About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
January 28, 2013
We medicinal chemists talk a good game when it comes to the the hydrophobic effect. It's the way that non-water-soluble molecules (or parts of molecules) like to associate with each other, right? Sure thing. And it works because of. . .well, van der Waals forces. Or displacement of water molecules from protein surfaces. Or entropic effects. Or all of those, plus some other stuff that, um, complicated to explain. Something like that.
Here's a paper in Angewandte Chemie that really bears down on the topic. The authors study the binding of simple ligands to thermolysin, a well-worked-out system for which very high-resolution X-ray structures are available. And what they find is, well, that things really are complicated to explain:
In summary, there are no universally valid reasons why the hydrophobic effect should be predominantly “entropic” or “enthalpic”; small structural changes in the binding features of water molecules on the molecular level determine whether hydrophobic binding is enthalpically or entropically driven.
Admittedly, this study reaches the limits of experimental accuracy accomplishable in contemporary protein–ligand structural work. . .Surprising pairwise systematic changes in the thermodynamic data are experienced for complexes of related ligands, and they are convincingly well reflected by the structural properties. The present study unravels small but important details. Computational methods simulate molecular properties at the atomic level, and are usually determined by the summation of many small details. However, details such as those observed here are usually not regarded by these computational methods as relevant, simply because we are not fully aware of their importance for protein–ligand binding, structure–activity relationships, and rational drug design in general. . .
I think that there are a lot of things in this area of which we're not fully aware. There are many others that we treat as unified phenomena, because we've given them names that make us imagine that they are. The hydrophobic effect is definitely one of these - George Whitesides is right when he says that there are many of them. But when all of these effects, on closer inspection, break down into tiny, shifting, tricky arrays of conflicting components, can you blame us for simplifying?
+ TrackBacks (0) | Category: "Me Too" Drugs | Chemical News | In Silico
August 13, 2012
Here's a response from Prof. Light to my post the other day attacking his positions on drug research. I've taken it out of that comments thread to highlight it - he no longer has to wonder if I'll let people here read what he has to say.
I'll have a response as well, but that'll most likely be up tomorrow - I actually have a very busy day ahead of me in the lab, working on a target that (as far as any of us in my group can tell) no one has ever attacked, for a disease that (as far as any of us in my group can tell) no one has ever found a therapy. And no, I am not making that up.
It's hard to respond to so many sarcastic and baiting trashings by Dr. Lowe and some of his fan club, but let me try. I wonder if Dr. Lowe allows his followers to read what I write here without cutting and editing.
First, let me clarify some of the mis-representations about the new BMJ article that claims the innovation crisis is a myth. While the pharmaceutical industry and its global network of journalists have been writing that the industry has been in real trouble because innovation has been dropping, all those articles and figures are based on the decline of new molecules approved since a sharp spike. FDA figures make it clear that the so-called crisis has been simply a return to the long-term average. In fact, in recent years, companies have been getting above-average approvals for new molecules. Is there any reasonably argument with these FDA figures? I see none from Dr. Lowe or in the 15 pages of comments.
Second, the reported costs of R&D have been rising sharply, and we do not go into these; but here are a couple of points. We note that the big picture, total additional investments in R&D (which are self-reported from closely held figures) over the past 15 years were matched by six times greater increase in revenues. We can all guess various reasons why, but surely a 6-fold return is not a crisis or "unsustainable." In fact, it's evidence that companies know what they are doing.
Another point from international observers is that the costs of clinical trials in the U.S. are much higher than in equally affluent countries and much higher than they need to be, because everyone seems to make money the higher they are in the U.S. market. I have not looked into this but I think it would be interesting to see in what ways costly clinical trials are a boon for several of the stakeholders.
Third, regarding that infamously low cost of R&D that Dr. Lowe and readers like to slam, consider this: The low estimate is based on the same costs of R&D reported by companies (which are self-reported from closely held figures) to their leading policy research center as were used to estimate the average cost is $1.3 bn (and soon to be raised again). Doesn't that make you curious enough to want to find out how we show what inflators were used to ramp the reported costs up, which use to do the same in reverse? Would it be unfair to ask you to actually read how we took this inflationary estimate apart? Or is it easier just to say our estimate is "idiotic" and "absurd"? How about reading the whole argument at www.pharmamyths.net and then discuss its merits?
Our estimate is for net, median corporate cost of D(evelopment) for that same of drugs from the 1990s that the health economists supported by the industry used to ramp up the high estimate. Net, because taxpayer subsidies which the industry has fought hard to expand pay for about 44% of gross R&D costs. Median, because a few costly cases which are always featured raise the average artificially. Corporate, because a lot of R(eseach) and some D is paid for by others "“ governments, foundations, institutes. We don't include an estimate for R(eseach) because no one knows what it is and it varies so much from a chance discovery that costs almost nothing to years and decades of research, failures, dead ends, new angles, before finally an effective drug is discovered.
So it's an unknown and highly variable R plus more knowable estimate of net, median, corporate costs. Even then, companies never so show their books, and they never compare their costs of R&D to revenues and profits. They just keep telling us their unverifiable costs of R&D are astronomical.
We make clear that neither we nor anyone else knows either the average gross cost or the net, median costs of R&D because major companies have made sure we cannot. Further, the "average cost of R&D" estimate began in 1976 as a lobbying strategy to come up with an artificial number that could be used to wow Congressmen. It's worked wonderfully, mythic as it may be.
Current layoffs need to be considered (as do most things) from a 10-year perspective. A lot industry observers have commented on companies being "bloated" and adding too many hires. Besides trimming back to earlier numbers, the big companies increasingly realize (it has taken them years) that it's smarter to let thousands of biotechs and research teams try to find good new drugs, rather than doing it in-house. To regard those layoffs as an abandonment of research misconstrues the corporate strategies.
Fourth, we never use "me-too." We speak of minor variations, and we say it's clinically valuable to have 3-4 in a given therapeutic class, but marginal gains fall quite low after that.
Fifth, our main point about innovation is that current criteria for approval and incentives strongly reward companies doing exactly what they are doing, developing scores of minor variations to fill their sales lines and market for good profits. We don't see any conspiracy here, only rational economic behavior by smart businessmen.
But while all new drug products are better than placebo or not too worse than a comparator, often against surrogate end points, most of those prove to be little better than last year's "better" drugs, or the years before"¦ You can read detailed assessments by independent teams at several sites. Of course companies are delighted when new drugs are really better against clinical outcomes; but meantime we cite evidence that 80 percent of additional pharmaceutical costs go to buying newly patented minor variations. The rewards to do anything to get another cancer drug approved are so great that independent reviewers find few of them help patients much, and the area is corrupted by conflict-of-interest marketing.
So we conclude there is a "hidden business model" behind the much touted business model, to spend billions on R&D to discover breakthrough drugs that greatly improve health and works fine until the "patent cliff" sends the company crashing to the canyon floor. The heroic tale is true to some extent and sometimes; but the hidden business model is to develop minor variations and make solid profits from them. That sounds like rational economic behavior to me.
The trouble is, all these drugs are under-tested for risks of harm, and all drugs are toxic to one degree or another. My book, The Risks of Prescription Drugs, assembles evidence that there is an epidemic of harmful side effects, largely from hundreds of drugs with few or no advantages to offset their risks of harm.
Is that what we want? My neighbors want clinically better drugs. They think the FDA approves clinically better drugs and don't realize that's far from the case. Most folks think "innovation" means clinically superior, but it doesn't. Most new molecules do not prove to be clinically superior. The term "innovation" is used vaguely to signal better drugs for patients; but while many new drugs are technically innovative, they do not help patients much. The false rhetoric of "innovative" and "innovation" needs to be replaced by what we want and mean: "clinically superior drugs."
If we want clinically better drugs, why don't we ask for them and pay according to added value "“ no more if no better and a lot more if substantially better? Instead, standards for testing effectiveness and risk of harms is being lowered, and "“ guess what "“ that will reward still more minor variations by rational economic executives, not more truly superior "innovative" drugs.
I hope you find some of these points worthwhile and interesting. I'm trying to reply to 20 single-space pages of largely inaccurate criticism, often with no reasoned explanation for a given slur or dismissal. I hope we can do better than that. I thought the comments by Matt #27 and John Wayne #45 were particularly interesting.
Donald W. Light
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Drug Prices
August 9, 2012
The British Medical Journal says that the "widely touted innovation crisis in pharmaceuticals is a myth". The British Medical Journal is wrong.
There, that's about as direct as I can make it. But allow me to go into more detail, because that's not the the only thing they're wrong about. This is a new article entitled "Pharmaceutical research and development: what do we get for all that money?", and it's by Joel Lexchin (York University) and Donald Light of UMDNJ. And that last name should be enough to tell you where this is all coming from, because Prof. Light is the man who's publicly attached his name to an estimate that developing a new drug costs about $43 million dollars.
I'm generally careful, when I bring up that figure around people who actually develop drugs, not to do so when they're in the middle of drinking coffee or working with anything fragile, because it always provokes startled expressions and sudden laughter. These posts go into some detail about how ludicrous that number is, but for now, I'll just note that it's hard to see how anyone who seriously advances that estimate can be taken seriously. But here we are again.
