Category Archives: Testimony & Briefings

Testimony of Dr. Laurén Doamekpor, senior fellow, on Sonoblate treatment for prostate cancer

Testimony & Briefings
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.

Testimony for FDA meeting on sunscreen active ingredient safety testing

Testimony & Briefings
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.

Comments on proposed rule to allow FDA to regulate all tobacco products

Testimony & Briefings

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 

Testimony of Dr. Anna E. Mazzucco, scientific advisor, on Ablatherm ultrasound treatment for prostate cancer

Testimony & Briefings
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 Mazzucco on morcellation devices for uterine fibroid removal

Testimony & Briefings
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.

Testimony of Dr. Anna E. Mazzucco to FDA advisory committee on olaparib

Testimony & Briefings, Uncategorized
June 25, 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 pharmaceutical companies, and therefore I have no conflicts of interest.

Maintenance therapy for ovarian cancer patients is vital to extending the recovery time between chemotherapeutic regimens and preserving the efficacy of those agents.  Under consideration today is whether there is sufficient evidence at this time to approve olaparib for a maintenance therapy indication for platinum-sensitive high-grade relapsed serous ovarian cancer.

The goal of maintenance therapy is to extend the time between therapeutic intervals with an optimal risk-benefit ratio.  Otherwise, these patients would not be taking any medication during this time and need this period to recover before additional chemotherapy is needed.  Therefore safety, efficacy, and quality-of-life measures are defining features of maintenance therapy.

Afterreviewing the study evidence, we have three major concerns about olaparib, which were also raised by the FDA.

Firstly, we are concerned about the reliability of the progression-free survival benefit of olaparib, especially since there was no improvement in overall survival during Study 19.

Secondly, we are concerned about the safety profile of olaparib in the context of maintenance therapy. Olaparib-treated patients were almost twice as likely to experience a serious adverse event, in addition to the potentially elevated occurrence of myelodysplastic syndrome orAML.

Lastly, we are concerned that there is not enough evidence of efficacy and low toxicity to ensure that use of olaparib will not compromise patient response to subsequent therapy, which is critical to successful maintenance therapy.

Previous studies of first-line therapy for ovarian cancer suggested that progression-free survival can be predictive of overall survival.  However, a recent paper by the Society of Gynecologic Oncology cautioned against extrapolation of progression-free survival to presumed overall survival benefit in the context of prolonged post-progression survival and multiple lines of treatment.

I’m sure we all agree with the FDA that overall survival is clearly the most significant efficacy measure.  Progression-free survival may only be an acceptable efficacy endpoint when certain criteria are met.  These criteria include low toxicity and efficacy which is both truly predictive of clinically significant benefit and is of robust magnitude, in this particular case, an extension of progression-free survival by six months or more.

Given these stipulations, the seven month extension of progression-free survival in gBRCAm patients may meet a minimal efficacy threshold, but there are strong concerns about the reliability of this observed effect.  In the exploratory analysis conducted by the FDA within the placebo arm, the gBRCAwt/vus population unexpectedly had a superior progression-free survival outcome when compared to the gBRCAm population.  This suggests that the placebo-treated gBRCAm population may have “underperformed”, meaning that the progression-free survival improvement observed in the gBRCAm population may be overestimated.  The SOLO-2 trial currently underway is powered to precisely detect changes in the hazard ratio.  That data is critical to clarifying the potential progression-free survival benefit of olaparib due to this uncertainty.

While the patient-reported FACT-O quality-of-life measures did not indicate detriment, there were significantly increased adverse events with olaparib treatment, including a 2-fold increase in nausea, a 4-fold increase in anemia, a 2-fold increased incidence of various infections, and a near 2-fold increase in gastrointestinal disorders.

As the FDA stated, the patient-reported measures may not capture all possible negative effects of olaparib treatment, and any reported improvements could also reflect cessation of previous platinum treatments.

