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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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May 2, 2013

Aveo Gets Bad News on Tivozanib

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Posted by Derek

The kinase inhibitor tivozanib (for renal cell carcinoma) was shot down this morning at an FDA committee hearing. There are going to be a lot of arguments about this decision, because feelings have been running high on both sides of the issue.

And this has been an issue for over a year now. As that FierceBiotech story puts it:

Tivozanib hit its primary endpoint, demonstrating a slim but statistically significant improvement in progression-free-survival of patients with advanced renal cell carcinoma when compared to Nexavar (sorafenib). But the sorafenib arm experienced a slightly better overall survival rate, and Aveo has been trying to explain it away ever since.

The developer had to start in the spring of 2012 at a pre-NDA meeting. According to the review document, "the FDA expressed concern about the adverse trend in overall survival in the single Phase III trial and recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the US."

The Phase III in question was performed in Eastern Europe, and one of the outcomes of today's decision may be a reluctance to rely on that part of the world for pivotal trials. I'm honestly not sure how much of tivozanib's problems were due to that (if the data had been stronger, no one would be wondering). But if the patient population in the trial was far enough off the intended US market to concern the FDA, then there was trouble coming from a long way away.

Aveo, though, may not have had many options by this time. This is one of those situations where a smaller company has enough resources to barely get something through Phase III, so they try to do it as inexpensively as they can (thus Eastern Europe). By the time things looked dicey, there wasn't enough cash to do anything over, so they took what they had to the FDA and hoped for the best. The agency's suggestion to do a US trial must have induced some despair, since (1) they apparently didn't have the money to do it, and (2) this meant that the chances of approval on the existing data were lower than they'd hoped.

One of the other big issues that this decision highlights is in trial design. This was a "crossover" trial, where patients started out on one medication and then could be switched to another as their condition progressed. So many crossed over to the comparison drug (Nexavar, sorafenib) that it seems to have impaired the statistics of the trial. Were the overall survival numbers slightly better in the eventual Nexavar group because they'd been switched to that drug, or because they'd gotten tivozanib first? That's something you'd hope that a more expensive/well-run Phase III would have addressed, but in the same way that this result casts some doubt on the Eastern European clinical data, it casts some doubt on crossover trial design in this area.

Update: a big problem here was that there were many more patients who crossed over to tivozanib from Nexavar than the other way around. That's a design problem for you. . .

What a mess - and what a mess for Aveo, and their investors. I'm not sure if they've got anything else; it looks like they'd pretty much bet the company on this. Which must have been like coming to the showdown at the poker table with a low three-of-a-kind, knowing that someone else probably has it beat. . .

Comments (27) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs


1. alig on May 2, 2013 12:06 PM writes...

You have to wonder if it was run in Eastern Europe because there are several other VEGFR inhibitors already on the market in the US. This would be the 4th or 5th for the same indication. It is difficult to recruit patients when there are so many other drugs already approved.

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2. pgwu on May 2, 2013 2:21 PM writes...

Wonder how many CROs were involved in the trial and if they did their part in properly monitoring the trial. Design flaws seemed to get most of the attention at today's meeting.

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3. Anonymous on May 2, 2013 2:56 PM writes...

#2 pgwu: "Design flaw" is not a monitoring problem. "Design flaw" is a sponsors problem. Don't blame the CRO for a management decision. Blame them for execution, if you want, but not strategy. This was a strategic decision to throw for the end zone with Tim Tebow as your quarterback.

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4. Anon on May 2, 2013 3:15 PM writes...

Your "update" is still off - the problem was that Nexavar patients crossed over to tivozanib, not the other way around. That's why the OS analysis trended in favor of the sorafenib arm (according to Aveo).

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5. Hap on May 2, 2013 3:43 PM writes...

Considering the Jets' plethora of receivers, who would Sanchez or McElroy have thrown to? The Jets' offense was primarily "QB goes down checklist of offensive options, remembers that he doesn't have any, and gets sacked by the defense" with a sprinkling of "QB blinks, starts on checklist, gets sacked". I would have assumed Tebow was their best option (ability to run to make up for a poor offensive line, no worries about throwing because no one can catch, anyway), not their worst.

