December 3, 2014
Dr. Anna E. Mazzucco

Thank you for the opportunity to participate in this meeting.  My name is Dr. Anna Mazzucco, and I am speaking on behalf of the Cancer Prevention and Treatment Fund.  I received my Ph.D. in cell biology from Harvard Medical School, and I conducted post-doctoral research at the National Cancer Institute.  Those are the perspectives I speak from today.

Our organization conducts research and shares information with health professionals, patients, and consumers.

We applaud the efforts of the EPA to protect the public from harmful chemicals in their food, water, air and products they use every day.  We strongly support the agency’s efforts to test chemicals more efficiently, and with the best possible scientific methods.  Research has implicated endocrine-disrupting chemicals in cancer, infertility, and other health problems.  We must be able to quickly identify such agents in order to prevent them from entering our food and environment, and from affecting our health for generations to come.

Use of high-throughput technologies is critical to expediting chemical screening, and we support the agency in these efforts.  However, we have several concerns regarding the high-throughput screening approach as described in the EPA White Paper.  Specifically,

• The EPA needs to spell out more clearly how prioritizing will be decided using this screening approach. The program should explicitly prioritize compounds based on risk contexts, such as those with widespread and persistent exposure profiles, and those with the most serious potential health effects.
• We know that chemical exposures during sensitive periods such as prenatal and adolescent development can greatly impact health in adulthood. These critical windows should be prioritized in bio-monitoring and population-based studies.  This approach would protect the most vulnerable among us, and also ensure the greatest public health benefits for everyone.
• Other stakeholders have expressed concern over lack of clarity regarding the relationship between the area-under-the-curve model and potency as indicated by traditional assays. We are also concerned that the model has not been tested on a sufficiently diverse set of chemical structures.  The agency needs to address these issues and provide additional evidence to support use of the current methodology, as opposed to other possible models.
• These screening assays must be relevant to real world exposures in order to be meaningful. Broad bio-monitoring and exposure studies are vital to informing extrapolation modeling in order to reap the benefits offered by high-throughput screening.
• As these high-throughput assays are further developed, the most orthogonal assays with the most downstream read-outs possible should be used, in order to capture the broadest possible range of mechanisms-of-actions.
• We agree with the EPA that metabolites could be missed using in vitro studies alone, and therefore some in vivo studies will be needed.
• We strongly urge the EPA to make the computational model fully accessible for independent assessment. That would increase transparency and stakeholder participation in this project.

Lastly, we share the concerns expressed in the Inspector General’s 2011 report that this process has not progressed as quickly as it should have.  We strongly urge that adequate resources be dedicated to these efforts, in order that the agency may meet its goals in a timely fashion.

Thank you for the opportunity to address the panel today.

October 16, 2014

Thank you for the opportunity to speak today.  I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  I’m trained in psychiatric epidemiology at Yale Medical School, I’m a former faculty member at Vassar and Yale and a researcher at Harvard , and I’ve taught Research Methods courses, and those are the perspectives I bring with me today.  Our Center has no financial ties to Chantix or its competitors or to Chantix lawsuits.

We all know that smoking kills thousands of Americans and it is very difficult to quit.  That’s why we believe that Chantix should be available as an option for those who can use it safely.

At the same time, patients and their physicians need a clear black box warning for Chantix so they know to stop taking it when necessary

The challenge today is: which data should the FDA believe?  Mark Twain once said there are 3 kinds of lies: Lies, damn lies, and statistics.  I am a scientist and I believe in statistics, but I also know they can be easily manipulated to support a particular point of view.

Your task today is to make sense of conflicting data and decide which to believe.  They include:

• Meta-analysis
• Observation Studies based on hospital records
• Adverse Reaction Reports from physicians
• Reports from Patients

Meta Analysis is a valuable tool but its accuracy depends on the quality of each study and whether they fit together.  Meta analysis results can be useful or inaccurate depending on which studies you include and exclude.  No justification was given of why most studies on Chantix were excluded and only 5 were included in the meta analysis, including one study of schizophrenics, one study of depressed patients, and 3 studies of mentally healthy patients.  It is important to study schizophrenics and depressed patients, but those data should not be mixed together with 3 studies that exclude such patients.  No justification was given for that decision, but you heard from the FDA that most psychiatric events were in those two groups of mentally ill patients, clearly biasing the results.

