Advisory committee votes against approval of SonoCare HIFU


According to a report posted yesterday on the Medscape web site, a Food and Drug Administration (FDA) advisory committee “voted October 1 not to recommend approval, at least for now” of a SonoCare Medical’s Sonablate high-intensity focused ultrasound (HIFU) device to treat patients with radio-recurrent .

Basically, it appears that the Gastroenterology and Urology Devices Panel of the FDA’s Medical Devices Advisory Committee

encouraged the device manufacturer to continue to conduct research but to come back when the ongoing pivotal trial at 20 sites in the United States and Canada is completed, not halfway through.

The pivotal trial was designed to enroll men with biopsy-proven, recurrent cancer in patients at any risk level who had failed primary external beam radiation therapy and had PSA levels of < 10 ng/ml.

According to the report on the Medscape web site

  • SonaCare Medical based its request on an interim analysis of results from a non-randomized, single-group clinical trial involving the first 100 of a planned 200 patients.
  • The patients’ ages ranged from 53 to 83 years (mean, 69.7 years).
  • Of the first 100 patients enrolled at 16 sites, 78 had completed 12 months of follow-up and had a biopsy.
  • 50/100 patients enrolled (50 percent) obtained local control of their prostate cancer — defined as achieving a PSA nadir of 0.5 ng/ml or lower and a negative prostate biopsy at 12 months.
  • 50/78 patients who met the study protocol requirements (64 percent) obtained local control of their prostate cancer.
  • Adverse events included
    • 7 rectal fistulas in 5 patients (a 5 percent fistula rate compared with the projected rate of 3 percent).
    • 44 patients experienced urinary incontinence post-HIFU.

Panel votes on the three key questions regarding efficacy and safety were:

  • 7 to 3 (with 1 abstention) against recommending that the treatment was safe if used as intended
  • 9 to 2 against recommending that the treatment was effective if used as intended, and
  • 10 to 0 (with 1 abstention) against recommending that the benefits outweigh the risks.

Now one has to say, immediately, that SonoCare Medical  (like EDAP TMS before it) seems not to have understood the importance of actually doing — let alone completing — the trial they committed to doing.

To try to obtain  approval for HIFU in the treatment of radio-recurrent prostate cancer on the basis of complete data from just 78 out of 100 patients when the trial was designed to enroll 200 (which in and of itself was hardly a large number) seems to be naive in the extreme.

On top of that, the rate of adverse events appears to be a good deal higher than advocates for HIFU would have been expecting. Of the 5 patients who experienced rectal fistula, three required medical management and two required surgery.

These are certainly not the sorts of results that anyone has been expecting that HIFU treatment might be capable of generating. And investors in SonoCare might well be wondering what the company thought it was doing in terms of seeking an approval based on data of this type.

The fact that on two occasions the developers of HIFU technology have utterly failed to be able to demonstrate the types of outcome that they claim be be able to achieve in Europe would seem to raise serious questions about the long-term approvability of this technology (at least for that from the two developers in  question). These data look a lot more like the data that have been reported by Emberton, Ahmed, et al. in the UK than others have wanted us to believe. As of 10:40 am this morning, there is no sign of any media release from SonoCare Medical.

 

11 Responses

  1. I attended the earlier Ablatherm HIFU hearing and am looking forward to information presented at this hearing. I am especially interested as a paper by the Uchida group in Japan demonstrated remarkable success using advanced Sonablate technology, in sharp contrast to prior HIFU treament by the same group with earlier Sonablate technology. Until convinced otherwise, it looks clear to me that HIFU is highly dependent on the technology and/or the expertise applied. I am curious whether the technology discussed at the October 1 hearing involved the advanced technology discussed in this summer’s paper by Uchida and colleagues or earlier technology. (This summer’s paper was the subject of an earlier article by Sitemaster.)

    Information about this hearing, including background material, is posted at the FDA site, but the transcript of all oral statements at the hearing typically is not available for a number of weeks, at least. There is some information at this URL under the Gastroenterology-Urology Devices Panel for September 29:

    — Post Approval Study: October 1, 2014 (PDF, 133 kb)
    — Spec Sheet: October 1, 2014 (PDF, 489 kb)
    — Patient Trifold: October 1, 2014 (PDF, 1.1 Mb)
    — Patient Poster: October 1, 2014 (PDF, 175 kB)
    — Patient Reference Card: October 1, 2014 (PDF, 162 kb)
    — User Manual: October 1, 2014 (PDF, 6.2 Mb)
    — Table of Contents: October 1, 2014 (PDF, 180 kb)
    — Proposed SSED: October 1, 2014 (PDF, 415 kb)
    — Sponsor Executive Summary: October 1, 2014 (PDF, 2.7 Mb)
    — Agenda: October 1, 2014 (PDF, 20 kb)

    The following was posted on October 1 at the same site for the same advisory committee panel:

    — Panel Questions: October 1, 2014 (PDF, 71 kb)
    — Sponsor Executive Summary Addendum: October 1, 2014 (PDF, 141 kb)
    — FDA Executive Summary: October 1, 2014 (PDF, 905 kb)
    — Roster: October 1, 2014 (PDF, 8 kb)

    Most of the panel members from the summer’s review of Ablatherm were also on the October 1 panel, under the same chairman, but there was at least one important difference, Dr. Eric Klein.