In addition, approximately four times as many patients in the olaparib-treated arm versus the placebo-treated arm underwent dose reductions, and about six times as many underwent dose interruptions due to adverse events.  Many adverse events also lasted longer in the olaparib-treated arm. There were ten adverse event categories which lasted more than a month longer for olaparib-treated patients, including abdominal, joint, musculoskeletal pain and nausea.  For these reasons, we are concerned that olaparib does not meet the low toxicity and quality-of-life parameters that are essential in the maintenance therapy setting.

The ongoing phase III SOLO-2 trial has the potential to clarify the potential progression-free survival benefit of olaparib, in addition to providing an additional analysis of overall survival and quality-of-life measures.

The results of SOLO-2 are needed In order to be able to guarantee patients an effective maintenance therapy that is not likely to jeopardize their quality-of-life and overall prognosis.  Therefore, we urge the committee to delay approval of olaparib until sufficient evidence has been provided.

Statement of Laurén Doamekpor on the importance of including women, minorities, and the elderly in studies of the safety and effectiveness of new drugs and devices (FDASIA section 907 hearing)

Policy, Testimony & Briefings,
April 1st, 2014

My name is Laurén Doamekpor, a senior fellow speaking on behalf of the National Research Center for Women & Families and our Cancer Prevention and Treatment Fund. Thank you for the chance to speak today.

Ourresearch center evaluates data and provides objective health information to patients, providers and policy makers. We strongly support the inclusion of women, racial and ethnic minorities, and the elderly in clinical trials for drugs and devices.

The Section 907 report reveals that there is more work to be done to achieve greater diversity in clinical trials.  We believe that the key question today should be: what can the FDA do to ensure:

  1. greater diversity in clinical trials submitted to FDA,
  2. subgroup analyses submitted to the FDA
  3. Information from subgroup analyses are used as a basis of approval and labeling decisions, and made widely available in a user-friendly format to providers, patients, and other stakeholders.

The responsibility of collecting sufficiently representative demographic subgroup data sits solely on the shoulders of device and drug companies. The companies know how to persuade – they do it everyday in commercials.  Similarly, if they identify persuasive incentives for patients to participate in studies, and minimize disincentives, patients will participate and be available for follow-up.

The FDA’s crucial role is to hold companies accountable. The FDA guidance regarding diversity and subgroup analyses is regularly ignored by companies, and unfortunately FDA then approves their drugs and devices anyway.  If the FDA’s actions clearly showed that sponsor applications will be rejected — or perhaps approved for White men under 60 only — if companies do not include the relevant demographic data and conduct the necessary subgroup analyses – we are confident that companies will find a way to comply.

To successfully persuade companies to conduct subgroup analyses for the major subpopulations that will use their products, the FDA must consistently demonstrate that they believe those data are essential for proving safety and efficacy.

This is essential because research tells us that naturally occurring genetic variations may influence the way certain drugs are metabolized and work in women compared to men, older patients compared to younger, and certain racial and ethnic groups. Currently, the main challenges in conducting subgroup analyses is that the sample sizes are too small, and get miniscule when age and race and sex are all considered.  We understand that not every ethnic group or age group can be separately analyzed. However, we disagree with the assumption that it is not feasible to power studies to detect subgroup differences. It can be done, and should be done for major subgroups. If the FDA required this practice and held companies accountable, companies will find a way to achieve this.

Our Center participates in many FDA Advisory Committee meetings, and rarely is the lack of diversity in clinical trial data mentioned for more than one second by anyone other than us.  When the FDA’s clinical summaries provided to Advisory Committee members and the public, do not criticize the lack of diversity or lack of subgroup analyses, the FDA sends the message that safety and efficacy for all subgroups are not important.

In the last week, for example, we spoke at one FDA Advisory Committee meetings for a drug for heart failure and 2 for drugs forMRSA. Heart failure is the #1 killer of men and women of all races in the U.S. and MRSA disproportionately harms minority patients.  However, African American patients comprised less than 5% of the cardiac drug trial and less than 6% for one of the MRSA drugs.  NONE of the companies did subgroup analyses for all the primary and secondary endpoints. The lack of data was similar for Hispanic patients.

