Tuesday, July 27, 2010

FDA Approves Amplify in 6 to 5 Vote

On Tuesday July 27th, 2010 a panel of FDA advisors voted 6 to 5, with 3 abstentions, that the benefits of MSD's experimental spinal fusion device (it's a device?), outweighs the risk. In a close vote, consenting panel advisors believed that the rhBMP-2 worked well enough to overcome major concerns that the studies may indicate a cancer risk for those receiving this material.

Considering that the Evil Empire's sales have been suffering, some analysts believe that this will be a shot in the arm for the company's revenue. The spine division had 3% growth last year, could this be mana from heaven? In addition, could this be the death knell for some of the early stage synthetic bone graft companies, if surgeons decide to jump on the Amplify love train?

The success rate for Amplify was 61% as compared to 56% for those receiving autograft. Results after five years found successful operations for 44% of Amplify patients versus 35% for standard care. I guess it goes to prove TSB's observation, if you have enough of capital and lobbying power anything is possible.


  1. "For Amplify, Medtronic studied 463 patients randomly chosen to receive the new device or the standard fusion procedure. After two years, 60.5 percent of Amplify procedures were judged a success compared with 55.5 percent in the control group."

    "At five years, cancer rates were 5 percent with Amplify and 1.8 percent in the standard fusion group. Medtronic said the differences were not statistically significant, meaning they could have been due to chance, and there was no biological reason to suggest Amplify caused cancer."

    Just to be a bit of a Richard, the fusion percentages for Amplify vs. control are 5% difference. The cancer rate is 1.8% to 5%. Please tell me where the line is drawn between benefit, no significant difference and harmful is. 3.2 % to 5 % is not that great of a difference. Hey, just talking numbers here!

  2. To say that there is no biological reason for the cancers is questionable. BMP is a growth factor, and growth factors are certainly related to tumorigenesis. Not to say there is causation, but the question is valid and it will need to be followed closely.

    Remember Vioxx got pulled for a stroke/MI events increase much smaller than this (3.5% for Vioxx versus 1.9% for placebo). And that turned into a CF of monumental proportions for Merck.

  3. I saw a product called HealosFX -

    Any news on it?


  5. I was at the panel meeting today. Going into it I had many concerns based on analist/media expectations regarding cancer safety. The three FDA cancer surgeon experts Dr's Kemery, Neugent and Allegra on the panel said there were " no red flags" regarding cancer safety and voted unanimously in favor of the safety, effectiveness, and risk/ benefit of Amplify. Pretty definitive.

  6. I'd be interested in hearing MM's feelings about new FDA panel voting format. The FDA panel voted 9-4 (1 abstention) in favor of safety, 10-3 (1 abstention) in favor of effectiveness and for the first time ever voted on the risk vs. benefit of an orthopedic device 6-5 in favor (3 abstentions). All members voted electronically without knowing any other panel members votes..... also a first.

    PMA's are rare. What impact will new format have on future new spine tech approvals and industry investment?

  7. For MDT and the panelists to say that there's no biological mechanism to suspect re the apparent increase in cancer rate is beyond irresponsible. Any one of us can search Pubmed for the terms "BMP-2" AND "tumor" and in 15 seconds find multiple potential biological mechanisms. How is it possible that nobody, not the FDA, or the cancer experts did this?

    Hospitals are struggling to pay for InFuse today. In the long run, assuming FDA follows the panels recommendation and approves Amplify - how will it be priced, and how many hospitals will purchase it after doing their own cost/benefit analysis?

    Remember also, the surgeons and hospitals bear medical/legal liability associated with the safety risks along with the manufacturer.

    How many hospitals will take a closer look at their current InFuse usage with all of the new safety data enumerated in the "Executive Summary for P050036 Medtronic's AMPLIFY(tm) rhBMP-2 Matrix" available on the FDA website?

  8. The panel meeting unfolded as so often. Tough questions asked, many left partially or completely unanswered, and than a meek vote which does not appear to reflect the data presentations and discussions that preceded it. Based on her closing statements, Susan Alpert (ex chief of ODE) obviously still knows how to play game, only she plays for a different team now. However, it is noteworthy that the NO votes were predominantly cast by the the spine surgeons on the panel. Those are the future customers of this product, should it inadvertently get approved. Kudos to FDA for finding spine surgeons who do not operate under the Medtronic bubble.

  9. Is there potential for CMS to not reimburse for this a la the Charite? Seems like it would be coded similar to Infuse, but I'm not the expert on that end of things.

