I can see, indicate too much cleaning and not enough real work - or, in the larger sense, too much of a concern for appearances at the expense of what matters. You don't want your lab bench to be a tourist attraction (or a standing joke), much less a safety hazard. But it doesn't (shouldn't!) be a showpiece, either, because to people who really understand the way research works, you're sending the wrong message.
I remember straightening up my lab once at a former job, and afterwards I noticed several people outside in the hall near my door. "What are you people doing loitering around?" I called out, and Stu McCombie (yep, that McCombie - he worked down the hall from me) answered "We're taking bets on how long your lab is going to look like that!"
"Well," I told him, "as soon as I start doing some real work in here it's going to go straight downhill." "That's what makes it a sporting bet," said Stu, "No one know when that's going to be!"
+ TrackBacks (0) | Category: Closing Time | Life in the Drug Labs
December 26, 2006
Well, I took a load of data home with me, along with a first draft of the paper I'm working on. But as usual, my attempts to get any actual work done over the Christmas holidays have shriveled up on contact with the actual days off. I'm not sure why this always seems so plausible while I'm finishing up the last working days of the year, and so laughable three or four days later.
My two children probably have a lot to do with it. They're ready to take me on in a whole list of games, and since they know as well as anyone that these days don't run on a normal schedule, they don't see any reason for me not to be available. (And they have a point!) I find that when I'm thinking hard about a problem, and most especially when I'm writing, that I can't do it with interruptions or extraneous noise. I was better about those when I was in college, but I've lost the ability to deal with them. Or, perhaps I'm just dealing with things that require more thought.
At any rate, my brain needs room to work in, so I'm an awful conversationalist when I have to think hard about something. There's a period in the first few seconds, especially, when I'm working on formulating an answer to something, where any interruption will send the whole thing crashing down. It's hard to describe - thinking about the problem in front of me, I can start to see how this piece might fit over here, and this section seems to be matching up with this one over here, and it feels right to make an analogy to this part, which was the thing that worked when - what? What? We're out of peanuts, and have I watered the Christmas tree today, and do I feel like being pulverized at foosball?
Ah well, my manuscript can wait a few days - it's not like I'm not going to have plenty of opportunities to work on it when I get back. Meeting will not interrupt: my work calendar has attained a state of clarity that Zen rock gardens can only strive for. For now, I need to go show my eight-year-old son that foosball wasn't invented yesterday.
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December 21, 2006
Well, since it's the Christmas season around here, posting will be intermittent. I'm going to be making cookies with my two children tomorrow, for example. (I've explained to them that you should be suspicious of an organic chemist who can't cook). Further kitchen work over the next few days will include crown roast of pork, leg of lamb for a crowd (I'm hoping it's good enough weather to do it outside on a spit), and the traditional (for me!) Christmas breakfast of country ham, scrambled eggs, biscuits, and red-eye gravy.
I'll post occasionally, though, in between all this cooking, present-wrapping, and the like, but the regular schedule won't resume until after New Year's. I hope to do some work on my "Vial 33" paper while I'm home, but that may be wishful thinking. I did mention that I have two young children, after all. . .
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December 20, 2006
Many readers are probably aware of this story, but those who aren't should be. A court in Libya has (re)sentenced six foreign medical workers to death for allegedly infecting hundreds of Libyan children with HIV. That sounds insane on the face of it, and (as you would well imagine) the evidence for any such thing is just not there.
Instead, this seems to be a problem with poor hygiene in the health care system in Benghazi, which is not something that stretches the imagination like, say, a deliberate plot to infect Libyan children does. The molecular biology evidence is that this is a local strain of the virus which was already spreading before the medics even arrived in the country. Nonetheless, the Libyan courts seem determined to make a huge case out of this, and the Libyan media (state-run, needless to say) have been whipping up the crowds.
No one can say how this will play out, because there are still many slow, painful steps to go in the Libyan legal process, which certainly seems rather baroque for a country not exactly used to the rule of law. With Libya trying to open up to the West and bring in foreign investment, a horribly circus like this would seem to be just what they don't need. But it's already been dragging on for a couple of years now, in the face of all evidence and reason.
