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

Derek Lowe The 2002 Model

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

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

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July 22, 2004

Another Shot Across the Bow

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Posted by Derek

Since I last wrote about Imclone, the stock has had a rather difficult time. That's largely the fault of the Imclone fan club: Erbitux sales have exceeded some of the responsible projections, but still haven't caught up with the fantasies of some of the stockholders.

And now comes a study in the New England Journal of Medicine (about as high-profile a place as you can publish this kind of thing) confirming that Erbitux does shows activity in late-stage colon cancer, when added to the standard irinotecan therapy. Good news, eh? But in the end, the publication may do as much harm as good to Erbitux's prospects, because the same issue has a rather sceptical editorial comment on the study, and a longer perspective piece on the costs of such treatments in general. (Full text isn't available to nonsubscribers - the beginning of the editorial is here and the beginning of the Perspective is here. I'm going to cover that one in the next post for Monday; it makes this one too long and unwieldy when they're combined.)

The editorial, from two physicians at the Mayo Clinic, isn't kind. It's enough to make you wonder why they accepted the study for publication in the first place: ". . .the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan. Nevertheless, the appropriateness of the authors' reporting methods warrants discussion." They point out that the trial was statistically underpowered to detect some clinically meaningful differences, and question whether the reported response rate can justify using Erbitux as a monotherapy. The authors attempted to test the patients for EGFR expression, but it's unclear if they did this in the right way (it's not as simple as you'd think.)

Even if you take the statistics as they are, Erbitux added less than two months to the lives of patients, on average, compared to the current standard of care. The authors' verdict: there may well be clinical settings or treatment regimens where Erbitux is more useful in such colon cancer patients, but we don't know what they are yet. The addition of Erbitux to the list of treatments, they say, "must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effects on survival. . ." Not to mention the cost, which we'll take up in the next post.

In light of all this, I'd like to take a moment to address the Imclone-boosting stock cult, those few of them who might have read this far, anyway. Get out. Take the money and run. The alarm bell has sounded, and more than once. If you bought Imclone when it was in the dumper, you've had a great run. Celebrate and cash in! But if you bought it when I was ranting on the subject back in late June, you're in the red, and I fear that it's going to be even worse in the long run. Flee!

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cancer


1. John J. Coupal on July 23, 2004 11:28 AM writes...

Whatever the financial fate of ImClone, it yielded one giant victory for the drug discovery business.

FDA in the past had demanded that a potential new drug show stand-alone effectiveness. Because of Erbitux, that narrow vision for "drug efficacy" is now semi-officially dead. And, about time!

Cancer, mental disorders, metabolic disorders, and others show multifactorial beginnings and maintenance. Why on earth should one drug with its one mechanism of action be mandated as the only thing acceptable for treatment?

Many fronts of attack on a foe? It works in warfare.

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2. qetzal on July 23, 2004 12:36 PM writes...

A requirement for stand-alone effectiveness?

Aren't there examples of drugs that are only approved for use as adjuncts to other drugs or treatments?

If Erbitux is breaking new ground, how did these other drugs get approved?

I'm not saying that you're wrong, Mr. Coupal. Just highlighting my own confusion at your statement. Maybe you (or another reader) can elaborate.

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3. John J. Coupal on July 23, 2004 4:37 PM writes...

Qetzal is correct that many drugs are approved for use in combination with other drugs or treatments.

However, my original point [poorly stated] is that FDA rejected Erbitux at the very end of 2001 because of displeasure with clinical trials performed. The FDA has to approve clinical protocols before they start, and monitors them during progress. Why did FDA express displeasure with the final results, when it had oversight on the entire process?

In February 2004, FDA approved Erbitux for use in combination, or as sole treatment. My complaint is that many colon cancer patients died between January 2002 and February 2004 when the disapproved drug suddenly becomes approved.

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4. qetzal on July 23, 2004 5:41 PM writes...

Thanks for clarifying your point, Mr. Coupal.

IIRC, FDA supposedly told IMCL repeatedly that their trial design might be inadequate for approval. IMCL supposedly did not make that info public. As I understand it, IMCL had their ideas on how to prove efficacy, and didn't want to modify their trial plans. Basically, I think they knowingly took a relatively risky development path in hopes of getting to market as quickly as possible.

In addition, to the way the trial was designed, FDA also had problems with the way the trial was run. Something like IMCL not being able to document whether certain patients really did improve after treatment, or including patients in the analysis that shouldn't have been.

Please note this is all from memory, so may be wrong in whole or part.

More generally, it's basically true that FDA oversees the initiation and monitoring of trials. But it's up to the sponsor to design the trial. If the design is unsafe to the patients, or has other major flaws, FDA will hold it up. But it's not FDA's job to design good studies for the sponsor.

Similarly, FDA will step in a scrutinize an ongoing trial if there's a real reason to. Like if there are some very unexpected adverse events or something. But ordinarily, FDA is not reviewing the data or conduct of trials in progress. That only happens once the sponsor submits their NDA. FDA doesn't have the staff to closely monitor even just the Phase III trials. Again, it's the sponsor's job to monitor and ensure the trials are properly conducted. FDA's job is mainly to review and confirm after the fact.

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5. John Johnson on July 24, 2004 11:34 AM writes...

Just because the FDA reviewers have suggestions on how to design a trial doesn't mean the pharma company has to follow those suggestions. There is always the option that the company can do their own thing and then spend years arguing about its correctness (sometimes successfully, sometimes not).

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6. Rouel Felson on July 27, 2004 8:34 AM writes...

The FDA is a farce. While it hounds clinical trials in some areas it falls asleep at the wheel in others.
The quality control of generics is a pure and simple joke. For example Quinaglute. The timing agent(s) that cause the medicine to equally disburse throughout the body are inconsistent at best. This can cause a severe problem resulting in death and for many of us death is a definite problem. Just ask any cardiologist who has tried to balance a patient's meds once coming off of the real thing. In the end it is a boom for the defibrillator market because the meds are to inconsistent to rely on.
So please lets not make the FDA so Godly.

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