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
October 31, 2004
I don't even want to try to estimate how many chromatography columns I've run over the years. I remember some of my first ones, from the early 1980s, an era that is beginning to sound alarmingly distant. I ran them at a fierce rate for the rest of that decade and most of the 1990s, only tapering off in the last few years.
For those outside the field, organic chemists spend a lot of time purifying compounds by running them through silica gel, which is similar to very pure, very finely ground sand. Usually that's done by dissolving the impure mixture in some solvent and pumping it through a column of the stuff. In the old days (up until the late 1970s/early 1980s) this was often done just by gravity, but then the fashion came in for "flash" chromatography, where you force the solvent through by air pressure. Younger chemists who've never done any other kind don't appreciate the flashy aspects of that method, since they've never sat around all day while a gravity column drips - it's like waiting for a stalactite to form.
The most refined form of column chromatography is HPLC, high pressure liquid chromatography, which uses metal columns, highly refined silica (and other solid supports), and special pumps to ram mixtures through at hundreds or thousands of pounds/sq. inch. But HPLC machines aren't cheap, and neither are the consumables, and they can be finicky to operate, no matter what the sales rep says.
Recent years have seen the advent of various pre-packed flash columns for benchtop use. Back in graduate school, those would have been the equivalent of having your compounds purified by dancing girls while the chef whipped up some appetizers - even if these things had been available, there's no way we would have been allowed to order such degenerate labware. So I went through my peak column-running years doing it the old-fashioned way, and now that I only do one once in a while, there are all these premade gizmos just sitting around. 'Twas ever thus.
+ TrackBacks (0) | Category: Life in the Drug Labs
October 30, 2004
Just in case there's anyone who hasn't had enough of the whole topic, the reasons for my (not-all-that-ringing) Bush endorsement are duplicated in greater detail by Megan McArdle guest-blogging on Instapundit. Her thoughts are an extremely close match to my own on most of the topics she covers (you'll particularly note the congruences on foreign policy and health care.)
So if you want to pick apart my choice, start by picking apart hers for practice. Hey, in a few days we'll know one way or another. . .I hope.
+ TrackBacks (0) | Category: Current Events
October 29, 2004
Yesterday's post suggests a question for the audience. The whole reason that big companies put up these satellite sites is to tap into a different labor force and generate ideas that wouldn't necessarily have happened back at the Mothership. I know that I have readers at Novartis-Cambridge and J&J-La Jolla, among other scattered sites, so here's my query: Does this work at all?
Does the hoped-for cross-fertilization take place between these sites and the academic/biotech environment they sit in? Is the work force really different from the people at the main site? And is there any not-invented-here rivalry between them? Are things really done differently, or does the corporate culture still permeate?
I'm particularly interested in hearing from people who've worked at both the main research site and the newer ones - I realize, though, that that isn't a big fraction of the work force at these places. Those of you who work at companies with research split between Europe and the US have some insights to offer, too, I think.
+ TrackBacks (0) | Category: Drug Industry History
October 27, 2004
If I were New Jersey, I'd be worried, and not just for the usual reasons. It's no longer the necessary place to go for a job in the drug industry. Novartis, which has been in the state forever, declined to expand in Switzerland but also passed on New Jersey, choosing the Boston area (Cambridge) instead. For the last year or two, they've been the major hiring force in the entire pharmaceutical industry - and it's a good thing, too, because there have been some losses at other companies in that time.
The Boston/Cambridge area has been pretty hot the last few years. AstraZeneca's main US research site is there, too, supplanting the old Astra sites in New York state and the Zeneca site in Wilmington. Merck decided to expand there, too, although with their recent troubles it's anyone's guess what's going to happen to the site and the people they're hiring. Their official opening was one week after the Vioxx news broke, which must have toned the celebration down a tad.
On the West coast, it's the San Diego area that's getting all the big names. Pfizer and Johnson & Johnson have both expanded out there, and there are plenty of small outfits springing up. It's like Cambridge with better weather, not that that's a very demanding criterion.
So where does that leave the good ol' Pharma Corridor, from Philadelphia to New York? Used to be, you could hit most of the big guys with a rock from the New Jersey Turnpike (or perhaps the Garden State Parkway, which was literally within a flung Erlenmeyer from the windows of the first industrial lab I ever worked in.) I don't know when the last major expansion in the area was - probably ten years ago. And there's some food for thought for the fish-nor-fowl Connecticut branch of the industry, too (Boehringer Ingleheim, Bayer, BMS-Wallingford, Pfizer's mothership). Some of those companies have expanded over the last ten years (Pfizer, most notably), but no new behemoths are moving in.
And it's too early to say if these new sites are going to do what they're supposed to: crank out lots of new discoveries. The whole point of moving to La Jolla or Cambridge is to tap into the wild, creative crowd that's supposed to inhabit these places. Can they deliver, or will it be time to be off to Little Rock, Albuquerque, or whatever the happening cities are twenty years from now?
+ TrackBacks (0) | Category: Drug Industry History
October 26, 2004
OK, enough politics for a little while. We're going to be soaking in the stuff for at least a week, and for God's sake I hope it's not longer than that.
I should qualify that. I'll take a break from national politics, but the day-to-day kind is always with us. You're going to have politics as long as you have people. Now, over the years, I've met a few folks who went into research because they thought they were going into an area where they could avoid the all the politicking. Hah! As you can imagine, they were rudely dunked in the cold pond of reality.
