Clinical Trials/Research

"If we knew what it was we were doing, it would not be called research, would it?"

Albert Einstein

On June 3, 2004, the Food and Drug Administration coordinated a meeting of the Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee to review the InSightec ExAblate 2000. This medical device is currently under clinical investigation for its safety and efficacy in the treatment of uterine fibroids.

After spending a considerable amount of time reviewing darn near every single piece of literature on the technology of focused ultrasound -- including clinical investigation materials for prostate cancer, breast cancer, liver cancer, and brain tumors -- and then reviewing the data presented thus far on this technology for uterine fibroids, I honestly cannot see how the FDA Panel would even consider recommending the approval of this device for treatment of uterine fibroids at this time with a limited amount of abysmal data.

But, sadly, it did.

The panel voted 8 to 5 for approval. Women dropped out of this study in the DROVES -- with a total of 61.5% of the 109 women enrolled with an "Intent to Treat" as subsequently being listed as a "loss to follow-up" by 12 months or as failures who went on to some other treatment. To put this into perspective, the FDA has indicated a 15% loss to follow-up rate as the maximum amount acceptable in other clinical trials. For reasons unbeknownst to me, this panel completely ignored the high number of women dropping out of this study. What in heaven's sake happened here?

Some news agencies have reported the following:

"According to clinical trial results presented by both InSightec and the FDA during the panel meeting, patient symptoms improved by about 71% over a six-month period. This surpassed the main goal of the trial, which was 50% success rate at six months."

Um, this statistical information is taken so blatantly out of context with the data presented as to actually be deliberately misleading. While it's not showing up in any of the press releases from Insightec, it is being spouted by their clinical investigators to the media and showing up in news stories anyway. (SIDENOTE: This may be a naive/ignorant question, but aren't clinical investigators hired/paid by a company accountable for their potentially misleading statements made to the press which could possibly be published in a manner which might influence the stock of a company? Or, do we simply write it off as poor journalism and trust that those quoted did, in fact, communicate the fuller picture to the media???)

You see, this 71% improvement rate is calculated on only those patients still "evaluable" in the study at the end of 6 and 12 months. It was not based on the collected data of all 109 patients enrolled with an "Intent To Treat."

Fact: This study consisted of 109 patients identified as being enrolled with "Intent To Treat". However, there were only 91 women left in the study at the 6 month mark (3 withdrew, 11 considered "non-evaluable", and 4 treatment FAILURES). By the 12 month mark, only 42 women were left in the study. These 42 women were then considered the "Evaluable" group. Out of the "Evaluable" group, there was indeed improvements in their symptom severity scores.

Fact: This study included women enrolled from 7 different clinical sites. This begs the question of how consistency in application was truly applied. Especially in relationship to the devices and software used at each site AND the differences in gyn/radiology clinical settings and care.

FACT: According to the FDA presentation on the Insightec data, 65 patients in this study FAILED TO MEET THE DEFINITION OF SUCCESS AT 12 MONTHS!

For those of you interested in this nonsurgical treatment for symptomatic fibroids, the following documents and websites may be of interest:

InSightec ExAblate® 2000 (P040003)

FDA Agenda
FDA Roster of Panel Member Attendees
FDA Discussion Questions

My written statement submitted to the FDA in response to the data presented/FDA Discussion Questions

In the end, we are all responsible for our choices -- and, I can only say that right now I'm very, very glad this treatment option was not in clinical trials during the time period when I was so desperately in need of relief from fibroids. I would have jumped at the chance of signing up for this. And, I probably would have been one of those who were counted as a 'loss to follow-up' in the data, too. Why? Because focused ultrasound might have killed one fibroid and left the other three to take off and blossom and then I'd be back where I started again with nowhere to go.

