Dumpster Diving for Data?

A comment to the last post wondered if drug companies ever do active intelligence against each other (as opposed to the passive kinds I mentioned). Active means would be rooting through dumpsters and the like, and the answer is - almost invariably - no.

That sort of thing is more trouble than it's worth, because it's easy to find out what's public knowledge at a given time and what isn't. If you dig around for nonpublic information, it doesn't do you much good unless you act on it. And if you act on it, you've admitted having something that you shouldn't, and you're faced with having to explain your psychic powers.

The same problem occurs in military and governmental intelligence gathering, on a rather larger scale. But there the theater the intelligence is gathered in is the same one where any repercussions will occur (in diplomatic relations or on the battlefield). In business, the retaliation will come through the courts, which is a completely different problem, and generally one you don't want.

If someone talks more than they should during a meeting, well, that's their problem. The listeners always have the defense that they didn't think that this was truly proprietary information, because if it was, the speaker wouldn't have let it out, right? But that said, I can't think of any major slip-ups of this kind - perhaps some of my readers know of a few.

The only active intelligence gathering I've heard was in a story that broke a few years ago. It seems that one or more large European pharma companies were trying to figure out what some of the patent-ignoring generic drug firms in Cyprus were up to, and hired some folks to sneak into some offices to see if their drugs were being pirated. A couple of people got caught in a break-in. I haven't seen a follow-up in some time, so I don't know what eventually happened. There was an interesting article in Fortune in 1998 or 1999 on the case, but it isn't online.

The Agents Report Back

Now that ASCO's wrapped up (and the American Diabetes Association meeting as well) every attendee from the drug industry has gone back to report on the news: copies of poster presentations, handwritten notes from the talks, and (most importantly) information that was only given verbally. That would be in answers to questions after a talk, in conversation around a poster, or in small gatherings all over the place.

That sort of stuff is often the real gold from a large meeting. No one is going to spill anything vital, but you can often learn more than is strictly contained in the official presentations, and everything helps. The drug industry being what it is, we have plenty of things we'd like to know about what the competition is up to: Are they still interested in compound X? Have they moved on to another one? What's better about it? Is that side effect something that's showing up in the whole class of compounds? How did they ever dose that stuff at those levels, anyway? Are they in Phase II? In what sort of patients?

It's a well-known psychological effect in the business that we treat new information as something that's just happened. But you have to keep in mind that the information in these meeting presentations is at best several months old, and maybe older than that. (At least it's better than getting excited about a paper that's just shown up in the literature.) That's another reason for all the one-on-one questioning, naturally - we want to know, for once, what's happening right now.

Your One-Stop Clinical Data Superstore?

There have been plans, over the years, for some sort of data repository for clinical trials. Nothing's ever worked out. The only place that all of this is collected is at the FDA, and they only have the ones that companies have submitted because they were requesting a new approval or a new indication. If companies run studies but they give up on regulatory filing, the data can never see the outside world at all.

That's the heart of the New York - GSK suit, as I was discussing yesterday (although, as I pointed out, in this case the data were made public, although nowhere near to the extent that the more positive study was). Presumably, the ideal that Eliot Spitzer seeks would be a central database of all clinical studies conducted on marketed drugs - along with, it seems, a requirement to go into the results of all of them in marketing presentations. (Actually, I think the ideal that Eliot Spitzer seeks is a world in which he is a senator from or the governor of New York, but that's another story. . .)

This sounds like a reasonably clear mandate, but in practice it's quite tricky. It's worth thinking about what a clinical data repository would look like. You'd have to include the statistical workup from the end of the trial, that's for sure. The raw data makes for quite a heap, and extracting the useful conclusions from it is not the work of a moment. You have to be well informed about how and why the trial was designed to even know where to start, and you have to be well informed about statistics to know when to stop.

Even with all the conclusions attached, an open raw-data repository would be a real invitation to cranks of all kinds to go in and massage the data. I've spoken about this issue before, because companies themselves can be guilty of trying to extract more conclusions than the data will support. Imagine the ax-grinding subgroup analysis and selective data mining that would go on - for one thing, the trial lawyers would be adding statisticians to their staffs to do nothing but comb through the numbers all day, looking for tort-worthy tangles.

