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Posted by Derek
How does the press cover stem cell work? You probably already know the answer to that one, but here's proof: this paper examines the media coverage from 2010 to 2013, and finds that "highly optimistic" timelines for translation to the clinic are the rule. Unfortunately, they also find that quotes from scientists are the main source for this sort of thing, too. My belief is that some journalists are just predisposed to go with whatever sounds good and exciting, so whomever gives the most hopeful prediction is the person that gets quoted.
The whole translation-to-a-real-therapy process, though, is terribly underestimated by the general public (and by some people who really should know better, too). That's one of the roots of the the NIH Fallacy, the idea that drugs are all discovered with NIH money and that drug companies just reach in and pluck those delicious fruits once they're good and ripe. You can only believe that if you don't know how much work it takes to go from a discovery to a drug, and how many, many things can go wrong along the way.
There's a related fallacy, the idea that there are all sorts of cures sitting on shelves (of both drug companies and universities) that no one has bothered to dust off. While it would not surprise me if there were, indeed, great ideas sitting around waiting for someone to rediscover them, they are surely surrounded by masses of not-so-great ideas. And figuring out the difference between those involves the piles of money and time that go into drug development - we haven't figured out any other way to do it.
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+ TrackBacks (0) | Category: Drug Development | Press Coverage
In case you were wondering, Chuck Norris does not know what he's talking about when he talks about drug discovery and development. In other news, I don't know what I'm talking about when I talk about martial arts or tv/movie production. But I'm not trying to tell Chuck Norris about those things, now, am I?
Update: Chemjobber finds that these are not only borrowed ideas on the part of Norris, but borrowed words as well.
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+ TrackBacks (0) | Category: Press Coverage
The New York Times Magazine has a piece on the current problems with drug discovery. I was interviewed by the author, and get I quoted at one point.
Nothing in the article will amaze any regular reader here, but it's probably the first time many of the magazine's readership are hearing about many of these issues, so I hope it'll be useful in that regard. Those readers might end up tying the concepts of genomics and target-based drug discovery together a bit too tightly, but it's a lot of catching up to do in a small space.
Yesterday's post on yet another possible Alzheimer's blood test illustrates, yet again, that understanding statistics is not a strength of most headline writers (or most headline readers). I'm no statistician myself, but I have a healthy mistrust of numbers, since I deal with the little rotters all day long in one form or another. Working in science will do that to you: every result, ideally, is greeted with the hearty welcoming phrase of "Hmm. I wonder if that's real?"
A constant source for the medical headline folks is the constant flow of observational studies. Eating broccoli is associated with this. Chocolate is associated with that. Standing on your head is associated with something else. When you see these sorts of stories in the news, you can bet, quite safely, that you're not looking at the result of a controlled trial - one cohort eating broccoli while hanging upside down from their ankles, another group eating it while being whipped around on a carousel, while the control group gets broccoli-shaped rice puffs or eats the real stuff while being duct-taped to the wall. No, it's hard to get funding for that sort of thing, and it's not so easy to round up subjects who will stay the course, either. Those news stories are generated from people who've combed through large piles of data, from other studies, looking for correlations.
And those correlations are, as far as anyone can tell, usually spurious. Have a look at the 2011 paper by Young and Karr to that effect (here's a PDF). If you go back and look at the instances where observational effects in nutritional studies have been tested by randomized, controlled trials, the track record is not good. In fact, it's so horrendous that the authors state baldly that "There is now enough evidence to say what many have long thought: that any claim coming from an observational study is most likely to be wrong."
They draw the analogy between scientific publications and manufacturing lines, in terms of quality control. If you just inspect the final product rolling off the line for defects, you're doing it the expensive way. You're far better off breaking the whole flow into processes and considering each of those in turn, isolating problems early and fixing them, so you don't make so many defective products in the first place. In the same way, Young and Karr have this to say about the observational study papers:
Consider the production of an observational study: Workers – that is, researchers – do data collection, data cleaning, statistical analysis, interpretation, writing a report/paper. It is a craft with essentially no managerial control at each step of the process. In contrast, management dictates control at multiple steps in the manufacture of computer chips, to name only one process control example. But journal editors and referees inspect only the final product of the observational study production process and they release a lot of bad product. The consumer is left to sort it all out. No amount of educating the consumer will fix the process. No amount of teaching – or of blaming – the worker will materially change the group behaviour.
They propose a process control for any proposed observational study that looks like this:
Step 0: Data are made publicly available. Anyone can go in and check it if they like.
Step 1: The people doing the data collection should be totally separate from the ones doing the analysis.
Step 2: All the data should be split, right at the start, into a modeling group and a group used for testing the hypothesis that the modeling suggests.
Step 3: A plan is drawn up for the statistical treatment of the data, but using only the modeling data set, and without the response that's being predicted.
Step 4: This plan is written down, agreed on, and not modified as the data start to come in. That way lies madness.
Step 5: The analysis is done according to the protocol, and a paper is written up if there's one to be written. Note that we still haven't seen the other data set.
Step 6: The journal reviews the paper as is, based on the modeling data set, and they agree to do this without knowing what will happen when the second data set get looked at.
Step 7: The second data set gets analyzed according to the same protocol, and the results of this are attached to the paper in its published form.
Now that's a hard-core way of doing it, to be sure, but wouldn't we all be better off if something like this were the norm? How many people would have the nerve, do you think, to put their hypothesis up on the chopping block in public like this? But shouldn't we all?
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+ TrackBacks (0) | Category: Clinical Trials | Press Coverage
Here's a good test for whatever news outlets you might be using for biotech information. How are they handling Pfizer's release of palbociclib information from the AACR meeting over the weekend?
Do a news search for the drug's name, and you'll see headline after headline. Many of them include the phrase "Promising Results". And from one standpoint, those words are justified. The drug showed a near-doubling in progression-free survival (PFS) when added to the standard of care, and you'd think that that has to be good. But a first analysis of overall survival (OS) shows no statistically significant improvement.
Now, how can that be? One possibility is that the drug helps hold advanced breast cancer back, until a population of cells breaks through - and when they do, it's a very fast-moving bunch indeed. Pfizer, for its part, is certainly hoping that further collection of data will start to show a real OS effect. They're going to need to - Avastin's provisional approval for breast cancer was based on earlier PFS numbers, which did not hold up when OS data came in. And that approval was revoked, as it should have been. Now, Avastin also had side effect issues, and quality-of-life issues, so these cases aren't directly comparable. But the FDA really wants to see a survival benefit, and that's what a new cancer drug really should offer. "You'll die at the same time, but with fewer tumors, and out more money" is not an appealing sales pitch. This issue has come up several times before, with other drugs, and it will come up again.
You'd think that a PFS effect like palbociclib's should translate into a real survival benefit, and as more data are added, it may well. But it's surely not going to be as impressive as people had hoped for, or it would have been apparent in the data we have. So take a look at the stories you're reading on the drug: if they mention this issue, good. If they just talk about what a promising drug for breast cancer palbociclib is, then that reporter (and that news outlet) is not providing the full story. (Here's one that does).
Update: there is an ongoing Phase III that's more specifically looking at overall survival. Its results will be awaited with great interest. . .
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+ TrackBacks (0) | Category: Cancer | Press Coverage
Here's a nice look at why you should always think about the source of the financial and business information you read. It details the response to a recent Pfizer press release about palbociclib, a CDK inhibitor that's in late clinical trials.
Someone at The Wall Street Journal wrote that it had "the potential. . .to transform the standard of care for post-menopausal women with ER+ and HER2- advanced breast cancer." Problem is, that phrase was lifted directly out of the press release itself (and sure sounds like it), and you really would hope for better from the WSJ. What we're seeing here is actually Pfizer's own spin on the (as yet unpresented) results of the PALOMA-1 clinical trial. Everything a company says at this point will be couched in terms of "could" and "has the potential" and "we hope", and will come with one of those paragraphs at the end about "forward-looking statements". When it comes to the first statements about clinical trials results, if there are no numbers, there is nothing to talk about.
Paul Raeburn, the Knight Science Journalism blog author who picked up on this, also found that someone at the AP (and others) went for Pfizer's spin, too:
The problem is that this story was covered by business reporters rather than medical reporters, who by and large are too smart to fall for a company's claim about a drug without seeing the evidence presented, reviewed, and debated.
The further problem is that because they are so smart, medical writers mostly declined to cover this story. Which left the business writers out there alone, telling the story the company wanted them to tell.
Well, "medical writer" is a broad term, and believe me, there are some slackjaws in that crowd, too. But point taken - anyone who's been paying attention, or anyone who's willing to spend a few minutes on Google, should have realized that Pfizer is trying to make the case for accelerated approval of palbociclib, especially after the recent failure of dacomitinib and strong competition from Novartis in exactly the same therapeutic space.
Pfizer, of course, is not going to come out and talk about how delighted they are about the Phase II results unless they can back that up with something. I hope that palbociclib bowls people over - a new therapy for breast cancer would be good news. But we haven't seen the data yet, and data are all that will (or should) make pulses race over at the FDA. So I think that the Pfizer press release was worth noting, but stories like the Fierce Biotech one linked in the paragraph above are the way to do it. Put the news in context - don't just reword the press release.
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+ TrackBacks (0) | Category: Cancer | Press Coverage
This morning I heard reports of formaldehyde being found in Charleston, West Virginia water samples as a result of the recent chemical spill there. My first thought, as a chemist, was "You know, that doesn't make any sense". A closer look confirmed that view, and led me to even more dubious things about this news story. Read on - there's some chemistry for a few paragraphs, and then near the end we get to the eyebrow-raising stuff.
The compound that spilled was (4-methylcyclohexane)methanol, abbreviated as 4-MCHM. That's its structure over there.
For the nonchemists in the audience, here's a chance to show how chemical nomenclature works. Those lines represent bonds between atoms, and if the atom isn't labeled with its own letter, it's a carbon (this compound has one one labeled atom, that O for oxygen). These sorts of carbons take four bonds each, and that means that there are a number of hydrogens bonded to them that aren't shown. You'd add one, two, or three hydrogens as needed to each to take each one up to four bonds.
The six-membered ring in the middle is "cyclohexane" in organic chemistry lingo. You'll note two things coming off it, at opposite ends of the ring. The small branch is a methyl group (one carbon), and the other one is a methyl group subsituted with an alcohol (OH). The one-carbon alcohol compound (CH3OH) is methanol, and the rules of chemical naming say that the "methanol-like" part of this structure takes priority, so it's named as a methanol molecule with a ring stuck to its carbon. And that ring has another methyl group, which means that its position needs to be specified. The ring carbon that has the "methanol" gets numbered as #1 (priority again), so the one with the methyl group, counting over, is #4. So this compound's full name is (4-methylcyclohexane)methanol.
I went into that naming detail because it turns out to be important. This spill, needless to say, was a terrible thing that never should have happened. Dumping a huge load of industrial solvent into a river is a crime in both the legal and moral senses of the word. Early indications are that negligence had a role in the accident, which I can easily believe, and if so, I hope that those responsible are prosecuted, both for justice to be served and as a warning to others. Handling industrial chemicals involves a great deal of responsibility, and as a working chemist it pisses me off to see people doing it so poorly. But this accident, like any news story involving any sort of chemistry, also manages to show how little anyone outside the field understands anything about chemicals at all.
I say that because among the many lawsuits being filed, there are some that show (thanks, Chemjobber!) that the lawyers appear to believe that the chemical spill was a mixture of 4-methylcyclohexane and methanol. Not so. This is a misreading of the name, a mistake that a non-chemist might make because the rest of the English language doesn't usually build up nouns the way organic chemistry does. Chemical nomenclature is way too logical and cut-and-dried to be anything like a natural language; you really can draw a complex compound's structure just by reading its name closely enough. This error is a little like deciding that a hairdryer must be a device made partly out of hair.
I'm not exaggerating. The court filing, by the law firm of Thompson and Barney, says explicitly:
30. The combination chemical 4-MCHM is artificially created by combining methylclyclohexane (sic) with methanol.
31. Two component parts of 4-MCHM are methylcyclohexane and methanol which are both known dangerous and toxic chemicals that can cause latent dread disease such as cancer.
Sure thing, guys, just like the two component parts of dogwood trees are dogs and wood. Chemically, this makes no sense whatsoever. Now, it's reasonable to ask if 4-MCHM can chemically degrade to methanol and 4-methylcyclohexane. Without going into too much detail, the answer is "No". You don't get to break carbon-carbon bonds that way, not without a lot of energy. If you ran the chemical (at high temperature) through some sort of catalytic cracking reactor at an oil refinery, you might be able to get something like that to happen (although I'd expect other things as well, probably all at the same time), but otherwise, no. For the same sorts of reasons, you're not going to be able to get formaldehyde out of this compound, either, not without similar conditions. Air and sunlight and water aren't going to do it, and if bacteria and fungi metabolize it, I'd expect things like (4-methylcyclohexane)carboxaldehyde and (4-methylcyclohexane)carboxylic acid, among others. I would not expect them to break off that single-carbon alcohol as formaldehyde.
So where does all this talk of formaldehyde come from? Well, one way that formaldehyde shows up is from oxidation of methanol, as shown in that reaction (this time I've drawn in all the hydrogens). This is, in fact, one of the reasons that methanol is toxic. In the body, it gets oxidized to formaldehyde, and that gets oxidized right away to formic acid, which shuts down an important enzyme. Exposure to formaldehyde itself is a different problem. It's so reactive that most cancers associated with exposure to it are in the upper respiratory tract; it doesn't get any further.
As that methanol oxidation reaction pathway shows, the body actually has ways of dealing with formaldehyde exposure, up to a point. In fact, it's found at low levels (around 20 to 30 nanograms/milliliter) in things like tomatoes and oranges, so we can assume that these exposure levels are easily handled. I am not aware of any environmental regulations on human exposure to orange juice or freshly cut tomatoes. So how much formaldehyde did Dr. Scott Simonton find in his Charleston water sample? Just over 30 nanograms per milliliter. Slightly above the tomato-juice level (27 ng/mL). For reference, the lowest amount that can be detected is about 6 ng/mL. Update: and the amount of formaldehyde in normal human blood is about 1 microgram/mL, which is over thirty times the levels that Simonton says he found in his water samples. This is produced by normal human metabolism (enzymatic removal of methyl groups and other reactions). Everyone has it. And another update: the amount of formaldehyde in normal human saliva can easily be one thousand times that in Simonton's water samples, especially in people who smoke or have cavities. If you went thousands of miles away from this chemical spill, found an untouched wilderness and had one of its natives spit in a collection vial, you'd find a higher concentration of formaldehyde.
But Simonton is a West Virginia water quality official, is he not? Well, not in this capacity. As this story shows, he is being paid in this matter by the law firm of Thompson and Barney to do water analysis. Yes, that's the same law firm that thinks that 4-MCHM is a mixture with methanol in it. And the water sample that he obtained was from the Vandalia Grille in Charleston, the owners of which are defendants in that Thompson and Barney lawsuit that Chemjobber found.
So let me state my opinion: this is a load of crap. The amounts of formaldehyde that Dr. Simonton states he found are within the range of ozonated drinking water as it is, and just above those of fresh tomato juice. These are levels that have never been shown to be harmful in humans. His statements about cancer and other harm coming to West Virginia residents seem to me to be irresponsible fear-mongering. The sort of irresponsible fear-mongering that someone might do if they're being paid by lawyers who don't understand any chemistry and are interested in whipping up as much panic as they can. Just my freely offered opinions. Do your own research and see what you think.
Update: I see that actual West Virginia public health officials agree.
Another update: I've had people point out that the mixture that spilled may have contained up to 1% methanol. But see this comment for why this probably doesn't have any bearing on the formaldehyde issue. Update, Jan 31: Here's the MSDS for the "crude MHCM" that was spilled. The other main constituent (4-methoxymethylcyclohexane)methanol is also unlikely to produce formaldehyde, for the same reasons given above. The fact remains that the levels reported (and sensationalized) by Dr. Simonton are negligible by any standard.
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+ TrackBacks (0) | Category: Chemical News | Current Events | Press Coverage | Toxicology
Here's a long article from the Raleigh News and Observer (part one and part two) on the Eaton/Feldheim/Franzen dispute in nanoparticles, which some readers may already be familiar with (I haven't covered it on the blog myself). The articles are clearly driven by Franzen's continued belief that research fraud has been committed, and the paper makes the most of it.
The original 2004 publication in Science claimed that RNA solutions could influence the crystal form of palladium nanoparticles, which opened up the possibility of applying the tools of molecular biology to catalysts and other inorganic chemistry applications. Two more papers in JACS extended this to platinum and looked at in vitro evolutionary experiments. But even by 2005, Franzen's lab (who had been asked to join the collaboration between Eaton and Feldheim, who were now at Colorado and a startup company) was generating disturbing data: the original hexagonal crystals (a very strange and interesting form for palladium) weren't pure palladium at all - on an elemental basis, they were mostly carbon. (Later work showed that they were unstable crystals of (roughly) Pd(dba)3, with solvated THF. And they were produced just as well in the negative control experiments, with no RNA added at all.
N. C. State investigated the matter, and the committee agreed that the results were spurious. But they found Feldheim guilty of sloppy work, rather than fraud, saying he should have checked things out more thoroughly. Franzen continued to feel as if justice hadn't been done, though:
In fall 2009, he spent $1,334 of his own money to hire Mike Tadych, a Raleigh lawyer who specializes in public records law and who has represented The News & Observer. In 2010, the university relented and allowed Franzen into the room where the investigation records were locked away.
Franzen found the lab notebooks, which track experiments and results. As he turned the pages, he recognized that Gugliotti kept a thorough and well-organized record.
"I found an open-and-shut case of research fraud," Franzen said.
The aqueous solution mentioned in the Science article? The experiments routinely used 50 percent solvent. The experiments only produced the hexagonal crystals when there was a high level of solvent, typically 50 percent or more. It was the solvent creating the hexagonal crystals, not the RNA.
On Page 43 of notebook 3, Franzen found what he called a "smoking gun."
(Graduate student Lina) Gugliotti had pasted four images of hexagonal crystals, ragged around the edges. The particles were degrading at room temperature. The same degradation was present in other samples, she noted.
The Science paper claimed the RNA-templated crystals were formed in aqueous solution with 5% THF and were stable. NC State apparently offered to revoke Gugliotti's doctorate (and another from the group), but the article says that the chemistry faculty objected, saying that the professors involved should be penalized, not the students. The university isn't commenting, saying that an investigation by the NSF is still ongoing, but Franzen points out that it's been going on for five years now, a delay that has probably set a record. He's published several papers characterizing the palladium "nanocrystals", though, including this recent one with one of Eaton and Feldheim's former collaborators and co-authors. And there the matter stands.
It's interesting that Franzen pursued this all the way to the newspaper (known when I Iived in North Carolina by its traditional nickname of the Nuisance and Disturber). He's clearly upset at having joined what looked like an important and fruitful avenue of research, only to find out - rather quickly - that it was based on sloppy, poorly-characterized results. And I think what really has him furious is that the originators of the idea (Feldheim and Eaton) have tried, all these years, to carry on as if nothing was wrong.
I think, though, that Franzen is having his revenge whether he realizes it or not. It's coming up on ten years now since the original RNA nanocrystal paper. If this work were going to lead somewhere, you'd think that it would have led somewhere by now. But it doesn't seem to be. The whole point of the molecular-biology-meets-materials-science aspect of this idea was that it would allow a wide variety of new materials to be made quickly, and from the looks of things, that just hasn't happened. I'll bet that if you went back and looked up the 2005 grant application for the Keck foundation that Eaton, Feldheim (and at the time, Franzen) wrote up, it would read like an alternate-history science fiction story by now.
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+ TrackBacks (0) | Category: Chemical News | Press Coverage | The Dark Side | The Scientific Literature
To go along with those nominations for worst press releases of the year, here's a roundup of stinkers in the biomedical field. And they do reek. I got some of these in my in-box as well, and I probably got even more of them than I remember. Sad to say, PR material (or at least the automated list variety) gets a very brief look from me. If there's a personal note to it, that shows that some thought went into the distribution, odds go up. But even then, I get people pitching me on all-natural coconut cure water and the like, apparently laboring under the idea that it's just the think that the readership here would like to hear about. (Those sometimes get "You don't seem to have every actually looked at the site. . ." replies from me).
As for the automated stuff, once in a while I'll actually click through to the release itself, but most of the time, I can tell from the subject line that it's not something that I need to be spending any effort on. My e-mail address has crept on to more and more lists with time, and it's amusing, in a grim way, to see the releasebots sending me automated PR notes on, say, the morning of Thanksgiving and other big news days like that (and no, that didn't appear to be an outlet outside the US in that case - I looked it over at the time, wondering who could be silly enough be sending it). I'll keep an eye out on Christmas and New Year's for the latest news.
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+ TrackBacks (0) | Category: Press Coverage
In the same spirit as Adam Feuerstein's "Worst Biotech CEO" nominations from the other day, here's Michael Eisen asking what the worst scientific press releases of the year were. Most Overhyped and Most Egregious Failure to Cite Earlier Work are two especially hard categories to win. If you have some examples that particularly got under your skin this year, head on over.
The British press (and to a lesser extent, the US one) was full of reports the other day about some startling breakthrough in Alzheimer's research. We could certainly use one, but is this it? What would an Alzheimer's breakthrough look like, anyway?
Given the complexity of the disease, and the difficulty of extrapolating from its putative animal models, I think that the only way you can be sure that there's been a breakthrough in Alzheimer's is when you see things happening in human clinical trials. Until then, things are interesting, or suggestive, or opening up new possibilities, what have you. But in this disease, breakthroughs happen in humans.
This latest news is nowhere close. That's not to say it's not very interesting - it certainly is, and it doesn't deserve the backlash it'll get from the eye-rolling headlines the press wrote for it. The paper that started all this hype looked at mice infected with a prion disease, which led inexorably to neurodegeneration and death. They seem to have significantly slowed that degenerative cascade (details below), and that really is a significant result. The mechanism behind this, the "unfolded protein response" (UPR) could well be general enough to benefit a number of misfolded-protein diseases, which include Alzheimer's, Parkinson's, and Huntington's, among others. (If you don't have access to the paper, this is a good summary).
The UPR, which is a highly conserved pathway, senses an accumulation of misfolded proteins inside the endoplasmic reticulum. If you want to set it off, just expose the cells you're studying to Brefeldin A; that's its mechanism. The UPR has two main components: a shutdown of translation (and thus further protein synthesis), and an increase in chaperones to try to get the folding pathways back on track. (If neither of these do the trick, things will eventually shunt over to apoptosis, so the UPR can be seen as an attempt to avoid having the apoptotic detonator switch set off too often.
Shutting down translation causes cell cycle arrest, as well it might, and there's a lot of evidence that it's mediated by PERK, the Protein kinase RNA-like Endoplasmic Reticulum Kinase. The team that reported this latest result had previously shown that two different genetic manipulations of this pathway could mediate prion disease in what I think is the exact same animal model. If you missed the wild excited headlines when that one came out, well, you're not alone - I don't remember there being any. Is it that when something comes along that involves treatment with a small molecule, it looks more real? We medicinal chemists should take our compliments where we can get them.
That is the difference between that earlier paper and this new one. It uses a small-molecule PERK inhibitor (GSK2606414), whose discovery and SAR is detailed here. And this pharmacological PERK inhibition recapitulated the siRNA and gain-of-function experiments very well. Treated mice did show some behavioralthis really does look quite solid, and establishes the whole PERK end of the UPR as a very interesting field to work in.
The problem is, getting a PERK inhibitor to perform in humans will not be easy. That GSK inhibitor, unfortunately, has side effects that killed it as a development compound. PERK also seems to be a key component of insulin secretion, and in this latest study, the team did indeed see elevated blood glucose and pronounced weight loss, to the point that that treated mice eventually had to be sacrificed. Frustratingly, PERK inhibition might actually be a target to treat insulin resistance in peripheral tissue, so if you could just keep an inhibitor out of the pancreas, you might be in business. Good luck with that. I can't imagine how you'd do it.
But there may well be other targets in the PERK-driven pathways that are better arranged for us, and that, I'd think, is where the research is going to swing next. This is a very interesting field, with a lot of promise. But those headlines! First of all, prion disease is not exactly a solid model for Alzheimer's or Parkinson's. Since this pathway works all the way back at the stage of protein misfolding, it might be just the thing to uncover the similarities in the clinic, but that remains to be proven in human trials. There are a lot of things that could go wrong, many of which we probably don't even realize yet. And as just detailed above, the specific inhibitor being used here is strictly a tool compound all the way - there's no way it can go into humans, as some of the news stories got around to mentioning in later paragraphs. Figuring out something that can is going to take significant amount of effort, and many years of work. Headlines may be in short supply along the way.
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+ TrackBacks (0) | Category: Press Coverage | The Central Nervous System
You may have seen some "wonder drug" news stories over the holiday break about compounds targeting p53 - many outlets picked up this New York Times story. The first paragraph probably got them:
For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.
Now, to read that, you might think we're talking mutated p53, which is indeed found in a wide variety of cancers. It's the absolute first thing you think of when you think of a defective protein that's strongly associated with cancer. And everyone has been trying to target it for years and years now, for just that reason, but without too much success. If you know drug development, you might have seen this article and done what I did - immediately read on wondering who the heck it was with a broad-based p53 therapy and how you missed it.
That's when you find, though, that this is p53 and MDM2. MDM2 is one of those Swiss-army-knife proteins that interacts with a list of other important regulatory proteins as long as your leg. (Take a look at the last paragraph of that Wikipedia link and you'll see what I mean). Its relationship with p53 has been the subject of intense research for many years now - it's a negative regulator, binding to p53 and keeping it from initiating its own transcriptional activity. Since a lot of that transcriptional activity is involved with telling a cell to kill itself, that's the sort of thing you'd normally want to have repressed, but the problem in some tumor lines is that MDM2 never gets around to leaving, allowing damaged cancerous cells to carry on regardless.
