Friday, March 11, 2011

It Might Get Loud

Amplify:  To make larger of more powerful, to exaggerate.  If only TSB was taking about the Jimmy Page, Jack White and The Edge Documentary.  In Medtronic's quest to amplify rhBMP-2, on March 9th, 2011, the FDA displayed a bit of feedback by issuing a non-approval letter.

So the million dollar a day question must be asked, what was the determining factor or factors?  Obviously, cooler heads prevailed.  Was the panel concerned with some of the papers that have been published regarding the role of BMP's in pancreatic cancer?  If there were spine surgeons on the panel, did they come to their legal and ethical senses?  So what's the buzz in the sound system?  TSB wonders what Marshall Urist would say if he was in the here and now?  Over the years there have been many papers and reports of adverse reactions in using rhBMP-2.  Let's take a look at some of these papers.

In 2008 The Department of Pharmacology and Cancer Biology, and Department of Medicine at The Duke University published a paper entitled, "BMP's Induce Pancreatic Cancer Cell Invasiveness through a small Smad1-Dependent Mechanism That Involves Matrix Metalloproteinase -2."  In addition to this paper,  a retrospective study reported in 2008 on 260 patients that underwent cervical spinal procedures with BMP resulting in acute airway obstruction due to extensive soft-tissue inflammatory response that was likely to occur 2-7 days post-op. Then there is the published paper in The Spine Journal in 2008 entitled. "Neurologic impairment from ectopic bone in the lumbar canal, a potential complication of off-label PLIF/TLIF use of BMP-2.

Yes fellow rockers, or may I say bloggers, contingent on whose data one wants to believe, it is estimated that 73-85% of BMP is used off label.  In a September 22, 2010 report, concerns were raised that there was bone formation in unwanted places.  WTF, was anyone listening to the people in the field that were being told by surgeons about their experience?    It doesn't take a spine surgeon to qualify the efficacy of BMP-2.  It takes someone that is willing to admit that BMP-2 is a pharmaceutical and not a device.  Retrospectively, flags were raised back in 2002 when Advisory Panel Members pointed out that 9 out of the doctors that authored the BMP-2 research submitted to the FDA had a financial stake in the product.

Unlike other industry platforms that report the news, TSB must admit, if its open season on INFUSE let's not kiss the ass of two companies that pander to one's commercial needs.  This is a golden opportunity for  everyone that plays in the biologics marketplace.  In all likelihood Medtronic has the capacity to sustain another blow, but this is a great opportunity for every company that competes in this space.  TSB wants to know what our blogger think?

44 comments:

  1. Why does there seem to be a desire to hope InFuse fails. It does appear to be a product with an application.

    It may require a bit more effort to clarify when & where it is most helpful but it would be a shame to see it fail.

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  2. It is interesting and surprising that FDA for the first time in a long while stands up against one of the big boys, and especially MSD. For one, it means that the influence of Susan Alpert at her former office is waning. It also shows that in spite of the understanding that FDA always goes by what is statistically proven, they here ignore the statistics and find the cancer numbers sufficiently worrying to allow logic and common sense to prevail.

    Now that OP-1 is buried and Infuse more and more put in its proper place, the prospects for other graft materials should improve. .... But will it?

    The stem cell mafia will try to muscle in, but the scientific rationale of these 21st century DBM variants is still very weak, and there are no good data. If they overreach, FDA could play a prank on them. Can Biomimetic profit, or did their regulatory hurdle just get higher? How about the plethora of synthetics? There's little risk of additional regulatory hurdles here, but the number of products with meaningful data is limited. And data are increasingly a necessary fact of life.

    In the end good old autograft may be the ultimate winner.

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  3. By the way, anyone who loves good Blues and solid Rock need to see the movie It Might Get Loud to get familiar with Jack White. He needs an introduction if you are an "old as the hills" guy like myself. When you see where he is coming from & where he is going, it is easy to see he is the best new blues guitarist to come along in a very long while. You will really enjoy his guitar riffs & rips!

    He understands the roots & blows the roof off.

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  4. Jesus who really cares? Amplify is a product that is trying to come to market at a price too high to sell in this environment and the reps that sell Infuse are not compensated due to the margins being so thin to pay the docs with financial stakes and Wyeth.

