About this site
Here we'll review recent developments in drug discovery and medicine and the IP issues and financial implications they have, along with general thoughts about research. Also likely to make an appearance: occasional digressions into useful topics like which lab reagents smell the worst.
About this author
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.
The "polypill" suggested in the latest issue of the British Medical Journal, while not completely wrong-headed, is the just sort of drug development idea that I'd expect a couple of epidemiologists to come up with. They're advocating a mixture of aspirin, a statin, folic acid, an ACE inhibitor, a diuretic, and a beta-blocker. The idea is to go after cardiovascular disease with pretty much all the known therapeutic options at once.
This is a touchingly linear approach to drug therapy. It's actually kind of sweet. Since the authors clearly mean well, I won't wave my fists around too much. But I would like to point out that these things may well work a bit differently in combination than they do in less crowded company. I realize that many people take subsets of these, which is a good starting point, but taking all six at once will be a new adventure. Drug interactions aren't easy to predict, and that's putting it mildly. Some people are going to feel more effects of one part of the mixture, and some will get hit by another. Some of the people taking this monster will also be taking (for example) diabetes medication, which sets off a whole new set of possible interactions.
And that would be a whopper of a pill, most likely. The doses themselves don't add up too terribly (since the statin and the ACE inhibitor are going to be there in small milligram amounts,) but there could be a beastly amount of binder and excipient. Getting these things to dissolve in an orderly fashion might be tricky. There's really no way to know without trying it and checking blood levels. And will the same formulation work equally well across a large patient population?
Finally, as others have pointed, there's the variation in the patients themselves. Dealing with that is hard enough with single medications. It's hard to imagine a one-size-fits-all pill that wouldn't simultaneously overdo and underdo its actions across the population. There's a reason these individual drugs come in so many different dose forms and amounts, you know.
It's worth a look at the comments section at the BMJ web site. Some of the responses are favorable, but there are many that really unload on the authors and their idea. Phrases like "one the most egregious presentations that I have ever come across," "it is very dangerous to take bits and pieces of research and cobble it together," "I would like to add my voice to those who are truly dumbfounded," "total disregard for scientific principles" and "It is almost impossible to know where to start" are flying around over there.
I've got a weakness for odd ideas, but this one is a little too troublesome for me. And I also have a weakness for solutions that people have overlooked, simple ideas that were right there all along. But, how can I put this? "Hey guys! Let's mix all six drugs together at once!" doesn't have that undiscovered-gem quality to it.
Passed On Without Comment
Excerpted from a Bloomberg News report from late last week:
German drug makers, which produced the first antibiotic and laid the basis for chemotherapy, are shifting research to the US to improve their access to the world's top prescription drug market. . .They also say ther's a richer pool of researchers and clearer regulatory procedures.
And they can charge more for their products there. "They have an excellent climate of innovation that's attractive to scientists," Schering (AG) CFO Joerg Spiekerkoetter said. . ."You need to be in the world's biggest market. You invest where you make your profit."
Back in the Saddle
I've returned, slightly tanned, not all that rested, and only moderately ready. That's what vacationing with two small children buys you! As usual, my biggest challenge will be remembering what I was doing when I left.
Long-time readers will have heard me talk about this before. I've found, over the years, that it's essential for me to write down what I was up to before leaving for more than a couple of days. Otherwise, it can be a bit hard to reconstruct. Back in grad school, my habit of labeling flasks with helpful legends like "second fraction" or "large batch" led to all kinds of trouble. Now I don't leave quite as many flasks around, but I still remember to label things more clearly than that, both on my bench and on my desk.
Hitting the reset button has a lot of advantages, though. Some of the things I forget deserve to be forgotten (in much the same way that much of the stuff that piles up on my desk should have gone into the waste can to start with.) A fresh-eyed look can lead to some new ideas, and new ideas are the fuel that runs the place.
There's some good material on this topic in Robert Root-Bernstein's
Discovering. It's an odd book, written as an occasionally irritating fictional discussion. But for all its quirks, it's full of gold. Root-Bernstein tries to work out what makes some people scientifically creative, and explores whether such behavior can be learned. (I'll return to this topic at another date, because it's an important one.)
I reread the book for inspiration every so often, particularly its collection of laws and advice near the end. One of the things that comes through is that more great ideas have come from people who spend time looking out the window than from people who spend their entire time staring at the problem to be solved. It's good to remind oneself of that while looking out the window!
The next post here will be for Friday morning. With any luck, I'll be lounging around near an uncrowded seashore, eating fried clams and watching my children try to find horseshoe crabs. I'll see everyone in a few days!
Amyloid and Alzheimer's - An Update
I wrote not long ago about some results from the ill-fated Alzheimer's vaccine trial conducted by Elan. It appeared that one of the patients who had an out-of-control inflammatory response also was largely cleared of brain amyloid deposits. Unfortunately, the inflammation proved fatal, and the level of histopathological detail the study reported was the kind that can only be obtained through an autopsy.
There's now a report (in the latest issue of the journal Neuron) on the survivors of the treatment group, and it's very interesting (and very encouraging.) The immune response shown by the patients seems to correlate very well with the further course of their Alzheimer's disease. The patients with the strongest antibody levels have shown no progression of the dementia, intermediate levels show slowed progression, and so on.