And, although many of these drugs are used primarily on elderly patients, few patients over 65 were included.  For one of the MRSA drugs, only one analysis of efficacy for patients over 65 was conducted and it clearly showed that the new drug was less effective than the comparison drug.  But, the FDA didn’t even mention that in their summary and the Advisory Committee recommended approval of the drug for all adults over 18 anyway.

On the rare occasion when our concerns about diversity inspires Advisory Committee members to speak up, the result is usually a recommendation to achieve better diversity in the post-market study.  Unfortunately, companies rarely do better in post-market studies, because the incentives to please FDA weaken greatly once their drug or device has already been approved for the general population.

In addition to showing companies that they must achieve diversity and conduct subgroup analyses, there is another action that the FDA should take.  FDA should gather information comparing recruitment and retention strategies from companies that are achieving greater and lesser diversity in their trials to determine which strategies are successful, and share that information with companies that need to improve.

Ultimately, patients and providers need to know whether subgroup data were collected, what the findings are, and how scientifically solid those results are. This information is essential for providers and patients to make well-informed medical decisions. The FDA should require that subgroup data be provided on labels and promotional efforts, using wording that is easy to understand by patients and providers.

Again, thank you for the opportunity to speak at this meeting. We hope that you will incorporate our comments and recommendations into the Action Plan.

 

Testimony of Dr. Anna E. Mazzucco on HPV test

Testimony & Briefings
March 12, 2014
by Dr. Anna E. Mazzucco

My name is Dr. Anna Mazzucco, and I thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund.   After completing my Ph.D. in Cell Biology at HarvardMedicalSchool, I conducted research at the National Cancer Institute.  Those are the perspectives I bring today.  Our organization does not accept funding from medical device companies, and therefore I have no conflicts of interest.

The question today is whether HPV tests should be the first-line screening tool for cervical cancer.  This would be a significant departure from current recommendations of the CDC and US Preventive Services Task Force as well as ACOG, ACS and AAFP.

Currently, HPV tests are recommended ONLY for co-testing with a Pap smear and only for  patients 30 and older.  Those recommendations are based on clear evidence as well as common sense because we all know that HPV usually goes away by itself, and encouraging colposcopies for young women based on HPV tests, if those women are sexually active with multiple partners, would result in a lot of unnecessary, invasive treatment with no real benefit.

What is the sponsor’s proposal based on?   In their study, the comparator arm triaged ALL abnormal cytology ASC-US or higher with immediate colposcopy.  That does NOT reflect current practice.  6% of all women in the trial had abnormal cytology at baseline, so this strange clinical trial design resulted in an artificially high colposcopy rate in the comparator arms.

Manipulating the control arms in that way made it seem that the proposed indication didn’t increase the percentage of colposcopies.  But, we can’t trust that result because of the FLAW in the research design.

We have other concerns as well:

  • Current, the Roche cobas test is approved to use the same sample vial as the Pap test.  As FDA points out, this cytology is also used to diagnose candida and trichomonas infections, herpes viral changes, atypical repair, and abnormal endometrial cells.  The HPV test can’t identify ANY of those.  Therefore, eliminating the Pap smear every 3 years would result in losing that important information which is currently easily obtained from the same Pap smear sample at little additional cost.  This will put women at risk.
  • Most cervical cancers occur in women who have never been screened or were not screened in the last five years.   What is needed is to increase patient compliance with screening.  The sponsor does not provide any evidence that HPV testing will increase patient compliance.  On the contrary, the sponsor’s plan, based on the trial population, would result in 7% of women ages 25 to 29 undergoing immediate colposcopy, which is more expensive AND more unpleasant than a Pap smear.  This is likely to reduce the chances of patients undergoing screening.   In this trial, for example, 14% of the patients were lost from the baseline colposcopy.
  • Colposcopy often results in biopsy, which can result in subfertility, pre-term labor, and perinatal death.  These are risks that are unnecessary but directly result from the sponsor’s plan.
  • The sponsor states that “Current U.S. screening guidelines already consider both cytology and HPV 16/18 genotyping to be established approaches to determining which HPV positive women require colposcopy”.   That is very misleading.  In fact, the US Preventive Services Task Force gives a “D” rating for HPV testing in women under age 30 because the risks outweigh the benefits, as shown in previous clinical trials.
  • The sponsor compares their proposed indication to other algorithms, but only relative to detection of CIN2 orCIN3.  Per10,000 women, the Candidate arm only detected 15 more cases >= CIN3, and 3 more cases of CIN2.  The vast majority of women will never develop CIN2 or CIN3, and CIN2 usually spontaneously goes away within 2 years.  These small benefits do not outweigh the risks of less screening compliance, pre-term labor, compromised fertility, and perinatal death.
  • The Comparator arm triages all cytology of ASC-US or greater with immediate colposcopy.  As the FDA noted, this is no longer current clinical practice.  The 2012 ASCCP guidelines recommend either repeat cytology in one year, or HPV testing, with only a positive result leading to colposcopy.  Similar observations can be made about the alternative comparator arms.  2012 ASCCP guidelines support a 1 year repeat of co-testing ONLY for women 30 or older who are cytology negative but HPV positive before recommending colposcopy.  USPSTF currently only sanctions co-testing for women over 30 who wish to lengthen the screening interval from 3 to 5 years, it does not explicitly prefer co-testing.  In order to accurately weight risks and benefits, we must have a comparator arm which represents current clinical practice and guidelines.
  • Of the patients in this clinical trial, 99% had not received the HPV vaccine, and the median age was 41, with one-third post-menopausal.  Only 6,654 women were between the ages of 25 and 29.  The proposed new indication would pose the greatest risks to young women who hope to have children, so they would need to be studied MUCH more carefully than the sponsor has done.

One last point: the sponsors identify economic and clinical complexities of performing two tests instead of one to justify elimination of cytology.  Economic considerations are outside of today’s considerations, but even if they were, HPV tests cost much more than cytology.  The clinical challenge of dealing with more information, rather than less, is also irrelevant, since the sponsor’s proposal would still often rely in colposcopy and cytology results as well as HPV results for clinical decision-making.

Moreover, to prevent cervical cancer while preserving young women’s ability to have children,  we should not be seeking less information, we should be seeking more information.

The data presented today are too discordant with current clinical practice and cannot be used to justify such sweeping change.  This proposed indication represents a radical shift in clinical practice which would affect millions of women for most of their adult lives.  These proposed indications also encroach on clinical practice, and FDA cannot “establish or recommend guidelines for medical practice.”

We urge the committee to consider the risks to young women and reject the proposed indication.

 

Comments of the Cancer Prevention and Treatment Fund on FDA draft guidance to industry on Acrylamide in foods

Testimony & Briefings, Uncategorized, , ,
January 14, 2014

The Cancer Prevention and Treatment Fund strongly supports the Food and Drug Administration in its efforts to advise industry on reduction of acrylamide in food products.  The Grocery Manufacturers Association estimates that acrylamide is present in approximately 40% of the total caloric intake in a typical American diet.6 Given this near-ubiquity, and the fact that the chemical reaction which produces acrylamide also produces commercially desirable color, taste and texture characteristics, reduction of acrylamide represents a challenge.  However, the evidence of possible human harm necessitates its treatment as a significant public health issue. While this report represents an important step in FDA regulation of acrylamide and suggests many possible acrylamide reduction methods, we are concerned that this guidance is not specific enough in providing clear and concrete recommendations that can be implemented.  Although FDA guidance does not have the force of law or regulation, the addition of terms such as “when feasible” implies that the FDA is not serious in its efforts to persuade companies to substantially reduce acrylamide.  FDA monitoring of acrylamide in 2002 indicated wide variation even among products from the same food category –as much as 5 or 10 fold differences in several categories.  This is clear evidence that significant acrylamide reduction can be accomplished without losing desirable product qualities. Thus, although there is clearly much room for improvement, this report contains few immediately implementable guidelines for industry. Since 2002, it has been known that acrylamide is created in food products as the result of a reaction between carbohydrates and the amino acid asparagine at high temperatures during browning (i.e., the Maillard reaction).7  In addition to its known neurotoxic properties, both animal toxicology and human epidemiological studies suggest that acrylamide may be cancer-promoting, which has led to its carcinogen classifications by EPA, NTP and IARC.8,9,10,11 Higher dietary acrylamide consumption has been associated with increased risk of endometrial, ovarian, pancreatic, renal and possibly breast cancer.12,13,14,15.  Acrylamide is already regulated in drinking water and was classified by EPA as “likely to be a carcinogen to humans” and was classified by the National Toxicology Program as “reasonably anticipated to be a human carcinogen,” both more than a decade ago.  The European Food Safety Authority has been overseeing acrylamide monitoring within the European Union since 2007, and the European Commission has set recommended indicative values for acrylamide in food products, providing a quantitative framework for both assessment of reduction efforts and investigative action.  This is a very important health issue and we strongly urge the FDA to intensify its efforts and assert leadership of both the national and international efforts to regulate acrylamide and ensure public safety. Our areas of specific concern are the following:

  • While encouraging manufacturers to conduct their own testing, FDA should update and expand its own monitoring efforts.  Monitoring of acrylamide in food products over time is needed for any reduction efforts to be assessed and successfully implemented.  The current FDA monitoring strategy tested only several hundred foods in four geographic regions annually between 2002 and 2006, and the last publicly available information is from 2006.16  Given the wide range of acrylamide levels even within a single food category, more extensive and up-to-date monitoring is needed to adequately evaluate acrylamide levels and the success of reduction methods.
  • While this report encourages manufacturers to monitor acrylamide levels, it does not give any specific values which should prompt corrective efforts.  Without such guideposts, monitoring alone is unlikely to result in significant reductions.  Recommended target values or action levels, together with active monitoring, will allow FDA and manufacturers to directly access efficacy of reduction efforts and trigger investigation when needed.  The European Commission has set indicative values for acrylamide in food products, including separate values for products intended for infants and young children, and these values are intended to be gradually reduced.17  Indeed, these indicative values have been broadened to include more specific categories and some have already been lowered since their release in 2011, and the European Food Safety Authority is currently conducting a risk assessment at the request of the European Commission to determine if current recommendations are sufficiently protective.  Such a system provides a quantitative framework for reduction efforts and allows increased surveillance of items of special health importance.  Values at least as low as the 2013 European Commission indicative values should be adopted, with the shared intent of gradual lowering of these values as reduction efforts improve.
  • Without accurate and affordable detection techniques, manufacturers are unlikely to measure acrylamide in their products, especially when participation is voluntary.  This guidance encourages manufacturers to be aware of acrylamide levels in their food products.  This is a crucial step towards evaluating reduction efforts.  However, this vital imperative is followed by a discussion of both the technical limitations and expense associated with current methods of acrylamide detection.  While FDA has committed to improving these techniques, they remain costly and fraught with technical limitations, making widespread voluntary use, especially by small manufacturers, unlikely.  FDA should continue to investigate means to improve acrylamide detection and make specific recommendations to industry regarding best possible techniques in order to facilitate participation in monitoring.  As an example, the European Commission has recently set measurement uncertainty (MU) values and tasked the European Committee for Standardisation (CEN) with analytical standardization of LC-MS and GC-MS for acrylamide detection.  Such efforts, in addition to adoption of standard references, will increase consistency and improve confidence in acrylamide detection efforts.
  • In this guidance, the FDA specifically states that it does not intend to recommend one method over another.  This is unfortunate because it leaves both guesswork and legwork to industry.  FDA states that “this guidance is intended to suggest a range of possible approaches to acrylamide reduction and not to identify specific recommended approaches.”  The role of federal agencies should include evaluating reduction approaches to determine which are more efficacious and feasible than others, and providing that potentially useful information to industry, even if only to help identify and encourage prioritization of those approaches first, in addition to continuing research in this area.  Clear communication of superior and cost-effective approaches to acrylamide reduction may result in higher industry participation and more successful reduction efforts.
  • FDA monitoring since 2002 has shown that many foods contain higher levels of acrylamide than the level considered safe by the EPA for drinking water.  Some of the highest acrylamide levels are found in potato and cereal products which are common in the American diet.  These surveys also show that a healthy diet which includes whole grains can have significant acrylamide levels, potentially even higher than a diet which includes less healthful choices such as potato chips and French fries.  The FDA has maintained its message to consumers that a balanced, healthy diet is a way to manage concern over acrylamide consumption, when the evidence shows that this advice is not accurate. 
  • The effects of acrylamide reduction on overall product nutrition should be considered in the context of all health risks and benefits.  For example, lower temperature frying reduces acrylamide, but also requires longer cooking time, resulting in higher fat content in fried foods.  While we commend thorough consideration of all possible health implications of acrylamide reduction methods, FDA should also consider which outcomes can be more easily mitigated by other dietary or lifestyle interventions in order to fully assess risks and benefits.