    Infuse was a product that did not have to be sold at a field level, it grew legs and ran on its own. If you hyper dose it and use if off label you will have problems that are well documented (Osteolysis, Hyperactive bone growth in places you don't want and swelling in confined placement).

    I dunno about this cancer BS, I would say many many more studies would be required to validate that claim. I imagine there are plenty of patients available for retro studies and lawyers frothing at the mouth awaiting the class action train.

    For the most part this has been another super gay post by TSB trying to slam MDT in any way shape or form he can. And yes I saw the previous post where he reluctantly (if not due to prompting in prior posts) posted about MDT dumping Novation, still think he hates MDT and its painfully obvious.

    None the less, great blog and I will continue to read!

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  5. "I dunno about this cancer BS" effectively sums up the general attitude towards patient care and science in spine. They come a distant 5th and 6th after surgeons, hospitals, companies and reps each have taken their cut.

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  6. When is Globus going to go public ?

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  7. It seems to me that this is another situation where the FDA may be meddling too closely in the practice of medicine. I'm ignorant about amplify specifically, but Infuse is a hell of an effective tool, and should absolutely be in the surgeon's arsenal. If amplify is similar, then it should be as well. If there are concerns about cancer or any other complications, especially when used in off label applications or doses, then it is up to the medical profession, i.e. doctors, to take that into account as they choose how and when to use it. But to take a hammer away from a carpenter because he might hit someone else's thumb with it is outright stupid. The FDA just flat out needs to get out of the way. If Amplify causes cancer and MDT does or should know it, then they will get the hell sued out of them. And if a doc puts it in in a bad or foolish application, then he will get the hell sued out of him/her. That's how we put accountability back where it belongs. Not in the hands of beaurocrats who are presuming to be able to answer qustions for which the answers simply are not known.

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  8. MSD never volunteers to share bad information it learns about its products. Only when the number of individual reports reaches critical mass they send out a letter warning about off-label use, also known as the VYA note. MSD has good products but no morals.

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  9. Talking about Amplify and Infuse, what ever happened to Hal Mathews???

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  10. To 5:06 pm : Your point is that the private sector / profit driven corporations with highly paid scientists to fudge data or downplay adverse events are more qualified than the FDA scientists? Or surgeons make the final call because they moonlight as scientists. Come on - it is the sales reps who educate surgeons about a product. Whoa -- that is what is really scarey when surgeons use a questionable bio-engineered protein off label - what do they care if it harms the patient - everyone in the industry has everyone's back anyway - except for the patient that dies in surgery - Synthes - Norian bone cement !! Finally, the FDA is doing its job - protecting Public Health first and putting innovation in its place -- which is 2nd place. Kudzos FDA***

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  11. This decision by the FDA guarantees a biologics monopoly for Medtronic with rhBMP2/INFUSE for a long, long time. What company in there right mind would invest the millions of dollars and a decade of research/IDE trials to bring another rhBMP to market when two in a row have now failed to be FDA approved? AMPLIFY received a positive vote from the "expert" FDA panel, had 5 year follow-up and the data shows superiority to iliac crest. The FDA still denied it. Medtronic's INFUSE product will continue to be the only real biologics show in town for the next decade. Bank on it!

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  12. This is a terrible decision by an anti-business, politicized FDA. Medical device is one of the few industries that the US has a competitive advantage in compared to other countries. Decisions like this will kill investment in domestic device start-ups and revolutionary PMA technology. Whatever your feelings about Medtronic or INFUSE it is truly a sad day for the future of innovation in US spine industry.

    Hope you all enjoy selling 510k, me too, products for the foreseeable future because that is where we're headed.

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  13. @5:57 Haven't you figured out yet that it's not about who knows better. Nobody knows the answer to these questions. The science simply isn't there yet. And waiting for someone to fund the study that may or may not yield the answer is denying the best possible treatment to hundred, thousands, or even millions of patients. I'd venture that for every patient the FDA prevents receiving a "bad" product, there are a hundred who don't receive a better one than they get.