This is some of the strongest evidence yet to support the amyloid hypothesis of Alzheimer's. Everyone's suspected that the amyloid plaques were the proximal cause of the neuronal damage, but for decades there's been no way to establish that link. There's always been the real chance that Alzheimer's gives you amyloid plaques, rather than the other way around.
(People outside the sciences often don't realize just how difficult it can be to figure out these chicken-and-egg questions. The answer often looks obvious, but the obvious ones can be the cases that really hose you. The hard part is not making too many assumptions, and admitting to yourself just how much you don't know for sure.)
So perhaps this notoriously open question is on its way to being closed. New peptides are being developed to attempt a less hazardous amyloid vaccination, and there's the all-amyloids-at-once approach I wrote about in May. The clinical progress of the enzyme inhibitors that are designed to stop amyloid formation will be interesting to watch, too. There are plenty of non-mechanistic ways that they could fail, of course, and there may well still be surprises in the way the protein is deposited. But the signs are looking good.
Magical Realism at Pfizer
Readers of this site may recall a few weeks back, when I took off after Pfizer and their growth prospects. Well, Pfizer now says not to worry, that it's going to deliver loads of revenue growth over the next five years. Today's New York Times has the story, with the headline "A Drug Giant Thinks It Can Grow Still Bigger." Readers of this site will find some familiar lines of argument in it:
Pfizer's enormous size makes achieving substantial revenue growth through the end of the decade an almost impossible task. By next year, Pfizer expects to have revenue of $54 billion. To achieve double-digit increases, it either has to introduce give or six drugs a year that each generate $1 billion in sales, or sharply increase the sales of existing drugs. No drug company has ever come close to that level of productivity.
And allow me to predict that Pfizer isn't going to be the first. I know that a lot of people who are paid a lot more than I am think differently, but I see no way that they can meet these growth targets. Not by their own productivity, not by cutting costs, not even by aggressive in-licensing. They're going to be doing all those things, believe it, but I just don't see how they can ever add up to enough.
The quotes in the Times article are a study in magical thinking. You see, Pfizer's a massive power, and they can in-license anything, because they have this massive sales force. And if they need to cut costs, they can. . .cut their sales force. "Pfizer's research is back," says their CEO, but he then says that future research spending is going to be tied to revenue growth. (That means that it's going to be cut.) Actually, all those things that Pfizer has so much of are wonderful, and they're also wonderful opportunities for cost savings. They can't lose! Why does this sound odd to me?
Pfizer plans to introduce fifteen new drugs by the end of 2006, hooray! - but even if they all turn into billion-dollar winners, it still won't even be close to what they need. That's right: if they break all records for research and regulatory productivity, and do what no drug company has ever come close to doing before - fifteen new billion-dollar drugs in a row! - it won't be enough. I don't think there are enough licensing candidates in the world to close that gap. That leaves cutting costs to do it, which just gets them further behind eventually.
I know people at Pfizer; there are a lot of good people there. But folks, I have to say that you're working at a very odd company these days, one whose executives seem to have convinced themselves of some very odd things. Good luck. And diversify your portfolios, OK?
Dosing: An Inexact Science
Apologies for the missed days; I've been off from work and it's been hard to get access to my computer. Next week I'll be out of town on vacation, and posting will be officially on hiatus.
Since I was talking about animal models, I wanted to pass on something from one of my friends in the industry. Some time back, I had an e-mail from him along these lines:
I'm going to start up a company, and this is going to be our competitive advantage: We're going to check the different dosing vehicles out in all our animal models. Yes, that's right: we're going to find out which ones are toxic before we actually use them to dose our drug candidates. And then we're not going to dose the toxic ones! Great, huh? The thing is, as far as I can tell, this would be the first time that any company had ever bothered to do this in the entire drug industry. . .
Well, you could certainly hear his teeth gritting together. And while he's exaggerating (I think,) it's true that almost everyone in the business has had the experience of a formulations group coming up with a dosing vehicle that turns out to be, well, suboptimal. In their defense, many of these would be fine in perfectly healthy animals, but don't work out in a disease model. Some of them, too, would be acceptable for shorter dosing periods or less frequent dosing regimens. (And the formulations folks are required to point out that none of this would be an issue if the medicinal chemists would deliver compounds that would dissolve in something besides boiling DMSO.)
But every time a mistake gets made, everyone shouts and waves their arms. "Don't we have a list of approved formulations around here?" "Didn't you say that this one would be OK?" "Hey, you didn't say that you went up to 10% of that dispersing agent; we've never dosed anything that high." What it comes down to is too many variables, and no way to really check out all the combinations. Eventually, you step over a line that you didn't even know was there.
Models and Reality
When I was doing academic chemistry (working on my doctorate,) I did total synthesis of natural products. That's tough chemistry, which is why pharmaceutical companies like to hire people who've done it. They figure that if you'll put up with that, you can put up with most anything (and that you've already had plenty of experience with things that don't work.)
For really complicated structures, you often have some key transformations that are really tough calls - are they going to work, or not? So in some cases, people will try to model the reaction, just to see if it's going to be feasible. It takes a long time to make the complex intermediate structure for the real synthesis, but a test case can be made with less effort and tried.
But you can see the pitfall here - if the model were really a good reflection of all the twists and turns of the real system, it would be as hard to make as the real system is. Not much savings of effort there! So in order for it to be a feasible model, it has to be a simplification, and you'd better have some good reasons why you should then believe the results it gives you. As one synthetic chemist put it: "If you run the model system, and it works, then you run the real system. If you run the model system and it doesn't work. . .you run the real system anyway."