To consider the studies showing no association between Chantix and psychiatric side effects, it is important to understand what happens to people with acute psychiatric events related to medication.  As the FDA speakers pointed out, most do not end up in hospitals or the ER.  Many of these psychiatric side effects are not reported in medical records.  Because psychiatric commitment laws depend on acts of violence, not threats of violence, many people with dramatic psychiatric symptoms end up in jail, not in hospitals.  In fact, some studies show that there are more mentally ill individuals in the criminal justice system than in psychiatric facilities — certainly those who suddenly behave violently toward others are likely to be put in jail, not in a hospital or ER.

There’s another, more positive reason why these psychiatric side effects might not be measured in a large study.  Fortunately, many stop quickly because patients or their doctors realize they should stop taking the drug, thanks to the black box.

For all these reasons, most of the studies that Pfizer is relying on are fatally flawed.

How can we make sense of the studies showing no impact in light of the thousands of reports of psychiatric side effects?

• The studies cited did not evaluate all psychiatric side effects, they focused on depression and suicidal thoughts and behaviors
• Those studies did not interview patients – a shortcoming of many large databases
• They relied on hospital records, which research shows missed 82% of adverse psychiatric events
• Some also relied on ER or medical records – which is better than hospital records, but will still miss a lot of data 

What about studies showing a significant increase in psychiatric events?  We all know that adverse reaction reports are the tip of the iceberg – it’s a voluntary system of reporting.  Compared to medical records, they can have a richness of information.  And while they are far from perfect, the sheer volume of thousands of reports – many more than for other drugs – is very compelling.

I’ve spoken with some patients who took Chantix, and their reactions are distinctly different from many other drug side effects, and don’t fit neatly into the categories that most of the Pfizer studies evaluated.  For example, I spoke to a man who was so besieged with uncontrollable thoughts that he locked his door at work and wouldn’t let anyone in.  His thoughts were so terrible that he just couldn’t deal with anyone.  That psychiatric reaction would be unlikely to fit into any of the studies.  Or a man who was so frightened that he hid in the corner of his bedroom under a blanket, trying to escape the uncontrollable thoughts by being as small as possible – trying to feel safe.  What study would accurate evaluate that?

If this Advisory Committee ignores the compelling psychiatric adverse reactions that have been reported, it would discredit thousands of doctors who made thousands of reports.  It would also discredit thousands of patients who reported them.  And it would send the message to the FDA to stop their Adverse Event Reporting systems, because what is the point of having such systems in place if you ignore thousand of such reports?

We need better studies, and I hope the post-market study underway will be better.  Based on previous research, we know that such studies must include very large numbers of patients, and must follow patients for a long enough time – not all reactions are within 30 days.  And, the studies must include patients’ reports of their side effects

In conclusion:

• The studies Pfizer is citing are fatally flawed because they omit most psychiatric adverse reactions
• Deleting the black box would send the message that thousands of doctors’ reports don’t count, including suicides and homicides

We strongly urge you to urge the FDA to keep the black box warning to protect patients and that you strengthen rather than weaken that boxed warning.  And, since the meta analyses are fatally flawed, as I and others have pointed out, the FDA should delete the misleading meta-analyses info from the Chantix label.

October 9, 2014

Division of Docket Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Comments of the Cancer Prevention and Treatment Fund on
“Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting”
Docket No. FDA-2014-N-0731

The Cancer Prevention and Treatment Fund appreciates the opportunity to comment on Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting.

Challenges

Due to its biological complexity and often long latency, cancer represents a challenge for monitoring in the pre-approval or postapproval setting.  Pre-market studies are usually too short-term or too small to adequately evaluate cancer as an adverse event.  Unfortunately, many postapproval studies are also too short-term, too small, or have too many patients lost to follow-up to accurately evaluate cancer as an adverse event.