Even if you just have the worked-up data in the repository, you still face the problem of data overload. Heavily studied drugs can have a long list of differently designed trials attached to them, all of which are either asking different questions or asking the same one in different ways. Digging through them is not something you can do on your lunch break.

An even tougher problem is what to do about poorly designed or poorly executed studies. That seems to be the case with the Paxil 377 data I spoke about yesterday, which is why one of the study's co-authors wanted to publicize it in the first place. Who gets to decide if a particular study is valid? Whose comments and conclusions will be attached to the results? Who gets to weight them against the other results collected on the same drug?

These are the sorts of issues that are wrangled about in the regulatory approval process, and the disagreements can be heated, even in a roomful of people who all know what they're doing. How many physicians would be willing to consult a Central Clinical Trial Database and do the wrestling themselves? How many would even have the time? For the most part, practioners have as their default setting to trust the FDA, since they've analyzed the data already.

As for what companies can say to doctors, limits in this area have banged right into free-speech considerations in the courts. Attorney General Spitzer's on-message response to this is that you can't use a First Amendment argument to justify fraud, and I'll let that one go by without swinging at it. But what would he have disclosure look like? Should it be verbal (and in that case, how would it be enforced?) Should it be a written handout on the total clinical data generated for a new drug? That makes more sense, but then we get back to the question of how summarized the results should be, and who gets to write the summaries.

The thing is, I think that a clinical data repository would be useful. I know that I'd like to go data-mining through previous studies, looking for things that are relevant to my current projects. And I'd like to see what happened in failed trials so we can be sure not to run ours in the same fashion (which was Dr. Miner's point about the 377 Paxil study). It could be worth trying, but I worry that it might require the world to be a little better than it really is to work. We'll see.

Cue the Music

New York Attorney General Eliot Spitzer has found what must look like another target-rich environment: the pharmaceutical industry. As many readers will have seen, he's initiated a lawsuit against GlaxoSmithKline for their handling of clinical trial data for the antidepressant Paxil (paroxetine). As far as anyone can tell, this suit is the first of its kind.

There's a specific side to this story, and a there's general one about the handling of all clinical trial data. I think I'm going to end up splitting the difference, but first things first: in this case, SmithKline (as it was at the time) ran different studies on the effectiveness of Paxil in adolescent patients. One study (#329) had positive results, and another (#377, slightly later) showed no benefit versus placebo. Spitzer points out that the successful first study was widely publicized, presented at several scientific meetings, and eventually published. SmithKline (and later GSK) made it part of their sales pitch to physicians.

Meanwhile, the 377 study was presented once, at the annual meeting of that same academy, and never showed up as a full paper in the literature. The presentation wasn't SmithKline's idea; they weren't going to publish or present at all. It was suggested by two of their academic collaborators (Robert Milin and Jovan Simeon). And as you can imagine, it has not been a feature of GSK's promotional literature.

All this, in the eyes of Attorney General Spitzer, adds up to an indictment for fraud - and yes, that's exactly the word he uses. Here we have all the elements of a great case: buried information that would have been harmful to a large corporation, and a whistleblower who brought it to light. It sounds more like a screenplay - as you read about it, you can start mentally casting the movie.

But there are complications. For one thing, SmithKline made no objection when Dr. Milin told them of his plans to present the 377 study. I don't know what the terms of the research agreement were in this case, but often enough the company can exercise a veto in such cases, since they paid for the study. And second, Milin himself is, according to Barry Meier's story in the New York Times last week, a strong believer in the use of Paxil in adolescents. He considers the 377 study to have failed because of a flawed design, not because the drug isn't useful. And as for publishing the results in a journal, that would have actually been quite difficult. Inconclusive or negative results are very hard to publish in general, and in this case even the positive study wasn't the easiest thing to get into the literature. According the Times article, the paper probably bounced around a couple of times before finding a home. It ended up in the Journal of the American Academy of Child and Adolescent Psychiatry, and appropriate venue but hardly the highest-impact journal in the world. And finally, GSK provided details of both studies to the FDA, as it is required to do.

So hiding information, which is the basis of the fraud allegation, lies in the way that GSK detailed physicians. I wouldn't expect them to go out of their way to present data showing that the drug didn't work, but if one of the study's own authors felt that it was flawed, then I really wouldn't expect them to talk about it much. I can see what Spitzer's trying to do, all right, and I can see what he thinks he has. But I don't think that's what's really there.