Which isn't far off the truth, unfortunately. The field is full of stories about complex reactions that looked just fine when modeled and turned into horrible tar pits in the real system. Well, as I said, I don't have to do that much any more. We try not to make anything that complex, if we can help it, and the idea of a model reaction almost never comes up. But what about the science after the chemistry?
That's when things start to get a bit disturbing. Once you hit the biology, everything is full of assumptions. Any assay that runs in vitro is based on a pyramid of assumptions and approximations, by definition. And I was talking a couple of weeks ago about how cells in culture can forget their origins and give you false results. It's a constant problem.
When you move on into the whole animal, rat or mouse dosing, then at least you're in a real living system. But a new set of assumptions has been made. We have a lot of diseased animal models, but some of them are not as relevant to human disease as they should be. They're better than nothing, but the results have to be looked at closely. Some kinds of cancer are poorly modeled, for example, and endocrine diseases like diabetes are tricky - a mixture of excellent correlations and some very poor ones, depending on your mode of attack.. And I won't even start again on the CNS diseases, the models for which require broad jumps of faith.
So I really shouldn't congratulate myself on having escaping models. I may be working much closer to reality in my chemistry lab, but the uses to which my work is put are something else again. Some of it is divorced from the real in ways that make a person nervous to even think about. Of course, some of it is just fine, too. The problem is, I'm not sure which parts are which.
Economy and Coach
Here's an interesting letter from the Pipeline mailbag, at least the parts of it that aren't piled up with exciting offers from hardy West African financiers. Douglas Ridgway writes:
You miss the principle reason for concern about the gray market for drugs between the US and Canada. It has nothing to do with who has an indigenous industry; since drugs are easily exported, where you develop and manufacture the stuff is completely disconnected from where you make the most money selling it. (Otherwise, the Europeans would have no industry at all, as they exert just as much control over pricing as Canada.) The basic reason for price differences is difference in ability or willingness to pay: since the marginal cost is near zero, just like software and movies, or airline seats, marketers can gain additional profit by charging less to more price sensitive customers who would otherwise not be customers at all. Yes, this means that the US market partially subsidizes the R&D costs for the rest of the world, just as business class travelers subsidize vacationers in the cheap seats, but the end result is better for everyone than going it alone. Differential pricing for segmented markets is basic economics.
The real risk, which does not seem to be widely appreciated in the media, is that cheating by the people who are paying the most threatens the system. If US end users reimport drugs that have been sold to Canada for use by Canadians, and end up paying the Canadian price, then pharmas will start treating sales to Canada as equivalent to the US, and charge the same price in both places. This is a net loss overall, but one born principally by Canadians. Canada should ban reexport, to protect our own selfish interests. I'm surprised that the pharmas haven't requested this already.
As I replied to him, I didn't mean to imply that the only reason that Canada (for example) has no real drug industry is that the country has price controls. He's right, Europe would seem a good counterexample. (The European companies are mostly expanding over here rather than at home, but that's largely due to labor concerns - yep, in Europe, anyone doing research below the level of a lab head is often "labor," time clocks, overtime and all. That's a topic for another day.) But it's worth noting that most of the large firms there have old roots, and were started before the current system completely gelled. The US is the only place that's had any tradition of companies come out of nowhere (Amgen, Genentech et al.) to become major players.
And his take on differential pricing is correct, too, up to a point. The problem is, I think, that not everyone sees it that way. Most consumers in the US don't realize that they're subsidizing the lower prices for everyone else, whereas I think most high-fare airline passengers have internalized it. They at least wouldn't be as surprised by it if it were brought to their attention, and there's no move afoot to force the airlines to lower all seats to the price of a coach ticket.
I realize that in the case of drugs I'm talking about the same pills, rather than first-class seats that deservedly cost more. But a last-minute coach seat will set you back, too, when the airline thinks someone will pay it. And, of course, there are only a certain number of seats available for a given itenerary, and people realize that. But knowing that those drugs are out there, all the time, available to someone else for lower prices. . .
Ridgway's absolutely right that "correct that "cheating by the people who are paying the most threatens the system." But there are plenty of people who could never be persuaded of that. They're convinced that, if they're paying the most, that they're the ones being cheated. Who wants to risk trying to persuade them otherwise? "Keep the world drug market afloat; vote down price controls" isn't a slogan to send anyone to the barricades. Not to the side of the barricades that it's supposed to, that's for sure. The fact that it's almost certainly true is of no political value, unfortunately.
It would be very hard, I think, for US pharma companies to try to treat Canadian sales as equivalents. The request Ridgway speaks of would best be made directly to the government agencies involved. It's a not-very-veiled threat, though, and you have to be willing to back those up. Since the drug industry would be up against Canada's national health care system, it would be quite a fight, the Novartis Glivec battles writ huge. I think it would also give the Canadian government a huge political windfall: look what these horrible companies are trying to do to us! Don't let these American bullies run over our wonderful system like this! No, it's not a fight that I think that the pharma industry is willing to pick. Not yet, anyway.
Man Conquers Virus
Or outlasts it, anyway. The alert reader will note from the time-stamp that I'm home from work today. I seem to finally be recovering from whatever this foul stuff was, not before passing it on to most of my family, though. That's made for an entertaining couple of evenings, with liberal spilling of just about every bodily fluid except the fun ones.
