February 11, 2019.

We are pleased to have the opportunity to express our strong concerns about the draft recommendations for the use of prophylactic hormonal treatments for women at increased risk for breast cancer.  The Cancer Prevention and Treatment Fund is a nonprofit program that conducts, analyzes, and reviews research, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers.  We do not accept funding from pharmaceutical companies and have no financial ties to this issue.

We have several concerns about the draft proposal and strongly urge USPSTF to reconsider the recommendation guidelines proposed for the following reasons:

1. Most importantly, the evidence does not include information on absolute risk, which is much more meaningful to patients than relative risk.  The overall lifetime risk of breast cancer attributed to Tamoxifen would be reduced from 12% to 8%[i]^,[ii] if tamoxifen is taken over 5 years.  At the same time however, it would increase the lifetime risk of endometrial cancer from 3% to 6.5%[iii],[ii] and the lifetime risk of thromboembolism from 20% to 39%.[iv] Similarly, raloxifene reduces the lifetime risk of breast cancer from 12% to 5%[i],[iii] but increases the risk of thromboembolism from 20% to 31%.[iv]  Aromatase inhibitors lower the absolute risk of breast cancer from 12% to 5%,[i],[ii] while the lifetime risk of venous thromboembolism increased from 20% to 25%4 and the average lifetime risk of stroke from 20% to 23% as well.[v]  The risk of fractures increases with AI and decreases with tamoxifen and raloxifene, but those comparisons are primarily based on x-rays and bone mineral density, rather than health outcomes of importance to patients, such as pain, other quality of life issues, or abilities regarding activities of daily living.[ii]  In summary, the increases in absolute risk for several serious outcomes are considerably higher than the decrease in absolute risk of breast cancer.
2. The importance of shared decision-makingthat was included in 2013 is missing in 2019.  The 2013 USPSTF recommendations included “shared informed decision-making” but the 2019 draft recommends that doctors “offer to prescribe.”  Research shows that informative discussions have a significant impact on patients’ decisions; those who are better informed of their associated risks are less likely to take these hormonal drugs.[vi],[vii]  As noted above, this discussion should focus on absolute risks, not relative risks.  The 2019 draft guidelines recommend physicians “offer to prescribe” these drugs to women who are at high risk of breast cancer but at low risk for adverse events; the ambivalence over risk-benefit ratio that was included in the evidence review draft is not reflected in this wording.[ii]
3. Another major concern is the definition of women at high risk of breast cancer.  Since the risk of breast cancer increases with age, most women over 65 with one or two other risk factors would be categorized by the NCI risk model as “high risk” because their risk would be above 1.7% in the following 5 years.[viii] In addition, the NCI risk model is based on certain characteristics, but not mitigating variables.  The USPSTF definition of high risk would expose many women who have a moderate to low increased risk of breast cancer to the many unpleasant and serious side effects of these drugs.  In 2013, the USPSTF referred to high risk of breast cancer as at least 3% over the next 5 years, and that is a much more appropriate definition.[ix]
4. Impact of side effects on quality of life is not adequately considered. Studies have shown that women on tamoxifen have significanly increased rates of hot flashes, arthralgia, vaginal dryness, and sexual dysfunction.  For these reasons, high-risk women on tamoxifen were more likely to discontinue these drugs within 5 years due to adverse events when compared to women in the placebo group.[x]

In addition to the specific issues above, we strongly urge the USPSTF to consider its recommendations regarding hormonal treatments in the context of other factors that can decrease the risk of breast cancer.  Healthy habits such as a healthy weight, a diet low in red meat and alcohol, as well as regular exercise have been known to reduce the overall risk of breast cancer.  For example, a major prospective study looking at health outcomes in postmenopausal women found that women with the healthiest diets and the most exercise will decrease their lifetime risk of breast cancer from 12% to 9%.[xi]

As noted above, the risks of these drugs are likely to outweigh the benefits for most women.  The USPSTF key questions focus too heavily on benefits of these drugs and do not give sufficient consideration to risks.  They should be revised to better assess cancer risk, potential benefit, and potential harm.  Only the women at very high risk of breast cancer and low risk of endometrial cancer and vascular disease should consider them.  We strongly urge USPSTF to substantially change the recommendations in light of the absolute risks involved, and that doctors engage in shared decision-making discussions, considering these drugs only for their highest-risk patients, focused on those absolute risks, in order to ensure informed decisions.

For questions or more information, please contact Dr. Diana Zuckerman at dz@center4research.org.