All this, presumably, is supposed to further the cause of releasing clinical trial data. Under the current system, the company can show it only to the FDA (or other regulatory agencies) if it chooses, and if they give up on the compound, no one has to see it at all. There have been calls over the years to establish a clinical trial database, but nothing's ever come together.

And you know, I actually think that a general trial database could be a good idea. (It could also be a disaster, and the industry has chosen to avoid the latter rather than seek the former - we'll go into some of the complications tomorrow.) But I think that Eliot Spitzer may have picked the wrong grandstand to make a speech from, and should have thought twice before striking up the band. Then again, that's not the sort of behavior that got him to where he is now. . .

Vox Populi

I wasn't planning on returning to this topic today, but tonight's e-mail seems to deserve a speedy reply. Says a loyal reader, one "Busterbuckeye":

You gave me a very impolite back hand slap in the above referenced blog. . .(on May 12) I posted in response to your April 28 blog in which you quoted Travers with approval: "Travers did indeed estimate Erbitux revenues at "peak" based solely on its one current crc indication. Your own April 29 response admits at least the possibility of other indications. After careful thought and perhaps after this coming ASCO, I invite you to reconsider adopting Travers' "peak" revenue estimates, and perhaps one of us (sic) my dine on crow."

In light of IMCL's ASCO data on Head & Neck, nsclc, and pancreatic cancer, you should be prepared to abandon Mr. Travers "peak" estimates and apologize for your rude treatment. . .

Let's take these points one at a time, skipping (for the moment) the back of the hand. Charley Travers of the Motley Fool did run his numbers based on the colon cancer indication. And in my April 29th post, "Yahoots", I did mention the possibility of other indications.

But take a look at the context in which I mentioned them. Here's the key part:

". . .don't let those shimmering waves of greed blind you to the facts: in their clinical trials, Imclone, BMS, and Merck-Darmstadt carefully picked the tumor types that would be expected to give the most robust response. That's how you get a drug approved, by going to the agencies with the best data you can get. Erbitux has already been tested in the areas where it's likely to gain the most market share and make the most profit."

Head and neck cancer, for example, is one of those carefully picked areas I was referring to. There's a good chance of a therapy targeted against EGFR showing efficacy against that kind of tumor, and it's an underserved patient population (although not an especially large one.) That's why they picked it for the clinical trial. It's not a new indication out of the blue.

So, let's remedy the situation. The numbers I linked to in yesterday's post speak of an SG Cowen estimate of a "$150 million market" for Imclone in head and neck cancer. It's unclear if that's the total market size, or the net to Imclone after they pay their royalties to BMS and Merck-Darmstadt. Let's be generous and say it's the latter. And let's double that figure, just to get in that optimistic frame of mind.

So, adding another $300 million means that it doubles the sales numbers that Travers estimated. The trouble is, by his figures, Imclone stock was already between 50% and 100% overvalued when he wrote his piece, and it's gone up more since then.

I'm prepared to modify my views, then: instead of saying that Imclone is that much overvalued, I'll put on my rose-colored glasses and say that under current conditions, it's valued about where it should be at its peak sales - a few years from now, mind you. Now, Imclone can pick up some sales in the more competitive NSCLC market, and some in pancreatic cancer too (a small market, but a cruelly underserved one.) But long before then, you Imclonites will have pushed the stock price up to take care of that slack, too. Hey, what am I talking about? You'll have the share price up there next week at this rate. Sell!

From a drug-company perspective, you're working on the assumption that everything will go perfectly. There will be no safety problems in any of these new indications, and no manufacturing or regulatory hitches. And you're choosing not to think too much about other new compounds hitting the market over the next few years. Some of them will take some market share, you know. For one thing, they won't cost $10,000 a month.

Now for the last point, that "apology" for "rude behavior". It's not happening. For one thing, my behavior was the expression of an opinion about the stock price of Imclone, and of those people who are willing to pay it. If you've made money on Imclone, that should be all the compensation you could ever want. I've lost money on them, myself, and believing that I'm right is of only limited consolation in such situations.

