Category Archives: Testimony & Briefings

Comments of the Cancer Prevention and Treatment Fund on FDA draft guidance to industry on Acrylamide in foods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.1 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).2  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.3,4,5,6 Higher dietary acrylamide consumption has been associated with increased risk of endometrial, ovarian, pancreatic, renal and possibly breast cancer.7,8,9,10.  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 2006.11  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.12  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.

Public Comments on NIOSH Draft Intelligence on Carcinogen Classification and Target Risk Level Policy for Chemical Hazards in the Workplace

Testimony & Briefings, , ,
By Anna E. Mazzucco
December 16, 2013

Thank you for the opportunity to speak today.  My name is Dr. Anna Mazzucco, and I speak on behalf of the National Research Center for Women & Families, and our Cancer Prevention and Treatment Fund.  After completing my Ph.D. in cell and developmental biology at Harvard Medical School, I conducted research at the National Cancer Institute.  I speak today as a cancer biologist gravely concerned that these regulations lag behind the state of the science, and fall far short of protecting Americans from occupational causes of cancer.

In 2013, more than half a million Americans will die from cancer.  A 2003 joint report from the National Cancer Institute and the National Institute for Environmental Health Sciences stated that “exposure to a wide variety of natural and man-made substances in the environment accounts for at least two-thirds of all the cases of cancer in the United States.” Yet after reviewing the current state of regulatory policy and research efforts, the President’s Cancer Panel reported in 2010 that “environmental health, including cancer risk, has been largely excluded from overall national policy on protecting and improving the health of Americans.”   When notorious and decades-known carcinogens such as asbestos and radon are still present at unsafe or unknown levels in American workplaces, how can the public have confidence that our regulations can handle new and complex occupational hazards arising every day?  Only a few hundred out of more than 80,000 chemicals in use in the United States have been tested for safety.  We should be concerned.

The National Institutes of Health estimated the total cost of cancer in 2008 at $201.5 billion in both direct health care costs and the indirect cost of lost productivity due to premature deaths.   Another recent study estimated that cancer is responsible for 20 percent of all health care spending.  Disability days alone cost $7.5 billion in lost productivity each year.  And these numbers cannot attempt to capture the human value of lives lost.

Unfortunately, the NIOSH draft report represents a continuation of the status quo.  It reinforces a reactive rather than proactive approach to regulation.  It maintains historical policy positions which are no longer appropriate.  It  places burdens on workers rather than on industry.  And, it overlooks glaring gaps in regulation. This report does not provide sufficient information on proposed new policies that would add to redundancy between agencies, rather than eliminating redundancy.  Even more troubling, these new policies could allow a more permissive stance towards carcinogens in the workplace despite more stringent regulation of the very same agents by other federal agencies.

We have 5 Areas of concern that we want to emphasize:

  1. Safe exposure limits must be based on actual, not theoretical, workplace exposures. Real-life workplace chemical use involves multiple agents and complex exposures.  This report does not give any concrete statements on how to address the true chemical milieu to which workers are exposed.  There is no scientific reason to limit our safety analyses to single agents.  If the goal is to prevent chemical hazard exposure in the workplace, then we must start with the workplace, and not a theoretical framework which likely applies to very few real-life situations.
  2. Acceptable occupational risk assessments should be based on up-to-date, circumspect and truly representative information.  NIOSH uses a lifetime cancer risk increase of 1 in 1,000 as the acceptable regulatory threshold, while stating that “controlling exposure to lower concentrations is always warranted.” NIOSH admits that “an excess risk of 1 in 1,000 is one or more orders of magnitude higher than what the United States permits for the general public.” NIOSH justifies this questionable threshold with two arguments:  The first is the historic “benzene decision” made by the U.S. Supreme Court in 1980, where a 1 in 1,000 risk was used in a seemingly rhetorical example.  The second justification is that workers are a very small subset of the general population, and higher exposures for small numbers of people may be considered acceptable if they are comparable to the overall risks of employment itself.  We disagree with these nonscientific justifications.  There is increasing evidence that occupational carcinogens spread into the greater environment.  For example, trichloroethylene (TCE), an industrial solvent, is now present in approximately one-third of the U.S. water supply.   The maximum risk threshold acceptable to the EPA is 10-fold less than the NIOSH threshold – and given the overlapping exposures, that does not make sense.  The EPA considers 1 in 1,000,000 to be the target threshold for as many people as possible, but that is 1000 times lower than the NIOSH threshold. The bottom line is that there is no scientific basis for these differential safety standards, and we now know that occupational and environmental exposures frequently become indistinguishable.  For that reason, the workforce should be afforded the same level of protection as the general public.
  3. Safety determinations will only be as effective as the quality of the science they are based on.  This report outlines the use of linear modeling to extrapolate low-dose effects of carcinogens.  But linear modeling isn’t appropriate for chemicals with non-monotonic dose-response curves, such as endocrine disruptors.  In addition, bioaccumulation and multigenerational effects must be considered — otherwise, limits will be simplistic and inaccurate. When NTP/EPA/IARC classifications disagree, NIOSH says they will “adopt the classification determined to be most relevant to occupational exposures“.  This policy would allow for “down-classifying” of carcinogens based on workplace considerations.  Given the technical difficulty in distinguishing between occupational and greater environmental exposures, the public needs detailed information about this decision-making process, so that we can ensure that any down-classifications are justified by scientific evidence.  NIOSH should also consider making full use of the NTP Executive Committee before investing their own time and resources in classifying agents, in order to focus their efforts on the stated goal of reducing risks.
  4. A safe exposure level based on technical feasibility rather than safety places workers at risk. NIOSH plans to set the recommended exposure limit (REL) to the higher, detectable dose (the reliable quantitation limit).   This would directly place workers in potentially unsafe conditions, while rendering them powerless to detect or remove the agent to ensure safe levels.  If we want to instead guarantee safety to workers in this situation, NIOSH needs to ban these chemicals until more sensitive detection methods are developed.  That policy would protect workers while creating an incentive for industry to develop more sensitive diagnostic capabilities or find safer alternatives.
  5. Sensitive subpopulations require protections too.  Birth defects, childhood cancer, and adult cancers can all caused by in utero exposures.  The NIOSH draft report does not provide details on how sensitive subpopulations will be protected.  Just as NIOSH sets risk thresholds for all workers, it must have regulations which sufficiently protect everyone in that group.