Lastly, as acrylamide accumulates in food as a result of the handling and cooking process, rather than in the raw food itself, and is a serious human health concern, it could be viewed as source of food adulteration and regulated as such under Section 402(a) of the Federal Food, Drug and Cosmetic Act with action levels.  We ask that FDA consider these improvements to this draft guidance, and use its full authority to ensure that the public is sufficiently protected.

The Cancer Prevention and Treatment Fund

 For additional information, contact Anna Mazzucco at am@center4research.org or (202) 223-4000.

Statement of Dr. Diana Zuckerman before the FDA Advisory Committee Regarding Dapagliflozin (Farxiga)

Testimony & Briefings, Uncategorized
By Diana Zuckerman, Ph.D.
December 12, 2013

Thank you for the opportunity to speak today.  I’m Dr. Diana Zuckerman. I’m president of the Cancer Prevention and Treatment Fund.

Our center is dedicated to improving the health and safety of adults and children, and we do that by conducting and scrutinizing research and explaining the findings to health professionals, patients, and the general public.   Our non-profit center does not accept funding from pharmaceutical companies, so I have no conflicts of interest.

Today I am speaking from my perspective as someone trained in epidemiology at YaleMedicalSchool. I also was on the faculty at Yale and at Vassar and conducted research at Harvard, and was a fellow at the Center for Bioethics at the University of Pennsylvania.  I’ve also discussed the data with an expert on our staff who previously worked at NCI, Dr. Anna Mazzucco.  I’m putting together all of those perspectives, as well as having worked for the U.S. Department of Health and Human Services, as a consultant to the Institute of Medicine., and as someone with several close family members with diabetes, one of whom died from the disease..

My concern about this drug is that there are just too many unanswered questions – and those unanswered questions are frightening ones.  That was true when the FDA rejected this application for approval 2 years ago, and it is still true today.

Question #1: How well does it work?

The results indicate that DAPA is NOT effective for patients with moderate to severe renal impairment.  As the FDA has noted, 20-40% of diabetes patients have compromised renal function.

DAPA is better than placebo but does not provide a significant improvement over currently available drugs.  Specifically, glipizide was superior in the short-term and comparable to DAPA at week 52.

So, in the context of these limited benefits what are the risks?

FDA stated that the animal studies conducted could not rule out the possibility that dapagliflozin contributes to bladder cancer.   We completely agree.  Experiments done using cell lines and tumor models which are not implanted in the bladder cannot answer questions about the risks to humans.  Because in humans, changes in the bladder microenvironment or urine flow may be most relevant to carcinogenesis.  FDA has already suggested use of an appropriate animal model which could address these concerns, specifically a “a (BBN) chemically-induced rodent bladder cancer model (4-hydroxybutyl(butyl)nitrosamine).

Why didn’t the company do the right kind of animal study?  That’s an important question to keep in mind.  But, until the correct type of animal studies are done, DAPA must be considered a possible cause of bladder cancer.  Since other effective diabetes drugs are already on the market, and those drugs are more effective for more patients, bladder cancer is an unacceptable risk.