    This smacks a bit of the FDA/Panel hoping someone else will do their job and be decisive. For Charite it was CMS. Same possibility here?

    Curious what the experts think.

  10. A couple observations by TSB:

    If the product has a mitigating and potential risk for women of child bearing years, women who are pregnant, and the fetus, what does this say about the product?

    Even though a cancer expert felt that the types of cancers that presented themselves were a random clustering, is anyone willing to take that risk to better the revenue stream for Medtronic?

    Would you let your mother, father, or loved one have this pharmaceutical product implanted?

    With surgeons propensity to use products off-label and salespeople penchant to push the envelop, how long after this product is approved by the FDA will we start seeing reports of misuse?

    Or, will we have to hear it in the hollowed halls of NASS where we heard about some of the disasters with dosing and delivery when Infuse was introduced?

    TSB wants to know what our experts think?

  11. This product will be a flop. The competitors marketing plan will assure this. "Doc, for a 5% improvement in fusion rate, you get a 250% increase in cancer. You don't think the lawyers will get ahold of this do you?"

  12. or better yet "Doc, 1 out of 20 patients you put Amplify in will get a cancer. How many fusions do you do in a year?"

  13. the lawyers will be all over informed consent. Hear ye all surgeons out there, better have that cancer risk on your consent form or have all your assets in your wife's name.
    If you don't believe this Google spineology and lawsuits. There is a firm that advertises looking for complications from the use of this in the intervertebral space since this is off label. Lawyers are going through a recession to and looking to be more agressive.
    Caveat emptor....

  14. My previous posting was not uploaded, because it was too long...So I'll only share this one article, which seems relevant to yesterday's panel and should give anyone pause.

    TSB, to answer your questions:

    No, my family will not get a BMP until they are very, very, old.
    Yes, we will have to learn about the new problems in the dark corridors of meetings, as reports will be few and very slow to come out. (see the history of Infuse in ACDF!!)

    Carcinogenesis. 2009 Feb;30(2):238-48. Epub 2008 Dec 4.
    Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.
    Gordon KJ, Kirkbride KC, How T, Blobe GC.

    Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.
    Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (TbetaRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TbetaRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.

  15. Anonymous 7:49

    Thanks for your commentary, its people like you that make our blog a successful platform. Our readers can appreciate your incite into this material.

  16. Re: 6:20's question about reimbursement: Insurers are able to effectively block discs as there is a distinct procedure code that goes with implanting it. BMP, on the other hand, is just part of the fusion, so more difficult to specifically block. They'll continue to try to compress payment amounts for fusion to make it cost prohibitive to use it, but that "indirect" method is much more difficult.

    To 7:49, outstanding post!

  17. If MDT are presenting a 5% better fusion rate than their controls for Amplify never mind the cancer risk you'd be better off sticking with InFuse which according to their website has a 5.8% better fusion rate..!

    I quote;

    "And most notably, rates of fusion were 94.5% in the INFUSE® Bone Graft group and 88.7% in the autograft group at 24 months.


  18. Not to be a stickler (and I have no allegiance to Medtronic in any way shape or form), the data actually shows fusion rates of 95.9% for Amplify vs. 89.3% for the Control (which is hip autograft), which was statistically superior. The numbers others are quoting are the Composite Success, which includes Neuro, ODI, Revisions, etc. The definition for fusion is also pretty rigorous.

    I know of no synthetic that can even dream of posting these numbers in a Level 1 study with the definition of fusion used here and with blinded radiologists.

  19. And with all these fusion numbers expressed in decimals we should not forget that still, after 35 years, the radiological assessment of fusion still is woefully imprecise. The only reliable method to asses fusions is re-exploration with histology, which unfortunately is not very practical. There where it has been possible, it shows CT scans to overestimate fusion results, and plain X-rays to be all over the map. If plain X-rays are truly judged on the presence of crossing continues trabecular bone, they tend to underestimate and be lower than the around 90% reported here.

    As somebody else has already remarked, the blinded read in this study may have been well intended but in reality is utterly impossible. Every clinician, let alone a radiologist or spine surgeon, can distinguish between the wads of TCP/HA as opposed to iliac crest cancellous bone. This is a major source of (probably unintended) bias which alone can easily explain any 5 to 10% difference. I also wonder who the independent reviewer was.

  20. Very informative post and replies.

  21. what about vitoss combined with bone marrow? Compares to infuse in fusion rates or that is what is marketed by the company.