So, as that newspaper piece says, there have been several long-running efforts to find compounds that will block the p53/MDM2 interaction. The first big splashes in the area were the "Nutlin" compounds, from Roche - named after Nutley, New Jersey, much good did it do the research site in the end. The tangled history of Nutlin-3 in the clinic is worth considering when you think about this field. But for some kinds of cancer, notably many lipsarcomas, this could be an excellent target. That link discusses some results with RG7112, which is one of the drugs that the Times is talking about. Note that the results are, on one level, quite good. This is a tumor type that isn't affected by much, and 14 out of the 20 patients showed stable disease on treatment. But then again, only one patient showed a response where the tumor actually became smaller, and some showed no effect at all. There were also twelve serious adverse events in eight patients. That's not the sort of thing that you might have expected, given the breathless tone of the press coverage. Now, these results are absolutely enough to go on to a larger trial, and if they replicate (safety profile permitting), I'd certainly expect the drug to be approved, and to save the lives of some liposarcoma patients who might otherwise have no options. That's good news.
But is it "the beginning of a new genetic age in cancer research", to quote Gina Kolata's article? I don't see how. The genetic age of cancer has been underway for some time now, and it's been underway in the popular press for even longer. As for this example, there are several types of cancer for which a p53/MDM2 compound could be useful, but liposarcoma is probably the first choice, which is why it's being concentrated on in the clinic. And as far as I know, the number of cancer patients with mutated p53 proteins well outnumber the ones with intact p53 and overexpressed MDM2. These new compounds won't do anything for those people at all.
I sound like such a curmudgeon. But shouldn't there be some level of press coverage in between total silence and Dawn Of A Glorious New Era? I suppose that "Progress Being Made On Tough Drug Target" isn't the sort of hed that makes Page One. But that's the sort of headline that research programs generate.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Press Coverage
Well, I've been away from the computer a good part of the day, but I return to find that the author of the NSF press release that I spoke unkindly of has shown up in the comments to that post. I'm going to bring those up here to make sure that his objections get a fair hearing:
I wrote this press release, and I am a bit concerned that instead of discussing the research with myself, or more importantly the researchers, you decide to attack the text.
We presented information based on research that has been underway for some time, at least two years with NSF peer-reviewed support.
Additionally, we were careful to not overstate either the technology or the impact, but to present an illustration of what the technology can do in the limited space that a press release allows.
A journalist is expected to follow the initial reading of the press release with questions for the researchers involved -- not attack the limited text that we provide as an introduction.
In my eleven years at NSF, I have never had someone attack my work -- particularly without first getting their facts straight.
Please contact the researchers to discuss the technology and limit your criticism for those thongs for which you are informed.
Thank you.
Josh Chamot
Media Officer for Engineering
National Science Foundation
(To add, my supervisor pointed out a stellar typo in my last line.
I'm fear that's where the discussion will go next, but if you do wish to learn more about the actual research you are disparaging, please do contact the researchers to learn more about the technology and the approach.)
Several regular readers have already responded in the comments section to that earlier post, making the point that experienced drug discovery scientists found the language in the press release hard to believe (and reminiscent of overhyped work from the past). Josh Chamot's response is reproduced here:
Thank you for the thoughtful responses. This is exactly the engagement I was hoping for.
First, I agree that hype is never what we want to communicate -- and I appreciate that skepticism is critical to ensuring accuracy and the complete communication of news. However, I do hope many of you will explore the research further so that any skepticism is completely informed.
I want to be clear that I have no intention of misleading the research or pharma communities, nor do I want to give false hope to those who might need any of the treatments that we referenced. Our language was intended to convey that the breakthrough to date is exciting, but clearly more work is needed before this can start producing drugs for patients -- and I believe we stated this.
Through links to additional information (such as the full patent application) and clear contact information for the principal investigator, it is our hope that the primary audience for the press release (reporters) will present a thorough and complete account of the work.
We do not wish to mislead, but we also cannot convey a full news story in press release format. The intent is to serve as an alert, and importantly, an accurate one.
Journalists are the primary audience for the press releases, and our system of information is reliant on their services. To the best of my knowledge, the information we presented on Parabon is accurate and states only results that Parabon has demonstrated and announced in their patent application -- the starting point for a journalist to explore the story further.
As background, the pieces I work on cover research efforts that are originally proposed to NSF in a review process informed by peers in the community. Parabon has received both Phase I and Phase II NSF small business funding, so they had succeeded in that competitive peer review twice.
That setting served as a baseline to inform my office that the research approach was a valid starting point -- however, as with almost all NSF research, this is research at the very earliest stages. I can accept that while I wrote the release to reflect this, I was not successful in conveying this clearly. However, the assertions that data in support of the research effort do not exist are incorrect.
The company first came to our office (public affairs) more than two years ago, and it is only now that the company had enough publicly available information for us to pull together an announcement of the technology and some introduction of how it works.
I have some lessons learned here in how to try to clarify caveats, but I stand by my original assertion that the research is valid and exciting. While I have no way to predict Parabon's ultimate success, I do believe that public discussion of their technique can only prove of value to the broader drug development effort -- including the identification of any obstacles that this, or a similar technique, must overcome.
Josh Chamot
I think what I'll do now is close off the comments to the previous post and have things move over to this entry, with appropriate pointers, so we don't have two discussion going on at the same time. Now, then. I'm not blaming Mr. Chamot for what went out on the wires, because I strongly suspect that he worked with what he was given. It's the people at Parabon that I'd really like to have a word with. If the press release is an accurate reflection of what they wanted to announce, then we have a problem, and it's not with Jack Chamot.
I realize that a press release is, in theory, supposed to be for the press - for reporters to use as a starting point for a real story. But how many of them do that, versus just rewording the release a bit? There are reporters who could pick up on all the problems, but there are many others who might not. The information in the Parabon release, as it stands, makes little sense to those of us who do drug discovery for a living, seems full of overstated claims, and raises many more questions than it answers. Specialists in the field (as many readers here are) will have an immediate and strong reaction to this sort of thing.
And that's one of the purposes of this blog (and of many others): to bring expertise out into the open, to provide people within some specialized area a chance to talk with each other, and to provide people outside it (anyone at all) a chance to sit in and learn about things they otherwise might never hear discussed. I think that the process that Mr. Chamot has described is an older one: scientists describe a discovery of theirs to some sort of press officer, who puts into some useful and coherent form in order to get the word out to reporters, who then can contact the people involved for more details as they write up their stories for a general readership. That's fine, but these days that whole multistep procedure is subject to disintermediation. And that's what we're seeing right now.
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+ TrackBacks (0) | Category: Chemical Biology | Press Coverage
I'm having a real problem understanding this press release from the NSF. I've been looking at it for a few days now (it's been sent to me a couple of times in e-mail), and I still can't get a handle on it. And I'm not the only one. I see just this morning that Chemobber is having the same problem. Here, try some. See how you do:
Using a simple "drag-and-drop" computer interface and DNA self-assembly techniques, researchers have developed a new approach for drug development that could drastically reduce the time required to create and test medications. . ."We can now 'print,' molecule by molecule, exactly the compound that we want," says Steven Armentrout, the principal investigator on the NSF grants and co-developer of Parabon's technology. "What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design."
Say what? Surely they don't mean what it sounds like they mean. But they apparently do:
"When designing a therapeutic compound, we combine knowledge of the cell receptors we are targeting or biological pathways we are trying to affect with an understanding of the linking chemistry that defines what is possible to assemble," says Hong Zhong, senior research scientist at Parabon and a collaborator on the grants. "It's a deliberate and methodical engineering process, which is quite different from most other drug development approaches in use today."
OK, enough. I'd love for atom-by-atom nanotech organic synthesis and precisely targeted drug discovery to be a reality, but they aren't. Not yet. The patent application referenced in the press release is a bit more grounded in reality, but not all that much more:
The present invention provides nanostructures that are particularly well suited for delivery of bioactive agents to organs, tissues, and cells of interest in vivo, and for diagnostic purposes. In exemplary embodiments, the nanostructures are complexes of DNA strands having fully defined nucleotide sequences that hybridize to each other in such a way as to provide a pre-designed three dimensional structure with binding sites for targeting molecules and bioactive agents. The nanostructures are of a pre-designed finite length and have a pre-defined three dimensional structure
Ah, and these complexes of DNA strands will survive after in vivo dosing just exactly how? And will be targeted, via that precisely defined structure, just how? And bind to what, exactly, and with what sort of affinities? And are the binding sites on these DNA thingies, or do they bind to other things, anyway? No, this is a mess. And this press release is an irresponsible mishmosh of hype. I'd be glad to hear about some real results with some real new technology, and I'd like to ask the Parabon people to cough some up. I'd be equally glad to feature them on this blog if they can do so, but not if they're going to start talking like they're from the future and come to save us all. Sheesh.
Update: the discussion on this press release features a number of interesting comments. It's now moved over to this post, for reasons explained there. Thanks!
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+ TrackBacks (0) | Category: Chemical Biology | Press Coverage
I wanted to congratulate the commenters around here - your knowledge (and your low-pH wit) have propelled the Pfizer gold dust speculation here to Peter Loftus' Corporate Intelligence blog at the Wall Street Journal. Don't expect any response from Pfizer, though. . .
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+ TrackBacks (0) | Category: Press Coverage
The overhyped nature of stem cell therapies is a topic that's come up here several times. In the latest developments, Pluristem, Inc., is threatening to sue Bloomberg New for their recent report, titled "Girl Dies As Pluristem Sells On Gains With Miracle Cells". Gosh, it's hard to see why the company would take exception to a headline like that, but here's how the piece leads off, in case things weren't clear:
Pluristem Therapeutics Inc.'s (PSTI) stock doubled in Nasdaq trading from May through September, helped by three news releases announcing that patients' lives had been saved by injections of the company's experimental stem cells.
After the stock soared on the positive news, two top executives profited by selling shares at the highest price in more than four years as part of a pre-determined program. When the first of those patients, a 7-year-old girl with a bone- marrow disease, died four months after the company said her life had been saved, Pluristem was silent. The company raised $34 million selling shares a week later.
Not so good. But as that link in the first paragraph shows, Pluristem's response has not cleared things up very much. In the same press release in which they demanded a correction from Bloombert, they revealed that another of their three initial patients had also died after four months, which also had not been announced before. The earlier press releases for all three patients are well-stocked with phrases like "medical miracle" and "life-saving". As long as this sort of thing is going on, the stem cell field will continue to have problems.
Update: interestingly, this post seems to have brought a lot of Pluristem's stock market fans flocking. And I mean this in the best possible way, but their appearance here does not inspire confidence.
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+ TrackBacks (0) | Category: Clinical Trials | Press Coverage
I've been meaning to write something about the M.D. Anderson announcement of "Moon Shot" programs for cancer therapies. Mostly something about how I'm very glad that they're spending a lot of time and money on this, because there are a lot of good people there, but also about how I truly hate the "Moon Shot" analogy for R&D. As has been said for years, decades. . .the Moon landing was a stupendous feat of applied engineering, but few (if any) new principles had to be discovered along the way. Attacking cancer, though, is like trying to engineer a moon landing when you're not sure where the moon is. Or what it's made out of. Or what the various kinds of rocket fuel might be.
And the whole thing was made much, much worse by CNN, who proclaimed "Cure for Cancer Close" as some sort of exclusive scoop. That ridiculous situation is summed up well here. As it turns out, this was a combination of the M.D. Anderson press release and one of those "We could save more people just by applying our existing knowledge more thoroughly" angles. All in all, a really shoddy performance, which I hope had people both at CNN and M. D. Anderson burying their heads in their hands.
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+ TrackBacks (0) | Category: Cancer | Press Coverage
Several readers sent along a link to this Radio 4 program ("The End of Drug Disocvery") from the BBC on drug discovery. From what I've heard, it's a very good overview of the current state of the field for people outside it, and gets across just how difficult it's been to find good drug candidates.
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+ TrackBacks (0) | Category: Press Coverage
Nobelist Roald Hoffman has directly taken on a topic that many chemists find painful: why aren't more chemistry Nobel prizes given, to, well. . .chemists?
". . .the last decade has been especially unkind to "pure" chemists, asa only four of ten Nobel awards could be classified as rewarding work comfortably ensconced in chemistry departments around the world. And five of the last ten awards have had a definite biological tinge to them.
I know that I speak from a privileged position, but I would urge my fellow chemists not to be upset."
He goes on to argue that the Nobel committee is actually pursuing a larger definition of chemistry than many chemists are, and that we should take it and run with it. Hoffmann says that the split between chemistry and biochemistry, back earlier in the 20th century, was a mistake. (And I think he's saying that if we don't watch out, we're going to make the same mistake again, all in the name of keeping the discipline pure).
We're going to run into the same problem over and over again. What if someone discovers some sort of modified graphene that's useful for mimicking photosynthesis, and possibly turning ambient carbon dioxide into a useful chemical feedstock? What if nanotechnology really does start to get off the ground, or another breakthrough is made towards room-temperature superconductors, this time containing organic molecules? What would a leap forward in battery technology be, if not chemistry? Or schemes to modify secreted proteins or antibodies to make them do useful things no one has ever seen? Are we going to tell everyone "No, no. Those are wonderful, those are great discoveries. But they're not chemistry. Chemistry is this stuff over here, that we complain about not getting prizes for".
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+ TrackBacks (0) | Category: General Scientific News | Press Coverage | Who Discovers and Why
In response to the press coverage on the FDA's Avastin decision on Friday, a reader forwarded a revised and extended version of the New York TImes article that appeared soon afterwards. Here are some excerpts, which I think get across the thinking of many medicinal chemists and drug researchers. His contributions are bolded for emphasis, although it's not all that hard to see where the original ends and his revisions start.
"The commissioner of the Food and Drug Administration on Friday revoked the approval of the drug Avastin as a treatment for breast cancer, ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials, two things that should never be compared, because that would be stupid.
The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.
. . .The F.D.A. "recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use." Also, they shouldn't take drugs that don't work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.
. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.
Yet pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.'s own staff and the strong recommendations of the outside experts on its advisory committee.
. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don't live as long and suffer more serious side effects from the control group.
. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."
The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.
. . .The F.D.A. "recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use." Also, they shouldn't take drugs that don't work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.
. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.
Yet pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.'s own staff and the strong recommendations of the outside experts on its advisory committee.
. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don't live as long and suffer more serious side effects from the control group.
. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."
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+ TrackBacks (0) | Category: Cancer | Press Coverage | Regulatory Affairs
Are stem cells overhyped? That topic has come up around here several times. But there have been headlines and more headlines, and breathless reports of advances, some of which might be working out, and many of which are never heard from again. (This review, just out today, attempts to separate reality from hype).
Today brings a bit of disturbing news. Geron, a company long associated with stem cell research, the company that started the first US trial of embryonic stem cell therapy, has announced that they're exiting the field. Now, a lot of of this is sheer finances. They have a couple of oncology drugs in the clinic, and they need all the cash they have to try to get them through. But still, you wonder - if their stem cell trial had been going really well, wouldn't the company have gotten a lot more favorable publicity and opportunities for financing by announcing that? As things stand, we don't know anything about the results at all; Geron is looking for someone to take over the whole program.
As it happens, there's another stem-cell report today, from a study in the Lancet of work that was just presented at the AHA. This one involves injecting heart attack patients with cultured doses of their own cardiac stem cells, and it does seem to have helped. It's a good result, done in a well-controlled study, and could lead to something very useful. But we still have to see if the gains continue, what the side effects might be, whether there's any advantage to doing this over other cell-based therapies, and so on. That'll take a while, although this looks to be on the right track. But the headlines, as usual, are way out in front of what's really happening.
No, I continue to think that stem cells are a very worthy subject of research. But years, quite a few years, are going to be needed before treatments using them can become a reality. Oh, and billions of dollars, too - let's not forget that. . .
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+ TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage
There's been an interesting dispute playing out over the last few weeks about science reporting. Here's a summary, but I'll give one as well: it all got started with David Kroll, aka "Abel Pharmboy" of the Terra Sigillata blog (and another, Take as Directed). On that latter site, he'd written about science articles in the popular press, and the line between having a scientist fact-check a piece about their work, and giving that same scientist editorial power.
Ananyo Bhattacharya, editor of Nature, then wrote a column in the Guardian on the topic, where he warned that there was indeed a line that could be crossed:
". . .It's a trap I've fallen into in the past. Either a scientist you have talked to insists on checking the final version of the story with the threat of "withdrawing" their contribution to your piece (it feels churlish to point out that they have already agreed to speak to you on the record) or, an hour or two before deadline you're struck by a creeping fear that somewhere, something is dreadfully wrong and so you call on one or more of your friendly sources to read it over. . .Part of the problem is that many scientists interpret the journalist's request that they "check the facts and your quotes only please" rather loosely. Some are under the impression that because their lab carried out the work being reported, they have some sort of ownership of the subsequent coverage. This is not the case."
But then the Guardian ran a strongly dissenting view from three neuroscientists from Cardiff University. Their take was that peer review is the secret sauce, and that accuracy is the greater good:
Science is different for four reasons, one categorical, three of degree. The categorical difference is the process of peer review. Every research article in a reputable scientific journal has been through a process in which between two and five independent experts (normally anonymous) have made extensive comments. . .
Overall, since press credibility relies on both accuracy and independence, and since the question of allowing sources to check articles (or parts of them) raises a tension between these pillars, the burning question is: where should the balance be struck?
We believe that public trust in science, and in science reporting, is harmed far more by inaccuracy than by non-independence. Contrary to Bhattacharya's claim that "the reader is not a scientist's first concern," public understanding is our overriding concern when communicating with journalists.
As it happens, these very authors had recently been scorched by sensationalized reporting of their work in the British tabloids. Now, I agree that for an accurate picture of any given scientific project, I'd sooner bring in a paleolithic Amazonian shaman for his take before turning to the Sun or the Daily Mail. But I still have to disagree that accuracy is the absolute trump card - I'm willing to accept some moronic misrepresentations in order to keep things more honest, and I think that honesty is best served when things don't run quite so smoothly. We should all keep each other on our toes - the alternative is an invitation to logrolling and groupthink, which can do more harm, in the long run, than sensationalism.
And it should go without saying that the Cardiff researchers' appeal to peer review just doesn't stand up. Five minutes over on Retraction Watch will show you what peer review is capable of letting through. And there are plenty of good scientists who will tell you about what peer review is capable of keeping out of the journals as well. No, it's a very imperfect system. I'm not saying that I can think of a better one at the moment, but appealing to it as if it's one of the glories of civilization is silly. (I see that I'm not alone in reacting this way).
And a bit more than silly - it's arrogant as well. This is what we as scientists have to look out for, the de haut en bas attitude where we come in and explain all the complicated stuff to the peasants. People can detect that, you know, and when they do they get suspicious (and rightly so, at times) that we have something to hide. No, speaking as a scientist, and a blogger, and (mostly on the opinion side) perhaps a journalist as well, I think we're better off with a system where everyone keeps an eye on everyone else. If we get too cozy and consensus-driven, we're going to invite real trouble.
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I wrote last year about Foldit, a collaborative effort to work on protein structure problems that's been structured as an open-access game. Now the team is back with another report on how the project is going, and it's interesting stuff. The headlines have generally taken the "Computer Gamers Solve Incredible Protein Problem That Baffled Scientists!" line, but that's not exactly the full story.
The Foldit collaboration participated in the latest iteration of a regular protein-structure prediction challenge, CASP9. And their results varied - in the category of proteins with known structural homologs, for example, they didn't perform all that well. The players, it turned out, sort of over-worked the structures, and made a lot of unnecessary changes to the peripheral parts of the proteins. Another category took on proteins that have no identified structural homologs, a much harder problem. But that had its problems, too, which illustrate both the difficulties of the Foldit approach and protein modeling in general:
For prediction problems for which there were no identifiable homologous protein structures—the CASP9 Free Modeling category—Foldit players were given the five Rosetta Server CASP9 submissions (which were publicly available to other prediction groups) as starting points, along with the Alignment Tool. . .In this Free Modeling category, some of the shortcomings of the Foldit predictions became clear. The main problem was a lack of diversity in the conformational space explored by Foldit players because the starting models were already minimized with the same Rosetta energy function used by Foldit. This made it very difficult for Foldit players to get out of these local minima, and the only way for the players to improve their Foldit scores was to make very small changes ('tunneling' to the nearest local minimum) to the starting structures. However, this tunneling did lead to one of the most spectacular successes in the CASP9 experiment.
. . .the Rosetta Server, which carried out a large-scale search for the lowest-energy structure using computing power from Rosetta@home volunteers, produced a remarkably accurate model . . . However, the server ranked this model fourth out of the five submissions. The Foldit Void Crushers team correctly selected this near-native model and further improved it by accurately moving the terminal helix, producing the best model for this target of any group and one of the best overall predictions at CASP9 . . . Thus, in a situation where one model out of several is in a near-native conformation, Foldit players can recognize it and improve it to become the best model. Unfortunately for the other Free Modeling targets, there were no similarly outstanding Rosetta Server starting models, so Foldit players simply tunneled to the nearest incorrect local minima.
In the Refinement challenge, where participants take a minimized structure and try to improve its accuracy, the Foldit players had similar problems with starting from structures that had already been minimized by the same tools that they were using. Every change tended to make things look worse. The team improved their performance by reposting one of the structures as a new challenge, this time keeping the parts that were known with confidence to be near-native, while more or less randomizing the other parts to give a greater diversity to the starting points.
And those really are some of the key problems in this work. There are an awful lot of energy minima out there, and which ones you can get to depend crucially on where you start looking. In order to get to a completely different manifold of protein structures, even ones with much better energies, you may well have to go through a zone where you look like you're ruining everything. (And most of the time, you probably are ruining everything - there's no way to know if there's a safe haven on the other side or not).
But this paper also reports the results that are getting the headlines, a structure for the Mason-Pfizer monkey retroviral protease. This is an interesting protein, because although it crystallizes readily (in several different forms), and although the structures of other retroviral proteases are known, no one has been able to solve this one from the available X-ray data. The Foldit players, however, came up with several proposals that fit the data well enough for the structure to finally fall out of the diffraction data. It does have some odd features in its protein loops, different enough from the other proteases for no one to have hit on it before.
And that really is an accomplishment, and the way it was solved (with different players building on the results of others, competing to get the best optimization scores) really is the way the Foldit is supposed to work. Their less impressive performance on the CASP9 problems, though, shows that the same protein prediction difficulties apply to Foldit players as apply to the rest of the modeling field. This isn't a magic technique, and Foldit gamers are not going to rampage through the structural biology world solving all the extant problems any time soon. But it's nothing to sneeze at, either.
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+ TrackBacks (0) | Category: In Silico | Press Coverage
I've been meaning to comment on this article from the Wall Street Journal - the authors take a look at the drug approval numbers so far this year, and speculate that the industry is turning around.
Well, put me in the "not so fast" category. And I have plenty of company there. Neither Bruce Booth (from the venture capital end), John LaMattina (ex-Pfizer R&D head) nor Matthew Herper at Forbes are buying it either.
One of the biggest problems with the WSJ thesis is that most of these drugs have been in development for longer than the authors seem to think. Bruce Booth's post goes over this in detail, and he's surely correct that these drugs were basically all born in the 1990s. Nothing that's changed in the research labs in the last 5 to 10 years is likely to have significantly affected their course; we're going to have to wait several more years to see any effects. (And even then it's unlikely that we're going to get any unambiguous signals; there are too many variables in play). That, as many people have pointed out over the years, is one of the trickiest parts about drug R&D: the timelines are so long and complex that it's very hard to assign cause and effect to any big changes that you make. If your car only responds to the brake pedal and steering wheel a half hour after you touch them, how can you tell if that fancy new GPS you bought is doing you any good?
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+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Press Coverage | Regulatory Affairs
I wanted to call attention to another blog roundtable, on several subjects related to how nonchemists see us and our business. The first post (at ScienceGeist) is on chemical safety (industrial chemicals = bad?). Day 2, at ChemJobber, is on whether the general public has any good idea of not only what chemists do (we work with chemicals, right?) but why and how we do it. Day 3, at ChemBark, takes things to a practical level, showing how lack of understanding can confuse people about energy policy (does growing corn to make ethanol make any sense?) And Day 4, at The Bunsen Boerner, is on a topic I've been known to go off on myself, the use (and mostly the misuse) of the word "organic".
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+ TrackBacks (0) | Category: Chemical News | Press Coverage
. . .you either have to go to the specialty press, or (sometimes) to the last couple of paragraphs of a mainstream article. For several years now, it's been hard to think of any medical field that's been more relentlessly overhyped than stem cell therapy (a worst-case example was its appearance in the 2004 elections, courtesy of the ever-reliable John Edwards?).
FiercePharma has a good short look at an article in Time that is much more well-balanced than most, but still has some of the usual problems. And don't get me wrong - I think that stem cells are an exciting area of research, an excellent thing to be investigating, and could quite possibly lead to some wonderful results. But not next week. And not without a few billion dollars, most likely. Anyone who tells you otherwise is, to my mind, to be regarded with suspicion.
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Here's a op-ed from Josh Bloom (ex-Wyeth) in the New York Post that will resonate with a lot of people out there. A sample:
The folks at Scientific American have launched "1,000 Scientists in 1,000 Days" -- a program to bring together scientists, teachers and students to improve America's "dismal" showing among wealthy countries (27th out of 29) in graduating college students with degrees in science or engineering. I'm sure they mean well -- but, at least as it applies to the field of chemistry, "1,000 Unemployed Scientists Living With Their Parents at Age 35 While Working at the Gap" would be a better name.
