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Exelixis, Inc. Message Board

  • valleyofloire valleyofloire Jun 29, 2011 10:35 AM Flag

    Avastin FDA dilemma

    I'm not an expert on such subjects. But it doesn't seem to bode well for Cabo. Or many other biotech drugs? Especially for a drug like Cabo that also cuts off the blood supply to tumors. I wonder how the more informed who post here view this subject? The FDA sure isn't going to easy to convince. Also the cost factors are most in focus these days. It all is so scary for this long time holder of Exel.

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    • You are correct and I am sure Cabo will have the same side effect but the numbers are quite small and if benefits are good, the drug will be approved. I cannot give you a link the article but it is in the currect issue of the J. of Clinical Oncology

    • Would you please give a link to the article? I thought Avastin cut off the blood supply to the tumor just like Cabo. But that it was discovered that in cutting off the blood flow it created a side effect of maybe stopping the blood flow where needed? I seem to remember there was some undisered effect related to that. I maybe wrong?

    • Avastin is used for colon cancer and lung cancer all the time because the data says the benefits outweight the risks. If Cabo meets this criterion it will be approved. Again, look at the JCO phase I article and the editorial. The drug looks real

    • Ernie,
      Not to worry, there's a lot to keep up with. As always, I appreciate your major contributions to this board.

      The "Wiz"

    • My main intial point was the fear put forward about the trouble created by Avastin's cutting off the blood supply. I believed that was a problem Avastin created? Since Cabo also cuts off the blood supply. I thought that was a problem Cabo could also face. I thought they both work in a similar way in this regard? I don't think that point was addressed by anyone? I should have worded the post differently and avoided the philosophical gov., medical, monetary, ethical debate. I sorry.

      • 1 Reply to valleyofloire
      • Scarcely reported, but the major problem with avastin is the so called "rebounding effect". That is, after the treatment, this drug appears very impressive and efficacious (that is the PFS for example), however, over time the cancer exploits other pathways to overcome avastin's effects. The net rsults is the cancer, especially after avastin is taken off..the cancer relapses much more strongly and the individuals die much faster. If one could evaluate this phenomenon more carefully, I suspect this is true with other indications as well. The only way out of this "Avastin Dilemma" may be drug like Cabo (that attacks multiple pathways or addition of another drug that targets yet another pathway.

        Overall, Cabo should do well as or better than Avastin in the short this case 2 pathways may be better than 1.

    • Conrad,
      I appreciate your point of view but must respectfully disagree and certainly would not use the current avastin in MBC as the argument.
      FDA reviewers (just for the record, I am not one nor have I ever been) are cought between a rock and a hard place. If drugs take too long to get approved, they are accused of killing people. If drugs turn out to be unsafe, they are accused of being in the pocket of big pharma. And usually being outgunned. There are appeals processes (Roche/Genentech just went about as far as you can go with appealing a decision and lost some credibility in the process IMO), but no mechanism by which an individual can compell someone else to do give them an investigational agent.
      Keep in mind that there are plenty of for-profit clinics operating off shore if people want to get "cures".
      Despite the tendency to blast FDA (and being a government agency with its bureaucracy there is plenty to blast), it is not uncommon for Sponsors to not heed FDA advice, then gripe when they don't get the desired outcome. Recall the cetuximab/Imclone disaster. The company didn't do the trial right and that delayed a new treatment for several years. In the case of DNDN, I suspect the agency was being conservative since the results didn't fit existing paradigms; could they have granted accelerated approval there, perhaps. There is always going to be a balance between moving quickly nad assuring safety and efficacy, but it is clear that Sponsors have a vested interest (MONEY!) in getting drugs approved for as large a population as possible. It's reasonable for FDA to act as a referee.

      The FDA's existence came about as a result of snake oil salesmen and over time has raised the bar for selling medicines. Demanding safety AND efficacy has only been around since the early 1960's and demanding efficacy is a good thing IMO.


      The "Wiz"

    • <<I think you're confusing two different but very interesting stories in oncology:>>

      I got to thinking about it after I posted, looked it up and was just about to self correct, but you beat me to it. I should stay away from the biological aspects of this to avoid embarrassing myself.

    • It is in fact outrageous when the budget battles are being waged and real pain is being inflicted on middle and lower class populations and medicare is under direct threat that cost does not enter into many things we do for patients. I understand the need for incentives for companies to spend the vast amount of money needed to develop and test a drug but there is no excuse for charging $73000 to prolong life 4 months or to charge $76,000/year for a drug that cost almost notheing to develop (Revlimid). There is some much waste in medical care that we have to make very unpleasant choices. You want to call it rationing; so be it.

    • Ernie,

      I think you're confusing two different but very interesting stories in oncology: the use of small molecule inhibitors in lung cancer (gefitinib and erlotinib- Iressa and Tarceva brand names) and antibody inhibitors in colorectal cancer (cetuximab and panitumumab). For Lung cancer, it became clear that patients with activating EGFR mutations respond quite well and there are now data that in this selected population (positive selection) that treatment with an EGFR inhibitor actually is superior to chemotherapy. Tarceva has been approved since it showed a survival benefit, Gefitinib ended up being approved in Asia with status in the US in flux.
      For the antibodies, initially cetuximab was approved in combination for CRC and panitumumab was subsequently. As genotyping became more common, it was found that the only patients deriving benefit were those with wild type KRAS (i.e. mutant KRAS patients had no benefit), and FDA subsequently changed the indication to reflect this.
      You are correct that companies can almost always make investigational agents available to patients on expanded access if they are convinced that they are active. There is a real problem with what seems to be a general assumption that more is always better. There are new treatments and many are great drugs and represent great science, but not all are and not for all patients.


      The "Wiz"

    • I find it odd that I am defending FDA. I am frequently critical of many of their decisions and policies, but I see much of your criticism as unjustified or misdirected.

      <<When considering approval they take into consideration any other effective treatment.only >>

      I can only speak to the oncology department, I don't keep up with the other departments. The current policy is that new drugs have to equal or improve on the current defined standard of care and this is put into practice by requiring clinical trials with a standard of care control arm. Sponsors do have the option of establishing either equivalence or superiority when they design their trials. I agree with this approach. Placebo controls are unethical when there are effective treatments and comparative trials are needed to establish what is most effective and focus R&D in a positive direction. The cost of new drugs is staggering, but the payoff for society comes as these drugs go off patent and are priced based on competitive pressures.

      <<and the ever dominant cost considerations play into the determinations of efficacy.>>

      Cost occasionally creeps into discussion at ODAC. When it does, the FDA representatives present have uniformly reminded the members that cost is not a consideration for drug approval. Other government entities are more proactive when it comes to measures to limit cost or ration/restrict reimbursement.

      <<It also makes testing an insurmountable task as each test becomes multiple tests when the drug and all of the competing drugs must be retested.>>

      It is a necessary evil. Historic controls do not work. The increasing complexity as indications become more fragmented and new drugs are approved is an indication that the system is working.

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