This is the sickest I've been since I once made the terrible mistake of flying out to a Keystone biology conference in Colorado, already in the grips of a sinus infection. Yep, that's what all the specialists prescribe for respiratory inflammation, a week at altitude in the middle of the winter. In much the same way, of course, that savvy mountaineers recommend that you avoid altitude sickness by getting bronchitis. At any rate, I had it all by the time I left, and how I managed to take coherent notes at the meeting is still a puzzle to me. The subject matter was very interesting, fortunately, or I might not have survived at all. As it was, I vividly recall walking back to my room each night, with pauses to sink to one knee on the corridor's carpet as I considered whether it would inconvenience folks if I slept right there.
At any rate, I'll have new content up tomorrow evening, assuming no more viral counterattacks. It'll be interesting to see if the gang at work has discovered anything wonderful in my absence, too, although I'm not sure what that'll say about my utility if they have. . .!
As is my policy, I want to mention that last week I went short Imclone stock (at 40.6, for those who are curious.) I'll mention this each time I talk about the stock, for as long as I have the position (and the same goes for anything else in my portfolio.)
Also for the curious, no, the last time I wrote about them, the stock was going straight up, which it continued to do - past reasonable levels, in my opinion, which is why I shorted them. This isn't 1999, and I'm not Tokyo Joe.
And that about does it for tonight, unfortuately. I came down with a rampaging GI-tract virus over the weekend. That made for some fun times, and I continue to feel as if my stomach has been stuffed with pine cones and broken Christmas ornaments. I've written several times about the poor state of anti-viral drug discovery, and here I sit, living proof.
Do You Have a Drug Industry? Take This Simple Test!
Meanwhile, over at Edmonton-based Colby Cosh's site, some of his readers are taking exception to my statement that Canada has no drug industry. It's true that there's some biotech action, specifically around Montreal (and a bit around Vancouver, too, I think.) But I don't count that for much. As Cosh notes, any list of Canadian pharma companies ends up including a lot of subsidiaries of outside companies (Pfizer Canada, Merck Frosst, and so on.)
And the small biotechs often head that way, too. It's true that BioChem Pharma used to be the big hope in that Montreal area, but I interviewed up there in 1989
when it was already part of Germany's Boehringer Ingleheim. It's gone through some twists and turns since then, but they've all involved being owned by someone else. (And so it goes with many other small outfits, and not just in Canada.) Note: My memory was playing tricks on me, as Canadian readers noted. Biochem Pharma merged with the UK's Shire two years ago. The company I interviewed with was Bio-Mega, who was indeed part of Boeringer Ingleheim. My apologies! If I'm going to go after a whole country, I should at least have my facts straight - DBL, 6/9)
My standard for deciding if a region has a drug industry is whether any companies there have developed any drugs. That sounds pretty simple, but the big money that has to be committed in pharma research isn't up at the front end, where the small outfits are. It's when you start to get serious about developing a compound. Then you need longer, more expensive toxicity testing, specialized chemical resources to do process improvements and scale-up under stricter regulatory controls. And you need plenty of folks doing the rest of the regulatory work to get your IND (Investigational New Drug) application together. There's no IND-EZ available, it's the long form every time.
Then you can start spending the real money, because it'll be time for clinical trials. And you'd better have spent enough up until now to convince yourself pretty thoroughly, because you're about to start seeing some major invoices. The drugs that fail in the later clinical stages eat hideous amounts of money and they don't give anything back. If you make it through, it's time to get the regulatory team cracking, because the paperwork for an NDA (New Drug Application) makes the stuff for the IND look like a form for a fishing license.
Now, many countries have some sort of small biotech presence, and many more have academic labs that produce useful science. But there just aren't many places in the world that have companies that can develop drugs from start to finish, while surviving the inevitable blowups and misses. The United States has the largest collection, definitely. England, Germany, and France all have drug industries, by my standards, and Switzerland has a strong one. Sweden is in there, and Denmark, on a smaller scale, and some other European countries (like the Netherlands) slip in, too. Italy and Spain are pretty marginal candidates, and the rest of the continent is barely on the drug research radar screen, for one reason or another (not that there aren't enough good chemists and biologists to staff some companies, though, which you could say about Canada as well.)
Continuing around the world in the same fish-or-cut-bait spirit, Japan makes the grade easily, although everyone has them in the "underperform" category. South America has virtually nothing, as does Africa, and the Middle East is a pharma desert save for some smaller outfits in Israel. Australia's hardly there, either (although there are plenty of good Australian drug researchers over here in the US.) And the Russian pharma industry really isn't on its feet, and it's hard to say when it will be (and in the meantime, there are plenty of Russians working in other countries, too.)
Then we come to a couple of special cases. India, as I mentioned last week, does not recognize the validity of patents from other countries. That's given them a robust and cutthroat generics industry, but it's also meant that no one wanted to develop new drugs there, either. That's changing, though. In a few years, India has promised that it's going to run down its pirate flag and join the World Intellectual Property Organization rules. And there's now a good-sized company (Dr. Reddy's) that's doing real drug discovery (although they're partnering with outside companies for most of the development work, so far.)
And then you have China, another country that has an unusual relationship with IP law. China has a large cohort of good scientists (and there are plenty working overseas, too) but they really haven't made an impression in drug discovery yet. They have all the tools, though. Perhaps one of the problems is that developing a new drug is about a ten-year process, give or take some, and no one's really sure what things will be like there in ten years.