    TECHNOLOGY DIFFERENCES VS. UCHIDA PAPER?

    At first glance, there appear to be technology differences between the apparently successful technology in the Uchida paper from this summer and the technology presented at the hearing. First of all, the Uchida paper highlighted Sonablate 500 technology with some important special features, while the hearing featured Sonablate 450 technology, signifying at least a software difference. Here are some key features of the Sonablate 500 special technology addressed in my comment “JimWaldenfels, on August 16, 2014 at 3:47 pm said:

    POSTSCRIPT AND CORRECTION — RESPONSE TO WOLFRAM”:
    “… the cycle time has been reduced from 16 sec to 6 sec per focus lesion. The focus volume has also enlarged from 2.0 x 2.0 x 10 mm (0.04 cc) to 3.0 x 3.0 x 12 mm (0.108 cc). SB devices incoporate additional safety features, including reflectivity measurements, stacking, and TCM systems.13 The stacking system can refine the treatment plan before or during the procedure. The TCM system quantifies tissue changes based on comparisons of radiofrequency ultrasound pulse-echo signals at each treatment site and monitors lesion temperatures by color changes.”

    It appears from the hearing background papers that a 3 second on-phase was used versus the 6 second phase noted by the Uchida group. That seems quite significant to my layman’s eyes, and there appear to be some other differences.

  2. Dear Jim:

    The differences between the data in the Uchida paper and the data being presented at the recent hearing are based on such utterly different patient types (as well as the technology) as to make any comparisons irrelevant to anything. The pateients being treated by Uchida et al, werre all “first-line” patients. The patients treated as part of the pivotal trial data presented to the FDA were all radiatiuon failures receiveing HIFU as salvage therapy. You can’t compare apples to oranges, regardless of the technology factor.

  3. The respected medical community and the enormous radiological surgical complex have deemed this the first prostate treatment that must pass their now stringent standards. Note how they are more receptive of the idea of HIFU after they have irradiated the patient and failed. It would seem that the less invasive procedure would be the first course of action, but not when the big $$$$ are in play. Just not enough money in the HIFU procedure for big pharma.

  4. Dear Steve:

    I think you have some perceptions out of kilter here.

    (1) Dozens of new medical devices are now being held to the same standards as HIFU for the treatment of prostate cancer, as they should be. This is hardly an isolated case. Why would you want to be treated by someone using a medical device that can’t be shown to produce decent outcomes?

    (2) No one told SonoCare that they “had to” do a trial in men who had failed radiation therapy. That was the company’s decision after they had completely failed to enroll patients into an earlier trial of HIFU as first-line therapy. I know of no reason why they should have failed to be able to do this (except for their own lack of ability to appropriately promote the trial).

    (3) EDAP-TMS has already failed to demonstrate efficacy and safety of HIFU in first-line therapy. Arguably they also made a massive mess of the attempt to conduct their trial. They certainly failed to do what they committed to do.

    (4) “Big pharma” doesn’t make or develop medical devices. It never has. It is a completely different business model. On the other hand, “big pharma” certainly does know how to carry out clinical trials, and no pharmaceutical company would have made the mess of the clinical trials in the way that SonoCare and EDAP-TMS did.

    As far as I am concerned, the only people deserving of “blame” here are the two companies. They made promises they couldn’t meet. They did not do what a wide range of advisors most certainly told them that they needed to do. And then they wanted to blame everyone else when their business strategy blew up in their faces.

  5. WHY THE UCHIDA SUCCESS MATTERS HERE (at least to me)

    Dear Sitemaster and Steve,

    I fully understand the point you raised about lack of comparability, Sitemaster, and agree. I also realize I was leaving out key links in what I was trying to express. My point was this: the only study I know of that demonstrates what appears to be decent success over an adequate follow-up period for HIFU as primary therapy is the Uchida group study of a specific version of the Sonablate 500 technology. No other version or versions in any other study appeared to achieve the decent or better levels of success that we see with other technologies, such as surgery and radiation.

    (Steve: challenge for you — find any decent study in addition to the Uchida study I mentioned that documents decent success of HIFU as primary therapy for even low-risk patients that is comparable to success levels typically achieved in surgery and radiation studies. Follow-up must be at least 4 to 5 years, as by that time HIFU results have, with one exception — Uchida — looked poor.)

