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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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 31, 2008

Drugs and Money

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Posted by Derek

Over at Megan McArdle's site at The Atlantic Monthly, there's been a run of posts on the pharmaceutical industry - touched off, I think, by this one from over here. Her readers are a diverse bunch, some of whom seem to stop by because they can't stand the posts there but can't seem to help commenting on them. So there are some interesting wrangles going on in the comments to this post on the return on investment for R&D, and the follow-up on why we can't necessarily just fund all of it with that marketing money. The next in the series was on the problem, which may have no solution, of getting other countries to pick up more of that investment than they do, and that was followed by one about why nationalizing the whole drug industry might not work out well, either. And today's entry is about what that return on investment might actually be, with an appropriate warning about survivor bias. (I'll add my two cents to that debate by pointing out the notorious Wall Street Journal article which suggested that the entire biotech industry, net, has lost money so far).

There have been some thought-provoking comments to these, some infuriatingly dense ones, and some from people who clearly have done drug discovery for a living. But perhaps my favorite comment of the bunch, in an otherwordly way, has been this one, from one "Mintun":

"Really, what drugs are there left to develop? I think the state of medicine we have now is pretty good now. If we can guarantee most people a reasonably good shot at 80 or 90 years before they die, what else needs to be done? It seems like we are shoveling resources down a pit to get ever diminishing returns? I'd be happy to live under the status quo of the medical technology for the rest of my life. In fact if it means I pay less for insurance etc. over my lifetime it seems like a good trade."

Other people have already let him have it for that one, which saves the rest of us some work. . .

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

January 30, 2008

Recycle, Reuse, Republish

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Posted by Derek

There’s an analysis in the latest Nature that puts some numbers on a problem that scientists the world over have suspected for some time: the number of duplicate papers that show up in the literature. The authors used this online text-similarity tool to go through papers in Pubmed, and found a small (but not as small as it should be) percentage of papers that seem to be the same damn things, recycled.

As it turns out, the “most similar papers” function over on the right-hand side of the Pubmed results was a good starting point for tracking these down, and this shortcut allowed them to search the entire Pubmed database. The authors have set up a web site where they've deposited their data and their lists of duplicate papers. Out of about 7 million abstracts, some 70,000 were flagged as being highly similar to their corresponding "most related article" on Medline. Manual checking suggests that about 50,000 of these are going to be true duplicates - they've gone through about 2700 by hand so far (statistics here).

They have drawn some preliminary conclusions from their data set. For one thing, duplication seems to have been steady or trending down in the database during the 1990s, but has been increasing since 2000 (and is currently at the highest level). Their explanation - the rising number of print and online journals, making copying easier to perform and harder to detect - seems right to me. Another interesting graph is the frequency of duplicates by country of origin, versus that country's relative contribution to the Medline database as a whole. Looked at that way, the US is under-represented in the duplicates (which is good to know), and Japan and China are quite over-represented. Several explanations for this are considered – original publication in a language less used for scientific publication, followed by a chance to expose the same work to a wider audience, for one. But the authors don't hesitate to cite "differences in ethics training and cultural norms" as a factor, too.

A further fascinating detail is that the papers which seem to have been duplicated in different journals by the same author (or authors) very often appear too soon after the first publication to have gone through the reviewing process sequence. In other words, they were most likely submitted simultaneously to both journals, which isn't a nice thing to do. By contrast, when the same stuff appears under someone else's name, there's generally an appropriate time lag.

This study notes that their manual inspections have, so far, found over seventy cases of what looks like outright plagiarism, and that they're starting to contact journal editors and universities for more details. And they also seem to have found a number of what they term "serial offenders", and are investigating those cases as well. They don't go into details, but my guess is that some of those people could possibly be found here.

Their hope is that if such authors realize that such tools exist, that plagiarism and duplication will be seen as more risky. Thus all the publicity. Want to try it out yourself? The list of potential duplicates can be found here. Here's the list of journals, and you can plug those into this search page and see what you come up with. Here are some of the manually checked papers - click on the left-hand side ID number to see a side-by-side comparison.

Comments (16) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

January 29, 2008

The Animal Testing Hierarchy

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Posted by Derek

I've had some questions about animal models and testing, so I thought I'd go over the general picture. As far as I can tell, my experience has been pretty representative.

There are plenty of animal models used in my line of work, but some of them you see more than others. Mice and rats are, of course, the front line. I’ve always been glad to have a reliable mouse model, personally, because that means the smallest amount of compound is used to get an in vivo readout. Rats burn up more hard-won material. That's not just because they're uglier, since we don’t dose based on per cent ugly, but rather because they're much larger and heavier. The worst were some elderly rodents I came across years ago that were being groomed for a possible Alzheimer’s assay – you don’t see many old rats in the normal course of things, but I can tell you that they do not age gracefully. They were big, they were mean, and they were, well, as ratty as an animal can get. (They were useless for Alzheimer's, too, which must have been their final revenge).

You can’t get away from the rats, though, because they’re the usual species for toxicity testing. So if your pharmacokinetics are bad in the rat, you’re looking at trouble later on – the whole point of tox screens is to run the compound at much higher than usual blood levels, which in the worst cases you may not be able to reach. Every toxicologist I’ve known has groaned, though, when asked if there isn’t some other species that can be used – just this time! – for tox evaluation. They’d much rather not do that, since they have such a baseline of data for the rat, and I can’t blame them. Toxicology is an inexact enough science already.

It’s been a while since I’ve personally seen the rodents at all, though, not that I miss them. The trend over the years has been for animal facilities to become more and more separated from the other parts of a research site – separate electronic access, etc. That’s partly for security, because of people like this, and partly because the fewer disturbances among the critters, the better the data. One bozo flipping on the wrong set of lights at the wrong time can ruin a huge amount of effort. The people authorized to work in the animal labs have enough on their hands keeping order – I recall a run of assay data that had an asterisk put next to it when it was realized that a male mouse had somehow been introduced into an all-female area. This proved disruptive, as you’d imagine, although he seemed to weather it OK.

Beyond the mouse and rat, things branch out. That’s often where the mechanistic models stop, though – there aren’t as many disease models in the larger animals, although I know that some cardiovascular disease studies are (or have been) run in pigs, the smallest pigs that could be found. And I was once in on an osteoporosis compound that went into macaque monkeys for efficacy. More commonly, the larger animals are used for pharmacokinetics: blood levels, distribution, half-life, etc. The next step for most compounds after the rat is blood levels in dogs – that’s if there’s a next step at all, because the huge majority of compounds don’t get anywhere near a dog.

That’s a big step in terms of the seriousness of the model, because we don’t use dogs lightly. If you’re getting dog PK, you have a compound that you’re seriously considering could be a drug. Similarly, when a compound is finally picked to go on toward human trials, it first goes through a more thorough rat tox screen (several weeks), then goes into two-week dog tox, which is probably the most severe test most drug candidates face. The old (and cold-hearted) saying is that “drugs kill dogs and dogs kill drugs”. I’ve only rarely seen the former happen (twice, I think, in 19 years), but I’ve seen the second half of that saying come true over and over. Dogs are quite sensitive – their cardiovascular systems, especially – and if you have trouble there, you’re very likely done. There’s always monkey data – but monkey blood levels are precious, and a monkey tox screen is extremely rare these days. I’ve never seen one, at any rate. And if you have trouble in the dog, how do you justify going into monkeys at all? No, if you get through dog tox, you're probably going into man, and if you don't, you almost certainly aren't.

Comments (8) + TrackBacks (0) | Category: Animal Testing | Drug Assays | Drug Development | Pharmacokinetics | Toxicology

January 28, 2008

Laissez-Faire?

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Posted by Derek

Reader B.C. noted this on Ezra Klein’s blog over at The American Prospect, talking about Mark Warner’s Senate candidacy in Virginia. He quotes Warner as saying:

” We need to rationalize drug costs. I won't stand up here and bash pharma. But it's not fair that Americans pay for research and development of the whole world, as other countries all have some pricing constraints."

And Klein then adds:

As readers of this site know, our decision to forgo national bargaining (or even Medicare bargaining) while every other country does use their size to drive down costs has led to a situation in which we pay far more so that Canadians and the French can pay far less. That's what Canadian Drug Reimportation is all about: Buying the same drugs we buy here, but at the prices negotiated by the Canadian government. It's galling, and I'm glad to hear Warner giving voice to it.