Existing voluntary databases for adverse event reporting in the post-market setting are known to greatly under-report and often do not contain sufficient information.  Postapproval studies with pre-specified endpoints often have poor patient retention or are not completed.  While cancer registries can provide another source of information they often do not contain detailed drug history and are not nationwide.  Therefore, comprehensive systems for monitoring cancer as an adverse event for drugs and biologics do not exist at this time.

Long-term surveillance is critical

Cancer development is a multi-step biological process that can occur over several years, making long-term surveillance critical to identifying a cancer safety signal.  Short pre-market studies that are not specifically designed to assess cancer outcomes are unlikely to identify this potential hazard.  In addition, patient subgroups that may be particularly susceptible to cancer risks, such as children, adolescents and elderly adults taking multiple medications, are typically under-represented in pre-market studies, further decreasing the likelihood of detecting a cancer risk.

Post-market surveillance should consider all cancer types           

While concerns over specific cancer types may arise from pre-market studies, post-market surveillance should include consideration of all cancer types.  As any cancer signal can be difficult to detect pre-market, post-market surveillance needs to account for all possibilities.  As mechanisms of carcinogenesis are often shared across different tissues of origin, the possibility of cancer at multiple sites cannot be ruled out.

In 2006, the Government Accountability Office issued a report stating that the FDA needs to address weaknesses in its post-market surveillance system, including the need for larger and more diverse datasets using uniform systems such as electronic health record information.  That same year, the Institute of Medicine recommended that the FDA should take action to partner with other federal agencies and use all available resources to bolster its post-market surveillance efforts.  We strongly agree.  We recommend that the Sentinel System be used to mine specific data on the possible increased cancer risk due to the effects of non-oncological prescription medications and biological products, but Sentinel should not replace postapproval studies designed to evaluate those risks.

Concerns about cancer risks in pre-market development

If concern over a potential cancer risk arises during pre-market development, well-designed preclinical and clinical studies to directly examine this possibility need to definitively address this issue.  Specifically, sponsors need to have a clear understanding of the biological mechanism of action of their product, and perform comprehensive carcinogenicity testing.  This should include sensitized animal model systems as appropriate, and should also address non-genotoxic mechanisms of carcinogenicity, such as hormonal effects, which may display non-traditional pharmacological behavior, i.e. non-monotonic dose responses.  Any cancer concerns identified in pre-market studies should also be adequately addressed in labeling information, special warnings, and post-market studies as needed, if the product is approved.

Conclusions

To better evaluate the challenges in designing postapproval studies to determine whether a non-oncological drug causes or influences cancer, the FDA should develop long-term studies that include susceptible subgroups such as children, adolescents and the elderly.  The post-market surveillance should consider all types of cancer, and include large and diverse data sets utilizing electronic health records and the Sentinel System.  However, Sentinel should not be used as a replacement for postapproval studies.  Also, if pre-market studies flag a cancer concern, it should be addressed in the label of the drug with a special warning.

Cancer Prevention and Treatment Fund

The Cancer Prevention and Treatment Fund can be reached through Paul Brown at (202) 223-4000 or at pb@center4research.org

October 1, 2014

Good morning. Thank you for the opportunity to speak today. My name is Dr. Laurén Doamekpor, and I am a senior fellow at the Cancer Prevention and Treatment Fund. Our research center scrutinizes scientific and medical data and provides objective health information to patients, providers and policy makers. We do not accept funding from device companies and therefore I have no conflicts of interest.

We all know that current treatments for prostate cancer have side effects that harm men’s quality of life. While most men diagnosed with localized, low-risk prostate cancer will likely die from something else, not from prostate cancer, recurrent prostate cancer frightens patients and needs to be treated. However, any new treatment should show clear evidence that the benefits outweigh the risks. We are not convinced that the HIFU device achieves this goal.

The analysis of the primary endpoint showed that 64% of the patients who were treated with this device had obtained local control of prostate cancer at 1 year after treatment. But that doesn’t tell us anything about long-term effectiveness, which is key for prostate cancer.  Proof of long-term effectiveness would also require a control group or comparison group, which this application lacks.