    Therefore, the apparently successful Uchida HIFU technology as a primary therapy struck me as one useful benchmark for what would be more likely to work for HIFU as a salvage therapy, in contrast to all the rest of the HIFU technologies with universally dismal levels of success as primary therapies, as documented by studies with adequate follow-up time of at least 4 to 5 years. There is no guarantee for the latest Uchida group technology as a salvage therapy, of course, and perhaps a HIFU technology that would not work as a primary might work for salvage. I see it as a matter of placing your research bets.

    In summary, I would have been more confident in the Sonablate approach at the hearing if they had used the same technology as the apparently successful Uchida Sonablate technology for primary therapy. I hope to have time to see if they made comparisons in their presentation. At a quick glance, I did not find such comparisons.

  6. Here is what I believe to be significant for this clinical trial on HIFU for radiation failure. The FDA ground rules are difficult in that a clinical trial physician, who has never performed a HIFU procedure, is asked to treat a highly complex patient that will have a high level of side effects. And they must be able to treat them with seemingly 100% success or the data looks to be a failure.

    In Dr. Emberton’s study last year, all of his HIFU procedures were done by his students and novice HIFU physicians. He did not do any of procedures. And the same thing happened in the FDA clinical trials for HIFU. The treating physicians were at best novices. At what point in time do we not only disaggregate the patient population but the physician population too?

  7. Dear Jim:

    Every trial of every new technology (from the use of a simple aspirin pill to the use of high-tech equipment that requires great skill to operate well) comes with the problem you describe. Perhaps the more relevant question is: “What is the level of skill that a clinical investigator needs to have before he or she can reasonably be expected to participate in a clinical trial using new and complex equipment?”

    I would point out that if HIFU was approved tomorrow, the new users who might start to apply this technique would also be highly inexperienced, and very few physicians would ever achieve the skill level attributed to someone like Dr. Scionti and a very few others. We know that this is true based on everything from the uptake of nerve-sparing radical prostatectomy to the time it takes to learn to use a da Vinci robot really well to the differing results obtainable by radiotherapists as they learn to use a CyberKnife.

    Arguably, it is completely appropriate that the people who are carrying out procedures with new equipment like this should have limited experience, because that is the “real life” scenario. Just because a few physicians appear to be able to use HIFU well doesn’t mean that most either can or will. Just look at the way large numbers of us drive our high-tech automobiles. … Half of us are barely paying attention to what is happening around us! And as someone who had to get a British driving license nearly 50 years ago now, I was horrified at the simplicity of the driving test I was asked to pass in Pennsylvania. Physicians are just people too.

  8. “High tech autos?” I didn’t think a high tech auto analogy was similar to FDA clinical trials where the very success of a medical device is dependent on novice physicians. Apparently they are not looked at as important to a clinical trial cohort. Isn’t it amazing that we can obsess about a patient population and resulting data in this FDA clinical trial on radiology failure, truly quite complex, and yet we have no idea as to the number of treating physicians or competence? Ah, yes, the translucent glass ceiling continues to be clouded.

  9. Dear Jim:

    My point about the autos is that there are people who are really good at driving them and there are people who aren’t. The same is true of physicians: there are really good ones and really not very good ones. As the old saw has it: “What do you call the person who graduated last in his class from medical school?”

  10. Well, considering that I do know some very bright physicians, I am not intimidated by medical school “last in the class” positions. There are some truly compromised doctors in the US who have been virtually passed by … by their own arrogance and self-obsessed billiance. Mike, I know you are a bright guy and intelligence is very important to you. But my point stands: Using novice physicians to measure the efficacy of HIFU in treating the very difficult radiorecurrence is suspect.

  11. Dear Jim:

    (1) “Intelligence” is actually not important to me at all. Being able to think clearly is, and so is doing what you tell others you are going to do.

    (2) If any developer of a HIFU product (or of any other product) uses “novice” and undertrained physicians to execute procedures for them in clinical trials, then they only have themselves to blame if the trial results aren’t what they (or you) think is possible. The FDA doesn’t select these investigators; the developer does. The developer has complete control over how the trials are conducted. All they have to do is meet the pre-agreed trial protocol, eligibility criteria, and endpoints negotiated with the FDA and keep meticulous records. I can’t understand why you keep trying to blame others for the failure of SonoCare and EDAP to do what they had told the FDA they agreed to do. After all, SonoCare supposedly knows multiple US-based clinicians with extensive experience. How many of the 100 patients treated in the SonoCare trial were actually treated by these experienced physicians?

    (3) Given item (2) above, using novice physicians … is not “suspect”, it is just dumb!

    (4) I fail to understand why you keep trying to make excuses for SonoCare and EDAP. They failed to do what they agreed to do, and now you seem to be telling me that, on top of that, they also failed to use suitably trained clinicians to execute their trials. And you wonder why I am underimpressed by the whole thing?

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