Light and Lexchin's article makes much of Bernard Munos' work (which we talked about here), which shows a relatively constant rate of new drug discovery. They should go back and look at his graph, because they might notice that the slope of the line in recent years has not kept up with the historical rate. And they completely leave out one of the other key points that Munos makes: that even if the rate of discovery were to have remained linear, the costs associated with it sure as hell haven't. No, it's all a conspiracy:
"Meanwhile, telling "innovation crisis" stories to politicians and the press serves as a ploy, a strategy to attract a range of government protections from free market, generic competition."
Ah, that must be why the industry has laid off thousands and thousands of people over the last few years: it's all a ploy to gain sympathy. We tell everyone else how hard it is to discover drugs, but when we're sure that there are no reporters or politicians around, we high-five each other at how successful our deception has been. Because that's our secret, according to Light and Lexchin. It's apparently not any harder to find something new and worthwhile, but we'd rather just sit on our rears and crank out "me-too" medications for the big bucks:
"This is the real innovation crisis: pharmaceutical research and development turns out mostly minor variations on existing drugs, and most new drugs are not superior on clinical measures. Although a steady stream of significantly superior drugs enlarges the medicine chest from which millions benefit, medicines have also produced an epidemic of serious adverse reactions that have added to national healthcare costs".
So let me get this straight: according to these folks, we mostly just make "minor variations", but the few really new drugs that come out aren't so great either, because of their "epidemic" of serious side effects. Let me advance an alternate set of explanations, one that I call, for lack of a better word, "reality". For one thing, "me-too" drugs are not identical, and their benefits are often overlooked by people who do not understand medicine. There are overcrowded therapeutic areas, but they're not common. The reason that some new drugs make only small advances on existing therapies is not because we like it that way, and it's especially not because we planned it that way. This happens because we try to make big advances, and we fail. Then we take what we can get.
No therapeutic area illustrates this better than oncology. Every new target in that field has come in with high hopes that this time we'll have something that really does the job. Angiogenesis inhibitors. Kinase inhibitors. Cell cycle disruptors. Microtubules, proteosomes, apoptosis, DNA repair, metabolic disruption of the Warburg effect. It goes on and on and on, and you know what? None of them work as well as we want them to. We take them into the clinic, give them to terrified people who have little hope left, and we watch as we provide with them, what? A few months of extra life? Was that what we were shooting for all along, do we grin and shake each others' hands when the results come in? "Another incremental advance! Rock and roll!"
Of course not. We're disappointed, and we're pissed off. But we don't know enough about cancer (yet) to do better, and cancer turns out to be a very hard condition to treat. It should also be noted that the financial incentives are there to discover something that really does pull people back from the edge of the grave, so you'd think that we money-grubbing, public-deceiving, expense-padding mercenaries might be attracted by that prospect. Apparently not.
The same goes for Alzheimer's disease. Just how much money has the industry spent over the last quarter of a century on Alzheimer's? I worked on it twenty years ago, and God knows that never came to anything. Look at the steady march, march, march of failure in the clinic - and keep in mind that these failures tend to come late in the game, during Phase III, and if you suggest to anyone in the business that you can run an Alzheimer's Phase III program and bring the whole thing in for $43 million dollars, you'll be invited to stop wasting everyone's time. Bapineuzumab's trials have surely cost several times that, and Pfizer/J&J are still pressing on. And before that you had Elan working on active immunization, which is still going on, and you have Lilly's other antibody, which is still going on, and Genentech's (which is still going on). No one has high hopes for any of these, but we're still burning piles of money to try to find something. And what about the secretase inhibitors? How much time and effort has gone into beta- and gamma-secretase? What did the folks at Lilly think when they took their inhibitor way into Phase III only to find out that it made Alzheimer's slightly worse instead of helping anyone? Didn't they realize that Professors Light and Lexchin were on to them? That they'd seen through the veil and figured out the real strategy of making tiny improvements on the existing drugs that attack the causes of Alzheimer's? What existing drugs to target the causes of Alzheimer are they talking about?
Honestly, I have trouble writing about this sort of thing, because I get too furious to be coherent. I've been doing this sort of work since 1989, and I have spent the great majority of my time working on diseases for which no good therapies existed. The rest of the time has been spent on new mechanisms, new classes of drugs that should (or should have) worked differently than the existing therapies. I cannot recall a time when I have worked on a real "me-too" drug of the sort of that Light and Lexchin seem to think the industry spends all its time on.
That's because of yet another factor they have not considered: simultaneous development. Take a look at that paragraph above, where I mentioned all those Alzheimer's therapies. Let's be wildly, crazily optimistic and pretend that bapineuzumab manages to eke out some sort of efficacy against Alzheimer's (which, by the way, would put it right into that "no real medical advance" category that Light and Lexchin make so much of). And let's throw caution out the third-floor window and pretend that Lilly's solanezumab actually does something, too. Not much - there's a limit to how optimistic a person can be without pharmacological assistance - but something, some actual efficacy. Now here's what you have to remember: according to people like the authors of this article, whichever of these antibodies that makes it though second is a "me-too" drug that offers only an incremental advance, if anything. Even though all this Alzheimer's work was started on a risk basis, in several different companies, with different antibodies developed in different ways, with no clue as to who (if anyone) might come out on top.
All right, now we get to another topic that articles like this latest one are simply not complete without. That's right, say it together: "Drug companies spend a lot more on marketing than they do on research!" Let's ignore, for the sake of argument, the large number of smaller companies that spend all of their money on R&D and none on marketing, because they have nothing to market yet. Let's even ignore the fact that over the years, the percentage of money being spent on drug R&D has actually been going up. No, let's instead go over this in a way that even professors at UMDNJ and York can understand it:
Company X spends, let's say, $10 a year on research. (We're lopping off a lot of zeros to make this easier). It has no revenues from selling drugs yet, and is burning through its cash while it tries to get its first on onto the market. It succeeds, and the new drug will bring in $100 dollars a year for the first two or three years, before the competition catches up with some of the incremental me-toos that everyone will switch to for mysterious reasons that apparently have nothing to do with anything working better. But I digress; let's get back to the key point. That $100 a year figure assumes that the company spends $30 a year on marketing (advertising, promotion, patient awareness, brand-building, all that stuff). If the company does not spend all that time and effort, the new drug will only bring in $60 a year, but that's pure profit. (We're going to ignore all the other costs, assuming that they're the same between the two cases).
So the company can bring in $60 dollars a year by doing no promotion, or it can bring in $70 a year after accounting for the expenses of marketing. The company will, of course, choose the latter. "But," you're saying, "what if all that marketing expense doesn't raise sales from $60 up to $100 a year?" Ah, then you are doing it wrong. The whole point, the raison d'etre of the marketing department is to bring in more money than they are spending. Marketing deals with the profitable side of the business; their job is to maximize those profits. If they spend more than those extra profits, well, it's time to fire them, isn't it?
R&D, on the other hand, is not the profitable side of the business. Far from it. We are black holes of finance: huge sums of money spiral in beyond our event horizons, emitting piteous cries and futile streams of braking radiation, and are never seen again. The point is, these are totally different parts of the company, doing totally different things. Complaining that the marketing budget is bigger than the R&D budget is like complaining that a car's passenger compartment is bigger than its gas tank, or that a ship's sail is bigger than its rudder.
OK, I've spend about enough time on this for one morning; I feel like I need a shower. Let's get on to the part where Light and Lexchin recommend what we should all be doing instead:
What can be done to change the business model of the pharmaceutical industry to focus on more cost effective, safer medicines? The first step should be to stop approving so many new drugs of little therapeutic value. . .We should also fully fund the EMA and other regulatory agencies with public funds, rather than relying on industry generated user fees, to end industry’s capture of its regulator. Finally, we should consider new ways of rewarding innovation directly, such as through the large cash prizes envisioned in US Senate Bill 1137, rather than through the high prices generated by patent protection. The bill proposes the collection of several billion dollars a year from all federal and non-federal health reimbursement and insurance programmes, and a committee would award prizes in proportion to how well new drugs fulfilled unmet clinical needs and constituted real therapeutic gains. Without patents new drugs are immediately open to generic competition, lowering prices, while at the same time innovators are rewarded quickly to innovate again. This approach would save countries billions in healthcare costs and produce real gains in people’s health.
One problem I have with this is that the health insurance industry would probably object to having "several billion dollars a year" collected from it. And that "several" would not mean "two or three", for sure. But even if we extract that cash somehow - an extraction that would surely raise health insurance costs as it got passed along - we now find ourselves depending on a committee that will determine the worth of each new drug. Will these people determine that when the drug is approved, or will they need to wait a few years to see how it does in the real world? If the drug under- or overperforms, does the reward get adjusted accordingly? How, exactly, do we decide how much a diabetes drug is worth compared to one for multiple sclerosis, or TB? What about a drug that doesn't help many people, but helps them tremendously, versus a drug that's taken by a lot of people, but has only milder improvements for them? What if a drug is worth a lot more to people in one demographic versus another? And what happens as various advocacy groups lobby to get their diseases moved further up the list of important ones that deserve higher prizes and more incentives?