The sponsor’s goal was a 40% success rate at 1 year, and they achieved that. However, even a 64% success rate at one year is very low compared to the long-term success rate of prostate surgery.  We share the FDA’s skepticism that this device should be approved based on this low 1-year success rate.

In addition, the safety profile is not impressive. Incontinence was reported in 43% of patients, and was still 31% after one year. That is worse than most studies of prostate surgery, which has a much higher long-term success rate.

With only 100 patients in the study and no long-term data, the sponsor has not provided enough data to justify approval.  The small sample includes only 13 Black patients, even though prostate cancer is more deadly for Blacks. There are only 5 Hispanic patients.  The sponsor says they did subgroup analysis of effectiveness and that Blacks did well with the treatment.  The Advisory Committee should demand to see the safety and effectiveness outcomes separately for Blacks and Whites.

The sponsor is already enrolling a 2nd cohort of 100 patients, and FDA should delay an approval decision until those data are submitted.  The FDA should also require at least 2-3 years of data before the agency decides whether to approve this device. While we commend the sponsor for its plan to conduct a 5-year post treatment study, it would be unfair to patients to pay for an unproven device based on such a small, short-term study.

In summary, the study is too small, too short term, and has no comparison sample.  It has too few Blacks and Hispanics. Evidence of long-term effectiveness is needed BEFORE approval, not as a post-approval study.

That’s why we urge you to vote NO 3 times: the data from the study do NOT support a reasonable assurance of safety OR  effectiveness for this device and that therefore we can NOT conclude that the benefits outweigh the risks.

At the end of the meeting, the panel voted 10 to 0 with 1 abstention that benefits of the device do NOT outweigh the risks.

Delivered by Dr. Anna Mazzucco
September 4, 2014

Thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. My name is Dr. Anna Mazzucco, and after completing my Ph.D. in Cell and Developmental Biology from Harvard Medical School I conducted research at the National Cancer Institute. I bring those perspectives today.

Our nonprofit research center conducts research and scrutinizes data to provide objective and reliable information to patients and providers.  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 pharmaceutical companies, and therefore I have no conflict of interest.

In 2014 almost 10,000 Americans died from melanoma skin cancer, and 76,000 new cases were diagnosed.¹  Despite warnings to avoid sun exposure, adults and children are spending a great deal of time in the sun, thus making safe and effective sunscreens essential to prevent skin cancer.  At the same time, Americans are using sunscreens more frequently and on a more long-term basis than ever before, as the FDA’s report noted.

Therefore, our safety and efficacy standards must reflect that Americans of all ages rely on these products regularly.  In its prepared questions, FDA scientists point out the lack of safety testing in pediatric populations.  I hope you’ll agree that we need conclusive evidence that these products are safe for children, and also for prenatal exposures when pregnant women use them.  Clinical studies must include separate analyses of these and other vulnerable populations before products can be marketed for widespread use.

Studies of several active ingredients currently on the market have raised concerns about photostability—how long the protections last under real-world conditions.²

Testing for photostability should be required as part of the pre-market testing of sunscreen active ingredients.  Consumers need to know how long products so that they can avoid increased skin cancer risk.

Several active ingredients currently on the market have also shown potential endocrine-disrupting or carcinogenic activity.^{3 4}   We support the FDA scientists’ proposal to require that active ingredients be tested for carcinogenic and developmental and reproductive toxicity prior to marketing.  Research shows that endocrine-disrupting agents often have greater risks at low doses,⁵ so dose-response testing is not appropriate for these studies.  Without well-designed studies, children and others who are particularly susceptible could be harmed by these hormone-altering ingredients.

There is also research evidence that certain active ingredients demonstrate potentially carcinogenic activity when exposed to UV light, such as generating free radicals that damage DNA and can cause harmful mutations.  Testing for carcinogenic activity should be done under conditions that reflect real-world use as closely as possible, i.e. during UV light exposure.  Such carefully designed testing is needed to ensure that safety data is reliable and meaningful.  Without such information, products intended to help prevent cancer may do just the opposite.

