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Exelixis, Inc. Message Board

  • erniewerner erniewerner Nov 26, 2010 4:18 AM Flag


    Hey Doc,
    Since we have you as a resource here I’d like to tap your experience and ask you to provide some professional insight on a particular topic. It’s a bit speculative in nature, but I’d be interested in your answers.

    Let me lay a bit of groundwork first. The general topic is off label use of oncology drugs. It is common practice to use many approved drugs for indications for which they are not approved. Sometimes indications are too small and the manufacturers are unwilling to do the necessary trials to seek approvals that are not considered profit worthy. Gaps in research are filled by government and quasigovernment organizations that do the trials to establish probable efficacy and a sort of de facto approval is given to drugs to treat indications other than those for which they are approved. Example: biliary cancer (cholangiocarcinoma) is a small indication for which there is not an approved drug, yet it is regularly treated with 5FU and even insurance companies generally cover the expense. Quite a while back, XL ran a phase 3 trial in this indication (XL119) and the FDA had them use an active control of 5FU despite the fact that 5FU itself is not an approved drug for biliary cancer. Gleevec was initially approved for CML in 2001. At the time of its approval the results of an uncontrolled study in GIST were made known that showed very good efficacy in that indication. To its credit, FDA moved quickly and added GIST as a supplemental indication within nine months. I have to wonder how many GIST patients received off label Gleevec while the FDA deliberated. I also wonder if insurance companies covered the expense.

    Okay Doc, here are my questions. If you would talk a bit about prescribing off label drugs in general---ie when you will and when you won’t. Also about the process required to get insurance companies to cover off label use.
    Now more specifically, let’s say that XL 184 is approved in late 2011 for MTC. Let’s also speculate and say that XL presents an uncontrolled data set at ASCO 2011 that confirms the activity of XL 184 in treating bony metastases in advanced HRPC patients. Under those circumstances would you prescribe XL 184 for an HRPC bony met patient? Would you suggest it yourself or only respond to a specific request? I understand this is a sensitive subject and a lot of these decisions are unfortunately driven by cost as well as patient welfare.

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    • Thx Doc, I hope your peers are as diligent as you seem to be wrt keeping up with latest developments in your field.

      You're right about the timeframe for MTC approval. Assuming Vandetanib approval, 184 probably will not get a priority review. Approval could come in late 2012 if that is the case.

      Agenda: On December 2, 2010, the committee will discuss new drug application (NDA) 022-405, with the proposed trade name Zictifa (vandetanib) Tablets, manufactured by iPR Pharmaceuticals, Inc., represented by AstraZeneca Pharmaceuticals LP (authorized U.S. agent). The proposed indication (use) for this product is for the treatment of patients with unresectable (non-operable) locally advanced or metastatic medullary thyroid cancer.

    • Hi Ernie,

      Thans for a very interesting and important question. As an oncologist, my inclination is to try to make available to patients the best therapy available. Oncology is pretty nototious for off label use and given the nature of terminal cancer, not waiting for FDA-approvable trials (to be honest, often a lower bar than is the standard for other specialties, but it's about risk/benefit). The landscape is changing and as costs have increased, payors have begun to weigh in. This is creating challenges in that an MD can prescribe something, but that doesn't necessarily mean it will be reimbursed. There is also the issue of what medications are on a partcular formulary. Given that Medicare will be paying for a lot of cancer meds, it's worthwhile following the debate over PRovenge and CMMS with regard to reimbursement). With all that said, I'd divide treatment decisions up as follows:
      1) the oncologist decision to treat- this is as varied as the number of medical oncologists. Personally, if I see good phase 2 data and there is nothing else available, I'm inclined to offer an agent off-label with a reasonable discussion with a patient. Other oncologists may lean to more aggressive treatment or more supportive care. Of course, I am a strong advocate of enrollment in clinical trials since that's the best way to see if something really does work.

      2) FDA-approved therapy. This will be based on one (or more) adequately controlled trials. Strictly speaking, this will be the population for which a specific agent will be approved. Usually this is based on the populaiton from the pivotal trail, though occasionally FDA will expand the indication. Typically if there is FDA approval for an agent, insurers have a hard time not covering something.

      3) The situation where there is preliminary encouraging data without a pivotal trial. This is a challenge. My rule of thumb in the past has been that if there are two published reports of an agent in an indication (e.g. two peer reviewed reports of drug X working in hormone refractory prostate cancer), in two separate trials, then you could reasonably expect to be reimbursed. This landscape has been changing lately with more insurers clamping back on reimbursement for these situations which are off-label.

      SO back to the scenario where XL184 gets approval for MTC. I wouldn't expect the opportunity for XL184 in CRPC to be too great at this point due to all the other agents and the lack of a clear treatment benefit. So let's assume the bone scan effects hold up and are durable. They are somewhat dischordant from some of the RECIST endpoints and appear to be very different than the PSA endpoints. To really understand these results would I think require to know what happens with XL184 in CRPR in patients who have failed abiraterone and who have also recieved the available treatments for bony mets (bisphosphonates like Zometa) and the recently approved denosumab. At present having an effect on bone scans is very encouraging and I believe will be reflected in improvement in more clinically meaningful endpoints (survival, QoL, decrease in pathologic fractures), but that will take some time.

      (more to come)

      • 1 Reply to oncodocbiotechwiz
      • (part 2)

        By the way, I'd worry a bit about your timeline for MTC. I suspect that initial results will be in Q2 with an NDA filing before the end of the year. There will undoubtably be some time for FDA review so I wouldn't expect to see an approval until early 2012 at best. If you've heard something new on that fron (and perhaps R&D day will shed light on this), feel free to respond accordingly.

        Those are my off the cuff thoughts and hopefully they address your questions in general. Needless to say, the medical field will be somewhat uncertain on these issues for some time, but I find discussion of different potential scenarios quite interesting.

        Happy Thanksgiving and good luck all. Sadly, the best advice I can give to all those concerned about medical coverage is to stay healthy.

        THe "Wiz"

    • The R&D day presentation should be interesting. I wonder if a big Prostate cancer trial will be announced.

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