References:

1. NCHR calculated the absolute risk based on the statistics provided by the National Cancer Institute; National Cancer Institute. (2012). Breast Cancer Risk in American Women. https://www.cancer.gov/types/breast/risk-fact-sheet
2. NCHR calculated the absolute risk based on the statistics provided by the United States Preventative Services Task Force Draft Recommendation Statement. (2019). Breast Cancer: Medication Use to Reduce Risk.
   https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/breast-cancer-medications-for-risk-reduction
3. NCHR calculated the absolute risk based on the statistics provided by the National Cancer Institute. (2013). Uterine Cancer – Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/corp.html
4. NCHR calculated the absolute risk based on the statistics provided by Bell EJ, Lutsey PL, et al. (2015). Lifetime Risk of Venous Thromboembolism in Two Cohort Studies. American Journal of Medicine.
5. NCHR calculated the absolute risk based on the statistics provided by Seshadri S., & Wolf, P.A. (2007). Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. The Lancet Neurology.
6. Fagerlin A, Zikmund-Fisher BJ, et al. (2010). Women’s decisions regarding tamoxifen for breast cancer prevention: responses to a tailored decision aid. Breast Cancer Res. Treatment.
7. Melnikow J, Paterniti D, et al. (2005). Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. Cancer.
8. National Cancer Institute. The Breast Cancer Risk Assessment tool. https://bcrisktool.cancer.gov/

9. United States Preventative Services Task Force. (2013). Breast Cancer: Medications for Risk Reduction. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-medications-for-risk-reduction

10. Day, R. (2001). Quality of Life and Tamoxifen in a Breast Cancer Prevention Trial. Annals of the New York Academy of Sciences.
11. Thomson, CA et al. (2014). Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women’s Health Initiative. Cancer Prevention Research.

Diana Zuckerman, PhD, National Center for Health Research: January 24, 2019.

January 24, 2019

Dear Madam Chairwoman and Members of the Greenwich Board of Estimate and Taxation:

I am Dr. Diana Zuckerman, President of the National Center for Health Research.  Our nonprofit think tank is located in Washington, D.C. Our scientists, physicians, and health experts conduct studies and scrutinize research. Our goal is to explain scientific and medical information that can be used to improve policies, programs, services, and products. 

As a scientist who has worked on health policy issues for more than 30 years, I don’t shock easily.  However, it is shocking and disturbing that artificial turf athletic fields and playgrounds are exposing children on a daily basis to chemicals and materials that are known to have the potential to increase obesity; contribute to early puberty; cause attention problems such as ADHD; harbor deadly bacteria; and exacerbate asthma.  

Federal agencies such as the EPA and the U.S. Consumer Product Safety Commission have been investigating the safety of these products. Despite claims to the contrary, none have concluded that artificial turf is safe.

Scientific Evidence of Cancer and Other Systemic Harm

First, it is important to distinguish between evidence of harm and evidence of safety.  Companies that sell and install artificial turf often claim there is “no evidence children are harmed” or “no evidence that the fields cause cancer.”  This is often misunderstood as meaning the products are safe or are proven to not cause harm. Neither is true.

The artificial turf industry will tell you there is no clear evidence that their fields caused any child to develop cancer.  That is true, but the statement is misleading because it is virtually impossible to prove any chemical exposure causes one specific individual to develop cancer.

As an epidemiologist, I can also tell you that for decades there was no evidence that smoking or Agent Orange caused cancer. It took many years to develop that evidence, and the same will be true for artificial turf.   

I have testified about the risks of these materials at the U.S. Consumer Product Safety Commission as well as state legislatures and city councils. I am sorry to say that I have repeatedly seen and heard scientists paid by the turf industry and other turf industry lobbyists say things that are absolutely false. They claim that these products are proven safe (not true) and that federal agencies have stated there are no health risks (also not true). 

What we do know is that the materials being used contain carcinogens, and when children are exposed to those carcinogens day after day, week after week, and year after year, they increase the chances of our children developing cancer, either in the next few years or later as adults. That should be adequate reason not to install them in your community. That’s why I have spoken out about the risks of artificial turf in my community and on a national level. The question must be asked: if they had all the facts, would Greenwich or any other community choose to spend millions of dollars on fields that are less safe than well-designed natural grass fields?

