How NOT to get your technology approved rapidly by the FDA


In a second statement to the media since an advisory panel to the U.S. Food and Drug Administration (FDA) decided not to recommend approval of EDAP TMS’s outdated form of Ablatherm technology for the treatment of low-risk prostate cancer, the company’s CEO seems to exhibit serious misunderstandings about how to work with the FDA.

Contrary to the beliefs of a few of our regular readers, the “New” Prostate Cancer InfoLink would actually really like to see some form of high-intensity focused ultrasound (HIFU) approved for the treatment of well-categorized patients with selected types of prostate cancer. However, this is going to (and always was going to) require data that clearly demonstrate a positive risk/benefit ratio favoring the use of HIFU compared to some other recognized management strategy. It is utterly clear to any neutral observer that EDAP TMS failed to provide anything approaching this type of data at the hearing on July 30.

On Tuesday, the CEO of EDAP TMS issued a media release which, on the one hand, states that the company is

committed to working closely with the FDA and its review team to identify a potential path to making Ablatherm-HIFU an available treatment choice for prostate cancer patients in the U.S.

and then, on the other hand, complains loudly and publicly that (in his interpretation of statements made by panel members at the advisory panel meeting)

the current approval path for new prostate cancer treatments is prohibitive and the likelihood that existing therapies, if evaluated on today’s requirements, would be unlikely to qualify for a positive vote.

He is probably correct in this statement. Most radiation oncologists would certainly argue that radical surgery is an inappropriate way to treat most men with low-risk prostate cancer, and most surgeons would probably say the same about radiation therapy (and there are some surgeons and some radiation oncologists who would state that neither form of treatment was appropriate). However, for complex legal and historical reasons, the FDA does not have the same authority over approval of surgery and radiation therapy as it does over a new form of technology like HIFU.

It is important for our readers (and perhaps for EDAP TMS’s CEO too) to appreciate that every FDA advisory panel or committee is asked to do a series of very specific tasks. These advisory panels do not represent the FDA. They are simply advisory panels of various types at which individual members may express their personal opinions about all sorts of things. The FDA makes its own decisions, taking into account the views of its advisory committees and panels.

Several years ago, when the company started to seek approval for its now outdated form of Ablatherm technology to treat low-risk prostate cancer in the USA, EDAP TMS agreed, after discussions with the FDA, to carry out a number of specific tasks, several of which they subsequently failed to do. One of these was to conduct a randomized clinical trial of their technology compared to whole-gland cryotherapy in the treatment of men with low-risk, localized prostate cancer. Why they ever agreed to do this, The “New” Prostate Cancer InfoLink cannot imagine. It seemed like a really bad idea to us at the time, and the company was subsequently unable to enroll anything approaching the 400+ patients that the trial protocol required. This came as no surprise at all to The “New” Prostate cancer InfoLink. If they had worked out a way to compare HIFU to active surveillance or to surgery or to some form of radiation therapy, and if they had invested appropriately in the implementation of the trial, they might have had a shot, but they never had a chance of completing the trial they committed to. The FDA’s advisory panel, consequently, had no choice but to agree with the FDA’s own reviewers that EDAP TMS had failed to demonstrate efficacy or safety in any well-conducted clinical study.

EDAP TMS complains in its press release that

the panel has been unable to provide concrete guidance on a potential, acceptable approval path for a new device to treat prostate cancer.

However, that was not, in any way, the responsibility of the recent advisory panel. And the advisory panel was not asked to address that issue. That issue has been discussed by other FDA advisory panels and committees over time. However, if EDAP TMS wants to be able “to identify a potential path to making Ablatherm-HIFU an available treatment choice for prostate cancer patients in the U.S.”, then the company and its leadership had better get a grip on the idea that it is the company itself that has the responsibility to collaborate with others (specifically including the FDA) to define that acceptable approval pathway, obtain the buy-in of the FDA, and then execute the studies necessary to demonstrate the pre-defined benefit/risk ratio.

It is also of no specific relevance to the FDA that EDAP TMS’s technology has been approved in other countries around the world. Try telling the French regulatory authorities that they should approve use of some form of treatment in France just because it has been approved in America. That’s going to get you a long way fast!