It is galling, I have to admit, and Warner’s correct that the US market must be paying for the majority of the R&D expenses of the pharmaceutical industry (since this is where the majority of the money is made, in most cases). My reply was, though, that I was worried that Klein (and Warner?) might think that the solution was to run US prices down to those of the other countries, presenting my industry quite a shortfall on its hands. Here's B.C.’s reply to that (this is him, not Ezra Klein or Mark Warner):

”I disagree with your conclusion. If you have three people bargaining to buy goods and one is willing to pay much more than the others without regard to what the other two will pay, you will sell to him at the higher price and sell excess supply to the others at the lower price, if you are so inclined.

But if all three bidders have the same market clout, then something will have to give. The market will probably reset pricing for all bidders. It might mean reductions in monies available for R&D, it might not. If the bidders are on a more or less even playing field, the market will determine that. I think that is what Klein is saying.

As things stand now, one of the buyers has given the drug companies have a massive put. That's not fair to the (involuntary) stakeholders of that buyer. If that put is removed, there is a much higher likelihood of a more equitable distribution of the burden of R&D. OTOH, as long as that put exists, there is zero likelihood that the current inequitable distribution will be corrected.”

My take on this is that health care spending is in a different category than many other things, for reasons both psychological and political. You’d expect some ordinary economic good to be divided up among three bidders in this way, but I wouldn’t expect medicine to be. It would be politically popular to see prescription drug prices go down here in the US, but it would be (almost certainly) politically impossible to see them go up by the the corresponding amount in Canada, France, Germany, etc.

Of course, I’ve made an assumption there, that the current revenues of the drug companies would remain roughly constant, and just be divided up in a different way. That's probably not how it would work. If you somehow put that idea to a vote across all the countries involved, I’m sure it wouldn’t pass. The majority of consumers, and probably the majority of politicians, would be glad to set the price of drugs by fiat, and that setting would be dialed down to “nice and cheap”. The time lag involved in drug discovery would let you do this and not notice many problems, at least on the pharmacy shelves, for several years.

And that’s the problem with setting prices that way: the temptation is for whoever is on the thick end of the whip – that is, whoever can determine prices by force of law – to set them and be damned. It’s not just drugs: I’m sure that people would, if they thought they could, vote themselves cheaper cars, not to mention the gasoline that runs them. But oil’s a commodity that trades freely, and there’s a constantly changing market price for it. A new medication, on the other hand, has just one supplier. There's just one neck presenting itself.

That turns negotiations between drug companies and governments into a rough business. Very quickly, things can come down to their ultimate positions: “We won’t let you sell in this country” versus “We won’t let you have this drug”. Note that both of these end up with the citizens involved being denied a chance at medical care. It’s as if rug-merchant transactions tended to escalate into threats to set the bazaar on fire.

Governments have another weapon when things get to that point: compulsory licensing. This has already come up with Brazil and Thailand, and will no doubt be threatened again in other places. And that brings me to my depressing point: this playing field will never be level.

Ideally, I would like to see drugs, and drug companies, compete strictly on price and on effectiveness. And I’d like to see that happen around the world, and let supply and demand sort things out. I think that prescription prices would go down a bit here, and up in many other countries. At the same time, generic drug prices would probably drop outside the US. But it won’t happen. The more I think about it, the more I fear that drugs and other health care will never trade on a free market. The temptations to do otherwise are just too great.

Comments (14) + TrackBacks (0) | Category: Business and Markets | Drug Prices

January 25, 2008

Extractions: A Way of Life

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Posted by Derek

Over at Org Prep Daily, Milkshake did an excellent post earlier this month on extraction techniques. It’s well worth looking over, even for experienced lab crew. Solvent extractions are a way of life for organic chemists, a fact that has not changed since the beginning days of the science, because (for one) we still do the bulk of our reactions in one sort of solvent or another, and (two) because the bulk of our reactions need to have garbage removed from them, and this is the first line of cleanup. (Here it is in real life - scroll down).

For those readers who aren’t chemists, three paragraphs of explanation: extraction works on the “like dissolves like” principle. A look at a bottle of oil-and-vinegar based salad dressing that’s been sitting for a while will show the familiar layers, with the oil on top and the aqueous layer below. If you were to take samples out of each and analyze them, you’d find that they contain rather different parts of the dressing mixture. The oil layer will have the compounds that can’t dissolve in water very well – organic pigments like carotenes or lycopenes, for example. They’re better off in with the oil molecules; they don’t have any polar molecular features strong enough to horn in on the hydrogen bonds that water uses to stick to itself.

Down in the water layer, on the other hand, is all the stuff that has such polarity. All the amino acids and most proteins will be there, as will the sugars and other soluble carbohydrates. These compounds have a lot of groups (hydroxyls, amines, carboxylic acids) that can interact strongly with the small, polar water molecules. Since there’s a lot of vinegar in there, too, acid-base chemistry will be a factor. The compounds with strongly basic groups (fishy amines and the like) will be protonated by that acetic acid, and the resulting salt is a natural for the water layer. A few base-containing things that might otherwise be just as happy in the oil layer will be pulled in by this effect.

So if you have a messy mixture of stuff, you can separate the greasy components from the polar ones by shaking up the lot in a mixture of water and some solvent that’ll form a separate layer. Sometimes you’ll want one layer, sometimes the other, depending on what your product is like, but most of the time organic chemists are throwing out the water layer and keeping the other one. There are other tricks – for example, if your compound’s acidic or basic, you can adjust the aqueous layer the other way to hold it as a salt, wash out all the other goo with solvent, and then change the acidity so that your compound will now go into a fresh solvent wash. In all these cases, you drain off the appropriate layers with one of these.

I would not like to hazard a guess at how many extractions I’ve done. Shaking a sep funnel is such a basic act of organic chemistry – every time you mix something up and wait for the layers to separate, you’re participating in a rite that goes back to the days when labs were only illuminated by sunlight or fire. It’s one of the few things that a scientist from the 1850s would immediately recognize if teleported in front of my fume hood, that’s for sure (the fume hood itself would be a revelation, for starters).

I have to say, though, that Milkshake’s nom de blog is an unfortunate one for the topic, since one of the worst things that can happen to you during an extraction is a thick emulsion. That’s when the layers don’t want to separate – millions of tiny droplets of each component decide, for various irritating reasons, that they’re happy where they are, thanks, and don’t pair off with their former comrades. The result is a thick, opaque mess, so the name for the most intractable emulsions is, naturally, “milkshake”.

One of the things he mentions as seldom seen these days is actually one of my favorite pieces of lab apparatus: the liquid-liquid continuous extractor. Sad to say, I don’t have one these days, but I could find or buy one if the need arose. There’s something appealing about setting up a continuous, automatic purification. Being able to see the results over time (the solvent pot in these things gets uglier) makes you feel as if you’re getting something done even if all you’re doing is standing there watching the extractor. A fine apparatus it is, and worth a post of its own some day. . .

Comments (4) + TrackBacks (0) | Category: Life in the Drug Labs

January 24, 2008

Cheap Happiness

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Posted by Derek

There are some well-known expensive ways to make scientists happy: buy them lots of equipment and put it in fancy new buildings, pay them lots of money to work there. Come to think of it, that works on just about anyone. But there are some cheap ways to make them happy, too, and companies are really hurting themselves if they don’t pick up on them.

Recognizing what the people in the lab do doesn’t cost very much. Odds are excellent (odds are downright overwhelming) that the people downstream in regulatory affairs and marketing have no idea of who the people were that came up with the latest drug they’re trying to get over the top. Some of them, in a large company, may have only a rough idea of where it came from at all.

Let ‘em know, but do it the right way. Company newsletters get thrown away, mass e-mail get deleted. No, next time there’s a department-wide meeting over there, give ten minutes or so to bring up some of the people who discovered and worked on the current hot compound. If one of them is up for it, have them say a few words. Seeing the hordes of people working on their compound will cheer up the scientists, and seeing where the compounds came from will be a new experience for marketing. Human contact is good; it’s harder to let people down after you’ve met them and seen them.