Synthetic rubber and plastic are made with different types of endocrine (hormone) disrupting chemicals as well as carcinogens.  There is very good evidence regarding these chemicals in tire crumb, based on studies done at Yale and by the California Office of Environmental Health Hazard Assessment (OEHHA). [1]

A 2015 report by Yale scientists detected 96 chemicals in samples from 5 different artificial turf companies, including unused bags of tire crumb. Unfortunately, the health risks of most of these chemicals had never been studied.  However, 20% of the chemicals that had been tested are classified as probable carcinogens and 40% are irritants that can cause asthma or other breathing problems, or can irritate skin or eyes. [2]

There are numerous studies on the impact of hormone-disrupting chemicals (also called endocrine disrupting chemicals or EDCs), and the evidence is clear that these chemicals found in rubber and plastic cause serious health problems.  Scientists at   the National Institute of Environmental Health Sciences have concluded that unlike most other chemicals, hormone-disrupting chemicals can be dangerous at very low levels, and the exposures can also be dangerous when they combine with other exposures in our environment. 

That is why the Consumer Product Safety Commission has banned numerous endocrine-disrupting chemicals from toys and products used by children. The products involved, such as pacifiers and teething toys, are banned even though they would result in very short-term exposures compared to artificial turf.

A report warning about possible harm to people who are exposed to rubber and other hormone disrupting chemicals at work explains that these chemicals “can mimic or block hormones and disrupt the body’s normal function, resulting in the potential for numerous health effects.  Similar to hormones, EDC can function at very low doses in a tissue-specific manner and may exert non-traditional dose–response because of the complicated dynamics of hormone receptor occupancy and saturation.”[3]

Studies are beginning to demonstrate the contribution of skin exposure to the development of respiratory sensitization and altered pulmonary function. Not only does skin exposure have the potential to contribute to total body burden of a chemical, but also the skin is a highly biologically active organ capable of chemical metabolism and the initiation of a cascade of immunological events, potentially leading to adverse outcomes in other organ systems.

Envirofill and Alternative Infills

Envirofill artificial turf fields is advertised as “cooler” and safer, but our research indicates that these fields are still at least 30-50 degrees hotter than natural grass.  Envirofill is composed of materials resembling plastic polymer pellets (similar in appearance to tic tacs) with silica inside.  Silica is classified as a hazardous material according to OSHA regulations, and the American Academy of Pediatrics specifically recommends avoiding it on playgrounds. The manufacturers and vendors of these products claim that the silica stays inside the plastic coating.  However, sunlight and the grinding force from playing on the field breaks down the plastic coating.   For that reason, even the product warranty admits that only 70% of the silica will remain encapsulated.  The other 30% can be very harmful as children are exposed to it in the air.  

In addition, the Envirofill pellets have been coated with an antibacterial called triclosan.  Triclosan is registered as a pesticide with the EPA and the FDA has banned triclosan from soaps because manufacturers were not able to prove that it is safe for long-term use.  Research shows a link to liver and inhalation toxicity and hormone disruption.  The manufacturer of Envirofill says that the company no longer uses triclosan, but they provide no scientific evidence that the antibacterial they are now using is any safer than triclosan.  Microscopic particles of this synthetic turf infill will be inhaled by children, and visible and invisible particles come off of the field, ending up in shoes, socks, pockets, and hair.

In response to the concerns of educated parents and government officials, other new materials are now being used instead of tire crumb and other very controversial materials.  However, all the materials being used (such as volcanic rock, corn husks, and Corkonut) have raised concerns and none are proven to be as safe or effective as well-designed grass fields.

Dangerously Hard Fields

I want to briefly mention safety issues pertaining to Gmax scores.  A Gmax score over 200 is considered extremely dangerous and is considered by industry to pose a death risk.  However, the synthetic turf industry and ASTM (American Society for Testing and Materials), suggest scores should be even lower — below 165 to ensure safety comparable to a grass field. 

The hardness of natural grass fields is substantially influenced by rain and other weather; if the field gets hard, rain or watering will make it safe again.  In contrast, once an artificial turf field has a Gmax score above 165, it needs to be replaced because while the scores can vary somewhat due to weather, the scores will inevitably get higher because the turf will get harder.  Gmax testing involves testing 10 different areas of a playing fields, and some officials average those 10 scores to determine safety.  However, experts explain that is not appropriate.  If a child (or adult) falls, it can be at the hardest part of the field, which is why that is the way safety is determined.

In addition to the health risks to school children and athletes, approximately three tons of infill materials migrate off of each synthetic turf field into the greater environment each year.  About 2-5 metric tons of infill must be replaced every year for each field, meaning that tons of the infill have migrated off the field into grass, water, and our homes.4 The fields also continuously shed microplastics as the plastic blades break down.5,6 These materials may contain additives such as PAHs, flame retardants, UV inhibitors, etc., which can be toxic to marine and aquatic life; and microplastics are known to migrate into the oceans, food chain, and drinking water and can absorb and concentrate other toxins from the environment.7,8,9

Synthetic surfaces also create heat islands.10,11 In contrast, organically managed natural grass saves energy by dissipating heat, cooling the air, and reducing energy to cool nearby buildings.  Natural grass and soil protect groundwater quality, biodegrade polluting chemicals and bacteria, reduce surface water runoff, and abate noise and reduce glare.1

Conclusions

There are currently no safety tests required prior to sale that prove that any artificial turf products are safe.  In many cases, the materials used are not made public, making independent research difficult to conduct. None of these products are proven to be as safe as natural grass in well-constructed fields. 

