Category Archives: Policy

Letter to The Honorable Kathleen Sebelius on comprehensive cessation benefit

Legislation, Policy, Uncategorized

To view letter, click here.

February 19, 2014

The Honorable Kathleen Sebelius
U.S. Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW, Room 120F
Washington, DC 20201

Dear Secretary Sebelius:

We are writing to ask your Department to clearly define a comprehensive tobacco cessation benefit in the Affordable Care Act regulations or, at the very least, in corresponding guidance documents.

Recently, your Department released the 50th anniversary Surgeon General’s report, The Health Consequences of Smoking – 50 Years of Progress, which found that smoking is even more hazardous and takes an even greater toll on the nation’s health than previously reported. We appreciate the work that went into producing this historic report and applaud your commitment to reducing tobacco use.

Noting that the “current rate of progress in tobacco control is not fast enough. More needs to be done,” the report calls for a number of specific actions, including: “Fulfilling the opportunity of the Affordable Care Act to provide access to barrier-free proven tobacco use cessation treatment including counseling and medication to all smokers”. As you noted during the release of the report, and on previous occasions, the Affordable Care Act (ACA) “requires insurance companies to provide tobacco cessation services to their customers.” But we are concerned that tobacco users who are ready to quit do not have access to free cessation services under the ACA.

The Surgeon General report notes that the implementation of tobacco cessation treatment coverage mandated by the ACA varies significantly across private health insurance contracts. In fact, evidence indicates that many health plans are not covering services that have been proven to help tobacco users to quit. A 2012 study by Georgetown University’s Health Policy Institute found that many health insurance plans are failing to provide the coverage mandated by the ACA for treatments to help smokers and other tobacco users quit. Specifically, researchers found that only four of the 39 private plans analyzed clearly covered a full-range of evidence-based tobacco cessation services (i.e., individual, group and phone counseling and both prescription and over-the-counter tobacco cessation medications). Contract language for these plans often contained vague or conflicting language that made it impossible to determine which, if any, tobacco cessation services were covered. When the extent of coverage could be determined, many of these plans excluded coverage of prescription and/or OTC medications for tobacco cessation and excluded certain types of counseling. Also troubling, some of the plans analyzed impose cost-sharing requirements for tobacco cessation treatments.

We believe that this study makes clear that many insurance issuers are not in compliance with the ACA. As a result, many tobacco users’ access to tobacco cessation treatment may be limited. This information has been shared with your Department, yet HHS has not taken any action to make clear to insurers what is required under the ACA.

Tobacco cessation treatments have received an ‘A’ rating by the United States Preventive Services Task Force (USPSTF), which means there is a high certainty that tobacco users will benefit substantially from receiving these services. As an ‘A’ rated service non-grandfathered group plans and insurance issuers must cover these evidence-based tobacco cessation services with no cost-sharing.

The Interim Final Rule implementing Section 2713 of the PHS Act did not attempt to translate the clinical recommendations of the USPSTF into an insurance coverage benefit. The only description in the Interim Final Rule of the tobacco cessation services that must be covered is the following: “The USPSTF recommends that clinicians ask all adults about tobacco use and provide tobacco cessation interventions for those who use tobacco products.” This statement is only the summary of the USPSTF recommendation. The full USPSTF recommendation clearly indicates that counseling and medications are both effective and a combination of counseling and medications “is more effective at increasing cessation rates than either component alone.” USPSTF references the United States Public Health Service Clinical Practice Guideline, Treating Tobacco Use and Dependence: A 2008 Update (the “PHS Guideline”), as the source for a detailed description of effective evidence-based tobacco dependence treatments. Without further guidance from HHS, group plans and health insurance issuers have been able to decide for themselves how to translate the USPSTF clinical recommendation for tobacco cessation services into a covered benefit. Based on the results of the Georgetown University study, many insurers are interpreting the coverage requirement too narrowly, failing to cover tobacco cessation services that the USPSTF has specifically found to be effective.

We are aware that the implementing regulations for section 2713 of the PHS Act permit issuers to “use reasonable medical management techniques to determine the frequency, method, treatment, or setting for an item or service to the extent such frequency, method, treatment or setting are not specified in the recommendation or guideline.” We do not believe that reasonable medical management should allow plans and issuers to ignore the full USPSTF recommendation that specifically lists both the types of medications and counseling that have proven to be effective. All tobacco cessation services that the USPSTF has found to be effective should be covered, not merely some of them. HHS has been provided evidence that many insurance issuers are ignoring the USPSTF recommendations, and without guidance from the Department, group plans and issuers will continue to not provide tobacco users with the effective set of cessation services that Congress intended.

We strongly recommend that the Department of Health and Human Services, Department of Labor, and Department of the Treasury issue guidance to industry clarifying that “tobacco cessation interventions” include coverage of both counseling sessions and FDA-approved medications and that these interventions will be covered whether or not they are delivered during an office visit. As you know, tobacco users need to be encouraged to use cessation services, and lack of clarity about cessation coverage will result in confusion among both health care providers and consumers, leading to fewer successful quit attempts.

Evidence suggests that providing comprehensive tobacco cessation benefits is cost-effective. In 2006, Massachusetts’ Medicaid program (MassHealth) initiated a program to provide tobacco cessation treatments (tobacco cessation medications and counseling) to smokers. A 2012 study published in PloS One shows that Massachusetts saved more than $3 for every $1 it spent on services to help beneficiaries in the state’s Medicaid program quit smoking. These savings are conservative as they do not include long-term savings, savings that may occur outside the Medicaid program, or savings beyond cardiovascular-related hospital admissions. An earlier study found that after Massachusetts implemented this program for all Medicaid beneficiaries, the smoking rate among beneficiaries declined by 26 percent in the first 2.5 years.