I have my opinions; you have yours. You don't have to read (or comment on) mine, and I probably wouldn't read yours on a salary. Perhaps you should start an Imclonocentric blog of your own - you'd probably get more traffic than I do, considering the fanatic following the company has.

As Goes ASCO. . .

The American Society of Clinical Oncology meeting is taking place as you read this. ASCO is a pretty high-pressure venue, because key clinical results for cancer therapies are often unveiled there. The audience has a much higher percentage of journalists and financial analysts than you'll see at most meetings. It's a sandstorm of hype, all right - try this news search for a blast of it.

The Imclonites have already started filling my inbox, since I'd taken a crack at the company's stock valuation a couple of months ago. Imclone's just presented data at this ASCO showing that their antibody extends survival time significantly in patients with head and neck cancer. That's good news for the patients, who could use some, and I'm sure that IMCL shareholders figure it's great news for them, too.

But that market is in the low tens of thousands of patients. Even with sizable market penetration, I still think that Imclone stock is no bargain at 70-odd dollars a share. Mind you, that's what it was on Friday. It'll be worth taking a look during Monday's trading to see what it's been inflated to since this news came out. My advice to IMCL shareholders continues to be: cash in and run laughing to the bank. That's what Carl Icahn is doing, guys.

But feel free to ignore me, of course, and go take the other end of Icahn's trades for him. And don't forget to write and tell me what a knuckle-dragging throwback I am. It's not like I catch any abuse at work - I have to depend on my weblog to generate some, don't you know.

Doublets, Triplets, Whateverlets

Another day spent rooting around in the archives, trying to appease the rapacious Taiwanese patent office. One more day should about do it, and not a moment too soon. I'm now unearthing NMR spectral data for compounds, and translating those to print is not enjoyable.

For those outside the field, an NMR spectrum of a typical organic molecule is a rather complex linear plot of multiple lines and peaks. After staring at it a while, it gets rendered into text as something like "1.63, t, 3H; 2.34, s, 3H; 3.1 - 3.39, m, 4H. . ." In plain text, that's "At 1.63 and 2.34, there are a triplet signals that represent three protons each, and between 3.1 and 3.39 there's a messy multiplet that adds up to four protons' worth. . ."

If you really want to get into it, you list the coupling constants, the spacings between the individual peaks of those triplets and etc. No thanks. A typical spectrum will go on for a reasonable paragraph in this way, and the Taiwanese would like nothing better than several pages of this sort of thing, or so they maintain. What they'll is get as much as I can stand.

I'll try to lead off next week with a discussion of today's news about everyone's pal, Elliot Spitzer, and his suit against GSK. It's a wide-ranging topic, and there wasn't enough time to wrestle it to the ground today.

This Isn't the Kind of Office Action You're Thinking Of

I've had enough staring at the computer monitor for one day, so this will be short. I've been dealing with an "office action" from Taiwan's patent office. They're reviewing an application on which I'm the lead inventor, so this one lands on my desk. Taiwan isn't a member of the Patent Cooperation Treaty; you have to file a separate application. And they have their own standards, which they lose few chances to demonstrate.

According to their examiner, we need to provide more biological data and more chemical characterization data for the compounds in the patent, which is not particularly enjoyable since these compounds were all made three or four years ago. Everyone in the drug industry is supposed to have data handling systems that make such queries light and breezy, but just try putting them to the test. It's all there, but you have to know which rock it's hiding under. And the numbering of the compounds in the patent is totally different from any of the numbering schemes used in our record keeping, and so on. You know the sort of thing.

The data provided have been perfectly acceptable to the patent offices in Europe and the US so far, but that cuts no ice in Taipei. I'm just glad that the other non-PCT countries don't engage in this sort of thing. Separate office actions, one after the other, from the likes of Peru, Pakistan, Thailand and Venezuela would probably push me over the edge. Like Taiwan, though, they have their own special application paperwork, which is enough of a racket as it is.

Industry vs. Academia: The Mental Aspect

It's been a while since I returned to this topic. Many differences remain for me to talk about, but I though that it was time to address the biggest one, which is psychological. Some of you probably thought that the biggest difference was money. Can't ignore that one - it probably contributes to some of the effects I'll be talking about. But there's a separate mental component to graduate school that never really recurs, which should be good news to my readers who are working on their degrees.

