Lessons For Drug Development From The Aveo Buzzsaw

5/6/13Follow @xconomy

Drug development is a tough business. Small companies that dare to try often end up in public train wrecks when they head to Washington to meet the FDA. It’s a shame, a colossal waste, every time a company gets that far and stumbles. And it doesn’t have to be that way.

The folks at Cambridge, MA-based Aveo Oncology (NASDAQ: AVEO), and their partners at Japan-based Astellas Pharma, know the feeling. They suffered last week as an FDA advisory panel voted 13-1 against Aveo’s application to start selling tivozanib to treat kidney cancer in the U.S. The drug had passed a large, well-controlled clinical trial and appeared to offer a small, but meaningful benefit for patients. Now, partly because of some mistakes the company made, and longstanding flaws in the way drugs get developed, it looks like the FDA is going to kick this drug to the curb. This painful verdict came down after 11 years of R&D and more than $320 million of investment.

Although Aveo appears to have fallen into some common errors that little companies make when they look to save time and money on trials, the experience truly exposes some deeper dysfunction in how clinical trials get conducted. The only way our society is going to get out of this bind, and start getting more of the cost-effective cancer drugs we demand, is by making some changes to the way we evaluate safety and effectiveness, and the ultimate bargain that’s being made with patients who participate in clinical trials.

Consider the Aveo experience. It had good reason to think it had a chance of winning FDA approval. It ran a 517-patient clinical trial that randomly assigned patients to get its drug or a different FDA-approved product. This was no straw man trial, designed to beat a mere lame placebo. Aveo’s drug kept tumors of kidney cancer patients from spreading for a median of 11.9 months, compared with 9.1 months for those on an active comparison agent—Bayer and Onyx Pharmaceuticals’s sorafenib (Nexavar). Side effects for the new compound were minimal. Aveo hit the main goal of the study, so it was time to go the FDA and ask for approval to hit the U.S. market.

While that all looked fine and good, Aveo’s application got ripped apart by the FDA advisors and staff for a couple of reasons. One is that too many patients—88 percent in the pivotal study—came from Central and Eastern Europe. Only about 8 percent of the patients in the key study came from North America and Western Europe, according to an FDA staff briefing document. That’s a problem, because the standard of care is different in the U.S. than it is in Eastern Europe, where patients tend to be poorer, medical standards are different, and there’s less access to advanced targeted drugs. That means it’s hard to extrapolate that a drug which performs a certain way there will perform the same way here.

The other problem in the Aveo application is that cancer drugs need to show they can extend lives, not just hold back tumors for a couple extra months. When the final survival numbers were tallied, they contradicted what was seen on the tumor progression scores. Patients lived a median of 28.8 months on the Aveo drug, and 29.3 months in the control group.

How could that be, that a drug which slows down tumors doesn’t help extend life? This happens occasionally in clinical trials, and sometimes the reasons elude scientists. But there was another explanation here, a quirk in the study design in which patients were allowed to “cross over.” What that means is that once patients were in the study, and saw their disease worsen, they were able to “cross over” to get another drug that might help.

Turns out that almost two-thirds of the patients who originally got the Bayer/Onyx drug (63 percent) ended up getting the Aveo drug later. What about the poor folks who were assigned the Aveo drug in the first place, and then had their disease worsen? They basically got nothing. Only 16 percent ended up getting any extra therapy after their disease worsened, according to the FDA staff document.

Now, no one will ever know for sure why those patients in the control group ended up living longer. Aveo advanced the notion that … Next Page »

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  • Argo

    1) A x-cross over design that was not communicated to the FDA

    2) Patients that do not mimic the US patient population

    3) A Hazard ratio that suggests increased possibility of death on tivo

    - I think the FDA did the right thing. sometimes Hubris sets in and managment doe snot want to listen to good advice from KOL’s and thought Leaders. They could have easily conducted an Ad board with some of the top clinical Trial design experts to give them great advice on how to do this study in an already crowded market of drugs in RCC.

  • http://twitter.com/chasingthealpha Patrick Crutcher

    AVEO deserves blame for the lack of secondary therapies for those on the Tivozanib arm, changing Phase 3 design without input and the lack of disclosure to investors over communications with the FDA. No question about it.

    However, the criticism over the design, number of US patients and fuss over the overall survival is ridiculous, especially by Dr Pazdur. The fact that journalists are not pointing out his lack of memory on these issues is astounding.

    1- Consider that the FDA approved Votrient in RCC based on an entirely EU based study(0% US patients). Only showed OS advantage since it was versus placebo, no crossover allowed.

    http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM184003.pdf

    2- FDA recently approved Axitinib for RCC. Axitinib initial HR=1.009 in 2nd line, final HR 0.967, not significant.

    3- Put into context the OS hazard ratio in the Tivozanib trial, HR=1.25, but median difference was only 2 weeks. OS reported in the TIVO-1 trial are some of the longest ever reported.

    http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ucm350074.htm

    4- Crossover certainly confounded the OS data. Recent analyses of sequential TKIs in RCC have shown differences in OS that were significant. I see no reason to believe the Tivozanib arm would perform worse than Sorafenib.

    At this point, maybe they resubmit with data from the BATON-RCC trial or TAURUS instead of a full-fledged Phase 3 trial.