You can run this in a negative sense, too, naturally, if you’re so inclined. Get one of the higher-ups in the company to mispronounce the name of a discovery project or two during a big speech, and watch what happens. I’ve seen it myself – it works like bug spray on morale, and one of the reasons is that everyone knows that it’s such an easy mistake to avoid.

Not being a hard case about time is another one. You’d think that this would cost money, as people abuse your generous spirit, but for the most part, it’s the opposite. I knew a lab at a former company where the lab head immediately swiveled to look at the wall clock whenever an associate arrived in the morning, or left in the afternoon. This person couldn’t seem to help it. They had to check to make sure they were getting their full day’s work out of the underlings. Morning, evening, check that clock. What did this buy them? A lab full of people who made sure to never set anything up that would take them one minute past Official Quitting Time, and who made the absolute most out of any sanctioned opportunity to not be in the lab with their boss. Not the outcome you want. The same goes, on a larger scale, for vacation days. Slip people a day here and there when they need it, and they’ll work when they’re there.

Keeping people informed isn’t that expensive either. I’ve worked in places where, once a compound went off to the clinic, it vanished off the edge of the earth as far as the people in the discovery labs could see. There was one time when a drug that had been years in development was canned, and chemists who had spent many of those years only heard about it by third-hand rumor. That’s just not right, and it sure didn’t improve anyone’s mood. Losing a drug from the clinic is never a happy occasion, for sure, but you don’t want to add to the pain. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs

January 23, 2008

Making the Adjustment to Smallness

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Posted by Derek

I have a reader here in the Northeast with a question about taking on a new job that I thought would be of some general interest. She’s been in the industry for a few years now, working at a pretty large site, but (as with many others), layoffs have sent her to a smaller company in another area.

Much smaller. The new gig has a dozen or so chemists on staff, and while it’s true that there are smaller places still than that, it’s still going to be quite a switch after BigCo. There aren’t many direct reports; it’s a pretty flat organization. She has several questions. For one thing, if it becomes necessary to seek another spot in a few more years – and with a site that size, that’s always in the cards – how will this job look on the c.v.? Can this be turned into a step up, or will it always look like a holding action? Second, how to adjust from having all kinds of equipment and instrumentation to the rather more Spartan lab environment of a small outfit?

My take on the first question is “It depends on what you do with it”. Duties in a place that size are going to be much different than in a large department, and you have to try to make sure that you take on things that will help out your career. You’re probably going to have a lot more say in how things are going than you did back in the old place, so make the most of it. You may, depending on how they’ve been hiring, even be one of the more experienced med-chem people there. If that’s so, try to get over your unease at the thought of someone listening to your advice and become a resource. There may be several of your fellow chemists who’ve never had the chance to see how a big research department does things.

Of course, some of those big company habits may be things you’ll have to shed. There’s no place to hide in a department that small, so you’ll have to step up and produce. You’ll also, after a suitable grace period, need to be heard in meetings – no more sitting in the back of the room, because the room isn’t going to be so crowded. And you’ll have to get used to decisions being made with less data, and in less time, than you’ve had to before. But that’s something that can be portrayed in a good light if you move on later.

The lack of direct reports for you will be something you’ll have to watch out for if it comes time for another job, as you’ve probably already figured. By that time, you’ll be at a level where people will expect you to be able to handle some people reporting to you. The best advice I can give you is, if it comes to that point, to sell/spin it as having had to work in a matrix-style organization, where you had to give some orders without line responsibility. Doing that well isn’t easy, so it’s valuable to show that you can.

The equipment problem is a harder one to deal with. Instrumentation withdrawal is nasty, but there’s no way to deal with it other than going cold turkey. You may feel at first like you don’t have enough equipment to do your job, but look around you: your colleagues are (presumably) doing theirs. Emulate their techniques, if they seem to be working for them. (If and when you move on, you can try to make people draw the conclusion that if you could accomplish as much as you did under those conditions, you must be pretty good). And try not to complain too much, or talk too much about what you had back in the old shop – it won’t make you feel much better, and it’ll definitely make other people around you feel worse (and lower their opinions of you).

Again, you may feel as if you’re being asked to move things along with less certainty than you’ve had to before, but the flip side of that is that the projects themselves will (or at least should!) move faster. If you find that things are really being run in a scientifically irresponsible manner, of course, you’ll need to either try to change that or (more likely) move on before things fall apart, but that’s an unlikely case. (And some pretty marginal projects and decisions can be found in the big departments, too, for that matter, as you’ve probably already noticed). All in all, you’ve most likely got a better chance of having your fingerprints on a clinical candidate than you did back at BigCo, so make the most of it. And keep your contacts with your old colleagues, and keep your resume updated, which is good advice no matter where you are.

Comments (8) + TrackBacks (0) | Category: How To Get a Pharma Job

January 22, 2008

These Fragments I Have Shored Against My Ruins

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Posted by Derek

There’s been a big trend the last few years in the industry to try to build our molecules up from much smaller pieces than usual. “Fragment-based” drug discovery is the subject of many conferences and review articles these days, and I’d guess that most decent-sized companies have some sort of fragment effort going on. (Recent reviews on the topic, for those who want them).

Many different approaches come under that heading, though. Generally, the theme is to screen a collection of small molecules, half the size or less of what you’d consider a reasonable molecular weight for a final compound, and look for something that binds. At those sizes, you’re not going to find the high affinities that you usually look for, though. We usually want our clinical candidates to be down in the single-digit nanomolar range for binding constants, and our screening hits to be as far under one micromolar as we can get. In the fragment world, though, from what I can see, people regard micromolar compounds as pretty hot stuff, and are just glad not to be up in the millimolar range. (For people outside the field, it’s worth noting that a nanomolar compound binds about a million times better than a millimolar one).

Not all the traditional methods of screening molecules will pick up weak binders like that. (Some assays are actually designed not to read out at those levels, but to only tell you about the really hot compounds). For the others, you’d think you could just run things like you usually do, just by loading up on the test compounds, but that’s problematic. For one thing, you’ll start to chew up a lot of compound supplies at that rate. Another problem is that not everything stays in solution for the assay when you try to run things at that concentration. And if you try to compensate by using more DMSO or whatever to dissolve your compounds, you can kill your protein targets with the stuff when it goes in. Proteins are happy in water (well, not pure distilled water, but water with lots of buffer and salts and junk like the inside of a cell has). They can take some DMSO, but it’ll eventually make even the sturdiest of them unhappy at some point. (More literature on fragment screening).

And once you’ve got your weak-binding low-molecular weight stuff, what then? First, you have to overcome the feeling, natural among experienced chemists, that you’re working on stuff you should be throwing away. Traditional medicinal chemistry – analog this part, add to that part, keep plugging away – may not be the appropriate thing to do for these leads. There are just too many possibilities – you could easily spend years wandering around. So many companies depend on structural information about the protein target and the fragments themselves to tell them where these little guys are binding and where the best places to build from might be. That can come from NMR studies or X-ray crystal determinations, most commonly.

Another hope, for some time now, has been that if you could discover two fragments that bound to different sites, but not that far from each other, that you could then stitch them together to make a far better compound. (See here for more on this idea). That’s been very hard to realize in practice, though. Finding suitable pairs of compounds is not easy, for starters. And getting them linked, as far as I can see, can be a real nightmare. A lot of the linking groups you can try will alter the binding of the fragments themselves – so instead of going from two weak compounds to one strong one, you go from two weak ones to something that’s worse than ever. Rather than linking two things up, a lot of fragment work seems to involve building out from a single piece.

But that brings up another problem, exemplified by this paper. These folks took a known beta-lactamase inhibitor, a fine nanomolar compound, and broke it up into plausible-looking fragments, to see if it could have been discovered that way. But what they found, each time they checked the individual pieces, was that each of them bound in a completely different way than it did when it was part of the finished molecule. The binding mode was emergent, not additive, and it seems clear that most (all?) of the current fragment approaches would have been unable to arrive at the final structure. The authors admit that this may be a special case, but there’s no reason to assume that it’s all that special.

So fragment approaches, although they seem to be working out in some cases, are probably always going to miss things. But hey, we miss plenty of things with the traditional methods, too. Overall, I’m for trying out all kinds of odd things, because we need all the help we can get. Good luck to the fragment folks.

