There is yet another twist in the ongoing and always interesting Provenge saga. The Centers for Medicare & Medicaid Services, which last June issued a surprise decision to conduct a National Coverage Analysis, which will be used for coverage guidance by Medicare contractors, has released the questions to be answered at a Nov. 17 panel meeting and the focus is on on-label efficacy.
The NCA, for those who may not recall, stunned all sorts of people because such reviews do not occur very often (see here and here). Dendreon execs subsequently downplayed the move by telling analysts NCA was sparked by concerns of off-label use, although CMS has been cryptic about its reasoning other than to point to the fact that Provenge is the first in a new class of treatments that use a patient's own cells to stimulate the body's immune system in an approach known as immunotherapy.
In any event, at least one analyst noted the questions are unexpectedly about approved usage. "Surprisingly, many of the questions focus on EFFICACY in the ON-LABEL indication. It asks the panel to rank efficacy on a scale of 1-5, leaving the possibility of an ambiguous outcome," writes ISI Group biotech analyst Marc Schoenebaum. "This is the first time we’ve seen Medicare analyze the efficacy of a drug."
However, RW Baird analyst Chris Raymond notes the quetions "aren't unprecedented." Of the nine questions, he agrees that the focus is on efficacy, "but multiple questions also focus on whether the evidence is applicable to off-label use." He then adds several recent such meetings contained similar lines of questioning.
Among other things, the panelists are asked to rate their confidence in Provenge's ability to improve overall survival, control disease related symptoms and minimize the burdens associated the vaccine while maintaining overall survival and control of disease-related symptoms. You can see the list of questions here.
17 Comments
The CMS question for the MEDCAC meeting (see link below) show that everyone is slowly getting sensitized to the real issues on the table. And they show that the CMS–unlike the media and the FDA–is not susceptible to company propaganda (the “Dendreon-edited” version of the data in the NEJM), legal pressure (from Caretolive, Dendreon’s militant arm that “promotes debate” by literally suing anyone who questions Provenge), and political pressure (senators who send blanket one-page missives to the CMS in a quest to get more patient votes in an election season).
The MEDCAC list of question show that the CMS considers the adequacy of the Provenge data questionable (questions 1 through 4), and is looking for suggestion for a robust design for a new clinical trial (question 8 and 9). 8 out of 9 questions are about *on-label* use. Only 1 out of 9 questions is about off-label use. And remember: this committee does not make recommendations to the CMS.
The new buzzword at the CMS is comparative efficacy. FDA or not, congress or not, the new CMS leadership is not hesitant about scrutinizing efficacy and roughing up the cost/benefit analysis unlike their predecessors, because this is what they were just appointed to do in the first place. This is their new job. This trend is bigger than Provenge, so we need to learn to think critically about our times, our limited reimbursement capability, and last but not least about the very questionable efficacy of this treatment. This is not about just Dendreon, though it will not end well for Dendreon.
http://www.cms.gov/mcd/viewmcac.asp?from2=viewmcac.asp&where=index&mid=56&
when dndn said that national coverage of provenge was a sure thing, the cms responded by opening an investigation. when asco and senators asked the cms to drop the investigation entirely, instead the cms scheduled the date for a panel. when dndn bulls said that the panel would only focus on restricting off-label use, the cms published a list of questions focused on adequacy of evidence for on-label efficacy, and is even bluntly soliciting recommendations for a new trial design. come on, people, these messages from the cms are not even mixed. they're crystal clear about where this is headed. start thinking with your own heads, don't let mitch gold and his pocket wall street bull analysts do the thinking for you.
Give me a break, bentham & mr. chance. Dendreon has been proven through several Phase 3 clinical trials. Efficacy is a given. The only ones who don't want to admit that are the chemo cartel members. Patients first. Let's all try to remember that. I realize that Provenge is revolutionary and it can be hard to wrap your mind around that, but at one time so was the polio vaccine.
Obviously, Mr. Chance you haven't much expertise in reading statistical design or study results. The FDA went over the Provenge BLA submittal with a fine tooth comb and could find no irregularities in the data. None whatsoever. Believe me if there had been any this therapy would have never been approved. It's dinosaur thinking like yours that will actually cost the US more in reimbursement dollars in the long run.