All too many developers of health care products see the FDA as a road block to their desire to sell specific products and services in the USA. Experience and wisdom has gradually taught smart CEOs and smart companies to look at the FDA as a “customer” with certain very specific and legally defined responsibilities. As many readers will recognize, there is a much-quoted aphorism that “the customer is always right.” If you see the FDA as an “enemy” that has to be overcome, you are approaching the whole concept of product approval in the USA (and most other nations) from entirely the wrong perspective.

In fact, the FDA has a long track record of trying very hard to help developers to bring important new products to market, particularly for treatment of patients with no, few, or poor therapeutic options. That track record is now so strong that some of the FDA critics have become much more concerned with the idea that the products the FDA is approving under “fast track”, “breakthrough therapy”, and “accelerated approval” processes are, in fact, too risky.

Nearly everyone agrees that the management options for many patients with low- and intermediate-risk forms of prostate cancer are poor. The well-known risks for complications and side effects often far outweigh the benefits of treatment, and treatments with significantly lower risk for complications and side effects may well offer much better treatment options (in terms of quality of life, if not in terms of overall survival) than existing options (active surveillance included).

There are (and long have been) three very clear sets of US-based prostate cancer patients who have the potential to benefit from treatment with HIFU:

  • Men with very low- and low-risk, localized prostate cancer who are highly appropriate candidates for active surveillance but who are unwilling to consider active surveillance or watchful waiting as a management strategy
  • Men with low-risk and some men with intermediate-risk, localized prostate cancer who are probably not appropriate candidates for active surveillance or watchful waiting (and who are frequently, today, being treated with surgery or radiation therapy of some type)
  • Men who fail first-line radiation therapy and who therefore need salvage therapy of some type (and for whom salvage surgery and/or immediate androgen ablation therapy are not exactly high-quality options)

In addition, there is another group of men who may be good candidates (for a number of reasons) for focal forms of HIFU in the same way that they are good candidates for focal laser ablation (FLA). The most recent form of the Ablatherm HIFU technology can certainly be used in this manner. Whether it is effective and safe — by US standards — when used in such patients is, of course, not known.

However, the fact that such men have the potential to be treated with and benefit from HIFU is by no means the same as proof that a sufficient proportion of them will so benefit.

We would politely suggest to EDAP TMS and its CEO that the company may want to think a great deal harder than they appear to have done in the past about how to demonstrate safety and efficacy of the very best form of their technology in one of these subsets of patients; to design one or more trials to demonstrate such efficacy and safety; to gain the buy-in of the FDA to the proposed trials; and then to actually execute against that commitment. Whining in public may make a few investors happy; it will never get your product approved by the FDA, and it has a strong tendency to aggravate the very people that you most need to be your collaborators and supporters.

We also look forward to the upcoming meeting of the same FDA advisory panel (on October 2), when it discusses the application filed by SonaCare Medical for the use of its Sonablate 450 technology in the salvage treatment of men with progressive disease after first-line radiation therapy. We very much hope that SonaCare has actually executed against the development plan agreed to with the FDA. If the Sonablate technology demonstrates a sufficient benefit/risk ratio and does get recommended for approval for this use, then we will all have taken a good step in the right direction … and EDAP TMS may be able to learn from the experience.

22 Responses

  1. The best line in this missive is: “However, for complex legal and historical reasons, the FDA does not have the same authority over approval of surgery and radiation therapy as it does over a new form of technology like HIFU.”

  2. Jim: It’s just a fact … It’s not the FDA’s fault. And it doesn’t change the fact that if you want to get a new product approved today in America, you are going to need to work out how to work well with the FDA to do it.

  3. I have no problem with the FDA demanding adequate performance from medical devices up for approval. EDAP obviously screwed up and instead of changing their clinical trials it seems they tried to just bully their way into approval. But since this “advisory committee” is only “advisory” it is going to be interesting to see how EDAP proceeds.