So there you have it. Looking at a map, it's clear that there's a lot of drug-related research going on in the world (although some parts of it are unable to contribute much.) But when it comes to applied research, things narrow down drastically.
Now That I Think About It. . .
. . .I could have saved myself a lot of time last night, by just quoting this from H. F. Saint's Memoirs of an Invisible Man: "And then it is always good to feel that one is serving humanity and one's own selfish interests at the same time: perhaps I would be responsible for giving someone at the Times a rudimentary notion of the concepts of supply and demand."
Novartis's Turn on Page One
The focus of the Times article today is Novartis and Glivec (Gleevec here in the US, presumably because they didn't want to go around hearing "Glih-vec" and "Gly-vec" all the time.) Specifically, it's about their program of making the drug available for free to people who can't afford it. The headline is true, as far as it goes, but the reasons for their "falling short" are interesting.
In some cases, it's because: "Novartis requires patients' treatments to match local drug regulators' guidelines for Glivec. While the United States has approved Glivec as a first-line treatment, many countries recommend it only after other drugs have failed. Yet the reports of Glivec's success have led doctors to prescribe it anyway. . ."
One of the Times articles I noted on my recent list concerned the efforts of Warner-Lambert (now a part of Pfizer) to push off-label indications for one of its drugs. (For an MD's perspective of the complexities of that situation, see DB over at Medrants.) Here, it appears that Novartis is actually trying to stay within the letter of the label, and apparently you can make the Times for that, too.
They've had other problems with their partner organization, the Max Foundation. In some cases, the Max folks don't seem up to the job. But, as the article mentions, larger groups (like the Red Cross and Doctors Without Borders) declined to be a part of the effort. The head of Novartis's Oncology division says that the vast majority of groups they spoke to recommended that they not even do such a free distribution program at all.
A main point of the article is the suspicion that Novartis has used the donations as a way to get national insurance programs to pay for the drug. When the drug is approved for sale in a given country, the donation program ends as the national insurance takes over. In New Zealand, the government appears to have tried to choose not to buy the drug at all, but changed its mind under patient pressure. South Korea and Hong Kong have wrangled with the company over the price, and recipients in the donation program campaigned hard for Novartis's side in the negotiations. (Although in Korea, once the national health insurance took over, patients protested the new price, which now varies between 11% and 22% of the average pre-insurance cost of the drug in the US. That's not corrected for purchasing power in the two countries, and I don't have the figures to correct for the cost of insurance in both countries, either. It would be an interesting calculation.)
I'm having trouble being appalled by this practice, although I suspect the authors of the Times article assume that I am. Drug price negotiations are fierce and nasty, and both sides are trying to drive the hardest bargains they can. If a company thinks that patients can usefully pressure the bulk buyer of the drug, I'm not surprised if they decide to give it a try. The Times reporters seem a bit surprised that it worked, though: "But instead of becoming angry at Novartis, patients have protested to governments and have helped win victories for the company." How dare they! Pressuring government agencies - what's the world come to? I might add that the governments involved have a pretty big stick to wave, too - access to the entire country's pharmaceutical market. It's just a question of who blinks first.
What I would respect Novartis even more for doing, though, is being up front about this. They clearly can't give the drug away to everyone. Someone, somewhere should pay for it (and thus pay both for Glivec's development and the attempted development of the umpteen stinkers that haven't worked. I've seen Novartis present at conferences - believe me, they have some hard-luck stories, as do we all.) As in the Canadian reimportation issue, I'd really rather treat everyone like thinking adults, and lay out the situation as it really exists, rather than a bunch of feel-good stuff about "patient education."
India is a big focus of the article. Novartis has followed through on their warning to stop the donation program if generic Glivec came on the market there. Their attitude was: if you want to make Glivec in India (and make money off Glivec in India,) then you can help take care of the Indian patients. Some readers may have said "generic Glivec? When did it go generic?" And there's a key point.
India laughs at patents. They always have. The companies there appropriate drugs, turn them over to their very competent process chemists, and crank them out on scale. Sometimes they've come up with more economical synthetic routes than the original company ever did. The Times calls India's drug market "brutally competitive," but it's a brutal competition to see who's quickest at ripping off the foreigners who actually discovered the drug. Getting approval to sell generic Glivec took a few months, "swift by American standards," says the article. Make that impossible i>by American standards, or more clearly, illegal by American standards (and the rest of the world's,) and you have a better picture. Mind you, this approval was "unusually long and tedious" by Indian reckoning.
Doctors in India, though, the article says, realized ". . .the pragmatic aims of the company's philanthropy. The giveaway was a means, they contend, to establish a commerical beachhead. . ." Shock me. This is how the market works, the seeking of competitive advantage. In this case, it turns out that there's an advantage to giving some of the drug out for free (or at least a disadvantage for not doing it.)
Haven't any of these people read anything by Adam Smith? Hasn't anyone at the Times? And, as it turns out, the Indian generic companies have felt the pressure, and are stepping up to supply the drug to people in the free program. Good for them. Smith would be able to tell them that it's not all coming from the goodness of their hearts, and properly so.
(By the way, I did see the pharma-related op-ed piece in today's Times as well. That one raises so many issues that it's going to be a separate blog entry, though. . .)
In Case Any of You Thought I Was Imagining Things. . .