I have cited several relevant scientific articles on artificial turf in this letter, and I can attest to the fact there are numerous studies and growing evidence of the harm caused by these synthetic materials. I would be happy to provide additional information upon request (dz@center4research.org).

I am not paid to write this statement. I am one of the many parents and scientists who are very concerned about the impact of artificial fields on our children.  Your decision about artificial turf can save lives and improve the health of children in Greenwich.  And, because of Greenwich’s reputation as a well-educated and affluent community, the decisions made by you about artificial turf in Greenwich will serve as a model to other communities.

Officials in communities all over the country have been misled by artificial turf salespeople. They were erroneously told that these products are safe.  But on the contrary, there is clear scientific evidence that these materials are potentially harmful. The only question is how harmful and how much exposure is likely to be harmful?  We should not be willing to take such a risk. Our children deserve better.

Sincerely,

Diana Zuckerman, Ph.D.

President

Footnotes

1. State of California-Office of Environmental Health Hazard Assessment (OEHHA), Contractor’s Report to the Board. Evaluation of Health Effects of Recycled Waste Tires in Playground and Track Products. January 2007. http://www.calrecycle.ca.gov/publications/Documents/Tires%5C62206013.pdf 
2. Yale Study Reveals Carcinogens and Skin Irritants in Synthetic Turf. http://wtnh.com/2015/09/03/new-yale-study-reveals-carcinogens-and-skin-irritants-in-synthetic-turf/
3. Anderson SE and Meade BJ, Potential Health Effects Associated with Dermal Exposure to Occupational Chemicals, Environ Health Insights. 2014; 8(Suppl 1): pgs 51–62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270264/
4. York T. Greener grass awaits: Environmental & fiscal responsibility team up in synthetic turf. Recreation Management. February 2012. http://recmanagement.com/feature_print.php?fid=201202fe02.
5. Magnusson K, Eliasson K, Fråne A, et al. Swedish sources and pathways for microplastics to the marine environment, a review of existing data. Stockholm: IVL- Swedish Environmental Research Institute. 2016. https://www.naturvardsverket.se/upload/miljoarbete-i-samhallet/miljoarbete-i-sverige/regeringsuppdrag/utslapp-mikroplaster-havet/RU-mikroplaster-english-5-april-2017.pdf
6. Kole PJ, Löhr AJ, Van Belleghem FGAJ, Ragas AMJ. Wear and tear of tyres: A stealthy source of microplastics in the environment. Int J Environ Res Public Health. 2017 14(10). pii: E1265. https://www.ncbi.nlm.nih.gov/pubmed/29053641/
7. Kosuth M, Mason SA, Wattenberg EV. Anthropogenic contamination of tap water, beer, and sea salt. PLoS One. 2018. 13(4): e0194970. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895013/
8. Oehlmann J, Schulte-Oehlmann U, Kloas W et al.  A critical analysis of the biological impacts of plasticizers on wildlife. Phil Trans R Soc B. 2009. 364: 2047–2062. http://rstb.royalsocietypublishing.org/content/364/1526/2047
9. Thompson RC, Moore CJ, vom Saal FS, Swan SH. Plastics, the environment and human health: Current consensus and future trends. Philos Trans R Soc Lond B. 2009. 364: 2153–2166. 
10. Thoms AW, Brosnana JT, Zidekb JM, Sorochana JC. Models for predicting surface temperatures on synthetic turf playing surfaces. Procedia Engineering. 2014. 72: 895-900. http://www.sciencedirect.com/science/article/pii/S1877705814006699
11. Penn State’s Center for Sports Surface Research. Synthetic turf heat evaluation- progress report. 012. http://plantscience.psu.edu/research/centers/ssrc/documents/heat-progress-report.pdf
12. Stier JC, Steinke K, Ervin EH, Higginson FR, McMaugh PE. Turfgrass benefits and issues. Turfgrass: Biology, Use, and Management, Agronomy Monograph 56. American Society of Agronomy, Crop Science Society of America, Soil Science Society of America. 2013. 105 – 145. https://dl.sciencesocieties.org/publications/books/tocs/agronomymonogra/turfgrassbiolog

Stephanie Fox-Rawlings, PhD, National Center for Health Research: November 1, 2018

Thank you for the chance to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest. More about ibebet bet in nigeria

As we’ve heard today, depression is a serious health issue. However, FDA approval requires proof that new drugs are safe and effective. New drugs have to work to help patients.