We urge you to consider these changes, and use every resource at your disposal to ensure that our national policies regarding occupational carcinogens meet their goal of protecting Americans at work.  This will ensure a healthy society, thriving economy, and also safeguard our environment for generations to come.

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

 

Testimony of Dr. Anna E. Mazzucco on MK-3475 and Nivolumab

Testimony & Briefings, ,
By Anna E. Mazzucco, Ph.D.
November 5, 2013

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 HarvardMedicalSchool I conducted research at the National Cancer Institute. I bring 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.

Pediatric cancers represent a dire unmet medical need.  Several pediatric cancers still cannot be cured, and patients relapse within a few years.  Cancer immunotherapy is an area of great excitement and promise for addressing these issues, as we seek non-genotoxic strategies for pediatric patients who are uniquely vulnerable to the long-term effects of such treatments.  Therapies of this class have shown the potential to synergize with existing standard of care, which is an essential aspect of the combination therapies ultimately required for curative care.

We support the FDA’s efforts to expedite medical advances for pediatric cancer patients, but this priority must not come at the cost of safety standards.  Although distinct from the side effects resulting from traditional chemotherapy, nivolumab and MK-3475 have significant risks.

Three deaths occurred in the trials of nivolumab in advanced malignancy adult patients due to uncontrollable pneumonitis, out of 296 patients – 1%.  Grade 3 and 4 adverse events occurred in 14% of these patients.  The assertion that pediatric patients will tolerate nivolumab comparably to adults relies on a single ongoing study of a different drug, ipilimumab, in only 6 patients under the age of 12.  While ipilimumab is also an immunomodulatory drug, it is a distinct agent with a different mechanism of action.  Thus, critical safety data cannot be extrapolated from these studies.  The Bristol-Myers Squibb studies do not include any preclinical data in non-adult primates.  As the Bristol-Myers Squibb briefing document acknowledges, these drugs may have different and more pronounced effects in pediatric patients since their immune systems are still developing.

I have 4 recommendations that I respectfully suggest that you seriously consider:

#1.  In the Merck preclinical studies, toxicity was evaluated in primates at an age roughly comparable to a “young toddler”, but the plan here calls for trials in infants as young as six months old. Before pediatric studies begin, longer-term preclinical studies of MK-3475 and nivolumab should be performed in primates at comparable stages of development so that human infants are not exposed to greater safety risks than those observed in adults.  Until such studies are conducted, I hope you will urge the FDA to oppose the Bristol-Myers Squibb plan to initiate pediatric studies of nivolumab immediately at the adult dose of 3mg/kg, without any further preclinical studies.  This could be fatal.

#2  The Bristol-Myers Squibb plan also includes pediatric trials using the combination of nivolumab with ipilimumab.  This combination resulted in markedly increased toxicity in preclinical studies, which were conducted for only 4 weeks, and also in the study of human adults.  In the melanoma study in adults, almost half of the patients (49%) experienced Grade 3 or 4 events. This percentage is higher than the 40% who showed a beneficial clinical response – in other words, the risks outweighed the benefits, with more patients experiencing serious adverse events than benefitting.  Combination treatment was discontinued in 21% of patients in this trial due to these adverse events.

Other studies have indicated that these serious adverse events are not always reversible; for example 2% of patients taking ipilimumab in a Phase III trial had hypopituitarism, which can be permanent.  This condition requires long-term hormone replacement therapy, but even that will not eliminate significant health risks.  Tragically, those health risks would be exacerbated in young patients who are still developing.  Longer preclinical studies are needed to evaluate safety before it would be ethical to begin combination trials with ipilimumab.