Some of this is due to age, naturally enough. The research cohort out in industry ranges from fresh-out-of-school to greybeards in their fifties and sixties. (I can say that, since I'm in my early forties, the color changes in my own short beard notwithstanding.) Everyone in graduate school is a transient of one sort of another, usually someone whose life is still just getting going. But in the workplace, most people are more settled in their lives and careers. There are still some unsettling waves that move through industry, mergers and layoffs and reorganizations. But people respond to them differently than they would in their 20s - often better, sometimes worse, but differently.

And not all your co-workers in grad school are actually stable individuals, either. Some of these people wash out of the field for very good reasons, and you don't see as many of the outer fringes later on in your career. It's not that we don't have some odd people in the industrial labs, believe me. But the variance isn't as high as it is in school. Some of those folks are off by so many standard deviations that they fall right off the edge of the table.

Another factor is something I've already spoken about, the way that most graduate careers come down to one make-or-break research project. The only industrial equivalents are in the most grad-school atmospheric edge of the field, small startup companies that have one shot to make it with an important project. But in most companies, no matter how big a project gets, there's always another one coming along. Clinical candidate went down in flames? Terrible news, but you're working on another one by then. There's a flow to the research environment that gives things more stability.

The finish-the-project-or-die environment of graduate study leads to the well-known working hours in many departments. Those will derange you after a while: days, nights, weekends, holidays, Saturday nights and Sunday mornings. I worked 'em all myself when I was trying to finish my PhD, but I don't now. If a project is very interesting or important, I'll stay late, or once in a while work during a weekend. But otherwise, I arrange my work so that I go home at night. For one thing, I have a wife and two small children who'd much rather have me there, but even when I was single I found many more things to do than work grad-school hours. It took me some months after defending my dissertation before I could decompress, but I did. Having a life outside the lab is valuable, but it's a net that graduate students often have to work without.

But beyond all these, there's one great big reason for why grad school feels so strange in retrospect, and I've saved it for last: your research advisor. There's no other time when you're so dependent on one person's opinion of your work. (At least, there had better not be!) If your advisor is competent and even-tempered, your graduate studies are going to be a lot smoother. If you pick one who turns out to have some psychological sinkholes, though, then you're in for a rough ride and there's not much that can be done about it. Everyone has a fund of horror stories and cautionary tales, and there's a reason for that: there are too damn many of these people around.

Naturally, there are bad bosses in the industrial world. But, for the most part, they don't get quite as crazy as the academic ones can (there's that variance at work again). And they generally aren't the only thing running (or ruining) your life, either. There's the much-maligned HR department, which can in fact help bail you out if things get really bad. Moving from group to group is a lot easier at most companies than it can ever be in graduate school, and it's not like you lose time off the big ticking clock when you do it.

I can see in retrospect that I was a lot harder to get along with when I was in grad school. I responded to the pressure by getting more ornery, and I think that many other personalities deformed similarly. When I've met up with my fellow grad students in the years since, we seem to be different people, and with good reason. It isn't just the years.

How Not to Do It: Sodium

We have a lot of pyrophoric substances in an organic chemistry lab - things that burst into flame when they encounter normal air. Liquids are handled by syringe and needle, using bottles fitted with gas-tight septae. That works pretty well, once you get the hang of it. The main things you have to learn are to provide some inert gas as a replacement if you're removing a large volume, and to not twitch your arm and hand muscles while you're holding a syringe full of stuff. (That can provide a spectacular flamethrower effect, which is fine if that's what you're after, but we rarely are.)

Pyrophoric solids are a bit trickier. Some of them (like sodium hydride) are often sold as a fine powder mixed with mineral oil, which coats everything and keeps it from igniting. Of course, you have to get rid of it at some point, because it's sure not going to go anywhere. You can either wash off the mineral oil before you begin, while the solid is inside your reaction flask, or clean it away from your compound at the end of the reaction. I usually opt for the latter, on practical grounds: by the time, I'll know if the reaction worked, and I won't have wasted the initial effort on a loser. Besides, most of those reactions need purification anyway.

