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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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March 22, 2005

Still Not All That Easy

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Posted by Derek

Speaking of cancer trials, I mentioned the other day how they tend to be smaller than those for many other diseases. But that doesn't mean that they're always easy to run, as a search for "clinical trial design oncology" will show. Note the number of people offering to help you out, via seminars, consulting visits, books, and entire journals devoted to the topic.

The problems start early. Patient recruitment is a big problem for many of the less common types of cancer, and it's getting to be a problem for the better-known ones, too. If you look at all the therapies that are being aimed at breast cancer, for example, and run the numbers, it looks like there aren't enough breast cancer patients in the US to fill out all the trials that would be needed. Cost is, of course, a big reason why a lot of clinical trial work is being done overseas these days, but access to a new pool of patients is a factor, too.

Which brings up another complication - do you want patients who've tried other drugs? That depends on where you're targeting your therapy. If you hope for it to be a first-line drug, you probably want patients that are newly diagnosed. There's a steady supply of those, but not everyone who's newly diagnosed is going to be willing to participate in a clinical trial, not when there might be more proven treatments available. The worst case is when you're looking for drug-naÔve patients with advanced types of cancer. That's feasible (in theory) for some of the ones that creep up on you (like colorectal cancer), but next to impossible for some others.

But if your drug is going to be a second-line therapy, then you should go ahead and see how it performs in patients who've already been through the first-line stuff. There is, unfortunately, a steady supply of those people, too, and they're often more willing to take a chance.

Your clinical trial design will also be influenced by the kind of cancer you're hoping to treat. If you're looking at a very specific type or two, as is the case with Novartis's Gleevec, you may have to cast the net pretty widely to round up enough people. (We'll ignore the fact, for now, that Gleevec sells a billion dollars a year, which means that a lot of people are getting it when it has very little chance of doing anything for them.) If you have a new mechanism that hits all kinds of cancer cells, then you may want to dip into all sorts of different patient populations to see if one of them looks like a good place to take your stand in later Phase II and III trials. The danger in doing that is that your patients may be such a mixed bag that you can't get good statistics on anything.

Ah, statistics. You'll have noticed that I'm referring to cancer patients as if they were so many terms in an equation, which from the standpoint of drug development is exactly what they are. That comes across, to those outside the medical and scientific areas, as a pretty cold way to talk. Guilty as charged - but keep this in mind: people who work for drug companies get cancer, too, as do our friends and relatives. And we're just as upset as anyone else when that happens. But without the icy numbers, and lots of them, we're not going to be able to do anything to help.

Comments (6) + TrackBacks (0) | Category: Cancer | Clinical Trials


1. TW on March 23, 2005 11:38 AM writes...

Your comments about cancer studies and enrollment issues makes me wonder about the overall economics and business challenges of developing new cancer treatments. Would you say that a number of companies developing cancer drugs simply want to file an NDA with the easiest indication they can get from a regulatory speed standpoint... which might be something for which they can win orphan drug status? A company picks a gnarly and untreatable indication (e.g. pancreatic cancer) and goes for a second line treatment like SuperGen has. I base this on the feeling that the idea of a rationally designed cancer treatment is pretty unlikely with today's technology, with successful molecules being more the product of luck or intuition than molecular design. FDA's risk/benefit analysis would let barely significant efficacy and pretty ugly safety profiles through since without some drug death is inevitable and comes quickly.

Then, once the company gets an approval to market, they let the oncology doctors do what they do and the revenue slowly builds like Gleevec. Anecdotal reports from desperate physicians and patients support/suggest more and more offbeat off-label uses. A friend who recently graduated medical school said the joke during his oncology rotations was, "Why do they nail down the lids on coffins? Answer: To keep the oncologists from trying one more dose of something."

The ethical discussion surrounding cancer treatments is about as complex as it gets. When do you stop trying something? When do you, as a patient, physician or managed care company, stop spending mega-bucks on increasingly unlikely chances of success? And how do you build a drug business around such uncertainties and conundrums?

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2. Derek Lowe on March 23, 2005 1:19 PM writes...

That is *exactly* what happens. Companies pick the indication with the best intersection of likely clinical trial success and unmet medical need, in order to present the best possible package to the FDA. And it's assumed that physicians will prescribe nearly everything to nearly everyone.

As I've written before, though, this model isn't going to last forever, as we get a better handle on which drugs will actually work for which patients. But it certainly has some years left in it.

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3. qetzal on March 23, 2005 7:22 PM writes...

I'd be interested to know how successful this strategy is on average.

Gleevec is probably an extreme case. Logically, given its design and supposed primary mechanism of action, it should only be useful for a handful of folks. In practice, the sales figures suggest it's being used far more broadly.

But Gleevec got a *lot* of attention, which probably drove the off-label much use higher than it might otherwise have been.

I agree it's often assumed that oncologists will try nearly everything on nearly everyone. Any idea how true that really is for the "average" oncology drug?

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4. Derek Lowe on March 23, 2005 8:53 PM writes...

I remember reading an op-ed a couple of years ago, where the author spoke of losing his wife to brain cancer. He mentioned that the doctors had tried everything, even the (at the time) as-yet-unapproved Iressa. And I thought, if they'll give Iressa for that kind of tumor, they really will give anything to anyone. . .

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5. Michael on March 25, 2005 8:14 AM writes...

I'm new to the clinical trials field. The first study out of school is an oncology study. While it's great to finally be paid for instead of graded on my work, I found that I was getting depressed coming home after seeing so many casebooks with "Death from study disease."

One thing that has helped, and this may seem like a wild tangent, was a performance by Robert Schimmel, a five-plus year survivor. His stand-up act usually ends with a tribute to all those who participated as subjects in trials, those who had the indication for which there was no proven therapy and chose to participate so that families in the future would be spared the greif of losing someone close to them. It really helps on the days when you review a book that the subject was younger than you but expired from the indication you're studying.

Like I said, this may seem like a wild tangent, but it's important to remember that human side of the subjects. They potentially put themselves in harm's way so that future generations may benefit. It makes it easier when you realize the sacrifice these people made for our children.

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6. Scott S. on March 30, 2005 5:11 PM writes...

I've not heard of oncologists throwing any old drug at chronic lymphocytic leukemia patients. There are a variety of drugs to use, of course, however, I only have heard of people using the standard repertoire.

The 'last-ditch' treatment is a bone marrow transplant, and since 40-50% of patients die from the treatment itself, that narrows down the supply of patients who could try something else.

With only about 30% of patients surviving, and generally given a long remission, there is little motivation to try anything else.

I suspect in many other cancers that are so acute they kill within months, there just isn't time to try off-beat treatments.

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