#3.  The Bristol-Myers Squibb briefing document emphasizes the importance of early detection for management of adverse events.  High doses of corticosteroids will undoubtedly be required to control drug-related adverse events. This could be dangerous for children.  We agree with the FDA that the long-term effects of immune modulation should be carefully considered in the context of a pediatric population.  The Pediatric Study Plan does not yet delineate specific steps for rapid clinical detection and management of these events, which will be more difficult in these patients.  It is essential that those specific steps be delineated before research is conducted.

#4.  Lastly, as the FDA has noted, the combination of these agents with others of non-overlapping mechanism of action should be a priority consideration in the ongoing studies in adults.  We also agree with FDA that the threshold of PD-L1 expression used for patient selection should be modified for combination therapy where PD-L1 expression could be induced, therefore a lower initial threshold of expression may still identify a responsive patient population, and that the planned biomarker studies explicitly address this possibility.   This will ensure that these agents are used to the greatest effect in all patients who need them.

In conclusion, the 4 steps I outlined above will help reduce the risks to children with pediatric cancer and also help assure that these therapies reach the patients most likely to benefit from them.

Comments of the National Research Center for Women & Families and the Cancer Prevention and Treatment Fund on FDA Safety and Innovation Act Section 907 Report

Testimony & Briefings,
NOVEMBER 20, 2013

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

Comments of the National Research Center for Women & Families and the Cancer Prevention and Treatment Fund
on FDA Safety and Innovation Act Section 907 Report

Docket no. FDA-2013-N-0745-0001

The National Research Center for Women & Families strongly supports the requirement of the Food and Drug Administration Safety and Innovation Act (FDASIA) for an action plan to include demographic subgroups in clinical trials and data analysis. Greater diversity in clinical trials, analyzing subgroup data, and reporting the results and explaining the implications in product labels and MedGuides will shed light on which medical products are safe and effective for which demographic subgroups, including racial and ethnic minorities.

The Section 907 report, which outlines the recent status of demographic subgroup’s inclusion in clinical trials and data analysis, creates a baseline measurement that indicates much room for improvement. Although there have been improvements in the last decade, this report is replete with examples (described in detail below) where lack of adequate demographic subgroup reporting not only hindered this analysis itself, but also obscures medically important information. Even when subgroup information has been collected, if crucial subgroup data are not explicitly included on labels, providers and patients may incorrectly assume that “no news is good news,” when in reality the drug or device may not have been adequately tested or analyzed for their subgroup.

Our major criticisms of the report are that, as reflected in the Executive Summary:

The inclusion of demographic subgroups is considered a measure of success, rather than acknowledging the importance of having large enough subgroups to analyze separately.
The lower prevalence of disease in those subgroups is given as justification for inadequate numbers of patients even when those diseases are very prevalent.
The summary optimistically states that “We also found that FDA shares this information with the public in a variety of ways.” We are disappointed with the small amount of useful information that is made public, particularly on the label, which is the easiest route to communicate with doctors and patients.
We respectfully urge the FDA to incorporate our comments and recommendations into the Action Plan.

On the matter of inclusion, although demographic subgroups were frequently included in the clinical trials described in the report, they were rarely analyzed separately. In many cases, their numbers were too small to be meaningfully analyzed as separate subgroups. There is little value in including subgroups if they are not analyzed separately to produce useful information on the safety and effectiveness of the products for these subgroups. Including subgroups that are so small that their data cannot be meaningfully analyzed renders their participation useless from a scientific point of view. In addition, the report sometimes generalizes the findings in ways that are not precisely accurate; for example, many studies had very limited diversity and yet the Executive Summary states that “For approved drugs and biologics, the extent to which patients were represented in clinical trials by age and sex tended to reflect the disease indication studied.”

In addition to minimizing the importance of subgroup analysis, that statement ignores the fact that there are many examples where a subgroup has a lower incidence of the disease, but also has much worse outcomes when they get the disease. Breast cancer is one such example: the disease is less prevalent among African Americans, but African American women tend to get a more aggressive form of the disease and their survival rate is lower.

If a treatment is substantially less effective in a particular subgroup, and that subgroup is too small to analyze separately, the results of the study will not provide the crucial information to warn that subgroup that the medical product is ineffective. On the other hand, if a treatment is more effective for some subgroups that are not analyzed separately, that crucial information would also be unavailable.

For example, all (100%) of the patients in the melanoma trials were white (See Table 1-3), but many reports before 2011 indicate an increasing incidence among non-white populations. These include a 20% increase in melanoma among Hispanic men and a 60% increase among non-Hispanic black women in Florida.13 Even more concerning, studies suggest melanoma is more likely to be diagnosed at later stages in minorities than in non-Hispanic whites, and has a poorer prognosis.14, 15, 16, 17 By not conducting trials that analyze Hispanics separately, there is no opportunity for medical advances for this disease where they are urgently needed.

Why It is Important to Improve Diversity in Clinical Trials Used as the Basis for FDA Approval

Even if a drug or device is more frequently used in one subgroup, whether males or a large minority population, or individuals of a particular age, it should be possible to conduct trials for treatments of common diseases that include sufficiently large subgroups in order to determine its safety and effectiveness for most if not all users. If the FDA was not willing to approve a drug or device for the subgroups that were not adequately studied, the companies would have the incentive they need to include adequate representation of those subgroups in their clinical trials.