I’ll focus on efficacy first. The evidence presented for buprenorphine/samidorphan (BUP/SAM) does not provide adequate evidence that it reduces depression more than placebo.

Two of the three trials designed to provide evidence of efficacy did not find any statistical benefit of the drug compared to placebo. The third trial, study 207, had a statistically significant reduction in depression on the MADRS for the 2mg/2mg dose. However, this trial also has major shortcomings. For example, it used the MADRS-6, which lacks important aspects of depression and therefore can’t prove efficacy.

Using the full MADRS, the only time the drug is more effective than placebo is for just a few weeks in the middle of a short trial. By the end of the trial, the placebo group was doing as well as the treatment group. This does not demonstrate a meaningful benefit for patients. And though statistically significant for that short time, treated patients improved less than 2 points more than placebo on a 60 point scale. This difference seems too small to be clinically meaningful for patients.

MADRS has clear standards for improvement. “Responders” are defined as those whose symptoms improve by at least 50%. Remission is defined by those scores are 10 or below on MADRS. Patients taking the drug were not more likely to be a responder or go into remission than patients taking placebo for any of the efficacy trials. This again raises questions about whether the benefit in study 207 is clinically meaningful compared to studies of other antidepressants. These trials may just be too short, but there needs to be confirmatory evidence that the statistically significant result is real.

Study 202 was designed as a proof of concept study and FDA points out that it can’t prove efficacy because it lacks the statistical controls to make sure that the difference did not occur by chance. Also, the relatively high dropout rate for patients in the drug arms could have a large effect on the results. We agree with the FDA reviewers that the lack of a dose response also raises red flags. If the drug is effective, the high dose (8mg/8mg) should at least show a statistical trend toward significance. It doesn’t.

As we all know, in studies of depression the placebo groups often do quite well. Placebo controls are essential because they help control for the natural ebb and flow of depression episodes. Instead, the sponsor tries to eliminate evidence of the placebo effect. Without the trial-long comparison of the placebo to drug arms, it is not possible to determine whether natural fluctuations in depression or the treatment are affecting the results.

There are concerns about safety.

The clinical trials included very few older patients. Older patients metabolize drugs more slowly and are more likely to have adverse reactions. They are also likely to be taking many other drugs that could interact with this drug.

Like all opioids, even ones with abuse-deterrent properties, this drug has the potential for misuse and abuse. This is a major concern because depressed patients are more likely to have substance abuse disorders and are at increased risk for opioid overdose.

In summary, the clinical trial data do not provide adequate evidence that BUP/SAM reduces the symptoms of depression. There are concerns about it potential for long-term harms to patients and others who might misuse or abuse it. BUP/SAM needs to provide strong evidence of efficacy before approval.

Although refractory depression is a serious condition, prescribing a treatment with unproven benefits and unknown risks is very dangerous. And, as you know, new drugs for depression tend to be more widely prescribed than the narrow indications that FDA approves. Approving this drug even for refractory depression could easily contribute greatly to our current opioid epidemic.

The joint Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted against approval (21 against and 2 for).

National Center for Health Research: November 15, 2018.

Good morning.  I’m Jack Mitchell, and while I’m with the National Center for Health Research, today I’m speaking on behalf of members of the Patient, Consumer and Public Health Coalition, an informal consortium of about two dozen public health and non-profit organizations which work together on policy and legislative issues.  I have no financial conflicts of interest.

We thank FDA for holding this meeting and for exploring these important patient-centric issues.  We appreciate Dr. Shuren and senior CDRH officials giving presentations on their latest efforts to enhance patient engagement and post-market surveillance and safety, which are primary areas of concern for our non-profit organizations.

As we’ve heard, social media, when utilized properly, can be a highly useful source of shared information for patients.  The independent USA Patient Network has reported to us that their members regularly use social media to communicate about drug and medical device safety and treatment issues; and to report device-related adverse events to FDA

However, concerns remain, especially when social media are used to collect data.  Patients have reported to us that industry-sponsored social media patient platforms can influence discussions in ways that are not always in patients’ interest.  For example, a recent news story in Stat News of the Boston Globe revealed how patients and non-patients alike can earn money as so-called “influencers”, to provide opinions or promotions on the Internet about medical devices and drugs.  In fact, there are a few companies which act as talent recruiters for such influencers, and facilitate their communications with device and drug companies.