He goes on to tell the readership what it's been like in drug discovery over the last few years, and it'll probably be news to many of them. I'm glad that people are getting the word out!
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I was going to take a shot at this article myself, a piece in The Atlantic called "The Triumph of New Age Medicine". But Matthew Herper at Forbes has done the job for me. The original article advances the thesis that modern medicine isn't doing much for chronic diseases, which is why people are turning to acupuncture, et al. Says Herper:
. . .that's all horse microbiome. Let's take those one by one. Saying we're not making strides against heart disease and cancer is just, well, wrong. Look at the below chart of mortality from both, courtesy of the Centers for Disease Control and Prevention. Notice something? They're both going down. . .Yes, the battle against heart disease and cancer is slow, grinding trench warfare, but that's because these our diseases written by evolution into our genetic code. And we're still winning.
He goes on to demolish one of the article's other sweeping claims - that alternative medicine focuses on prevention, but mainstream medicine doesn't. And he's got an interesting reason (which may have occurred to you before) for why most "alternative" therapies have such ardent fans. Hint: there really is a secret ingredient, which has been gradually removed from a lot of modern medical practice. . .
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There have been quite a few headlines over the last few days like this one: "A New Drug Makes Hearts Repair Themselves". Unfortunately, that's not quite true. Not yet.
It's this paper in Nature that's getting the attention, and it is a very interesting one. The authors have identified a population of progenitor cells in the adult heart that can be induced to turn into fully differentiated myocytes after an infarction. In fewer syllables, and reasonably accurately: stem cells, already in the heart, can be made to repair it after a heart attack. And that's getting closer to that headline I was just complaining about - so what's the gap between the two?
Well, there are several rather huge factors. One of them is that the way that these cells were stimulated into action was by treatment with thymosin beta-4, which is a potent regulator of cardiac cells and blood vessel development. Tβ4 is not quite a drug yet, although RegeneRx is giving it a shot. There have been some phamacokinetic studies in animals and other preliminary work, and I wish them every good fortune. But it's got a ways to go.
Second, this study treated the animals with Tβ4 for seven days before inducing the cardiac injury. That's perfectly reasonable for a proof-of-concept study like this one, but it's not the real-world therapeutic option that you'd imagine from the press coverage. As one correspondent put it to me in an e-mail, "if you're a mouse, and you know that later on this week you're going to have an MI, then this is the treatment for you". That might be unfair to the original authors, who are working their way up carefully through some very tricky biology, but it's not unfair at all to the people who write headlines like the one I quoted above.
No, this is very interesting stuff, but it's quite a ways from being ready to help any of us out. This is where such therapies start, though, and we can only hope that something makes it through this time. The authors themselves know the score:
". . .The induced differentiation of the progenitor pool described into cardiomyocytes by Tβ4 is at present an inefficient process relative to the activated progenitor population as a whole. Consequently, the search is on via chemical and genetic screens to identify efficacious small molecules and other trophic factors to underpin optimal progenitor activation and replacement of destroyed myocardium.
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I found this article in The American Scholar via Arts and Letters Daily, entitled "Flacking for Big Pharma". As you might have possibly guessed from the title, it's a broadside against the advertising practices of the drug industry, and particularly against its interactions with physicians and the medical journals.
And I'll say up front that the piece is not, in fact, completely wrong. It's probably not even mostly wrong. There really are big problems in these areas, such as too-aggressive promotion, minimization of side effects, too many payments to "key opinion leaders", too many studies that don't see the light of day, and so on. And these things really do lower the respect that people have for the drug industry - assuming, by this point, that there's much respect left. But overall, this article is sort of a summary version of Marcia Angell's book, for people who would like to hate the drug industry but find themselves pressed for time. And as such, it manages to get some important things wrong in the process of getting some things right.
For example, it makes much of subgroup analysis of clinical trials, but as a way for drug companies to pull the wool over readers' eyes. I wonder how much this really happens, though, since overzealous data mining of a trial that wasn't powered to generate such conclusion is (you'd think) a well-known pitfall by now. Perhaps not, though. But the example given in the article is BiDil:
BiDil proponents published studies that supported their claim of a racially mediated genetic anomaly that was addressed by BiDil, making it an ideal drug for blacks but not for whites.. . .
NitroMed won FDA approval of a new trial that included only 1,050 black subjects, with no white subjects to provide comparison data. Furthermore, BiDil was not tested alone, but only in concert with heart medications that are already known to work, such as diuretics, beta-blockers, and angiotensin-converting enzyme (or ACE) inhibitors. The published results of the trial were heralded as a success when subjects taking the drug combinations that included BiDil enjoyed 43 percent fewer heart-failure deaths.
. . .excluding whites was a medically illogical but financially strategic move because it eliminated the possibility that the drug would test well in whites, thereby robbing NitroMed of its already thin rationale for calling BiDil a black drug. The "black" label was crucial, because BiDil's patent covering use in all ethnic groups expired in 2007, but the patent for blacks only allows NitroMed to profit from it until 2020. BiDil is a case study in research methodology "flaws" that mask strategies calculated to make a dodgy drug look good on paper, for profit.
But this doesn't appear to be correct. First off, as the article itself mentioned earlier, the BiDil combination was originally tested (twice) in racially mixed (in fact, I believe, mostly white) trial groups. Secondly, the 1,050-patient trial in black patients was done with other therapies because to do otherwise would be unethical (see below). And what you wouldn't realize by reading all this is the BiDil, in fact, was a failure. No one's making piles of profits on BiDil until 2020, especially not NitroMed. You wouldn't even know that NitroMed itself gave up trying to sell BiDil three years ago, and that the company itself was acquired (for a whopping 80 cents a share) in 2009.
Now, about those placebo-controlled trials. This article makes much of a British Medical Journal satire from 2003 on how to make a drug look good. But it's confused:
A placebo, such as a sham or "sugar" pill, has no active ingredient, and, although placebos may evoke some poorly understood medical benefits, called the "placebo effect," they are weak: medications tend to outperform placebos. Placebo studies are not ethical when a treatment already exists for a disorder, because it means that some in the study go untreated. However, if you care only that your new drug shines in print, testing against placebo is the way to go.
Well, which is it? We can't, in fact, run placebo-controlled trials just to "shine in print" when there's a standard of care, you know. You can only do that when there's no standard of care at all. And in those cases, what exactly should we use as a comparison? Using nothing at all (no pills, nothing) would, in fact, make our drugs look even better than they are, because of that placebo effect. This is a specious objection.
And when there's a standard of care that a new drug will be added to (as was the case with BiDil), then you actually do have to run it with those therapies in place, at least when you get to Phase III. The FDA (and the medical community) want to know how your drug is going to perform in the real world, and if patients out in that real world are taking other medications, well, you can't pretend that they aren't.
In another section, the article makes much of the Merck/Elsevier affair, where Elsevier's "Excerpta Medica" division set up some not-really-journals in Australia (blogged about here). That was, in fact, disgraceful (as I said at the time), but disgraceful apparently isn't enough:
. . .Elsevier, the Dutch publisher of both The Lancet and Gray's Anatomy, sullied its pristine reputation by publishing an entire sham medical journal devoted solely to promoting Merck products. Elsevier publishes 2,000 scientific journals and 20,000 book-length works, but its Australasian Journal of Bone and Joint Medicine, which looks just like a medical journal, and was described as such, was not a peer-reviewed medical journal but rather a collection of reprinted articles that Merck paid Elsevier to publish. At least some of the articles were ghostwritten, and all lavished unalloyed praise on Merck drugs, such as its troubled painkiller Vioxx. There was no disclosure of Merck's sponsorship. Librarian and analyst Jonathan Rochkind found five similar mock journals, also paid for by Merck and touted as genuine. The ersatz journals are still being printed and circulated, according to Rochkind, and 50 more Elsevier journals appear to be Big Pharma advertisements passed off as medical publications. Rochkind's forensic librarianship has exposed the all-but-inaccessible queen of medical publishing as a high-priced call girl.
Fifty journals? Really? As far as I can tell, that figure comes from this analysis at the time, and seems to be mostly nonce publications, one-off conference proceedings, and the like. There is a whole list of "Australasian Journal of So-and-Sos", which would be the same reprint advertorials as the other Excerpta Medica stuff, but do these still exist? (Did all of them on the list, in fact, ever actually publish anything?)
You'd get the impression that Elsevier is (or was, until Big Pharma came along) an absolute shining pinnacle of the medical establishment - but, with apologies to the people I know who work there, that is unfortunately not the case. They're big, and they're very far from the worst scientific publishers out there, but some of their titles are, in fact, not adding much to the total of human knowledge. Nor has the conduct of their marketing department always been above reproach. But no, this has to be built up to look even worse than it is.
The irritating thing is that there's plenty to criticize about this industry without misrepresenting reality. But does that sell?
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What's going on over at Slate, anyway? So far this week we've been talking about that Timothy Noah article over there publicizing the bizarre Light and Warburton estimate for drug development. Now one of their house blogs erupts with a geyser of idiocy about the looming patent cliff in the industry:
So this sudden terrible problem has been obvious and on schedule for at least 10 years.
It honestly is that simple and that stupid. The pharmaceutical industry turned all its energy toward wringing as much money as possible out of the drugs it already had, and quit making any sort of plans that would lead to having a new (and, you know: medically useful) batch of drugs under patent in the future, when the patents on the old batch expired.
Now the pharmaceutical companies are laying off tens of thousands of workers because they are worried about their financial future, because although they are officially in the business of producing and selling drugs, they stopped producing drugs.
It goes on in that vein; in fact, it gets even more stupid. And the point isn't that someone wrote something like this, so much as that this reflects, I fear, what a lot of other people think. Writing this blog has exposed me to a lot of smart, interesting people, which is something I really enjoy. But it's also exposed me to a lot of troglodytes who have no idea of what they're talking about. And here we have another one. Unfortunately, if enough people believe something idiotic, those beliefs can have consequences.
Now, we can argue about pharma strategy, which we do all the time around here. Where to spend the time and money, which programs to push and which to walk away from - everyone's got their own opinions. But if the line you're pushing is that drug companies just haven't been doing any research at all for the last ten or twenty years. . .well, then you're a moron. On the evidence of this column, Slate's Tom Scocca is one, at best, and his piece is a waste of electrons.
For one thing, there actually have been a few drugs introduced over the last ten years or so. Not as many as we'd like, or as many as we were planning on, but still. And then there are the failures. I mean, I say a lot of nasty things about Pfizer here, for example, but we can list off the big drug projects that they've had die on them over the last few years. Same for Merck, for Novartis, for BMS and AZ and for everyone else.
Honestly, I really think that we should make a bigger deal out of clinical failures in this industry, so that people realize that (1) we're always trying to do something, (2) it doesn't always work, and (3) it costs a godawful amount of money. As it is now, no one outside of the industry really notices or remembers when the giant multi-year research programs go down in expensive flames. And that leaves the door open for knuckle-dragging stuff as quoted above, and for the fools who believe it.
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Update: call off the dogs! I've heard from a colleague of Dr. Pepys, who strongly believes that this was a tongue-in-cheek remark. He assures me that Pepys has been around the clinical development block a number of times in the field of amyloidosis, which is a hard enough area to give anyone a good idea of what discovering a useful therapy is really like.
This would not be unheard of - both for a newspaper story to quote a flippant remark out of context, and for the tone of such a remark to be completely lost once it appeared on paper. After looking the situation over, I think that's just what's happened here. It's a sad thing, though, that a remark like this is close enough to some real opinions that it could be taken as read. . .
From the Financial Times:
GlaxoSmithKline aims to sign up 10 academic "superstars" this year for long-term partnerships to help develop medicines more effectively and cheaply. . .
The move comes as the UK pharma group cuts back on costly but unproductive early-stage in-house research and attempts to shift from investment in fixed assets towards more flexible partnerships with external developers.
GSK has recently finalised its first such contract with Professor Mark Pepys, head of medicine at the Royal Free and University College Medical School in London, designed to develop a treatment for a rare form of amyloidosis. (Glaxo senior VP Patrick) Vallance said he planned to sign 10 such deals this year. . .
"It's a wonderful idea," said Prof Pepys. "We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else."
Were I working for GSK, I would be very, very excited. Finally, a clear statement of what the company thinks of its own employees. The Sirtris deal (and others) have hinted at the contempt under the surface, but it's good to get it out into the open. Isn't it?
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I noticed this editorial in Nature Structural and Molecular Biology, on getting scientific results out to the public. It's worth reading, but not in the way that they think. It starts out reasonably well:
As members of the research community, we know we can't rely on the popular media to correct the misperceptions the public might harbor about science-related issues. According to a 2009 Pew Research Center survey of Americans, carried out in conjunction with the American Association for the Advancement of Science (AAAS), 76% of scientists feel the media do not adequately distinguish between substantial findings and those that are unfounded. Although it would be easy to say that the public "just doesn't get it," the burden of passing along the understanding and implications of contemporary science falls squarely on the shoulders of those actively engaged in funding, publishing and carrying out research.
That's been said before, as the editorial itself notes, but it's no less true for all that. And the advice that follows is sound, if still rather boring: when you talk to non-scientists, try to gauge how much they know about the subject (without offending people), lay off the acronyms and jargon, look for helpful (and accurate) analogies, and so on. All fine.
But then the piece floats off into the mist - or, more accurately, floats off into about the year 1976.How do we get the word out to the public? Well, we need public officials on our side, it says. But take heart! "Globally, several world leaders have voiced support for increasing the promotion of science in their countries", and that should cheer anyone up on a rainy Monday morning. How anyone was able to type that line without burying their head in their hands is beyond me.
There's more. "It is important that we engage the public where they are", says the editorial, and I can't argue with that one, since trying to engage 'em where they ain't is unlikely to prove fruitful. And here comes the rain of musty pillows again: "A growing number of organizations and institutions are seeking to do this through several different approaches", says the next line. You can just hear the (unsigned) writer thinking "Dang it, what's the word count supposed to be on this thing again?" Whoever it is goes on to point out that Sloan-Kettering hosts an annual seminar for just that purpose.
It's only in the last couple of lines that anything useful gets said. Because if we agree that the public should know more about science, and if we've decided that we should go where they are to realize that, then the two places I'm sure that they might be found are online and watching TV, and maybe both at the same time. Just under the wire, the editorial manages to mention that there are these things called web sites, and even (quickly and quietly) suggests that people start their own.
I like that one, understandably. And although it's not like I get millions of readers here, I still get a lot more than I ever thought (between 350,000 and 400,000 page views a month these days). Many are people who are already in the sciences, but I continue to hear from readers with no particular science background at all, which makes me very happy indeed.
But how much science do I really get across? Well, it's not like I'm trying to teach people to do drug discovery, since it's unfortunately not well suited to trying at home. What I'd like for all science outreach activities to do, though, is get across what science really is, what research is like, and broadly how it works. There are so many things that people outside the field don't necessarily get to experience or realize: how much time we spend chasing ideas that weren't right, for one. How much time we spend making sure that we made what we thought we made, or that we did what we thought we did, and trying to nail down how much we can believe what we think that we know. How little that is, in many cases, and how we're always getting surprised even in the areas that looked well-understood.
Real scientific research is quite bizarre by the standards of many other occupations, and I don't think that people get to understand that. (I might add that the ways in which science gets compressed for dramatic effect tends to obscure all these things - TV and movie scientists are always so sure of themselves, and get their rock-solid results so quickly). So rather than start off by trying to teach everyone lots of details, I'd rather that more people understood what the whole effort is like. . .
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Emily Yoffe at Slate has a very accurate piece up on just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases. The contrast with the hopes of patients - and the hype often surrounding the initial discoveries - is painful.
And we're back to that optimism/realism tightrope. On the one hand, I don't see any reason why we shouldn't be able - eventually - to stop such conditions in their tracks, or to keep them from starting in the first place. (Reversing the damage once it's done, though, is much more of a stretch, to me). But on the other hand - sheesh, we really, really have a lot to learn about these things. The likelihood of any one discovery being the key breakthrough is small - nonzero, but small. So in the long term, I'm an optimist, but in the short term, well. . .every little bit helps, and most of the bits are going to be little.
That's not the sort of news you want to give to someone suffering from these conditions, of course. That desire for encouraging news, along with plenty of other good intentions (and a few not-so-good-ones) leads to the cycles of hype that we've seen over and over. Stem cell research is a perfect example. There really are huge possibilities there, extraordinary ones. But our level of ignorance is also extraordinary. And to go out and make claims that we're going to be able to cure X and reverse Y soon, based on our present knowledge, is just plain irresponsible.
But plenty of people do just that - politicians, headline writers, and others. And then people who only know what they see in the news wonder where things went wrong, and how come these wonderful cures haven't arrived yet. It all makes explaining the real situation that much harder.
It's not like the real situation is even all that terrible. As I said above, I really do think that these diseases - and many others - are eventually going to be treatable. No one likes that word "eventually", though.
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I'm of two minds on this New York Times article on Alzheimer's research. It details some recent progress on biomarkers for the disease, and that work does look to be useful. A lot of people have proposed diagnostics and markers for Alzheimer's and its progression over the years, but none of them have really panned out. If these do, that's something we haven't had before.
But my first problem is something we were talking about here the other day. Biomarkers are not necessarily going to help you in drug development, not unless they're very well validated indeed. We really do need them in Alzheimer's research, because the disease progression is so slow. And this effort is really the only way to find such things - a good-sized patient sample, followed over many years. But unfortunately, 800 people (divided out into different patient populations) may or may not be enough, statistically. We're now going to have to take the potential assays and markers that this work has brought up and see how well they work on larger populations - that's the only way that they'll be solid enough to commit a clinical trial to them. Both the companies developing drugs and the regulatory agencies will have to see convincing numbers.
That general biomarker problem is something we really can't do anything about; the only cures are time, effort, money, and statistical power. So it's not a problem peculiar to Alzheimer's (although that's a tough proving ground), or to this collaborative effort. But now we come to the collaborative effort part. . .overall, I think that these sorts of things are good. (This gets back to the discussions about open-source drug discovery we've been having here). Bigger problems need sheer manpower, and smaller ones can always benefit from other sets of eyes on them.
The way that this Alzheimer's work puts all the data out into the open actually helps with that latter effect. All sorts of people can dig through the data set, try out their hypotheses, and see what they get. But I think it's important to realize that this is where the benefit comes from. What I don't want is for people to come away thinking that the answer is that we need One Big Centralized Effort to solve these things.
My problem with the OBCE model, if I can give it an acronym, is that it tends to cut back on the number of ideas and hypotheses advanced. Big teams under one management structure don't tend to work out well when they're split up all over the place. There's managerial (and psychological) pressure, from all directions, to get everyone on the same idea, to really get in and push that one forward with all the resources. This is why I worry about all the consolidation in the drug industry: fewer different approaches get an airing when it's all under the roof of one big company.
So this Alzheimer's work is just the sort of collaboration I can admire: working on a big problem, sharing the data, and leaving things open so that everyone with an idea can have a crack at it. I just hope that people don't get the wrong idea.
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+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Press Coverage | Who Discovers and Why
John Lechleiter of Eli Lilly has an op-ed in today's Wall Street Journal on innovation in the US. Needless to say, he's worried:
A recent study ranked the U.S. sixth among the top 40 industrialized nations in innovative competitiveness, but 40th out of 40 in "the rate of change in innovation capacity" over the past decade. The ranking, published last year by the Information Technology and Innovation Foundation, measured what countries are doing—in higher education, investment in research and development, corporate tax rates, and more—to become more innovative in the future. The U.S. ranked dead last.
He goes on to say that we need a climate that appreciates new technology (which I certainly think we have), the financial system to support it (which is where he makes the case for favorable tax treatment), and the people who can do it. That's the longest single section of the whole piece:
The final and most important elements are the seeds of innovation, which equate to talented people and their ideas. Human beings—with their talent and energy, creativity and insights—are a priceless resource, but one that is woefully underdeveloped in this country.
There are three policies necessary to cultivate these seeds of innovation. First, with our kids falling further behind on international comparisons in education, we've got to get serious about broad improvement in science and math instruction in our grade schools and high schools.
Second, we need immigration laws that allow and encourage top scientists from other countries to choose to work in the United States. This does not entail drastic changes, but a sensible increase in visas for highly skilled immigrants and a shorter, simpler green-card application process.
Third, we need a well-funded basic research infrastructure within academic and government labs. What's required is not some new "Manhattan Project," but a long-term funding commitment necessary to attract more outstanding scientists to basic research and keep them engaged in productive work throughout their careers.
Well, there are going to be a lot of people reading this who will snort and say "Great, domestic science policy advice from Lilly, the company that's outsourcing everything short of what has to be picked up by a crane". And that call for better science education, together with the immigration reform paragraph, takes us into the "Danger! Undersupply of Scientists!" territory that drives many actual scientists crazy as they scan the employment ads and reformat their CVs.
I agree that science and engineering should be valued more in this country. But given our culture, what would make it so would be the perception that these fields are great places to have lucrative jobs, and that perception is currently taking an awful beating. Justifiably. So I'm not seeing this as a supply-of-scientists problem, as much as I see it as a shortage-of-ways-for-scientists-to-make-a-living one. . .
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Here's a good piece from Megan McArdle on the pipeline problem in the drug industry. It'll be familiar ground to many readers of this blog (and not just because I was a source for the piece), but it's good to get the word out on these things to as wide an audience as possible.
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A reporter from a major newspaper has contacted me while working on a story about GlaxoSmithKline's new R&D structure. They've noticed a lot of comments to posts here, and wonder if anyone would like to provide their opinions as to how things are going. If anyone's interested, drop me an e-mail, and I'll provide contact information. At that point, I'll drop out of the process entirely.
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The folks at the New Yorker sent along this link to a new article by Malcolm Gladwell about Synta and their attempts to get elesclomol (STA-4783) to work as a melanoma therapy. (If you don't know how this one turns out, you might want to read the article before clicking on that second link).
Update: didn't realize that the full article was subscriber-only at the New Yorker site. Not sure if there's anything to be done about that, but I've dropped them a line. . .
Gladwell (an occasional reader of this blog) often takes some hits from experts in the fields he writes about, but after reading the article this morning, I think he's done a fine job of showing what drug discovery is like. His division between screening and rational drug design is a bit too sharply defined, to my eyes, but he gets all the important stuff right - namely, just how hard a business this is, how much luck is involved, and how much we don't know. Those are messages that a lot of people need to hear, and I hope that this piece helps get them out to a wide audience.
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I'll be traveling Monday, so no new posts during the day. But I'm traveling to something that's of interest to many of the readers here, so I wanted to throw the floor open to questions. I've been invited to be on the editorial advisory board of Chemical and Engineering News, and I'll be meeting with the staff there later this week.
So I wanted to ask the chemists in the crowd: what do you think that C&E News does well, and what do you think it does poorly? Are there topics that you think are covered too much, or some that you think aren't being addressed? Please feel free to add comments - I'll collate them and pass them on to the staff there.
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I haven't written anything about Generex, a company developing an oral insulin spray for Type I diabetes, although they have come up in the comments here once or twice. I'm now regretting my lack of coverage, since if I'd said something uncomplimentary about them (an even bet), I might have had my chance to get sued by them as well. That's what's happening to Adam Feuerstein of TheStreet.com.
Feuerstein wrote two recent columns about the company. The first one was quite skeptical of the company's prospects, saying that he thought the company's Oral-lyn was "a total bust". Said Feuerstein:
"Common sense should tell you that an insulin spray like Oral-lyn is more fiction than science. If Oral-lyn was real, Big Pharma would have snatched up the technology a long time ago. Instead, Pfizer lost millions with an insulin bong, and Al Mann, billionaire healthcare entrepreneur and MannKind's founder, is spending hundreds of millions of dollars of his own money to build another inhalable insulin device. For that kind of money, Mann could have bought Generex several times over. He didn't."
There were also some unkind comments about the way the company touts its regulatory approvals in Ecuador, India, Lebanon and Algeria. (You'll notice that India is by far the most serious regulatory and financial market in that list - read on!) He also had things to say about the size of the company's potential market, given the effectiveness of insulin injections for Type I patients. But his second column (written in response to a flood of e-mail and a hostile legal letter from the company about the first one) was even more blunt:
"The more I dig into Generex Biotechnology(GNBT) and its insulin spray for diabetics, the more preposterous the story becomes. . .it becomes apparent almost immediately that the company is using science and the quest to develop an alternative insulin delivery method not to actually help diabetics but as a ruse to perpetuate a 15 year-long stock promotion scheme. In the process, investors are getting fleeced while Generex management earns millions of dollars in compensation."
Read the rest of his article to get the story on the clinical data, which include things like a ten-day trial in two dozen patients in Ecuador. Actually, that's the centerpiece of the clinical story, come to think of it. The company recently press-released "Successful Phase III Data", although they only had data on 60 patients out of the targeted 750. And so on. No, something seems odd about all this.
If you ask me, Feuerstein's likely in the right here. I, too, have trouble believing that an oral insulin spray can reliably treat the type I diabetes population, for whom careful insulin dosing is crucial. And I think that if there were a realistic chance of that happening, that the likes of Novo Nordisk and Eli Lilly would probably have at least looked into the possibility. And even if they'd missed out, if Generex were the company to discover a real opportunity here, I don't see how they wouldn't be able to raise more money (or do a co-development deal) with more convincing clinical data, if they had any. Why treat a handful of people in Ecuador and let your stock value sit at 60 cents a share, if you have the chance to raise the serious money needed to get a real diabetes therapy through some convincing Phase III trials instead? That's not how this business tends to work.