In addition to requiring companies to include demographic subgroups in adequate numbers in Phase III clinical trials, the FDA should broaden their requirements to include adequate demographic subgroup representation in early phase trials and post-market studies, in order to obtain a broader picture of how safe and effective these products are for subgroups.

Devices

Diversity in clinical trials was even more limited for devices than for drugs and biologics. The report concluded that age and sex were usually described in the PMA studies, but in fact, women were less than one-third of the patients in 21% of the device trials. Almost one-third of the PMA applications did not report any information about race or ethnicity. Subgroup analysis was even less likely. Twelve percent of the PMA applications did not include analysis by sex, 30% did not include analysis by age, and 73% did not include analysis by race or ethnicity.

Women

Female subjects were often underrepresented in the drug and device trials even when the diseases were prevalent among women. For example, Figure 1-2 shows that the two COPD medication trials had only 20% and 30% women, and yet a 2010 report indicates that 2006 was the sixth consecutive year in which more women (63,006) than men (57,970) died of COPD.18 Only 10 out of 33 medical device studies had greater than 40% female representation, as shown in Figure 2-2. The PMA for an endovascular occlusion device had only 18% female representation, but this under-representation of women was justified by stating that patients are often selected for such devices if they have larger coronary size and less diffuse nature of coronary disease – and hence typically male. However, this product was not approved only for men; it was approved for all adults.

Racial and Ethnic Minorities

Racial and ethnic subgroups were also not adequately represented in drug or device trials. Hispanics composed 17% of the U.S. population in 2012.19 However, 17 out of 23 (74%) of device trials were less than 10% Hispanic, as shown in Figure 2-3. Therefore, the majority of device trials were not representative of the Hispanic population. African Americans make up approximately 13% of the U.S. population,20 but 87% of the CDER/CBER trials included fewer than 13% African Americans. To give an example with important public health implications, approximately 13% of African Americans have diabetes,21 but African Americans represented only 2% of participants for type 2 diabetes clinical trials. Such inadequate representation is not useful for determining whether a medical product is safe or effective for African Americans, and is particularly disturbing given the prevalence of diabetes in that population.

The 2011 census indicates that Asians are approximately 5% of the U.S. population, but most (54%) of the trials cited had less than 5% Asian participants. For example, Table 1-3 indicates that both Hepatitis C trials had only 2% Asian composition, whereas there is significantly higher prevalence of Hepatitis C in this population, and a higher rate of liver cancer and a differential response to antiviral therapy in this population.22

Demographic data was often collected inconsistently; sometimes race and ethnicity were collected together, and sometimes they were collected as two separate categories. For CDER/CBER, ethnicity was not analyzed for the report since some applications reported race and ethnicity as one item. For medical devices, 23 out of 33 trials (70%) included separate ethnic data. Hispanic ethnicity was sometimes separated into subcategories, and sometimes it was kept as a single ethnic category. Such inconsistent data collection leads to results that are very difficult to interpret and use.

Age Groups

Age group data were also reported inconsistently, reducing the usefulness of the data. In 8 of the 31 drugs approved (26%), age was reported as a median with range or with a cut-off of 60 instead of 65, rather than actual numbers. These inconsistencies, due to lack of specifics in the guidance, resulted in omission of this 26% of studies from this analysis. For CBER and medical devices, age data were presented as ranges without medians, and were spread over such large age windows that the information was not useful for comparing age groups (Figures 1-4 and 2-1). Although all the device studies included patients up to age 75, for example, the report does not specify how many patients in each study were in any specific age group, such as over 65. A specific example of where a lack of elderly representation is problematic is ALCL. Although it is arguably less common in elderly (20-50% of all cases), the subtype which occurs in elderly is biologically distinct, thus requiring a different treatment, and has poorer clinical outcomes.23, 24, 25 Lack of children is also a problem in clinical trials; despite 2007 PREA legislation, a 2012 study showed that 96% of all intensive care pediatric patients, and 100% of those ages 13-17, receive off-label medications that have not been tested in those age groups.26

Labels

Even the limited information gained from demographic subgroup analyses in these trials was rarely presented in the medical products’ labeling. In subgroup analysis of safety based on sex shown in figure 1-8, only 5 of 30 drugs had data information in the label (17%). In most of these 30 drugs (57%), subgroup analyses were not included on the label, but only in public review material. In another 5 out of the 30 drugs (17%), the label did not include any subgroup analysis by sex, despite it being mentioned in the public review. For subgroup analysis of efficacy by sex as shown in Figure 1-8, only 6 out of 30 (20%) had efficacy subgroup analysis on the label. Although inadequate, this is not surprising, because there is no requirement for that information to be included on the label. For medical devices, 63% had a statement in device labeling about sex subgroup analyses, 57% about age analyses and 16% about race/ethnicity analyses. The report then glossed over these unimpressive statistics, stating that, “This demonstrates that FDA publicly communicated information on subgroup analyses for sex and age for more than 50% of the PMA applications approved in 2011.”