Comments (7) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays

January 21, 2008

Breaking the Contract of Aging

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Posted by Derek

Update: Prof. de Grey responds to Jim Hu's criticisms below

I didn’t note it at the time here, but back in November there was a very interesting paper in Nature that bears on aging and life extension. A group at the Hutchinson Center in Seattle did a survey of compounds, looking for whatever might show up that seemed to extend lifespan. (That’s just the sort of see-what-falls-out screen that C. elegans is good for, since the little beasts are so small, and they only live for about 20 days or so).

They screened 88,000 compounds - by far the largest direct survey ever run for longevity, as far as anyone knows, but (I should point out) still a tiny run by industrial standards. But they came up with a few hits: 1083 compounds made the first cut (roundworms still alive longer than they should be), and 115 of those repeated with statistical significance. 13 compounds increased lifespan by 30 to 60%. Interestingly, I don't think that they list all of them in the paper, but they did note that one of the strong hits looked very much like a known hit set of serotinergic antagonists.

They ran a set of analogs through the assay, and had a high hit rate. All the compounds that worked were 5-HT2 antagonists, such as marketed drug mianserin, although they each have some other activities as well. (It should be noted that the reuptake inhibitors, the Prozac/Zoloft type compounds, had no effect). But the 5-HT2 subtype, particularly 5-HT2c, has long been regarded as important in food intake, so the guess is that these compounds also tie into the whole caloric restriction story for aging. Restricting food intake and giving one of these drugs at the same time didn't add anything, the group found. It may be that these compounds set off metabolic signals that tell the roundworms that they’re short of food, even they they really aren’t, and thus do a sort of fake caloric restriction on them. At any rate, mutant nematodes that can't make serotonin showed no lifespan extension with exposure to these compounds, so one way or another, it seems to be involved.

Now, I wouldn’t advocate running out and trying this on a human being just yet, though, since we’ve come up with several higher brain functions for our serotinergic receptors that roundworms don’t have much call for. There’s also the question of what this strategy would feel like in a higher animal: would you want to live longer, but always feel as if you were starving, for example? I know that the people who are trying CR on themselves say that this isn’t the case, at least after the first few weeks or months (!), but there’s no telling what would happen with a pharmacological approach.

What this study does point out, though, is something that I think that a lot of people haven’t really caught on to yet: first, it’s increasingly clear that there are deep connections between metabolism and lifespan. All sorts of genes related to food intake and insulin signaling affect how long model organisms live, and there’s every reason to expect that the same is true of us.

Second, the settings for our lifespans may not be optimal – or what we’d now consider optimal. There’s every reason to expect that this relationship has been under very heavy selection pressure. Evolutionarily, this would be the balance between reproductive fitness and everything else an organism might do, and evolutionarily, reproductive fitness is going to be the big winner every time. But there’s no reason that we necessarily have to accept whatever tradeoffs were made during the development of our species.

We’re going to have to be very careful, of course. There may be all kinds of catches to extending lifespan – susceptibility to cancer and other diseases being the first one that everyone thinks of. But ever since our brains became large and complex enough for language and culture, and ever since we started growing our own food, we’ve been altering the evolutionary bargains that all other species have had to make – predator/prey relationships, availability of food, and so on. We may yet be able to draw a black line through another paragraph of the contract, and make it stick.

I don’t think that many people realize that this is possible, or that it’s an area of active research. Most of the large drug companies, in fact, seem to be staying away from it for now, content to let the smaller ones take on the (considerable) risks. Some people may not be able to get past Aubrey de Grey’s hair, and may have decided the whole subject is out on the fringe. But, increasingly, I don’t think it is. This stuff could work, eventually, and if it does, it’ll be one of the biggest inflection points in the history of the species.

Update: Jim Hu has more to criticize about de Grey than his hair - see here and here, for starters. Of course, as Jim himself points out in the comments, criticizing de Grey isn't the same as criticizing research on aging. Perhaps de Grey's high profile is doing as much harm as good for the field. . .

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan

January 18, 2008

Eat It, Breath It, Soak in It?

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Posted by Derek

After Pfizer’s Exubera inhaled-insulin product died so horribly in the market last year, the other companies working in the same space had to be worried. Lilly and Alkermes have had a long-running program, as has a smaller company called Mannkind. But recently, another contender, Novo Nordisk, has announced that they and partner Aradigm have decided to cut their losses. The In Vivo Blog has an excellent roundup.

According to Novo’s CEO, they (like Pfizer) were focusing on prandial insulin because that was basically the only thing they could get to work through inhalation. Now that they’ve seen how well that went over, they’ve decided to spend the money on different proteins (basal insulin, glucagon-like-peptide 1 analogs, etc.) They have a GLP-1 analog in Phase III, but apparently are heading toward the clinic with a second-generation one that can work by the inhaled route.

I wish them luck. We really need new routes of administration for drugs, and every seemingly good candidate has some real problems. There’s a limit to how much compound you can administer transdermally through a patch, for example, and a limit to how quickly it can be administered. Long, slow, continuous delivery is fine, but no one’s going to be marketing an epinephrine patch for anaphylactic shock any time soon. Similarly, you can probably forget about antibiotic-sized total doses, too, because nobody’s skin has enough surface area. (I know, I know, on some people you might think it would work – but if you weigh a lot, you probably need more antibiotic to start with on a mg/kilo basis, and meanwhile your surface area goes up as a square while your volume goes up as a cube, and it’s a losing battle).

No, unless we find some way to make the skin crazily permeable, it’s never going to be a great delivery system. And crazily permeable is just what the skin is not, for good reason. That’s why pulmonary delivery makes sense, to a first approximation. The lungs have huge surface area, just like the small intestine does for oral dosing, because both those organs live to absorb things from the environment (as opposed to the skin). The lungs absorb a gas, unfortunately, as opposed to the small molecules absorbed by the intestines, but a gas is just a special subset of small molecule.

But there’s the downside of the idea. While an oral drug is piggybacking on machinery that’s doing what it’s supposed to be doing, lung delivery is making the organ do something it’s not. (Thus the idea of dosing peptides by this route, since the lungs aren’t a soup of proteolytic enzymes, and pulmonary circulation does not feed your compounds right into the sawmill of the liver). While the intestine absorbs all kinds of stuff, the lungs are there to absorb only one gas and excrete only one. And that primary function of oxygen / carbon dioxide transfer is rather vital, so if you’re going to horn in on it, you’d better be sure that you’re not going to degrade things.

That’s always been the worry with inhalation dosing. We can get around the acute problem of choking the patients, but the chronic problem of potential lung damage is always a worry. Lung function varies quite a bit, too, even under normal conditions, That variation is both patient-to-patient and from time to time – how do you take your inhaled medicine when you have a chest cold, or if you pull a muscle? (And that’s another reason why it’s sort of a grim cosmic joke that insulin turns out to be the big test for peptide drug delivery through the lungs, since its safe dosing window can be so narrow).

I’ll go into the ups and downs of other potential administration routes in another post. Most of them involve sharp objects, though, so they take on a certain similarity, and have the same only-if-I-have-to reputation.

Comments (3) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Pharmacokinetics

January 17, 2008

The EU Suspects No One, And Suspects Everyone

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Posted by Derek

Thanks to a longtime reader in Germany, I have the scoop from the EU and the respected Frankfurter Allgemeine Zeitung newspaper. In an article about drug prices and drug approvals, titled “The European Pharmaceutical Industry Under Suspicion”, we find (my translation following):

”Die Kommission betonte, bislang lägen keine konkreten Indizien für wettbewerbswidrige Absprachen zwischen einzelnen Herstellern vor. Es sei aber auffällig, dass die Zahl neu angemeldeter Arzneimittel-Patente von durchschnittlich 40 in den Jahren 1995 bis 1999 auf durchschnittlich 28 im Zeitraum von 2000 bis 2004 zurückgegangen sei.

„Wenn innovative Arzneimittel nicht hergestellt werden und kostengünstige Generika zum Teil erst mit Verzögerung auf den Markt gelangen, dann müssen wir nach den Gründen suchen“, erklärte EU-Wettbewerbskommissarin Neelie Kroes.

The Commission stressed that so far there was no concrete evidence of anti-competitive agreements between individual manfacturers. It was striking, however, that the number of new registered patented medicines declined from an average of 40 in the years 1995 to 1999 to an average of 28 from 2000 to 2004.