As I've said before, one of my general rules is that questions which begin with "I wonder how come they. . ." are often answered with "money". And that's probably the case here. Speculation is that all of this will come down to paying Libya some sort of "compensation". That's a nice word for what's really just an ugly, immoral shakedown - the sort of thing that the better class of gangster might feel is beneath them. Not the government of Libya, however. The Libyan people deserve better. The medics in this case, for their part, deserve to be freed immediately.
+ TrackBacks (0) | Category: Current Events
December 19, 2006
I've had several inquiries about how the job hunt is going. Actually I'm not expecting a lot of news until well after the first of the year. Many of my lab associate colleagues are getting hired already, which is good to see. But it takes longer to decide to bring on someone in my position, whose duties are both more expensive, in theory more critical, and in practice certainly less well-defined than those of a Master's-level chemist. And, of course, there are just fewer such positions to be had in general.
Still, I'm going to be out today talking with some folks about how eminently employable I am, which is a good start. A number of companies in the area are coming over to check out the sudden release of talent from the Wonder Drug Factory - I'm picturing something like a rugby scrum, but with everyone wearing better clothing. I've also had several interesting calls from readers, both in and near the biotech/pharma industry, with opportunities that likely wouldn't have come my way if I hadn't been writing this site over the last few years. I'd hoped that would be the case, and my fellow researchers will appreciate the less-frequent-than-you'd-think experience of being right about something.
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December 18, 2006
There are two recent items about Eli Lilly that I'm going to cover this week. They're both Big Corporation Throws Weight Around headlines but, they reflect different underlying behavior. Today we'll do the more defensible one, and tackle the harder stuff in the next installment.
The first one, then, is Lilly's purchase of their Cialis partner ICOS. They came in offering $32/share, but one of the big ICOS shareholders objected, saying the company should go for $40. I see that Lilly is out today with what they say is a final offer of $34, so we'll see if the big shareholders find that insulting or not. If the whole process reminds you of someone pretending to walk out of a stall in the bazaar while bargaining over a carpet, you've got the right idea about how M&A deals work.
The thing is, Lilly has made it clear that if the deal goes through, all the employees at ICOS will be laid off. There are various efforts up in Washington state to alter this decision, but I don't think that they're going to get anywhere. Lilly wants all the rights to Cialis, and to the intellectual property ICOS might have, but they don't need several hundred more employees two time zones away from Indianapolis.
My feelings about this are mixed. For obvious reasons, the phrase "laid off" is not a favorite around here these days. But on the other hand, Lilly has every right to do what they're doing, and no doubt it makes sense from the business end to do it. When you work for a small company (and especially a small company that's done a lucrative deal with a big one), you know that being bought out is one of the things that can happen to you, with results that can't be predicted.
Still, I'm not a fan of the buy-'em-and-fire-'em style, which I associate with Pfizer more than with Lilly. There's more value in a small reseach company than its patent portfolio shows, or at least there should be. The more I've thought about it, the more I think that startups and small pharma/biotech are going to be a bigger and bigger part of the research environment here in the US in the years to come. (For the details, you'll have to read my next Contract Pharma column). And although I think that Schumpeter's creative destruction is necessary, there's always room to try to make it a bit more creative and a bit less destructive. Wiping out a possible biotech cluster by razing the largest local firm isn't an outcome that I'm happy with.
The only alternative I can come up with, though, is to have some mechanism where a portion of such buyout money is available for employees of the smaller firm to try to start another one (or more). That's tricky, though, since you'd figure that most of the IP that you could start a new company with is being purchased already. Any other ideas?
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December 14, 2006
Glenn Reynolds gave the pharma industry a much-appreciated thank-you card over at Instapundit:
Only a moron would want to live in a society where people are ashamed to work for drug companies. And yet, I'm not surprised to see that resulting from the demagogy that abounds among politicians and "public interest" types who are not serving the public interest whatsoever.