No, scientific research is as political as the next field, and a minimum amount of skill at the game is probably necessary for any kind of happy career. Even if you're generating world-class academic science, you need to know how to make the most effective use of your discoveries. Do you collaborate with others in the field, compete cheerfully with them, or treat them as bitter rivals? How long do you keep new results to yourself to flesh things out, and when do you finally publish (or patent?) And then what journal do you send this great work to? Which speaking invitations do you accept? These decisions all matter.
And if you're turning out great work in industry, you need to make sure that you're getting proper credit for it. Believe me, there's no clearer example of nature abhoring a vacuum then when it comes time to claim credit for good results. If you don't step up, someone else will. There are people who live for such opportunities.
Another example of industrial politics comes when you have to keep everyone together on a big project. There are bound to be people in some of your subgroups (chemistry, biology, pharmacokinetics, in vivo, toxicology, etc.) who are going to feel slighted if they think another area is getting an easier ride. You have to find a way to reward the right people and spur the laggards without making them spend their time fighting back at you.
So there's plenty of maneuvering in industry, and the situation in academia is, if anything, even worse. No one seems to be sure about who said it first, but the standard observation is that the disputes in academia are so bitter because the stakes are so small. (Mind you, I'm not sure that this theory holds water when you're talking about people pulling in seven-figure grants with whacking big overhead allowances in them.)
+ TrackBacks (0) | Category: Life in the Drug Labs
October 25, 2004
Here we are, with one week to go before the election. Several bloggers that I read regularly have called on the other opinion-spouters in this business to state who they're voting for, so readers can know where they're writing from. Since I talk about the politics of health care and drug industry (in between lab stories and bizarre patents, that is) I think I should go ahead and turn over my cards. The point of a blog is to have an opinion, after all, which opinion is expressed both in what I choose to write about and overtly within the writing itself.
So it shouldn't come as a surprise to regular readers that I will be casting my vote for President Bush next week. I'm not exactly going to be whistling as I walk into the booth, though, because Bush has done several things that would, under other circumstances, be deal-breakers for me. The limits on federal funding for embryonic stem cell research are one example. Since the issue turned into a political football it's been distorted past recognition, but while recognizing that embryonic stem cells are not going to suddenly send people leaping out of wheelchairs, and realizing that private money can (and is) funding such research, I still dislike the limits that the Bush administration has proposed. I understand their reasons, but I disagree with them and I worry about the precedent that they set.
Another problem has been the administration's wobbly attitude toward free trade. I don't like seeing tariffs anywhere on much of anything, so the steel and textile actions of the last few years don't sit well with me. I think that free trade is the closest we come to getting something for nothing in this world, and I worry every time someone messes with it for political advantage. (If I thought that Sen. Kerry would be any better, my decision to vote for Bush would be that much harder.)
Next we come to the nominal subject of this blog, pharmaceutical research. As you'd expect, Sen. Kerry's constant hammering on the drug companies make it next to impossible for me to consider voting for him. His proposals would significantly raise my chances of being tossed out into the street, unable to make a living at my chosen trade. And given the state of the industry, those odds are already quite large enough, thanks. I recognize that some of Kerry's statements are just campaign rhetoric, and that a Republican-controlled Congress would be unlikely to act on many of his plans. But it seems foolhardy to vote for someone on the assumption that he doesn't really mean what he says.
So under other circumstances, I'd be back to my situation in 1992. I was disappointed in Bush(41), did not trust Clinton (remember, I'm from Arkansas), and considered Ross Perot to be dangerously unstable. I took an awful long time in the voting booth, and finally cast a protest vote for the Libertarians, which required a bit of nose-holding even then. Ah, those 1990s. But this much too serious a year for protest votes. It would take a truly un-Libertarian amount of coercion to get me to vote for them this year.
My personal worries are about continued pharmaceutical employment, but the biggest issue in this election is foreign policy. And I simply cannot trust Senator Kerry's instincts in that area. I have disagreements with some of the things that the Bush administration has done and how it's done them, but those are nothing compared to the ones I can see having with a Kerry presidency. I believe that he, as well as many of his supporters, are living with a view of the world that correlates rather weakly with reality. And yes, I well realize that they believe the same thing about people like me.
There you have it. I'm not necessarily trying to bring anyone around to my point of view, since I don't think there's much convincing left to do at this late date. But now you know where I'm coming from, and can adjust your dials accordingly.
+ TrackBacks (0) | Category: Current Events
October 24, 2004
I'm working on my next column for Contract Pharma, and it reminded me of a conversation I had a few years ago with a former colleague. He and I had worked at the same drug company for a few years, then he went on to an MBA degree and a job on Wall Street.
How, I asked him, did the two of us spend all those years in school, and spend all the mental effort that we did every day in the course of our jobs, but end up working in fields that are so dominated by chance? Picking winners in the stock market is a lucrative business, as is picking winners in drug discovery, but doing it consistently in either profession is next to impossible. Why, I wondered didn't we have the sense to end up doing work whose rewards were more closely correlated with the effort that went into them?