. . .the front page of the New York Times today runs the story "Drug Maker's Vow to Donate Cancer Medicine Falls Short." This jumps to a full page in the business section
I'm getting ready to go off to my job in the Evil Pharma Industry right now - and I can't find my new black robe and mask, either; they're supposed to be back from the dry cleaner's - so I won't have time to address the article until this evening's post. But address it I will. The Times is going to keep me hopping, I can tell.
What's the Cure for the Cure?
Since I've mentioned some anticancer agents recently, I thought I should point out that, to the other therapeutic areas in a drug company, it's a weird business. The reason has to do with the severity of the disease, and the lack of reasonable treatments.
If you're working in diabetes, say, you know that there's always insulin. People would prefer not to inject themselves with it, sure, and monitoring your blood sugar as closely as you need to is a pain, true - but if you've gotten to the point (as either a Type I or a Type II diabetic) where you need insulin, it's there, and it'll help. And there are the other medicines available for Type II diabetics - thiazolidinediones, sulfonylureas, metformin. Something will help.
The same goes for several other diseases. High blood pressure? The problem is choosing among a host of therapeutic options, and a host of drugs for each one. Infection? Here's the list of antibiotics that are known to kill the bacterium, some of which are slightly better than others for a given application.
But then there are the diseases that will kill you quickly, not slowly like Type II diabetes or hypertension. Pancreatic cancer, say. Surviving even a year or two past diagnosis of that one is a rare event indeed. One reason is that there's not a whole heck of a lot that can be done about it.
So the standards are a bit different. Everyone wants an oral drug that's taken once a day, but if it has to be taken three times for pancreatic cancer, hey, that's fine if it does something. If it's not oral, but has to be given i.v., well, it still beats the alternative. If it has some foul side effects. . .that's a shame, but they'd have to be pretty impressive ones to be worse than the disease.
The difficulty of treatment tends to lead toward nasty side effects and tough dosing regimens, anyway, and the severity of the disease make these harrowing therapies viable options. It's hard for researchers from other areas to get used to, watching the cancer folks express interest in drug candidates that would have other groups running for the exits. I tell my colleagues in that department that they'd try to develop fuming nitric acid as a clincial candidate if they could figure out a dosing protocol.
The flip side of this is that it's easier, in a way, to make a big advance in treatment. Note how everyone's excited about Avastin for colon cancer: it added about five months to the lives of the people that took it. The terrible thing is, that really is an improvement. With any luck, we'll be able in a few years to make such therapies look barbaric. For now, they're the best we have.
Drug Companies, The Times, and More
My piece on the New York Times and its pharma coverage seems to have come straight up from the Zeitgeist. Simultaneously, this letter came in from Steven Brill to Jim Romanesko's Media News site, asking why the most recent Times story (on drug industry lobbying) included no quotes (not even a denial or "no comment") from the industry side. Andrew Sullivan, who's certainly had his dealings with the Times over the last couple of years, chimed in as well. (no permalink on the post; it's in his Tuesday material.) I've seemingly worked up enough antibodies to the Times style, because I didn't even notice the lack when I read the story, but he's right: you want to do advocacy pieces, hit the Op-Ed page, or do one of those "News Analysis" editorials the Times runs above the fold anyway. (Or write your own blog - that'll do it, too!)
Yesterday also brought this piece from Robert Goldberg of the Manhattan Institute, who's noticed the Times coverage as well. The one that did it for him was one of the ones on my list below, on the side effects of antipsychotic medicines. As he discovered, a "study" cited in the article is unpublished data, unavailable for review.
Meanwhile, Ross over at The Bloviator - who, like me, is a blogger with a day job, not a full-time journalist, noticed the latest Times article, but was much more impressed with it. (For starters, to him the Times story was "buried on page A19." My thought was "What's this doing in Section A?") He's a public health guy, so this is just the sort of issue to put the two of us on opposite sides. And the same holds true for Sydney Smith over at Medpundit. She's no particular fan of the Times, but concludes that "Someone has to keep the industry honest."
The thing is, I agree with a good number of the points that these two med-bloggers make. Do drug companies go after every edge they can think of in promotion and advertising? Absolutely. They'll push it as far as possible if they think it'll increase sales. Does the industry produce drugs with little or no benefit over existing therapies? Yep, sad to say. Longtime readers know that I've been quite nasty on the subject of two of these, Nexium and Clarinex, which I feel add little or nothing to medical practice. (The line is harder to draw with multiple compounds that are in the same therapeutic class - I think there's room for several drugs before diminishing returns set in, but the definition of "several" is necessarily elastic.) Will the industry pull out all the stops it can think of to fight price controls? Oh, yes indeed. But I invite readers to think of one that wouldn't. I can't deny that my industry needs watching - but all industries need watching, to some degree.
But I have trouble getting as worked up about the lobbying efforts detailed in the Times articles. For one thing, I agree with Mickey Kaus's Sunday post that the amounts involved are, um, inadequate to accomplish the stated goals. $450,000 to stem drug reimportation from Canada? Get real. Considering the amount of revenue lost to the industry by this route, accomplishing anything with that amount of money would make our drug profit margins look like the wholesale grocery business. I'm not sure what my industry is up to here (needless to say, they don't consult us over in the research buildings,) but I remind everyone that these are the same wizards whose response to Canadian reimportation has been to wave their hands and talk about contaminated drugs. I hope this money is better spent, at least, because that line of argument is a loser right out of the shrink-wrap.