You can buy dry sodium hydride, but I'm not a fan of the stuff. It goes bad too quickly, and an NaH fire is a beast to put out if it really gets going. A carbon dioxide extinguisher usually isn't up to the job, and it'll blow the powder all over your lab, which isn't recommended. And you most surely don't want to throw water on the stuff, although you'd have to be the village idiot to try that one. You'd certainly get a village idiot's reward for your efforts. The only reliable way to put one of these things out is to bury it in sand or some other inert powder. Then you have to let it cool down for a while - if you don't, it'll just whoomph up on you again when you try to clean the place up. If that doesn't make you feel like you're wasting your day, I don't know what will.

The related potassium hydride is invariably sold in a hard-to-handle suspension that's mostly oil. I've never seen it packaged dry, and I don't want to. It ignites much more easily than the sodium compound, to the point that people even manage to start fires with the oil-soaked item. At least the flames are prettier.

And the metals themselves are usually sold and stored under oil. Sodium metal, as my fellow chemists know, is interesting stuff. It's soft enough to cut with a metal spatula (the texture is rather like cold butter), and is very shiny indeed until the air hits it. You can work with it out like that, if you move with reasonable speed and get it under some inert solvent. Potassium metal is much less forgiving, and I have no desire to work with the heavier metals in the series (rubidium, cesium) as their elemental metals, because they just get worse as they go up.

You can mess up the area with just plain sodium, though, oh yeah. Some collagues of mine had a summer undergraduate (here's where experienced chemists start to grin and pull their chairs closer), and they were teaching him how to handle sodium metal: take it out of the oil, have your beaker of hexane ready, cut it like so, pick it up (the point of the spatula works well), drop it in the solvent, and so on. Everything went fine. So the next day, one of the guys tells him to go down and weigh out, say, five grams of sodium for a reaction. The summer student scampers off, and a few minutes later, the grad student wanders down to have a look, just to make sure things are going OK.

And there the guy is, with his beaker of hexane, sawing away with a spatula at a big cylinder of sodium metal which he is gripping in his bare left hand. Well, he hadn't been told not to do that, true, but neither had he been warned not to fetch it in his teeth. You just sort of take these things for granted. The summer student had no doubt taken the skin of his left hand for granted, too. (It took a few weeks, but he recovered.)

The Latest From the Fishing Hole

Here's an update on my "Catfishing" post from a couple of days ago. I set up around thirty small reactions, with a different potential catalyst in each, looking for something to happen. They sat at room temperature over the weekend, looking very picturesque - with all the transition metals, I had various shades of yellow, red, orange, blue and green scattered around the array.

This excursion has added to my life list of elements used, that's for sure. I'm not sure if I ever would have a chance to use some of these things if it weren't for expeditions like this. Unfortunately, the exotica that I mentioned in the first post has failed to do very much. The vials with things like zirconium, ytterbium or praseodymium salts are just sitting there, as are the fancy iridiums. The coppers have copped out, and a range of rhodiums and rheniums are laughing at me.

The only vials that are showing real changes are the ones with palladium catalysts. That's not too surprising, because Pd is a real workhorse in the catalyst world, for good reason. But I don't think that they're doing what I want. Rather, they seem to be tearing up one of my starting materials and rearranging it into interestingly useless structures, which then find their own list of things to decompose into.

I have another collection of catalysts to try, though, and I'll run those before declaring defeat. I'm going to send a bunch of nickel, iron, and cobalt compounds in to see if they can accomplish anything. If nothing else, they're sure to be decorative. On the other hand, the palladium reactions all look like hot chocolate, which is rarely a good sign.

The first time I tried doing an experiment like this was back in graduate school - I remember going through the labs looking for every Lewis acid that we had in the place. (To a good extent, those reagents parallel Tolstoy's quote from Anna Karenina, in that protic acids are all alike, but every Lewis acid is an acid in its own way). I set those up in vials, too, in a rather more low-tech manner, as befits early-1980s equipment. And here it is, twenty years later, and I'm doing the same thing. It's still fun.

Down the Hatch

We have a lot of received wisdom in the drug business, rules of thumb and things that everybody knows. One of the things that we all know is that the gut wall isn't much fun for our drugs to get across sometimes. That's inconvenient, since most people would prefer to swallow their medicine rather than take part in the more strenuous dosage forms.