These will have to be some very, very wise and prudent people on this committee. You certainly wouldn't want anyone who's ever been involved with the drug industry on there, no indeed. And you wouldn't want any politicians - why, they might use that influential position to do who knows what. No, you'd want honest, intelligent, reliable people, who know a tremendous amount about medical care and pharmaceuticals, but have no financial or personal interests involved. I'm sure there are plenty of them out there, somewhere. And when we find them, why stop with drugs? Why not set up committees to determine the true worth of the other vital things that people in this country need each day - food, transportation, consumer goods? Surely this model can be extended; it all sounds so rational. I doubt if anything like it has ever been tried before, and it's certainly a lot better than the grubby business of deciding prices and values based on what people will pay for things (what do they know, anyway, compared to a panel of dispassionate experts?)
Enough. I should mention that when Prof. Light's earlier figure for drug expense came out that I had a brief correspondence with him, and I invited him to come to this site and try out his reasoning on people who develop drugs for a living. Communication seemed to dry up after that, I have to report. But that offer is still open. Reading his publications makes me think that he (and his co-authors) have never actually spoken with anyone who does this work or has any actual experience with it. Come on down, I say! We're real people, just like you. OK, we're more evil, fine. But otherwise. . .
+ TrackBacks (0) | Category: "Me Too" Drugs | Business and Markets | Cancer | Drug Development | Drug Industry History | Drug Prices | The Central Nervous System | Why Everyone Loves Us
May 5, 2011
The "Opinionator" blog at the New York Times is trying here, but there's something not quite right. David Bornstein, in fact, gets off on the wrong foot entirely with this opening:
Consider two numbers: 800,000 and 21.
The first is the number of medical research papers that were published in 2008. The second is the number of new drugs that were approved by the Food and Drug Administration last year.
That’s an ocean of research producing treatments by the drop. Indeed, in recent decades, one of the most sobering realities in the field of biomedical research has been the fact that, despite significant increases in funding — as well as extraordinary advances in things like genomics, computerized molecular modeling, and drug screening and synthesization — the number of new treatments for illnesses that make it to market each year has flatlined at historically low levels.
Now, "synthesization" appears to be a new word, and it's not one that we've been waiting for, either. "Synthesis" is what we call it in the labs; I've never heard of synthesization in my life, and hope never to again. That's a minor point, perhaps, but it's an immediate giveaway that this piece is being written by someone who knows nothing about their chosen topic. How far would you keep reading an article that talked about mental health and psychosization? A sermon on the Book of Genesization? Right.
The point about drug approvals being flat is correct, of course, although not exactly news by now, But comparing it to the total number of medical papers published that same year is bizarre. Many of these papers have no bearing on the discovery of drugs, not even potentially. Even if you wanted to make such a comparison, you'd want to run the clock back at least twelve years to find the papers that might have influenced the current crop of drug approvals. All in all, it's a lurching start.
Things pick up a bit when Bornstein starts focusing on the Myelin Repair Foundation as an example of current ways to change drug discovery. (Perhaps it's just because he starts relaying information directly that he's been given?) The MRF is an interesting organization that's obviously working on a very tough problem - having tried to make neurons grow and repair themselves more than once in my career, I can testify that it's most definitely nontrivial. And the article tries to make a big distinction between they way that they're funding research as opposed to the "traditional NIH way".
The primary mechanism for getting funding for biomedical research is to write a grant proposal and submit it to the N.I.H. or a large foundation. Proposals are reviewed by scientists, who decide which ones are most likely to produce novel discoveries. Only a fraction get funded and there is little encouragement for investigators to coordinate research with other laboratories. Discoveries are kept quiet until they are published in peer-reviewed journals, so other scientists learn about them only after a delay of years. In theory, once findings are published, they will be picked up by pharmaceutical companies. In practice, that doesn’t happen nearly as often as it should.
Now we're back to what I'm starting to think of as the "translational research fallacy". I wrote about that here; it's the belief that there are all kinds of great ideas and leads in drug discovery that are sitting on the shelf, because no one in the industry has bothered to take a look. And while it's true that some things do slip past, I'm really not sure that I can buy into this whole worldview. My belief is that many of these things are not as immediately actionable as their academic discoverers believe them to be, for one thing. (And as for the ones that clearly are, those are worth starting a company around, right?) There's also the problem that not all of these discoveries can even be reproduced.
Bornstein's article does get it right about this topic, though:
What’s missing? For a discovery to reach the threshold where a pharmaceutical company will move it forward what’s needed is called “translational” research — research that validates targets and reduces the risk. This involves things like replicating and standardizing studies, testing chemicals (potentially millions) against targets, and if something produces a desired reaction, modifying compounds or varying concentration levels to balance efficacy and safety (usually in rats). It is repetitive, time consuming work — often described as “grunt work.” It’s vital for developing cures, but it’s not the kind of research that will advance the career of a young scientist in a university setting.
“Pure science is what you’re rewarded for,” notes Dr. Barres. “That’s what you get promoted for. That’s what they give the Nobel Prizes for. And yet developing a drug is a hundred times harder than getting a Nobel Prize. . .
That kind of research is what a lot of us spend all our days doing, and there's plenty of work to fill them. As for developing a drug being harder than getting a Nobel Prize, well, apples and oranges, but there's something to it, still. The drug will cost you a lot more money along the way, but with the potential of making a lot more at the end. Bornstein's article goes off the rails again, though, when he says that companies are reluctant to go into this kind of work when someone else owns the IP rights. That's technically true, but overall, the Bayh-Dole Act on commercialization of academic research (despite complications) has brought many more discoveries to light than it's hindered, I'd say. And he's also off base about how this is the reason that drug companies make "me too" compounds. No, it's not because we don't have enough ideas to work on, unfortunately. It's because most of them (and more over the years) don't go anywhere.
Bornstein's going to do a follow-up piece focusing more on the Myelin Repair people, so I'll revisit the topic then. What I'm seeing so far is an earnest, well-meaning attempt to figure out what's going on with drug discovery - but it's not a topic that admits of many easy answers. That's a problem for journalists, and a problem for those of us who do it, too.
+ TrackBacks (0) | Category: "Me Too" Drugs | Academia (vs. Industry) | Drug Development | Who Discovers and Why
January 26, 2011
So, me-too drugs, knock-offs, copycats: what say you? If you're a critic of the industry, you generally say quite a bit, and it's about lack of innovation, seeking easy profits and playing it safe, putting marketing over science, and so on. But what if that's not true?
We've talked about this here before, but now we can put some numbers on the topic, thanks to this article in Nature Reviews Drug Discovery. The authors have covered a lot of ground, looking at first-in-class drugs approved from the early 1960s up to 2003, with later entrants in the same areas accepted up to 2007. There are 94 of those different therapeutic classes over that period, with a total of 287 follow-on drugs coming after the pioneer compounds in each. So there you have it - case closed, eh?
Not so fast. Look at the timing. For one thing, over that nearly 50-year period, the time it takes for a second entry into a therapeutic area has declined steeply. Back in the 1970s, it took over nine years (on average) for another drug to come in and compete, but that's gone down to 1.7 years. (The same sort of speed-up has taken place for third and later entries as well). Here's what that implies:
Implicit in some of the criticism of the development of me-too drugs has been the assumption that their development occurs following the demonstration of clinical and commercial success by the first-in-class drug. However, given assessments of the length of time that is typically required for drug development — estimated at between 10 to 15 years — the data on the timing of entry of follow-on drugs in a particular class, in this study and in our previous study, suggest that much of the development of what turn out to be follow-on drugs must occur before the approval of the breakthrough drug.
That it does, and the overlap has been increasing. I've been in the drug industry since 1989, and for every drug class that's been introduced during my career, at least one of the eventual follow-on drugs has already been synthesized before the first one's been approved by the FDA. In fact, since the early 1990s, it's been the case 90% of the time that a second drug has already filed to go into clinical trials before the first one has been approved, and 64% of the time another compound has, in fact, already started Phase III testing. Patent filings tell the story even more graphically, as is often the case in this industry. For new drug classes approved since the 1970s, 90% have had at least one of the eventual follow-on drugs showing its first worldwide patent filing before the first-in-class compound was approved.
So the mental picture you'd get from some quarters, of drug companies sitting around and thinking "Hmmm. . .that's a big seller. Let's hang a methyl off it now that those guys have done the work and rake in the cash" is. . .inaccurate. As this paper shows (and as has been the case in my own experience), what happens is that a new therapeutic idea becomes possible or plausible, and everyone takes off at roughly the same time. At most, the later entrants jump in when they've heard that Company X is working in the same area, but that's a long time before Company X's drug (or anyone's) has shown that it's going to really work.
If you wait that long, you'd be better off waiting even longer to see what shortcomings the first drug has out in the real marketplace, and seeing if you can overcome them. Otherwise, you're too late to go in blind (like the first wave does). And blind it is - I can't count the number of times I've been working on a project where we know that some other company is in the same area, and wondering just how good their compound is versus ours. If you know what the structure is (and you don't always), then you'll make it yourself and check your lead structure out head-to-head in all the preclinical models you care about. But when it comes to the clinical trials, well, you just have to hold your breath and cross your fingers.