I still don't have an answer for that one. But a part of it might be that I'd find a job like that a bit. . .well, boring. I like not knowing what's going to happen next, wondering if the next compound is going to be the one that finally works. The jobs where effort and results are most perfectly matched are done by machines, not people. And any job that can by done by a machine should be, as far as I'm concerned. I guess I'll stick with the sort of craziness that only a human can appreciate.
+ TrackBacks (0) | Category: Life in the Drug Labs
October 22, 2004
I'll finish up the week with something a bit out of my usual range. I talk about patents and intellectual property around here from time to time, and it's easy for me to think of pharmaceutical patents as the centerpiece of the whole system. They're important, but it's good to be reminded that there are a lot of other things that people feel are worth claiming.
A lot of other things. . .via Greg Aharonian's patent mailing list, I present for your perusal US Patent 6,805,663, freshly issued as of October 19th. If you have a TIFF viewer plugin for your browser (or are using a Mac with a recent version of QuickTime), you can see the images for this patent. I'm not sure if this direct link will work, but
it's worth trying for the front page drawing to see if you can figure out what it's for. Believe me, you can't. (UPDATE: that link doesn't work very well, but courtesy of the deviants at Fark.com, here's a link to a PDF of the patent drawings. But you still won't be able to guess what's going on.)
Give up? Here's the full text, which should make everything clear. Why, it's a "Method of Shared Erotic Experience and Facilities For Same," of course. The claims and specifications make this the first patent I've encountered that I would be uncomfortable reading aloud in public.
The inventors appear to be a husband-and-wife team from California, and they must be a fun couple indeed. What I find particularly interesting is their description of the prior art. They actually cite 10 relevant patents, which means that there's a whole world of intellectual property I'd never dreamed of. Here's hoping that none of us have inadvertently infringed any of these.
Actually, there could be a pharma angle to all this. Note that the facility theyre describing includes some sort of concession stand. Perhaps this is a marketing opportunity in the vicious promotional fight between Viagra, Levitra, and Cialis! I can imagine blue- or purple-painted domes, with a helpful MD distributing free samples. . .but then, I have a pretty good imagination. But not as good as the folks who came up with this patent.
+ TrackBacks (0) | Category: Patents and IP
October 20, 2004
I was using hydrogen chloride gas straight out of the cylinder today, first time I've done that in many years. That's a very different substance from regular hydrochloric acid, which is technically a solution of HCl gas in water. The straight stuff will really snap your head back if you get a whiff of it, which you'd better not since it does Bad Stuff to your lungs, as you'd imagine.
You need to rig up a trap for the vented gas, since it's rather bad form just to send it up the fume hood. The standard way is to bubble the excess through aqueous base to neutralize it, preferably rigged up so that the water doesn't have a clear path to go siphoning back into your reaction if the pressure goes haywire. Bubbling the HCl into a solvent like methanol always looks a little odd. You can send a pretty vigorous stream of the gas in one side and have very little coming out through the trap at all, since the methanol is soaking up so much of it.
These gas cylinders are under pressure, and the large ones look just like the helium tanks that non-scientists are familiar with from balloon vendors. The regulator valves on top of them need to be made of rather more robust material for an HCl tank than for helium - which is, after all, totally inert under all conditions short of the interior of the sun. Back in grad school, a corroded regulator (on a whopping big HCl cylinder) gave me a real scare as it threatened to give way and vent all the gas at the full tank-neck pressure of about 1500 psi. I had to go sit down for a while after that one.
But today's work was with a lecture bottle, a much smaller cylinder that holds only a couple of hundred grams of the gas. That's enough to do some damage, true, but not on the scale of the free-standing ones. I saw that happen back in graduate school as well. One day I was sitting in the library, looking up some references, when I noticed the occupants of the third floor research labs pouring out onto the lawn from the rarely-used side stairwells. They were hustling right along, too, which suggested some sort of liveliness upstairs.
As it turned out, it was in the lab next door to mine. One of the guys had another HCl tank, a medium-sized one, which was also corroded and jammed. He went for the cylinder wrench, which he then used for the non-standard purpose of vigorously whanging the valve with strong overhand strokes. One of the other guys in the lab summed up the sound of this process as "PING. . .PING. . .PING. . .hisssssSSSSSSS oh @!?#!"
The hood wasn't enhanced by having a kilo or two of hydrogen chloride vented all over it, that's for sure. It looked as if it had been subjected to some sort of accelerated aging process - if there were a market for antiquing lab equipment, this would be a good way to do it. All the exposed metal was pitted and flecked with green. The stainless steel was hazed with rust, having reached its carrying capacity for corrosion. And everything still had a fine mist of concentrated hydrochloric acid all over it where the gas had sucked the water out of the air and condensed on the nearest surface. Cleaning it up is not the way you want to spend your Friday afternoon.
None of that for me today, though. I ran the stuff in uneventfully, with the reaction turning to a clear yellow, which is nothing compared to the colors I'd turn if you sprayed that much on me. I'll find out tomorrow if things have worked according to plan. One thing's certain: something will have happened. Nothing escapes from HCl gas unchanged.
+ TrackBacks (0) | Category: How Not to Do It | Life in the Drug Labs
October 19, 2004
The COX-2 story is continuing to thrash around, as it will for some time. The latest news has Pfizer's second-generation compound, Bextra, linked to possible cardiovascular risks. This is data from patients who have undergone open-heart surgery, so we can argue about how applicable this is to the general population, but it's still not good news. The whole drug class didn't need any more clouds over it.