Generex, though, decided after the second Feuerstein column that they'd had enough, and has sued. For two hundred and fifty million dollars, yet. The company has some very vocal defenders, and I believe that they're completely sincere, but this lawsuit makes me think even less of Generex than I did after reading about their product. Why are they wasting time and money on this sort of thing? These kinds of lawsuits have virtually no chance of going anywhere - the only reason I can see for filing one (if indeed they have) is to get more publicity (and look noble and beleaguered).
The same day the lawsuit was announced, Feuerstein dropped another article into the mix, returning to that regulatory-approval-in-India issue. As it happens, the Indian government revoked the approval a year ago, only three months after the product was offered for sale. You can search (and Feuerstein does, gleefully) through all of Generex's press releases, conference call transcripts, and regulatory filings for any mention at all of this material event. There's nothing. Now, the original approval in India was covered extensively by the company, as you'd imagine, but the withdrawal seems to have passed in total silence - with even a denial last fall that there were any delays or problems in India at all. According to Feuerstein, Generex has completed several financing deals without apparently getting around to mentioning this little detail.
Wagering may now commence as to whether either the lawsuit or the oral insulin spray are going anywhere. If the company really has failed to disclose a material event, though, they may be going somewhere themselves.
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Yesterday's Wall Street Journal ran a story on Eli Lilly, all about how the company is outsourcing a lot of their drug development work. Since Lilly signed a big deal with Covance in 2008 to do just that sort of thing, the first thing you have to wonder is "Is this news?"
But some of the spin in this piece is interesting. Here, see what you think:
Not long ago, a big pharmaceutical company wouldn't have considered farming out the development of a compound found in-house. But expiring patents on top-selling drugs and high-profile failures in finding their replacements have pushed the biggest drug makers to "externalize" much of their R&D, said Peter Tollman, who advises drug makers at Boston Consulting Group. . .
. . .Lilly is relying on outside firms called contract research organizations to do the work. Company researchers, Mr. Tollman said, can get too attached to their own compounds to know when to let them go.
I'm not buying that last part at all. To me, the main reason that Lilly has been using CROs so much (through an R&D unit named Chorus) is that they feel that they can do the job more cheaply. The next most important reasons after that one are (1) that they can do the job for less money, (2) that they can do the job without Lilly spending so much cash, and (3) that they can do the job at lower cost. Have I left anything out?
As a correspondent put it, once you get into the clinic, "the data are the data", whether you're attached to the compound or not. The bigger danger is in how you set up the trials in the first place, whether you've done them in a realistic fashion, and a CRO can fall victim to that just as much as anyone else can. The same incentives are there to fool yourself. So I don't see any special magic in outsourcing clinical work, other than the fact that CROs tend to work their people harder and pay them less money.
To be fair, the rest of the article does show the flip side:
Skeptics say such results may cut R&D costs, but don't address big pharma's main problem of finding new therapies that pan out.
"You get more negative results faster and cheaper," said James Niedel, a former GlaxoSmithKline executive who is now a partner at New Leaf Venture Partners fund. "But the problem with the industry is they're not getting enough positive results and that depends on knowledge and insight about biology and disease" that might be lacking among CROs. . ."Neither the cost cuts nor the structural changes help R&D productivity," said Keyur Parekh, a UBS analyst who thinks Lilly might need to make acquisitions to replenish its pipeline.
Indeed. It's important not to spend money where you don't have to, but it's also important to have things to spend the money on in the first place.
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Forest Labs has done very, very well with Lexapro (escitalopram) over the years. They're a comparatively small company, and their collaboration with Lundbeck (also a comparatively small company) in the antidepressant field has been the biggest event in their history.
Lexapro is the pure enantiomer of the earlier Lundbeck drug Celexa (citalopram), and it's been a very successful follow-on. (For a nasty spat over generic production of citalopram, see here). I'm generally not too keen on the follow-up-with-the-single-enantiomer strategy, I have to say. In general, I think it's slowly disappearing from the world as regulatory agencies look down on racemic mixtures. (I've never worked on a program myself where we seriously considered taking a racemate to the clinic - we always assumed that we'd end up developing a single enantiomer).
The New York Times has an article out detailing some of Forest's marketing plans, as revealed in documents before a Senate committee. Some of what the article has to say I agree with, and some of it I have to raise an eyebrow at, and we'll get to both of those. First off, in an area as large and competitive as antidepressants, I don't think that anyone should be surprised at what was in Forest's plan: lots and lots of lunches for physicians' offices, plenty of continuing medical education lectures (with plenty of food), and so on. One line shows that the company budgeted $34.7 million dollars to pay 2,000 physicians to deliver about 15,000 talks on the drug to their colleagues.
The Senate seems to be shocked at all this - well, pretending to be shocked, because no national politician can ever really be surprised at any way that money is used to influence anyone's decisions. But I'm not shocked, either. Leaving aside (just for a moment) the question of whether drugs should be promoted this way, the fact is that they are promoted this way, and have been for a very long time. And breaking down that lecture figure, that means a bit over $2,000 per lecture, and we don't know if that figure is supposed to cover just the honoraria for the speakers, or the whole cost of the lectures. Even if we assume the former, that comes to nearly eight lectures per physician per year, giving each of them about $17,000, pre-tax. Compared to the cost of advertising in the medical journals, general-interest magazines, or especially on television, that probably represents an excellent return for the money.
And Forest has been spending plenty of it. The article mentions that Vermont, for example, found that Forest (despite their size) was outspent in that state only by Lilly, Pfizer, Novartis, and Merck. Considering that those companies have many more drugs to sell than Forest does, that's an impressive figure. Of course, the only reason you spend money on marketing is to make even more of it back in sales, and they've certainly been doing that, too.
There are several questions here, and perhaps it's best to take them one by one. First off, is Lexapro worth what people (and insurance companies) are paying for it? The snappy economic answer is that of course it is, since that's the price that's willingly being paid, but let's talk utility instead. It does seem to be a good drug, arguably better than many of the others. It's been run head-to-head with Cymbalta (duloxetine), which is no poor performer itself, and shown to be superior And earlier this year, a Lancet article analyzed 117 controlled trials and found that there were clear clinical differences between the various antidepressants, and that Lexapro and Zoloft (sertraline) stood out as better than the rest.
The article recommended starting with the latter in new patients, I should note, and sertraline's now generic. I think that Forest's battle in the market is both against their similarly expensive competitors (where I think that they can claim to have an edge) and against cheap sertraline, where they may well not. (Update: and against their own (now generic) racemate - I'm digging into that comparison, and it'll be the subject of a follow-up post.) That said, depression is a famously heterogeneous field, and patients often have to try several drugs before somethings works, for reasons that are unclear. So yes, overall, I think that Lexapro is a useful drug, and that patients are getting benefit for their money.
The New York Times article is rather disingenuous on this point, by the way - you'd never know from it that there were differences between antidepressants, since they treat Lexapro and Prozac as interchangable, and you'd never know that there was evidence that Forest's drug might well be near the top of the list.
Next question: is Lexapro worth what Forest is spending to promote it? That question also splits into two, economically, depending on what we mean by "worth". As in the price question, from a strictly accounting perspective, we have to presume that Forest is seeing a financial benefit from their marketing activities; marketing does not run at a loss, not for long, it doesn't. And from a utility/societal benefit perspective, if Lexapro really is superior to most of their competitors, then I think the company is justified in making that case as loudly as they can.
Now we get to the tough one: are Forest's marketing activities appropriate or ethical? The arguing can now commence, because this is where we try to figure out what "as loudly as they can" actually means. I think the industry would be better off if there were less of an arms race in the marketing area. (Update: just to pick one benefit, it would make us look, in general, less sleazy, which is not to be underestimated). Even though marketing doesn't run at a loss, the return from it could be still higher if it were less expensive to do. Huge sales forces are expensive, and one of the reasons the sales forces are so big is that the competition's sales forces are so big, and so on. It's hard for any one company to climb down from its position, just from a game-theory point of view, so the most likely way for this to happen is through across-the-board restrictions on marketing, as enforced by the FDA, the FTC, or by physicians themselves. (I should mention, though, that there has been a voluntary retreat in the area of brand-covered swag). We're already seeing this pendulum swing back in the last few years, and it's fine with me if the process continues for a while longer. Doctors are perfectly free to close their doors in the faces of drug reps, and if I were in their position, I'd be tempted to do just that in many cases.
So if we come back around to that Times headine, it reads "Document Details Plan to Promote Costly Drug". And to that, I can say yes, it's a costly drug, set as high as the company thinks that people will pay for it, and to a level that they think they can make the most money with before its patent expires. And yes, Forest has a plan to maximize those profits, and if I were a shareholder (I'm not), I'd be righteously steamed if they didn't. And they did indeed write that plan down, so there are plenty of documents. I'd rather, myself, that the plan looked different than it does, and that's the way the world seems to be heading. But no matter what regulations come into force, there will always be plans to promote things that cost money.
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Moore's Law: number of semiconductors on a chip doubling every 18 months or so, etc. Everyone's heard of it. But can we agree that anyone who uses it as a metaphor or perscription for drug research doesn't know what they're talking about?
I first came across the comparison back during the genomics frenzy. One company that had bought into the craze in a big way press-released (after a rather interval) that they'd advanced their first compound to the clinic based on this wonderful genomics information. I remember rolling my eyes and thinking "Oh, yeah", but on a hunch I went to the Yahoo! stock message boards (often a teeming heap of crazy, then as now). And there I found people just levitating with delight at this news. "This is Moore's Law as applied to drug discovery!" shouted one enthusiast. "Do you people realize what this means?" What it meant, apparently, was not only that this announcement had come rather quickly. It also meant that this genomics stuff was going to discover twice as many drugs as this real soon. And real soon after that, twice as many more, and so on until the guy posting the comment was as rich as Warren Buffet, because he was a visionary who'd been smart enough to load himself into the catapult and help cut the rope. (For those who don't know how that story ended, the answer is Not Well: the stock that occasioned all this hyperventilation ended up dropping by a factor of nearly a hundred over the next couple of years. The press-released clinical candidate was never, ever, heard of again).
I bring this up because a reader in the industry forwarded me this column from Bio-IT World, entitled, yes, "Only Moore's Law Can Save Big Pharma". I've read it three times now, and I still have only the vaguest idea of what it's talking about. Let's see if any of you can do better.
The author starts off by talking about the pressures that the drug industry is under, and I have no problem with him there. That is, until he gets to the scientific pressures, which he sketches out thusly:
Scientifically, the classic drug discovery paradigm has reached the end of its long road. Penicillin, stumbled on by accident, was a bona fide magic bullet. The industry has since been organized to conduct programs of discovery, not design. The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident. This approach is perhaps best characterized by the Chief Scientific Officer of a prominent biotech company who recently said, "Drug discovery is all about passion and faith. It has nothing to do with analytics."
The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor's jungle brew is not science. It's desperation.
The only way to escape this downward spiral is new science. Fortunately, the fuzzy outlines of a revolution are just emerging. For lack of a better word, call it Digital Chemistry.
The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor's jungle brew is not science. It's desperation.
The only way to escape this downward spiral is new science. Fortunately, the fuzzy outlines of a revolution are just emerging. For lack of a better word, call it Digital Chemistry.
And when the man says "fuzzy outline", well, you'd better take him at his word. What, I know you're all asking, is this Digital Chemistry stuff? Here, wade into this:
Tomorrow's drug companies will build rationally engineered multi-component molecular machines, not small molecule drugs isolated from tree bark or bread mold. These molecular machines will be assembled from discrete interchangeable modules designed using hierarchical simulation tools that resemble the tool chains used to build complex integrated circuits from simple nanoscale components. Guess-and-check wet chemistry can't scale. Hit or miss discovery lacks cross-product synergy. Digital Chemistry will change that.
Honestly, if I start talking like this, I hope that onlookers will forgo taking notes and catch on quickly enough to call the ambulance. I know that I'm quoting too much, but I have to tell you more about how all this is going to work:
But modeling protein-protein interaction is computationally intractable, you say? True. But the kinetic behavior of the component molecules that will one day constitute the expanding design library for Digital Chemistry will be synthetically constrained. This will allow engineers to deliver ever more complex functional behavior as the drugs and the tools used to design them co-evolve.
How will drugs of the future function? Intracellular microtherapeutic action will be triggered if and only if precisely targeted DNA or RNA pathologies are detected within individual sick cells. Normal cells will be unaffected. Corrective action shutting down only malfunctioning cells will have the potential of delivering 99% cure rates. Some therapies will be broad based and others will be personalized, programmed using DNA from the patient's own tumor that has been extracted, sequenced, and used to configure "target codes" that can be custom loaded into the detection module of these molecular machines.
Look, I know where this is coming from. And I freely admit that I hope that, eventually, a really detailed molecular-level knowledge of disease pathology, coupled with a really robust nanotechnology, will allow us to treat disease in ways that we can't even approach now. Speed the day! But the day is not sped by acting as if this is the short-term solution for the ills of the drug industry, or by talking as if we already have any idea at all about how to go about these things. We don't.
And what does that paragraph up there mean? "The kinetic behavior. . .will be synthetically constrained"? Honestly, I should be qualified to make sense of that, but I can't. And how do we go from protein-protein interactions at the beginning of all that to DNA and RNA pathologies at the end, anyway? If all the genomics business has taught us anything, it's that these are two very, very different worlds - both important, but separated by a rather wide zone of very lightly-filled-in knowledge.
Let's take this step by step; there's no other way. In the future, according to this piece, we will detect pathologies by detecting cell-by-cell variations in DNA and/or RNA. How will we do that? At present, you have to rip open cells and kill them to sequence their nucleic acids, and the sensitivities are not good enough to do it one cell at a time. So we're going to find some way to do that in a specific non-lethal way, either from the outside of the cells (by a technology that we cannot even yet envision) or by getting inside them (by a technology that we cannot even envision) and reading off their sequences in situ (by a technology that we cannot even envision). Moreover, we're going to do that not only with the permanent DNA, but with the various transiently expressed RNA species, which are localized to all sort of different cell compartments, present in minute amounts and often for short periods of time, and handled in ways that we're only beginning to grasp and for purposes that are not at all yet clear. Right.
Then. . .then we're going to take "corrective action". By this I presume that we're either going to selectively kill those cells or alter them through gene therapy. I should note that gene therapy, though incredibly promising as ever, is something that so far we have been unable, in most cases, to get to work. Never mind. We're going to do this cell by cell, selectively picking out just the ones we want out of the trillions of possibilities in the living organism, using technologies that, I cannot emphasize enough, we do not yet have. We do not yet know how to find most individual cells types in a complex living tissue; huge arguments ensue about whether certain rare types (such as stem cells) are present at all. We cannot find and pick out, for example, every precancerous cell in a given volume of tissue, not even by slicing pieces out of it, taking it out into the lab, and using all the modern techniques of instrumental analysis and molecular biology.
What will we use to do any of this inside the living organism? What will such things be made of? How will you dose them, whatever they are? Will they be taken up though the gut? Doesn't seem likely, given the size and complexity we're talking about. So, intravenous then, fine - how will they distribute through the body? Everything spreads out a bit differently, you know. How do you keep them from sticking to all kinds of proteins and surfaces that you're not interested in? How long will they last in vivo? How will you keep them from being cleared out by the liver, or from setting off a potentially deadly immune response? All of these could vary from patient to patient, just to make things more interesting. How will we get any of these things into cells, when we only roughly understand the dozens of different transport mechanisms involved? And how will we keep the cells from pumping them right back out? They do that, you know. And when it's time to kill the cells, how do you make absolutely sure that you're only killing the ones you want? And when it's time to do the gene therapy, what's the energy source for all the chemistry involved, as we cut out some sequences and splice in the others? Are we absolutely sure that we're only doing that in just the right places in just the right cells, or will we (disastrously) be sticking in copies into the DNA of a quarter of a per cent of all the others?
And what does all this nucleic acid focus have to do with protein expression and processing? You can't fix a lot of things at the DNA level. Misfolding, misglycosylation, defects in transport and removal - a lot of this stuff is post-genomic. Are we going to be able to sequence proteins in vivo, cell by cell, as well? Detect tertiary structure problems? How? And fix them, how?
Alright, you get the idea. The thing is, and this may be surprising considering those last few paragraphs, that I don't consider all of this to be intrinsically impossible. Many people who beat up on nanotechnology would disagree, but I think that some of these things are, at least in broad hazy theory, possibly doable. But they will require technologies that we are nowhere close to owning. Babbling, as the Bio-IT World piece does, about "detection modules" and "target codes" and "corrective action" is absolutely no help at all. Every one of those phrases unpacks into a gigantic tangle of incredibly complex details and total unknowns. I'm not ready to rule some of this stuff out. But I'm not ready to rule it in just by waving my hands.
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What's really going on with Medarex and ipilimumab? The company made news over the weekend with a press release from the Mayo Clinic, detailed what appears to be a substantial response in two prostate cancer patients. But the more you look at the story, the harder it is to figure out anything useful.
As this WebMD piece makes clear, this study is not a trial of ipilimumab as a single agent. The patients are undergoing prolonged androgen ablation, the testosterone-suppressing therapy that's been around for many years and is one of the standard options for prostate cancer. The trial is to see if ipilimumab has any benefit when it's added to this protocol - basically, to see if it can advance the standard of care a bit.
WebMD quotes Derek Raghavan at the Cleveland Clinic as saying that androgen ablation can sometimes have dramatic results in patients with locally advanced prostate cancer, so it's impossible to say if ipilimumab is helping or not. That's why we run clinical trials, you know, to see if there's a real effect across a meaningful number of patients. But (as this AP story notes) we don't know how many patients are in this particular study, what its endpoints are, or really anything about its design. All we know is that two patients opted out of it for surgery instead. (Credit goes to the AP's Linda Johnson for laying all this out).
Ipilimumab is an antibody against CTLA-4, which is an inhibitory regulator of lymphocytes. Blocking it should, in theory, turn these cells loose to engage tumor cells more robustly. (It also turns them loose to engage normal tissue more robustly, too - most of the side effects seem to be autoimmune responses like colitis, which can be very severe. The antibody has been studied most thoroughly in melanoma, where it does seem to be of value, although the side effect profile is certainly complicating things.
So overall, I think it's way too early to conclude that Medarex has hit on some miracle prostate cure. This press release, in fact, hasn't been too helpful at all, and the Mayo people really should know better.
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There's a report over at Genetic Future of some problems stemming from blogging a scientific meeting at Cold Spring Harbor. The organizers have a rule that reporters have to obtain permission from speakers before writing up a story on any given presentation, but no one thought about whether this covered bloggers. This caused a dispute between the blog's owner, the conference organizers, and Genomeweb about what was going on, and whose rules applied to whom.
This is a particular case of the larger blogs-versus-journalism question. I think it's being resolved the right way: Cold Spring Harbor Labs will apply the same rules to people blogging, tweeting, or what have you as apply to people writing up stories for more conventional outlets. That makes sense to me, because in each case, there's a report for public consumption on what's being presented. What sort of medium it appears on (newsprint, glossy paper, or pixels) shouldn't matter. Neither, actually, should the issue of whether the piece will earn the writer any money or whether that's the writer's full-time job.
In any of these cases, the writer has an obligation to present an accurate report, of course. That's one factor where science journalism (be it amateur or pro) has a potential edge on, say, politics. In the end, science isn't (or shouldn't be) so much a matter of opinion, of who yells the loudest or who has the most persuasive speaking style. The ideas and the data should speak for themselves, and conference reporting should, ideally, help them to do so.
I think that conference organizers should first be aware that people could be live-blogging. But after that, I think that they should be encouraging it. Information, as they say, wants to be free. And scientific meetings are one of the ways that it takes wing.
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Last week's discussions around here about the merits (and demerits) of pharma-industry research seem to be coming at what's either a really good or a really bad time. Take a look at this Washington Post article on the handling of clinical data at AstraZeneca.
These details have come up during a large array of lawsuits over Seroquel (quetiapine). And if they're as represented in this article, it doesn't make AZ's marketing folks look very good, and (by extension) the rest of the industry's. We shouldn't be doing this sort of thing, on general principle. But if that's not enough, and it probably isn't, here's a more practical concern: does it take much imagination or vision to think that, with all kinds of health care reform ideas in the air, this sort of behavior might just make Congress want to reform our industry really good and hard?
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So, in light of the Reuben scandal of forged data about pain management in surgery patients, the question naturally comes to mind: how much role did industry play? I've seen articles (and had comments here) to the effect that industry-sponsored research is worthless: discount it, can't trust it, bought and paid for, and so on.
The problem is, you can't completely shake that accusation. Industries (and not just the drug industry, by any means) are willing to pay for results that tell them what they want to hear. And while at times that's crossed over into outright fraud, many times it's just that you can set up all kinds of studies, in all kinds of ways, and get all kinds of answers. Run enough of them, and you can choose the ones you like and pretend the others aren't there.
The whole idea of scientific research is that you don't operate like this, of course, and eventually these things do get settled out. If the drug industry really did make sure that only happy results came out, we'd never have catastrophic clinical trial failures, and never have any drugs recalled from the market. And things like the (Nobel-worthy) H. pylori story behind stomach ulcer formation never would have seen the light of day if the industry were capable (on the other hand) of burying everything it didn't want to hear about.
But there are biases, real and potential, and they always have to be looked out for. One error, though, is to assume that these biases can be eliminated by turning to academic research instead. That's the point of a recent Op-Ed in the Washington Post by David Shaywitz, who's worked both sides of the business:
Part of the problem is that we've been conditioned to trust university research. It is based, after all, on the presumably lofty motives of its practitioners. What's not to like about science carried out by academics who have nobly dedicated their lives to understanding the unknown, furthering knowledge and serving humanity?
. . .University researchers are in a constant battle for recognition and the rewards associated with success: research space, speaking engagements, funding and autonomy. Consequently, while academic research is often described as "curiosity-driven," the reality is messier, as (curiously) many researchers tend to pursue the trendiest technologies and explore topics that happen to be associated with the most generous levels of research support.
Moreover, since academic success is determined almost exclusively by the number and prestige of research publications, the incentives to generate results are exceedingly powerful and can encourage investigators to see patterns that may not exist, to disregard contradictory observations that might be important, to overvalue data that might be preliminary or unreliable, and to embrace conclusions that deserve to be viewed with far greater skepticism.
. . .University researchers are in a constant battle for recognition and the rewards associated with success: research space, speaking engagements, funding and autonomy. Consequently, while academic research is often described as "curiosity-driven," the reality is messier, as (curiously) many researchers tend to pursue the trendiest technologies and explore topics that happen to be associated with the most generous levels of research support.
Moreover, since academic success is determined almost exclusively by the number and prestige of research publications, the incentives to generate results are exceedingly powerful and can encourage investigators to see patterns that may not exist, to disregard contradictory observations that might be important, to overvalue data that might be preliminary or unreliable, and to embrace conclusions that deserve to be viewed with far greater skepticism.
Shaywitz goes on to make the same point I did above - that the system is ultimately self-correcting - but is calling for people to recognize that academic research is also done by human beings, with all that entails. John Tierney at the New York Times had taken up this topic last fall, and wondered about what would happen if enough researchers decided to stop taking industry funding because they were tired of having their integrity questioned.
Tierney's responded to the Shaywitz piece now as well. The comments from his readers are all over the place each time. Some of them are (correctly, to my mind) going along with the idea that research always comes in with various potential biases and agendas, and should be judged case-by-case no matter the source. There are, naturally, some who aren't buying anything that might get industrial research off the hook.
"In industry sponsored comparative studies of medical treatments, the sponsor's product always comes out on top," says one commenter there. But that's not true. I can give you plenty of examples right off the top of my head. For sure, we try to run studies that will show a benefit for our therapies - but we also have to pin these down to the real world for people (and the FDA) to have a better chance of trusting the results. We're not going to set up a trial that we have good reason to think will fail: life is too short, and the supply of funds is not infinite. You target the diseases (and the patients) that you think will benefit the most (and show the most impressive results, naturally).
And that's a bias to consider right there: we don't set up our trials randomly, so keep that in mind. But no one sets up drug trials randomly, anywhere. There's always a reason to do something so expensive and time-consuming - you should always keep that in mind, weigh it in your calculations, and decide from there.
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As you may well have heard by now, Ben Goldacre over at Bad Science has been involved in a wonderful altercation with both the anti-vaccination people there and with one of London's big talk radio stations, LBC. And yes, this is happening just as Andrew Wakefield, one of the originators of the whole MMR vaccine flap, is being accused of falsifying data to make his case.
The full story can be found on Goldacre's blog; see the link above for a starting point. The short version: LBC allowed Jeni Barnett, an outspoken opponent of vaccination, to vent her views for some 45 minutes in a prominent time slot. As Goldacre points out, she seems to have covered every possible anti-vaccine trope, despite the fact that some of them were mutually contradictory and many of them made little sense to start with. The British media – many parts of it, anyway – has not covered itself in glory on the whole vaccine-risk story, and this latest outburst was too much for Goldacre to take.
He posted the entire audio of the LBC show on his website, and that brought on threats of legal action from the radio station. And that move, as anyone who's hung around the internet can tell you, made sure that the audio was immediately scattered around the world, with commentary, transcripts, and plenty of bad publicity. (You can find plenty of links to all of it here; I'm late to this particular party myself).