As you consider FDA’s questions, please pay special attention to the issue of combining active ingredients with different vehicles, to make sure that does NOT result in final product formulations which are marketed over-the-counter without any additional testing.  We agree with FDA scientists that different vehicles could change the properties or absorption of active ingredients in ways that could affect safety or efficacy of the final product.  As medical professionals, please urge the FDA to directly confront this problem through additional testing requirements that can ensure products that will be safe and effective for all consumers.

Division of Dockets Management
Food and Drug Administration
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, Maryland 20852

August 8, 2014

Comments of members of the Patient, Consumer, and Public Health Coalition
On proposed Deeming Rule
Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Regulations on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products; Extension of Comment Period
Docket No. FDA-2014-N-0189

As members of the Patient, Consumer, and Public Health Coalition we are writing to comment on various aspects of the proposed rule to extend FDA’s jurisdiction to tobacco (including made or derived from tobacco) products other than cigarettes, including e-cigarettes. It is essential that the proposed rule be strengthened, since nicotine is highly addictive.

1.      We strongly oppose exempting any cigars from the rule, including those designated as “premium.”  According to the FDA’s deeming rule, “a large cigar may contain as much tobacco as a whole pack of cigarettes” and “nicotine levels in cigar smoke can be up to 8 times higher than levels in cigarette smoke.”  We concur with the FDA that “all cigars are harmful and potentially addictive,” and this is true regardless of their price, the size of the manufacturer, and whether or not they are handmade. In addition, providing cigars special treatment encourages cigarette and other tobacco-related product manufacturers to continue to misclassify products that are actually cigarettes as cigars, in order to take advantage of this regulatory loophole.

2.      We also strongly oppose exempting or weakening the rules for smaller manufacturers or manufacturer of “premium” tobacco products, regardless of their so-called “unique challenges.” As noted above, cigars can be more dangerous than cigarettes.  Regardless of the cost or whether they are manufactured on a small scale, cigars have large-scale, long-term health consequences.

3.      The FDA’s proposed rule does not go far enough to safeguard the health of young people. It proposes a national minimum age of 18 for the purchase of the newly deemed products, which we wholeheartedly endorse, but it permits sale through the internet where age verification is difficult if not impossible to enforce. For this reason, we urge the FDA to prohibit internet sales of the deemed products (and eventually all tobacco products), or  require sellers to adopt the same age verification procedures established under the 2009 Prevent All Cigarette Trafficking Act for internet sales of cigarettes and smokeless tobacco.

4.       The proposed rule does not go far enough to restrict the marketing and advertising of e-cigarettes and cigars to minors. The number of middle and high school students who reported ever using e-cigarettes doubled between 2011 and 2012; and high school boys are just as likely to smoke cigars as they are cigarettes (16.4% vs. 16.5%). E-cigarettes, cigars and other newly deemed tobacco products should be kept behind store counters just like cigarettes.  They should not be displayed in the open, like the candy that many of these newer tobacco products try to emulate, with flavors like “Cinnamon Apple Crunch,” “Tahitian Punch,” and “Iced Berry.

The proposed rule permits self-service displays, does not prohibit low-cost, mini packs of cigars (that are obviously more affordable to children) and also allows brand sponsorship of concerts or sporting events popular with teenagers. These should all be strictly prohibited. Moreover, the FDA has not proposed limiting the advertising of the deemed products the way cigarettes and smokeless tobacco advertising has been limited. By allowing unfettered advertisement of e-cigarettes and cigars, the FDA is ensuring that youth will continue to be exposed to ad campaigns as effective as the ones in years past, which equated cigarette use with glamour, sex appeal, and cartoon characters like Joe Camel.

5.      We strongly support the FDA’s proposal to include health warnings about nicotine addiction on all nicotine-containing tobacco products, including e-cigarettes and cigars. We also support the FDA proposal to require that all cigars, including premium cigars, carry additional rotating health warnings on the risk of mouth and throat cancer; the risk of lung cancer and heart disease; the risk of lung cancer and heart disease from secondhand smoke; and stating that cigars are not a safe alternative to cigarettes. However, we strongly urge the FDA to include a fifth warning on the increased risk of infertility, stillbirth and low birth weight. This is particularly important, given the growing popularity of cigars among teenagers and the fact that teenage girls and young women have the highest rates of smoking during pregnancy (16.6% for girls 15-19 and 18.6% for women 20-24 in 2005). We also urge the FDA to revert to the 12-month compliance period (from the date of the final rule) which was changed after OMB review to an unacceptably long 24 months.