Backward thinking like this CMS review will export another industry off shore. Sadly the US will no longer be king in biotech innovation if these zealots with questionable connections are allowed to carry out this farce.
The first two posters are obviously paid posters of hedge funds spewing this garbage here and in other sites.
Just ask the basic question. Does CMS have the qualification and capability to decide on the faith of a drug especially the one that FDA approved? What does this say about the FDA charter if CMS who is totally unqualified second gusses it? Wouldn't this be the end of FDA as we know it? What would be quality of the decision that CMS makes given the fact that they don't even have 1/100 of the technical and medical capability of FDA. It is bad enough for FDA to be able to make a sound decision given its vast capability of medical and technical staff they have? How could CMS filled with bunch of non-medical and non-technical staff be able to make such a decision? What kind of goverment and congress allow such a duplication in decision making take place? I can't imagine our Congress especially the one controlled by Republicans after the November election allow such a stupidity to continue.
So let me get this straight, the FDA and Dendreon confer and eventually agree upon an SPA which lays out the endpoint requirements of a phase III trial. Despite a positive advisory committee recommendation in 2007 the FDA required Dendreon to run an additional trial. The FDA spent over 6 mos. reviewing the trial result data. Finally this spring the FDA reached the same conclusion that its advisory committee did in 2007 that there was sufficient evidence that Provenge was safe and effective. Now CMS is going to read some letters, hold a one day hearing and substitute it's judgement for the FDA's regarding the EFFICACY in ON-LABEL use of Provenge? As a taxpayer I'm curious as to why tens of millions of our tax dollars are spent on the FDA when it is obviously redundant with the omnipotent CMS.
Where is the FDA? Oh I forgot, it's FDA/CMS/FCC after signing MOU's recently. They may as well go ahead and sign a Memo of Understanding with the FBI so they can incarcerate anyone that speaks out against the czarist government(I wonder if they signed those MOU things with Fan/fred, taken over banks, GM, etc.). It is dangerous to meld all these separate entities together, in this fashion; unnaccountable, and unnelected officials, heck, entire agencies all hopping to the tune of one man, the President. Is this for more control; keeping with czarist, Marxist themes? Or maybe a funneling move to course the flood of bribes into one mans hands? I guess both of those amount to the same thing, power. The worse kind; unincumbered, concintrated and absolute power; where one man controls every nuance from the color of the chef in the White house, to the cancer treatments payed for, not because of law, but because he controls, period, poke a dot(learned that from Biden). By the way, you notice they aren't cutting any bureaucrats from the doles after melding these agencies together; too much noise that way, got to get that MOU with the FBI signed first. Maybe these people don't get that we have an MOU already. It is that bothersome little, died for much, freedom enabling, document called the Constitution. Loathsome thing.
-Paladin
To GloriaJ; There is no such thing as a chemo cartel. Taxotere is going generic on Nov 14th. To SteveB: I design clinical trials for a living. IMPACT is the worst design I've ever seen. The CMS & EMA know that. To Tommy: The CMS' new mission is exactly what it is doing. To Malloy: Why are we wasting tax money on the FDA if it is not doing it's job? Good question. Write them a letter and ask them to stop being spineless and not yield to frivolous lawsuits from third parties during regulatory review. To all: Why do i have the impression that 3 out of 4 of you are the same person?
Has the CMS considered doing a question panel on the use of the poison chemo Taxotera? To me, ingesting dying patients with a poison like Taxotera which debilitates the human body into additional suffering is unconscionable and Medicare pays for this. My 35 year old friend passed away a few months ago of Colon Cancer. He had 4 children under 8 years old who would have paid 1 million dollars to have 1 more day with their father. He had taken as much Chemo as he could and it finally took his life. What about all the additional medical costs that a chemo patients takes on? Additional medications, additional days in the hospital and additional labor hours to assist the patient. Is anyone else concerned there is possibly a high powered lobbyist pushing the CMS into this review of Provenge? Who does this lobbyist work for? Something smells awfully rotten with this CMS review.