At the same time Pfizer has announced a large cardiac trial of Celebrex. Pfizer's positioning this as a trial to look for cardiovascular benefits, actually, but it's going to be hard to shake the impression that they're looking for risks. It'll be interesting to see how quickly they can enroll patients in that one, although odds are we're not going to be able to find that out.
And over at Merck, they've presented data from a study of their own second-generation drug, Arcoxia. In a trial against diclofenac (a classic antiinflammation drug), Arcoxia didn't seem to show an increased risk of heart attack or stroke. But what it did show was a correlation with slightly increased blood pressure, and that's not what Merck or anyone else wanted to hear. You could, in a pessimistic mood, link increased blood pressure to long-term cardiac effects, although there's no way to know if that's what's going on yet.
Remember, the Vioxx problems didn't really show up until the drug had been on the market for some time. You'd think, to read some of the stories (or to hear some of the ads from law firms) that the drug was just mowing down its patients, but that's not what happened. Vioxx's side effects might never have been noticed in the normal course of use - although severe, they're too uncommon to pick up for sure except in a large sample. Patients had to take the drug for over a year to show any problems at all, for one thing.
Without trials specifically designed (and statistically powered) to look for them, the side effects of other COX-2 medications might be invisible. But invisibility isn't an option.
+ TrackBacks (0) | Category: Cardiovascular Disease | Toxicology
Thanks to the Red Sox and the Cardinals, I'm pressed for blogging time today. But I wanted to point out an article by Malcolm Gladwell that was just posted at the New Yorker site. Entitled "Don't Blame Big Pharma", it's a look at Marcia Angell's book - with which he's not impressed - and at the drug pricing issue in general. It contains indisputably sensible stuff like the following, regarding the prices of prescription versus generic drugs:
"It is not accurate to say, then, that the United States has higher prescription-drug prices than other countries. It is accurate to say only that the United States has a different pricing system from that of other countries. Americans pay more for drugs when they first come out and less as the drugs get older, while the rest of the world pays less in the beginning and more later. Whose pricing system is cheaper? It depends. . ."
I think Gladwell's key point is this one, and it's well worth thinking about:
"The core problem in bringing drug spending under control, in other words, is persuading the users and buyers and prescribers of drugs to behave rationally, and the reason we’re in the mess we’re in is that, so far, we simply haven’t done a very good job of that."
Of course, that would mean that a good part of my industry's profits might well be made through the suboptimal decisions of its customers - not that we we'd be alone in that category, for sure. But it's not a group I feel comfortable being a member of, and I'd rather we found a way out of it. More thoughts on this to come.
+ TrackBacks (0) | Category:
October 17, 2004
Saturday's New York Times had an astonishingly sensible article about the drug reimportation issue. (You can go ahead and insert the phrase ". . .especially for the New York Times") Some highlights:
"It may make political sense to point to Canada as a solution to high prescription drug prices in the United States. But many economists and health care experts say that importing drugs from countries that control their prices would do little to solve the problem of expensive drugs in the United States, where companies are free to set their own prices. Even the nonpartisan Congressional Budget Office estimated that allowing Canadian drug imports would have a "negligible" impact on drug spending. To begin with, there are not enough Canadians, or drugs in Canada, to make much of a dent in the United States. There are 16 million American patients on Lipitor, for instance - more than half the entire Canadian population."
Quite so, and as the article goes on to point out, we in the drug industry have no incentive to ship Canadian pharmacies ten times as much stock as they need for their own country. It's not going to be pretty, but cutting things off at the supply end is what's going to happen - unless, of course, Congress manages to make that particular business decision illegal, as they're threatened to do. Here's some more:
". . .the measures proposed so far would do little to change the fundamental economics of the drug industry as it exists today. Prescription drugs cost a lot to invent, but once invented cost little to manufacture. That is why patents are granted to drug companies - to prevent other companies from copying their inventions long enough for the inventors to set prices high enough to recover their investment and make a profit. But price controls short-circuit this system."
That's absolutely correct in every detail, and such is the state of journalism today that I could not believe my eyes when I read it. I starting waving the paper around, clutching my chest and calling out to my wife: "It's the big one! I can feel it!" She's used to me. And one last quote:
"But the United States market is hard to compare with any other. It represented more than half of the global drug industry's sales of $410 billion last year and was the country in which drug companies make the bulk of their profits. Whatever one thinks of the pricing disparity, efforts to force down American prices to Canadian or European levels could radically change the economics of the pharmaceutical industry - which effectively depends on United States profits for all of its activities, including a substantial portion of its spending on research and development.
American consumers are "subsidizing everyone's R&D,'' said Mr. Love, the consumer advocate. "We're paying way more than everyone else. Others should pay more.''
This article is bylined Eduardo Porter, and I wish to publicly salute the man. I'll think of this every time I'm about to get the vapors about reimportation and remind myself that good sense can break out.
