Tag Archives: FDA

Comments of the Cancer Prevention and Treatment Fund on FDA draft guidance to industry on Acrylamide in foods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

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.

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.

 

The Op-Ed: FDA panels: too many conflicts or too little expertise?

Press Releases
By Diana Zuckerman, PhD
June 12, 2013

This Op-Ed was published by Pharmalive.com, to see the original post, click here.

Last week, a paper in the journal Science argued that a 2012 law that loosened conflict-of-interest restrictions on FDA advisory panels could not only allow more drugs with troubling side effects to enter the marketplace, but was actually unnecessary. The discussion, which analyzed the utility of caps placed on waivers, once again raised the thorny debate over conflicts and panel members (read more here). But Diana Zuckerman who is president of the National Research Center for Women & Families, a think tank, and long-time FDA observer, argues this only tells part of the story…

Should FDA Advisory Committee members be allowed to have financial conflicts of interest regarding the medical product they are recommending for approval (or recommending against approval)?  The answer is not as simple as it might seem.

The Searle Civil Justice Institute of George Mason University held a Congressional briefing this week on the subject and I was invited to participate. The funding for the institute came from the late Daniel Searle, former ceo of the pharmaceutical company GD Searle. The focus  was a report entitled “FDA Advisory Committees: An Empirical Examination of Conflicts of Interest,” that is being written by Joe Golec, Professor of Finance at the University of Connecticut, and two of his colleagues at the George Mason University School of Law.

The statistics compiled for the report focus on voting patterns for all the FDA advisory committee meetings on new prescription drugs in recent years. The results indicate that the committee members who get waivers allowing them to serve on the committee despite conflicts of interest vote very similarly to the committee members who don’t get waivers. The authors conclude that this shows that conflicts of interest don’t unduly influence voting patterns on FDA advisory committees. They also conclude that the members with conflict of interest waivers tend to have more expertise, and therefore are an important addition to the committees.

I do not doubt the data that the authors presented, but I question their conclusions. The publicly available information about conflicts of interest on FDA advisory committees is too limited, and the analysis misses the flavor of advisory committee meetings, as well as the not-so-subtle nuances regarding conflicts of interest.

FDA defines conflicts of interest as financial ties during the last 12 months, so even extensive financial ties in the recent past – or even 12 months plus one day earlier — would not be included and would not require a waiver. The FDA advisory committee that met over a year ago to discuss whether Yaz oral contraceptives are too risky to stay on the market is a perfect example.  Advisory committee members with previous extensive financial ties to Bayer, which sells the pills, but who did not have waivers voted in support of Yaz (and Yasmin, Beyaz, and other contraceptives made with the hormone drosperinone). This shifted the vote to keep these pills on the market.

In addition to the many conflicted advisory committee members who don’t get waivers because their financial ties are more than a year old, voting patterns don’t tell the whole story.

I’ve been to dozen of advisory committee meetings, and I’ve seen how members with financial ties to the company or product often talk more at the meetings. They may talk more because they know more. They may talk more because they want to show the company how smart or helpful they are. Whatever the reason, their greater participation can be influential. Many advisory committee members ask no questions and make no comments at these meetings, until required to explain their votes. The advisory committee members with more direct knowledge of the products, including those with financial ties to the company or the product can greatly influence the vote when they talk more, ask softball questions or steer the conversation toward topics of benefit to the company. These members may have grants or consulting relationships with the company.

For committee meetings reconsidering safety issues for popular products such as Vioxx, Avandia, Yaz, osteoporosis drugs, surgical mesh, hip joints, and breast implants, advisory members who have frequently prescribed or implanted the products being reviewed are not considered biased and also do not have waivers. These potentially more knowledgeable but less objective members influence how others vote, making a comparison between members with waivers and members without waivers rather meaningless.

After attending so many advisory committee meetings, and studying 89 of these meetings in ourreport what is striking to me is how many of the members are not truly experts worthy of giving advice to the FDA. In fact, many of these voting members don’t understand statistics and ignore the clinical trial data unless they support their desire to get the drug on the market or keep it on the market.

Advisory committee members tend to be clinicians who want more drugs to be approved, making comments like “if this drug can help one patient, we should get it on the market.” For example, I recently went to an advisory committee meeting for Merck’s new sleeping pill, suvorexant, where the members ignored the FDA’s concerns that the data indicated many patients would have trouble driving to work the next day and could even fall asleep at the wheel (read here).

These sleeping pills had a half-life of 12 hours. Most of the advisory committee members didn’t care about that at all. Instead, they focused on the fact that people have insomnia and need help falling asleep. I think that people who take sleeping pills are mostly concerned about getting enough sleep so that they can function well the next day. A good night’s sleep doesn’t seem so beneficial if it means falling asleep while driving to work the next day.

At a meeting a few months ago, FDA advisory committee members recommended approval for a TB drug that was five times as likely to kill the patients as the current standard of care, a statistically significant difference. The sponsor, Janssen, speculated that the high death rate happened by chance in this randomized double blind clinical trial.  Amazingly, that ridiculous justification was good enough to convince most of the advisory committee members. Apparently, they didn’t understand that the entire purpose of a statistical analysis of a randomized double blind clinical trial is to determine whether or not a difference in outcome occurred by chance – and this one almost definitely didn’t.

I am very pleased that FDA Commissioner Margaret Hamburg has asked agency officials to reduce the number of advisory committee members with waivers. Unfortunately, the waivers are just the tip of the conflict of interest iceberg. FDA advisory committee members continue to have many members with financial ties to the companies and no disclosure of who they are. The media have publicly outed some of those advisory committee members, but most of the time that information is not known to the public, or the reporters covering advisory committee meetings.

Meantime, the bigger problem is that so many FDA advisory committee members don’t understand statistics or truly value or understand the results of clinical trials. FDA is supposed to make decisions based on scientific evidence that patients are more likely to be helped than harmed by a new medication or medical device. FDA approval should not be based on speculation or wishful thinking about whether a drug might “help at least one patient.” When committee members ignore the documented risks and focus on their hope for unproven benefits, thousands of patients die unnecessarily.

The number of FDA advisory committee members with conflict of interest waivers is lower than ever, but many members still show clear bias in favor of approving drugs and medical devices that are not proven safe or not proven effective. Whether those FDA advisors have financial conflicts of interest, other types of bias, or lack of interest in scientific evidence will not matter to the patients who are harmed by these medical products. Unfortunately, that will be the legacy of too many FDA advisory committee meetings.