Overall, the Jets' roster (such as it is) supports your point about design flaws rather than execution failures being on the company and not its CROs.

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6. Hap on May 2, 2013 4:09 PM writes...

How are patients counted in a crossover trial? If more patients didn't improve on Nexavar than sorafenib (so that the burden of Nexavar non-responders fell on sorafenib while the burden of sorafenib nonresponders was not enough to skew Nexavar's results), shouldn't sorafenib show a significant and non-slight difference somewhere?

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7. jojo on May 2, 2013 4:10 PM writes...

@5 Hap: best comment ever on this site.

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8. Hap on May 2, 2013 4:42 PM writes...

Please (mentally) replace all my "sorafenib"s in comment 6 with tivozanib (if you care). Sorry.

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9. Anonymous 2 on May 2, 2013 4:46 PM writes...

The design was poor. Should of been tivo. vs. sutent.

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10. Derek Lowe on May 2, 2013 4:47 PM writes...

Fixed the update - sorry about that!

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11. Anon on May 2, 2013 7:46 PM writes...

As far as money goes...I think they may have been throwing it away. Why were they paying people like Depinho as consultants when they already had a stake in the company? (This came up the newspapers were writing about his conflicts of interest).

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12. Researchfella on May 2, 2013 7:59 PM writes...

The FDA is out of control. What's wrong with approving another multikinase inhibitor with efficacy comparable to sorafenib, to give physicians and patients another option? There doesn't seem to be a significant problem with efficacy or safety, so why not approve it and let the market take care of it? We have several options for statins and NSAIDS, and that's a good thing. Competition in the marketplace is good - isn't that the American way?

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13. David Young MD on May 2, 2013 11:58 PM writes...

Sutent (Sunitinib) is a pretty good drug for renal cell carcinoma. Trouble is, there are tough cumulative side effects, primarily the soreness and tenderness of the skin (fingers, toes) and the oral cavity (tongue soreness and sensitivity) that makes it difficult to remain on treatment. If Tivozanib was as effective as Sutent but less toxic (that it, a drug that can continued on for a longer time) then it would be a very attractive replacement for Sutent. It would good to compare the two in a trial for first line therapy, to see which drug could be tolerated for a longer time.

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14. Electrochemist on May 3, 2013 6:38 AM writes...

#12 Researchfella is spot on - and not just because of free market arguments. "Clinical efficacy" is a composite assessment of a wide variety of patients and outcomes. If one patient is "cured" and a second patient is a non-responder, the efficacy is 50%. But if you were the patient who was "cured" you might not consider the drug 50% effective.

The FDA has grossly overstepped its bounds by now basing approvals (in part) on comparative *average* efficacy to SoC (standard of care).

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15. Morten G on May 3, 2013 8:57 AM writes...

I'm not sure I understand clinical trials. Aren't they supposed to be approved by the FDA before being run with endpoints etc? Or do they simply have to have been submitted so the endpoints can't be changed?

I'm with #12. I don't understand why this was shot down if it was ~ as good as what else is available.

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16. Anon on May 3, 2013 9:05 AM writes...

@14 If that is the case then they can do a post hoc analysis and run another trial...maybe taking into consideration the committee's input on shoddy/manipulative trial design.

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17. anonymous on May 3, 2013 9:34 AM writes...

@12 "The FDA is out of control" and @14 "The FDA has grossly overstepped its bounds"

Maybe, but it should be pointed out that what happened today is an independent advisory committee recommended that FDA not approve tivozanib, which is different than FDA not approving tivozanib.

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18. researchfella on May 3, 2013 9:37 AM writes...

@17: The FDA selects the members of the advisory committee...

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19. alig on May 3, 2013 9:55 AM writes...

@12 -- you missed the point of what the FDA said. The FDA asked for a second trial to be run with American patients (instead of Eastern European). It didn't say they would never approve the drug. They asked for a trial in the intended treatment population. Doesn't seem too big of a burden to actually test the drug in the population you intend to use it. This isn't a breaktrough treatment, there are several other options for patients.

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20. fenichel on May 3, 2013 11:42 AM writes...