Goldacre makes an important point, one that's been made before but has to be kept in mind when you're listening to the news coverage of any disputed issue. He quotes Jeni Barnett as:
". . . explaining endlessly that all she wanted to do was "start a debate" (because in the media everything is 50:50, and the truth lies exactly half way between the two most extreme views)
He's right; you run into that sort of thing all the time – readers who've had occasion to deal with Intelligent Design people and other creationists will recognize it immediately. "Teach the controversy" "Let's hear both sides of the debate", and all that. It's another example of the disconnect between science works (or should work) and the political and social arenas. There are some big differences in the way disputes are resolved.
One of them is that, to a certain degree, questions do not remain open in scientific debate in the same way they do in politics. Fistfights are currently erupting over whether Keynes had a point about deficit spending in a recession (and if he did, how much is appropriate and in what way). Huge, ever-inflamed arguments take place over welfare, regulatory policy, defense spending, and other perennials. There are more than two sides to these kinds of issues. But come over here to the scientific world, where gravity really does diminish as the square of the distance between two objects; bacteria really do cause infections; sodium really reacts with water and yes, living organisms do evolve and change over time. Proclaiming that you disagree with these things just because you don't like them, just think that they're wrong, or don't happen to believe them will get you nowhere in scientific debate. (That's as opposed to political or religious debates, where those are all-too-common starting points).
But, at the same time, every question in science is potentially open. Look at all those facts I listed above – you can find ways around all of them. Gravity stops behaving in a perfect inverse-square way close to large masses. Not all bacteria cause infections, of course, and not all infections are caused by bacteria - and some bacteria that might kill one person could cause no problems for someone else. Sodium doesn't do anything spectacular at all when it's in the plus-one oxidation state, and even the metal probably doesn't do much when exposed to water at, say, three degrees Kelvin. And organisms evolve at startlingly different rates and through a variety of mechanisms.
These two simultaneous principles – that questions really do get answered, but that the answers are always open to question – are what puzzle a lot of people about science. And they don't fit well with the way that many people are used to arguing about issues. They can dwell on the first point and whack the scientific community over the head for having closed minds and unchallenged dogmas, or dwell on the second and claim that hey, they're all unproven theories, and here are some more theories to put on the table while we're at it.
But if you're going to challenge some science that we think we understand, you're going to have to bring the data. The bigger the topic, the better the evidence you're going to need. You can do it – all kinds of cherished theories have gone down – but it's not easy. If you're going to claim that evolution doesn't happen, or that we're thinking about it all wrong, you'd better have some really impressive evidence (and coming up with an alternative with the same kind of explanatory power would help, too). If you're going to claim that vaccines do more harm than good, or that they're the cause of a specific terrible condition, you'd better have the numbers to back it up, not a mish-mosh of talking points.
Einstein's work, for example, has stood up against all comers, taking on all kinds of extraordinarily painstaking experimental tests and passing every single one of them. If you're going to beat relativity, you're going to have to show up with absolutely epic skills. And that brings up a last point. When Einstein explained Mercury's orbit (and more besides), he didn't come in proclaiming that Newton was an idiot and that he'd gotten it all wrong. Isaac Newton, though an exceptionally weird human being, was very far indeed from being an idiot. No, relativity shows how under "normal" circumstances, Newton's gravitational laws work wonderfully. Then it shows under what conditions they go off track, and predicts when that will happen and exactly to what degree. If you're going to proclaim any new way of looking at the scientific evidence, you're going to have to show how your breakthrough allows for something new to be seen, and you're going to have to call your shots and be ready for the experimentalists to have a crack at you.
I find all this wonderfully exciting, and I've devoted my career to it. But it doesn't necessarily make for a quick TV or radio segment that will bring in a big audience, stir up a lot of noise and chatter, and (most importantly) raise the advertising rates. For that, you want politics, religion, or some tasty mixture thereof. . .
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+ TrackBacks (0) | Category: Autism | Current Events | Press Coverage | Who Discovers and Why
Update: a follow-up post is here, for those who want more on Qi Gong, placebo effects and the like.
Well, we don't even know who the new FDA commissioner is going to be under the Obama administration, but people are already making their bid for a change in direction. In Friday's Wall Street Journal, you can find Deepak Chopra, Rustum Roy, and Andrew Weil with an op-ed titled "Alternative Medicine is Mainstream". I think you can go ahead and silently append ". . .And Deserves Serious Mainstream Funding".
My hopes for this piece were not high – Deepak Chopra, for one, I consider to be an absolute firehose of nonsense. Both he and Andrew Weil should be whacked with sticks every time they say the word "quantum". But they manage to avoid that one here - the op-ed turns out to be a marbled blend of things that I can agree with and things that make me raise both eyebrows. Its general thrust is:
1. Chronic diseases related to lifestyle (diet, physical habits, etc.) account for a large percentage of health care costs. These could be ameliorated or downright prevented through changes that don't involve medical procedures.
2. "Integrative medicine" (by which the authors mean, among other things, plant-based diets, yoga, meditation, acupuncture and herbal therapies, have been shown (they claim) to help with such lifestyle changes, and with less expense. The definition of integrative medicine is not provided, nor is the boundary line between it and "regular" (disintegrative?) medicine drawn.
3. Therefore, the incoming administration should make these a big part of the health care system as soon as possible. Did we mention the funding?
Now, I can't argue with that first point. Cardiovascular disease and Type II diabetes could both be much smaller problems if people in the industrialized nations would just eat less food (and better food) and exercise more. The editorial makes it sound as if no one believes this or has ever heard of such a thing, but come on. No one's heard anything else for decades. However, it seems equally clear that jawboning people about this issue does not do nearly as much good as one might hope.
Whether "integrative medicine" is any more effective is something that I would very much like to see someone prove. The authors seem to be familiar with a bunch of well-controlled studies that I haven't heard about, and I invite them to trot out some data. But some of the statements in the op-ed make me think that my cardiovascular health won't be able to stand it if I hold my breath while waiting for that. For example, we have:
"Chronic pain is one of the major sources of worker's compensation claims costs, yet studies show that it is often susceptible to acupuncture and Qi Gong. Herbs usually have far fewer side effects than pharmaceuticals".
Studies show, do they? Is there really a believable study that shows that Qi-freaking-Gong, of all things, is good for chronic pain? Ancient hokum about "energy fields" and "life force" does the trick, does it? My idea of a good trial of Qi Gong would involve one group of patients getting the full hand-waving treatment according to the best practitioners of the art. The other cohort gets random hand motions from a system I will gladly invent on request, and which I will have to be forcibly restrained from naming Don Ki Kong. It'll be full of talk about holistic energies and connections to the universal flow, don't you doubt it, and I'll round up some impressive-looking worthies to administer the laying on of hands. Their passes and taps will be carefully screened by the Qi Gongers beforehand to make sure that none of them, according to their system, have any chance of actually having any effects on the Qi (assuming that any of them can agree). We call that a controlled trial to investigate placebo effects.
And I hardly know where to start with those beneficial herbs. The literature I've been reading has been showing that many of the herbal treatments show no effects when they're looked at closely – St. John's Wort, Echinacea, and so on. The larger and more well-run the trial, the smaller the effects go, in too many cases. But I have no problem with the idea that plants and plant extracts can have medicinal effects, of course: they're full of chemicals. My whole career is predicated on the idea that taking chemicals of various sorts can alter one's health. Where I jump off the parade float is at the nature's-bounty-of-beneficial-herbs stuff, the idea that things are somehow more benign because they come from natural sources. Vitalism, they used to call that. It's hooey. Strychnine. Ricin. Come on.
The editorial is full of fountains of happy talk like this one:
Joy, pleasure and freedom are sustainable, deprivation and austerity are not. When you eat a healthier diet, quit smoking, exercise, meditate and have more love in your life, then your brain receives more blood and oxygen, so you think more clearly, have more energy, need less sleep. Your brain may grow so many new neurons that it could get measurably bigger in only a few months. Your face gets more blood flow, so your skin glows more and wrinkles less. Your heart gets more blood flow, so you have more stamina and can even begin to reverse heart disease. Your sexual organs receive more blood flow, so you may become more potent -- similar to the way that circulation-increasing drugs like Viagra work.
Calling Dr. Love! All I have to do is change one letter in my last name, and I'm in business, expanding brains and other useful body parts. Unfortunately, that first sentence typifies a lot of thinking in this area. It's one of those "isn't it pretty to think so" statements. As far as I can see, deprivation and austerity have been the norm for most people throughout most of human history, even though they were eating natural foods and getting lots of exercise and fresh air. And one of the big reasons that people put on weight is that they have the freedom to experience the joy of tasty food a bit too often. No, this is noble-sounding stuff, but there's nothing behind it.
Update: Orac's take, with more on those "studies".
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+ TrackBacks (0) | Category: Press Coverage | Snake Oil
I have a few short links for everyone today. One series of posts that you might not have seen from Xconomy is a tour of the technological hot spots of India by Boston University's Vinit Nijhawan. It's interesting stuff for people like me who haven't been to the country, and he isn't shy about pointing out both the good and the bad about India's current situation. He's not focusing on the chemistry/pharmaceutical sector, but it's an interesting read in general. I would very much enjoy seeing a similar series written from China - perhaps the Xconomy folks are working on that one?
Next: if Sanjay Gupta really is going to be surgeon general (and why not?), it's worth watching his exchange with Michael Moore when Moore's movie "Sicko" came out. This is a 17-minute YouTube clip, and you may not make it through if you can't stand Michael Moore, but it has some good moments. Gupta is a *lot* more reasonable dealing the Moore than I would have been, but gets hammered on for his pains anyway.
And here's an interesting one, from a financial standpoint. Raising money for startup companies has, in the last few months, gone from the usual state of "not so easy" to "nearly impossible". Everyone's hoping for that to improve, but for now, this is a nasty time to try to float a new startup. That goes for follow-on financing, too, naturally, and that can hurt even more than troubles with start-up money. You can potentially delay the launch of your new venture – after all, no one else is getting anything off the ground, either – but if you're already got a company going, the funds need to keep flowing. Companies that lined up more money in the middle of 2007 are shivering over the narrowness of their escape.
So it's impressive that an outfit called Satori Pharmaceuticals has made it through a full round of venture funding, and for Alzheimer's therapies, no less. That's a notorious graveyard for good ideas, but (at the same time) it's equally notorious for being hugely under-served. Good luck to them - they'll need it (and don't we all?)
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+ TrackBacks (0) | Category: Alzheimer's Disease | Current Events | Press Coverage
I noted with sadness yesterday that Ed Silverman has packed in the Pharmalot blog. He did an excellent job there, picking up a lot of industry news from all over. Most of it was in the "Trouble for Company X" vein, but that's to be expected. Ed's a good reporter, and "Things Going Fine Over at Company X" is not much of a story. If this item is correct, though, we'll be seeing more of him, which I'm glad to hear. The newspaper business is in even worse shape than the drug industry, so I'm glad to see it when someone there lands safely. (People still need pharmaceuticals; they're not so sure if they need newspapers so much).
Today's ration of scientific confusion comes courtesy of Wired, in an article that talks about using a modified form of TMV (tobacco mosaic virus) for delivering silencing RNAs. A group at Maryland has used the virus to deliver various siRNAs to cell lines in vitro, which is an interesting idea. But then it gets the Wired treatment:
The short, double-stranded RNA molecules known as siRNA can program cells to destroy disease-causing proteins. Their molecules turn on a cell's own built-in disease-fighting mechanisms. They can be programmed for a wide range of ailments -- from cancers to viruses -- and because they use the cell's own defense mechanisms, they produce minimal side effects.
In addition to treating cancers and genetic disorders, siRNA could prove useful against a variety of rare diseases that have, and always will be, overlooked by big pharmaceutical companies -- the long tail of disease.
People suffering from similar, exotic maladies could band together and recruit a small team of scientists, as if they were the Seven Samurai, to champion their cause and quickly design a cure.
In addition to treating cancers and genetic disorders, siRNA could prove useful against a variety of rare diseases that have, and always will be, overlooked by big pharmaceutical companies -- the long tail of disease.
People suffering from similar, exotic maladies could band together and recruit a small team of scientists, as if they were the Seven Samurai, to champion their cause and quickly design a cure.
Let's unravel some of that yarn. What siRNA does, actually, is cause proteins not to be produced, rather than "program cells" to destroy them. The effect lasts for as long as the siRNA is present, so I wouldn't use the analogy to programming. And it's true that siRNAs can "turn on a cell's own built-in disease-fighting mechanisms", but that's mostly considered an undesired off-target side effect, which people are still trying to get a handle on. You don't want to set off immune responses to your RNA therapies, believe me.
And in the next sentence, we get to hear more about programming. But what's glossed over is that we don't know how to "program" siRNAs for a wide range of ailments yet, because in most cases we don't know what causes a wide range of ailments to start with. If you don't know what protein you want to knock down, you're not going to get very far with siRNA. And what about the diseases that aren't caused by single proteins (which is most of them?) Putting cancer in a list like that is a sure sign that the author is either exaggerating or doesn't understand what's going on, because cancer is not a disease. It's several thousand diseases, each of which may need to be addressed differently if we're going to use the word "cure".
The next paragraph works in the "long tail" concept, another hook for the intended audience. But look, for example, at something like Gaucher's disease, which you'd think was pretty far down that tail. Genzyme is doing tremendous business there, because they actually have something – basically the only thing - that helps. For many of these obscure conditions, it's not so much that we in the drug industry don't do anything, it's that we don't know what to do. And if we're going to work on something that we're not sure we can treat or not, which is the usual situation, we'd rather take our chances on something more potentially lucrative.
And that last line, with the Kurosawa reference, is just great. Programming, long-tail, classic foreign movies – this piece must have gone through the editorial process at Wired in about ten minutes. I'll bet my readers in the drug industry are wondering how they can get together in small teams, whip out their samurai swords, and quickly design cures – admit, you are, aren't you? Well, the next paragraph of the piece quotes Stephen Hyde of Oxford:
" "The speed with which you develop siRNA drugs is truly amazing," said Stephen Hyde. "In the past, a traditional small molecule drug might take several years of intensive research effort by a large team of scientists to develop. Today, with siRNA technology, it is possible for a single researcher to develop a drug candidate in a few weeks."
It's hard to know which end of that statement to untangle first. If you know exactly which protein you want to target for a disease, then yes, you can then know what sort of siRNA sequence you want to try to knock it down. But is that a drug, as the first line suggests? Nowhere near. Sad to say, you still have those years and years of clinical testing for safety and efficacy to go through.
Now, where Prof. Hyde's statement makes some sense is in the preclinical world. It does take longer for a team of chemists and biologists to come up with a small-molecule drug candidate, and that's where the promises of siRNA (and antisense DNA) come in. If you're targeting the expression of a particular protein (a big if, as I've said), then you immediately have a relatively short list of sequences to try, as opposed to the wide-open world of small molecule screening. Chemistry really is only one way to get to a drug candidate, and just because it's been the way for most drugs until now doesn't mean it always will be.
But it's not going to go away, either. Small molecules can do things that changes in protein expression can't – we can make agonists and antagonists of receptors, for one thing, and we can make inhibitors with varying selectivities across related targets. And there will always be diseases – the majority of diseases – where several things will have to be affected at the same time for any kind of cure to be realized. We're going to need all the modes of attack we can get.
The rest of the Wired article, to its credit, does mention the single biggest problem with siRNAs: their delivery in vivo. And if you get down to the last few sentences, you can find out that the TMV delivery system has not yet been shown to work in a living animal, could cause immune responses even when it does, and has (as yet) no way to target its delivery to a specific cell population. It is, in other words, an ingenious idea – one of many – that has a long way to go before it sees a sick patient. And we have a long way to go before we have seven-scientist samurai teams cranking out cures in a few weeks. Perhaps we'll live long enough to see it.
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+ TrackBacks (0) | Category: Drug Development | Press Coverage
A good rule to follow: hold onto your wallet when two exciting, complicated fields of research are combined. Nature reported earlier this spring on a good example of this, the announcement by a small biotech called Primegen that they'd used carbon nanotubes to reprogram stem cells. (Here's a good article from VentureBeat on the same announcement, and there's an excellent piece on the announcement and the company in Forbes).
Stem cells and nanostructures are two undeniably hot areas of research. And also undeniable is that fact that they're both in their very early days - the amount of important information we don't know about both of these topics must be really impressive, which is why so many people are beavering away at them. So what are the odds of getting them to work together? Not as good as the odds that someone thought the combination would make a good press release, I'm afraid.
The PrimeGen web site, though a bit better than that VentureBeat article describes it, still has some odd notes to it. I particularly like this phrase: "PrimeGen's broad intellectual property portfolio is founded on groundbreaking platform technologies invented by our team of dedicated and visionary scientists." Yep, we talk that way all the time in this business. You also have to raise an eyebrow at this part: "Disease and injury applications of PrimeCell™ include Alzheimer's Disease, Cardiac Disease, Diabetes, Lupus, Multiple Sclerosis, Leukemia, Muscular Dystrophy, Parkinson's Disease, Rheumatoid Arthritis, Spinal Cord Injury, Autoimmune Disease, Stroke, Skin Regeneration and Wound Healing." It'll mow your yard, too, if you're willing to participate in the next funding round.
The next sentence is the key one: "The extent to which stem cells can be used to treat injury and illness has yet to be fully evaluated. . ." You can say that again! In fact, I wouldn't mind seeing that in 36-point bold across the top of every stem cell company web page and press release. But what are the chances of that? As good as the chance that nanotechnology will suddenly going provide us a way to make the stem cells do what we want, I'm afraid. . .
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There's talk again about an idea that's been kicking around for some years: are drug companies shielded from liability after the FDA has approved their drugs for sale?
Obviously, the current answer is "Not at all": consider the lawsuits over Vioxx. But the decision by the Supreme Court in February in Riegel v. Medtronic has the idea being taken seriously again. That ruling seems to shield medical device companies from lawsuits over safety or efficacy after the FDA has signed off on those issues - as long as the device is the same, and used in the approved manner. And no, for the politically motivated among the readership, this wasn't some barely-realized 5:4 scheme from Justice Scalia; the decision went 8 to 1.
There's a roughly similar case before the court now, Wyeth v. Levine. At issue is the labeling and usage of Wyeth's histamine antagonist Phenergan (promethazine), with the suit being brought by a patient who was injured after the drug was used in a method warned against on the label. This one hinges on a federal/state dispute, though, as the petition for certiorari (PDF) makes clear:
"Whether the prescription drug labeling judgments imposed on manufacturers by the Food and Drug Administration pursuant to the FDA's comprehensive safety and efficacy authority. . .preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe to use".
This seems, if it goes Wyeth's way, as if it would keep various state jurisdictions from coming in with different liability claims, but the situation seems less stark to me if a state's standards were the same as the federal government's. Would this really pre-empt liability suits entirely? I'll let actual lawyers set me straight on that if I'm looking at it incorrectly.
There's another case that was granted cert. last fall, Warner-Lambert v. Kent, which could also have a bearing on the whole issue. This hinges on the approval (and later withdrawal) of the PPAR drug Rezulin (troglitazone), and whether Michigan state law on pre-emption of lawsuits is in conflict with the federal law. Again, I would have thought this one would probably be decided as a state-versus-federal issue, without extending to any sweeping thoughts on pre-emption in general. But that Medtronic decision makes a person wonder if the Court is in the mood for just that.
So, there's the background. Arguing will now commence on whether pre-emption is a good idea or not. I've thought for some time that all approved medications should be labeled as "investigational new drugs", and that everyone taking them agrees that they are participating in a post-approval clinical study of their safety and efficacy. (I suppose that's my own form of pre-emption). But there's room to argue if the FDA is ready to take on the full responsibility of drug approval, without the option of later redress in the courts if something goes wrong. (Counterargument: that's what they're supposed to be doing now. . .) And all of these schemes have to make room for new information turning up, or for outright fraud (which is most definitely in the eye of the beholder). Personally, I'm glad not to be a judge.
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Ezetimibe, known as Zetia and as the key component of Vytorin, was invented by friends and colleagues of mine. It was the first drug I ever saw discovered after I joined the drug industry. The initial discovery of the whole compound class happened around the corner from my lab, and the compound that became ezetimibe itself was synthesized down the hall. So, no, I'm not taking the current news about it very well. The situation is still quite confused, but there looks to have been enough stupidity, greed, and plain bad luck involved to make anyone despair. Read on – but I should warn you, I'm probably just going to get madder and madder as the post continues.
As anyone unfortunate enough to be holding Merck or Schering-Plough stock already knows, both companies took a pounding yesterday after the American College of Cardiology issued its recommendation on the use of Vytorin (ezetimibe / simvastatin). This call was based on the now-infamous ENHANCE trial, which was just published in the New England Journal of Medicine. The main points of the study had already come out in January, of course, but a closer look at the data has done nothing to help explain its results: no improvement over existing therapy. Addition of the cholesterol absorption inhibitor to the statin appears to have done nothing to help clear arteries (based on measurement of intima-media thickness) over what could be done with the statin alone. Ezetimibe seems to have had no bad effects, fortunately, but no good ones, either.
The ACC's verdict is that Vytorin should only be used as a last resort, and that patients currently taking it should strongly consider going back to plain statin therapy. Based on these study results, that seems like a reasonable recommendation. There's a large outcome trial (IMPROVE-IT) underway comparing the two treatments, but we're not going to see results from that one for another three years at the earliest. Until then, there doesn't seem to be any reason to recommend Vytorin. (There may not be any reason to recommend it afterwards, either, but we'll have to wait to see about that). Fortunately for everyone involved, no one seems to have been harmed, outside of the insurance companies who have paid out for Vytorin for the last few years – they not doubt have their own views on the subject.
It's important to remember that this result is indeed a surprise, since the combination definitely does do a better job at lowering LDL. (As an editorial in the NEJM puts it, this "dramatically contradicts our expectations"). You'd think that extra LDL reduction would be associated with a better outcome, but one of the panelists at the ACC, Dr. Harlan Krumholz, points out (PDF) that hormone therapy lowers LDL as a side effect, but isn't associated in that case with better atherosclerosis outcomes, either. Does that mean that there's more to the effect of statins than just lowering LDL, too? That possibility has to be taken seriously. The non-lipid effects of inhibiting HMGCoA reductase, the statin target, may be part of the answer, although the authors of the NEJM paper are reluctant to make that their whole explanation.
What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse.
If that's true, there is, in fact, a chance that the IMPROVE-IT trial could show a clear benefit for Vytorin, since it's being run in a broader population. (Just watch the confusion if that happens). But what will that mean? The results will be far too late to help Merck and Schering-Plough, and will be a clear disservice to the patients that could have benefited from the drug before then. ENHANCE would then turn out to have been a huge mistake.
But not content with that, the companies have managed to make it into a complete disaster. The controversy has been whether Merck and Schering-Plough sat on the results of the trial or spent extra time trying to find a way to make them look more appealing. This has drawn the attention of Sen. Charles Grassley and an investigative committee, which is the sort of thing that no company can wish for. Yesterday Grassley released some of the text of his letters to the management of both companies, and these include quotes from e-mails sent by John Kastelein, the lead investigator on ENHANCE. They do not look good, not by any stretch of the imagination:
" Is it correct that SP has decided not to present at AHA, but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??
If this is true, SP must have taken this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over…This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that."
In another e-mail, Kastelein expresses more frustration that the results would not be presented at that AHA meeting (as indeed they weren't, in the end), and says that ". . . you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!"
Schering-Plough, for its part, says that these statements are taken out of context, but good grief, what other context could that possibly be? Kastelein has also backed off, saying that he wasn't accusing the company of "deliberately withholding data for political reasons", but again, it's hard to read those excerpts in any other way. These days, no one should make statements in e-mail that they're not comfortable seeing printed in the Wall Street Journal, which is where I got these.
And does it need to be said that this is exactly, I mean exactly the kind of thing that the drug industry does not need? Vytorin as a drug is easy to forgive – the combination makes perfect sense, and the fact that it didn't show a good result in ENHANCE took everyone by surprise. (And, as mentioned above, it may in the end turn out to be a good therapy in the end). But the marketing of Vytorin is perhaps another thing – the companies really made a huge aggressive push to get as much of the cholesterol-lowering market as they could. That's no sin by itself, unless business is a sin, but if you're going to push that hard, you'd better make sure that you're standing on something firm.
This trial definitely wasn't that sort of foundation, and the fallout from it has been made much, much worse by its handling. It's distressing to me that the management at Merck and Schering-Plough would even take the chance, in this climate, of being seen as data-massaging study-burying slime. What words do I find if that's what they turn out to be?
Ezetimibe was (and is) a wonderful scientific story in the drug discovery labs, and its development is a testament to some very dedicated and persistent people. What a pity that it's all come to this.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us
Thanks to a longtime reader in Germany, I have the scoop from the EU and the respected Frankfurter Allgemeine Zeitung newspaper. In an article about drug prices and drug approvals, titled "The European Pharmaceutical Industry Under Suspicion", we find (my translation following):
"Die Kommission betonte, bislang lägen keine konkreten Indizien für wettbewerbswidrige Absprachen zwischen einzelnen Herstellern vor. Es sei aber auffällig, dass die Zahl neu angemeldeter Arzneimittel-Patente von durchschnittlich 40 in den Jahren 1995 bis 1999 auf durchschnittlich 28 im Zeitraum von 2000 bis 2004 zurückgegangen sei.
"Wenn innovative Arzneimittel nicht hergestellt werden und kostengünstige Generika zum Teil erst mit Verzögerung auf den Markt gelangen, dann müssen wir nach den Gründen suchen", erklärte EU-Wettbewerbskommissarin Neelie Kroes.
The Commission stressed that so far there was no concrete evidence of anti-competitive agreements between individual manfacturers. It was striking, however, that the number of new registered patented medicines declined from an average of 40 in the years 1995 to 1999 to an average of 28 from 2000 to 2004.