According to the CDC’s June 2014 report, nearly one-quarter of all male high school seniors smoke cigars (23%). To save lives, the FDA should mandate its proposed warning about nicotine addiction for all tobacco products; require all cigar manufacturers to rotate all five of the warnings that the FTC imposed on seven cigar manufacturers in 2000; and stipulate that all warnings must be in effect no later than 12 months from the final rule.

6.      We also urge the FDA to strengthen the proposed rule regarding characterizing flavors in cigars or e-cigarettes.  Cigarettes, for instance, can only be sold with tobacco-flavor or menthol flavor; the newly deemed products should be held to the same standard as they are similarly addictive, nicotine-containing products. More than 80% of adult cigarette smokers began smoking before the age of 18; flavors like “bubble gum” and “banana split” are specifically designed to appeal to children and teens and attract people who otherwise would not use a tobacco product.

The bottom line regarding flavored nicotine products: any flavor that makes the use of tobacco products more palatable should be banned. If a major benefit of e-cigarettes is to cut back on regular cigarette use, then those buying e-cigarettes will not be seeking candy or fruit flavors.  These flavored options clearly promote the use of tobacco products by new customers.

7.      The proposed rule does not mention requiring child-resistant packaging of liquid nicotine for use in e-cigarettes. Given the alarming rise in nicotine poisonings resulting from children coming into contact with “e-juice,” FDA should issue a proposed rule to prevent this public health problem.

8.      The FDA is proposing a premarket review requirement for all newly deemed products, while recommending that manufacturers have 24 months from the final rule to file substantial equivalence and new product applications. This would allow manufacturers to keep existing products on the market and introduce new deemed products for two full years following the promulgation of the final rule. It would also allow products for which an application has been submitted to stay on the market unless or until FDA denies it. These loopholes are unacceptable, given that there has already been a 3-year delay in issuing the deeming rule, giving companies more than enough time to prepare for regulatory requirements. To reduce any further delay, the FDA  should: a) issue a final rule within a year of the proposed rule’s issuance, and no later than April 25, 2015, and b) shorten the period for submitting new application or proving substantial equivalence to one year from the final rule.

The Tobacco Control Act (TCA) was enacted in 2009 to give FDA the authority to prevent and control tobacco use. The deeming rule is meant to extend that authority so as to protect children and adults from the harms of cigars and e-cigarettes. We recommend further strengthening the deeming rule in the ways described above and/or concurrently issuing additional proposed rules. The FDA’s mission is to protect and advance public health, and unfortunately the proposed rule falls short.

American Medical Women’s Association
Annie Appleseed Project
Breast Cancer Action
Cancer Prevention and Treatment Fund
Connecticut Center for Patient Safety
National Alliance for Hispanic Health
National Consumers League
National Organization for Women
Our Bodies Ourselves
Women Advocating Reproductive Safety
WomenHeart

The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at (202) 223-4000 or at pb@center4research.org 

July 30, 2014

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.

Comment:

The FDA advisory panel voted against approval for the Ablatherm device, expressing concerns about lack of data on safety and effectiveness.

Click here to see our testimony slides.

Testimony of Dr. Anna E. Mazzucco

Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee

July 11, 2014

Thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. My name is Dr. Anna Mazzucco, and after completing my Ph.D. in Cell and Developmental Biology from Harvard Medical School I conducted research at the National Cancer Institute. I speak from those perspectives today.

Our nonprofit organization conducts research, scrutinizes data in the research literature, and then explains the evidence of risks and benefits to patients and providers.  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.