To SBResident: I am truly sorry for your friend; it sounds like a nightmare. I also know several people who are battling cancer. However, in prostate cancer specifically, Provenge does not avoid the need or the cost of taxotere. The cancer of a Provenge patient will eventually still progress and he will still receive taxotere. The IMPACT study showed that Provenge patients eventually receive taxotere in same numbers as non-Provenge patients.Questions 1C and 4 in the CMS/MEDCAC list ask specifically this question (does provenge avoid the burden of other anti-cancer therapy?). The answer from the IMPACT trial itself is: It does not. However don't take my word, wait to hear the committee's opinion.
To Christopher Chance: In your comments here, you have stated that Dendreon has not been entirely forthcoming with their data, you have questioned the efficacy of Provenge, you have predicted that the MEDCAC meeting will hurt Dendreon considerably, and you have said that Dendreon's IMPACT study was poorly designed... among other things.
And then one can see that you have commented on other Dendreon articles on the web, such as the FiercePharma.com story that GSK will supply antigen for Dendreon: http://www.fiercepharma.com/story/gsk-signs-supply-provenge-antigen/2010-09-21
In those comments, you suggest that Dendreon will have to run new, expensive & lengthy trials in Europe. You imply that the studies will include taxotere as the comparator. In all your comments on all of the websites with stories, you mention taxotere. Everything you say about Dendreon is a negative or an implied negative, and effectively defends the drug taxotere.
If I wasn't a trusting person, I would assume you have a vested interest in taxotere and and a vendetta against Dendreon and Provenge.
But I am sure that is not the case. Nobody who reads the comments of these fringe articles/blog postings is smart enough to pick up on that.
God Bless.
To Mark W: Personally, I hate taxotere. I think it's a horrible drug. But I refuse to spectate while Dendreon misinforms the world that Provenge is going to help patients avoid taxotere. This is simply not true. Taxotere, bad as it is, is not a competitor treatment to Provenge. They are indicated for two different stages of prostate cancer. Provenge is for asymptomatic or minimally symptomatic mHRPC patients (on non-prescription pain management), while taxotere is for symptomatic mHRCP patients (on opioid pain management). Both stages are different clinically for treatment as well as for reimbursement purposes. So, when the disease progresses far enough, everyone ends up getting taxotere independently of whether they receive Provenge. In fact, in the IMPACT trial, slightly more patients who received Provenge rather than placebo went on to receive taxotere (feel free to check the data). So you see: painting Provenge critics as taxotere supporters and then dismissing them makes no sense; that way you miss their (as well as my) main point: they are not implying that taxotere works better, but that Provenge does not work at all.
From a UK perspective, we would expect a rough ride from NICE for a $90k per patient treatment. Isn't CMS simply trying the emulate this approach?
NICE and the EMA will require an experimental comparator arm with the standard of care treatment (i.e. chemo). there will be no way around that, especially since the study design and benefit conferred here were so controversial. ps. kudos to you christopher chance ... you should be on the CMS panel ... for all i know, you're probably on it already.
Provenge significantly improves overall survial (the gold standard end point in any metastic cancer trial). Provenge also exceeded SPA criteria set by FDA. It's tolerability profile is also relatively managable compared with other therapies. Ok, so it doesn't delay progression or prevent needed for Taxotere treatment, but it would be an impossible task to ask a new drug to essentially 'cure' metastatic castrate resistant patients. All patients with metastic disease will ultimately progress and require chemo. But the fact still remains Provenge significantly improves survival. Therefore it is a valid drug. It seems as though this CMS review is based just on the hight cost and the fact it is a big gamble upfront for reimbursers because it's an 'all or nothing' cost because of the short treatment duration. Surely because Provenge is FDA approved and listed on NCCN compendia Medicare have a legal requirement to cover Provenge (at least in the labelled indication)? They can't really refuse coverage can they!?