I'm thinking of having that first sentence engraved on something expensive. Glenn's post prompted Dean Esmay to write a short post on the ethics of drug companies, though, and he's rather less positive. I suppose I shouldn't be surprised, given some of the things he's gone in for in the past. As usual, some of the problem is the difficulty that people have coming to terms with the fact that drug discovery is a for-profit industry.
One comment on his post came from Jerry Kindall, which is mostly favorable to the industry, but nonetheless contains this paragraph:
Drug discovery used to be a total crap-shoot but it's getting more and more targeted as the years go by thanks to ever more sophisticated computer modeling. They are now able to say "okay, this is the chemical receptor that we think we need to address, let's design a molecule that fits into it." This is essentially a nanotechnology, although not the type most people think of when they hear the term.
Ay, would that it were true. As my industry readers know, and as I've been ranting abouit here fairly often, drug discovery is just as much of a crap-shoot as it's ever been. And wouldn't it be great if "sophisticated computer modeling" helped that much? Instead, we get things like this. No, I think what's happening here is that we're being underestimated by our enemies and overestimated by our friends. . .
+ TrackBacks (0) | Category: In Silico | Why Everyone Loves Us
December 13, 2006
Aaron Haspel over at God of the Machine took some good cuts at the English-Comp warhorse "The Elements of Style" the other day. He's good at invective, and the book deserves some, although arguably not as much as he had on hand. But then his post inspired another at a blog called Petrona, written by Maxine Clarke, a senior editor at Nature. Her take:
I don't have much, if any, problem with (Strunk and White). Scientists do well to follow the advice when writing up original research, because descriptions of technical concepts, methods and so on are vastly improved by brevity. In particular, the common habit among US authors of applying six or seven adjectives to a noun can be very hard to comprehend when many of the adjectives could equally well be nouns, and the whole consists of polysyllabic specialist terminology (oh, OK, then -- jargon).
Given her day job, I have to assume that she knows of what she speaks. That's especially true because Nature is one of the very few scientific journals to do real line editing - they'll take your manuscript and rework it after it's been accepted, as strange as that may seem to many people.
Scientific writing is notoriously poor. Some of the problem comes from younger scientists trying to emulate what they've already been exposed to. I remember a colleague of mine in the early years of my first job who couldn't have written a report on whether it was raining and make it in under ten pages. I remember talking with this person about their draft of an internal report, which spoke about how they'd systematically investigated the various steric and electronic factors involved by varying the substituents in the distal portion of the aromatic ring in an attempt to learn the effects of these variations on a number of parameters, including oral absorption, activity at the target, clearance, and selectivity, and. . .well, it went on like that, for quite a long time.
"What are you trying to say here", I asked. "Oh, I'm just saying that we did the SAR for the 4-position of the ring", was the reply. "Then say that" was my advice. Ruthless application would have trimmed things down by about 90%, but no, it wouldn't sound like a real report then, would it?
Some of the worst writing in the scientific journals, though, comes from people who are trying to turn out the best. I've seen several people who are overly impressed with their writing skills, and try to dress up their papers with knotty sentence structure, recondite vocabulary, and other cheap tricks. Unfortunately, many readers fall for it. If they can recognize the author's style, they figure, he must be some writer. A journal article doesn't give you much room for style, that's for sure. Having an individual voice for your publications is a real challenge, but here's the trouble: most of the ways you can do it are bad ideas. Better to have no style at all than a lousy one.
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December 11, 2006
Since I've been getting some more less-than-friendly email from Kevin Trudeau fans recently, I thought I'd take a minute to point out something that may not have been generally appreciated. What does the complete failure of a drug like Pfizer's torcetrapib say about the evil-pharma conspiracy theories that Trudeau and his type like to spin?
I mean, think it through: Pfizer spends hundreds of millions of dollars, only to find that their drug has unexpected toxicity. Not the horrible, chemical-weapon toxicity that the conspiracy mongers talk about, mind you: 11 deaths per thousand versus 6 deaths per thousand. But development stops immediately, as it should, the very day that Pfizer's executives get the news. Two days after trumpeting the compound as the biggest thing in their pipeline, they pull it and walk away from the billions of dollars that could have been.