    Apparently safety and efficacy are important pieces to the FDA puzzle, so one wonders why the FDA has not further scrutinized da Vinci surgery for PCa. That medical devices has had serious performance issues with side effects, along with poorly trained physicians who are unable to master the steep learning curve. And yet this is the number one treatment in the US for prostate cancer. Is the FDA now impotent, pun intended, to improve the da Vinci results or has the cat walked so far out of the bag that everyone just looks the other way?

  4. Jim:

    If you look carefully at both the FDA web site and the Intuitive web site (as well as various other sources on the web), you will find that over the past 3 years the FDA has been scrutinizing the underlying technology of the da Vinci equipment with great care and has requested a variety of information from Inuitive that has led to several changes in the way that the equipment actually works. This is something that the FDA has the regulatory authority to do. However, the FDA has no regulatory authority over the actual use of the equipment by individual surgeons, and no regulatory authority over the way in which individual hospitals promote the use of this equipment to treat prostate cancer.

  5. Mike,

    Good to have you back posting. Thank goodness we do have some companies working on new era MRI-guided HIFU. For any manufacturer to put a label on a treatment as focal, it will first need to show how they intend to hit the target.

  6. Dear Ken:

    Actually, that may be the easy part of problem!

  7. LONG AWAITED BREAKTHROUGH IN HIFU FINALLY HERE? — REALLY IMPRESSED WITH LATEST UCHIDA TEAM PAPER

    Right on the money, Mike! Hope you don’t mind my going slightly off topic — still HIFU, but looking at the latest, hot-off-the-press (almost – using electrons instead) paper. I figured this more recent article was a better place for my review than the post-hearing HIFU article with its multitude of posts.

    By way of introduction, I gave a “public”, 5-minute statement at the HIFU hearing on July 30, as described in comments under the previous HIFU article. I was skeptical based on the evidence presented and additionally was not aware of any other studies that sparked enthusiasm compared to other therapies, though some were interesting. That has changed with this study by Uchida et al., which I have reviewed in detail (even catching one error).

    This latest study from the Uchida team in Japan updates and expands their previous series of studies using various versions of Sonablate equipment. (I would love to see you take a look at this Mike.) The bottom line: far superior efficacy in achieving biochemical disease-free survival (BDFS) for latest version over two previous versions, with other encouraging data as well (including negative biopsies).

    I found this just published paper (July 28) as I was trying to understand how frequent bounces under HIFU might be artificially making BDFS success (a.k.a. keeping PSA down) look poor. I did not get more insight on that score, but I’m thinking that does not matter much based on the excellent results the Uchida team is seeing with the latest Sonablate SB500 TCM equipment. Here are some key data:

    Effectiveness: For the latest SB500 TCM technology, the team reports BDFS success for low-risk (D’Amico) patients as 95% at the 5-year point, but I’m especially impressed that the success line is essentially flat from about 40 months through 72 months. That strikes me as comparable to well-done radiation and surgery outcomes. Moreover, the success at 5 years is 80.9% for intermediate-risk and 71.9% for high-risk patients, both fairly decent figures; though the curves continue to decline a bit, they are fairly flat for both the intermediate- and high-risk groups.

    Here’s the possible game-changer, at 60 through 72 months (flat), with the latest SB500 TCM technology, the success rate of 71.9% for the high-risk group is only a few points below the previous generation (the intermediate SB500 version 4) success for the low-risk group at 72 months! Looking at low-risk vs. low-risk at 5 years, the latest technology’s success is 95% versus an unimpressive 77.4% for the previous generation SB500 version 4. In line with these “technology generational” results, the original patient group treated with SB200/500 technology scores quite a bit lower than the intermediate technology group (SB500 version 4). (This analysis is based primarily on Figure 3 which presents results by risk group for overall, SB200/500, SB500 ver. 4, and SB500 TCM.)

    However, it is not a free ride. While complications are generally similar with small proportions of patients affected over the three patient groups (by treatment technology), the rate of erectile dysfunction at 2 years is much higher for the latest SB500 TCM technology at 52.0% than for the earliest group (20.7%) and the intermediate group (18.5%). Much greater success may be a result of much less nerve sparing.

    Here are some other relevant figures:

    Survival: Overall, for all technologies, cancer-specific survival is 99.5% at 5 years and 97.5% at 10 years. These results are about on par for US results per the American Cancer Society.