+ TrackBacks (0) | Category: Drug Prices | Press Coverage
October 14, 2004
Talking about the fix that Merck (and the rest of the industry) is in, Jesse Eisinger of the Wall Street Journal used some strong words in his Wednesday "Long & Short" column:
"How did the pharmaceuticals industry get into this situation? Most followed the imperiatives of Wall Street. Investors and analysts demand fast growth from drug companies, but can't abide the risks. They want to be able to draw a ruler under their earnings projections. So most big drug companies relied on brand extensions and raising prices, not breakthrough drugs. They merged with each other to smooth out earnings in bad times, thinking that they were diversifying. But since the industry has huddled around a small number of huge therapeutic categories like hypertension and cholesterol-lowering, the diversification turned out to be largely illusory."
Well, one reason we ended up in those categories is that we know how to do something about them - they have good druggable therapeutic targets, and it sure doesn't hurt that they're huge markets. (Of course, there are other huge markets that we don't have a clue of how to go after.) But he's right that Wall Street (and too many pharma executives) want our earnings to be much more predictable than they ever can be.
What business and accounting types don't want to recognize is the level of crazy risk-taking that the drug industry is founded on. As I've pointed out before, in business school they teach you all about risk: how to avoid it, amortize it, outsource it, hedge it and minimize it. But what if risk is your whole business? How do you get around it then? Being the first to market with an innovative therapy, which is what both pharma management and the industry's worst critics both would like for us to spend more time doing, is insanely risky. No one wants to admit it, but it is.
Remember that 90% attrition rate I was quoting the other day? We can go years and years before we ever find anything, and it takes years of work before we know if it's any good. If we make it all the way to the market, there's no way we can know everything our compounds are capable of doing. We have to do what we can to find out, then get them out into the real world and hope for the best. Then we can spend huge amounts of money promoting something that not many people want to buy (Clarinex! Get your Clarinex!), or watch our biggest sellers turn into horrible hydras of liability (Baycol! Vioxx!)
Despite the huge financial rewards waiting for anyone who solves these problems, they're still out there and they're not a bit smaller than they ever were. But some investors and managers would rather convince themselves, against all evidence, that the world is a more orderly place. So let me be blunt: if anyone thinks that a pharmaceutical company can deliver predictable earnings under the current conditions, they're delusional. Or grievously misinformed, or just plain slow. You pick.
Eisinger goes on to point out that analysts say that they love Pfizer's get-big-and-sell-like-crazy strategy, but Prizer's stock is back where it was in 1998. Meanwhile, they're spending much more per new molecule than, say, Merck or Lilly, two of the industry's go-it-alones, and they have major trouble looming with competition and patent expirations:
"Merck is the ghost of Pfizer's future. . .Investors are slowly realizing that pharmaceutical companies should stay as small as they can, avoid distracting megamergers, invest large amounts in R&D, partner aggressively across the biotech spectrum and strive for novel, breakthrough medicines that add value."
These are noble goals, which I endorse while having few good ideas of how to live up to them. That's especially true in a publicly traded company, which brings us right back around to the beginning, and a question I'd like to throw out: how would some drug companies fare if they were held privately, away from the glare of the stock market? There aren't many of them, but should there be more?
+ TrackBacks (0) | Category: Business and Markets
This is a somewhat reworked version of an early post from my old site, Lagniappe, which I doubt if many of my current readers have ever seen:
I came across a quote from V. S. Naipul which set me to thinking. It's from Among the Believers, his famous (infamous, for some) book on the Islamic world. About the slow post-independence rot of Pakistan, he wrote:
"The state withered. But faith didn't. Failure only led back to the faith. . .If the state failed, it wasn't because the dream was flawed, or the faith flawed; it could only be because men had failed the faith. A purer and purer faith began to be called for."
This seems to me to not only be true, but to be true about many more things than Islamic politics. What it reminded me of was from a David Foster Wallace essay in A Supposedly Fun Thing I'll Never Do Again, where he defines a harmful addiction as something that presents itself as the cure for the very problems it causes. This applies immediately to physical dependencies like alcoholism ("If you had my problems, you'd drink too",) but Wallace goes on to show how it fits the habit of, say, watching five hours of TV a night.
I'm not making Islam = addiction connections here (or TV watching = religion ones, either!) No, what occurred to me is the general problem of systems whose only remedy for failure is to cycle back around again. And if that doesn't work, the only remedy is to do it again, preferably longer, louder, and harder the next time.
A blind spot is built into these systems which allows them to get to the harmful stage. No failure can be the fault of using the system itself - if that were possible, then other courses of action would be possible, too. And that can't be right, can it? But without that choice, you're on a circular highway without any exit ramps.
Look around, and you'll see plenty of these. At your workplace, is there some policy that does nothing but worsen the problem it addresses? And is there any mechanism at all for the policy itself to ever be at fault? Everyone's encountered folks who are so convinced of their own correctness that they just get crazier and crazier. Lots of terrible managers work the same way.
One of the things that has made science, as a system, work so well for so long is that it doesn't rule explanations out very readily. The possibility that a whole system might be at fault is always there; what's more, there are usually some eager researchers ready to try to tear it down. Individuals will make the circular-problem mistake, holding on to untenable theories by making them more and more complicated rather than abandoning them. But it's harder for a whole field of research to get bogged down in this way, and we're the better for it.
The connection between this line of thinking and the pharmaceutical slump of recent years has not escaped me. Is the answer to make even bigger screening libraries, that are then run through even faster? To dig around even more thoroughly in the genome? Or do we need something completely new - in other words, have we failed our ideas, or have they failed us? The fact that we can even ask the questions is the first step in being able to answer them.