I'll let the authors sum things up:
Overall, these results indicate that new drug development is better characterized as a race to market among drugs in a new therapeutic class, rather than a lower risk imitation of a proven breakthrough. . .a race in which several firms pursue investigational drugs with similar chemical structures or with the same mechanism of action before any drug in the class obtains regulatory marketing approval. So, the distinctions that are often drawn between the relative innovative value of the development of the first-in-class and the me-too drugs in the same class may be misguided. . .
Over to you, Marcia Angell and the rest.
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May 18, 2010
This post drew a lot of comments here about how the big companies are going after follow-on biologic drugs. As a late-2008 article put it:
Merck already has one FOB in clinical development: a pegylated erythropoietin for anemia similar to Amgen's Aranesp (darbapoetin alfa) called MK-2578, which is being developed using a sugar-modification technology the pharma obtained via its 2006 purchase of GlycoFi. The company hopes to launch its EPO product in dialysis and pre-dialysis patients with chronic kidney disease in 2012.
Clyburn declined to offer any sales projections for that product or the MBV unit in general, nor would he identify any of the other products or therapeutic areas Merck will attempt to develop. He said MBV will identify product candidates by looking at their value in the marketplace.
Good move to decline those speculations, because Merck just announced recently that they're discontinuing that whole Aranesp-oid project. The FDA made it clear that they'd expect a full human cardiovascular safety workup before approval, which appears to have thrown Merck's numbers off severely, as you might imagine.
There is, and continues to be, no easy way.
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development
April 28, 2010
The Wall Street Journal has an article detailing some of Pfizer's plans in the biologics area: stepping in with second-generation versions of current winners from other companies. New versions of Rituxan and Enbrel are in the works, with the improvements mostly coming in how often the drugs need to be given.
They're not alone in this - Merck has announced that they're going to go after the same sorts of markets. And I can see the business rationale, since the original products have been such huge successes. But these new versions are going to be different enough that they're certainly not "biosimilars" or "biogenerics" - they're new substances, which will require their own complete safety/efficacy clinical workup. And by the time they get to market, some of these may be up against (or close to being up against) lower-cost versions of the original therapies, so the insurance companies are going to have to see some real benefit before they switch away.
So while some of these may well work out, not all of them will. It looks like a worthwhile thing to try, but it's not a sure road to riches. That's the thing about this industry these days - all those roads appear to be blocked off and plastered with "Detour" signs. . .
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Drug Prices
August 24, 2009
Eli Lilly announced some bad news last week when they dropped arzoxifene, a once-promising osteoporosis treatment (and successor to Evista (raloxifene), which has been one of the company's big successes).
If this drug had been found ten or fifteen years ago, it might have made it though. But the trial data showed that while it made its primary endpoints (reducing vertebral fractures, for example), it missed several secondary ones (such as, well, non-vertebral fractures). And the side effect profile wasn't good, either. That combination meant that the drug was going to face at hard time at the FDA for starters, and even if it somehow got through, it would face a hard time competing with generic Fosamax (and Lilly's own Evista).
So down it went, and it sound like the right decision to make. Unfortunately, given the complexities of estrogen receptor signaling, the clinic is the only place that you can find out about such things. And there are no short, inexpensive clinical trials in osteoporosis, so the company had to run one of the big, expensive ones only to find out that arzoxifene didn't quite measure up. That's why this is a territory for the deep-pocketed, or (at the very least) for those who hope to do a deal with them at the first opportunity.
One more point is worth emphasizing. Take a look at the structures of the two compounds (from those Wikipedia links in the first paragraph). Pretty darn similar, aren't they? Arzoxifene is clearly a follow-up drug in every way - modified a bit here and there, but absolutely in the same family. A "me-too" drug, in other words, an attempt to come up with something that works similarly but sands off some of the rough edges of the previous compound. But anyone who thinks that development of a follow-up compound is easy - and a lot of people outside the industry do - should consider what happened to this one.
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Drug Development | Toxicology
March 19, 2008
One of the less appealing ways that companies have tried to fill their drug portfolios over the years has been to look through their current drugs in search of one with a main active metabolite. That altered structure then becomes a clinical candidate for the next generation. I’ve said bad things before about Clarinex (desloratadine), son of Claritin (loratadine), the most famous example of this practice. That “des” prefix tells you that the newer drug is just the older one minus some part of its structure, in this case, minus a carbamate group that the liver clips off anyway. Even non-chemists can see the change, looking at the top parts of the structures in those Wikipedia articles.
Now comes Pristiq (desvenlafaxine), spawn of Effexor (you guessed it, venlafaxine). This one's also a simple metabolic change, OH from O-methyl. Wyeth has done very well with Effexor over the last few years, and they’re not ready to give up on that market share once it goes off patent this year. The timing of this new drug is, as they say, no coincidence. The Carlat Psychiatry Blog, not a place to go to find lots of warm feelings for the drug industry, has its “Top Five Reasons to Forget About Pristiq”. From the way things look, I have to agree with them; at the moment it’s hard to see much need for the stuff.
But there’s a good point made there by an investigator on the clinical trials, Dr. Michael Liebowitz of Columbia. He, quite reasonably, is waiting for the market to settle whether the drug is of any use or not: “If it is useful, then it will make money for the company, and if it is not, it won’t.” Update: there's more from Liebowitz on this topic, and on follow-on CNS drugs in general.
Exactly. I’m very much in favor of letting drugs stand or fall on their merits, if any. My first guess is that Pristiq is not much of an addition to the pharmacopeia – and if it isn’t, Wyeth deserves to lose the money they’ve put into it, since that, frankly, would have been the presumption from very early in the drug’s development. They took this drug forward at their own risk, and should profit or lose by it accordingly.
One thing I’ll say for the company, though: they actually seem to be running a head-to-head study between the two drugs. That’s good to see, and it’ll be quite interesting to see what case Wyeth can make, if any, after the data come in. At least they’re not just banging on tin cans and shouting “Now with the great taste of fish!” or something. Interestingly, as a comment on the Carlat blog points out, the company has already published data on one unimpressive trial with Pristiq, and I have to thank them for doing that, too. If there was ever a head-to-head efficacy study run between Claritin and Clarinex, I definitely missed it – I’m willing to be corrected, of course, but I’m pretty sure that there never was one).
So one-and-a-half cheers for Wyeth. I wish, in most cases, that companies would avoid the metabolite-drug idea. Alternatively, I wish that everyone’s drug pipeline was well stocked enough that such follow-ups didn’t look financially appealing. But if you’re going to have them, taking an honest look at their benefits is the only way to go.
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | The Central Nervous System | Why Everyone Loves Us
February 4, 2008
The topic of “me too” drugs has come up quite a bit around here over the years. For the most part, I’m a defender, although there are some places I draw the line (Clarinex for Claritin comes to mind as a particularly useless advance). A reader pointed out the amount of advertising he’s seeing for Aciphex (rabeprazole), another proton pump inhibitor for gastrointestinal reflux and general stomach acid problems, and wonders what side of the line this one is on.
I’m already on record as wondering just how much of an advance Nexium (esomeprazole) was over its racemic form, Prilosec (omeprazole), so the bar is set pretty high in this area already. Looking through PubMed, I find numerous comparisons between the drugs, which suggest some small differences in PK. Some earlier studies suggested that rabeprazole works more quickly over a course of therapy, but this is in dispute. There do seem to be differences in drug interactions between the various drugs in this category, which could be important in older patients who are already taking other medications. (Protonix (pantoprazole) may also be in this category). Perhaps reflecting this, this study found that rabeprazole was "significantly more effective" in elderly patients.
So, overall, there do seem to be some differences between the various drugs in this category (summarized here, among other places). In most cases, though, they're pretty much the same. This looks like a fight among near-equals, with the occasional tiebreaker going to one compound or another. This would explain why the ads for the various compounds are pretty interchangeable as well, featuring people holding their stomachs when confronted with a plate of barbecue. (Living in the Boston area, I can understand that reaction to some of the local stuff, but that's another topic).
As I say, I generally defend the idea of several drugs entering the same therapeutic space. In theory, and for the most part in practice, each new entrant provides something that the previous ones didn’t, and can thus carve out a space for itself. In this case, though, the differences between these drugs, though real, are comparatively small and subtle. There are patients who benefit from the number of choices in this category, but not as many as the advertising dollars would suggest. The whole proton-pump inhibitor market seems to be a fight among near-equals to carve up a large and lucrative market. The parallels that occur to me are the markets for SUVs and laundry detergent.
That means that it's a fight made for the big companies, for one thing. A smaller outfit would have been crazy to get into the PPI arena without a big partner. Given the current state of the art, it would seem crazy for anyone else to be contemplating an entry at all, unless they have some huge advance that they can demonstrate clinically. The existence of so many PPIs is not a scandal - yet - but it's not a glorious chapter in the history of drug research, either.
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November 28, 2007
Novartis must wonder what they did to deserve this one. A few years ago, it looked as if they ruled the potentially lucrative world of dipeptidylylpeptidase-IV (DPP-IV) inhibitors for diabetes. (Note - name of enzyme corrected after brain hiccup - DBL). Novartis seemed to be the first big company to come up with good chemical matter in the area, and they published a whole string of papers while their lead compound went through the clinic.