    Negative biopsies: The rate has increased impressively with the succeeding generations of technology, from 80.6% for the earliest, through 93.3% for the intermediate equipment, to a virtually equal 93.9% for the latest equipment. I doubt that follow-up time would substantially alter these figures as the latest equipment racks up more years of follow-up. The negative biopsy rate was a prominent concern at the FDA hearing on July 30, and the data presented by EDAP were not even close to as good as 93%. This strikes me as pretty significant.

    HIFU sessions needed (through 5 total): for 1: 62.2% for the earliest, 78.7% for the intermediate, and 95.2% for the latest. I doubt extended follow-up for the latest beyond present data would affect this much.

    Patients with salvage treatment: 37.7% for the earliest, 31.0% for the intermediate, and 9.6% for the latest. Again, while longer follow-up is likely to boost that 9.6%, I doubt it will be a major boost because current follow-up has been pretty decent.

    Well, that’s my now-savvy layman survivor’s take. I’m impressed. It strikes me this is comparable to what EBRT radiation went through when doses were increased from the low to mid 70 Gy to around 78-80 Gy. I hope this stands up. I’ll be happy to address questions about details in the paper if there are any.

  8. The Ablatherm HIFU system is used in Europe, Canada, South America, Asia (decision in China in December) and reimbursed in France. The Ablatherm HIFU device is recommended by the European Association of Urologists as first-in-line and salvage treatment for low- and mid-risk prostate cancer. Sales are increasing (positive net income last quarter) so it seems that the worldwide medical community is convinced about the advantage of the Ablatherm HIFU system (except adcomm with e.g. Dr. Klein from Cleveland Clinic USA, while his colleagues from Cleveland Clinic Canada have performed +700 treatments with Ablatherm with a high success rate). Also there are studies that show Ablatherm is much better than Sonablate. I hope the FDA is less corrupt than their adcomm and will approve Ablatherm (with possible post-approval study). Hey, if the FDA can approve a vaccine that was only tested on animals to use it in Africa, they can certainly approve Ablatherm.

  9. Dear Annicka:

    Again … The FDA has not approved any form of treatment for ebola. It has permitted the use of certain experimental products under experimental protocols on humanitarian grounds in exactly the same way as it permitted clinical trial’s of Ablatherm equipment in the USA. It is not the FDA’s fault that Ablatherm failed to come close to complete the trials that the EDAP TMS itself agreed to carry out.

    And just to be clear, I see no way that the FDA will approve Ablatherm HIFU in the USA based on the available data. You may not like this, but — with the single exception of InSightec — the HIFU industry as a whole has done a very poor job to date of convincing most people in the USA of the value of this type of technology in the management of prostate cancer.

  10. SUBJECT UCHIDA TEAM’S PAPER’S COMPARISONS OF HIFU TO RADIATION, SURGERY AND CRYO

    This paper reports some very nice biochemical disease-free survival rates (bDFS, a.k.a. success based on PSA tracking after treatment) for the SB500 TCM equipment (Group C). In the discussion section the authors compare these success rates to rates for IMRT, cryotherapy, and robotic surgery. Unfortunately, the comparison for IMRT cites a paper on older IMRT technology that employed a median dose of 75.6 Gy and achieved bDFS rates of 77.4% in low-risk patients, 69.6% in intermediate-risk patients, and 53.3% for high-risk patients. As a patient who reviewed radiation technology in a lot of detail prior to selecting TomoTherapy in 2012 (delivered in 2013), I know these rates are substantially lower than rates achievable with more current radiation technology.

    That dose of 75.6 Gy in the paper described by the HIFU authors is several grey lower than IMRT doses currently considered optimal — about 78 to about 81 Gy, delivered with image guidance, and both the additional few grey and the image guidance make quite a difference per other published research. (My own program last year with TomoTherapy IMRT was 78 Gy with 46 Gy to the pelvis, using updated image guidance for each of 39 therapy sessions.) In short, the authors have used a weak point of comparison to represent IMRT. Results displayed by the Prostate Cancer Results Study Group (PCRSG), published by BJU International (PMID 22239226) show several EBRT results for low-risk patients near or exceeding 90% with around 5 to around 7 years of maximum follow-up.