+ TrackBacks (0) | Category: Drug Industry History
October 12, 2004
OK, I've got dry dichloromethane ready to go, right out of the Aldrich bottle. It's not like dichloromethane ever gets all that wet, not compared to something like THF. Stuff's a sponge. Man, I remember the days when we had to distill that fresh from sodium metal. And the fires! Now we just pay more money and it comes in a syringe-sealed bottle. What a deal. Beats calling the fire department once a month.
Bottled dry solvents! I'd have called that the height of decadent luxury back in grad school. Of course, a lot of stuff looked like the H. of D. L. at the time, have to keep that in mind - minimum wage would have been a real pay raise, considering the hours. . .took years before I could look at ramen noodles again, and that week where all I had in the place was a jar of peanut butter - smooth, too, worse luck. . .
Where was I? Dichloromethane. And my starting material, which was the right stuff two weeks ago and better not have changed into something else. Looks the same, anyway. I should take better care of this stuff. And thionyl chloride, hmmm - used to be a big bottle of it over here, but stuff moves around. I only do a fraction of the chemistry that goes on in this lab any more, and things get rearranged without me finding out about it.
Nope, not here. Must be some next door. . .what kind of research organization is this, anyway, that doesn't have thionyl chloride lying around? Sheesh. I spent half an hour the other day looking for a bottle of iodine. Everyone was supposed to have it, according to the Infallible Inventory System, but half the folks I asked had just loaned it out to someone - couldn't remember who - and the other half looked at me as if I'd asked them for Eye of Newt or something.
Ah, here we go, and the label's not even scorched off or anything. Must be good stuff. You've got to be either a serious chemist or an idiot to order an 800-mL bottle of reagents like this, though. Going to go bad by the time you get to the end of it, unless you've got a couple of big 250-mL chunk-style reactions to get through. Sure isn't one of 'em here. . .zero-point-three-five mL, right. You feel like a fool taking 0.35 mL out of an 800 mL bottle, but what the hey.
And a drop of DMF, to move things along, and that's that. I'm not sure that I'd trust a synthetic chemist who doesn't know the drop-of-DMF trick to speed up a thionyl chloride reaction. Something lacking in their education. . .probably didn't spend enough hours in the lab during grad school. Or maybe they didn't eat enough peanut butter. . .yeah. . .that must be it. . .
+ TrackBacks (0) | Category: Life in the Drug Labs
October 11, 2004
What if we nationalized the drug industry? Just turned all of us into national research institutes, a public utility of the sort beloved by Martha Angell: like the post office, but with Erlenmeyer flasks?
I think something would be missing, and you might be surprised to hear what it is. It's fear. Oh, and greed, too - mustn't forget greed. Those two are the main movers of capitalism, which is why, aesthetically, the whole system drives some people nuts. Wouldn't it be nicer to let some finer feelings run things for a while? Well, who knows, because we're not going to find out as long as we're the species we are. Attempts to substitute allegedly higher-octane fuels haven't worked out as planned, to put it delicately.
Not that I have anything against altruism. I like the fact that the work I do could eventually help desperate people. But clinical success is so far away, off in the hazy distance, that it would be easy just to roll along at a comfortable pace. It looks about as close as it did last week, so what's the difference? But that doesn't cut it. To really keep things moving along in the drug industry, we need what every other industry needs, namely, the feeling of someone else's breath on our necks. Believe it, every time someone in my business makes a big discovery, the next thing they do is start wondering if someone else hasn't just done the same thing a week before at another company. Scooped! Aargh!
It happens. I've seen several photo finishes in my research career, and the order can be worth tens or hundreds of millions of dollars. The times are posted on the first page of the patent filings, which is where you can see the earliest priority date. (In the US, the date at the bottom of the lab notebook page is important, too.) Every day we haven't filed on a new drug series is a day that we wonder if someone else will, and the jitters continue even after the patent's been submitted. You won't see the applications publish for many months, and that lag time could be when you find out that someone beat you. The longer it takes to find out, the worse it feels when it happens.
So we race each other in the clinic, all the way through, trying to figure out what everyone else is up to, and then we fight it out in the market. And it's a mess! It's inefficient and it's wasteful! But the hellacious part is, it's the best way that anyone's found to do it. We chase the reward of a successful drug, and we fear failure - losing out to another company, or worse, losing out to hordes of swarming lawyers. What else would make us jump as high, what else would make us run as fast?
+ TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs
Alex Tabarrok over at Marginal Revolution has called attention to a very interesting study on the financial aspects of drug discovery. Price reductions could have a disproportionate effect on R&D, the authors say, which fits in with my personal industry experience. If you cut everything by, say, 20%, you're not going to have just 20% fewer drugs to show for it. It isn't linear (not much is, as far as I'm concerned. . .) (Note his correction, though, which makes the effect less drastic, but also see Tyler Cowen's post just above the original post.)
That inspired this post over at Asymmetrical Information. Jane Galt finds the prospect "frankly terrifying". There are 80 comments so far - it's quite a discussion, and I encourage anyone interested in the issue to have a look.