1. There is a gross misconception that Dendreon followed a strict SPA with the IMPACT trial. Yes, there was an original SPA, approved by the FDA and used for study 9901, however it contained PFS as primary endpoint. The IMPACT study (originally called 9902B) began under that SPA, then underwent a number of amendments while patients were being enrolled and treated. Among these amendments were the scratching of PFS as primary endpoint, incorporation and elevation of overall survival as primary endpoint, restriction and later re-inclusion of different ranges of Gleason scores. So the "SPA" for IMPACT is hodge-podge of seesaw tweaks of a study in progress which should have never been allowed to take place. Whoever approved these real-time tweaks at the FDA and whoever implemented them at Dendreon was either patently stupid or criminally insane. 2. It is more likely than not that Provenge has no effect at all on overall survival. The observed median 4 months difference between the placebo group and the Provenge arm is more likely a result of the multiple irregularities and imbalances in the study design than due to the experimental treatment which comes with no mechanism of action or hints of antitumor activity. Among the major design flaws are: (a) unblinding of patients at progression, (b) imbalance between the timing of chemo salvage between the arms, (c) imbalance in amount of chemo salvage administered between the arms, (d) inequivalence of ratio of cells withdrawn/reinfused between study arms (i.e placebo patients were reinfused only 1/3 of their cells), (e) inequivalence of exposure of cells between study arms (i.e. placebo cells should have been exposed to GM-CSF), (f) inequivalence of storage conditions of cells (i.e. placebo cells should have never been stored at 4 degrees while experimental cells were exposed to antigen at 37 degrees). This list goes on, and at the end it is in fact surprising that the measured survival difference between the study arms was only 4 months and not more; lack of blinding alone can generate false months. 3. The overall safety of Provenge, or the comparative safety relative to chemotherapy is completely inconsequential if the efficacy is questionable. Administering and reimbursing a treatment with good safety but null efficacy is not only wasteful but criminal. Really. 4. The CMS can and should and will act in line with its new mission of maximizing the cost/benefit equation of treatment. Yes, in the past they have been required to cover FDA-approved treatments, but that mode of operation has only contributed to bankruptcy and is now redrafted. The Dendreon-originated argument "if CMS breaks the law by not covering Provenge then Congress will cut its funding" is ridiculous. Congress does not retaliate and cannot and will not cut Medicare funding any further. Why would Congress retaliate on behalf of Dendreon and the legally-hyperactive Caretolive by denying the CMS funds to cover other existing treatments?
... Do not fall prey of Dendreon's medical and political misinformation campaign. They have made this hand last too many years and their management has made a lot of money. Only one CEO in the history of healthcare has sold 60% of his company holdings on the day after his only pipeline drug received approval--that was Dendreon's CEO. In retrospect, everything Dendreon has announced since the approval has been a way to buy time (see Bentham's post above--a very smart synthesis of the timeline of events). When Dendreon's house of cards finally comes down some will be surprised while all will be disappointed . It's alright to be one of the disappointed. Just do not be one of the surprised.
Why is it that a tool to be added to the arsenal of fighting metastatic prostate cancer is under such scrutiny after an FDA approval? When the novel field of immunotherapy is added to treatment protocol in addition to chemotherapy, and widens the survival median 4 month to the right, we start launching duplicate investigations? Is this only because healthcare money is so obviously limited and everyone is just so paranoid about spending money up front? Can't we look at the potential cost savings of avoiding chemo? We are talking about 29,000 to 36,000 AIPC cases per year in recent years- men who die miserable deaths when left to one choice of chemo. Is anyone scrutinizing the wasting of money with radiation therapy and radical surgeries done at improper times (unfavorable prediction upon calculation with Partin's tables) If we make this protocol based on economics, and we choose chemo first then immunotherapy, then the patient is poorly educated and the system has failed. The patients should have this as a covered option, and chemo FINALLY should be moved to last resort- and cost savings would be entertained by the most important committee of 1- the patient! And his increased quality of life and lack of violent side effects!!! When I went to the City of Hope GU Oncology convention, years ago...jaws dropped at the exciting promise that immunotherapy would hold. One economic crisis later, one election later, and one FDA approval later- we have lost sight of the goal- treating patients with the best available tools and watching outcome data while in the field in order to improve immunotherapy!!! Wake up American healthcare providers and biotech leaders!! Before you fail your patients and farm out your industries to Europe, give your patients the option of deciding!!!!
My patients and I are hoping that the CMS does more to foster growth of immunotherapy, Provenge or not, and sets appropriate guidelines for its usage in the field, and fosters a more cooperative environment on the expansion of this new technology.