These influencers can be paid for posting about a device or drug, or for bringing opinions of people like them to the companies which are developing these medical products.  Industry companies have paid fees and travel expenses for some of these influencers to sit in on sponsored patient engagement meetings. The companies also gain insights into the patients from these interactions.

Some regard this activity as a form of relatively inexpensive advertising for industry, and often there is not much, if any, transparency concerning exactly who the influencer might be representing or being paid by.  The Federal Trade Commission has cited influencers who fail to reveal that they are being paid for an endorsement of a device or drug. There are a lot of confusing ethical thickets to wade through with these kinds of social media influencing.

There’s certainly nothing wrong with the industry trying to gain insights into its potential patients and customers.  But members of our Coalition, and the USA Patient Network, represent independent, non-sponsored patient voices who wish to gain helpful information on their conditions from FDA and other legitimate medical sources, and that is why we are concerned about hidden commercial influences on social media.  The patient groups which we work with also would prefer a balanced approach to reporting: adverse events should be clearly reported in social media, not just positive experiences.

Along those lines, USA Patient Network members have told us that the very helpful MedWatcher app has recently not been functioning properly, a complaint you have also heard from another speaker today.  When the MedWatcher app was functioning properly, patients were able to report and edit their adverse events to FDA.

These same patients have used Facebook, Twitter, Instagram, and other social media to report problems with the birth control device Essure, vaginal mesh, hip implants, breast implants, and other medical device issues.  That type of interactive communication, which was not technologically possible a decade or so ago, is a critically important tool for patients who sometimes mistakenly feel they are the only person with their particular type of medical condition.  On social media they learn that there is a community of patients just like them who can share information, do research, and suggest qualified medical professionals to consult.

Social media can serve as an invaluable, interactive forum both for patients and the FDA, provided that some of the financial and ethical conflicts that can arise from their use does not interfere with patients’ ability to access accurate and unbiased medical information.

Thanks to the Committee for the opportunity to speak today.

Stephanie Fox-Rawlings, PhD, National Center for Health Research: November 1, 2018

Thank you for the chance to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

As we’ve heard today, depression is a serious health issue. However, FDA approval requires proof that new drugs are safe and effective. New drugs have to work to help patients.

I’ll focus on efficacy first. The evidence presented for buprenorphine/samidorphan (BUP/SAM) does not provide adequate evidence that it reduces depression more than placebo.

Two of the three trials designed to provide evidence of efficacy did not find any statistical benefit of the drug compared to placebo. The third trial, study 207, had a statistically significant reduction in depression on the MADRS for the 2mg/2mg dose. However, this trial also has major shortcomings. For example, it used the MADRS-6, which lacks important aspects of depression and therefore can’t prove efficacy.

Using the full MADRS, the only time the drug is more effective than placebo is for just a few weeks in the middle of a short trial. By the end of the trial, the placebo group was doing as well as the treatment group. This does not demonstrate a meaningful benefit for patients. And though statistically significant for that short time, treated patients improved less than 2 points more than placebo on a 60 point scale. This difference seems too small to be clinically meaningful for patients.

MADRS has clear standards for improvement. “Responders” are defined as those whose symptoms improve by at least 50%. Remission is defined by those scores are 10 or below on MADRS. Patients taking the drug were not more likely to be a responder or go into remission than patients taking placebo for any of the efficacy trials. This again raises questions about whether the benefit in study 207 is clinically meaningful compared to studies of other antidepressants. These trials may just be too short, but there needs to be confirmatory evidence that the statistically significant result is real.

Study 202 was designed as a proof of concept study and FDA points out that it can’t prove efficacy because it lacks the statistical controls to make sure that the difference did not occur by chance. Also, the relatively high dropout rate for patients in the drug arms could have a large effect on the results. We agree with the FDA reviewers that the lack of a dose response also raises red flags. If the drug is effective, the high dose (8mg/8mg) should at least show a statistical trend toward significance. It doesn’t.

As we all know, in studies of depression the placebo groups often do quite well. Placebo controls are essential because they help control for the natural ebb and flow of depression episodes. Instead, the sponsor tries to eliminate evidence of the placebo effect. Without the trial-long comparison of the placebo to drug arms, it is not possible to determine whether natural fluctuations in depression or the treatment are affecting the results.

There are concerns about safety.

The clinical trials included very few older patients. Older patients metabolize drugs more slowly and are more likely to have adverse reactions. They are also likely to be taking many other drugs that could interact with this drug.