About 600,000 hysterectomies are performed annually in the United States, according to the Centers for Disease Control and Prevention, and approximately 65,000 myomectomies.  Of the hystectomies alone, the FDA estimates that 50,000 to 150,000 use power morcellation.  The FDA also estimates that 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids has unsuspected uterine sarcoma which could be spread and worsened if a power morcellator is used.  Based on these numbers, as many as 400 women could have undiagnosed malignancy spread each year from hystectomy alone  — when you add myomectomies, it is probably much higher.  We agree with the FDA that there is currently no reliable method to distinguish between uterine fibroids and sarcoma before surgery.  Training physicians is, unfortunately, not the answer.

The estimate of one in 350 women undergoing surgery having an unsuspected uterine cancer is based on recent studies and is much higher than the 1-in-10,000 chance of undiagnosed cancer typically quoted to patients.  The FDA has also estimated that undiagnosed cancer will be spread or worsened by morcellation in 25-65% of cases.  The estimated 5-year survival is 60% for patients with stage I disease, compared with 22% for those with stage III and 15% for those with stage IV.

Minimally invasive surgery can offer many advantages to patients, but as you have heard at this meeting, the mortality benefits of such procedures are unclear. In contrast, it is absolutely certain that malignancy spread by morcellation can be life-threatening.  In light of these findings, we agree with the FDA’s statement in their safety communication that power morcellators should no longer be used during removal of uterine fibroids. 

The question is whether this warning from the FDA is enough to save lives?  Or, is this new evidence sufficient to alter the classification and labeling of these devices?

Power morcellators were originally approved as class II moderate -risk devices under the 510(k) process, which does not require clinical trials prior to allowing the device on the market.  It also does not require inspections to make sure the device is made and working as designed — such inspections are required for all prescription drugs.  Since morecellators were not studied in clinical trials, the risk of undiagnosed sarcoma spreading was not detected prior to clearance through the 510(K) pathway.  As a result, patients were irreparably harmed.  We’ve heard some of those tragic stories at this meeting.

Class III devices are defined as those which pose a significant risk of illness or injury, and require clinical testing for safety and efficacy.  Clearly, power morcellators meet this definition and should be classified as Class III devices.  Therefore, they should undergo clinical studies before any more patients are harmed.  Non-clinical performance testing studies are simply not sufficient to address these safety concerns.   If an adequate number of patients had been studied in clinical trials, we would have known years ago that morcellators could cause a fatal spread of uterine cancer.

I think everyone on this panel agrees that more research is needed. Clinical studies must evaluate risk mitigation strategies, such as use of a companion containment bag. However, as the FDA briefing material cites, there are adverse events associated with current specimen bags.  For this reason, bags need to be specifically designed for use with power morcellators specifically for uterine fibroids.  Surgical techniques must also be refined for use with these bags.

Clinical trials are also needed to improve the accuracy of patients’ diagnostic outcomes when morcellators are used.

After these studies are completed, the FDA should consider whether and under what circumstances power morcellators can be used for uterine fibroids.   On the basis of research, black box warnings must inform physicians and patients of the risk of spreading malignancy and the required risk mitigation strategies.  This label should also include the warning that these devices should never be used in patients with suspected malignancy.  Training and certification should also be required before physicians can use power morcellators to ensure that these risk mitigation techniques have been mastered.

As the FDA has stated in its summary for today’s meeting, the current voluntary reporting system for medical devices is underused, and thus underreports adverse events for all medical devices, including power morcellators. Unfortunately, surgeons and other medical personnel are not reporting these incidents to the FDA, and their reporting is voluntary, so they don’t have to.  On the other hand, the hospitals where these incidents occur are required to report them to the device companies, and the device companies are required to report them to the FDA.  For some reason, those reports were not being made either.  As a result, many more patients died before the risks of morcellation became known — primarily as the result of a physician whose life was put at risk when a morcellator used for a uterine fibroid resulted in Stage 4 uterine cancer.

We agree with the American Congress of Obstetricians and Gynecologists that a patient registry should be created to follow patients whose fibroids were previously removed with the assistance of power morcellation to more scientifically monitor their health outcomes. But, that is not enough.  And the current FDA warnings are not enough.

We need higher standards to ensure that morcellation devices are safe and effective, and that require clinical trials with sufficient numbers of patients to determine the risks of rare but fatal outcomes.