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Derek Lowe The 2002 Model

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

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

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« How Much Success? | Main | A Drug's Target, Finally »

June 5, 2005

Biotech At Last, Eh?

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Posted by Derek

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. . .

Comments (9) + TrackBacks (0) | Category: Cancer | Drug Industry History | Press Coverage


1. AE on June 6, 2005 12:48 AM writes...

you forgot to close an italic tag.

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2. x on June 6, 2005 6:19 AM writes...

I enjoy your article. However, I found that Italic letters are very difficult to read.

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3. Carlos N Velez on June 6, 2005 10:19 AM writes...

I read that article as well. The entire thing is absurd. I'm surprised they didn't flaunt the $800 MM figure as well...

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4. Allan B Haberman on June 6, 2005 11:45 AM writes...

My quote in that article was a "synthetic quote", designed to fit the reporter's point of view.

What I really said was that pharmaceutical companies need to collaborate better with academic researchers. I then gave the example of Dr. Druker and Gleevec, and how he and other cancer researchers served as product champions from the outside. This experience led the CEO of Novartis to build a new R &D headquarters in Cambridge, MA, to help the company collaborate more effectively with biotech companies and academics.

"Synthetic quoting" is a very common practice among journalists, as most people realize. It is even, for good or for ill, considered legitimate by many people. But you should be careful about over-interpreting a quote, and assuming that it is exactly what an interviewed expert said.

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5. Ward on June 6, 2005 8:56 PM writes...

I wonder how such lousy reporting gets through, even though I'm not surprised. I think it is a combination of at least 3 things; the reporter does not understand the subject matter; they think they must portray everything as some sort of battle of good and evil as defined by their biases to keep the reader's attention; they don't teach economics in journalism school.

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6. Matt Maurano on June 7, 2005 1:12 AM writes...

So a "synthetic quotation" is an indirect quotation, surrounded by quotation marks? It seems underhanded to me, and disrespectful to punctuation.

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7. Allan B Haberman on June 7, 2005 10:45 AM writes...

By a "synthetic quote", I meant a quote based on rough notes, not a fabrication. (When we do phone interviews, we all make running notes, and then later use them to reconstruct what the interviewee said.)

In further contacts with the reporter, the misquote may have been more the result of a misunderstanding than a true "synthetic quote". In any case, she did nothing underhanded.

However, although I do believe that pharmaceutical companies need to do a lot better job of collaborating with academic researchers, I of course realize the leading role of industry in moving from a target or mechanism to an approved and marketed drug, and in bearing the economic risk of drug development.

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8. SRC on June 7, 2005 2:12 PM writes...

Re-engineered proteins and such sound sexy and high tech, but are always vulnerable to replacement by low molecular weight compounds.

Given threshold efficacy, the economics of the latter (COGS, storage lifetime, handling requirements), coupled with lack of immunogenicity and greater convenience (oral administration) are compelling, and probably always will be.

Biopharmaceuticals are a stopgap until corresponding low MW compounds are developed. Who would choose repeated injections over taking a pill?

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9. Charlie Hendrix on June 10, 2005 5:31 PM writes...

Derek wrote: "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."

In the recent ImClone "discovery" that Erbitux reduces the frequency of cancer spreading from the neck to the head, etc. the many media presentations of this made it sound like a major discovery. I've lost some facts, so I'm going to reconstruct from memory what I recall of these. 424 people were in the trial. More... in 56% of the instances cancer did not
spread (a favorable outcome) when Erbitux was used with radiation and in 48% of the instances cancer did not spread when alone radiation was used. The total number of subjects was 424. They (the media... ImClone... whatever) did not tell us how many of these 424 received the Erbitux + Rad and how many received the Rad treatment alone.
For the sake of discussion let's assume an equal split.... 212 in each group. 56% of 212 is 120 and 48% of 212 is 102 with some liberal rounding.
So we have 212 subjects (E+R) of which 120 were favorable and another 212 subjects (R only) of which 102 were favorable. Is this improvement "statistically significant" or is it more likely just due to chance? Fisher's Exact Test and the Chi-square approximation to it both produce a probability of 0.049. That is, the prob of getting a difference this large or larger by chance alone is 0.049. That's just slightly below the customary 0.05 level often cited in student textbooks. But in this context that's hardly sufficient to proclaim a "discovery". A tentative claim, yes. But a definitive claim, no.
It comes down to the fact that they needed more data. N = 424 not sufficiently large. Running another calculation with a split other than 212 vs 212 will only make matters worse; prob will be larger. I think I saw one media article in which this "improvement" was proclaimed as "statistically significant" and another which said the opposite. Again, this is from memory. No matter how we slice it, an "improvement" of about 8 percentage points is hardly noteworthy. If someone has more accurate numbers or information, please feel free to send it to me. Point: ImClone does indeed have a remarkable ability to generate headlines. However, they are not the only one that fails to provide "all the numbers" necessary to do a proper analysis.
In short, I'm not impressed with ImClone and I'm not impressed with the financial pundits who jumped on this as another score for ImClone.

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