But bladder cancer isn’t the only concern.  What about breast cancer?  The FDA consultant gave several reasons why DAPA is unlikely to have caused the breast cancers that were observed.

These reasons included:

  • short treatment time prior to onset,
  • the decline in incidence risk ratio over time, and
  • the fact that the breast cancers were estrogen receptor positive.

 

Let’s start with the short treatment time before onset.  We all know that cancer usually takes years to develop.  So, it would be easy to assume – or perhaps hope – that the increase in cancer happened by chance.  But wishful thinking isn’t enough.  We need to know.

When the percentage of women taking hormone replacement therapy for menopause dropped dramatically, the rate of new cancers in the U.S. went down for the first time ever.  Experts in the field agree that this unexpected quick effect was because of the drop in use of hormone therapy.  So, we know from that experience that even a slow growing cancer can be stimulated by a drug.

We challenge the other 2 assumptions as well.  Hormone receptor status is irrelevant because the potential mechanism for this drug to cause breast cancer is unknown.  It is entirely possible that dapagliflozin could act in multiple biological pathways, including hormone receptor signaling, or in a biological pathway that is common to breast cancers regardless of hormone receptor status.

Similarly, long-term biological responses to dapagliflozin and potential feedback mechanisms in breast tissue are also unknown.  Thus, the decline in incidence risk ratio over time doesn’t mean the drug is safe — because the body could respond differently to dapagliflozin over time.

Diabetes and the prior use of hypoglycemic medications were also listed as reasons to doubt potential breast cancer risk, but these factors are common among all patient groups in these trials.

In summary, these arguments cannot rule out the possibility that dapagliflozin causes breast cancer.  The only way to answer this question is with appropriately designed animal models of mammary tumors, or human patients.

Other Safety Issues:

Renal impairment/failure adverse events were associated with dapagliflozin treatment in data based on 13 short-term studies (3.2% in dapagliflozin-treated patients vs. 1.8% with placebo) and the 9-short-term plus long-term studies (6.7% vs. 4.2%) studies.  As many diabetes patients already have compromised renal function, this risk represents a significant health hazard primarily for the patients most likely to receive this drug.

At two different doses, the DAPA patients had elevated LDL levels, while placebo patients did not.  This increase raises concerns that any potential cardiovascular benefits – which are questionable — cannot justify the additional risks.

Lack of Diversity in the Studies

In the entire clinical program, less than 4% of the patient s were African American.  And yet 13% of African Americans have type II diabetes.  They should have been tested if the intent was to approve the drug for all Americans, not just white Americans.

But, given the risks, it would be difficult to justify recruiting African Americans or whites for more research at this time.

When I speak at FDA advisory committee meetings it is always as a scientist, but today I also want to speak on behalf of patients.  My Dad developed diabetes at the age of 90, probably because he took lupron for prostate cancer.   In retrospect, that was probably not a good treatment decision, since prostate cancer is rarely fatal.   It would certainly be ironic if a diabetes patient developed bladder cancer, which is often fatal, or breast cancer, which can be fatal, as a result of taking a diabetes medication that is no more effective, and often less effective, than other diabetes treatments on the market.

It’s hard to imagine a well- informed patient choosing DAPA, but unfortunately, patients are rarely well-informed.   I assume that the physicians on this panel would clearly and carefully inform their patients of the risks of this drug, but in the real world, many doctors won’t be well-informed because the company that makes DAPA is telling doctors very clearly that DAPA is safe and does NOT cause cancer, when the truth is we don’t know, but it might.

We can’t solve this with a black box warning on a label, because many doctors and patients don’t read the labels.  We can’t ethically rely on post-market studies, because it would not be ethical to prescribe this medication with all these unanswered questions.

I sympathize with the companies’ repeated efforts to get this drug approved, but I wonder why they didn’t do the animal study that the FDA recommended.   And I would not want anyone I care about to take a drug with such serious potential risks when so many alternatives are on the market that do not cause cancer.