How, exactly, does this fit the Evil Conspiracy worldview? Isn't this, according to Trudeau, exactly the same as all the other drugs already on the market? Why would a company walk away from all that cash just because of a measly little figure like 5 excess patient deaths per thousand? If you believe Kevin Trudeau, everyone who takes anything is being poisoned already.
I know I'm going to regret making this offer, but here goes: I'd be interested in hearing a Trudeau-ite explain this one to me. If you buy into his story, why any drug ever fails in the clinic must be a real head-scratcher, since you'd think that the Evil Pharma Overlords would be able to hocus the data enough to make any sort of toxic junk look good. And this one must seem especially weird.
So tell me, you folks who are convinced that I and all my colleagues in the drug industry are poisoning the world: why did torcetrapib fail? Ground rules: you have to know what torcetrapib is, and you have to have some basic understanding of what it was (in theory) supposed to do. ("Improve cholesterol to try to prevent heart attacks" is enough of an answer for that one - there's a free one for you). And you have to be able to spell Pfizer, and to have read at least one news story about the drug's demise. Have at it in the comments section.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Snake Oil
I was looking through some old pictures the other day, and found a set that were taken in my grad-school lab, back in the mid-1980s. One thing struck me, because I'd always had a mental picture of my bench being an impossible mess: it wasn't that bad. "You call that clutter?" I thought. "I'll show you clutter!" My desk, on the other hand, was indeed a mess, and I haven't been able to surpass it. (Equal it, yeah, OK, every few months. But not surpass it).
I think one reason the bench didn't look so bad was because there just wasn't enough money for it to reach its full potential. After all, I only had a certain number of round-bottom flasks, with no more set to arrive, so I had to be vigilant about transferring things to vials and doing the dishes. When you have drawers full of the things, though, you can afford to cut loose a bit. The same goes for other lab supplies - I didn't have a lot of spare boxes of pipets and disposable test tubes sitting around back in the old lab, because we tried not to dispose of them so cavalierly.
The other thing that hit me about these shots was that I could easily do what I do now using that same equipment. I'd like a Biotage or Isco chromatography system, true, neither of which had been invented back then. But most of the equipment is exactly the same - round bottom flasks, Erlenmeyers, rota-vaps, sep funnels, TLC plates - everything you need. (Bet you didn't know you could buy some of that stuff at Amazon, eh? That sure hadn't been invented yet, either. . .)
I don't know whether to be happy that all the things I've learned have stood by me so well, or to be a little worried that my field isn't a bit more dynamic. It's a good thing I don't have any lab photos from the 1960s for comparison, because that might just tip the balance.
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December 8, 2006
As that discreet logo over on the left sidebar shows, this site has been nominated for a weblog award. This is the vote-once-a-day-per-computer one, and clicking on the banner will take you to the voting page. First prize, as I understand it, is basically a hearty handshake, but if you feel inclined to help out the site's standing in the vote tally, by all means please do. I've already got several of the other finalists on the blogroll, but I encourage you to check them out as well if you're not familiar with them.
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December 7, 2006
Here's a mighty topical question for some of my associate colleagues these days: what is it that people are looking for in a presentation from a MS-level candidate?
Associates are expected, first and foremost, to make SAR analogs. If you can crank out a stream of reasonable compounds, you're probably going to do fine, and if you can't, you almost certainly won't. But making a pitch to get hired somewhere can be difficult if you've worked, say, on several projects, but none of them long enough to make a big coherent story based on your own analogs. You don't want to look like you're taking credit for the work of others, and it doesn't look good to complain about being shuttled around from project to project, either. What to do?
It's also tricky if you've had a fair amount of boring-but-necessary analog work. This gets at the tension between neat chemistry and good med-chem, which two fields don't always overlap very well. What if you made a fine string of compounds, important for the direction of the project, with maybe a solid contender or two for the clinic in there - but you made them via yawner reactions that undergrads learn in the first semester of Organic?