"When innovative medicines are not being made and cost-effective generics come first on the market only with delays, then we must search for the reasons," said EU Competition Commissioner Neelie Kroes.“

(Update: Here’s more, in English, on the same story.)

Well, I’m glad they’re on the case. Hey, I’m not proud – I’ll take help from anywhere. If a commission of bureaucrats can figure out how to increase our success rates, I’m willing to listen. Mind you, I’m probably going to find something else to do with my time while I’m waiting for Neelie and the gang to get back to us, but still. I note, though, that their other concern is the “delay” in getting generics to market, and I’d like to address those accusations of shady dealing in there.

Here’s a minor problem with that theory: generics come out, on average, rather quickly over here in the US. I mean, right when those patents expire – and the generic companies are often in court, pitching various theories about how the various patents should be expiring even earlier. “Ah,” but you may be saying, “but that’s because prices in the US are so high – they’re looking to scoop up those profits as soon as they can”.

I’m not one to say bad things about the profit motive, of course, and the size of the US market is a big incentive all its own. But here’s something that a lot of people don’t realize, including perhaps members of EU commissions: generic drugs are cheaper in the US than in Europe. We have more expensive drugs on patent, but once they go generic, competition really slices them down, and the generic companies make it up on volume. The profit margin on generics is, last I heard, higher in Europe.

So that would be mighty crafty of the various drug companies, to hold back on entering a profitable market that way. What, then, could be the reason? Regulatory delays, anyone? Courtesy of the same EU superstructure that’s looking into said delays? Think of how many meetings, committees, and conferences it could take to work that one out. I’ll try to speed things up for them: Here in the US, generic companies are free to work on production and regulatory issues even before the relevant patents expire, thanks to the “research exemption”. This has not generally been the case in Europe. There’s also the problem that in many EU member states, generics account for only a tiny bit of the market, apparently due to decisions by the health insurance carriers themselves – which are either arms of the state, or heavily regulated by it.

There, maybe that will help. Of course, if the process of investigating all these suspicions were to move more quickly, the impact would be felt by various restaurants in Brussels and conference hotels all over the place, so we have to consider the economic factors. Good luck, folks!

Comments (16) + TrackBacks (0) | Category: Drug Development | Drug Prices | Press Coverage

January 16, 2008

Judah Folkman

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Posted by Derek

So Judah Folkman is no longer with us. He's considered to be the father of the idea that many tumors help to make their own blood supply, through angiogenesis, and that this could be a way to impede their growth. Since his first papers on the topic were published back in 1971, I think he does indeed get the credit. And he should not only get the credit for having the idea, but for publishing it and sticking with it. (Here's an interview with Folkman where he talks about this and much more).

Interestingly, it had been noted as long ago as 1941 that transplanted tumors in animals managed to link in to the existing blood supply through the formation of new vessels, but no one knew what to do with this result. (Here's a history of the field from a few years ago). It's not surprising that it took so long for the idea to catch on, though. It was by no means clear back in 1971, much less 1941, how blood vessels could be raised up by signaling from their target tissue. It wasn't until much later that the signaling pathways for blood vessel growth were discovered. Vascular endothelial growth factor, for example, was only found in 1983, and its functions didn't become clear until 1989 (timeline).

Folkman's death (which took place in the Denver airport, of all places) has brought back memories of the (in)famous Gina Kolata article on Folkman's work in the New York Times from 1998, a front-pager which featured James Watson's notorious quote about how Folkman was going to cure cancer in two years. I wrote about that one in the early days of my blog, and again here when Entremed finally gave up on the compounds that Kolata and the Times had hyped to the skies. The year 2000 came and went without a cancer cure, and many more years are going to go by as well. That's because, as I and many others never tire of pointing out, cancer isn't a single disease, and will never have a single cure. It's like looking for a cure for bad writing - it comes in so many different varieties, for so many different reasons, and therefore needs many different fixes.

Comments (6) + TrackBacks (0) | Category: Cancer | Current Events | Drug Industry History

January 14, 2008

Vytorin, Holed Under the Waterline

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Posted by Derek

Merck and Schering-Plough have released the data on a study of genetically high-LDL patients taking a statin alone (Zocor, simvastatin) or the combination of the statin and Schering-Plough's cholesterol absorption inhibitor (Vytorin, simvastatin and ezetimibe). Vytorin has a good share of the market, and has already been shown to lower cholesterol.

And so it did this time: the Vytorin patients showed a 58% decrease in LDL, while the Zocor group showed a 41% reduction. But this trial went further, looking at the growth of atherosclerotic plaques. You'd figure that a greater decrease in LDL would mean a greater decrease in the size and growth of plaques.

You'd be wrong. The Vytorin group's carotid arteries, measured in a standard way (intima-medial thickness, IMT) came out as 0.0111 mm, while the Zocor group's came out as 0.0058 mm. This is making the headlines as "twice as bad as Zocor", but the difference actually isn't statistically significant (p = 0.29). Steve Nissen of the Cleveland Clinic is quoted as saying that this is "as bad a result for the drug as anybody could have feared", but that's not quite right. If that p value had been, say, 0.01, that would be worse. Strictly speaking, you can't call the two groups different. They don't seem to have been different in cardiovascular outcomes.

But here's the real point: that's bad enough. The whole point of Vytorin is that it's supposed to be more effective than a statin alone, and what you can say about this trial is that it sure didn't prove that. But that carotid artery thickness is definitely a concern - the numbers appear to have big error bars on them, but they're certainly not pointing in a good direction. And it's going to be difficult, perhaps impossible, to ever know if that effect is real, because it'll be mighty hard to get another trial of this sort off the ground after results like this. How can you enroll a treatment group for a drug that has been shown to have no benefit?

Well, OK, there's that LDL reduction. But the downstream clinical data (the artery measurements and outcomes) overrule that. The point of taking a cholesterol medication is not to make your lab test numbers go up and down, the point is to have fewer heart attacks and strokes. We use those blood lipid numbers as a convenient surrogate, but it's been obvious for a long time now that we have, to put it delicately, an imperfect understanding of their relevance. Data closer to real mortality and morbidity outcomes will win.

Now what? This is clearly terrible news for Merck and (especially) for Schering Plough. The companies already were under pressure for having taken so long to work up the data for this trial, which delay ended up just drawing even more attention to these bad results. Now, how do you go out and sell Vytorin (or Zetia, the cholesterol absorption inhibitor alone)? Why do insurance companies have motivation to pay for it? And when are we ever going to understand the complexities human lipid behavior and cardiology?

More on ezetimibe, written in happier days, here , here, here, and here. .

Comments (35) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage

January 11, 2008

They Can Be Ranked - Somehow

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Posted by Derek

I really should call attention to this blast against journal impact factors from the folks at Rockefeller University Press. They have a number of complaints, among them that the folks at Thomson who put the numbers together are inconsistent about what gets counted as a citable article and what gets tossed aside as “front matter” (editorials, news updates, etc.)

They went so far as to purchase the Thompson data to check the impact factors for their own journals, but despite several attempts, they could never get anything that matched up with the official figures. The explanations they received for this problem were of gradually decreasing credibility.

” When we requested the database used to calculate the published impact factors (i.e., including the erroneous records), Thomson Scientific sent us a second database. But these data still did not match the published impact factor data. This database appeared to have been assembled in an ad hoc manner to create a facsimile of the published data that might appease us. It did not.

It became clear that Thomson Scientific could not or (for some as yet unexplained reason) would not sell us the data used to calculate their published impact factor. If an author is unable to produce original data to verify a figure in one of our papers, we revoke the acceptance of the paper. We hope this account will convince some scientists and funding organizations to revoke their acceptance of impact factors as an accurate representation of the quality—or impact—of a paper published in a given journal.”

There’s now some competition for journal ratings, at any rate. You can search this list for free – they have their own system for ranking journals, which I don’t completely understand, but the order of the chemistry titles is not obviously crazy. It’s hard to keep the review journals from dominating any such list, and that’s what they do here. Accounts of Chemical Research, for example, usually come out pretty high, although its actual let’s-see-what’s-in-there readership is probably not too impressive.