RECOMMENDATIONS:

FDA should issue regulations to require that all applications for devices, drugs, and biologics provide data on safety and effectiveness by sex, age, race and ethnicity.
FDA should finalize the draft guidance for sex-specific analysis that the agency proposed in 2011 and issue similar guidance for racial and ethnic minorities and the aged.
CBER should require biologics sponsors to report summary subgroup data, just as the CDER requires.
In its regulations, guidance documents, and decisions, the FDA should make it clear that the agency will not approve medical products for all populations if the product was not tested on major demographic subgroups with meaningful subgroup analysis.
FDA should require that ethnicity and race information be recorded and reported separately, as they have already described in their draft guidance Collection of Race and Ethnicity Data in Clinical Trials in 2005. Unless this happens, data will continue to be collected in an inconsistent manner, making it useless for analysis, as this report demonstrated.
Postmarket study requirements should never be a substitute for demographic subgroup analyses in pre-market studies, but post-market studies should be required to provide additional information about long-term safety and efficacy for subgroups.
Labels should include subgroup-specific analyses in language that is understandable by health professionals and patients. If not enough information on subgroups was collected to analyze and draw conclusions about potential differences, FDA should be required to state that on the label, and approval should not be assumed for major subgroups that were not analyzed. If lack of subgroup data and analysis is not explicitly stated, physicians and patients will erroneously assume that those groups have been adequately tested. Similarly, as for pediatrics and geriatrics, sex, race and ethnicity should be mandatory, standardized, easy-to-understand sections on the label, so that patients and doctors can quickly find this information or be aware where information does not exist.
FDA should issue a public report every 2 years that evaluates compliance with these recommendations.
In conclusion, if the FDA took the firm stance of not approving medical products for the general population unless they have been adequately tested on subgroups instead of simply recommending it, all medical products on the market would have information on safety and efficacy for most potential users.

Comments to FDA on Draft “Endocrine Disruption Potential of Drugs: Nonclinical Evaluation.”

Testimony & Briefings

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

 

Re: Draft guidance for industry entitled
“Endocrine Disruption Potential of Drugs: Nonclinical Evaluation.”
Docket ID: FDA-2013-D-1039

 

We welcome the opportunity to comment on the FDA’s guidance to industry on preclinical detection of endocrine disruption potential in drug and biologics applications.

There is increasing awareness in the medical community that the human endocrine system is very vulnerable to disruption, whether from pharmaceutical or other environmental sources.  In 2009, the American Medical Association adopted the recommendations of The Endocrine Society, calling for increased action on this issue by FDA.27

Between 1982 and 1995, infertility rates almost doubled in American women ages 18-25,28 and in 2002 alone, Americans spent 2.9 billion dollars on fertility treatments.29  While these are complex medical issues likely stemming from multiple factors, it is clear that FDA could be doing more to address this public health concern.

Several well-documented pharmacological features of endocrine disruptors are disregarded in FDA’s proposed preclinical study guidelines.  These policies would unfortunately set the stage for unintended endocrine-disrupting function to be obfuscated in preclinical studies, with potentially disastrous consequences.

Our specific areas of concern include:

  1. Many studies have shown that endocrine disruptors display non-traditional, non-monotonic dose-response curves in toxicology studies, consistent with historical work in hormone receptor biology.30 This issue has been clearly described by the Director of the National Institute of Environmental Health Sciences, Dr. Linda Birnbaum, who is a leading expert on this issue.31  The FDA’s draft guidance ignores this issue, citing only the need for toxicology studies over “a wide range of doses,” when the weight of evidence clearly indicates that higher doses would be expected to have different, if not opposite effects, when compared to lower doses.   The weight of evidence strongly challenges the FDA’s statement that “endocrine activities that only occur in animals at exposures substantially above the human exposure usually do not warrant additional investigation. Additional assessment likely would be appropriate for endocrine-active drugs for which human exposure is comparable to or exceeds the exposure level at which activity on endocrine-sensitive tissues is observed in standard nonclinical studies.” Toxicology studies must be done at the doses that humans are likely to experience in order to be acceptable.
  2. The use of inappropriate laboratory animal strains and uncontrolled experimental design is a notorious problem in toxicology studies of endocrine disruptors.  Several studies have demonstrated that certain rodent strains do not respond to endocrine disrupting chemicals, likely due to inherent genetic differences.32  Without rationally chosen animal models combined with relevant positive controls, these studies are useless and do not meet the basic requirements of responsible science.  Standardization of animal models and positive controls in these studies would do much to improve scientific quality, and would also prevent the waste of resources which comes from performing studies only to repeat them due to inconclusive findings.
  3. Many scientific studies have shown that endocrine disrupting agents exert their strongest effects during developmental windows when delicate hormone balance is required for biological events to properly occur, such as during prepregnancy (i.e. before and including the time when pregnancy is possible for all women of reproductive age),  prenatal and prepubescent stages.6   FDA is aware of this fact, stating that “Some developmental stages (e.g., gestational, neonatal, peripubertal) are particularly sensitive to endocrine disruption effects” while at the same time acknowledging insufficiency in their guidance on this issue.   For example, FDA states that “Standard developmental and reproductive toxicity (DART) studies generally capture gestational developmental time points effectively, but might not be adequate for evaluation of effects on postnatal development unless the neonates are dosed directly during the lactation period.”   And yet, in this guidance, such studies are inappropriately left to the discretion of the sponsor, rather than required by the FDA.  The FDA needs to take a stronger stand regarding the need for these studies, since otherwise such studies may never be conducted.  Direct dosing during these developmental stages could be included in preclinical studies without requiring the initiation of new studies with additional animals, while generating critical information about endocrine disrupting function when it would be most obvious.
  4. “Inactive” ingredients and delivery agents, such as enteric coating, in pharmaceuticals have been shown to possess endocrine disrupting function.33 Toxicology studies must be conducted using the same formulation intended for human use in order to be relevant.  Similarly, the route of exposure, such as through vaginal delivery, can significantly alter the dose-response behavior of hormonally active agents.34  Drug administration in preclinical studies must mirror the route of administration intended for human use.
  5. Gross anatomical assays described here, such as preputial separation and anogenital distance, may not be as sensitive or quantitative as direct measurement of hormones levels, which are mentioned only as a suggested alternative or addition to these standard tests.  As such assays are not laborious or expensive and could be performed simultaneously with preclinical studies already being done, why should they be held in reserve for only special cases?  Similarly, FDA acknowledges that other animal models, such as castration studies, are more sensitive than standard ones.  What is the scientific rationale for not performing the most sensitive assays available?  Logic suggests that starting with the most sensitive assays, rather than the least, to detect endocrine disrupting function is the most judicious use of resources, and most likely to ensure that critical safety information is not overlooked.