"When innovative medicines are not being made and cost-effective generics come first on the market only with delays, then we must search for the reasons," said EU Competition Commissioner Neelie Kroes."
(Update: Here's more, in English, on the same story.)
Well, I'm glad they're on the case. Hey, I'm not proud – I'll take help from anywhere. If a commission of bureaucrats can figure out how to increase our success rates, I'm willing to listen. Mind you, I'm probably going to find something else to do with my time while I'm waiting for Neelie and the gang to get back to us, but still. I note, though, that their other concern is the "delay" in getting generics to market, and I'd like to address those accusations of shady dealing in there.
Here's a minor problem with that theory: generics come out, on average, rather quickly over here in the US. I mean, right when those patents expire – and the generic companies are often in court, pitching various theories about how the various patents should be expiring even earlier. "Ah," but you may be saying, "but that's because prices in the US are so high – they're looking to scoop up those profits as soon as they can".
I'm not one to say bad things about the profit motive, of course, and the size of the US market is a big incentive all its own. But here's something that a lot of people don't realize, including perhaps members of EU commissions: generic drugs are cheaper in the US than in Europe. We have more expensive drugs on patent, but once they go generic, competition really slices them down, and the generic companies make it up on volume. The profit margin on generics is, last I heard, higher in Europe.
So that would be mighty crafty of the various drug companies, to hold back on entering a profitable market that way. What, then, could be the reason? Regulatory delays, anyone? Courtesy of the same EU superstructure that's looking into said delays? Think of how many meetings, committees, and conferences it could take to work that one out. I'll try to speed things up for them: Here in the US, generic companies are free to work on production and regulatory issues even before the relevant patents expire, thanks to the "research exemption". This has not generally been the case in Europe. There's also the problem that in many EU member states, generics account for only a tiny bit of the market, apparently due to decisions by the health insurance carriers themselves – which are either arms of the state, or heavily regulated by it.
There, maybe that will help. Of course, if the process of investigating all these suspicions were to move more quickly, the impact would be felt by various restaurants in Brussels and conference hotels all over the place, so we have to consider the economic factors. Good luck, folks!
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Merck and Schering-Plough have released the data on a study of genetically high-LDL patients taking a statin alone (Zocor, simvastatin) or the combination of the statin and Schering-Plough's cholesterol absorption inhibitor (Vytorin, simvastatin and ezetimibe). Vytorin has a good share of the market, and has already been shown to lower cholesterol.
And so it did this time: the Vytorin patients showed a 58% decrease in LDL, while the Zocor group showed a 41% reduction. But this trial went further, looking at the growth of atherosclerotic plaques. You'd figure that a greater decrease in LDL would mean a greater decrease in the size and growth of plaques.
You'd be wrong. The Vytorin group's carotid arteries, measured in a standard way (intima-medial thickness, IMT) came out as 0.0111 mm, while the Zocor group's came out as 0.0058 mm. This is making the headlines as "twice as bad as Zocor", but the difference actually isn't statistically significant (p = 0.29). Steve Nissen of the Cleveland Clinic is quoted as saying that this is "as bad a result for the drug as anybody could have feared", but that's not quite right. If that p value had been, say, 0.01, that would be worse. Strictly speaking, you can't call the two groups different. They don't seem to have been different in cardiovascular outcomes.
But here's the real point: that's bad enough. The whole point of Vytorin is that it's supposed to be more effective than a statin alone, and what you can say about this trial is that it sure didn't prove that. But that carotid artery thickness is definitely a concern - the numbers appear to have big error bars on them, but they're certainly not pointing in a good direction. And it's going to be difficult, perhaps impossible, to ever know if that effect is real, because it'll be mighty hard to get another trial of this sort off the ground after results like this. How can you enroll a treatment group for a drug that has been shown to have no benefit?
Well, OK, there's that LDL reduction. But the downstream clinical data (the artery measurements and outcomes) overrule that. The point of taking a cholesterol medication is not to make your lab test numbers go up and down, the point is to have fewer heart attacks and strokes. We use those blood lipid numbers as a convenient surrogate, but it's been obvious for a long time now that we have, to put it delicately, an imperfect understanding of their relevance. Data closer to real mortality and morbidity outcomes will win.
Now what? This is clearly terrible news for Merck and (especially) for Schering Plough. The companies already were under pressure for having taken so long to work up the data for this trial, which delay ended up just drawing even more attention to these bad results. Now, how do you go out and sell Vytorin (or Zetia, the cholesterol absorption inhibitor alone)? Why do insurance companies have motivation to pay for it? And when are we ever going to understand the complexities human lipid behavior and cardiology?
More on ezetimibe, written in happier days, here , here, here, and here. .
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GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):
"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.
These observations support a view expressed by Nissen and Wolski them-selves: "a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest."
He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.
These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.
Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.
My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".
Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.
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Insider, author of the Pharmagossip site, sent along this link to an article on Avandia at the Health Care Renewal site, flagged as "essential reading". After looking it over, I don't think I agree, and I thought it might be worthwhile to explain why.
The HCR piece quotes extensively from this New York Times article, headlined "Years Ago, Agency Was Warned of a Drug's Risks". Its focus is a letter that Dr. John Buse of UNC (now president-elect of the American Diabetes Association) sent to the FDA in 2000 on the possible cardiovascular risks of Avandia. Reading HCR's summary is a somewhat different experience than reading the original article, though - for one thing, you miss out on the part about how even now Dr. Buse isn't calling for Avandia to be be taken off the market. Rather than finding the Nissen New England Journal of Medicine paper to be the smoking gun he's been waiting for, he advocates waiting for the GSK cardiovascular risk study to be completed before making any decisions.
The HCR article has some good points in it, but to my ear they're phrased oddly. For example, it advocates a skeptical attitude toward the marketing claims made by drug companies, which is very good advice. But that's very good advice for evaluating the marketing claims of companies in every other industry, too. They're trying to sell you something. They will present their product in the most favorable light possible, whether that product is a car, a diabetes drug, or a burrito.
And that's the part that drives some people crazy, because it seems wrong to have potential life-saving drugs handled the same way as pickup trucks and enchiladas. They're not, though: the reason we can argue about drug company marketing is that drugs already have something that almost no other product has, which is a body of statistically valid comparison data. No data exist as to the long-term advantages and disadvantages of consuming a given brand of burrito versus its competition or versus an alternative meal. Cars are somewhat more data-rich, thanks to government and insurance company testing, and frequency-of-repair databases like those kept by Consumer Reports. But that's about the highest standard for comparison data outside of the drug industry, and you'll look in vain for P values and other tests of statistical significance, because there aren't any. In short, marketing claims in virtually every other industry can go relatively unchallenged, because there's little to measure them against.
So, that's why one of the things that I dislike about the Health Care Renewal piece is the hand-rubbing now-we've-got-'em tone that I detect in it. You don't have to go far to find it from plenty of other sources, either, which is why people like me are perhaps too touchy on the subject.
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Jim Hu has a good post on some proposed new FDA rules for its advisory panel members. Some sort of changes have been coming for a while now - here's an op-ed that I wrote on the subject back in 2005. I argued that many of the best scientists and clinicians in a given field already work with the industry (which isn't such a bad thing when you think about it), and that restrictive requirements for serving on advisory panels could do more harm than good.
Well, here's the new proposal: the cutoff is $50,000 in the previous 12 months. At that or above, you won't be allowed on the panel. Between $1 (presumably) and $50,000, you can sit on the panel, but won't be allowed to vote. My guess is that that's going to have a pretty big impact if it goes through, and that we're going to see some very different committee rosters.
Or, of course, maybe we're going to see some new forms of relationships between drug companies and their consultants. That's what happens whenever efforts are made to regulate money in the political world, and it wouldn't surprise me a bit here. There are two ways to look at this: if you're suspicious of the FDA's motives (like, say, Rep. Maurice Hinchley of New York, who has a bill mandating these changes and more coming along), then you'll probably see the whole process as a form of organized bribery, wheel-greasing to get defective drugs past the regulatory authorities. Another way to look at it, though, is that outside experts have something that the drug companies need (expertise, and more importantly, expertise from another point of view than the one from inside the company), and that they're willing to pay for it. This may seem odd, but these consultants don't always tell us what we want to hear.
The tough part is when a drug is on the edge of getting approved or not - it has some good points, some bad ones, and the decision could go either way. That's when suspicions are raised that an extra $50,000 here and there is what tipped things over to approval. I don't see that happening, myself (although readers are invited to submit counterexamples). Many approvals can be honestly argued either way, because these medical questions are inherently one big grey area.
The media reaction to this story is rather more toward the former point of view, though. The Washington Post's take on the story is that ". . .the new guidelines implicitly acknowledge what critics have long said -- that it is possible to find enough qualified experts who do not have ties to drug and device manufacturers." And Gardiner Harris in the New York Times gives one sentence to someone at the American Enterprise Institute, while leaving plenty of space for words from Rep. Hinchley and my own representative, Rosa DeLauro, both of whom are good places to go for "corporate poisoners" quotes.
Well, this is the first act of a rather long session of political theatre. There are 60 days of public comment on this proposal, then more wrangling comes along after that. Then there are the bills in the House, which if things go on long enough will get thrown into the next election cycle, and on it goes. It's worth watching, but be ready for a protracted show.
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The last panel of the day (I missed a good part of one in between, unfortunately) is on the FDA's Critical Path initiative and personalized medicine in general. It's moderated by Greg Simon of FasterCures, and features Michelle Hoffman of Drug Discovery and Development, Robert McBurney of BG Medicine, Gualberto Ruaño of Genomas, John Swen of Pfizer, and Janet Woodcock of the FDA.
Hoffman makes the point that some of the hyper-sceptical reporting of drug and medical issues is a reaction to the genomics hype of a few years ago. (I know, some of you out there who've seen stories that were ripped right from an idiotic press release are wondering where this sceptical reporting is, but I think she's talking about, say, the New York Times.
McBurney spoke about his academic background, saying that he cares even more about data now than he did back then, since millions of dollars are riding on the results. He also mentions the genomic craze, using a good analogy - that a caterpillar and the corresponding butterfly have exactly the same genetic sequence. "I have the same genome I did when I was born," he said, "but some things have changed along the way". His company has recently signed a deal with the FDA to look at preclinical liver toxicity, wirh funding from several large drug companies.
Ruaño is speaking about reverse genomics, "bedside to bench" work for figuring out drug and tox mechanisms. He's summarizing a recent paper in Mol. Psych. on the metabolic effects of antipsychotic drugs - the weight gain and prediabetic symptoms seen in a subset of patients. He and his company did a large parallel search for DNA markers between the patient populations on the two ends of the weight-gain distribution. As it turned out, in olanzapine-treated patients, an ApoE marker was higher in the heavy group, and and ApoE4 one was higher in the lean. For risperidone-treated patients, the leptin receptor and the NPY5 receptor fit the same pattern. They're starting to use their markers prospectively to predict how new patients will respond.
That leads into John Swen's view from Pfizer. He makes the point right at first that he doesn't blame the media for the overhyping of new technologies, as opposed to the people promoting them. (He's got a point, although I'd share the blame out a bit more - compare Michelle Hoffman's view at the beginning of this post). His view of the Critical Path initiatives is that it's going to be long slog to get biomarkers and transitional medicine to work out - worth it, certainly, but not something that's going to start delivering in a short time frame. (No argument here!) He also thinks that we could be doing a lot better than we are in things like new clinical trial designs (which is interesting coming from a company that's run the first large published Bayesian clinical trial).
And finally, Woodcock of the FDA is being asked about how the whole Critical Path initiative is going to fare at its current level of funding. She also feels that the media are very cynical about the sorts of technologies that are being promoted, which corroborates the over-reaction theme. She also says that the parts of the scientific community that are "more vested in the reductionist model" are also pushing back a bit. (My take is that the minute something useful comes out of the whole personalized medicine field, most of the critics will shut up with great alacrity. Success has a thousand fathers, for sure, and nowhere more than in a drug company). She largely dodges the funding question, saying that's it not really the agency's job to lobby for funds, but says that the biggest obstacle she faces right now is getting enough reviewer time to evaluate proposals properly. She thinks that the single best use of the money, though, is personalized medicine (which I find a bit arguable at this point, but eventually she may well be right).
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The third conference is on the CATIE and ALLHAT trials, the large comparative studies of antipsychotic and hypertensive medications. These studies are taking a real beating, I have to say. Herbert Meltzer of Vanderbilt took on the CATIE work, saying that its design was too complex and tried to do too many things at once. He pointed out that the study's results - that older and newer antipsychotics were essentially equivalent - is very much at odds with evidence-based medicine. He says that its conclusions haven't had that much effect with clinicians, because it's so at variance with their experience.
Michael Weber of SUNY-Downstate has a lot of bad things to say about the ALLHAT study, too. He points out that the HAT part stood for "Heart Attack Treatment", and that although the diuretic treatment group showed somewhat better blood pressure data, the heart attack outcomes were no different. His other surprising claim was that a large number of African-American trial subjects ended up in groups that did not meet the best standard of care for that population, and asked what would have happened if a drug company ran a similar trial. He was clearly frustrated with the initial coverage of the results in places like the New York Times, which he said were the result of a very well-planned press offensive by the study's authors.
Ralph Snyderman of Duke spoke about the problem of working on complex diseases that aren't driven by a single molecular defect (which, more and more, is what we're left to work on). These things are terribly heterogeneous, on more than one level - for instance, referring to his specialty, he said that as far as he's concerned rheumatoid arthritis is at least three diseases, and perhaps as many as six or seven.
Susan Horn of the Institute for Clinical Outcomes Research made the case for "practice-based medicine", trying to work out the real-world effects of compounds after they've been launched. Meltzer wasn't so sure about how well these sorts of studies replicate, though.
In other news, Matt Herper of Forbes has reluctantly admitted that he doesn't find medical journals to be the most exciting reading in the world - his challenge is turning these results into things that people will read voluntarily. He had a great quote about the difficulty of turning ambiguity into a story, mimicing an editor: "What you you mean these experts don't know? Call them back and get them to tell you!"
Post updated in sections - I've been recharging my laptop batteries - DBL
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Now I'm listening to Andy von Eschenbach, the new FDA commissioner, who's giving a speech on communication and regulation. I think I can refer to him as "Andy", since I'm eating a ham and cheese sandwich in front of him (not to mention blogging his speech).
The main thing I've taken away is that the agency plans to announce some new outlets and methods to disclose information - he's not ready to say what those are yet, but promises that details will be forthcoming. Now questions are coming from the floor - the first one is on direct-to-consumer ads and the recent recommendations by the Institute of Medicine. von Eschenbach answers by saying that the FDA has to recognize the right to free speech, but has to make sure that things are factual. (Not the time to get into a discussion of commercial speech, clearly).
Answering another question, von Eschenbach seems to want to move the FDA away from a reactive stance on drug-safety issues. That's probably a good idea, but considering the kinds of events that bring these things to the front page, reaction is surely always going to be a big part of the process.
Now there's a question about the adverse event reporting system - how to make it useful without overloading people. (This was a feature of the second panel discussion). He's answering that adverse events are only part of the problem - there's unexpected efficacy as well, and any system needs to be able to pick up on all sorts of events. (I agree, but I think that the former will always far outweight the latter).
Now a representative of PhRMA is asking about transparency - as an MD, he's contrasting the open discussion at at mortality and morbidity conference among physicians with what takes place at the FDA/national press level. von Eschenbach replies that acquiring the data is only the first step, and that transforming raw information into knowledge needs to be more transparent. He's saying that the general public wants the end product, not so much all the raw data. (I'd add that these days there will always be people, far between but very committed and vocal, who will want to see the raw numbers, too).
An attendee from Pharmaceutical Executive magazine asks about making sure that different points of view are considered, and on whistleblowers in general. von Eschenbach's reply is that he'd like to have things run so that people wouldn't feel the need to go outside the usual processed. "If people wanted Andy von Eschenbach to do everything himself," he says, "there would just be the Andy Agency". He expects people to adhere to the way the FDA does business, and wants them to come to him if they have a problem.
Steve Projan of Wyeth is now saying that the FDA doesn't seem to have the resources to do what it wants to do, and asks about the renewal of the PDUFA legislation. (There's a whole panel on that in the afternoon). von Eschenbach's reply isn't very specific, as probably befits an issue that's the subject of current legislative wrangling. He regards PDUFA fees as straight fee-for-service, and regards them as useful, but only one part of his resourcing.
The last two questions are on drug labels - the questioner is asking about the inclusion of genomic information on warfarin and tamoxifen labels. And the final question is on regulation of diagnostic test regulation, and the burden on direct-to-consumer genetic tests - the questioner is saying that many primary care physicians aren't that well trained in genetics, and that these tests might as well go to the consumer rather than using the MD as a gatekeeper. "Uh. . .how much time do I have left?" says von Eschenbach, mock-nervously.
He answers that drug labels are changing constantly, and that the agency has to be certain that any infomation that's given out so broadly is really accurate and valuable. He says that the various "omic" disciplines are going to have to make sure that they've got very well established data before it can go on a drug label, but that he knows that this is coming on. As for the regulatory burden on tests, he seems leery of turning these things loose on the public, and would rather have these "integrated into the medical model".
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The second panel is going on now, moderated by Steve Usdin of BioCentury, and featuring Helen Boucher of Tufts, Frank Burroughs of the Abigail Alliance, Scott Gottleib of the American Enterprise Institute, and Steve Projan of Wyeth.
One subject that's coming up a lot (as it did in the first panel) is the associate of SSRI therapy with suicide (or suicidality). That's a good example of the tricky nature of drug regulation, crossing over from pre-approval to marketed compounds. Some of the earlier panelists (and questioners from the audience) bemoaned the media coverage on the issue - the current panel is talking about it as an example (some parts good, some bad) of how to study ongoing safety issues, with a big problem being who's going to pay for such things. Surveillance, everyone agrees, is probably the best way to get useful data on drugs and their performance in the real world, but (as has been pointed out), no one wants to hear about how that's surely going to drive up drug costs.
Other areas coming up are antibiotics (and the dearth of new ones) and off-label use of cancer therapies (and other drugs) and how much to regulate it.
The conflict between openness and giving lawyers bait to sue everyone is also being discussed - tort reform has been referred to more than once, as you'd figure. The debate about whether you want to report only data that's reached statistical significance has shown up as well (I think that the alternative is chaos, personally, but not everyone agrees).
Steve Projan made a good point about the problems with Ketek (which, as others have noted, haven't had anywhere near the coverage that the Vioxx problems did). As he says, if you drop Ketek and switch to ampicillin, you'll end up killing more people through anaphylactic shock.
Note: post edited after original version, to incorporate more info - DBL
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Well, I'm sitting in the audience now at the CMPI conference. My panel was the first of the day, and was pretty lively. Moderated by Rob Pollock of the Wall Street Journal, it featured Ed Silverman of the Newark Star-Ledger (and now of the very useful Pharmalot, Paul Coplan (who does risk managment at Wyeth), Tim Hunt (public affairs at Biogen-Idec), and Paul Seligman (safety policy at the FDA), and Diedtra Henderson of the Boston Globe.
Vioxx was a big point of discussion, as an example of media reporting on medical and pharma issues. There was a noticeable split between the reporters on the panel and the pharma people on this - the discussion was civil, but you could see the differences in opinion on how well the issue had been covered. With Biogen represented, the Tysabri withdrawal (and return) was also a big topic.
I suppose the main point I'd make in reference to that split came when Ed Silverman mentioned that a good thing that came out of the Vioxx coverage was that it started debate, and that that was always a good thing. I agreed with him, up to a point, adding, though, that I thought that informed debate was more useful. My problem with much of the Vioxx coverage was (as I said about that Michael Crichton op-ed the other day) that it made people feel as if they'd been informed when they hadn't been.
There was general agreement that risk/reward (especially absolute risk versus relative risk) was a key concept in reporting these things, but that it could be difficult to get across to a general readership. The other agreement was the companies should try to be as open as possible about clinical data and adverse events, with (naturally) different ideas about where the cutoff of possibility would fall.
Today's New York Times has a passionate op-ed by Michael Crichton on the subject of gene patents. Now, as my previous posts will demonstrate, I'm no fan of over-patenting. And the whole topic of gene (and protein) patents is a very interesting and important one.
Unfortunately, though, it's also very complex, and Crichton's piece manages to complete reduce the subject to tinkling fragments. The op-ed is so vigorously argued that its readers will probably come away feeling as if they've been informed, but I'm afraid that they're going to end up knowing less than when they started. I hate to be this blunt about it, but Crichton's done his cause a great disservice by spreading ignorance and confusion.
The official position of the Patent Office is that products of nature are not patentable. But. . .an isolated or purified one, in a form not found naturally, can be. Single genes, ripped out of their context in genomic DNA and expressed as a pure form, are considered to be new chemical substances, and thus can indeed be patented. We can argue about whether this is a proper interpretation or whether it's a good idea, but to ignore the point completely (as Crichton's piece does) isn't going to help anyone understand the problem.
You'd also never guess from reading Crichton that the subject of utility is of great importance in patent law. There's a profound difference between a patent on a gene, and a patent on a use for a gene. (That may sound trivial, but only if you've never been involved in writing or analyzing any patents). Ten years ago, the US Patent Office was getting swamped by gene applications with very little thought to their use (other than some pro forma statements, but they raised their standardsper se shouldn't be allowed, you'd still have the use issue to deal with. The word "utility" does not appear in today's op-ed.
You'd also never know that the whole subject is being contested, very seriously and expensively, in court cases all over the world. The Metabolite case, which the Supreme Court recently dodged, is the one with the highest recent profile, and there will be more. It's not like the topic hasn't created controversy.
If you want a thoughtful analysis of the problems of gene patenting, start with this analysis (PDF) from the Congressional Research Service. Reading and understanding it will put you way ahead of the readers of the New York Times and, it seems, way ahead of Michael Crichton.
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There was an interview in yesterday's New York Times with Harvard Business School professor Clayton Christensen. (Not one of your shy and retiring professors, I should add). He's saying that the US healthcare system is terribly inefficient, and proposes (among other things) that some diagnostic tasks be opened up to a larger field of practitioners than just M.D.s. That's a worthy topic of discussion, but for one of the pure med-blogs, I'd say, rather than over here.
What struck me about the interview was something else - the tone of some of the questions. It's part of an "Armchair MBA" series by William J. Holstein, but the interview seems to have been conducted by Elizabeth Olson, so I'm not sure of the source. Here's the part that gave me pause:
Q. An example of what you mean?
A. A hundred years ago, there was a big disease that nobody understood and was often fatal, called consumption. . .what we thought was a single disease was a whole bunch of different diseases. You had tuberculosis there, at least three types, and you had pneumonia. We thought it was all one disease. So the care had to be left with doctors because they were the ones with the training and the judgment, but once you could precisely diagnose the cause of the disease, you could then develop a cure. It was so rules-based that you didn't need a doctor any longer. Today a technician can diagnose those diseases and a nurse can treat them.
Q. Are you saying doctors rather than the pharmaceutical industry are the root cause of what's gone wrong?
A. The pharmaceutical industry has been focused on therapy, not diagnosis. The medical profession has simply accepted that many of these diseases are well-diagnosed, when in fact they aren't. As a consequence, we haven't moved the health care profession into a world where nurses can provide diagnosis and care. Regulation is keeping the treatment in expensive hospitals when in fact much lower cost-delivery models are available.
Q. Wouldn't your solution require a dramatically different regulatory environment?
A. It differs state by state. In Massachusetts, nurses cannot write prescriptions. But in Minnesota, nurse practitioners can. So there has emerged in Minnesota a clinic called the MinuteClinic. These clinics operate in Target stores and CVS drugstores. They are staffed only by nurse practitioners. There's a big sign on the door that says, "We treat these 16 rules-based disorders." They include strep throat, pink eye, urinary tract infection, earaches and sinus infections.
These are things for which very unambiguous, "go, no-go" tests exist. You're in and out in 15 minutes or it's free, and it's a $39 flat fee. These things are just booming because high-quality health care at that level is defined by convenience and accessibility. That's a commoditization of the expertise. . .
Q. Aren't the pharmaceutical companies also profiting?
A. They are. But in general, pharmaceutical breakthroughs that involve a precise diagnosis of a disease and an effective therapy save the system a tremendous amount of money even though the drugs may appear to be high-cost.
Now, I've never found the tone of the NYT's business section particularly warm where drug companies were concerned. But this really seems to be pushing things along. "You mean it isn't all Big Pharma's fault? But your idea would still allow them to make money!" Do I have my gain setting turned up too far, or is this as obvious to other readers as it is to me?
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There are all sorts of excellent reasons not to cut down the rainforests of Borneo. Biological diversity, erosion, local climate, sheer aesthetics. . .no one should have to scratch their head for very long. But this isn't one of them, at least not the way it's being sold:
"Plants thought to help treat or cure cancer, AIDS and malaria have been found in the rainforests of Borneo, a report from the Swiss-based global conservation group WWF said on Thursday. . . A promising anti-cancer substance has been found in a Borneo shrub by researchers for an Australian pharmaceutical firm, while a chemical found in latex produced by a tree appears to be effective against the replication of HIV, the report said.
In the bark of another species of tree, the researchers discovered a previously unknown substance which in laboratory tests appeared to kill the human malaria parasite, it added."
Going to the source of the story, one finds more details:
"According to the report, Cerylid Biosciences – an Australian pharmaceutical company – has identified a promising anti-cancer substance in a shrub found in Sarawak. A compound present in the plant Aglaia leptantha has been found to effectively kill 20 kinds of human cancer cells in laboratory tests, including those that cause brain and breast cancer, and melanoma.