    That's not the point, anyway. It's about accountability. It's about treating patients, and it's about responsibility. The patient places their trust in their doctor, not in the FDA. Their doctor shouldn't be hamstrung in their choices of the tools they are able to use, and the information they have to exercise their profession. They went to medical school for a reason, and they are held accountable for their judgment, i.e. the information they use and experience they rely upon to make a decision in the absence of hard facts. And the best part about it is that their judgment is tailored to the very specific patient and situation, something the FDA scientists you laud will never face.

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  14. 8:10, the first paragraph make perfect sense, and the second would if only today's surgeons would base their decisions on the well-being of the patients, and not the health of their bank accounts. This problem is nowhere as rampant as in spine. Take a look at the Medtronic physician registry and you see the tip of the iceberg that I'm referring to.

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  15. Is a non-union considered an adverse event? Is recurring pain from a hip graft considered an adverse event?

    These were common occurrences in lumbar spinal fusions before Infuse. You rarely hear about them now. Published clinical studies exist regarding Infuse dosing and placement techniques which could be used to proactively educate surgeons on the safer use of the product thus minimizing the possibility of adverse events. If anything FDA restrictions around off-label promotion limit Medtronic from sharing that information.

    TSB please explain how exactly is it that denying FDA approval to AMPLIFY a good thing for patients? Consider that it has an rhBMP2 dose and carrier specifically designed for a posterolateral fusion backed up by a prospective, randomized IDE showing both safety and efficacy compared to iliac crest.

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  16. Truth be told, I'm a little tired, and I'd usually blow past this thread on a Friday night but comments like:

    1. "I'm ignorant about amplify specifically"
    2. "another super gay post by TSB trying to slam MDT"
    3. "I dunno about this cancer BS"

    ...are symbolic of why I fear for our collective future: we seem to relish in our pandemic lack of common sense.

    Perspective, if you'll afford me:

    1. Mr. Ignorant, meet The Google:

    http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/OrthopaedicandRehabilitationDevicesPanel/UCM220741.pdf

    (While pulling from the gut on biologics might not be the best move professionally, you get the 'Heck of a job Brownie' award for the post.)

    2. Common on brother, market leadership has it's perils. Can't take the heat, well then step away from the easy bake oven.

    3. Ah, taking the ole' big tabacco route. Bold, and retro*, but I think we know where that story ends.

    Best I can tell, approval for Amplify is tantamount to legalizing gambling. "I mean, everyone's doing it, just let us put up a sign on the freeway and build a hotel so they have some where to sleep."

    Yes, BMP-2 IS a great biologic and a great product with key limitations (but it's not going anywhere). The mistake, it was sold for the better part of a decade in spine like any other bone graft (i.e. 'more the better doc', huh? I dunno [nothing] about that cancer BS!'). Too bad they didn't do the concentration/dosage work sooner than later.

    Last time I checked this decision doesn't stop docs from using BMP anywhere they want.

    Enjoy the weekend.

    *Like your style.

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  17. Is a non-union considered an adverse event? Is recurring pain from a hip graft considered an adverse event?

    These were common occurrences in lumbar spinal fusions before Infuse. You rarely hear about them now. Published clinical studies exist regarding Infuse dosing and placement techniques which could be used to proactively educate surgeons on the safer use of the product thus minimizing the possibility of adverse events. If anything FDA restrictions around off-label promotion limit Medtronic from sharing that information.

    TSB please explain how exactly is it that denying FDA approval to AMPLIFY a good thing for patients? Consider that it has an rhBMP2 dose and carrier specifically designed for a posterolateral fusion backed up by a prospective, randomized IDE showing both safety and efficacy compared to iliac crest.

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  18. Nelson Muntz said it best when he said "HA-ha!"

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  19. what about the pharma patent that Wyeth holds - generic will soon be on the way

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  20. 4:49, the point is that the study did not convincingly show it is safe. Compare it to Viox and similar drug stories: the incidence of people experiencing a cardiovascular event goes from 7 to 7.2% and the drug gets pulled and the company sued. I don't remember the exact numbers, but in the Amplify study 5 or so more people who received Amplify got cancer out of 300, which is 1.7%. But since it is quite effective to grow bone, even where we don't want it, we should just let that go? Or accept the explanation that as we don't understand the mechanism by which this could happen it probably is just a fluke? That is the science of creationism. All this for clinical outcomes which are essentially the same.