Then came trouble. Merck turned out to have a big program of their own in the area, which in Merckian fashion they’d kept very quiet about, and they actually beat Novartis to the FDA. And then they beat them to market, because the agency had some questions about the Novartis compound. Those questions have done nothing but multiply. Now the problem appears to be liver tox, one of the last things the diabetic population needs. It’s looking very likely that Novartis’s compound may never get to the market in the US at all.
So here’s a question: if both compounds had made it to market, wouldn’t the people who tally up lists of “me-too” drugs have considered the first compound (from Merck) to be the original, and the Novartis one to be the copycat? After all, they target the same enzyme for the same disease in the same way. (I should mention that a DPP-IV inhibitor itself is just the sort of thing the industry is supposed to be turning out, a completely new way to treat a major and growing public health problem, but we'll pass over that for now).
But these compounds were developed more or less simultaneously, with the two companies racing each other to the market. It’s not like either company sat back and watched the big profits roll in, and said “I need to latch on to some of that – let’s make one of those, too.” The whole thing was done on a risk basis, because while the biochemical rationale behind DPP-IV inhibition makes sense, a lot of things make sense and still go nowhere. No one really knew how the drugs would perform, either in the clinic or in the marketplace.
And take a look at the problems that the Novartis compound has. Like so many other toxicology hits, these came out of the cloudless sky. Well, actually, it’s more accurate to say that the sky over the toxicologists is never cloudless, because you never know what’s going to happen. In this case, Novartis has taken an especially painful and expensive beating, since the drug had advanced so far before the problems began to make themselves clear.
I’d like to ask some of the critics of the industry what they think about this situation. Me-too drugs are a particular arguing point with many of these people, so here we go: does that term apply in this case? If not, then why not? Should companies go after the same target in the same way at the same time? If not, then why not? How do we deal with the fact that any compound can fail at any time, other than turning companies loose to compete with each other and take as many shots at a target as possible? Do you have a better solution – and if not, well, then, why not?
+ TrackBacks (0) | Category: "Me Too" Drugs | Diabetes and Obesity | Drug Development
July 24, 2007
Arnold Relman is back. The co-author, with Marcia Angell, of The Truth About The Drug Companies, has a long review in The New Republic of Richard Epstein's new book on the industry, Overdose.
Not everything in Epstein's book is right, and not everything in Relman's review of it is wrong. But when Relman misses, he misses big. Take, for example, this:
"Indeed, the industry's greatest enemy is itself. Innovation by the major pharmaceutical firms has certainly fallen off sharply in recent years, but there is good evidence that the cause lies with the industry's own policies rather than with government regulation. The drug companies are being driven more by financial ambition and marketing considerations than by scientific or public health objectives, and that is the root of their current problems."
That must be why we plowed all that money into genomics, among other technologies: marketing made us do it. I knew we'd track down the culprits eventually! OK, Relman's targets here are the "me-too" drugs, which I've written about many times on this site. I get the strong impression that he underestimates the cost and difficulty of developing these - he seems to think that it's pretty much a breeze once the first drug in a class has hit the market. Actually, to my mind, one of the main advantages companies are seeking in a me-too is that the first drug has proven that a market exists, and that its mechanism actually works. The development costs for the later drugs, though, aren't hugely cheaper than for the first one. And, I might add, they still don't always work.
Inside the industry, people spend a lot of time talking about why productivity has gone down (we're in agreement on that point). But you don't hear many people advancing Relman's pet thesis, that we're spending too much time chasing each other. That's because I think he's confusing cause and effect a bit: we're not unproductive because of the me-too drugs - we're making me-too drugs because a lot of our other stuff doesn't work.
Believe me, companies would love to come up with new therapies for underserved markets - Alzheimer's, say - or to come up with anticancer compounds that would do for the many what the likes of Gleevec do for the few. And we'd certainly make money at these, too - if we could find a way to do them. Saying that it's for lack of trying just doesn't ring true.
That mention of making money brings up another favorite part of Relman's review:
"Regardless of the disease it targets, and whatever the benefit, no one has ever adequately explained exactly how the "value" of any new drug can be translated into dollars. It seems more likely that the price of newly approved patented drugs is simply set at whatever the manufacturer believes the market will bear. "
Good Lord! Where will it end, if companies price things according to what they think that people will pay for them? I look forward to the establishment of the Relman Board, which will determine, by means doubtless beyond my abilities to understand, the True Price (trademark applied for) of all drugs. Problem is, Relman himself probably looks forward to that, too. . .
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Industry History | Drug Prices
September 22, 2005
One of the other incorrect lessons that people might take away from the press accounts of the antipsychotic trial is that drug companies have been comparing their medications to placebo too often. And why would you do that unless you were scared that you wouldn't be better than the competition? What's with these people, anyway?
Well, there are fields where placebo-controlled trials take place, and fields where they don't. It depends on the disease and options available to treat it. Cancer trials, for example, are very rarely run against placebo, unless there's just nothing left to do. (You'll see this with drugs that are meant for late-stage patients or those who have failed existing therapies.)
Antipsychotics are generally compared to an existing standard of care, because it's unethical to leave someone untreated when they've already been diagnosed as schizophrenic. The problem that the CATIE trial uncovered, though, is that many trials are run against haloperidol (known as Haldol). That's a typical older drug, and companies have been showing that they have better efficacy and fewer side effects than it does. (It's known to have significant problems with tardive dyskinesia, among other things).
But now we know that perphenazine is a better standard among the older drugs, mostly because of fewer side effects. I don't think that anyone is going to be able to run a haloperidol-controlled trial for a new antipsychotic. Now you're going to have to beat perphenazine, which will be a higher standard. The newer drugs have been able to get rid of the so-called extrapyramidal side effects, like tardive dyskinesia, but they haven't been able to increase their efficacy that much. That's not going to be enough any more - the ante has gone up in the field of schizophrenia therapy.
Now, if you think that your new drug is really going to cream the competition, running a trial against them is a smart move. There's no better way to persuade people to prescribe your drug than to show that it's clearly better than what's out there now. Another time you see head-to-head trials is when a company is making a run at the leader in a given category. The various attempts to out-do Lipitor are good examples, not that any of them have succeeded. But there really wasn't a clear leader in the antipsychotic area, and thus no real target to try to knock down. I'd bet that the companies involved strongly suspected that their own drugs weren't head and shoulders above everything else, either. This is the perfect situation for an outside agency like the NIH to do a comparison study, because if you're waiting for the companies involved to do it, you're going to have a pretty long wait.
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
September 21, 2005
You've probably seen the headlines about the recent NIH-sponsored "CATIE" study comparing five anti-psychotic medications. The result, which is what made the whole thing newsworthy to the popular press, was that it was hard to distinguish among them, with the oldest generic working as well as (or better than) the newer drugs.
But I think that people outside of the medical world are going to learn the wrong lessons from all this. Does this study mean that everyone taking anti-schizophrenia medication should switch to the old generic? Not at all, although if they need to try a different medication, they should definitely consider it. Does it mean that all these newer drugs are unnecessary? No, again. There's an awful lot of patient-to-patient variation in central nervous system drugs. Says the study's principal investigator, Dr. Jeffrey Lieberman of Columbia:
"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another."
But I think that this study does make clear that the newer antipsychotics aren't as good as they should be. The field is a tough one, as I know from personal experience, having played a small role in helping a company spend I've-no-idea-how-many millions of dollars to find out that a potential schizophrenia medication didn't do squat. There's a lot of room for improvement, and we haven't been able to improve things very much.
It's important to emphasize that this was a surprising result. No one expected the side effect profiles of the four "second-generation" drugs to be so similar to the older one (perphenazine), and so similar to each other. That's one reason that a study like this is so valuable - huge clinical trials that tell you something that you already knew aren't too wonderful. I think that this is an excellent thing for the NIH to be doing. Tomorrow: what this says about head-to-head trials in general.
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
August 23, 2005
I'll tell you a company that's been watching what's happened to Merck and thinking hard about it: Sanofi. Well, OK, everyone in the industry has been looking at Merck's situation and shuddering, but I suspect the people at Sanofi(-Aventis) are especially jumpy. Why? Rimonabant.
Rimonabant, which will come to the market next year (most likely) under the name Acomplia, is one everyone's short list of potential multibillion dollar drugs. It'll be the first new drug treatment for obesity in years, and it's the first one ever with its mechanism of action (antagonism of the CB(1) receptor). It has potential for many sorts of addiction therapy as well. Although there's room to argue about just how effective it is compared to existing therapies, and there's some concern about how many HMOs will pay for it, there's little doubt that it's going to sell like crazy.
And there's the worry. There is absolutely no way that large enough clinical trials could be run on a drug like this to predict everything that might happen when millions of people start taking it. Can't be done. You can get down to a margin of safety that will get you past the FDA, but that isn't enough, now is it? No, if one person out of a hundred thousand has a nasty side effect, that's enough to bring the sky down on your head. And we can't test down to the level of one-per-hundred-thousand effects.
A fine situation, isn't it? This same argument applies to every new drug, naturally, but especially to a groundbreaking compound like rimonabant. That's just what we needed, an incentive not to be first in class with a new drug. What, exactly, are we doing to ourselves?