"The fact that the compound is very effective against a number of tumour cells, presents a very good argument for preserving the plant's habitat in Borneo," said Dr Murray Tait, Vice President of Drug Discovery at Cerylid Biosciences."
No, it doesn't. The reason I say this is that we have oh, so many compounds already that will kill off twenty different kinds of human cancer cells in the lab. I mean that - tens of thousands of the damn things. Killing cancer cells in a dish is not as hard as it sounds, unfortunately. Now, killing any of them off effectively in a mouse model, that's another story. We probably only have hundreds and hundreds of those around, maybe a few thousand. And getting these things to work in humans? Well, you already know how many of those we have. It's a rather stiff attrition rate, y'know. I note without comment that Cerylid itself doesn't seem to be doing all that well right now.
Keeping Borneo from being clear-cut is a proposition that can be sold on its real merits. It doesn't need this kind of whoop-whoop. All these arguments do, in the long run, is make the people advancing them look like fools or con artists (Rain forest medicine! Jungle cures! Real soon now!). And it makes people think that discovering cancer drugs is actually not all that hard - just look in the right plant, and there it is. We already have enough people who don't realize how long the road is between some neat result in a culture dish and a real drug, thanks very much.
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Some readers will have heard that Michael Fumento, well-known pundit and controversialist, has been fired from his post at Scripps-Howard. Eamon Javers of Business Week broke the story of how Fumento had received some $60,000 from Monsanto without disclosing the relationship. If you look in the comments after that article, you'll see a lot of arguing about whether this was money for a book, for op-eds, whether it went directly to Fumento or not, and so on.
The problem is, none of that matters much. This column by Cathy Seipp is a good explanation of why that is. If you're going to set yourself up as a journalist, you can't take money from the people that you're going to be writing about. Even if there's room to argue, you have to at least disclose what's going on.
Update: here's Fumento's published response to Seipp and the Business Week article.
Fumento has been a vigorous defender of the pharmaceutical and biotech industries over the years, of course. And according to Seipp, there had been suspicions that he had been well-rewarded for his enthusiasm. "Has anyone read a pro-biotech piece. . .that doesn't practically smell like solicited spin?" she asks.
Well, yeah, I have, but it's one that I wrote, so maybe that doesn't count. I'm in an odd position here, because the journalism is a nights-and-weekends thing with me, while the day job is in the very industry that I write about. That gives me some unique strengths - I like to imagine, anyway - but it also means that anything I write can automatically be discounted as the product of someone who's already been paid for.
That's why I spend little or no time talking about the products of the Wonder Drug Factory where I work, because you can count them on one hand that wouldn't be right. I'm definitely not a spokesman for the company where I work. But for the industry in general? Yeah, informally I guess I am, because I find the work interesting and important enough to speak up for it.
That doesn't mean that I get paid extra for that role, and it doesn't mean that I like everything that goes on in the drug business, either. It is, after all, a business, not some sort of higher calling. Scientific research might qualify as a higher calling, under the right circumstances, but that's only one part of the drug industry. I'm just fortunate that doing the science overlaps as well as it does with making a living.
So there's my disclosure statement. I'm never going to do the under-the-table pay-for-punditry thing, because where I stand should already be clear. Where a byline of mine appears will be where the money's coming from. I'm pro-research and pro-pharmaceutical, because that's what I do for a living. But it isn't love, and it isn't blind.
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Nicholas Kristof had a column today (available on one of those private, subscription-only web sites here) with the title "The Hubris of the Humanities". It's a C.P. Snow-style "Two Cultures" lament, but at least it's one from the non-science side of the gap:
"In the U.S. and most of the Western world, it's considered barbaric in educated circles to be unfamiliar with Plato or Monet or Dickens, but quite natural to be oblivious of quarks and chi-squares. A century ago, Einstein published his first paper on relativity - making 1905 as important a milestone for world history as 1066 or 1789 - but relativity has yet to filter into the consciousness of otherwise educated people."
As someone who couldn't decide for a while between a humanities major and a science one as an undergraduate, I have to agree. I finally decided that it was going to be a lot easier to have a library in my basement than a lab. It also dawned on me, slowly, that many English majors had an entirely different approach to literature than I did, and that I wouldn't be very happy over there at all. And while graduate school in chemistry was often unpleasant, graduate school in English would have finished me off for sure.
I recall one day in my junior-year biochemistry class, with the professor telling us that we would be expected to have the whole citric acid pathway memorized for the test on Monday (great lamentation). Then I went straight to my Southern Literature class, where the professor came down hard on us by reminding us that we had to have finished the required William Faulkner reading by Monday, too. Groans from the English majors ensued, but I felt like yelling at them. "Look, you dolts", I wanted to say, "people read Faulkner for fun. No one memorizes the citric acid cycle because they enjoy it!" Of course, that's a major reason why many more people are familiar with Faulkner, isn't it? But not everyone likes "As I Lay Dying" (I do!), and not all parts of a science education have to be tedious.
This is a fundamental problem that my industry has. We're capable of making our own bad PR, of course, but even under blameless conditions we're doing something that most people don't understand very well and didn't enjoy having to try. So when we tell them it's hard, they think "Well, sure, of course it's hard. Tell me something I didn't know." And when we try to explain why there isn't a cure yet for (your least favorite disease here), it's hard to do so in terms that someone without a science background can really appreciate.
And that's one reason why the more irritating conspiracy theories still circulate. You know, the ones about how we pharma types really do have cures but we just aren't selling them (yet). Or how we caused those diseases in the first place, just so we could sell more drugs - I always take that one really well. Or how there are simple, cheap, safe herbal remedies for just about everything, only we Evil Pharma Overlords won't let them on the market. And so on, and so on. I've been arguing recently by e-mail with one of the "drug companies do nothing but rip off NIH" crowd, and it isn't easy. The guy has no idea of what he's talking about, or what I'm talking about, and it would take a fair amount of (unwanted) education to convince him.
But that's one of the things I try to do here - no, not convince idiots, I mean provide some education for those who might be interested. I think that the broad concepts of drug discovery (or pretty much any scientific field) can be understood by any reasonably intelligent person. They have to be explained the right way, of course, because the sad corollary to that statement is that there is no field of knowledge that can't be rendered incomprhensible. And still, even if it's done well, there are gaps. If someone lacks experience in research, there are things that have to be taken on trust.
For example: no, we don't have a machine that'll immediately print out the structure of any unknown compound you stick into it, no matter that such a device makes occasional appearances in movies and on TV. There are a lot of good reasons why that gizmo isn't available yet, and I could probably explain most of them to an interested lay party, given enough time. (For that, you could also read "given enough blog posts".) But in explaining drug discovery as a whole, it's easier to stipulate (in this case) that some time and effort has to go into make sure that the compounds you're looking at are really the ones you think you're looking at. Keep in mind that we scientists have to do the same thing if we're talking with someone in a scientific field that we don't know much about.
So, what to do? Science isn't getting any less important. I really don't think anyone can be considered well-educated without a grasp of the basic concepts of physics, chemistry, and biology. It's not as painful as it might sound. I appreciate the way that Arts and Letters Daily works in some links to science-overview articles - that kind of thing is bound to help. I wish that attitude were more widely shared, and I'm glad that Kristof made his point where he did.
Postscript: I should mention that Kristof goes on to talk about the consequences of scientific ignorance, but he makes the kind of mistake one makes after being marinated in the New York Timesfor years:
"It's true that antagonism to science seems peculiarly American. The European right, for example, frets about taxes and immigration, but not about evolution."
Which is a bizarre thing to say, on several levels. For one thing, hostility to science doesn't come merely from "the right". I'd say that science is equally admired (or used as a whipping boy) by both sides of the political spectrum. And if Kristof thinks that the Europeans can't be scared of scientific innovations, he must have somehow missed the long, loud upheavals about genetically engineered organisms and food over there. The European public cedes second place to no one in their fear of engineered food, and they don't mind going completely past any rational arguments to maintain their lead.
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Reader Jeff G. pointed out this blog post, which quotes the letters column in the most recent issue of Vanity Fair. The magazine ran a profile of Paris Hilton, about whom the less said the better, and quoted her in-the-same-category sister, Nicky, to the effect that she was working so hard, running multimillion-dollar companies and all, and what were the people writing about her doing at her age (21) that was so important?
The magazine published a letter from one Steven Sabes of Minnesota, who said:
. . . I would like to repond to that. When I was 21, I was busy working toward my Ph.D. in organic chemistry at the University of Minnesota. I was the first to synthesize the compound okadaic acid -- shown to be the leading cause of breast cancer.
Well, I'm glad to see some organic chemistry make it into the pages of a magazine as empty-headed as Vanity Fair usually is. Face it, those of you readers who are fellow chem-geeks - our jobs might as well be voodoo hoodoo as far as the VF demographic is concerned. And Sabes and his okadaic acid work appear to be real. He's a graduate of Craig Forsyth's group at UMN.
The problem is, someone at the magazine seems to have mangled his point. Okadaic acid isn't the "leading cause" of breast cancer - it's a marine natural product that few people have ever encountered, unless they've had some really, really bad shellfish. It's a phosphatase inhibitor, which puts it in an interesting class of activity that's been hard to approach through traditional med-chem, and it's been used for many in vitro and in vivo research studies in cancer and other fields.
So I appreciate Sabes taking a whack at the Hilton sisters, and letting people know that organic synthesis actually exists. I just wish that his meaning had stayed intact.
I mentioned that the Wall Street Journal is running a free-access week. That'll give you a chance to check out the Nov. 11th column by their science columnist, Sharon Begley, who sounds an appropriate note of caution about genomic-based drug discovery. (And I'm not saying that just because she quotes me). It'll be good to get these concepts out to a wider audience.
From the editorial pages of the Washington Post we have this, and I could not have said it better myself:
. . .Unfortunately for Merck, scientific facts didn't play much of a role in the first Vioxx trial, which ended on Aug. 19. The Texas jury in that case awarded $253.4 million to the widow of a man who died of a heart attack triggered by arrhythmia, which is not a condition Vioxx has been proven to cause. The jury, declaring that it wished to "send a message" to Merck, decided to make an enormous symbolic award anyway. Besides, said one juror afterward, the medical evidence was confusing: "We didn't know what the heck they were talking about." Because Texas law limits the size of jury awards, the final cost to Merck is likely to be closer to $2 million. But the precedent set by the jury is ominous. Merck is facing about 5,000 similar lawsuits. If every one of those costs the company $2 million, the total price will come to $10 billion -- if, of course, a company called Merck is still around to pay it.
Politicians and regulators should be asking themselves whether a system of massive cash awards to people who may or may not have been adversely affected by Vioxx is a logical, fair or efficient way to run a drug regulatory system. They should also be asking whether juries that scorn medical evidence are the right judges of what information should or should not have been on a prescription label. After all, Vioxx was produced and sold legally. The drug was approved by the Food and Drug Administration, and its label did warn of coronary side effects. It is possible, even probable, that Merck was negligent in its decision to ignore early warnings of the cardiovascular risks of Vioxx. But the company has already paid a price for that negligence, in the losses it has suffered after abruptly taking Vioxx off the market. Fair compensation for the injured needn't entail disproportionate financial punishment as well. . .
That is exactly my opinion on the matter, and it is a weird experience, for me at least, to have my views line up so perfectly with those of a major newspaper's editorial page. If the New York Times had come out with this one, I'd have to sit down and fan myself for a while. Let us celebrate this gust of good sense and hope for more of the same, as the second Merck/Vioxx trial (in New Jersey, this time) goes hammering along. . .
(Link via Marginal Revolution.)
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I couldn't resist linking to this article, part of a series in the Guardian. I'm afraid that he's pretty much on target for most science stories in the news:
"Science is done by scientists, who write it up. Then a press release is written by a non-scientist, who runs it by their non-scientist boss, who then sends it to journalists without a science education who try to convey difficult new ideas to an audience of either lay people, or more likely - since they'll be the ones interested in reading the stuff - people who know their way around a t-test a lot better than any of these intermediaries. Finally, it's edited by a whole team of people who don't understand it. You can be sure that at least one person in any given "science communication" chain is just juggling words about on a page, without having the first clue what they mean, pretending they've got a proper job, their pens all lined up neatly on the desk."
As he points out, there are only a few templates available for science-based stories in the popular press - "Big Breakthrough!", "What You Thought You Knew is Wrong", and "Those Crazy Scientists" are the ones that get used the most. And let's not forget "Scientific Confirmation of (insert pre-existing bias here.)"
But, to be depressingly fair about it, there aren't many more templates for reporting any other subject. Just look at how many stories are whacked with mallets until they fit the Brave Feisty Underdog story line, or some of the others that might as well be run in italics above the stories in the newspaper or in the corner of the TV screen: Babies In Danger, How the Mighty Are Fallen, Lowlifes on Parade, Sanctimony Unmasked. There are more. Those are merely some of the non-ideological ones.
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You know, there is one more thing about the Merck case I'd like address. This is brought on partly by the general press coverage of whether Merck knew this or hid that, and partly by an intensely irritating comment to Friday afternoon's post.
You would think, to hear the way some people talk, that no one at Merck ever took Vioxx. That they just launched it onto the market with an evil cackle and a shout of "Caveat emptor", then sat back to watch the money roll in. Actually, employees of Merck very likely took Vioxx at a rate above that of their cohorts in the general population - employee discounts, you know. I've no doubt that this applies to Merck's marketing department, to their clinical development groups, and to their toxicologists. Why shouldn't they take their own company's drug if they're in need of a COX-2 inhibitor?
It's not very far to the conspiracy theories that pop up about cancer, about HIV, about every awful disease you can imagine. "You know," some fool will whisper to you, "that the drug companies really have a cure for it. They're just waiting until more people get sick. In fact, they're probably making sure that as many people get it as possible."
It's difficult for me to express coherently my contempt for that idea. Let me assure you that employees of pharmaceutical companies, and their relatives, and their friends, are potential heirs to every disease that this world offers, just like everyone else. I might add that it's particularly hard to watch someone you know suffer and die from a disease that you've been working for years to treat, but still have nothing to offer for.
So enough of this division between Merck and the rest of the world. Merck is a large company, with tens of thousands of people in it. Many of them took Vioxx. No small number of those people probably worked on it. I'd like to hear how that pulpit-pounding Texas attorney would work them into his world view.
Update: For plenty of good commentary on the legal aspects of the Merck verdict, see Ted Frank's post at Point of Law.
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Glenn Reynolds, of Instapundit fame, has some nice things to say about the drug industry in this piece on MSNBC.com. I appreciate it; we need all the good press we can get these days. Says Glenn:
"The pharmaceutical industry isn't beyond criticism, of course. But I find most of the criticism rather strained, and all of the critics far too slow to give the industry the credit it deserves for the tremendous good it does"
There are some who will say that Reynolds is hardly disinterested, since his wife is responding well to an antiarrythmic medication which she badly needed. I'd respond that this is just the sort of thing we need more of. The more people with reason to like our industry, the better. Those are people that we've helped, who think that they've gotten something worthwhile for their money, who are satisfied with what we've been able to produce. I wish it were harder than it is to find disinterested parties, frankly.
As it is, very few people who've had to deal with Alzheimer's, say, have much reason to feel good about the pharma industry. There are many infectious diseases for which we don't have much to offer. And while some cancers are truly yielding to treatment, many others are just as much of a death sentence as they've always been. The people who encounter those have a right to wonder about what the deal is with all those breakthroughs they read about.
I've said it before, and here it comes again, that the best way for the drug industry to improve its image is to deliver the goods. That's not going to be easy - the disease areas I've named are pretty rough, and the other key ones aren't any better. It's going to cost an insane amount of money and effort to get our good names back.
And while we're at it, we're going to have to make a better case for some of the drugs we're already selling and working on. Glenn's piece is a response to this book, which makes the argument that the industry is spending too much time "treating people who aren't sick". If we're preventing diseases and improving quality of life, and we'd better be, then we need to make people aware of it.
What's left out? Lifestyle drugs - sexual performance, cosmetic enhancement, that sort of thing. They can be profitable, but I think if we spend too much time in those areas, we're going to get hammered on. The grindstone is the place to be.
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I'd like to recommend the latest issue of Science, which has a multi-part special section on drug discovery. (Problem is, that link will only work if you're a subscriber, and none of the content is outside the wall.)
I'm not just plugging the articles because one of them quotes me, although that was a nice surprise. The section is a well-done, realistic view of what drug research is like, which should be of interest to the journal's readers (who skew academic). Helping to close the often surprisingly large gap between academia and industry is probably a good deed.
I think that researchers on the industrial side usually feel they have more perspective on that issue, since all of us came from university science departments to start with. Of course, we're not a random sample, since we're disproportionately made up of people who high-tailed it out of academia at the first opportunity. At the very least, we have plenty of people who didn't find the life appealing enough to stay.
Of course, anyone who finds the life of a grad student or post-doc wonderfully appealing probably has some kinks in their psychological hose. I'm sure that being a professor is a much better lifestyle. It is, isn't it?
It's no wonder that there's still so much argument over autism and vaccines. Paranoia is an endlessly renewable resource - big glowing hunks of it are always being dug out of the ground and put to use. For an unfortunately typical example, take a look at this piece from the New York Times. Some fifteen years ago, studies were carried out in New York to determine the safety and efficacy of pediatric doses of the existing HIV medications:
The controversy extends back to a bleak period in New York City history when well over a hundred children a year were dying of AIDS, most under the age of 5. As many as one in every five children infected with H.I.V. were dead by 2, doctors now say; up to 50 percent were dead by 4.
There were no AIDS drugs approved for children in those years. The first AIDS drug, AZT, was approved for adults in 1987. Babies were being abandoned in hospitals, their mothers unable to care for them and with no foster homes available. About 40 percent of the children with H.I.V. were in foster care.
As a result, pediatricians began pressing pharmaceutical companies to let them try drugs shown to work in adults. . .
. . .One center that took part in the trials was a small boarding home for H.I.V.-infected foster children called Incarnation Children's Center, the brainchild of Dr. Stephen W. Nicholas, now director of pediatrics at Harlem Hospital Center. With as many as 24 infected children abandoned in the hospital in 1988, the idea of finding them a home outside the hospital came to him after a young patient greeted him with, "Hi, Daddy."
Working with Columbia University and the Catholic Archdiocese of New York, Dr. Nicholas became the medical director of Incarnation, on Audubon Avenue in Washington Heights, which opened in 1989 and added an outpatient clinic in 1992. Foster children there and elsewhere were enrolled in trials - at first, trials of single drugs like AZT, and later, of multiple-drug cocktails and protease inhibitors, which by 1996 were helping turn AIDS into a manageable, if still chronic, disease.
For his trouble, Dr. Nicholas became the focus of attention from one Liam Scheff, who published a screed 18 months ago on Indymedia (and didn't I groan when I saw that phrase in the article) accusing the Incarnacion facility of forcing poisonous drugs down the throats of innocent children, killing who knows how many in the process, et cetera, et cetera. I should mention that Scheff doesn't think that HIV is likely to be the cause of AIDS, doesn't think that the drugs against it necessarily have done any good, and so on - just so you all know where he's coming from.
Witness now how avalanches start: That Indymedia piece set off a group called the Alliance for Human Research Protection, whose publicity got the New York Post going, which led to a BBC-financed film ("The New York Experiment - Guinea Pig Kids"), which ignited the activists at a Brooklyn-based group that seeks reparations for slavery and whose leader claims (with no apparent evidence) that many of the children didn't even have HIV:
What we know already," he said, "is that 98 percent of the children experimented on were black and Latino and that the fundamental basis of why they chose those kids was racism. They have the arrogance to say it was for their own good, but we know it was racism."
That brought a couple of city councilmen into camera range, and things have continued to deteriorate. At this point, what really happened in the late 1980s doesn't seem to matter much, but for the record:
"Pediatricians involved in the trials say they are mystified by the onslaught. While powerful drugs do have side effects, many said, they remembered no fatal reactions. At Incarnation, Dr. Nicholas said, no child had died of a reaction and "no child ever had an unexpected side effect."
He said that, with one exception, no children had been included in the trials without "absolute proof" by advanced testing methods that they were infected and not simply carrying their mother's antibodies. He said the exception was a trial that proved that by giving AZT to pregnant, infected women and then to their newborns in the first six weeks of life it was possible to sharply reduce the rate of H.I.V. transmission from mother to child. He called that study "the most important clinical trial in the history of AIDS."
Well, yeah, fine - but what about the secret experiments? Evil corporations and secretive government agencies? Racist plots and toxic drugs administered by sinister doctors? What about the good stuff? Hasn't Dr. Nicholas watched any TV, seen any hit movies? Doesn't he know how this country really works?
My heart goes out to him, actually. From all I can tell, he has done the world a real service, and saved more children than could we can count from awful, lingering deaths. For this, he and his co-workers get the Mengele/Tuskegee treatment from publicity hounds and people who've rotted their brains reading Indymedia. What a reward.
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I last wrote about Pfizer executive Peter Rost back in September, after he'd unburdened himself on the subject of Canadian drug reimportation. As readers will recall, his position on this issue is roughly that Canadian drug reimportation is a wonderful idea that needs to be implemented with all possible speed, which puts him rather at odds with the views of most pharmaceutical executives.
So, you're wondering, how's Rost doing these days? Today's New York Times catches up with him:
"No man is an island. But Peter Rost is getting close.
Dr. Rost, a vice president for marketing at Pfizer with a history of corporate whistle-blowing, has for the last year publicly criticized the pharmaceutical industry over the price of drugs. Along the way, Dr. Rost has become increasingly isolated at Pfizer, the world's largest drug company.
First, his employees stopped reporting to him. Then his supervisors stopped returning his calls and now he does not know whom to report to. His secretary left, he said, and he was moved to an office near Pfizer's security department at a company building in Peapack, N.J."
The article goes on to say that Rost tried to log in to his Pfizer e-mail the morning after he recently appeared on "60 Minutes", and found his access denied. If you read to the end, though, you find that by that afternoon, he was connected again, and that Pfizer claims that this is a glitch that has affected other employees.
And if you don't read carefully, you'll miss the line about how this was the first time Rost has tried to access his Pfizer e-mail in two weeks. Now, that makes the case for his isolation better than anything else in the article. Who on earth could go without their office e-mail for two weeks? As it turns out, Rost also got word out to the Newark Star-Ledger about his problem, and mentioned to them that he doesn't get in to the office much. The Associated Press seems to have received an update from him, too.
I don't doubt that Rost is being treated by Pfizer as if he were giving off neutrons. Anyone who makes statements like he has, in any industry, is going to get the same, if they're not pitched out onto the street first. Rost has escaped that fate, apparently, because Pfizer's marketing of the growth hormone genotropin is under investigation, and Rost was in charge of that at Pharmacia when Pfizer took over. He's likely to be protected under whistle-blower law, and firing him would be a public relations problem for Pfizer under any circumstances. So, they can mostly hope that he leaves, and try to make that an attractive option, but that's about it.
There are worse fates. If you haven't lived in the area, "Peapack, NJ" sounds like it must be surrounded by oil refineries or something. It's actually surrounded by beautifully landscaped estates. That's the horsey, expensive part of New Jersey, not the asphalty 24-hour-check-cashing part. But Rost seems to be able to afford it, since at the very end of the article we find that his annual compensation is over $600,000. Many Times readers probably found themselves wishing that their own companies disliked them as much.
Now, Rost is telling the truth as he sees it, and any information he has about misconduct has to be put in a different category than his ideas about reimportation. Given the career consequences (paycheck aside, along with his recent raise,) I have to respect him for speaking his mind, while still largely disagreeing with his opinions. But he shouldn't have expected anything much different than what he's getting from Pfizer, and calling the news organizations about it with updates seems a bit much.
There's a recent piece in Business Week Online that says nice things about the biotech and pharma industries, and I should be happy about that. But there are so many misconceptions in it that I'm going to fisk the darn thing instead.
After a lead-in which discusses a patient who responded to the Sugen/Pfizer kinase inhibitor for kidney cancer, the BW pieces says that cases like this:
". . .have convinced many doctors that medical care is reaching a tipping point. Not that most patients will be healed right away -- the vast majority of sick people continue to dose themselves with tiny bits of chemicals, otherwise known as pills, that represent medicine's Old Guard.
But the times are changing. The past 30 years of biological discoveries, insights into the human genome, and exotic chemical manipulation have unleashed a wave of biological drugs, many of them reengineered human proteins. These molecules have the power to change the prognoses for a huge range of diseases all but untreatable just five years ago. "
Well, first off, Malcolm Gladwell should ask for royalties for use of the phrase "tipping point." But as he doubtless knows, and the authors of the Business Week article should, the drug industry doesn't quite work that way. This isn't a marketing campaign. Advances come on independently, each at its own pace and with its own problems. If several come at roughly the same time, coincidence is as much a factor as anything else. And it's worth remembering that this particular inflection point has been proclaimed about every ten months since the mid-1980s.
Second, the Sugen/Pfizer compound is nothing more than one of those "tiny bits of chemicals" (known as pills, it seems) straight from the Old Guard. It is nothing even close to a reengineered protein. No exotic chemical manipulations are required to make it; a talented undergraduate could whip up a batch (although I wouldn't recommend that to any talented undergrads who might be reading this.) That's just how we folks in the Old Guard like our compounds to be - not terribly expensive to make.
Later on, we get into the academia (good!) versus the pharmaceutical industry (bad!) debate:
""What's interesting is that it is really the academic researchers that pushed biotech forward, not corporate research and development," says Allan B. Haberman, principal of pharmaceutical consulting firm Haberman Associates in Wayland, Mass.