We strongly urge that the FDA modify the guidance to better reflect the concerns above as well as the scientific issues that have been raised by a sister PHS agency, NIEHS.  We also urge the FDA to make it clear to sponsors that these important preclinical studies are not mere theoretical suggestion, but are essential for approval.

Sincerely,

The National Research Center for Women & Families

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

 

Comment for Proposed Rulemaking, Menthol in Cigarettes, Tobacco Products; Docket No. FDA-2013-N-0521

Testimony & Briefings, , , , , ,
November 2013

We write today to urge the FDA to remove menthol cigarettes from the market as quickly as possible.

Tobacco use is responsible for more than 400,000 deaths each year in the United States and is the leading preventable cause of death. A quarter of all cigarettes sold are menthol cigarettes, which studies show are preferred by younger smokers and new smokers. Since almost 9 out of 10 (88%) adult smokers began smoking before age 18, it will save lives to make smoking as unappealing as possible for teenagers and young adults. Menthol’s “cooling effect” does the opposite: it makes smoking as palatable (perhaps more palatable) to young people and nonsmokers as candy flavoring, which was banned in 2009 under the Family Smoking Prevention and Tobacco Control Act. According to the FDA’s Preliminary Scientific Evaluation of the Possible Public Health Effects of Menthol Versus Nonmenthol Cigarettes, “the weight of the evidence supports the conclusion that menthol in cigarettes is likely associated with increased initiation and progression to regular cigarette smoking.”

Not only are menthol cigarettes a starter product for youth, they are harder to quit because they are likely associated with: 1) “increased dependence,” and 2) “reduced success in smoking cessation, especially among African American menthol smokers.”  For these reasons, we strongly agree with the FDA conclusions that “menthol cigarettes pose a public health risk above that seen with nonmenthol cigarettes.”

The Tobacco Products Scientific Advisory Committee (TPSAC), before which we testified, concluded over two years ago that “removal of menthol cigarettes from the marketplace would benefit public health in the United States.” A conservative modeling scenario published in a peer-reviewed medical journal estimated that over 320,000 deaths—most of them among African Americans—could be averted by 2050 had menthol been banned in 2011 as recommended.35 The FDA must not drag its feet any longer. The decision to extend the comment period an additional two months itself cost thousands of lives.

The Cancer Prevention and Treatment Fund represents the millions of American families whose lives have been touched by cancer, and our mission is to gather and scrutinize research to determine how programs and policies can reduce the incidence of cancer and improve treatment options for cancer patients.  Our scientific analysis indicates that hundreds of thousands of lives will be saved when the FDA removes menthol cigarettes from the market, and we strongly urge the FDA to protect the public health by implementing a final rule to do so.

Sincerely,

Cancer Prevention and Treatment Fund

Testimony of Brandel France de Bravo, MPH, at the Gastroenterology-Urology Devices Panel on Computed Tomography Colonography (Virtual Colonoscopy)

Policy, Testimony & Briefings,
September 9, 2013

I am Brandel France de Bravo, and I am speaking on behalf of the Cancer Prevention and Treatment Fund of the National Research Center for Women & Families. Our non-profit research center scrutinizes medical data, evaluating scientific evidence of benefits and risks for patients.  We analyze and review research and provide objective and understandable health information to patients, health care providers, and policy makers.  Our organization does not accept funding from companies that make medical products, and therefore I have no conflict of interest.