Like all opioids, even ones with abuse-deterrent properties, this drug has the potential for misuse and abuse. This is a major concern because depressed patients are more likely to have substance abuse disorders and are at increased risk for opioid overdose.

In summary, the clinical trial data do not provide adequate evidence that BUP/SAM reduces the symptoms of depression. There are concerns about it potential for long-term harms to patients and others who might misuse or abuse it. BUP/SAM needs to provide strong evidence of efficacy before approval.

Although refractory depression is a serious condition, prescribing a treatment with unproven benefits and unknown risks is very dangerous. And, as you know, new drugs for depression tend to be more widely prescribed than the narrow indications that FDA approves. Approving this drug even for refractory depression could easily contribute greatly to our current opioid epidemic.

The joint Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted against approval (21 against and 2 for).

Varuna Srinivasan MBBS MPH, National Center for Health Research: October 12, 2018

Thank you for the opportunity to speak today. My name is Dr. Varuna Srinivasan. I am a physician with a Master of Public Health from Johns Hopkins University. I am a Senior Fellow at the National Center for Health Research, which analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

We have strong concerns about the safety of the drug in question today: Sufentanil.

First, we are concerned that the level of pain relief provided by sufentanil is not clinically meaningful. Patients taking the drug had statistically lower levels of pain than patients taking placebo based on their SPID score, but this difference was so small I would not consider it helpful to my patients. Just as important, there was no difference in how long it took for patients to experience “meaningful pain relief” between placebo and this drug that is supposedly five times more potent than fentanyl! If it was really more effective than placebo, surely it would work more quickly to relieve pain.

The weak results are even more problematic because there was only one pivotal phase 3 clinical trial. We have an opioid epidemic and it is crucial that the FDA not approve opioids that are not proven to work.

There is limited diversity in the clinical trials. Most of the study patients were white and younger. We would assume that a wide variety of patients visit the ER or undergo surgery, but that diversity of demographic background is not reflected in the study population. In fact, the FDA memorandum provides is no information on any racial and ethnic subgroups. They combined trials where they gave 15mcg and 30 mcg to different patients. These have different profiles but they controlled by the study sites and FDA finds it to be relevant. While there are no older patients in the trial with 30mcg, they are extrapolating the safety data as a whole and the mean age for the trial with 15 mcg is 58 so keeping this in mind, how do I phrase this sentence – The sponsor also failed to look at older patients, even though we know that pain tends to increase with age..

In summary, this drug is not proven to have a meaningful impact on reducing pain in post-operative settings. I respectfully urge you to let the FDA know that the agency should require better evidence of the efficacy of this drug. The sponsor should submit more conclusive data to this advisory committee before it can consider recommending approval for sufentanil.

On October 12th, the advisory committee voted 10-3 in favor of approving Sufentanil

Stephanie Fox-Rawlings, National Center for Health Research: August 3, 2018

Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

Our Center worked with Congress to create the REMS [risk evaluation and mitigation strategy] program in legislation that became law quite a few years ago.  The goal always was to enable FDA to approve effective drugs even if they had worrisome risks. The REMS were intended to lower those risks as much as possible, so that patients taking the drug were most likely to be helped and least likely to be harmed.

A major shortcoming of these risk mitigation strategies has always been ensuring that they are effective in lowering risks.  It is difficult to evaluate the effects of the REMS on prescribers, pharmacists, patients, and others who accidentally or intentionally misuse the drugs.

The data before you today that evaluated these REMS are limited.  However, we commend the efforts of TRIG [TIRF REMS Industry Group] and the FDA to assess these REMS and to improve the data as well as the effectiveness of these REMS. We strongly urge that TRIG implements the FDA recommendations in a timely and complete manner to more fully understand to what extent the REMS are or are not working, so that they can increase the benefit to risk ratio of their products.

The data are especially limited regarding the proportion of prescriptions for cancer pain or other indications.  That is a big problem since this product is only approved for cancer pain.

And, also like the FDA reviewers, we are very concerned about the increased rate of adverse events after implementing REMS.  Even though the reports are voluntary and therefore could be biased, the increase after REMS is very disturbing. The quality of the REMS data are also low because only a subset of potential events are evaluated.  This makes the data very difficult to interpret. However, other sources of data also suggest that there are concerning numbers of therapeutic errors, misuse and exposures with severe consequences.