    And lastly, restrictions on off-label promotion do not in any way, shape, or form preclude Medtronic from sharing information about adverse events. A more likely reason for not sharing this, at least in a timely fashion, are commercial interests.

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  21. I'm still skeptical of the ability for INFUSE to grow bone in the spine. If it did surely Doug King would have one by now.

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  22. 5:55--haven't you heard? He's with the Viscogliosi Brothers--head of Medical--Gary Lowery's boss--heard he was pissed he didn't get the President position at MDT's S&B.

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  23. 8:44, Nope. Generic rhbmp2 would have to do an IDE then get a PMA approval from the FDA. Good luck with that. Monopoly.

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  24. 9:05, regarding Amplify safety. Explain the FDA panel vote of 9-4-1 for safety in which all of the FDA cancer panel experts except one voted in favor of safety. Guess you know more than they do.

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  25. 10.12, they were surgical oncologists, not the brainy internal medicine and molecular biology ones.

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  26. Let's give TSB a break, there isn't anything exciting in spine these days, kinda hard to strike up an exciting conversation.

    Really, what are his options? I'm sure he is tired of writing about Globus going public, POD's being unfair...and who doesn't rip on MSD?

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  27. I think it is just a sad state of affairs when we have to take steps backwards in patient care. Infuse and specifically Amplify are the best option for PLF. The study of this will prove Superiority to IGB. Any one who looks at this would want this product for themselves or any family having a PLF. The market shift back to DBMs and Ceramics is just scary and the increase in non-unions will remind everyone why they "by choice" moved to Infuse years ago. It works better and eliminates the need to take a bone graft.

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  28. 2:26, as a physician involved in spine I respectfully disagree. My loved ones, or myself, will not get Infuse. If we need a fusion it will be done with local bone, a synthetic extender and locally harvested bone marrow.

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  29. Thank you Dr 2:44!
    2:26 is, I am sure a nice and loyal employee, but naive and unable to think for himself and indicative of the average rep. Just b/c the company feeds you a line doesn't mean you have to bite it!
    "The study of this will prove Superiority to IGB. Any one who looks at this would want this product for themselves or any family having a PLF"

    Please reread your comments and think about what you have said.

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  30. 2:44, Can you explain why you'd make that choice? There are considerably more peer reviewed, level 1 studies to support the use of rhBMP-2 than there are for local bone + synthetic + BMA.

    3:00, Your comments are arrogant and condescending to both sales reps and and the thousands of spine surgeons that use rhBMP-2 on their patients every day with excellent results.

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  31. 4.42, fact #1 is that clinical outcome is only marginally related to radiological fusion success, fact #2 is that the one factor that is not taken into account in any study is the surgical skill of the operator who performs the surgery, which probably accounts for at least half of what is going to happen with the graft, and fact #3 is that the reported fusion rates are all over the map. After wading through all the reports it appears that the fusion rates for the 'cocktail' are at most only a couple of percentage points off from those for the BMPs. Not enough to run the known and unknown risks of BMPs, except in the most difficult of cases, let's say a diabetic pseudarthrosis who smokes a pack a day.

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  32. "Let's give TSB a break, there isn't anything exciting in spine these days, kinda hard to strike up an exciting conversation."

    - Anonymous 11:33

    Quote of the year (though it is early). Not to mention it's exceedingly representative of the backward looking / product-focused bias of most of the commentary on this blog.

    What's to talk about, except, perhaps, the rapid endemic deceleration and constriction of the spine industry as we have come to love it.

    Pray TSB figures a way to muddle through...

    Oh, but before I go, 2:26, I thought about your comment. Imagine a world without BMP...the horror! But comfort came to me in brushing up on InFuse's Summary of Safety and Effectiveness were I was reminded:

    "The study demonstrated that treatment of DDD with the InFUSE™ Bone Graft/LTCAGE
    ™ Lumbar Tapered Fusion Device was as effective as the control treatment (the
    LT-CAGE™ Lumbar Tapered Fusion Device filled with iliac crest autograft). The
    results for the primary effectiveness outcome parameters for both investigational groups
    were equivalent to the control group. The InFUSE™ Bone Graft/LT-CAGE™ Lumbar
    Tapered Fusion Device was able to achieve comparable clinical performance while
    avoiding the necessity of an iliac crest graft site and its associated pain.'

    http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=P000058

    Hope this, and the fact that procedurally, DBM, synthetics and allograft currently dwarf BMP help you find the peace of mind to live life in a world without Amplify.