The research presented in the FDA summary makes clear five points that are essential in considering the benefits and safety of Computed Tomography Colonography or CTC:

1)      There is NO ONE method of screening asymptomatic patients for colon cancer that meets the three necessary criteria for increasing compliance with screening guidelines: that the method be highly accurate; very low risk; and involve little to no discomfort—either physical or psychological – including the “yuck”  factor. Optical colonoscopy has not been as widely embraced as many health experts would have liked, except perhaps by unscrupulous surgical centers, which The New York Times reports are charging insurance companies as much as $6,000.   The Times noted that colonoscopies “are the most expensive screening test that healthy Americans routinely undergo — and often cost more than childbirth or an appendectomy in most other developed countries.” While traditional colonoscopy has downsides, it at least offers a “two-for”: it screens patients for colon cancer and removes potentially pre-cancerous polyps all in the same procedure.

2)      Virtual colonoscopies don’t screen and treat; they just screen, which is why the term “virtual colonoscopy” is a misnomer. It is, however, a great marketing tool as it implies a clean, no-muss-no-fuss approach. In fact, patients still have to go through the grueling process of bowel preparation.

3)      CTC is not as good as optical colonoscopy at detecting polyps or lesions of 10 mm or smaller. This, however, may not be so important given that polyps under 10mm are less likely to be suspicious and in need of removal. Smaller polyps grow slowly, and some will even shrink and disappear on their own.

4)      While CTC is less sensitive for smaller lesions and exposes patients to relatively high doses of radiation, it does offer one major benefit over colonoscopy: it reduces the risk of major bleeding and disease transmission—both of which are of particular concern in older patients.

5)      Besides exposing patients to radiation and missing smaller polyps, CTC opens a Pandora’s box of “extra-colonic findings”—suspicious findings in nearby organs. These findings can lead to more diagnostic tests, some of which may be invasive or harmful, but they also sometimes save lives.

While radiologists often dismiss worries about excessive exposure to radiation, our Center continues to be concerned because so many patients are being exposed to radiation from so many different medical tests, as discussed today by Dr. Berrington de González. Two pieces of information or safeguards that would help make the decision about CTC easier are missing:

  • We need to know if patients in the U.S. are more likely to undergo regular screening with so-called virtual colonoscopies than regular ones. This is the purpose of patient-centered outcomes research—how do real patients in the real world respond to these two options, and what are the benefits of each in attracting patients who should get screened?Dr. Summers shared data on patient acceptance, showing a preference for CTC, but that data was based on answers to questionnaires—given either after the procedure or about a hypothetical screening.  To date there are no studies in the U.S. where asymptomatic patients who have never before been screened are given a choice between CTC and regular colonoscopy and then actually undergo their preferred screening.
  • When is a professional society or government agency going to address the health threat of increased lifelong exposure to radiation from medical tests and treatments? The advent of electronic medical records provides the opportunity to implement a plan to reduce patients’ total exposure to radiation. It wouldn’t cap exposure but rather allow providers to make informed decisions: by enabling them to review a patient’s previous radiation exposure before choosing what kind of screening to recommend.  For example, a heavy smoker undergoing regular CT scans for her lungs should probably be screened with colonoscopy rather than CTC, since the latter also exposes part of the lungs to radiation.

There are no easy answers, but we trust the US Preventive Services Task Force to stay on top of this important issue, providing unbiased information on the risks and benefits as new data become available.  We agree with the Task Force that at this point, there is no reason to recommend virtual colonoscopies for most patients who need screening.  We would add, however, that if specific patients are unwilling to undergo regular colonoscopies, then a virtual colonoscopy is a reasonable alternative.

 

Comments of the Patient, Consumer, and Public Health Coalition on Proposed Order “General and Plastic Surgery Devices: Reclassification of Ultraviolet Lamps for Tanning, Henceforth To Be Known as Sunlamp Products”

Testimony & Briefings, ,
August 7, 2013
[Docket No. FDA-2013-N-0461]

As members of the Patient, Consumer, and Public Health Coalition, we urge you to finally follow the recommendations made by FDA classification panels[end The General and Plastic Surgery Device Classification Panel and the Physical Medicine Device Classification Panel.] in 1977 and upclassify sunlamp products. All sunlamps should be reclassified as Class III devices because of their known risks, especially the increased likelihood of developing the most serious type of skin cancer.

By law, high-risk devices that can cause substantial harm or even death are Class III.  Clearly, sunlamps satisfy those criteria.

Over 30 million Americans, including 2 million adolescents between age 11 and 18, use tanning devices each year. Those who began using tanning beds before age 30 are 75 percent more likely to develop cutaneous melanoma, a potentially fatal cancer. There are virtually no medical benefits to using sunlamp products.  Despite claims, there is no clear evidence that sunlamp products are safe and effective for treating depression, seasonal affective disorder, or vitamin D deficiency. A device that has only minor cosmetic benefits and that the World Health Organization’s International Agency for Research on Cancer has called “carcinogenic to humans” is a threat to public health and should be more strictly regulated.