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Diabetes and Obesity
December 10, 2004
Alex Tabarrok has finished up his short series on me-too drugs, and he's done a fine job of hitting the nail on the head. It's gratifying to see people from outside the field who really know what they're talking about:
"(Marcia) Angell is also skeptical that me-too drugs can have different effects in different people. Frankly, I was shocked at this argument. Every clinical trial that has ever been run demonstrates that the same drugs have different effects in different people - it's hardly a surprise that different drugs have different effects. And me-toos are different - different enough not to violate the patent on the innovator drug almost certainly means different enough to have different effects in some people. My local supermarket carries at least a dozen different styles of peanut butter, a fact of which I approve, but Angell thinks two angiotensin-converting-enzyme (ACE) inhibitors may be one too many (p.90). Give me a break.
Finally, it's important to recognize that small changes can actually make for important improvements. What could be more me-too than a once-a-day pill replacing a twice-a-day pill? Yet, to dismiss this change is to overlook the people factor. A once-a-day regime that people stick to is much better than a twice-a-day regime that people fail to follow. Forget the chemical structure the economics says a drug that people actually take is a better drug."
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December 7, 2004
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December 2, 2004
Via Tyler Cowen at Marginal Revolution, I came across this editorial by John Gapper in the Financial Times on me-too drugs. Its points will be familiar to readers of this blog:
"If there is one product that annoys people, it is the me-too drug. Pharmaceuticals companies should take advantage of the genetics revolution to find cures for intractable diseases such as cancer and cystic fibrosis, the critics moan. Instead, they spend billions trying to match the pills already made by others."
Ay-yep, that they do, and that we do, too. But this piece goes a bit further than usual, pointing out to Financial Times readers that:
". . .drugs can make it through clinical trials only for side-effects to be discovered when they are prescribed to millions of patients. If all drugs in each therapeutic class were identical, Celebrex would now be off the market along with Vioxx. In fact, one pill can turn out to be safer than another. Indeed, without going into details about Levitra and Viagra, their effects can also vary. . ."
The author goes on to point how how head-to-head trials of drugs are becoming more common, and how in the post-Vioxx world they're likely be even more widely conducted:
"From the perspective of drugs companies, this makes life trickier. Not only is the least safe drug in any class liable to be knocked out in the same way as Vioxx, but even safe ones will have to face off against each other to establish the best of all.
This may all sound terribly wasteful to a doctor, but it is the same thing that is good for consumers in other markets: open competition. The problem until now has not been too much of it, but too little. The last thing that a patient should want is a choice of only one drug. As the Vioxx withdrawal shows, me-too pills may inspire little affection, but they would be missed if they were not there."
Reading this, Tyler wonders:
"Why have me-too drugs been so prevalent? Are they an inefficient form of product mimicry? An artifact of bad patent or FDA policies? The long-run path to affordable medical care?"
I've talked about this before (see the category over on the right), but here's the short answer: that the first drug in a category proves that the mechanism is a viable one in the market. ACE inhibitors really do lower blood pressure, HMG CoA reductase inhibitors really do lower cholesterol, and so on, and to a degree that people are willing to pay for. That's a big hurdle, one that not every new first-in-class drug makes it over. There are numerous new-mechanism drugs that few people have heard of, because they didn't work well enough to attract a market. No me-toos follow them.
But when something takes off, later drugs in the category are attracted by the proven mechanism and sales potential. Then they try to go a bit better, to take market share - more convenient dosing, better efficacy, fewer side effects - whatever we can come up with. There are also situations like Vioxx and Celebrex, where the two drugs were developed at roughly the same time. In those cases, we don't know much about your competition while the development is going on. We just have to try to get to the market first and hope for the best.
So there's some product mimicry, but real mimicry is impossible. No two drugs are, or even can be, completely identical. That gives new ones a shot at being better, or at just being better in some situations, or, likewise, a shot at being worse in some (or all) of them, too. But not the same.
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September 2, 2004
What sort of markets breed multiple therapies? The ones with the largest number of potential (paying) patients, for one thing, which shouldn't surprise anyone. Fortunately, that also corresponds pretty well with the markets that could be better served with another drug. The success of the first compound in a new market shows that it can be done, and proves that there's money to be made, and that attracts more companies to the field. The path has been cleared, up to a point - but remember, all the following compounds have to go through the same degree of efficacy and safety testing as the first one did, although the later entries at least know, broadly, how to set up their clinical trials.
But entering an existing market is no guarantee of riches. There are no guarantees of riches. Look at Bristol-Meyers Squibb and their statin, Pravachor, which has been weighed in the balance against Lipitor and been found wanting (with BMS paying for the whole process). Now what? You can be sure that AstraZeneca is beavering away, trying to show that their big statin hope (Crestor) has even more of the effects that Lipitor has shown. It'll need to.
Or look at the erectile dysfunction field. Pfizer showed that it could be a moneymaker with Viagra, and don't believe for a minute that this was obvious beforehand. There were plenty of sceptics, doubtless some of them within Pfizer itself. But Viagra's success attracted a lot of interest around the industry, since many companies had a stable of potential PDE inhibitor leads. Now Bayer (partnered with Glaxo SmithKline) and Icos (partnered with Lilly) are in the field with Levitra and Cialis, respectively. A glance at your e-mail spam will have already familiarized you with both compounds, in case you've somehow missed the massive advertising campaigns.
The hope was the the new compounds, which differ from Viagra (and each other) in side effects, onset, and duration of action, would expand the market even more to people who had never tried Viagra. But as far as anyone can see, neither of them has been the as big a hit as the companies involved might have hoped for. It looks like the size of the market is still roughly the same, only now there are three compounds beating each other up inside the same box. The promotional costs for everyone involved are not trivial, and they would have been a lot easier to bear if a lot more patients had decided to try the therapies for the first time. It doesn't seem to have happened, at least not yet. Those are the breaks. We make money in this business, true, but if you think it comes easy, well, come on down with your leaf blower and scoop some up.
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease
August 31, 2004
As came up in the comments to the previous post, there's not as much price competition inside a given drug category as you'd think. That's not because we're Evil Price Gougers, at least not necessarily. As I was pointed out yesterday, "me-too" type drugs aren't as equivalent as some people think. The main reason we go ahead with a drug in a category where there's already competition is because we think we have some advantage that we can use to gain market share.
This is a constant worry in every drug development effort where there's already a compound out there. I've personally, many times, been in drug project meetings where we've looked at the best competing compound (one that's either already marketed or well into clinical trials) and said "We haven't beaten them yet. We're not going to make it without some kind of unique selling point." The best of those, naturally, would be superior efficacy or a superior safety profile. Then you have easier dosing, fewer interactions with other drugs, and so on. I need to emphasize this: I have seen drug projects killed because no case for an advantage could be made.
Now, there's room to argue about how much better efficacy a drug needs to be a real advance in the field, or at least a bigger seller. You can argue about any of those possible advantages I listed, and it's true that drug companies push some compounds that aren't exactly huge leaps over the previous state of the art. (You see more of that when there's a case of shriveled pipeline in progress.) But there has to be something, and the bigger the difference, the better it is for us. We're motivated, by market forces, to come up with the biggest advances we can. The sales force would much, much rather be out there with data to show that the new drug beats the competition in a clean fight, as opposed to saying that it beats the old one on points, in a subset of patients, if you massage the data enough and squint hard, and besides it tastes better, too. . .
And as I've pointed out before, we often find out things about compounds long after they've reached the market. Lipitor, as discussed yesterday, is a case in point. I have not been a Lipitor fan in the past. The statin field seemed already pretty well served to me (as it did to a number of people inside Warner-Lambert during the drug's development, frankly.) The drug made its way forward based on efficacy in the clinic: it seemed to do a better job lowering cholesterol and improving the LDL/HDL ratio. How much advantage that is in the long term is another question, but those are the best markers we have.
The whole antiinflammatory c-reactive-protein story about the drug only came up after it was already on the market. The marked differences between it and the other statins, which I have to assume at this point are real, are a pleasant surprise to everyone involved. Warner-Lambert (and then Pfizer) thought it was a better compound, but not to this degree or for these reasons, I'l bet. I'd say that this is another argument for having multiple drugs in the same category. We don't, and can't, know everything that they'll do.
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Prices
Allow me to get a little defensive. If I understand some of the critics of my industry, we spend most of our time making "me-too" ripoff drugs rather than doing something that provides any clinical benefit to patients. And, if I have this right, here's how we determine efficacy: we run clinical studies until we get the answer we want, and then we bury all the other ones. (Mind you, we bury the data by giving it to the FDA, but stay with me here.)
OK, now let's try to explain this. Merck has just released a study on its statin drug, Zocor. Following in the footsteps of two other studies with Pfizer's statin, the market-leading Lipitor, Merck dosed patients who had just suffered heart attacks. Lipitor treatment seemed to show a real benefit in these situations, lowering the rate of later cardiovascular trouble, and Merck was hoping for (and no doubt expecting) the same thing.
But they were rudely surprised. At the lower doses of Zocor, they failed to show any benefit at all. And at the highest dose, while they managed to show a lower rate of second heart attacks, they still didn't reach significance versus the placebo group. Worst of all, several of the high-doses patients showed the muscle-weakening condition rhabdomyolosis. That's the bane of statin drugs, and the reason why Bayer pulled their compound (Baycol) from the market. (Just to complicate things, one of Merck's placebo patients showed rhabdomyolosis, too, which is food for thought and should give you an idea of how much fun it is to interpret clinical trial data.)