    Again, BMP, right product for the right patient.

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  33. Re "this cancer BS":

    While not statistically significant because of sample size, the cancer rate was roughly double for Amplify vs Autograft. The FDA pointed out at the panel meeting that the cancer rate was approximately double in all 18 IDE studies with Infuse to date.

    Still think this is something that should be ignored and blindly accepted?

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  34. Anybody know anything about SpinalMotion?

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  35. "...except in the most difficult of cases, let's say a diabetic pseudarthrosis who smokes a pack a day."

    @6:08, and thanks to others who share your cautious view point and omnipotent approach it won't even be available for intelligent and well informed surgeons to provide for the well justified application you mention.

    Surgeons differ in opinion. Why can't we just allow those who want to use it to use it, and those who don't don't? There are professional consequences for those who make the incorrect decision, as it should be.

    And if you say, the financial or other inappropriate motivations will cause many to use it who otherwise wouldn't, then I say fix that problem, don't create another by taking it out of the hands of those who genuinely believe it is an appropriate tool for treating their patients. Just because you view the balance of the data as unfavorable doesn't mean that all of the others do.

    Clearly the data is there to enable surgeons to make well informed decisions. Now the FDA should step aside and allow them to do it, not tell them what they should think.

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  36. @ 10:01 Great point, and certainly something that surgeons should take into account and explain to their patients as they consider using BMP.

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  37. 1:23. Completely and wholeheartedly agree. That was how things were done in the days before 1978 (USA) and 1994 (Europe). In spite of the huge costs and time involved with the FDA and Notified Body imposed regulations, patients are not better off, or safer, now than they were then.

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  38. Just use Actifuse It is osteo-stimulative just like BMP. Works the same. Same high prices so the stocking distributors can make huge profits. No studies to prove it...but they claim they have one. Wait...is it the HA making it glow...or is it a fusion? Can't wait for all the smoke and mirrors for these products with the downfall of Infuse. Be careful what you wish for.

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  39. I wish I was Charlie Sheen!
    I would inject Infuse right into my Magic Johnson and have a permanent Warlock Wand to cast spells on all my Goddesses!
    Is that off label?

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  40. @12:28PM... HA!...your exactly right.

    osteostimulatiive (v.): to tickle the grundle of ossification.

    If your not truly osteoinductive are you truly a replacement for Infuse? The best thing that can happen for actifuse is for Stem cell technology to get the boot.

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  41. ... watched "It might get loud" again last night. Truly a cool insight into the minds and careers of three guitarists from different generations. Really illuminates the similarities in the ingredients for their success without beating you over the head with it. Must see for any guitarist or music fan.

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  42. To all of you it goes back to the facts that rh bmp2 is being used in OFF LABEL USE as PROMOTED, like it or not by MEDTRONICS through their methods of utilizing docs to share information with other docs and they paid them to do so. I was talked into having it put into me even though I questioned its use, but felt I had no choice but to use it. It gets down to GREED, it has to be the reason for its over use. If physicians had the time to read the original studies and know the true outcomes of what could truly happen they wouldn't have put in my cervical spine in five levels resulting in ADVERSE REACTIONS. Yes, due to the volume used. My surgeon didn't know what was wrong until I brought up the possibilty of the BMP reaction and his partner was one of the highest paid surgeons by Medtronics to promote the use of Infuse. I would have preferred the ADVERSE reaction of pain in my hip over a feeding tube for months, immune problems for three years plus and a non-union resulting in another five level fusion posterior, with a renowned surgeon insisting that he could still used rh-bmp in that surgery. Medtronics needs to own up to their responsibility and stop putting this "device" into people! Even one person having to go through what I am going through due to rh-bmp 2 is too many! So get over the ego's sales reps, doctors, etc. and think about the patients!

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  43. And, oh by the way, my adverse reaction was never reported to the FDA! Mine, and how many others...

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