+ TrackBacks (0) | Category: Drug Prices
October 7, 2004
Since Merck pulled Vioxx (rofecoxib) off the market, the big question has been whether its cardiovascular problems are specific or general. Do all COX-2 inhibitors have this liability? If so, do they all have it to the same extent? The analogy that comes to mind is the statins - all of them have been shown, at high enough dosages, to be associated with a potential for rhabdomyolosis, a serious muscle side effect. But Bayer's entry into the class, Baycol, showed it more than the others and had to be pulled.
Pfizer's been saying that they have seen no evidence of trouble for their Celebrex (celecoxib). But there's an interesting perspective in the latest New England Journal of Medicine. (That link will allow you to download a free PDF of the article.) The author, Garret Fitzgerald of U Penn, suggests that there could be trouble enough to go around.
The story involves two signaling molecules formed from the COX enzymes, thromboxane A2 and prostaglandin I2. Aspirin inhibits both COX-1 and COX-2, and suppresses the formation of both of them. The thromboxane, formed by COX-1, causes vasoconstriction and platelet aggregation, while the prostaglandin causes the opposite - it dilates blood vessels and inhibits platelet aggregation.
Neither Vioxx and Celebrex touch the thromboxane A2 pathway, naturally, but they both suppress the formation of prostaglandin I2 in humans. This was a weird result when it came out, because it was assumed that this molecule was made via COX-1 too, which these drugs don't inhibit. It later turned out that it's also made by COX-2 - which at least made sense from the drug standpoint - but that was still odd, because that enzyme wasn't supposed to be in the blood vessels at all.
But it seems that COX-2 can be induced there, especially when the vessel walls are subject to shear stress from blood flow. Problem is, when you inhibit that prostaglandin's formation, you've taken off a brake to platelet aggregation and you've probably caused some vasoconstriction, too. They're trying to make more of the prostaglandin, but the drug is preventing that from happening.
FitzGerald doesn't put any sugar on it:
"We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs. (Emphasis mine - DL) It seems to be time for the FDA urgently to adjust its guidance to patients and doctors to reflect this new reality. . .The burden of proof now rests with those who claim that this is a problem for rofecoxib alone and does not extend to the other coxibs."
Over to you, Pfizer! Uh, Pfizer? Oh. . .I see. . .
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology
October 6, 2004
I was telling some people the other day about a summer undergraduate student that I once had assisting me. (As with many of those, perhaps the verb should have quotation marks around it.) At any rate, this fellow read all the labels on all the reagents, looking for hazards. He believed every word. He read the MSDS forms and everything it said in the catalog and the handbooks. In other words, he did just what many lab safety campaigns would like for everyone to do all the time. And, naturally enough, he ended up terrified of working with any actual chemicals.
Who could blame him? Look at his choice of reading material: the sea sand container in my lab says that I should wear suitable protective clothing before I dare to open it. I note that the protective garment in which I've faced most of the sea sand in my life is a bathing suit. The label on the sodium bicarbonate - y'know, baking soda - says to wash thoroughly after any skin contact and call a physician if I've been exposed. How about something a little more hazardous? The sodium chloride bottle says, among other things, "Do not ingest", and "Target Organs: Skin, Eyes, Stomach". It cautions me to keep the container in a cool, well-ventilated place and to call that physician again if I'm rash enough to come into contact with the stuff.
So you can imagine what the bottles of dichloromethane and ether say, much less the labels on things like cyanide, where you might at last want to start paying some real attention. But by now, who does? In the same way that the Iranian theocracy has raised the most irreligious generation that the mullahs have ever seen, the Safety Mullahs have bred indifference to all but the most strident warning labels. For an example of debased speech, look no further.
+ TrackBacks (0) | Category: Life in the Drug Labs
October 5, 2004
In a comment to yesterday's post, William Knight says:
"While the initial challenges of developing and delivering therapeutic proteins are no doubt far greater, it seems to me that in the long run, proteins, peptides and nucleic acids are the right tools for the job, not small molecule analogues."
Well, I don't quite agree, but he's not the first person to think that way. An awful lot of money has been thrown at the problem of using antisense DNA therapeutically, for example, and I think that a similar amount is in the process of flowing into RNA interference. On the protein front, things have been more successful. There are quite a few protein-based therapeutics out there, starting with insulin and ethythropoetin.
One problem, as he correctly states, is delivery. There have been any number of ingenious approaches to oral delivery of large biomolecules, but there's still no solution in sight. We have enough trouble dosing small molecules and getting them absorbed and distributed; the problems facing large proteins and oligonucleotides are still worse. The gut is designed to rip these things apart, and the gut wall is designed to not absorb them. There are alternate dosing routes, but those are no stroll to riches either, as witness the multiyear campaigns to develop an inhaled form of insulin.
You'd think that biomolecules would be less toxic and more efficacious than small molecules, too - this was one of the early promises of the whole biotech industry. But that's been tricky to realize. A recent example is found with Amgen's attempted use of glial-derived neurotrophic factor for Parkinson's disease. Early results were promising, despite the fact that the protein had to be administered directly into the brain. But things haven't worked out:
"One of the most promising experimental therapies for Parkinson's disease could be shelved after scientists revealed today that a clinical trial has been stopped because of safety concerns. . .Hopes for the treatment soared last year when it was announced that the first five people treated with GDNF experienced a dramatic recovery in their movements. But on Tuesday, Anthony Lang of Toronto Western Hospital in Canada revealed that a second, more extensive clinical trial of GDNF has been halted because the drug showed little signs of working and some potentially dangerous side effects."