So what's going on here? Zocor and Lipitor both work by inhibiting HMG-CoA reductase. They hit the same mechanism. Were the patients different? The study's authors say it's possible. The patients in the Lipitor studies seem to have been receiving more aggressive therapy in addition to the drug. Are the drugs different? That's possible, too. Lipitor, as it turns out, seems to lower the inflammation marker C-reactive protein much more than Zocor, and that could potentially make a difference.
But if the drugs are really different, what happens to the idea that Lipitor is just a me-too, yet another statin piling on the profits? If we in the industry hadn't kept banging away at these drugs, we wouldn't have ever known that better ones could be found. Would we? As I've pointed out in the past, if you're going to market a drug in a category where the competition is ahead of you, you'd better have some improvement to point at or set about finding one. Lipitor came into the market under the banner of "lower dose / higher efficacy", and it may be picking up more advantages as time goes on.
Now, if we believe that the drugs aren't different, which will be an interesting thing to try to prove at this point, then we have to figure out how much weight to put on this study. How does it go into the Great Clinical Trial Repository? With an asterisk? Then shouldn't the earlier two studies with Lipitor have one, too? This is the same situation I spoke of before.
And what about this clinical trial data in general? Isn't this the sort of bad news that we're supposed to be sweeping under the rug over here? A full article in JAMA complete with vigorous editorial commentary. . .some rug. Oh, and one other thing: those two earlier Lipitor studies that showed a benefit. One of them was from Pfizer(/Pharmacia), as you'd expect. But the other one was from their competition. Bristol-Meyers Squibb has been trying to prove that their statin, Pravachor, is better than Lipitor, and failing. Where's that damn rug when you need it?
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials
December 18, 2002
There were plenty of stories in the press today about the ALLHAT study, which showed that diuretics are still the most effective way to treat hypertension in most people. Let me say right off that I really like this kind of study, and I think that there should be more of them (more on this tomorrow - the Wall Street Journal did the best job covering this angle today.) And I don't disagree with these findings, either - the study seems, as much as I've seen of it, to have been done very well and I think the data speak pretty clearly.
Most of the press coverage has been heavy on the "if not for drug company greed" angle. The New York Times gave this aspect its own story and headline. The critics have a point: pharma companies have aggressively marketed the newer mechanisms as they've come along, both by saying the new ones are good and that the old ones aren't.
But if there's any business that works differently, then I'd like the Times to tell me what it is. Some of the coverage makes it sound like Big Pharma is one large company, and Big Pharma abandoned diuretics in order to blow the horn for its more expensive drugs. But these were individual companies, and the first companies with, say, ACE inhibitors (like Merck) naturally came into the market talking about how great their new drug with the new mechanism of action was. This wasn't Big Pharma talking, this was Merck trying to gain advantage over its competition. Nobody sent around an industry memo saying Drop Diuretics, Push ACE Inhibitors.
And as the ACE inhibitors became wildly successful, other companies got into the field, or decided that they needed to come up with new mechanisms of their own. That's part of the free market, too - we in the pharmaceutical business get forced to come up with new stuff, because the me-too business can only go on so long. (In the case of the ACE inhibitors, it went on longer than usual, because the first generation of them had a dry cough side effect that made people stop taking them.)
You don't hear about many of those other hypertension projects, because they didn't live up to their potential: endothelin converting enzyme, anyone? Renin inhibitors? There were quotes today about all the excess money spent by patients over the years (by not taking diuretics.) The various drug companies who chased these (and other) mechanisms during the 1980s and 1990s would like to have some of that money back, too.
So, once we got them to work, did the drug companies push the newer hypertension medications? Well, yeah, like crazy. That's what we do. But what we do includes the "new" part as well as the "push" part of that sentence. (The "crazy" part is another subject!)
A couple of other points: the main Times story waits until paragraph 26 to mention that there were other factors other than the Greed of Big Pharma for the move away from diuretics:
A factor in the switch from use of diuretics to newer drugs was a Swedish study reported in The New England Journal of Medicine in 1989. It found that diuretics could cause biochemical changes that were thought to increase susceptibility to heart attacks.
The other thing I'd like to mention is that some of the figures given for market share of diuretics make them seem more ignored than they are. The Wall Street Journal ran a pie chart, but it's done by dollar sales. Because the diuretics are cheaper, they don't make nearly as much impact in that sort of presentation. The Times ran a better graphic showing total number of prescriptions, and there's some interesting stuff there:
While it's true that diuretics only have about 27% of the total number of prescriptions for hypertension, they outdid ACE inhibitors every year until 2001. And they've beaten calcium-channel blockers (another big part of the ALLHAT study) every year, because those drugs, heavily marketed though they are, have only grown 3% in prescription volume since 1997. ACE inhibitor scrips have been up 39% in that period - and diuretics, with virtually no advertising, have been up 29%. Maybe Big Pharma isn't getting as much bang-for-the-buck as it could with all those marketing campaigns (and maybe physicians are doing a better job exercising their judgment than today's coverage gives them credit for.)
(Post edited next morning for clarity, emphasis, and to correct late-night typos.)
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September 8, 2002
There's an interesting interview up at Business Week's site with Anthony Ford-Hutchinson, a Merck research honcho. Much of the interview is routine: "How's the new drug for XYZ coming along?" "Why, just fine!" But he does get in a few good cuts:
Q: How would you describe the culture of Merck's research and development?
A:" If you look at Pfizer's annual report and compare it to Merck's, theirs says something about wanting to be the most valued company in the world, whereas Merck's talks mainly about curing diseases."
That's the sound of a catapult in Rahway unloading a bag of overripe Jersey tomatoes in the direction of Groton. He goes on to say that "we don't go after the Nexiums and Clarinexes of the world." I have to applaud that sentiment, and I'm glad to hear someone say it out loud. But I have to note that Merck is coming along with a follow-up COX-2 inhibitor to bring up the slack behind Vioxx. . .I also note that that's a slam against Merck's current development buddy, Schering-Plough, which takes some nerve.
As for merging, he sticks with the Merck line of "no way." Some of his comments really make him sound like my soul brother:
" . . .every time you see a big drug merger, the research at those two companies grinds to a halt. Everybody starts worrying about their jobs. . . "
". . .the research can easily get screwed up when two companies merge. I think the effects of this may not be so apparent right away, but a decade from now the effects will undoubtedly be apparent."
All I can say to that is "Preach it!" Let's hope that we're all doing well enough in ten years to see who's right.
As an aside, if I ever form my own company, it's going to be hard to resist the temptation to have official titles like "research honcho" or "exalted pooh-bah." Maybe if one of my colleagues gets his drug company off the ground, he can use those. Right now, all he has is an evocative name, considering the genomics era. He wants to call it "InVivogen," and I can see the point!
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July 28, 2002
Another question I've had posed to me is whether the FDA standards for drug approval are too tight (no one who writes to me seems to worry that they might be too loose, although you can find groups who'd argue just that.)
Overall, I don't think so. There are really two sets of standards, for safety and for efficacy, and neither are really set in stone. From drug to drug and disease to disease, things can slide around - which is how it should be. Safety is an open-ended problem that has to be addressed by closed-ended regulatory solutions, and as time goes one, the bar is raised. We know a lot more that we used to about, say, QT-interval prolongation as a cardiac side effect, and that means that we have to test for it instead of crossing our fingers. If this weren't getting harder, neither the drug companies nor the FDA would be doing their jobs.
As for efficacy, I see the suggestion every so often that this requirement be done away with. I'm firmly opposed to that idea. It would open the door to even more Miraculous Herbal Tonics than we have already - all you'd need to do to get past the safety requirement is make sure your snake-oil doesn't have anything active in it. Honestly, you'd have people springing up selling powdered drink mix at $5 the glass to cleanse your liver, grow new hair, and make your genitalia go out in the morning and fetch the newspaper. What? You say we have that already? Well, now they'd be "FDA-approved" on top of it.
No, I'm all for making companies show that their drugs actually do something. In fact, I'm all for making sure that any medicine entering a served market is tested head-to-head with the competition. Of course, this is often mandated already. And companies often do it themselves so they'll have an edge in marketing - exceptwhen it's a patent extension of one of their own drugs. As I mentioned a while back, I'd make Astra-Zeneca test Nexium against Prilosec, for example, and we'd see who's fooling whom.
There's no doubt that the FDA's gotten pickier in the last couple of years, and all of us in the industry are feeling it. But it hasn't gotten to the point where I think they're stepping over the line.
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Toxicology
June 6, 2002
As readers will have noted in my comments on drugs like Clarinex and Nexium, I certainly don't think the industry I work in is always a one-hundred-percent benefactor of humanity. Drug companies are here to make money, and (like any business) they're trying to make the most money they can, consistent with their tolerance for the chance of losing it.
The much-written-about report on innovation in the drug industry (PDF here) turned out, on inspection, to be much less confrontational than I had feared. The authors point out, correctly, that pharmaceutical companies are reacting rationally to their environment. Big, money-making drugs are coming off patent, and not enough new ones have been discovered in the last few years to take up the slack. Therefore, the companies will do whatever they can think of to keep the profits coming in for as long as possible.