Go around asking random medicinal chemists about oral absorption of drugs, and you'll get more things that everyone knows. There will be lots of talk about solubility and allied topics like particle size, salt forms, formulations and so on. Some of this is valid (I'd vote for particle size), but some of it is hooey. For example, I'm not convinced that solubility has much to do with oral dosing (once you get past the powdered-glass stage, naturally.) I've had wonderfully soluble drug candidates that went nowhere, and I've had brick dust that showed reasonable blood levels. I'm just barely willing to admit that there's a trend (in a really wide data set), but I'm not willing to admit that it's a very useful trend. But solubility can be measured (over and over!), so there's a constituency for it.

You'll also get a lot of stuff about P-glycoprotein, and the necessity of doing some sort of cellular assay to see if your compound is affected by it. That's a protein I've spoken about from time to time, which sits in the cell membrane and pumps a variety of compounds from one side to the other. Now, Pgp is a real thing, both in the gut and in the brain. But there are a lot more transporter proteins out there than most of us realize, hundreds and hundreds of the damn things, and we don't have much of a handle on them. I think that they're a big opportunity for drug development in the coming years, assuming we start to get a clue.

People get excited about Pgp because it was one of the first ones characterized, and because it does seem to explain the failure of a few drugs. There's a cellular assay, using the famous Caco-2 colon cells that express the protein, which is supposed to give you some idea of Pgp's effect on the membrane permeability of cour compounds. Unfortunately, I'm not convinced that it gives you much more than a reading of how they behave in the Caco-2 assay, which probably isn't worth knowing for its own sake, to put it kindly. But folks are so desperate to know why their drugs don't get absorbed well (and how they can avoid wasting any more of their working lives on such) that they'll seize on any technique that offers hope.

You'll also hear about metabolism of drug by enzymes in the gut wall, but as far as I can see, that's an overrated fear. (There was a review article on this a few years back from a group at Merck, and that's what they concluded.) People like this explanation because it makes some sense. We all know about liver enzymes ripping our compounds to bits, and here they are in the gut wall! No wonder our compounds stink! And this is also something you can screen for, so you're not left sitting there alone with the black box. Far better to be able to tell everyone that you think you have a handle on the problem and that you're running assays to get around it, even if it isn't true.

Nope, our understanding of drug absorption still reeks of voodoo vapors, despite many attempts at exorcism. It's annoying and it's disturbing, but it's the state of the art. Anyone that can do better will make a fortune.

What Ails Us

Before getting started, I'd like to recommend the discussion going on in the Comments section of the "All the Myriad Ways" post below. If you find the topic of gene patents at all interesting, it's worth keeping up with. Me, I'm just watching for now, feeling like Teresa Nielsen Hayden as the discussion takes off on its own. (I show up in her comments section every so often myself, although I largely stay out of the political discussions because I think they'd throw things at me.)

On to the main topic tonight. There's an article in the latest Nature Reviews: Drug Discovery called "Prospects for Productivity" from Bruce Booth and Rodney Zimmel at McKinsey Consulting. They're talking about the now-familiar drug drought that seems to have affected everyone the last few years. It's real enough, although they make the point (which I've brought up myself, in a column for Contract Pharmamagazine) that people have been complaining about a drug shortage for decades.

Booth and Zimmel do a good job of running down the usual suspects. In their order, they have:

1. Lack of payoff from genomics. This one, they say, has "clearly driven part of the productivity decline." I can second that, because I (and friends of mine around the industry) have seen it at work right in front of them. There was a panic that made everyone start working on genome-derived targets, long before we knew enough to accomplish anything. In most cases, we still don't.

2. Poor chemical libraries. This is an earlier problem, but one whose effects are still working their way through the portfolio. The combinatorial chemistry craze (the craze before genomics, if you're keeping score at home) caused a lot of people to make a lot of compounds that had no chance of ever becoming drugs. Why? Because they could make them! And someone else might make them first! We're smarter now, theoretically. B & Z don't go into the details, but this one hit some companies harder than others, depending on how early and how hard they fell for combichem evangelism. Some careers never really recovered.

3. Tougher regulation. B & Z discount this, for the most part, as whining from the drug companies (not their exact wording!) They're probably right, although they correctly note that seemingly minor changes at the FDA have ended up costing huge amounts of money and time on our end. But this still isn't the major thing hurting us, not that it isn't still fun to complain about.