The list of influential heavy hitters that Ross cites from the Times article doesn't inspire the same awe and dread in me, unfortunately. As someone whose mortgage payment depends on the health of the industry, my first reaction is "That's it?" I had assumed we had more connections. It's not like people on the other side of the issue - the insurance companies, for example - are exactly powerless.
Well, whichever side of this you come down on, it's for sure that drug prices are going to be a political football for some time to come. My fear is that the issue is going to look more and more like a great big vote-getting populist honey pot: Down with the evil drug companies! Fight for the little guy! It's too easy to make this look like a crusade (Ross's reference to "Sauron's armies" is, unfortunately, just the sort of thing I'm thinking of, although I'm not expecting any Lord of the Rings references to show up in the national ad buys. . .)
You know, I get sick myself. Drug company insider or not, I pay health insurance, and my employer, drug company though it be, pays a good piece of that health insurance, too. We don't live in a privileged world; I can't just wander over to the production line and swipe my prescription off the conveyer belt. So it's not like we don't notice the cost of drugs, although they make an interesting comparison to the cost of being sick.
I worry that once we decide that the government - through its elected representatives, of course - should decide what pharmaceutical prices should be, that said elected representatives are going to decide that drugs should be really nice and cheap. But I keep thinking of Milton Friedman's quote to the effect that economists may not know much, but they sure know how to cause shortages: just mandate price controls.
Perhaps we'll legislate the drugs to be cheap as they are in Canada, oh happy day. But before we do that, I'd like for people to know that I work with a number of talented Canadian researchers. We have folks from Newfoundland to Vancouver; all I have to do is go up and down the hall to cover the whole country. Doubtless several of them would prefer to have stayed and worked in the country they grew up in. It's not like Canada lacks the infrastructure - there are plenty of high tech companies up there, of course. But those companies are allowed to charge what they think the market will bear. What Canada doesn't have, for some reason, is a drug industry. . .
Return of Erbitux
So we finally have the Erbitux (cetuximab) data from the trials that Germany's Merck KGaA conducted for colon and lung cancer. Do we know anything more than we did a couple of years ago? Let's set the stage with something from the archives of my Lagniappe site, from June a year ago. I was yelling at the Wall Street Journal at the time, which is a bit like yelling at the side of a building (or at the New York Times, for that matter.) Here was my take on Imclone's original clinical trial:
. . .the FDA made its requirements for clinical trials very clear, and it was Imclone that obfuscated. The dispute, which came to light during the recent congressional hearings, centers on the Phase II trial, a combination therapy of Imclone's Erbitux and the current chemotherapy agent irinotecan for colorectal cancer. Originally, as of August 1999, patients were going to get the combination of the two drugs only if their disease had still progressed after two cycles of irinotecan alone. Imclone amended this in October to allow combination therapy after any irinotecan treatment at all, and it appears that the FDA didn't completely catch on. And as it turned out, this plan eventually muddied the data thoroughly enough to make it hard to see if Imclone's drug did anything at all. But it sure did speed things up, which seems to have been what really mattered. . .
Imclone's colorectal cancer trial. . .relied on giving Erbitux as a combination therapy. When they asked for fast-track approval status, the FDA did indeed get recommendations to turn them down, since the drug had never been tried as a stand-alone therapy. Imclone made great protestations that their drug was not effective by itself, that it had synergistic effects with irinotecan, and that it would be downright unethical to run a trial as a monotherapy. The FDA bought it, and gave them fast-track.
But the data that Imclone backed all this up with wasn't from colorectal cancer patients - it was from renal cancer, which is a very different disease. In January 2001, the FDA (feeling that they'd been had) told Imclone that they needed a monotherapy trial, which they ran. . .in the quickest, shoddiest way possible, with a total of only 57 patients. Six of them responded to Erbitux as a single therapy, but the small number of data points made the results a statistical hairball. Maybe it worked, maybe it didn't.
Sam Waksal told Bristol-Meyers Squibb that this was good news, and that the FDA was pleased with it - but the agency has no record of ever having seen the data at that point, and "pleased" wasn't the right word when it finally showed up. Remember, this study could have shown that Erbitux worked by itself, which would have surprised people after Imclone's earlier statements, but would have been strong data for approval nonetheless. Or it could have confirmed their contention that the drug wouldn't work solo. It did neither, undermining both arguments.
That was the state of things, all right. And now? Merck KGaA ran an arm of the study with Erbitux as a monotherapy as well as in combination with irinotecan, all in patients who had failed on irinotecan alone and whose tumors expressed the receptor that the drug targets. And it worked, about as well as it seemed to back in 2001. But (in both cases) that's only true for certain values of the verb "to work." The primary endpoint of the European trial was response rate, and the combination of Erbitux and irinotecan definitely was better than Erbitux alone. Another endpoint, time to disease progression, also improved in the combination therapy.
What didn't improve was the survival time. Patients getting Erbitux monotherapy survived an average of 6.9 months, and those getting the combination survived 8.6 months. The difference wasn't statistically significant. All patients in the trials eventually succumbed to their disease, which given its severity isn't a surprise. The same holds true for the colon cancer patients treated in the Avastin trial, but they survived a lot longer compared to plain chemotherapy.
The run-up in Imclone's stock, which has been going on for a while now and moved along smartly today, would be more justified if there had been more of a survival effect. You can get a drug approved without showing a clear survival benefit, but you have to choose your clinical markers very carefully and make a compelling case to the FDA. I'm not sure if this is going to do it (analysts seem split on the question as well.) The FDA's seemingly more lenient approval stance is a bit of a wild card.