  22. Good point, they seem to have at least some data to back it up. Here is another interesting fact that does not seem to get too much airtime, in spite of being published:

    Proceedings of the NASS 22nd Annual Meeting / The Spine Journal 7 (2007) 1S–163S
    10. BMP-2 Causes Increased Postoperative Radiculitis Following TLIF James A. Sanfilippo, Jr., MD1, Joon Y. Lee, MD2, Jeffrey Rihn, MD2, Todd J. Albert, MD1, Alan S. Hilibrand, MD1; 1Thomas Jefferson University, Philadelphia, PA, USA; 2University of Pittsburgh, Pittsburgh, PA, USA

    CONCLUSIONS: The placement of BMP-2 within the disc space inside and around an interbody cage placed via a transforaminal approach signif- icantly increased the incidence of post-operative radiculitis. Whether this is due to BMP-induced exuberant new bone formation near the nerve root sleeve/foramina, or strictly due to the direct inflammatory effects of the BMP on the nearby neural elements is a subject of future study.

    SPINE 2009 Volume 34, Number 14, pp 1480 –1484
    Recombinant Human Bone Morphogenetic Protein-2-Induced Radiculitis in Elective Minimally Invasive Transforaminal Lumbar Interbody Fusions
    Stefan A. Mindea, MD, Patrick Shih, MD, and John K. Song, MD
    Department of Neurological Surgery, Northwestern University

    Conclusion. Our analysis suggest that patients undergoing minimally invasive transforaminal lumbar interbody fusions procedures have a higher incidence of developing new radicular symptoms that could be attributed to BMP.

  23. To Anonymous 7:49:

    Thank you for this reference. While I can only understand a fraction of the article not being a cellular microbiologist, it's a really interesting study. If you take nothing else away from reading it, I suggest those who are interested see Figure 6. "Proposed mechanism for BMP-induced invasion of pancreatic cancer cells." The study specifically studied and found activity with BMP's 2,4, and 7.
    So much for Medtronic's "No biological mechanism" argument re the increased cancer rates in the BMP-2 studies. It's unfortunate that none of the authors of this paper were invited to sit on the FDA's panel...

  24. Does a 5-6% increase in fusion or success rate mean anything to the average spinal fusion patient? I'm guessing they want to know the ballpark endpoint (85% better than 65% fusion rates). But combine that with knowledge of potential side effects, contraindications, etc., and my guess is they would opt to have their own bone used over Infuse/Amplify.

    Does anyone else see elephant in the room in that the fusion rates are 80+% for instrumented fusions (w/ and w/o BMPs) but the actual clinical outcome success rate is so much lower? Put the juice in my back and I have a 60% chance that my pain will go down or go away, or use my own bone and it's 55%? Seems to be an expensive example of the law of diminishing returns.

    And to the comment earlier on CF...I hope that was Spine Industry naivete thinking it stood for Compression Fracture. I think we all know several products, plans, and companies that qualify for official clusterf*** status. The compression fracture of the company comes after the true CF has taken place.

    Keep up the good dialogue! Excellent journal citations by the other posters.

  25. seriously, what is it like working for the juggernaut of an empire, the evil empire, MEDTRONIC ?
    lanx, no thanks.

  26. Does AMPLIFY=Infuse+Mastergrapht?(or was it Mastercraft?) SMD's TCP?

  27. AMPLIFY is in-fact lots of InFuse + Mastergraft Matrix.

    40 mg BMP-2 + 20 cc's Mastergraft.

    More detail can be found on the FDA website in the Executive Summary for P050036.

  28. Is there any other bone grafting product that has gone thru as extensive clinical studies? Anyone else done a Level 1 human clinical trial on any Allograft, Ceramic or DBM? the answer is no! No one else is talking about the risks of disease and ineffectiveness of Allograft........which is NOT FDA regulated! Does the safety and effectiveness in a rabbit or rat comforting enough for you all to use it in your family members? Quit bitching about Medtronic.......you are either jealous or naive. Thanks to those who make their arguments based on scientific data and not emotions. The system is obviously broken and every spine company out there takes advantage of it

    And yes, I would have Infuse used on me!

  29. I have to agree with Anon Aug 5 12:40PM. I have not seen any level 1 data on anything else that is at least as good at ICBG. I think reports of radiculitis, swelling, etc are dose issues. At least for ALIFs, where obtaining ICBG is an issue, it's been great for me. I used to do CT scans in the beginning but not anymore since they all were fused. I don't particularly like Medtronic and I don't get paid a dime by them. Just have to admit, Infuse has changed my practice. Amplify is a different matter however. Just too expensive and the high dose required (much more than for an ALIF) concerns me.