Congress supported REMS because they were intended to reduce the risk of serious harms, while continuing to make the product available to those who need it. The data indicate that these REMS need improvements. For example:

• 42% of new users were not opioid-tolerant. That is not the indication, so that means at least 42% are prescribed off label.  This increases the risk for central nervous system and breathing problems.
• Relatively high proportion of survey respondents did not know the correct indication or that TIRFs need to be stopped if around-the-clock opioid medication is stopped.  They learned this in the training, but could not remember it when surveyed later.

Changes to the REMS should be designed to make them more effective at protecting patients. Changes in REMS should not be aimed primarily at increasing the number of prescriptions.  An increase in prescriptions without ensuring appropriate prescribing, dispensing, use, and disposal increases the risk that more patients will be harmed, and that the drugs will be used accidentally or misused by individuals who were not prescribed the drug.

Bottom line: TIRFs [transmucosal immediate-release fentanyl] provide important options for cancer patients dealing with pain. However, we all know that they carry very serious risks and that’s why we need REMS that protect patients’ these risks.  These REMS are not working as well as the should to protect patients and need to be improved.

National Center for Health Research: March 19, 2018

Public Comment of National Center for Health Research, National Women’s Health Network, and Our Bodies Ourselves for
USPSTF Draft Recommendation Statement: Weight Loss to Prevent Obesity-Related Morbidity and Mortality in Adults: Behavioral Interventions

Thank you for the opportunity to share our views regarding the U.S. Preventive Services Task Force (USPSTF) draft recommendation statement concerning behavioral interventions for weight loss in adults.

The National Center for Health Research, National Women’s Health Network, and Our Bodies Ourselves are all nonprofit organizations that strongly support the role of USPSTF in reviewing and assessing scientific evidence about the harms and benefits of specific preventive care services to provide science-based recommendations for the public. In 2012, USPSTF made the same recommendation for behavior-based weight loss interventions with a “B” grade.^[1] Since then, researchers have published additional studies on this topic, and changes in science or medical practice could alter the benefit risk ratio. Thus, we support the USPSTF’s current efforts to re-evaluate their 2012 based on updated evidence.

Based on the draft evidence review, we concur with the Task Force that there is sufficient evidence that behavior-based weight-loss interventions for adults with obesity (BMI ≥ 30) can help patients reduce weight and decrease incidence of type 2 diabetes and elevated plasma glucose levels.^[2]

Prevention of obesity-related morbidity and mortality is an important public health issue, and providers need the most current information to help their patients. More than 35% of men and 40% of women living in the United States are obese.³ Obesity is associated with increased risk of numerous health issues, including: heart disease, type 2 diabetes, cancer, stroke, renal disease, dementia, sleep apnea, osteoarthritis, and premature death.

Primary care screenings identify many patients with obesity who could benefit from behavioral weight loss interventions. As discussed in the review prepared for USPSTF, research indicates that intensive behavior-based weight loss and maintenance interventions can be effective in helping individuals lose weight and prevent weight regain.^[3] Although weight reduction was moderate, interventions were associated with meaningful health improvements, such as reduced incidence of type 2 diabetes. Importantly, the review did not identify any long-term or serious harms, so that even moderate benefits outweigh the risks.

Given the differences in BMI cutoffs and disparities between racial/ethnic subgroups and older adults, we strongly agree with the USPSTF that future research on important subpopulations should be a high priority.^[2] This information could provide insight into how different populations will benefit from behavior-based weight loss interventions.

In conclusion, we support the USPSTF draft recommendation for behavior-based interventions for weight loss to prevent obesity-related health problems and death. We further support USPSTF’s efforts to improve the health of all Americans by making evidence-based recommendations about clinical preventive services. As more information becomes available, we encourage the re-evaluation and potential development of additional recommendation to improve the health of individuals with weight-related health concerns.

If you have questions about these comments please contact NCHR through Stephanie Fox-Rawlings at sfr@center4research.org.

Respectfully,

National Center for Health Research
National Women’s Health Network
Our Bodies Ourselves

References:

1. Moyer VA, U.S. Preventive Services Task Force. Screening for and Management of Obesity in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2012;157:373–378. doi: 10.7326/0003-4819-157-5-201209040-00475. http://annals.org/aim/fullarticle/1355696/screening-management-obesity-adults-u-s-preventive-services-task-force
2. Draft Recommendation Statement: Weight Loss to Prevent Obesity-Related Morbidity and Mortality in Adults: Behavioral Interventions. U.S. Preventive Services Task Force. February 2018. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/obesity-in-adults-interventions1
3. Draft Evidence Review: Weight Loss to Prevent Obesity-Related Morbidity and Mortality in Adults: Behavioral Interventions. U.S. Preventive Services Task Force. February 2018. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-evidence-review/obesity-in-adults-interventions1