What fascinates me, though, are the lower reaches. I have a grim curiosity about the least impactful titles, the unciteable compost bins whose pages never flip. Sorting things out that way, you find journals in which, it's safe to say, every single author wishes that their paper could have gone somewhere else. In this better-than-nothing league (an arguable assertion, in many cases) you find what you expect to find: Egyptian Journal of Chemistry, the evocatively abbreviated J. Chem. Soc. Pak. andBull. Chem. Soc. Ethiop., among others. You may have seen these things come up in particularly diligent online searches.

But have you ever seen anything from Chemical Papers? There's an exciting name for you - that one's from Slovakia. Or Oxidation Communications? Did you even know that a journal with that title existed? (It's Bulgarian). Journal of Natural Gas Chemistry? Chemical Journal on Internet, from Switzerland, of all places? Maybe I don't get around enough.

Another thing you learn is that some journals you've heard of are not doing very well. It seems safe to say, for example, that the Beilstein Journal of Organic Chemistry is not working out so far, since it's face-down in the mud at number 468 out of 470 titles. The Journal of Structural Chemistry could apparently vanish from the earth without many people noticing, as could Chemistry of Natural Compounds, and there's a whole list of Russian and Chinese journals that publish large numbers of manuscripts to very little effect.

Comments (12) + TrackBacks (0) | Category: The Scientific Literature

January 10, 2008

Drugs and Money and How It Feels

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Posted by Derek

Imagine that if you wanted to buy a car, you had to first visit a car consultant. This would be an expert who would place your order with a car dealer, after first looking over your transportation needs, financial status, and other factors. No one would be able to order a car on their own. Advertisements for cars would look similar to the ones we have today, except there would be a phrase at the end to “Ask your car consultant”. Much more advertising and promotion, though, would be directed at the consultants themselves, as you’d figure. A steady stream of representatives from the various automakers would come by, extolling the virtues of the latest models and leaving stacks of glossy literature, DVDs, etc., along with offers of free trips to come by for some test-drives.

Let’s move the analogy over to something a bit more realistic: mortgages. Given the current subprime meltdown, it wouldn’t surprise me much if someone, somewhere, has called for the creation of a class of mortgage advisors. Anyone looking to borrow money for a real-estate transaction would be required to go through at least a cursory visit with one. The advisor would look over your finances, explain the different mortgage options out there, and make sure that you understood what you were getting into if you had a particular offer in mind. In fact, the advisor would do more than that – if you didn’t meet certain criteria, they would not put you in touch with a lender. Some advisors would be more lenient than others, but you’d have to see one, and have them sign off on your mortgage, before you could legally borrow money.

Ads for low interest rates and creative refinances would still be around, but they’d always end with an urgent request to call your mortgage advisor immediately, before the great deal evaporated. And the bulk of the promotion money would, again, surely find it way to trying to influence the mortgage advisors themselves. Lenders would come in with figures showing how few people had defaulted with them, what percentage of the loans in a given market they underwrote, and so on. As gatekeepers in an important industry, they’d be much in demand.

Of course, in the world we live in, we trust adult consumers to be able to make decisions about which car to buy. The car companies lose no opportunity to try to make people think about the advantages of a new car, both emotional and tangible, and to suggest that it would be easy to purchase one. The car dealers themselves stress the same points, and add more details about how easy they are to deal with. People do get into bad leases or buy more car than they can really afford, but that’s considered largely the customer’s problem.

And (for now, anyway) we trust adult consumers to be able to decide for themselves if they’re ready to buy a house, which houses they might be interested in purchasing, and how they might wish to do so. This is a harder decision, since it involves a much greater commitment of time and money than purchasing a car, and there are many more options available. The existence of real estate agents and attorneys show that more people feel the need for and are (more or less) willing to pay for outside assistance in buying or selling the property itself, but there are as yet no licensed mortgage agents of the kind I describe above. That’s typically left up to the customer.

So we finally come to prescription drugs. Medical care is even more complicated than real estate – you can obtain licenses to sell properties or mortgages far more easily and with far less schooling than you need to obtain one to practice medicine, and that’s a good thing. You also cannot obtain new medicines, or any drugs for major diseases, without seeing a doctor first, both to make sure of the disease and to advise on its treatment. Consumers – and by this time, we use the word “patients” – are free to follow or not follow this advice, or to shop around until they find a doctor whose opinions they like better (if any), but they are not free to purchase and dose themselves (or others) with prescription drugs.

The difference is, as anyone will tell you, that health is an intensely personal category unto itself. A person’s health affects every aspect of their life, immediately and continuously, in a way that not even the roof over their heads can. Medical issues are unavoidably saturated with thoughts (and fears) of death or grave disability, and always have been. This has receded in places as medical science has reduced the incidence of some causes of death, but overall, this emotional entanglement is very much with us, and will be for a very long time. Look closely, and you’ll see it: as mentioned above, we have a whole special word for “customer of a physician”, because we don’t usually think of the relationship in business terms. “Patient” connotes someone who is in the care of someone else, whose fate rests partly or wholly in another’s hands.

The unusual quality of a medical transaction is understandable for another reason as well, since traditionally the course of a physical ailment has been uncertain, and the ability of medicine to do anything about it has been likewise in doubt. For most of human history, seeing a doctor has been very much like seeing a priest. It has not been looked at as a business interaction, and in most cases it had no hope of ever being one in the usual sense. (See Lewis Thomas’s The Youngest Science for more on that – he points out that almost everything his physician father prescribed in his day was a placebo of one kind or another).

The personal and emotional importance of disease (and of treatment) leads to behavior that is seen less often in other activities. People will spend terrifying amounts of their own money in the hopes of helping themselves or close family members, even in cases where the probability of success is tiny. Huge sums are spent in this country on people who are clearly near death. A person who would never dream of taking their savings to the racetrack and betting it all on a 50-to-1 longshot horse will take the same amount and put it down, with hardly a second thought, on a 500-to-1 chance of a successful medical treatment. This changed attitude extends further: medical personnel are often paid well for their efforts, but they can also give a great deal of themselves in the process, since lives are at stake. There’s an urgency, a justifiable sense of importance, which is hard for people in other professions to feel as often or as intensely.

So medicine, will probably always be special – at least, I don’t see that changing in the lifetime of anyone reading this. That complicates things, though, because (like it or not) money is involved. How could it not be? In fact, I’d say that this is one of the most obvious grinding points of friction between the worlds of private emotion and of commerce. Many people find the whole idea of medicine for profit unappealing and somehow unseemly. Since this is an area where altruism is more common (and more easily recognized) than usual, the contrast between selfless sacrifice and self-interested capitalism is especially disconcerting.

But the value people place on effective medical care, and the difficulties of discovering and providing it, ensures that large amounts of money will always be involved. Medical care works better than it used to, and it has reached that state through vast efforts, which deserve to be compensated. It’s true that when money changes hands, it can be an evil sign, as with charlatans cynically exploiting desperate people with snake-oil cancer treatments and the like. But it doesn’t have to be. We all work for a living; money does not have to stain everything it touches. Physicians deserve to be compensated for their work, proportional to its value and difficulty, and to their skills in performing it. And drug companies should be compensated for their efforts in discovering new drugs, also according to their value.

Not even the harshest critic of the industry would balk at that last statement, but that because we haven’t come down to numbers yet. If you believe that virtually all the work of drug discovery is done through federal funding, with the drug industry stepping in at the end to decide on the price and the packaging, then you will feel that this compensation should be rather minimal. (If you think that, you’re mistaken, but that’s another topic).

How, then, to decide how much a given drug therapy is worth? Any economist will tell you that the price of some good is, finally, what people are willing to pay for it. This principle works silently, for the most part, until someone offers to resell tickets for the big game for five times what they paid for them, or when the price of lumber and gasoline goes up after a hurricane comes through. At such points it stops seeming so reasonable to many observers (although nothing has changed, in terms of supply and demand). It also stops looking so reasonable to many people in the case of pharmaceuticals, but under completely normal conditions – no hurricane is necessary.

My industry realizes this (any fool realizes this). But it’s never known quite what to do about it. Pointing out that drug discovery is expensive has been a traditional argument, and it’s one that I’ve made myself. But that doesn’t address the underlying reasons for the uneasiness. Paying money for health care does not descend to the same mental category as paying money for car repairs just because someone has tried to make a case for the accounting involved. People don’t believe the numbers, anyway, but even the most believable numbers in the world would not do the trick.