There is precedent for HHS to provide guidance beyond the Interim Final Rule on how plans and issuers should comply with the required coverage of USPSTF-recommended services, such as through the FAQs released by the Departments of Labor and Health and Human Services. The failure to clearly define a comprehensive tobacco cessation benefit in regulations or in supplemental information will allow insurers to continue to provide inadequate coverage and impose cost-sharing requirements, contrary to the ACA.

As noted in the recent Surgeon General report, the tobacco cessation benefits contained in the ACA hold great promise but in order to ensure access to cessation services and coverage that reflects the full USPSTF recommendation, we urge you to provide additional guidance on the requirement for coverage of tobacco cessation treatment. With additional guidance, we believe you can make tremendous progress toward accomplishing the specific recommendation laid out in the Surgeon General report and fully maximize the public health benefit of CDC’s Tips from Former Smokers media campaign and other HHS efforts to reduce tobacco use.

The following groups stand ready to help in any way in these efforts, which will save lives and money.

Sincerely,

American Academy of Family Physicians
American Academy of Otolaryngology-Head and Neck Surgery
American Association for Cancer Research
American Association for Respiratory Care
American Cancer Society Cancer Action Network
American College of Cardiology
American College of Chest Physicians
American College of Physicians
American College of Preventive Medicine
American Congress of Obstetricians and Gynecologists
American Dental Association
American Heart Association
American Lung Association
American Psychological Association
American Public Health Association
American Society of Clinical Oncology
American Thoracic Society
Association of Maternal and Child Health Programs
Association of State and Territorial Health Officials
Association of Women’s Health, Obstetric and Neonatal Nurses
Campaign for Tobacco-Free Kids
Cancer Prevention and Treatment Fund
Legacy
Lung Cancer Alliance
National Association of City and County Health Officials
National Physicians Alliance
North American Quitline Consortium
Oncology Nursing Society
Society for Cardiovascular Angiography and Interventions
Society for Research on Nicotine and Tobacco

cc:
Marilyn Tavenner, Administrator, Centers for Medicare and Medicaid Services

Gary Cohen, Deputy Administrator and Director, Center for Consumer Information and Insurance
Oversight, Centers for Medicare and Medicaid Services

Open letter to America’s retailers, especially those with pharmacies from leading public health and medical organizations

Legislation, Policy

To view as PDF click here. 

Open Letter to America’s Retailers, Especially Those with Pharmacies

From Leading Public Health and Medical Organizations

February 26, 2014

As organizations committed to ending the tobacco epidemic in the United States, we applaud the bold decision by CVS Caremark to eliminate the sale of cigarettes and other tobacco products in all its stores. We urge other retailers, especially those with pharmacies, to move quickly to end tobacco sales in their stores. CVS Caremark is absolutely right: The sale of tobacco products – the number one cause of preventable death and disease – is fundamentally inconsistent with a commitment to improving health.

As we observe the 50th Anniversary of the landmark 1964 U.S. Surgeon General’s Report on Smoking and Health, the science on tobacco is unequivocal and inescapable. Tobacco products are uniquely lethal and addictive. They rob us of 480,000 American lives each year, sicken millions more and cost the nation at least $289 billion annually in healthcare expenses and other economic losses.

The latest Surgeon General’s report also underscored that tobacco use is a pediatric epidemic – 90 percent of adult smokers start by age 18 or earlier, and 5.6 million children alive today will die prematurely of smoking-caused disease unless all segments of our society join together to take strong action. 

No corporation truly devoted to saving lives – like the nation’s pharmacies are – can continue to simultaneously reap billions in profits from products that kill nearly half of the people who use them. Neither can any corporation committed to the well-being of our nation’s children. 

CVS Caremark’s decision was met with cheers from their customers and the public at large because it is simply the right thing to do. We urge other retailers, especially those with pharmacies, to put our nation’s children and health before tobacco profits and move quickly to end tobacco sales. Such action would reduce the availability and marketing of tobacco products, accelerate progress in reducing tobacco use and ultimately help end the tobacco epidemic for good. 

Respectfully,


American Association for Respiratory Care
American Association for Cancer Research
American Academy of Otolaryngology—Head and Neck Surgery
American Academy of Pediatrics
American College of Cardiology
American Congress of Obstetricians and Gynecologists
American Lung Association
American Public Health Association
American Society of Clinical Oncology
American Thoracic Society
Americans for Nonsmokers’ Rights
Action on Smoking & Health
Campaign for Tobacco-Free Kids
Cancer Prevention and Treatment Fund
CASA Columbia
Legacy
LIVESTRONG
Lung Cancer Alliance
National Consumers League
National African American Tobacco Prevention Network
National Association of City and County Health Officials
National Latino Alliance for Health Equity
National Physicians Alliance
North American Quitline Consortium
Oncology Nursing Society
Partnership for Prevention
Smoking Cessation Leadership Center
Trust for American’s Health

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

Policy, Testimony & Briefings,
April 1st, 2014

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Testimony of Dr. Anna E. Mazzucco on HPV test

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

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

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

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

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

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

We have other concerns as well:

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

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

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

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

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

 

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

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

The Cancer Prevention and Treatment Fund strongly supports the Food and Drug Administration in its efforts to advise industry on reduction of acrylamide in food products.  The Grocery Manufacturers Association estimates that acrylamide is present in approximately 40% of the total caloric intake in a typical American diet.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