    Similarly for brachytherapy, the Uchida paper cites one paper showing 10-year bDFS rates of 74% and 61% for low- and intermediate-risk groups, while the PCRSG paper shows a number of median results in the mid-to upper 90% values with maximum follow-up ranging from 8 to 12 years.

    Cryotherapy studies apparently did not satisfy the PCRSG criteria for studies for low-risk cases where cryotherapy was used.

    Regarding surgery, one study notched about 90% bDFS at the 10-year point for maximum follow-up.

    It would take further detailed analysis to provide a more apples-to-apples comparison with the HIFU results, such as by homing in on comparable median follow-up, but it appears that the selections of studies for comparison by the authors of the subject paper on HIFU did not represent existing examples of excellence among the other technologies. Also, as Sitemaster has already noted, many of the HIFU patients using the SB500 TCM technology also were treated with adjuvant androgen deprivation therapy.

  11. Dear Jim:

    These types of cohort comparisons are really of very little value at all (including, in my opinion, the PCRSG comparions study). Every cohort is rife with investigator and patient preference and bias, and on can have absolutely no sense of confidence that the patients and the outcomes are actually comparable in any meaningful way. Trying to compare them is just misleading for all concerned because everyone just sees and finds what they want to see and find.

  12. THOUGHTS ON COMPARING GROUPS (COHORTS) ACROSS TREATMENTS, STUDIES

    Hi Sitemaster,

    In a very important sense I agree with you: these comparisons fall far short of definitive evidence.

    But there is a different viewing point from which we can gain valuable information for making decisions and tentative evaluations: the viewing point of patients and doctors striving to do the best for their patients in the face of inadequate information.

    Definitive head-to-head clinical trials are virtually impossible for several reasons that you have discussed now and then, including prominently great cultural resistance to accepting randomization to one arm of a trial, including serious problems with meaningful score-keeping endpoints, including rapidly emerging technology for treating patients who do not do well, and including the very long survival, even metastasis-free survival, of the vast majority of prostate cancer patients.

    When comparing trials, it is imperative that confounding factors be reduced to a degree that is acceptable. Sometimes that cannot be done, but often it can be, and my impression is that the many, noted experts who serve on the Prostate Cancer Results Study Group (PCRSG) have gone a long way toward succeeding in that. If I may use my own case as an example, in 2012 when I was deciding whether to try for a cure for my challenging case and what cure to go for, I used the PCRSG to home in on therapies that appeared to be in the lead for cases like mine, and then I got copies of many abstracts of studies referenced in the PCRSG graphs and studied those abstracts. I found many that were much less relevant than they appeared at first glance, which is in line with your point. But I also found a number that were quite helpful in leading me to a therapy that appeared to fit my case. Among other points, the studies bolstered my view that any radiation therapy had to be image guided, had to be a form of IMRT for my case, had to have long-term ADT in support, and had to be at least 78 Gy, probably with extra radiation to the general pelvic area. I believe that the PCRSG graphs also help rule out therapies that are not competitively successful.

    I recognize that many patients will not be able to do this on their own, and some of it gets tricky. For instance, some studies have Gleason scoring done locally that may not be up to standard. That said, such comparisons at least give patients and doctors leads and points to think about. For instance, until the study of proton therapy from the Jacksonville facility a year or two ago, there was no very impressive long-term evidence supporting proton-beam therapy, and HIFU research barely made the cut. (I think the latest Uchida study will be added to the PCRSG set.) The original PCRSG graphs have been updated as qualifying studies are published, and that Jacksonville proton study is now included (and has been for many months).

    Isn’t the bottom line problem that there is no good practical alternative to such comparisons?

  13. Dear Jim: Actually there are very good alternatives, most prominent among them being carefully managed national registry databases that all include certain standardized data on all patients. Getting everyone to “Go” is going to be the challenge, but is has become increasingly evident that “expert opinion” all too often leads to poor decisions.

