NCHR Testimony on Ablatherm High-Intensity Focused Ultrasound Device

My name is Dr. Anna Mazzucco. Thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. After completing my Ph.D. at Harvard Medical School, I conducted research at the National Cancer Institute. Those are the perspectives I bring today.

Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to policymakers and consumers. Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the resources that the FDA needs to do its job. Our organization does not accept funding from medical device companies, and therefore I have no conflicts of interest.

Prostate cancer is a very common cancer and all the current treatments have serious side effects that harm men’s quality of life. The question today is whether the Ablatherm high-intensity focused ultrasound device is safe and effective for the treatment of low-risk, localized prostate cancer. Most men diagnosed with localized, low-risk prostate cancer will not die from prostate cancer, but from something else. Recent studies support active surveillance as a very reasonable option for these patients, since interventions do not improve overall survival and often harm quality-of-life. The decision to treat low-risk early-stage prostate cancer, if at all, is already a challenging one for both patients and clinicians. They deserve to be able to make important decisions which can affect quality-of-life for years to come based on solid scientific information.

For these reasons, any proposed treatment for this patient group must provide solid research evidence about the risks and benefits, so that patients and their families can make an informed decision. I think we can agree that a new device, such as this ultrasound device, will not truly benefit patients unless it demonstrates a superior safety and quality-of-life profile. Or, if you believe that options are good, at least the evidence should be solid that it provides an equally safe and effective result.

This is not the case with the Ablatherm ultrasound device.

First of all, we know almost nothing about its safety or effectiveness because the company has provided registry data on 62 patients, and of these, safety data were provided for more than 3 months for only 35 patients. As the FDA noted in its executive summary, this is a very small number of patients to assess the safety of a treatment which could be used for thousands of patients.

In our opinion, the FDA should not even ask for your advice for a device studied on so few patients, given that other alternatives are available.

The lack of long-term safety data is especially important because on the average, a man diagnosed with prostate cancer will live at least 15 years before he will die of something other than prostate cancer.

Another methodological problem is that the patients whose safety was studied is not identical to the patients analyzed for effectiveness. In fact, the two patient groups differ in several clinically meaningful ways, including age and concomitant therapy. Patients and physicians need to be able to consider both the risks and benefits of any treatment together as it relates to their particular situation.

Despite these shortcomings, the sponsor attempted to make cross-study comparisons between this safety cohort and the radical prostatectomy arm of the PIVOT trial. As the FDA scientists pointed out, unlike the Ablatherm data, the safety analysis from the PIVOT trial was not limited to a low-risk group, but included all risk groups, and the two trials also had completely different follow-up schedules. These differences make any comparisons between these two groups completely meaningless.

The sponsor also attempted to perform a second safety analysis using the single arm of the incomplete Ablatherm IDE trial, again attempting to cross-compare to the PIVOT study. This is also highly problematic for all the reasons stated by FDA scientists in their executive summary, including inability to compensate for differences in prognostic factors, follow-up schedules, and clinical endpoints.

As FDA scientists also noted, it could have been informative to compare the safety profile of Ablatherm to the active surveillance arm of the PIVOT trial, as that is a common approach to clinical management of this patient group. But this was not done, and is impossible to do because of insufficient information. Therefore, we are asked to judge the safety of this device with very little data indeed.

Despite these complications, several observations about the safety of the Ablatherm device can be made.
As you all know, quality-of life-is a particular problem for men treated for prostate cancer. Two years after being treated with Ablatherm, 43.7% of patients still had erectile dysfunction and 11.1% still had incontinence.

There is no high-quality evidence of effectiveness either. The only data are cross-study comparisons with the PIVOT study. The primary efficacy endpoint was 8 year metastasis-free survival. As the FDA scientists pointed out, due to the low event rate of metastasis in this low-risk patient group, and the high likelihood that these patients will not die of prostate cancer, this surrogate endpoint has little value. Furthermore, attempting a cross-study comparison of a time-to-event endpoint, when the trials had different bone scan schedules, is again highly questionable.

The FDA scientists also highlight the fact that in the PIVOT trial being used here, radical prostatectomy was not superior to active surveillance in terms of metastasis — or overall survival.

In other words, it makes no sense to try to prove that this new device is equal to surgical treatment regarding metastasized cancer when the surgical treatment is NO BETTER THAN NO TREATMENT.

The FDA scientists also point out similar methodological challenges comparing the Ablatherm data and registry and meta-analysis data from cryotherapy studies.

In summary, we simply do not have any properly controlled clinical data to support either the safety or effectiveness of the Ablatherm device. Only 1 % of medical devices go through the PMA approval process. The goal is to provide solid scientific evidence to prove safety and effectiveness so that patients and their physicians can make treatment decisions which can affect quality-of-life for years. Registry data of only 62 patients, no minority patients, with no control group, and only 35 with safety data past 3 months is completely inadequate. I can’t stress that enough.

We respectfully urge the committee to recommend that FDA reject this PMA application until better quality data are available.