The run in the stock price would also be more justifiable if we knew how good the drug was as a first-line therapy. The entire clinical development of the drug has been shaped by Imclone's early decision to go for the quickest route they could think of - this trial was mostly to correct the problems with the first, and didn't address the first-line possibility. All the patients had refractory cancer, and there was thus no arm of the study with conventional chemotherapy alone. Bristol-Meyers Squibb and Imclone are working on such a trial, but it'll be quite a while before we see any results; I don't believe it's even started.
In the time that's been wasted by Imclone's attempt to hit a home run, other therapies targeting the same biochemical pathway have come along. There's Iressa, from AstraZeneca, for one - it failed in a combination trial against colon cancer, so its only real place is as a monotherapy for refractory cases. There are other small molecules (from Novartis, among others) that have had two years to get further along, and another antibody from Amgen and Abgenix that has advanced as well.
Imclone's going to need all the uses, and all the market share, that it can get. From something that was hyped to investors (and sold to Bristol-Meyers Squibb) as a groundbreaking near-miracle, Erbitux is coming into focus as a potentially useful second-line therapy - an adjunct to chemotherapy, something to put into the cocktail. In one way, that's nothing to sneer at. There will be some desperate patients who will be helped by the drug, although it's an open question to what extent or for how long.
But that doesn't mean you should buy the stock, not that you'd be able to work that out from the press. Most of the coverage of Imclone recently has been of the "look at that stock go" variety, or some sort of "comeback trail" piece. I can recommend a take that's much closer to my own from Matthew Herper at Forbes, though.
A Suspicious Glance at the New York Times
Readers may have noticed that I've referred to several articles recently that have appeared in the New York Times. They usually do a reasonable job of covering the drug industry - not great, not awful. (I think that the Wall Street Journal pays more attention, and gets more details right.) But I'm starting to wonder if something is up.
The Times has a well-documented tendency for what the current editors call "flood the zone" coverage. Well, the last few weeks have seen a run of stories on the pharmaceutical business. They've been long, prominently placed, and rather unfriendly. Is the zone where I work taking on water, or not?
Here's a scorecard for the last month's worth of coverage. You be the judge:
June 1: Drug Companies Increase Spending to Lobby Congress and Governments Just what it sounds like. Inside the front section, but referred to on Page One.
May 31: Big Drug Company Says It May Face Obstruction Case Page One story on Schering-Plough's latest woes. More prominent placement than the WSJ gave it, actually.
May 30: Court Papers Suggest Scale of Drug's Use Latest on the whistleblower case against Warner-Lambert (now Pfizer, of course) and their sales tactics for Neurontin. Certainly some new info, but nothing that should amaze anyone following the story.
May 25: Private Sector; A Drug Company's Man in Tweed A reasonable profile of Mark Fishman of Novartis's new Cambridge site. Nothing here that their sister paper (the Boston Globe) hasn't done months ago, though. By far the shortest article on this list.
May 22: 2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas Page One, 3600 words on Bayer's blood products division in the 1980s (blogged here as well.)
May 20: Leading Drugs for Psychosis Come Under New Scrutiny 3500 words on side effects of current antipsychotics and their cost-effectiveness.
May 18: Trial Lawyers Are Now Focusing On Lawsuits Against Drug Makers Blogged about at length below. Some good balancing quotes included, actually.
May 18: Will the Pain Ever Let Up At Bristol-Myers? Mentioned below as well. 2500 words of heavy hammering on their CEO. Not necessarily undeserved, mind you, but not breaking news, either.
May 8: Claritin's Price Falls, but Drug Costs More Unintended consequences of the drug going off-patent. An emphasis on the need to lower drug prices comes through.
May 7: A Respected Face, but Is It News or an Ad? Well-known newsmen paid for infomercials - deep pockets of drug companies highlighted throughout 2100 words.
May 4: For Glaxo, the Answers Are in the Pipeline We may have moved beyond the current take on the industry. This is a look at Glaxo's research efforts, and whether or not they're going to pay off. Quite reasonable reporting, overall.
While there have been some real stories during this period, I can't help but think that my industry is getting rather over-covered. Did any other major newspaper go Page One with the latest news about Schering-Plough, for example?
I'm going to be watching carefully over the next week or two. If we keep getting these Page Ones, I'm going to have to assume that there's an agenda at work. Heaven forbid that the Times have any political motives for its reporting, of course. This is the Newspaper of Record we're talking about (ahem.) But I can't help but note that drug prices will likely be a big domestic policy issue in the coming year of national political campaigning.
We're not up to relentless-drumbeat "Augusta National" levels of Times coverage yet. And I hope we don't get there. But perhaps it's just that the night is still young. . .
I'll be writing in more detail over the next few days on some of the news out of the American Society for Clinical Oncology meeting that's going on right now. I can recommend this site for a round-up of links to articles about the presentations at the meeting. Hey, they're comprehensive enough to include me, so they probably have things covered pretty well.
The article ASCO Springs a Leak, Again over at TheStreet.com is also worth a look. It points out that the group's efforts to embargo presentation data have had some rather obvious breakdowns in the last few years, to judge from stock trading activity in the days or hours before abstracts officially become available. No surprise to me; I'm just impressed that it works even to the extent that it does. But with the way information flows now, how long can scientific meetings keep up this practice?
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