4. Tougher internal scrutiny. This is a real one, too, although it's hard to quantify. We've gotten more cautious over the years, as we've tried to keep from taking drugs deep into clinical trials before finding out that they have some ruinous problem. The early-stage filters and hurdles we've put in probably work a little too well, though. Unnervingly, there are any number of drugs on the market now that never would have made it through the current regimes. The verdict all depends on how many loser projects we're avoiding at the same time, a number that's pretty much unknowable. Ah, what an industry.

5. Unfulfilled technological hopes. This overlaps with some of their other categories (such as all that genomics money we're never going to see again). But Booth and Zimmel draw special attention to the problem of the industry spending huge amounts on better and better in vitro technology (as in the previous point), only to find that it still doesn't translate well to animal models, much less clinical practice. Presumably, we're eventually going to figure out what we're doing, but we're probably going to hose away still more cash while we're doing it, too.

6. Too big to innovate? Readers will recognize this as a particular favorite of mine, what with my happy attitude toward huge mergers. Proponents of such would do well do digest this quote: "Whether size itself is good or bad for R&D; remains to be seen, (Heresy! Says the board at Pfizer! - DBL) but the simple fact is that a greater proportion of innovation is occurring outside the industry leaders." Their estimates show a meaningful decline just over the past seven years or so, which is rather alarming for the big guys.

Not a bad roundup. The article has a lot of other useful stuff in it, too; I highly recommend it. They have a few ideas for getting out of our current fix, which I'll try to get to in a future post. None of them strike me as particularly resonant rallying calls ("Improve investment discipline"), but that doesn't mean that they're wrong, either.

Catalyst Catfishing

I've just spent some time shoveling out piles of spam in the comments of my posts, so this will be a short one tonight. Tomorrow I'll head into the lab and take a look at an unusual setup, something I haven't done in quite a while.

I have about thirty small (20 mg) reactions going, all with the same starting materials. They differ only in the metal catalyst I've added, and I went for the most wide-ranging bunch I could find. I have elements in there that I've never even contemplated using before - stuff like indium, tantalum, ytterbium, and praseodymium. It's quite a sight.

Clearly, I have no idea of what I'm doing. Actually, I know the reaction that I'm trying to accelerate, and I have a rough idea of how it might happen. But beyond that, I don't know enough to guess what might work, so I'm just trying everything that looked reasonable (and a few that didn't, frankly, like the tantalum.) You can come across some interesting things this way, but, truth be told, you usually have to run a lot more than thirty variations to find it.

But it's a start, and I'm looking forward to seeing if anything has happened. I feel like a fisherman going off to check his trot lines. What's it going to be? Empty hooks? Tasty fish? Ugly snapping turtle? I'll report back in the next post.

A Capacious Rat-Hole Indeed

Today's Wall Street Journal kicks off, right in the pole position above the fold, with an article about the total profit/loss figure for publically traded biotech firms, 1990-date. Care to hazard a guess? I surveyed lab colleagues today, and most guesses were something like "Hmm. . .must be a loss, I reckon." One optimist thought they might have been even, or running to a slight profit ("Mostly because of Amgen," he explained.)

Well, the figure is indeed a loss, a 40 billion dollar loss so far. And keep in mind, that's not counting all the venture capital money that's evaporated when companies vanished even before floating stock. An impressive figure!

The natural question is why investors continue to throw money at the sector, and the answer is, as the Journal puts it, "boundless optimism." Reminds me of the chapter title in the stockbroker's classic "Where Are the Customer's Yachts?", titled "Customers: That Hardy Breed." People remember the Amgens of the world, few and far between though they are. As the article points out, a dollar put into Amgen when it went public is worth $165 today. (For comparison, a biotech index fund would have returned 8-fold over that period, and the Dow about 20-fold.)

But there have been a lot more than 165 biotech companies to invest in during that time, so (on the face of it) that 165-to-one payoff is something of a sucker's bet. Of course, we're not just throwing money down on a huge roulette wheel. Biotech stocks are subject to analysis, to a cold-eyed appraisal of their technology and their finances, their burn rates and scientific boards, their patent portfolios and licensing deals and FDA filings. Right? I invest in them too, you know. We're not just buying lottery tickets. We're investing. Right? Anybody?