My advice would be to make a virtue out of necessity. The thing is, it's actually a good thing when compounds can be made by old-fashioned reactions. Rather than apologize for it, I'd say make it a selling point. Of course, you would want to find some way to show that you're capable of fancy stuff (or at least fancier than what you're showing). If there aren't any examples you can dredge up from your project work, it may be worth including some slides from your graduate work if they're more showy.
The same technique can be applied to work done on a large number of projects. The best thing I can think of in that case is to show it off as a wide range of experience, and demonstrating the ability to pick up new projects quickly without getting distracted.
Anyway, I'll throw this one open to my lab-head level readers. If you're hiring an associate with some industry experience, what do you most want to see from them? Comments welcome. . .
+ TrackBacks (0) | Category: How To Get a Pharma Job
December 6, 2006
Several people have remarked on how large and greasy a molecule torcetrapib is, and speculated about whether that could have been one of its problems. Now, I have as much dislike of large and greasy molecules as any good medicinal chemist, but somehow I don't think that was the problem here.
For the non-medicinal-chemists, the reason we're suspicious of those things is that the body is suspicious of them, too. There aren't all that many non-peptidic, non-carbohydrate, non-lipid, non-nucleic acid molecules in the body to start with - those categories take care of an awful lot of what's available, and they're all handled by their own special systems. A drug molecule is an interloper right from the start, and living organisms have several mechanisms designed to seek out and destroy anything that isn't on the guest list.
An early line of defense is the gut wall. Molecules that are too large or too hydrophobic won't even get taken up well. The digestive system spends most of its time breaking everything down into small polar building blocks and handing them over to the portal circulation, there to be scrutinized by the liver before heading out into the general circulation. So anything that isn't a small polar building block had better be ready to explain itself. There are dedicated systems that handle absorption of fatty acids and cholesterol, and odds are that they're not going to recognize your greaseball molecule. It's going to have to diffuse in on its own, which puts difficult to define, but nonetheless real limits on its size and polarity.
Then there's that darn liver. It's full of metabolizing enzymes, many of which are basically high-capacity shredding machines with binding sites that are especially excellent for nonpolar molecules. That first-pass metabolism right out of the gut is a real killer, and many good drug candidates don't survive it. For many (most?) others, destruction by liver enzymes is still the main route of clearance.
Finally, hydrophobic drug molecules can end up in places you don't want. The dominant solvent of the body is water, of course, albeit water with a lot of gunk in it. But even at their thickest, biological fluids are a lot more aqueous than not, especially when compared to the kinds of solvents we tend to make our molecules in. A hydrophobic molecule will stick to all sorts of things (like the greasier exposed parts of proteins) rather than wander around in solution, and this can lead to unpredictable behavior (and difficulty getting to the real target).
That last paragraph is the one that could be relevant to torcetrapib's failure. The others had already been looked at, or the drug wouldn't have made it as far as it did. But the problem is that for a target like CETP, a greasy molecule may be the only thing that'll work. After all, if you're trying to mess up a system for moving cholesteryl esters around, your molecule may have to adopt a when-in-Rome level of polarity. The body may be largely polar, but some of the local environments aren't. The challenge is getting to them.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Pharmacokinetics | Toxicology
December 4, 2006
One thing that the Pfizer debacle makes you wonder about is: were they trying too hard? Torcetrapib seems to have done a fine job raising HDL on its own - so it was only natural to think of combining it with an LDL-lowering statin. If it turns out, though, that the fatal problems that have turned up were the result of the combination therapy, what then? Will the story be that Pfizer brought the roof down on itself by trying to extend the profitable lifetime of Lipitor?
It turns out that we can answer that question. What if the compound had been developed by a company that didn't have a statin of its own to promote? We don't have to wonder: that's the situation with the Roche/JTT compound. Roche has no statin in its stable. But when you look at the trials they they've been running, well. . .
. . .patients will be randomized to receive either CETP inhibitor (900mg po) or placebo po daily for 24 weeks, with concomitant atorvastatin 10 to 80 mg daily. . .