  14. I have followed several back and forth discussions here regarding the need to have efficacy and safety proven superior to standard of care. What is troubling is that if I had prostate cancer, I would like to have a choice between a procedure that might not have demonstrated superior long-term efficacy results in comparison, but could offer a better quality of life. That risk should be explained by my doctor(s) but left up to me. The U.S. gets too focused on protecting public health, ignoring the fact that our healthcare overall ranks dead last in developed countries, and that should be a wake-up call.

    Being a person that has closely watched drug approvals in the U.S. for decades, I find that some FDA advisory committee meetings can be as entertaining as a three-ring circus. One great memory of this is the Provenge “re-phrase the question” that remarkably changed the panel vote within minutes. There is certainly value to advisory committee discussions, but these three-part votes taken as gospel are another thing. Reminds me of what the definition of is, is.

    As far as HIFU is concerned, the FDA has a choice to shut this out and require convincing data or allow this in with post-approval confirmation. By definition, it is safe when you consider that it has been used for decades without one product recall for safety. For the FDA to tell the sponsors to go back and run a 20-year trial is giving HIFU for prostate cancer the death sentence. We all know a head-to head trial won’t happen. I doubt the FDA will apply common sense and offer a meaningful approval path but instead will issue a CRL with hogtie rope. In the meantime, patients have a choice of going elsewhere if they can afford to, or living with amputated organs without being part of a quality of life choice for an alternative once they leave to operating table. Pretty sad.

    I watched my dad’s quality of life go downhill once his prostate was removed. If needed, I will not make the same decision but instead explore my “world of opportunities” and that means, not limited to the U.S.

  15. Dear Alvin:

    I think that if you read all of the available information you would find that the FDA actually wants to be able to approve some form of HIFU for use in the treatment of selected subgroups of patients with prostate cancer (which would then, of course, lead to the possibility of its widespread use in the US off-label; although whether payers would reimburse for such off-label use without compelling data is questionable).

    However, despite what I see as a pretty clear desire on the part of the FDA to be able to approve the use of HIFU in, for example, salvage treatment of radiorecurrent prostate cancer, where there is no other good form of local therapy at this time, there is still an obligation on HIFU equipment manufacturers to provide compelling data that the benefit of such treatment outweighs the risk. The FDA is required by law to reach that conclusion. To date, no manufacturer has provided such data.

  16. The most compelling question I have on this topic is this: If 99% of salvage treatment radiorecurrent prostate cancer is palliative, at what point in time do we offer Americans more choices? Is cryo now the only approved choice? How many radiation failure patients would have loved to have HIFU as a choice for their situation?

  17. Let me add another question to that.

    “How many men with radiorecurrent prostate cancer know that salvage HIFU comes with something like a 40 to 50% risk for urinary incontinence at up to 2 years of follow-up; that there is a 6 to 7 percent risk for rectourethral fistulae; and that 57% of patients had biochemical progression within 2 years?”

    If they don’t get this information, there’s no way they could possibly be making a reasonable decision about whether they want to consider salvage HIFU.

    Let me be clear … I am not in any way suggesting that salvage HIFU is an inappropriate option. I am simply pointing out that the benefits are limited; that the risks are not insignificant; and that the available data are limited.

  18. Thank you Sitemaster. The problem I am having is understanding the compelling data requirement that suggests randomized control group comparisons in a head-to-head trial that could take decades to complete. I do understand that this is a class III medical device but there are other FDA approved medical devices for tumor ablation.

    Apparently EDAP’s Ablatherm ran into a roadblock trying to enroll a cryo comparator and instead reverted to cross-study comparators that was not well received in review. Sonacare has been running their PIVOT trial for years and had incomplete data at application. And the irony is Alblatherm and Sonablate 450 are the dinosaurs compared to new advances.

    To me running these long trials is absurd when there are many peer-reviewed abstracts that prove that HIFU is safe, and without Grade 5 device-related adverse effects. I see no harm in closely monitored post-approval studies. I am very disappointed with the bar set here and would like your opinion on what the course for U.S. approval for HIFU besides subset studies and off label. I believe both Sonablate and EDAP will be forced into U.S. co-marketing agreements with deep pockets that can run trials if they ever want to get this FDA approved. Again, I think patient quality of life alternatives are the biggest loser here with these delays.