Those included neuronal death in monkey studies, and the appearance of antibody responses to GDNF in several of the patients. Raising antibodies to close relatives of your own proteins is not something you want to do. They're still trying to figure out what went wrong - it could be that GDNF was never much good from the start. A five-person trial is capable of producing just about any result under the heavens.
But this illustrates some of the problems. For now, until we understand things much better, biomolecules will have more liabilities than small synthetic ones, and just as good a chance at failure. Perhaps, eventually, the odds will shift.
+ TrackBacks (0) | Category: Drug Development
A while back, I had a question from a reader about the stories you hear on the news: "New Genetic Discovery Could Lead to Therapy For Disease X". Just how large is the gap between DNA and a drug? The short answer: mighty spacious. Once in a while, you're set up for a short cut. But to balance those out, in the majority of cases you can't get there at all. There are all kinds of ways the process can go off track.
At the genetic level, it's unusual for a single defect to cause an entire disease. There are all sorts of rare conditions caused by such mutations, but most of these are known through only a handful of examples. People have searched the genome back and forth for genes linked to, say, Type II diabetes or schizophrenia, but those diseases just aren't that simple. As is also the case with many types of cancer, there seems to be a constellation of genetic factors that can make you more or less susceptible to the disease, but there's not going to be one single cause. That makes drug therapy hard, because we need those important bottlenecks and pivot points to aim our molecules at.
Even if you find one of those, the next big question is what kind of protein has been implicated from the genetic study. Medicinal chemistry can do pretty well with inhibition of enzymes or blockade of receptors, since those pathways just involve gumming up the works somewhere. Still, there are still large classes of enzymes with no good inhibitors (phosphatases!) and finding small molecules for big protein-liganded receptors isn't easy, either.
But if you need gain-of-function to treat the disease, well, you're almost always out of luck. There's often no handle for a drug to hit to make things work better. For a receptor, we could try to find more and more potent agonists, but a genetic problem with a receptor usually means that it's not signaling properly in the first place. Shouting louder into the phone doesn't work when the connection is broken.
A third level of difficulty is that many disease pathways don't have an obvious place for small molecules at all. Receptors and enzymes have binding pockets already built into them, which we can try to exploit. But there are untold zillions of protein-protein and protein-DNA interactions, and getting small molecules to work on those is a real challenge. It's actually been done, but you can count the successful examples on your fingers. (And if by successful you mean "on the market", I'm not even sure if you need any fingers at all. . .) My usual analogy is that it's like trying to keep two battleships from banging together by sticking a rowboat in between them.
Those levels of difficulty don't leave you very much to work with. If everything is lined up just right, you can take your chances with drug development the way it usually goes - otherwise, it's even harder. A huge amount of money has been spent over the last five to ten years in the drug business, digging through the genome for new targets. It's safe to say that most of that expenditure is a sunk cost on the level of, say, the Andrea Doria.
+ TrackBacks (0) | Category: Drug Development
October 3, 2004
I see that some of the Merck/Vioxx coverage has been along the lines of "Company Finally Heeds Warnings of Unsafe Drug." Boy, the tort attorneys have to love that sort of thing. It's true that Merck had some signs that Vioxx could have cardiovascular problems, but there are a lot of drugs, unfortunately, that show rumblings of this sort. Some of them turn out to be false alarms, and some of them turn out to be real. This one turned out to be real with fangs.
If we immediately pulled every drug that showed any indication of trouble, it's for sure that no patients would come to harm. But we wouldn't have very many drugs, either. It's possible that Merck could have moved more aggressively to see if Vioxx had these problems or not - but if companies immediately ran fully-powered studies to address every red light that comes on, we'd have even more enormous costs to make up than we do already. Nothing's free.
Our job, on the discovery and development side, is naturally to try to find things with the largest positive footprint and the smallest negative one. The size of the latter one never goes to zero; it can't. We try to figure out how big it is, but you can never be really sure until after the drug goes onto the market. It's sad, it's unnerving, but it's absolutely true. The mission of the FDA, in an ideal world, would be to ensure that only drugs that can cause no harm make it to market. In the world we find ourselves in, though, the mission is to balance the potential harm a new drug could cause with the good it could do. That's an awfully tough assignment.
And the job of the injury lawyers is to swoop down after the worst happens, cawing about "defective products" and "willful negligence", and bearing away the biggest chunks their beaks can carry. The sky over Merck is getting dark with them right now.
Speaking of carrying away things in beaks, remember the University of Rochester? A group there made some of the early COX-2 discoveries, and on the strength of a patent, wanted a piece of all the earnings of COX-2 inhibitor drugs. The suit failed, after years of wrangling, on the grounds that the patent did not provide any such compounds, nor did it (or could it) describe what such a drug would look like or be composed of. But if they'd won, do you think they'd be willing to pick up some of the liability? Soak up a little of the lawsuit pain? Or were they only in it for the sunny days while the money was flowing? What do you think?
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Toxicology
October 2, 2004
Something appears to have unraveled in the site's commenting function; it won't let anyone post anything. We'll try to have that fixed soon - in the meantime, I'll try to think of ways to abuse this newfound freedom from contradiction.
+ TrackBacks (0) | Category: Blog Housekeeping