. . .This study will evaluate the efficacy and safety of three doses of CETP Inhibitor when co-administered with pravastatin. . .
. . .Patients eligible to participate in the extension study will continue on the treatment they were originally assigned to ie CETP inhibitor (900mg po) or placebo daily, with concomitant daily atorvastatin (10 to 80mg po). . .
So why the constant statin drumbeat? There's actually a good reason. As it happens, monotherapy trials of torcetrapib seemed to show that it could lower LDL a bit on its own - but only in patients without high triglycerides. Unfortunately, most of the patient population for the drug has high triglycerides, so there you are. You could always try to make the argument that HDL elevation alone might be beneficial, but no one's quite sure if that would be enough, especially given that lowered LDL has been shown to be beneficial in cardiac outcomes.
Roche, of course, is at the moment just packed with people who'd like to know what (if anything) there is about the statin/CETP combination that could turn awful. I wonder how long it'll be before we find out?
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
December 3, 2006
This is a complete clinical disaster: the world's largest drug company just ditched their potential biggest drug. And this comes two days after a press conference where they talked about how they were planning to submit it for approval within months. Development of torcetrapib, the cholesteryl-ester transfer protein inhibitor designed to raise HDL levels, has been halted. Last week, that sentence would have been the subject of nightmares at Pfizer, but now it's the top of the news. No alarm clock buzz will make it go away. If you're looking for an example of just how difficult drug development is, look no more.
The story broke on Saturday: the 15,000-patient trial that was underway (half on Lipitor, half on Lipitor plus torcetrapib) showed excess deaths in the combination group (82 versus 51). That figure's impossible to ignore or explain away, and now the problem will be to explain what caused it. There are other CETP inhibitors in development, such as JTT-705 (from Japan Tobacco and Roche) and one from Merck as well. Both these companies have just had a tremendous shock, since we don't know (yet) if the patient deaths were due to CETP inhibition itself, the combination of it with the HMG CoA reductase inhibition of the statin, an off-target effect of torcetrapib with the statin, or just an off-target effect of the drug on its own. I'm sure that intense reviews of all the clinical data are going on. Things just got much more complicated.
As for Pfizer, they now have a monstrous hole in their near-term pipeline. Looking back, they've had a terrible run the last couple of years, with a number of promising drugs dropping on them, but nothing compared to this. I don't think anyone's had one to compare with this, at least in terms of the expectations for a drug. I was just talking with some people from the company last week (along with many of my colleagues), looking into employment possibilities. After this, I think we may have to keep moving. I don't think that Pfizer's going to be in the mood for hiring.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
December 1, 2006
I've been remiss in not commenting on Pfizer's reduction of its sales force. (Back almost two years ago I speculated on why they might (or might not) do such a thing).
The first thing to keep in mind is that even with these layoffs, Pfizer's sales organization still looks like the crowd scene from "Gandhi". They're not giving up their position as a marketing monster - rather, it looks like they've just decided that they could be a somewhat more effective marketing monster if they didn't have their sales reps scraping each other's fenders in physicians' parking lots.
But I have to cheer on any drug company decision that doesn't just involve Getting More Humongous. I've thought for a long time that the Humungous strategy (though initially attractive) has its limits, and that these limits are necessarily hard to discern while you're crossing them. Sales forces scale a lot better than research productivity, but you can go too far even there. Perhaps now we can put a number on it.
Pfizer's going to be an interesting place over the next couple of years. They were out beating the drum for their late-stage pipeline, but the part of it that everyone's watching is torcetrapib, their HDL-elevating compound that they're hoping to sell mostly) in combination with Lipitor. A mighty bolus of clinical data on that combination is coming next spring, and it had better look good. There have been concerns about effects on blood pressure, and no one's going to happy until those are quantified better.
The company's talking about all sorts of restructuring plans, but these will surely be adjusted (for better or worse) based on the torcetrapib situation. For purely selfish reasons, I hope that they don't feel the need to release any research staff any time soon. . .
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease