An Interview with Dr. Charles Rosen on Artificial Disc Clinical Trials
BY JOHN MCCORMICK, MAY 23, 2005
In our efforts to poll surgeons on the subject of artificial lumbar discs, we have been tracking down advocates as well as dissenters in order to get a balanced view. Last month at AANS we interviewed Dr. Fred Geisler who was one of the investigators in the Johnson & Johnson Charite artificial disc clinical trial. Dr. Geisler discussed artificial discs and clinical trial design with an enthusiasm tempered by a cautious scientific empiricism. Our interview with Dr. Geisler is published in our archive for our subscribers.
Two weeks ago, we noticed an article on thestreet.com entitled "J&J Discs Face Backlash". We then noted that the article was ominously reprinted on legal websites such as yourlawyer.com. We wanted to dig deeper into the question of surgeons questioning lumber artificial discs, so we followed up with Dr. Charles Rosen, a Professor at the University of California (Irvine) Spine Center, who was quoted in the article. While we do hear about legions of enthusiastic physicians lining up to be trained to implant the discs at J&J's facilities, we also observe events like CMS taking a "wait and see" approach on allowing add-on payments. The heart of the issue is data and so we thought Dr. Rosen's refreshing and shrewdly empirical "show me the results" perspective would be interesting.
JM: Let's discuss the FDA clinical trial for the Charite [artificial lumbar disc] and how you view the data.
CR: I originally started when the disc was FDA approved in order to see whether I wanted to implant it or not. As with any new procedure, I researched all the literature even though I have been following this. So I looked at the FDA study itself and the first thing I noticed is that there were 71 patients (that were the initial 25% or so of the patients) excluded from the results in consideration of whether to approve the device or not. The criticism of this in the FDA transcript was done by the FDA's own statistician. It's generally accepted, and something that I have seen in my own experience, that in a randomized clinical trial, you can't exclude those you want to exclude and include those you want to include otherwise it's not randomized.
JM: Who or what was excluded in the trial?
CR: The data of the first 71 patients was not included in the results in consideration of whether to approve the disc or not.
JM: And why were they excluded?
CR: There is no good reason. If you want the reason that is offered, you can look at it in the paper and it says these were the "learning curve" patients. When I called the FDA, they said it was the "doctors getting their feet wet" which is why they didn't include it. So from an objective scientific standpoint, whenever there are outliers - which there may be - you have to take that into account. When there is such a large portion of outliers that are excluded from the data, it makes the data somewhat skeptical. Just looking at this from a randomized perspective, it's not the kind of thing where you exclude the initial patients for whatever reason e.g. just because you want to exclude them. You have to include everything!
JM: Do we know the results with these 71 patients that were excluded?
CR: Well, I wanted to find out. First, I e-mailed and spoke with DePuy reps in the area. Second, I spoke with the FDA. The FDA's Michael Courtney said I had to file a Freedom of Information Act [request] to get this which I had never done before, so I went ahead and did it. The reply I got was that my Freedom of Information Act [request] was denied because the results of the 71 patients were a trade secret. I then sent a reply back asking how is this a trade secret when it's the same prosthesis that went into the first 71 as the last 204. They came back and said that is the basis for denying it legally: it's a trade secret. Period. So I never got the data from them. I can't find it in any of the literature. I also asked the DePuy rep to have one of their experts contact me. So I asked all around for this data, was never given any and was even told by the FDA that it was trade secret information and I couldn't see it.
JM: Has anyone even offered an opinion about these training cases? Conjecture about what the outcomes might have been?
CR: That goes into speculation. The side that says it's all OK could speculate that there is no problem. I actually did get an email from a DePuy rep who sells the disc saying that there is no difference in the results except for some longer operating time. So I said, "can I see the results?" and I didn't. So whoever you ask, it's speculation and therefore I do not have the results. It is not reasonable for us to speculate.
JM: I'd like to get back to the study from a statistical standpoint.
CR: The FDA's own statistician, who is a dedicated professional, in the transcript noted that what we are talking about is a deficiency in the study. He goes through a very elegant statistical analysis that suggests that the study is biased in favor of the Charite. In the transcript, he essentially condemns - in better statistical terms than I'll ever know - about why you can't do this.
JM: I have to imagine in a study where you are essentially testing for non-inferiority, the introduction of bias in favor of the disc...
CR: ...I simply would refer you to the pages in the transcript where Dr. JianXiong "George" Chu, who was a presenter at the meeting, says it's biased... pretty unequivocally.
JM: How therefore do you react to this recent CMS (e.g. Medicare) "wait and see" answer on their willingness to do add-on reimbursements for the disc? CMS asserts that there is a lack of statistically significant proof that the disc is superior to the [fusion] control.
CR: I can comment more specifically on the FDA study about the fusion control. The BAK stand-alone cage [the control] is not done any longer. The last time period that treatment was done is five or six years ago! There was even a paper that came out recently in a 2005 Spine Journal1 that showed a high failure rate. [I am looking at the paper here and the 3-6 year follow up on 33 of 46 patients... 10 patients had 14 total complications requiring revision surgery. About 70% of patients had a fair or poor outcome and 58% patients. I couldn't have picked a worse operation to compare this to. It was out of favor at the time the study was done even though it was designed at a time (five years earlier) when it wasn't.] So taking a control that is a failed operation five years ago and putting it into a study in the last two or three years, I just don't understand why they didn't compare it to something more reasonable. If I was going to construct a non-inferiority study with a control that has a high failure rate, I don't think I'd have too tough a time passing the non-inferiority test.
JM: As a surgeon, are you also taking your own "wait and see approach"?
CR: I am definitely taking a "wait and see" approach. Because of the exclusion of the data being released by the FDA or the Company, I have an even bigger question mark as to what is going on here. I have never come across a randomized controlled trial where data is excluded because it is simply the initial data. The learning curve aspect to the argument only tells me there are mistakes that they don't want revealed. That's what it implies.
JM: Then what do you think about the actual fact of implantation in the market where surgeons all have their own learning curves, many of whom were in the proverbial bottom 50% of their medical school class?
CR: Even if they were in the top 10% of their medical school class, there is still a learning curve. I was thinking about doing this surgery myself and I wanted to know what kinds of problems to anticipate in my initial cases and the fact they are not even revealing what that was makes me loathe to try it. This lack of data implies that there are problems that they don't want to tell me about. If you translate that to the tens of thousands of operations that they want to have done in the country then you are talking about increasing the number of problems there were to a large degree... to large numbers. Your point is well put.
JM: Does the new wave of IDEs in artificial discs give you any confidence? For example, the SpinalMotion Kineflex study is going to be randomized against the Charite itself.
CR: No. As you state, it's comparing an artificial disc to an artificial disc. It's the equivalent of comparing one stand-alone BAK cage to another type of stand-alone cage. You are comparing the same thing... something that's problematic to something that's problematic. If you compare a disc replacement to a more modern fusion technique with the same comparable controls, randomization and a follow up period - longer than two years as the FDA people say - and if I saw that then I might start to say this is a good thing.
JM: That's interesting. The modern studies essentially have the same problem. It's rather like Aristotle's syllogism: if a=b and b=c, then a=c. The Kineflex is effectively being randomized against the BAK cage...
CR: Right. Right... The clinical question (as opposed to the financial question) should be: is the current standard of care using an up to date modern fusion technique whether it's laparoscopic or mini-incision anterior or percutaneous posterior... is that going to be surpassed in results - not just short term, but long term - by disc replacement? And are the complications of the initial ones being done going to be understood and comparable as well? If they are... I'll be the first in line to do it. But given what we've just discussed, there are reasons to think that this is not the case.
JM: This is interesting to us. We find docs who are enthusiastic about discs...