That includes stepping up the marketing campaigns for what drugs they have. It includes ripping off their own expiring profit center drugs (as in the two mentioned above,) and doing whatever they can to get patients to ask for them and physicians to write for them. And that includes all sorts of schemes to delay generic competition. Some of them are bare-knuckled, but within the letter of the law (fighting patent claims.) Some are apparently legal, but have a certain shady aura around them (such as paying generic companies to go away.) And still others, like this accusation against Bristol-Meyers Squibb, are (if true) flat-out illegal.
It's capitalism in action, and it's not always - not even usually - a pretty sight. The same sorts of things go on in every other industry, in any number of variations. I think the same thing about individual economic competition, for that matter. One reason I like capitalism better than the other schemes that have sought to supplant it is that it seems to me to line up more closely with human nature. Not an original thought, but its validity is why it's so well known.
People are going to act in their own interest, to serve what they see as their needs and desires. You can't get rid of it, so you might as well set things up so they do some good while they're at it. Wouldn't it be more efficient if everyone worked that hard for the common good, though? Sure! Should some other zoological phylum develop intelligence, maybe they can give it a try. We, as far as I can tell, are wired for what we're doing.
And so are companies. Wouldn't it be more efficient if all of us in the drug industry just stopped trying to outdo each other? Open up the labs, put all our compounds in one gigantic screening file, pool our efforts? Well. . .it's a tempting idea, in some ways. But what keeps us going is the competition, the knowledge that (like the sharks we are,) that we have to keep moving or die. I fear that a Monolithic MegaPharm would become so bureaucratized and lethargic that whatever good came of getting larger would be more than canceled out. Some of the large merged companies we have now are showing signs of this disease as we speak.
Knowing that other people are working on the same targets keeps us moving. The ticking clock of patent expirations, the arm-wrestling with the regulatory agencies, the demands of shareholders keep us moving. I think the best thing to do would be to, again, arrange it so that the maximum amount of good gets done while we're out there pursuing our own agendas.
That means that I wouldn't, frankly, object to making it harder to put drugs like Clarinex, Nexium and so on on the market. If I were the FDA, I'd raise the bar in such cases for advantageous efficacy, and if I were an HMO, I'd raise it for what I'd reimburse. But at the same time, I'd make it easier to find and sell new drugs, so there would be less incentive for all these activities that don't lead to any real benefit. Faster regulatory approval, no method-of-treatment patent claims, more incentives like the orphan drug designation, some sort of tort reform: all these would help.
It boggles the mind, the amount of effort and ingenuity pulsing through a high-tech area like pharmaceuticals. But political grandstanding about the evil drug companies, schemes to clamp down good and hard on them: these could wipe out the crazy risk-taking that's at the heart of the industry. Whack the ones that get out of line, sure. But while you're doing that, set the system up so that we can whack on each other with even more ferocity than ever. That's where the good stuff comes from.
+ TrackBacks (0) | Category: "Me Too" Drugs | Why Everyone Loves Us
May 30, 2002
Yesterday's report on pharmaceutical cost and innovation got a lot of play in the media, including the ABC special last night (which I didn't see much of.) I'm of two minds about it: there's some truth in it, but there are important things that it misses.
Companies will do everything they can think of to hold on to a lucrative market. It needs, as Shakespeare said, no ghost come from the grave to tell us this. Drug companies exist to make money, and this is a way to make money. Legal maneuvers to extend the patent life and make things difficult for generic companies are one strategy; internal me-too drugs are another.
As my May 2 post on Claritin and Clarinex shows, I believe that the industry does come up with drugs that have few (if any) advantages over their predecessors. Nexium vs. Prilosec is another example of this, as far as I can tell. Both these are largely designed to replace drugs that the companies already had which are going off-patent.
But the "me-too" label gets thrown around a bit too liberally when it comes to competition between companies. I can tell you, from personal experience, that for a serious R&D effort to be mounted, a project simply has to have some advantage versus the competition. I've never seen a project start off by saying "We're going to make the exact same thing as those guys did, and make up the difference with a huge ad campaign." Huge ad campaigns work better with something to hang them on.
The complexities of pharmacology give you plenty of chances to have differences between drugs that (in theory) might well work the same. Companies try to develop and promote those differences. If the combined size of the total market and the space for differentiation is large enough, you can have several companies piling into the same field, fighting it out.
That could be just plain old better efficacy, as Lipitor seems to have in the crowded field of cholesterol-lowering statins. It could be once-a-day dosing versus after-meals, fewer side effects, or fewer interactions with other drugs. It could be plain old lower price, too: the uncertainties of clinical development make it risky to start a project based on that alone, but it can come up by the end of the project. Ciba-Geigy (now Novartis) tried that with one of their statins a few years back, to pick one from the same area.
That's the free market, and may the best compounds win. Sometimes the differences that are promoted may not be enough to justify a new drug's existence, though. This happens (in my experience) along the way in the development process, when the plan for a bigger market advantage doesn't work out in the clinic. Ideally, such drugs wouldn't fly in the marketplace, but companies will sometimes try to make them take off anyway.
Physicians can feel stampeded when their patents come in asking for a new drug that they don't think is worth the cost. If they don't write for it, they think, someone else will. What we're seeing now, though, is a reluctance for managed-care plans to pay for some of these, a decision which is certainly their right to make. HMOs get to have their free-market fistfights, as well.
As for the general question of innovation, I can tell you that no company tries to make a living from just hopping into crowded fields where there's already competition. You have to innovate to survive. On the flip side, trying to break absolutely new ground every time out is a risky strategy, too, given the failure rate and the expenses involved. We can argue all day about just how much it takes to develop a new drug, but if you're the first-in-class in a new area, it's going to cost you more. But the potential payoff is bigger, too - you can have some real fun calculating the risk/reward, especially since some of the key numbers are impossible to truly quantify.
I'd also like to see a study like yesterday's address what happens to some of the groundbreaking drugs that they cite favorably. For example, they mention Avandia and Actos (rosiglitazone and pioglitazone) for diabetes in the category. Leave aside the fact that these two drugs work via almost identical mechanisms (with some slight differences, which the companies are, as per the above, trying to exploit.) And leave aside that they were developed at the same exact time, in sull knowledge that they'd be going head-to-head in the marketplace (which one was the me-too, if either one was?)
No, what I'd like to point out is that these innovative therapies weren't the first in that class. That would be Rezulin (troglitazone.) That was absolutely the first drug on the market to work by that mechanism, and the first to do what these compounds do for diabetes. Avandia and Actos were expected to have to go out and dethrone it; that's what the companies planned for. But Rezulin went down in flames due to toxicity, which only showed up when it got into a broad patient population. The lawsuits are still flying. If it had made it, then the other two drugs would surely be cited as more of those nasty, money-grubbing me-toos.
Where's that one in the sound bites about "nothing new in the drug industry"? The money spent to develop and market Rezulin is gone, and it's not coming back. Lots more is going to vanish, is vanishing right now, going to plaintiffs and lawyers. How do we make up for that?
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May 6, 2002
I get a lot of Google search hits about those two drugs, so I thought I'd give the public what it wants. I've mentioned that I still hold some Schering-Plough stock (dog though it's been recently,) and I'm about to do my holdings some minor amount of further harm.
That's because, frankly I don't think very much of Clarinex. I've already written (on March 10) about Sepracor and their role in its development. Fitting in with their business plan, Clarinex is another active-metabolite drug idea.
As I've been mentioning in connection with all the acrylamide business, the liver does a fine job ripping up organic compounds. Most of these altered compounds don't do much except go sluicing out the kidneys, but some of them are active. As it happens, Claritin has one main metabolite, and it still has the antihistamine effect that Claritin itself has. (This situation is becoming less frequent, by the way, since the FDA has come more and more to frown on active metabolites in general. Your regulatory path will be simpler now if you don't have any.)
And it's not an exotic transformation, either. For the organic chemists in the audience, it's loss of an ethyl N-carbamate group, down to the NH. Looking at the structure of Claritin, this is the absolute first thing that any competent medicinal chemist would predict as a main metabolite, and so it is.
That means that if you've taken Claritin, you've taken Clarinex. You starting taking it about twenty minutes after you swallowed the Claritin, when that dose started going through the hepatic portal vein and into your liver. It also means that the synthesis of the compound is essentially identical to Claritin, with really only a one-step difference to change the amine.
And, unfortunately, it also means that Clarinex is one of the more blatant me-too drugs out there, this time an internal one. I can't blame Schering, actually. It was clear for years that they'd need something to take up the slack of the Claritin franchise, and there have been some very good shots taken at that in several therapeutic areas. But none of them have paid off yet, and the company decided to do whatever it took to keep a revenue stream coming in. The other choice was virtuous penury, culminating in firing employees who are now occupied, instead, with finding something more useful. It's hard to see that as a better path.
But that still doesn't make Clarinex any better as a drug. I haven't gone over all the clinical data, but I find it hard to imagine that there's any particular advantage over Claritin. And if perchance there is, I find it hard to imagine that it's worth the price disparity versus (generic) Claritin. I may get some feedback setting me straight on this, but it'll have to be pretty convincing to change my mind.
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