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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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"Me Too" Drugs | Academia (vs. Industry) »

January 28, 2013

The Hydrophobic Effect: I Don't Understand It, Either

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Posted by Derek

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?

Comments (14) + TrackBacks (0) | Category: "Me Too" Drugs | Chemical News | In Silico

August 13, 2012

Donald Light Responds on Drug Innovation and Costs

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Posted by Derek

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

Comments (72) + TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Drug Prices

August 9, 2012

Getting Drug Research Really, Really Wrong

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Posted by Derek

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. . .

Comments (74) + 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

Translation Needed

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Posted by Derek

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.

Comments (26) + TrackBacks (0) | Category: "Me Too" Drugs | Academia (vs. Industry) | Drug Development | Who Discovers and Why

January 26, 2011

Those Me-Too Drugs

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Posted by Derek

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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