While we agree with the FDA that sunlamp products should be reclassified, we do not agree that the proposed special controls will adequately protect consumers from the harms associated with indoor tanning. We strongly urge the FDA to require the following safeguards:

  1. Sunlamp products currently are allowed to use a mix of UVA and UVB rays. FDA should set a standard for the UVA/UVB mix that is based on scientific research. Performance testing should disclose the percent of UVA and UVB rays used and this information should be included in labeling.
  2. Because of how sunlamps are used, even the best labeling would not be sufficient to inform consumers of the risks of using sunlamp products. Patients should have to read and sign a patient disclosure form prior to a tanning session. This disclosure form, written at a 6th grade reading level,  should briefly describe the risks of indoor tanning, skin cancer warning signs, and recommended limits on using sunlamps for tanning. Copies of the disclosure form should be given to consumers to take home.
  3. Tanning facilities should be required to post very visible warning information about cancer risks in waiting/reception areas and also on or near the machine itself.
  4. The American Academy of Pediatrics and American Academy of Dermatology both recommend banning minors from tanning salons. We strongly agree.  If no ban is imposed, parents should be required to sign informed consent forms in person at the time a minor is using the tanning facility.
  5. The FDA should consult with scientific advisors to create a recommended limit on sunlamp use for tanning. The limits should include time per exposure, amount of UV radiation per exposure, and number of exposures per year. Customers should be limited to a number of minutes per year that the FDA advisors consider safe. Recommended limits should be included on labels, posted warnings, and patient disclosure forms. Safety and performance testing of sunlamp products should meet the limits.

The classification of sunlamp products should reflect the known safety risks and lack of medical benefits of these devices. Skin cancer is preventable, and requiring higher safety standards for unsafe devices will reduce healthcare costs and save millions of Americans from developing this disease.

 

American Medical Women’s Association
American Public Health Association
Cancer Prevention and Treatment Fund
Connecticut Center for Patient Safety
National Consumers League
National Physicians Alliance
National Women’s Health Network
Our Bodies Ourselves
Center for Science and Democracy, Union of Concerned Scientists
WoodyMatters

 

For more information, contact Paul Brown at (202) 223-4000 or pb@center4research.org

Testimony of Dr. Jennifer Yttri at FDA Advisory Committee on Tivozanib

Other Cancers, Other Cancers, Policy, Testimony & Briefings
May 2013

I am Dr. Jennifer Yttri and I am speaking on behalf of the Cancer Prevention and Treatment Fund of the National Research Center for Women & Families. Our non-profit research center scrutinizes medical data, evaluating scientific evidence of benefits and risks for patients.  We analyze and review research and provide objective and understandable health information to patients, health care providers, and policy makers.  Our organization does not accept funding from pharmaceutical companies and therefore I have no conflict of interest.

Today’s fundamental question is whether the one completed Phase 3 clinical trial is enough to approve the new drug tivozanib as a treatment for patients with renal cell carcinoma.

FDA guidelines recommend two trials that support efficacy of a drug. In some cases, FDA will approve a new drug based on only one trial if that trial shows a significant improvement over existing therapy. In the FDA’s own words: “A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study. Reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity… and [when] confirmation of the result in a second trial would be practically or ethically impossible.”

The NDA submitted for tivozanib relies on one phase 3 study comparing tivozanib to sorafenib. While tivozanib was shown to increase progression free survival by 3 months in patients with renal cell carcinoma, it did not improve overall survival. In fact, there was a non-significant lower overall survival for tivozanib, suggesting the drug may actually harm patients more than it helps them. This one study alone is not enough to meet the FDA’s guidelines for drug approval.

In addition, the study results have inconsistencies that raise red flags about the research and about the drug itself.

1.       Patients receiving tivozanib had increased progression free survival, so why were they more likely to die in the first 30 days due to disease progression, compared to sorafenib. This does not make sense. The deaths in the first 30 days could be due to chance, but the disease free survival could also be due to chance.  More research is needed to clarify the risks as well as the long-term benefits.

2.       FDA noted that 70% of sorafenib patients stopped taking the drug at least temporarily and 44% ended up with a reduced dose. This is much higher than other studies – for example one study highlighted by the FDA had only 14% interruption and 10% reduction.  There is no logical explanation for this, but these unusual problems could make sorafenib seem inferior to tivozanib, when in fact it might be superior.

These inconsistencies may be due to chance or to irregularities in how the studies were conducted in other countries.  Standard of care and assessment of disease varies in the US and other countries, and fewer than 10% of patients enrolled in the trial were in the US.  We agree with the FDA reviewer that it is preferable to enroll US patients, so that the study reflects the disease burden and treatment in the US and can provide better insight into treatment outcomes for US patients.

Regardless of the reason for the inconsistencies in the study, a second, independent, phase 3 study would help determine the safety and efficacy of this drug for treatment of renal cancer.

We urge you to recommend that the FDA require the sponsor to complete a second trial to confirm the positive effect of tivozanib on PFS; address the concern over lower OS; and provide better information on how generalizable the results are in the US population. Based on the data provided, there are no ethical concerns with requiring another trial. With the additional information, the FDA can make an informed decision as to whether tivozanib meets their standards of safety and efficacy.  That is not possible based on this one study with such inconsistent results.