Pointing out that these are, in some cases, life-saving therapies (important things, worth the price) is another tactic. That has a better chance of working, because it gets closer to the psychological core of the problem, but in the end it’s not effective, either. The more important, the more involved with matters of life and death something appears to be, the more uneasy people feel about paying market prices. The industry, if it stresses the power and efficacy of its drugs, risks looking like someone charging rent for the use of a fire hydrant.

And another tactic is to put a personal face on things – to show testimonials from people whose lives have been saved, or from researchers working hard to come up with new treatments. This also has a better chance of addressing the psychology of the problem, but also risks heightening the conflict between matters of emotion and matters of commerce. These appeals are a bid for sympathy, on at least one level, which means that they really can’t talk about money. That connection has to be made later, and the mixture is as incompatible as ever.

This is where I should come right out and say that I don’t have a solution to this problem. But I think that it’s worthwhile to consider why it exists, and where (to my mind) it’s coming from.

Comments (28) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Why Everyone Loves Us

January 9, 2008

Ah, Politics

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Posted by Derek

I’ve got a big post ready to go on the subject of money and the drug industry, but since I figure everyone has a political hangover this morning, I’ll wait until tomorrow to put that one up. I was up in New Hampshire last weekend with my wife and kids, and I’m surprised that we didn’t trip over one candidate or another. Their campaign signs decorated every snowbank in Nashua, that’s for sure – I even saw a “Duncan Hunter 2008” one, which I should have loaded into the trunk as a collector’s item.

It’s far too early for me to talk about the various candidates in terms of their attitudes toward research and towards my industry – most of these people are going to be gone soon, anyway – but I will say that the lackluster showing (so far) of John Edwards pleases me. The idea of an Edwards presidency gives me the shakes, frankly (I see that he scares Alex Tabarrok, too).

At least this time he’s not promising that if he’s elected that the halt and the lame shall forthwith rise on the healing powers of stem cells. He did that in 2004, and in much stronger tent-meeting tones than that last sentence. It’s not that stem cells will never bring anyone up out of a wheelchair – I very much hope that that’s possible, and who knows, it may well be. But it’s not going to take place during the timetable of one presidential administration, that’s for sure.

No doubt everyone running for president is in favor of research, and of science in the abstract. (Well, OK, maybe we can make an exception for my fellow Arkansan Mike Huckabee, when it comes to some scientific theories). Their attitudes toward the drug industry, though, make for a much livelier spread of opinion. There will be time enough to talk about that once we’re down to the single candidates, though.

Comments (27) + TrackBacks (0) | Category: Current Events

January 8, 2008

Rainbows and Fishing Expeditions

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Posted by Derek

I came across a neat article in Nature from a group working on a new technique in neuroscience imaging. They expressed an array of four differently colored fluorescent proteins in developing neurons in vivo, and placed them so that recombination events would scramble the relative expression of the multiple transgenes as the cell population expands. That leads to what they’re calling a “brainbow”: a striking array of about a hundred different shades of fluorescent neurons, tangled into what looks like a close-up of a Seurat painting.

The good part is that the entire neuron fluoresces, not just a particular structure inside it. Being able to see all those axons opens up the possibility of tracking how the cells interact in the developing brain – where synapses form and when. That should keep everyone in this research group occupied for a good long while.

What I particularly enjoyed, though, was the attitude of the lab head, Jeff Lichtman of Harvard. He states that he doesn’t really know exactly what they’re looking for, but that this technique will allow them to just sit back and see what there is to see. That’s a scientific mode with a long history, basically good old Francis-Bacon style induction, but we don’t actually get a chance to do it as much as you’d think.

That varies by the area being under investigation. In general, the more complex and poorly understood the object of study, the more appropriate it is to sit back and take notes, rather than go in trying to prove some particular hypothesis. (Neuroscience, then, is a natural!) In a chemistry setting, though, I wouldn’t recommend setting up five thousand sulfonamide formations just to see what happens, because we already have a pretty good idea of what’ll happen. But if you’re working on new metal-catalyzed reactions, a big screen of every variety of metal complex you can find might not be such a bad idea, if you’ve got the time and material. There’s a lot that we don’t know about those things, and you could come across an interesting lead.

Some people get uncomfortable with “fishing expedition” work like this, though. In the med-chem labs, I’ve seen some fishy glances directed at people who just made a bunch of compounds in a series because no one else had made them and they just wanted to see what would happen. While I agree that you don’t want to run a whole project like that, I think that the suspicion is often misplaced, considering how many projects start from high-throughput screening. We don’t, a priori, usually have any good idea of what molecules should bind to a new drug target. Going in with an advanced hypothesis-driven approach often isn’t as productive as just saying “OK, let’s run everything we’ve got past the thing, see what sticks, and take it from there”.

But the feeling seems to be that a drug project (and its team members) should somehow outgrow the random approach as more knowledge comes in. Ideally, that would be the case. I’m not convinced, though, that enough med-chem projects generate enough detailed knowledge about what will work and what won’t to be able to do that. (There’s no percentage in beating against structural trends that you have evidence for, but trying out things that no one’s tried yet is another story). It’s true that a project has to narrow down in order to deliver a lead compound to the clinic, but getting to the narrowing-down stage doesn’t have to be (and usually isn’t) a very orderly process.

Comments (8) + TrackBacks (0) | Category: Biological News | Drug Development | The Central Nervous System | Who Discovers and Why

January 6, 2008

Dollar, Drugs, and Advertising

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Posted by Derek

Well, it's the first full working week of the year, so let's dive right into some controversy. There's an article on PloS Medicine on the amount that the drug industry spends on marketing. They at least try to avoid the problem of mixed administrative and marketing expenses, but the authors come up higher than the other estimates that have been arrived at. That's because they take the varying figures from the two major sources and decide to take the larger figure every time the two disagree.

The final tally? About $57.5 billion spent in 2004. Most of that is in detailing to physicians and the cost of free samples. Direct-to-consumer ads, although they get a lot of attention and collect a lot of flak, account for only 7% of the total. The authors lose no opportunity to point out that this figure is not only larger than the industry's own statements, but is just shy of twice the estimated industrial R&D expenditures for that year. And, of course:

". . .These numbers clearly show how promotion predominates over R&D in the pharmaceutical industry, contrary to the industry's claim. . .it confirms the public image of a marketing-driven industry and provides an important argument to petition in favor of transforming the workings of the industry in the direction of more research and less promotion."

Well, we do spend a lot on marketing, that's for sure. US pharmaceutical sales in 2004 were about $235 billion. If these latest figures are correct, then promotion was about 24% of sales. I don't know how that compares to other industries, but it wouldn't surprise me if it ran high. Several things lead to that - the drug industry is quite fragmented, for one thing, with even the largest companies having a fairly small market share. And patent terms mean that the bulk of the profits on new drugs have to be earned back relatively quickly before they go generic. The distribution channels in the prescription drug business lead to a concentration on the gatekeepers (physicians) as well.

But the authors of this paper have missed an important concept. As I've pointed out here before, the idea of spending money on marketing is that it brings in more money in return. If it didn't, why bother? Marketing campaigns are supposed to pay for themselves, and more besides. That doesn't always work, of course - Prizer sure didn't make back the money spent promoting Exubera - but the failures are made up for by the successes, or at least they'd better be.

So it's not like we have this huge pile of money (X) and choose to divide it up so that we spend 0.65X buying ads and 0.35X on research. Those ads are responsible for the size of the pile in the first place. If they didn't exist, X would be smaller. If the advertising is working, that whole 0.65X is being paid for by increased sales: why on earth would you spend more on advertising than you make in return for it, year after year? And some of that 0.35X comes from those increased sales, too: why on earth would you spend that huge amount on advertising and get only that same amount back in revenues, year after year?

No, as far as I can see, most of the "why don't you spend some of that money on research" question is founded on a misconception. It breaks down when you look at where "that money" comes from. I freely admit that it's not an aesthetically pleasing state of affairs. And maybe that's the root of the problem.

My industry would apparently prefer not to put it in such crude terms, but drug research involves money, and plenty of it. Advertising brings in more money, which is why it exists. The nature of our industry probably allows a higher profitable level of advertising, which is why we do so much of it. My industry may, in the long run, be doing itself no favors by avoiding this topic and encouraging the saintly-white-coated-researcher picture instead. We do help sick people, and we are glad of that (and I do have a white lab coat hanging in my lab across the hall). But helping sick people by discovering new drugs takes big piles of cash. That's how the world is.