  19. Dear Alvin:

    As I understand the situation, the FDA did not require SonaCare to conduct a randomized trial to seek approval for the treatment of radiorecurrent disease. So that really isn’t an issue in this case.

    The problem with HIFU in the treatment of localized prostate cancer is really whether HIFU is any better than active surveillance for men with low-risk disease. To be fair to all concerned, this is also a problem related to the use of surgery, radiation therapy, etc.

    If HIFU was a truly “breakthrough” form of therapy for the first-line treatment of localized prostate cancer, then the need for randomized trials would have disappeared in that case too. Unfortunately, my suspicion is that one of the problems all along has been that neither company got really good regulatory guidance about how to negotiate with the FDA from Day 1. They saw the FDA as a “regulator” who simply needed to be given some data, as opposed to a very sophisticated “customer” whose needs were going to have to be satisfied. With hindsight (which is all that is available to me since I don’t know all of the details in the background, going back at least 8 years now), I think there were much better ways for both companies to have approached the whole issue.

    Also, you are quite correct about the fact that the trials have been done with outdated equipment. This seems to me to be one more signal that the companies weren’t (and still aren’t) very good at the rapid enrollment of patients into their clinical trials (and that is a marketing problem).

  20. Mike, you probably have more information on the FDA and prostate cancer protocol of treatments than anyone here. But to simplistically dismiss Sonacare’s FDA approval on your “suspicions” is humorous. That is of course unless you have proprietary information that I would love to see in a citation.

    I do agree that if we are going to be “fair to all concerned” that there is a problem related to surgery, radiation, etc. when compared to the benefits of active surveillance. And I would suggest that the “problem related to surgery and radiation” is epidemic in the US and is life changing when one considers that “pilot error” in said procedures along with the very popular side effects of incontinence and impotence that seem to go underreported by the patient and underexplained by the treating physicians.

  21. Dear Jim:

    I have no more information than anyone else. I have no access to any privileged “sources” whatsoever. What I do know is that if I had been trying to get Ablatherm or Sonablate equipment approved for the treatment of prostate cancer in the USA, and I knew that I was going to have to demonstrate effectiveness and safety, I wouldn’t have started by doing these trials in the people for whom proving the efficacy and safety of a new form of therapy was going to be the hardest — men with low-risk, localized prostate cancer. I would have started in men who had an unmet medical need (radiorecurrent disease). If they had done this and if they had enrolled and monitored sufficient patients before they sought approval, it would appear to me that Sonablate 450 might have been approved many years ago. And that trial might have required only 200 patients, with no randomization and no “control” arm. However, as I said, I am not privy to the advice that SonaCare was receiving from their regulatory consultants; nor am I privy to whether SonaCare acted on that advice.

    I don’t see anything “humorous” in this at all. I think it is just sad.

    I would point out that you very rarely see any drug company trying to get a new drug approved in prostate cancer by starting with the least sick patients. Indeed, the last time this happened was with the attempts to demonstrate that finasteride and dutasteride could prevent prostate cancer. Those trials required thousands of patients (18,000 in the finasteride trial); they showed a statistically significant benefit, and yet they still didn’t get approved because several of the FDA’s advisors were concerned about the very small risk for diagnosis with more aggressive disease in the men treated with finasteride and dutasteride as opposed to a placebo (even though there are serious questions about whether this effect was “real” at all).

  22. Thank you for the thoughtful response Mike. Taking a look at some of the key personnel within these organizations, Sonacare has a seasoned veteran with many years of FDA medical device experience and EDAP sought Greenleaf consulting which has former FDA device heavy hitters. Also since both have HIFU medical devices already FDA approved, you would think there might be good lines of communication established years ago, but that doesn’t appear to be the case.

    Also interesting is Sonacares’ announcement that their CEO, Michael Klein, has been replaced.

    BTW: I was in the finasteride trial; still on the drug as a preventative, and will be for the rest of my life. Was able to read through the FDA decision and so was my primary care doctor.

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