CR: I have no financial interest in any of this. I never have had any money come from anybody, any company or anything! I was really just looking to do this [surgery]. A lot of my opinions come from the statistician at the FDA as you know. More comes from the engineer at the FDA! If you look at his stuff, he says this number of millions of cycles is not adequate and two years is not adequate. Then if you look at the stuff Van Ooij said...
JM: ... yeah but I was at the FDA panel meeting last year myself, and we have to admit Van Ooij was biased. He works for Medtronic!
CR: Nevertheless what he said is what he said.
JM: What did he say? I don't remember...
CR: He talked about the failure rate. He did a study and said that he thought it was not a good procedure, had complications and therefore - I don't want to misquote, you should look at the FDA transcript - but basically he didn't recommend approval. He had a negative opinion of it. Yes, he was flown in from Medtronic, but nevertheless... In essence, what I am trying to say is that my opinion [of the disc] is based on the opinion of others including the statistician, the engineer and the other people who have done it - people who know more about this than me who are criticizing it significantly, the study itself, the validity and the actual procedure. So I am saying a lot of these things based on what I am reading. Another thing that has been influencing me is a 17-year study that actually came out of the Charite Center in Berlin and it was 23 showed excellent or good results whereas 29 patients had fair or poor results. Now that's not a great number. In fact, many of the excellent or good results were in patients who had spontaneous fusions. This is from the center that is named after the thing in Berlin with 17 year follow up! Compare that to the two year follow up. So these are all the questions that come to mind from the manipulation and exclusion of data and the criticism that comes from people that know more about statistical significance than I do. And the fact that I asked people for the data and was just stonewalled. This is what has caused me to question what is going on.
JM: Any other thoughts?
CR: Yes. The literature from Europe seems to indicate that there is not a good salvage procedure so there is a majority that continues to have unremitting pain without any good solution. I am looking at two articles here... actually one was from Van Ooij on another series of 43 patients that had complications from the Charite prosthesis where patients were repeated on. 17 had some or good relief and 25 experienced no benefit whatsoever. In 5 patients, the prosthesis were removed, in 19 patients in this group posterior instrumentation was used... 10 times with mostly unsatisfactory results. So that means that 50% have no good salvage. In other words, if you have a bad total knee replacement and you redo it, you get 80% - 90% good results. Here you get 50% miserable results. I have other papers, that are not in front of me, that correspond to these results; that there is no good salvage procedure.
JM: [Revision] is also known to be dangerous.
CR: Oh yes. The iliac veins - after they are scarred down - it's very difficult to do. In fact, one of the vascular surgeons in our place refuses to do any repeat anterior surgery on the spine. It's just too life threatening. So you're exact about that. The other thing is that I have had patients email me that have had failures and they are miserable - in continued pain. The one patient that contacted me last night had a total disc replacement, then had a procedure done because of the pain and they are miserable. A total fusion may not work, because of the [anterior] motion which is what Van Ooij found. I have another patient who had one put in a couple of years ago that failed, had it taken out and re-fused and they are absolutely miserable. They have had a fusion, front and back, with the prosthesis. These people are coming out of the woodwork here so, well... I don't know what it means. Those cases are as anecdotal as the good stories that you hear. Again, that's not looking at the hard numbers.
JM: Right. When the national unemployment rate is 6% it's 6%, but when you are unemployed - the unemployment rate is 100% and that applies to clinical results.
CR: Right... and that's what I initially wanted to find out. I wanted to anticipate what the problems could be with this and I wasn't told and now - at least anecdotally - there are problems. Getting back to the hard data which is your purpose and should be anybody's purpose, that's what I have an issue with and it's certainly not being satisfied by anything. The attacks I am getting don't even address the facts either (I didn't plan on getting involved at this level - it's not like I am a social crusader). It's just that no one comes to me and says "here's the data with the 71 patients" or "here's the long term follow up". None of those are being addressed objectively.
JM: Dr. Rosen, we greatly appreciate your time.
CR: Thank you.