Comments (24) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Why Everyone Loves Us

January 4, 2008

Plants For Cancer?

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Posted by Derek

A reader sends along this article from the New York Times about Chris Kilham, an ethnobiotanist from U. Mass - Amherst looking for medicinally active plants in Peru. The article has lots of local Peruvian color, but it doesn’t neglect the money involved:

” Products that once seemed exotic, like ginseng, ginkgo biloba or aloe vera, now roll off the tongues of Westerners. All told, natural plant substances generate more than $75 billion in sales each year for the pharmaceutical industry, $20 billion in herbal supplement sales, and around $3 billion in cosmetics sales, according to a study by the European Commission.”

It’s worth noting, though, that none of those three once-exotic plants (exotic when – twenty-five years ago?) are the source of any major revenue for the pharmaceutical industry, unless you count aloe-vera sunscreen line extensions and the like. Kilham himself has some definite opinions on the value of plant-derived drugs:

Mr. Kilham believes multinational drug companies underutilize the medicinal properties in plants. They pack pills with artificial compounds and sell them at huge markups, he says. He wants Westerners to use the pure plant medicines that indigenous peoples have used for thousands of years.

“People in the U.S. are more cranked up on pharmaceutical drugs than any other culture in the world today,” Mr. Kilham said. “I want people using safer medicine. And that means plant medicine.”

Unpacking those statements is a chore, though. Just to pick a big one, “pure plant medicine” is a tricky concept, as any natural products chemist will tell you. Are we talking ground whole plants here (and if so, which parts, grown where?) Extracts (and if so, which fractions?) Purified single compounds?

Moving to the next difficulties, would these plant medicines somehow not be sold at such huge markups? Take a look at the herbal supplement industry for a reality check on that one. And if we in the drug industry could get such drugs with less trouble and effort than our “artificial” ones, why wouldn’t we do so – especially if they have fewer side effects? (Side effects cost us money, too, you know). Finally, are those natural compounds really safer than the nasty artificial ones? Not as far as I’ve ever seen – they come out the same in genotoxicity studies, for one thing. The whole “artificial” versus “natural” division is generally a sign of lazy thinking, in my experience. There’s no wholesome Gaia-derived goodness to be found in a plant-derived natural products, and they weren’t somehow made for us to use as medicines. Some are harmless, some are toxic – same as everything else.

Then there’s this interesting part:

“So-called bioprospectors can make their fortunes by bringing those advantages to the attention of companies who identify the plant’s active compound and use it as a base ingredient for new products that they patent.

Some 62 percent of all cancer drugs approved by the Food and Drug Administration come from such discoveries, according to a study by the United Nations University, a scholarly institution affiliated with the United Nations.”

Hmm. Examples? The only “bioprospector” that I can recall making a fortune in this way was Russell Marker, the founder of Syntex, who realized that Mexican yams contained an excellent starting material for steroid synthesis. Mind you, that was in 1944. If anyone has a more recent example of an Indiana Jones figure stumbling out of the jungle clutching a profitable wonder root, please do let me know. Whole companies have been founded on the idea of cashing in on active natural products and indigenous medicines. None of them, as far as I can tell, have made any fortunes yet, and some of them have done the reverse. Shaman Pharmaceuticals is the obvious example. I know someone who was right in the middle of their drug discovery effort. It wasn’t pretty, and it sure wasn’t profitable.

Besides, the Times reporter should have asked Kilham himself about cancer therapies. Here's a 2005 interview with him:

"I don't see the cancer herb category becoming a major category any time soon. I believe that the majority of people who get cancer are still going to turn to a conventional medical doctor. I think the greatest majority will. . ."

And that study by the UN doesn’t appear to have dug all that deeply. (It should be noted up front that oncology and anti-infectives are the two areas where natural product-derived compounds are by far the most well-represented). That 62 per cent figure for cancer drugs would seem to come directly from this 2003 paper in the Journal of Natural Products, from a group at the Natural Products branch of the National Cancer Institute. A closer look at the figures show that they list 140 drugs available over the years 1981-2003 (note that many of these are no longer first-line therapies). The 62% figure comes from excluding all the antibodies, proteins, and vaccines (10% of the total) and counting straight natural products (14%), semisynthetic compounds derived from them (26%) and synthetic compounds whose active pharmacophore came from a natural product lead (14%).

You can draw the line wherever you like, but by rigorously crunchy standards only that first 14% qualifies. If we’re going to draw some line between “natural” and “artificial”, everything else is on the other side of it. There’s no denying that natural products are and have been a great source of active compounds and structural leads, of course. But the vast majority of drugs come from us chemists, cranking out the man-made (and man-improved) structures.

The other problem with that number is that, if anything, it may represent a peak. The kinase inhibitors that have been approved in recent years are all completely synthetic compounds, and the antibody and vaccine ranks are swelling, too. Ranked by sales, there are 19 oncology drugs in the most recent top 200 list I can find, and only one of them is a straight natural product (taxol, at #169). Taxotere, at #37, is a semisynthetic derivative of taxol, and irinotecan at 122 is a semisynthetic as well. But to my eyes, that’s about it. Getting data by usage is harder (without paying for it!), but the older natural products would come out looking better ranked by total prescriptions filled. In most cases, though, they’re no longer first-line therapies.

So natural products aren’t dead, by any means. But they aren’t an untouched gold mine, either. Someone tell the Times.

Comments (38) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

January 3, 2008

Top of the Heap

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Posted by Derek

There are quite a few news items to catch up on after the break – I’ll start off with a note that John Lechleiter has become the CEO of Eli Lilly. The main reason this catches the eye (and the main reason it got e-mailed to me!) is that he’s a medicinal chemist who worked his way up the ranks.

And that doesn’t happen very much, which is a topic that came up around here a couple of years ago. There are several companies run by chemists, but most of them got there as founders. Going from the bench all the way up to the top of an organization, that’s taking the long route for sure, especially in a place the size of Lilly.

Is there a reason for that? The sample size of large drug company CEOs isn’t particularly large, so it feels risky to generalize, but it’s been my impression that in many companies the scientific talent is under-represented in the top executive ranks. (That would make business degree holders and lawyers over-represented, I suppose). If that’s true, there are several possible explanations.

One is that fewer scientists are willing to devote themselves totally to the job of climbing said ladder, as opposed to their regular work. Many go into research because they like to do research, and don’t have as much of a taste for managing. But if you’re on the business side of things, the climb is much more related to your job description to start with, I’d say. Starting at the bench means that at some point you’re going to have to completely drop the work you were first hired to do and start doing something different.

That’s not to say that there aren’t plenty of chemists (and biologists) who do just that, but they’re generally aiming at positions lower than CEO. Scientists who become managers usually end up managing other scientists, as section heads, associate directors, directors of research, and so on. That makes a lot of sense, because they understand the work that’s going on under them – you’re not going to import a lawyer to be Director of Translational Biology, right?

And that brings up another possible problem. Scientists, taken as a class, do not always turn into the best managers. No particular group produces a huge number of good managers, to be sure, but I’m pretty sure that researchers run on the low side. Putting it delicately, there are a number of personality types reasonably well-suited for science, but not so well-suited for supervising and developing other people. Such subsets exist in every other profession, but those categories are particularly roomy in the research labs. Ugly situations can ensue when these people are perforce given direct reports. It’s even worse in academia, where some truly borderline personalities are year after year turned loose on 22-year-old grad students.

But inter caecos regnat luscus, and if a scientist does have good skills as a manager or leader, then so much the better. These people will stand out all the more.

Comments (13) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

January 2, 2008

Back On the Air

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Posted by Derek

Just wanted everyone to know that we're back in business around here, after a holiday break and some technical problems behind the scenes. Regular blogging resumes tomorrow!

In the meantime (and for some time to come, since there's a lot of it) I can recommend this year's Edge.org question: "What have you changed your mind about?". The index page will get you started. Plenty of good essays are to be found - for example, I just read some extremely sensible stuff from Brian Eno. Enjoy!

Comments (2) + TrackBacks (0) | Category: Blog Housekeeping