Academic researchers, unlike traditional drug companies, were willing to champion biotech approaches to drugs even when they were long shots. ImClone Systems' (IMCL) Erbitux, a colon-cancer treatment approved last year, would not exist today if not for the efforts of its discoverer, Dr. John Mendelsohn. The scientist-clinician spent 20 years working to find a company willing to commercialize his discovery that some tumors could be stopped by blocking a certain growth enzyme.
Even Gleevec, the most effective cancer drug of the past decade, was almost abandoned by Novartis (NVS). An outside cancer specialist, Dr. Brian J. Druker of Oregon Health & Science University, coaxed the company into pursuing its development."
Let's take those one at a time. It's true that many of the basic discoveries that have led to the current biotechnology industry came from academic research. That's just as it should be. But none of it would have been turned into human therapies without that "corporate research and development." Allan Haberman's statement makes it sound like the industry just sat around while the universities cranked out all the gold, which is untrue. [Note: see Haberman's own take on this in the comment section.]
The examples that follow help prove the point. The thing is, for every Erbitux and Gleevec story, there's a Cell Pathways counterexample - scrappy outsiders who pushed long-shot drugs with all their might, and all the venture-capital and equity funding they could get, only to find that they didn't work. Only the success stories are remembered, it seems. If the Cell Pathways drug had worked, it would be in this story, too. But it didn't, and it wasn't because it wasn't "biotechy" enough, either.
And it's not like Erbitux is that great a drug, either, frankly, as I've pointed out here numerous times. Imclone has been just fantastic at generating headlines, some of them inadvertent, so Erbitux is one of the things that people think of first. But it's hardly the stuff of a revolution. And Gleevec (another one of those small chemicals, by the way) is only "the most effective cancer drug of the last decade" if you have the rare cancers known as GIST or subtypes of CML. But if you don't, it's basically useless, not that that's stopping thousands of desperate people from trying it out. The reason Novartis didn't want to push the compound was that they thought that its potential market was just too small. They didn't realize that they were developing the world's first billion-dollar orphan drug.
Then comes this whopper:
"Traditional pharmaceutical companies shied away from biotech for years, unwilling to bet on unproven technologies. It didn't help that biotech's earliest accomplishments met with setback after setback in the 1980s and '90s.
Today, Big Pharma is paying for its risk-averse stance: Major players have few promising products in their development pipelines, and most are stuck with a business model heavily dependent on blockbuster drugs. Boston Consulting Group estimates that, as a result, biotech firms produced 67% of the drugs in clinical trials last year but shouldered only about 3% of the $40 billion that the drug industry spent on R&D."
Shied away from biotech for years? We pumped uncountable billions into it, much of which we never saw again. And as for that business model, the one heavily dependent on blockbusters? That's what we logic choppers call post hoc, ergo propter hoc. Once a company finds a huge winner, it becomes dependent on that revenue by default. And I have trouble imagining anyone saying "You know, this drug could sell two billion dollars a year. We'd better drop it. I don't think we can handle that kind of money."
Later, the article takes a look at some specific therapeutic areas, such as cancer. The next excerpt contains a couple of nearly unnoticeable palmed cards - see if you can spot them:
"Unlike heart disease, where patients choose between seven nearly identical cholesterol-lowering statins, targeted cancer therapies come in many forms. There are drugs that block tumor-growth factors, starve the tumor by inhibiting blood-vessel growth, combine radioactive isotopes with tumor-seeking proteins, and use vaccines to train the body's immune system to attack cancer cells.
There is even a next wave of multitargeted drugs that could start winning FDA approval as early as next year. Sutent, the drug keeping Julia Barchitta alive, is a member of this emerging class, known as multi-kinase inhibitors. They block blood-circulating proteins that are responsible for both tumor growth and blood vessel creation. Other closely watched candidates in this class include sorafenib, developed by Bayer (BAY) and Onyx Pharmaceuticals (ONXX) for kidney cancer, and lapatinib, a breast cancer drug from GlaxoSmithKline (GSK). These multitargeted therapies seem particularly effective against the hardest to treat cancers, giving hope to some of the sickest patients."
The idea that "cancer" is a single disease category just like "heart disease" is ridiculous. And note that "heart disease" is being defined as equivalent to "high cholesterol" - thus the mention of the statins. But Pfizer has gone to great lengths to prove that Lipitor is actually different from the other statins (and other companies have gone to great lengths only to end up proving the same thing, to their sorrow.)
Cancer is a constellation of hundreds of diseases, all characterized by uncontrolled cell growth. The complexities of the pathways involved give us plenty of potential mechanisms to target, and there we have the second switcheroo in this section. Those wonderful drugs that were being held up as examples earlier in the article - Erbitux, Gleevec - are targeted to only one or two of those mechanisms. And although that was their big selling point at the time, that's probably why they don't work very well. Those "multitargeted" drugs are not a refinement on this idea, they're the opposite idea.
The popular press is having quite a time catching up with this. You still see articles extolling the bold new era of tightly targeted cancer drugs, but they're being overtaken by the articles extolling the bold new era of messy blunderbuss cancer drugs. It's true that these compounds aren't in the same side-effect league as, say, the old cytotoxic agents like cisplatin, but they're a long way from the lasering-in-on-the-single-important-factor storyline from a few years ago.
The rest of the article focuses on stem cell therapies, and that will have to wait for another long post all its own. The cancer section closes out with a quote from Judah Folkman, who is an honest man:
". . .cancer specialists are hopeful that, as more targeted therapies come on line, they can be combined into cocktails that will keep cancer patients alive for years. Renowned cancer researcher Dr. M. Judah Folkman of Children's Hospital in Boston says the most important thing is that the drugs give patients hope: "We have something to offer [patients] now, and if it keeps them alive a little longer, something else might come along."
That sort of deflates the buzzing balloon that the rest of the article represents, doesn't it? Try turning that quote into a headline, won't you? But it's the truth. . .
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+ TrackBacks (0) | Category: Cancer | Drug Industry History | Press Coverage
Saturday's New York Times had an astonishingly sensible article about the drug reimportation issue. (You can go ahead and insert the phrase ". . .especially for the New York Times") Some highlights:
"It may make political sense to point to Canada as a solution to high prescription drug prices in the United States. But many economists and health care experts say that importing drugs from countries that control their prices would do little to solve the problem of expensive drugs in the United States, where companies are free to set their own prices. Even the nonpartisan Congressional Budget Office estimated that allowing Canadian drug imports would have a "negligible" impact on drug spending. To begin with, there are not enough Canadians, or drugs in Canada, to make much of a dent in the United States. There are 16 million American patients on Lipitor, for instance - more than half the entire Canadian population."
Quite so, and as the article goes on to point out, we in the drug industry have no incentive to ship Canadian pharmacies ten times as much stock as they need for their own country. It's not going to be pretty, but cutting things off at the supply end is what's going to happen - unless, of course, Congress manages to make that particular business decision illegal, as they're threatened to do. Here's some more:
". . .the measures proposed so far would do little to change the fundamental economics of the drug industry as it exists today. Prescription drugs cost a lot to invent, but once invented cost little to manufacture. That is why patents are granted to drug companies - to prevent other companies from copying their inventions long enough for the inventors to set prices high enough to recover their investment and make a profit. But price controls short-circuit this system."
That's absolutely correct in every detail, and such is the state of journalism today that I could not believe my eyes when I read it. I starting waving the paper around, clutching my chest and calling out to my wife: "It's the big one! I can feel it!" She's used to me. And one last quote:
"But the United States market is hard to compare with any other. It represented more than half of the global drug industry's sales of $410 billion last year and was the country in which drug companies make the bulk of their profits. Whatever one thinks of the pricing disparity, efforts to force down American prices to Canadian or European levels could radically change the economics of the pharmaceutical industry - which effectively depends on United States profits for all of its activities, including a substantial portion of its spending on research and development.
American consumers are "subsidizing everyone's R&D,'' said Mr. Love, the consumer advocate. "We're paying way more than everyone else. Others should pay more.''
This article is bylined Eduardo Porter, and I wish to publicly salute the man. I'll think of this every time I'm about to get the vapors about reimportation and remind myself that good sense can break out.
Comments (8)
+ TrackBacks (0) | Category: Drug Prices | Press Coverage
Update: (Much) more on this topic here.
Readers are already asking me if I've read Marcia Angell's new book, "The Truth About the Drug Companies." I think that some of you are trying to do me in, hoping I'll completely throw a piston rod or something. It's a real possibility. Angell's take on my industry profoundly irritates me. Here's Janet Maslin's New York Times review of the book from yesterday. She finds the book to be "tough, persuasive, and troubling" although she says that Angell is "likely to be on the receiving end of some angry rebuttals."
I'm glad to pitch in on that worthy effort, but I'm going to try to do it in a larger (and larger-paying!) forum. The thing is, the drug industry deserves some criticism. I've handed out a bit myself. Maslin's review points out Angell's angry words about Claritin/Clarinex and Prilosec/Nexium - hey, join the flippin' club, Marcia. But in this kind of book, the worthwhile stuff gets buried in all the flying horse manure.
To pick just one road apple, Angell is a great fan of the "All The Drug Companies Do Is Rip Off NIH" line - which, I can tell you, most folks in the drug industry have never heard of. (And you should see the expressions on their faces when they do.) There are people who call for drug companies to immediately give up every penny they've made on any marketed drug that had anything to do with an NIH grant. I've spoken about this before, and I'm sure that I will again, but for now, I have just one question:
Can we get reimbursed for all the ones that didn't work?
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+ TrackBacks (0) | Category: Press Coverage | Why Everyone Loves Us
Last Wednesday's Wall Street Journal had a very interesting article on the front page: "In Two Generations, Drug Research Sees a Big Shift." It profiles Leo Sternbach, discoverer of the diazepams (Valium being the most famous) and other drugs, and his son, Dan Sternbach of GlaxoSmithKline. The elder Sternbach has been at this stuff since 1940, so he's seen the lot. (The article isn't online, but an earlier account of his research is here.)
He began work in the era of open buckets, wooden paddles, and trying drugs out on yourself to see if they did anything. After one of those, he recounts, "For two days I was not at all well." In my first job, I overlapped with just a few people from the last of the era, and they had similar stories. The thought of eating one of my own research compounds has always given me the shakes. No thanks - not before a whole long list of mice, rats, and larger mammals have had their turn. Believe me, no one does that today, and anyone who did would be asking for huge amounts of trouble. It's interesting to note, though, that the practice doesn't seem to have done Sternbach any long-term harm, since he's 95 and all. I should note, for balance's sake, that other chemists from even earlier days are known to have poisoned themselves but good through such techniques.
I found the article particularly interesting because Dan Sternbach was a professor of mine when I was in graduate school at Duke in the mid-1980s. He left for greener Glaxo pastures while I was there, but I did take his class in frontier molecular orbital theory. (That's yet another of the things I learned in grad school whose applications since then I can count on my fingers. It's hard to explain briefly for my non-chemist readers, but here's a PDF to give you the flavor of it.) I would have found it pretty interesting to know, back in 1984, that Sternbach and I would end up at competing drug companies. At least once, to my knowledge, we've been competing in the same area of research at the same time. His years at Duke meant that he started in industry just three years before I did, actually, although with his running start he certainly came in at a higher level.
One Sternbach story I have is when a group of us were grading exam papers for a section of sophomore organic chemistry he was teaching. We attacked it as a team, each person taking on a set of questions and grading the whole class's answers to them, passing the papers on to the next person for them to check their section. One of us hit a paper where the student had made it about halfway through an answer, and had scribbled in a frustrated "I can't remember the goddamn equation!" We all enjoyed that one, but as his paper made it around the table, it turned out that he had a couple more similar fits: "Don't know the goddamn reaction!" and so on. When it came time to total up the scores, Sternbach looked at the guy's exam and mused "I should just write on there: '148 out of 200, Goddamnit!' "
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+ TrackBacks (0) | Category: Drug Industry History | Press Coverage
So Entremed is finally giving up on its celebrated peptide drug candidates, angiostatin and endostatin. I'm sorry to see what the company, and its employees have been through, but I'm even sorrier when I think about what cancer patients have been through during this story. Especially those of them who read that (in)famous New York Times story back in 1998, with the (in)famous James Watson quote about curing cancer in two years. (He might as well wear a sign: Loosest Cannon in the Room - Come Here For Quotes!)
I wrote about this whole issue back on my Lagniappe site a couple of years ago, which led to an interesting exchange with Mickey Kaus about whether the Times article had been vindicated or not. Kaus is a wonderful political journalist, but would be the first to admit that he's no pharmaceutical expert, and his take was that the focus on angiogenesis made the Times article look better, in retrospect. My contention was that angiogenesis was already known to be a good area to work in. This was thanks in good part, it's true, to Judah Folkman, who was also a main subject of the article. But the emphasis on angiostatin and endostatin was perverse.
By the time the Times ran their front-page above-the-fold horn-honker, legions of people had already decided that Folkman was on to something. And they were working on better compounds to try the theory out. The problem with Folkman's peptides was that they were, well, peptides, and unusually painful ones to work with, at that. Angiostatin and endostatin are not that easy to produce, to purify, to store, or to dose, as opposed to the small molecules that were also already in clinical trials.
Once you dose peptides, they get hammered, chain-sawed, and burned down to the ground. I love coming up with verbs to describe the process, I have to admit. If you saw a plot of blood levels after dosing a typical peptide drug, you'd see just what I mean. It takes a pretty specialized protein to circulate around after an i.v. dose without getting enzymatically ripped to shreds, and as for oral dosing, you can forget it. The gut is very efficient at grinding every protein it sees down to its component amino acids.
So Entremed's compounds were flying into a stiff breeze from the beginning. And, as so often happens, anti-angiogenesis as a cancer therapy has turned out to be more complicated than anyone thought. (If you work in the drug industry, you could take that last phrase and turn it into a keyboard macro to save time. It's practically our motto.) There are many, many possible targets in the field, and we're not that sure which ones are most likely to work. And a lot of them are so biologically similar that it's hard to make selective drugs that work against them, anyway, thus many clinical candidates turn out to have a large and ill-defined footprint. To add to the confusion, different types of tumors express different amounts of these various target proteins, and their relative importance is surely all over the place as well. Not that we know yet, of course. And I'm only talking about the cases where vascularization is thought to be important; many other sorts of tumors are poor candidates for anti-angiogeneic therapies right from the start.
No, these compounds have been doomed for years, as far as I can see. They were long shots even when the Times sent Entremed on its insane ride up to nearly $100/share. I remember scoffing at the article when it came out, and I remember trying to go short the company's stock (couldn't get the shares to borrow.) But while all this was happening, people were getting their hopes up, desperate patients who thought that this might be their chance for survival. How many of them who read that article are still alive today?
I'm normally a pretty optimistic person, but I make an exception for my work. We should never let people get their hopes up. Not until we're really, really sure. We don't know enough. This whole situation wasn't Entremed's fault, and it certainly wasn't Judah Folkman's. This one gets chalked up to the New York Times.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Press Coverage
I'm late to this particular party - see Charles Murtaugh and Medpundit for the low-down on a particularly irritating LA Times column. (It requires registration to read, which is fairly irritating all by itself.)
In a nutshell, the writer attempts to blame environmental factors for many cases of breast cancer, specifically chemicals produced by the very companies that are working on treatments. This comes very close to one of the things that will set off even the most mild-mannered pharmaceutical researcher: the conspiracy theory that says that They're Making Us Sick Just So They Can Sell Us Their Drugs. (That one's right next to They've Really Got A Cure, But They're Just Waiting Until More People Are Sick.)
Well, I'm not exactly the most mild-mannered pharmaceutical researcher, myself. And this stuff makes want to throw a one-liter filter flask at the person who espouses it. If the author wants to indulge in stupid breast cancer etiology, why not go for the deodorant theory? That one's even more mindless.
I understand the human tendency to look for a proximate cause for everything, and to search for patterns even in random noise. It's even more tempting to think that the answer's been right under our nose (or under our arms!) the whole time. "Aha! We should have known!"
But this is offensively foolish stuff. I don't have the time to dismantle it thoroughly enough tonight, but perhaps I'll give it another kick in the shins next week. We'll talk about real epidemiology instead of inflammatory guano.
Comments (0)
+ TrackBacks (0) | Category: Cancer | Press Coverage
Here we are again. Back in February (see the Feb. 27th post), the FDA asked for more data for Imclone's cancer therapy, Erbitux, saying the existing studies were not sufficient to approve the drug. The Wall Street Journal's editorial page threw a memorable fit about what they saw as the FDA's intransigence (to which piece I responded on June 18th.)
Now comes AstraZeneca to the FDA, similarly looking for fast-track approval of their similarly targeted (see the August 20th post) small molecule therapy, Iressa. The FDA's advisory panel met today, and ended up appoving the drug. The reviewer comments in the briefing documents suggested on Monday, though, that AZN was in for a hard time - and because of similarly unconvincing data.
And once again, the Journal weighed in today with a table-pounding editorial. Allow me to comment on their worldview:
Earlier this year, Astra-Zeneca reported very encouraging results from a couple of small trials totaling about 400 patients. The drug shrank tumors in 10 to 19% of lung cancer patients who had not responded to chemotherapy, and improved symptoms in about 40%. Most importantly, it appeared to add to the length and quality of life.
Sounds impressive when you put it that way! Let's look at the trial that AstraZeneca is using as their showpiece: 216 patients with non-small cell lung cancer who had failed standard chemotherapy. Unfortunately, the FDA contends that only 139 of those patients had truly not responded to earlier treatments. (The presence of these patients muddies the statistical evidence quite a bit, and it's just this sort of thing that helped to get Imclone's application in trouble.)
How many of these 139 responded to Iressa? Ten percent. Is a 10% response rate good enough to provide real-world clinical benefits? Is it enough reason to approve a drug on an accelerated schedule? Both those questions are very much open to argument, and even if the answer to the first one is "yes," reasonable people can believe that the answer to the second one is "no"
How about those improved symptoms? We have AstraZeneca's word that 40% showed some improvement in coughing and shortness of breath. But these results are not compared to any sort of control group, making them very hard to interpret - actually, it flat out makes it hard to determine that they're not an illusion. Other medications were also administered during the trial, and the study design makes it difficult (perhaps impossible) to say if those were responsible.
Most importantly, it appeared to add to the length and quality of life. Studies of Iressa in other cancers, such as head-and-neck, and yielding similar results.
That last statement is, unfortunately, true. The overall response rate in the head and neck trial (reported in May at the ASCO meeting) was 11%. As for quality of life, measuring that is hard enough under any circumstances, and measuring it without a control group is, I believe, basically impossible.
How about the other studies? The ones that this impassioned editorial doesn't mention? The two lung cancer studies that dosed Iressa plus standard chemotherapies - you know, the studies that actually had control groups? Iressa didn't have a 10% response rate in those. It had a zero per cent response rate - it didn't add to the effects of either one of the standard agents at all. The FDA found itself in the position of being asked to approve a drug that has completely failed to work in two studies, and shown marginal effects in two more.
. . .it is actually a repudiation of the speedier approval process the FDA has come to accept in drugs for terminal disease. . .that means approval base don smaller, so-called Phase 2 trials, along with compassionate use data to help establish safety. . .compassionate use programs can make a nit-picking bureaucrat's life difficult, by getting good drugs into the hands of many doctors and patients, who thereafter become a constituency urging formal FDA approval.
Nice use of the adjective. Compassionate use can also make a drug company's life difficult, as an avalanche of requests comes pouring in. It can make a scientist's life difficult, because the data obtained are usually of poor quality - heterogeneous and not well controlled.
But let's get emotional, since the Journal does: compassionate use can also make things damned difficult for terminally ill patients and their families. Remember, patients know they're getting an experimental drug, their last chance for survival. The FDA heard from some of those patients today, and I'm glad that they're still here to testify. And let's talk about those "good drugs": remember, in the lung cancer trials, 90% of the patients who took Iressa as monotherapy did not respond. And 100% of the patients who took it in combination therapy saw no added benefit. We didn't hear from these patients today. Many of them aren't around to talk about how hopeful they were that this new drug might save their lives.
The point here isn't to quibble with the FDA's suggestion yesterday that the data could be better. Studies can always be larger.
Yep. That helps. And drugs could always show some convincing efficacy; that would help, too. That's one good definition of the data being better.
The point is that this isn't a good reason, and certainly not an ethical one, for delaying approval. Particularly in cases of terminal disease, any safe drug with even a hint of effectiveness should be brought to market as quickly as possible.
An uncontrolled trial of powdered milk could end up showing "a hint of effectiveness," guys. Iressa's better than that, of course, but where do we draw the line? If we don't insist on solid statistics from well-run trials, we might as well just throw open the floodgates. The FDA is trying to get companies focused on proving that their therapies actually do something, while (because of the state of the industry) many companies are focused on trying to get their drugs on the market by the quickest route possible, cutting the clinical trials as thin as they can. Imclone's a much more spectacular example of that, but AstraZeneca should still count itself lucky to have gotten Iressa through.
Reading the editorials that the Journal has pumped out over the last few months, you get the mental picture of mustache-twirling FDA baddies snickering as cancer patients expire all around them. It's a caricature of the truth. It feels odd for me to stick up for a regulatory agency, but I'll stick up for this one. Speaking as a researcher in the industry, I can say that the FDA drives us all nuts, but we need them. We need people to poke holes in the studies, to question the data, to give us a hard time. It's called science. It's how we've made it as far as we have.
I've received some mail pointing out that James Watson denied the "cure cancer in two years" quote which appeared in the 1998 Times article. I was aware of those denials, but (since you have to make a judgment call on these things,) I believe that he probably did say it.
Why? First of all, because it's hard for me to believe that Gina Kolata, the Times reporter, would invent such a doozy of a quote. It's one of the main things that people remember about the article, four years later. It would take nerves of steel (and some other metallic parts) to fabricate that one. Second, Watson has a history of, well, outspokenness. No one I heard at the time had much trouble believing that Watson would have said it. Or that he'd deny it. The incident occurred at a dinner party; I don't know if other witnesses came forward.
I'm also sticking to my interpretation of the Times story as well. Angiogenesis wasn't a new concept when the piece came out. Folkman certainly had been one of the main movers behind it for many years, and his story was well worth telling, but the article centered just as much on the peptides he was working on. Note the link above, which was written at the time of the initial furor. Its whole focus is on the two peptide drugs, and whether they were miracle cures or not. Here's another 1998 story from Time with the same take.
Over at the new home of Kausfiles, Mickey Kaus wondered on Monday about all the news coming out of the ASCO (American Society for Clinical Oncology) meeting. Does it show that the hype in the famous 1998 NY Times front-page story on Judah Folkman and his cancer therapy was actually justified? Does the world owe Gina Kolata (the reporter) an apology?
You won't catch me offering too many opinions on welfare reform over here, so I can't resist weighing in when Mickey Kaus has some on drug discovery. Some background: the ASCO meeting is one of the most Wall Street-ocentric of the medical meetings. It's a forum for late-stage cancer trial results to be presented, and investors watch everything for signs. The headlines from the meeting tend to be out of proportion to the actual news.
Witness the NY Times the other day, saying that Imclone's Erbitux drug "fails" against a placebo. Nothing of the kind! (I seem to have imported some Kausfiles exclamation points.) I'm intensely sceptical of anything Imclone has to say, but these results (as the Times story pointed out about 3/4 of the way through) just failed to show Erbitux working well. Absence of evidence isn't evidence of absence. This was a small study, and the placebo group fared much better than expected, which blew the statistical significance of the Erbitux results. It happens, and that's why you try to run big studies when you can: a larger sample has less chance of showing this sort of jumpiness.
It's true, though, that there's a lot of anti-angiogenic drug news at the meeting this year. But there was a lot last year, and the year before. Angiogenesis has been the hot topic for many years now. Judah Folkman deserves the credit for pushing this idea, and for sticking with it for a long time without much company. But that was well before the Kolata article; by the time it came out, every major drug company (and plenty of minor ones) was on the case, and had been for years. There are a lot of different angiogenesis mechanisms, and a lot of room to work in.
That's why, when I read that article, I smiled to myself at the breathless tone it took about Folkman's peptide drug candidate (a tone that wasn't Folkman's fault.) Because peptides, like his Endostatin, generally make lousy drugs. For one thing, you can almost never give them orally; they have to be injected, like insulin. (The biggest reason is that your gut treats the peptides from a pharmacy exactly like it treats the ones from a hamburger: it digests them, rapidly tearing them down to amino acids.)
And angiogenesis inhibitors, like many of the other new cancer therapies, are probably going to be every-day drugs, which are no fun to inject. It's doubtful that they'll make the cancer disappear completely, and in some cases they'll do well just make it stop growing. If you stop taking the drug, the tumor will probably pick right up where it left off. I can't imagine anyone wanting to find out. (Combinations of the newer drugs with the older cytotoxic ones might deliver the knockout punch, but again, who wants to find out that it didn't? Those will be difficult trials. . .)
Orally active small molecules are the way to go - and I don't say that just because I get paid to discover them. They're cheaper to make, easier to purify, and you can take them with the beverage of your choice. Entremed, the company that licensed Endostatin, is still trying to turn it into a drug (burning through heaps of Bristol-Meyers Squibb money for a few years along the way.) Meanwhile, small molecules targeting angiogenesis are already closer to being approved. I honestly don't see what a difficult, unstable peptide is going to have that these compounds don't.
The person associated with the Kolata article who really deserved to be whacked over the head is James Watson. He grabbed the spotlight with his ill-considered statement that "Judah is going to cure cancer in two years." Well, it's been four years now, and it's not happening. Judah Folkman's concept is already going a long way toward curing cancer, but his compound isn't. And that's the real problem with Kolata's article: angiogenesis wasn't news, and endostatin wasn't news. Drug development is the news, but it's slow, expensive, and doesn't make a snappy above-the-fold very often.
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