"I'm not sure I understand clinical trials. Aren't they supposed to be approved by the FDA before being run with endpoints etc? Or do they simply have to have been submitted so the endpoints can't be changed?"
A sponsor could, having done all its trials outside of the US, legally show up at FDA with a complete NDA, with FDA never having heard of the sponsor or the drug before.
Of course, that happens rarely or never. Any experimental human use of a drug in the US must be done under an IND registered with FDA. But even then, only the first study in an IND must wait for an FDA go-ahead. Thereafter, studies must be described to FDA, and FDA may insist that they be suspended ("clinical hold"), but many (early) trials are completed before FDA is even aware of them.
At the NDA stage, a sponsor may arrange for a "Special Protocol Assessment," thereby getting (or not getting) agreement that a proposed trial would, if its results were satisfactory, be sufficient for approval. This may be what #15 is referring to.
But: An SPA is not a binding contract, nor could it be. Trial outcomes are full of surprises: If the primary endpoint is a surrogate outcome (like progression-free survival), then a statistically-significant win might need to be interpreted in the light of contrary results on patient-visible endpoints (overall survival, days out of hospital, etc.). That may be what happened with tivozanib, although I don't know the data.

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21. Robert Fenichel on May 3, 2013 11:55 AM writes...

@17: "The FDA selects the members of the advisory committee..."
True, but more related to dumb error than to bias.
Advisory-Committee members are selected by an arm of the Commissioner's office, mostly far in advance of when any meeting's agenda is known. The people doing the selection are not scientists, and they are generally only moderately aware that one medical subspecialty is different from another. Their main concerns are apparent conflicts of interest, making sure that the Committee is not all white males, and so on.

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22. researchfella on May 3, 2013 3:17 PM writes...

@19: Unfortunately, what the FDA advisory committee has asked for is probably an unmanageable burden for Aveo to handle, and this will likely be the end of the drug (and maybe Aveo). My point is, even with that European patient population, the drug was demonstrated to be safe and effective, and comparable to sorafenib. Again, I see no harm and only potential benefit to allow this drug to be another option for patients and physicians. See #14's comments as well.

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23. Bboooooya on May 3, 2013 3:19 PM writes...

The FDA doesn't approve clinical trials, it gives permission for the study to proceed. The primary hurdle here is good data re potential harm to patients and realistic potential for efficacy.

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24. Hap on May 3, 2013 3:46 PM writes...

Why should it matter who is bringing the drug to market? If the safety and efficacy of the drug matters, then Aveo needed to perform the trial in a population relevant to who is going to use the drug. Not having the money to do so isn't an excuse - patients and the FDA shouldn't care if the drug was developed by a small or a big company. They just want to know if it's safe and works.

There is indeed potential harm - you may not know what tivozanib will do in the target population. It could work better, but it could also work worse. With multiple drugs of similar nature, opportunity costs for someone choosing a cancer drug could be pretty high if they choose the wrong one (or choose one that they think works but doesn't). Those are risks with current drugs, but current drugs have better data on how they work in the target population (so you know going in or have an idea how well they might or might not work).

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25. pgwu on May 3, 2013 4:09 PM writes...

#3. A sponsor bears the ultimate responsibility but I wonder for such a small company, how much it relied on CROs in the design of, in addition to execution of a trial, and if the design and the execution were somewhat interwound.

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26. researchfella on May 3, 2013 4:13 PM writes...

@24: Yes, yes, and if you're a renal carcinoma patient and you can't tolerate the standard of care, e.g., sunitinib, you would sure like to have several other viable options to try. The NCCN defines guidelines to help physicians and patients make educated choices for the right drug, so more options are not a problem. And maybe you happen to be someone who immigrated to the US from Europe or Asia, so what the heck is the relevance of the "target population" for some individuals?

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27. Hap on May 4, 2013 9:05 AM writes...

It sure doesn't look like Eastern Europe, unless you're selling in Chicago, maybe.

Having more options isn't helpful if you don't know what they'll do. Someone with cancer probably won't get more than one kinase inhibitor at a time, so having four versus five options isn't likely to do much good - by the time they would need the third or fourth option, they may not be around to use it.

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