You see, even with the approval of this device, the use of MRI makes it too expensive for any insurance company to allow a patient to be treated over, and over, and over again with it. And, once this device is approved for the treatment of cancerous tumors (in the future), a fibroid patient will be so low on the totem pole of treatment priority as to be buried 6 feet under. (That is to say, it will be in such high demand for more critical masses that it will be a "dead on arrival" treatment for women with uterine fibroids!)

So, why was this device tentatively approved on such limited data and evidence of safety and efficacy to the patients? A very good question, indeed. Wish I had the answer. I don't. However, I do have a few thoughts about what MAY have contributed.

• 13 panel members. 7 of them radiologists with a future potential to benefit from approval of this device. One, very vocal, interventional radiologist (Anne Roberts) was absolutely insistent on the approval of this device. As it turns out, it was this IR who also disclosed to the FDA pre-meeting that she is a significant stockholder in a competing firm also studying high-intensity focused ultrasound. If this isn't a clear conflict of interest that should have excluded her from voting on this panel, then I'm not certain what is! In addition to Dr. Roberts, three additional physicians on the panel were given waivers for their potential conflict of interest for this panel review.
  
  
• A so-called Consumer Representative on the panel who didn't represent the interests of women with fibroids at all. Not even remotely. Check out the FDA's idea of a "Consumer Representative" by reviewing this panel member's curriculum vitae here. Looks like a 30+ year career medical professional, to me. In fact, she introduced herself as a "Hospital Administrator." Not the typical "Consumer" I might expect to be representative of the public, at all.
  
  
• An FDA that requires written statements from the public to be turned in one week prior to the meeting AND one week prior to the time when ANY of the data to be discussed is released to the public. It's pretty hard to respond via written statement or even public commentary on information which is being withheld from the public until the very day before the meeting. (Sometimes it's not even released until AFTER the meeting!) In this case, it was released in a scaled down version on June 2, 2004. The vast majority of information available to the panel for review was not made public until the actual day of the meeting -- and even then it was not put online. It was distributed only to those in attendance.
  
  The written statement I submitted would not have been possible had it not been pre-arranged with the FDA coordinator to be faxed to the meeting hotel the actual day of the meeting. And, I had less than 24 hours to write that statement and have it reviewed by board members from the National Uterine Fibroids Foundation. Thank goodness I knew enough about the focused ultrasound technology by then to even be able to consider taking on that written task! Otherwise, how could any member of the "public" participate in these meetings at all????? They can't. Furthermore, comments based on the limited data provided online by the FDA one day before the meeting are truly made blindly and without the benefit of additional details or background information on the study. Is that truly fair to either the public trying to assess the facts and make commentary OR the company under review for their study?
  
  
• The general dismissal of public comments and/or written statements. Regardless of who it comes from. You can speak up -- but that doesn't mean your words will be met with any kind of respect whatsoever. Comical expressions, disdain, mockery, whining about having to read a written statement...this is what the public who might be willing to submit their words for review may be faced with at a typical FDA panel review meeting. Nice, don't you think?
  
  After viewing a tape of this meeting, the phrase "blatant disrespect" come to mind. Upon questioning the panel coordinator about the unprofessional behavior of FDA panel members, her comments in reply to my queries over this disrespect included "...I would agree that it was sloppily conducted..." and "...there was some confusion...". Yeah, right.

• contrast allergies
• impaired renal function
• claustrophobia (~15% of the population has claustrophobia severe enough to NOT tolerate the enclosure of MRI)
• presence of any metallic substances or implanted materials (such as: heart pacemaker, surgical clips from prior surgery--sometimes applied during c-section or myomectomy to the uterine artery OR via tubal ligation, insulin pumps, cochlear implants, jewelry, etc.)
• presence of abdominal/pelvic tattoos -- depending on location they may contain enough trace elements of metal as to interfere with clarity of MRI
• weight/girth of no greater than 250 pounds (table limit of 350 pounds--but abdominal GIRTH limit of women with fibroids lowers the acceptable weight for this procedure to 250)

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This page last updated Thursday, June 9, 2004