Category Archives: Testimony & Briefings

NCHR Comment on FDA’s 510(k) Third Party Review Program Draft Guidance

National Center for Health Research: December 13, 2018


Comment of the National Center for Health Research Regarding the
510(k) Third Party Review Program:
Draft Guidance for Industry, FDA Staff, and Third Party Review Organizations.
OMB Control Number 0910-0375

The National Center for Health Research (NCHR) is a non-profit organization which conducts original research to better inform policy makers, health professionals, and patients.   NCHR accepts no funding from any entity which manufactures or distributes medical products.

We appreciate the opportunity to comment on this draft guidance.  We note that this draft guidance applies to low-to-medium risk medical devices, which concerns us because many Class II devices are permanent implants that have the potential to cause permanent harm to patients.  In fact, our research indicates that even Class I devices have been subjected to high-risk recalls by the FDA due to the potential for causing death or permanent harm.1 2 3

We have several serious concerns about the draft guidance.  First, Original Equipment Manufacturers (OEM) are accountable for the efficacy and safety of their medical devices.  FDA standards require that devices manufactured by OEM’s comply with relevant regulatory standards.  OEMs are required to track, monitor, and report product issues to FDA.  Overseeing the OEMs and their reporting are FDA’s responsibility to ensure patient safety.

Second, in the past FDA has had the opportunity to review the work of any third party reviewer, and reject it if deemed inadequate or shoddy.  In fact, the agency has often found problems with the third party reviews.  The proposed guidance would sharply reduce the agency’s oversight of third party reviews, which will clearly compromise safety.  Even if certified as qualified, third party review companies have an inherent conflict of interest: If their standards are too high, no device company will hire them and they will go out of business.  The system is similar to the EU regulation of medical devices, which has resulted in very harmful decisions, such as the clearance of the PIP breast implants that were found to use non-medical grade silicone.4  In addition, investigative reporters recently obtained CE clearance for a “surgical” mesh that was made out of a plastic mesh bag used for oranges.

Transparency is also a crucial factor.  Currently, third party review companies are not required to clearly label an OEM device indicating that a critical repair has been completed by someone other than the OEM.  Once that repair is made, the device is no longer the same device that was approved or cleared by FDA.  It is important that this chain of accountability is not broken or interrupted.

While we understand the desire of FDA officials to reduce medical device review times and reduce the burden on FDA staff and industry, the 510(k) program already is a quick way to get devices to market and the device industry has clearly benefitted from it.  The 510(k) pathway has been widely criticized by the Institute of Medicine, physicians, patients, and the media for its lack of clinical trials and lack of scientific evidence.5  Despite its weaknesses, the 510(k) pathway is considered superior to the EU regulatory system, however.  By reducing the “burden” for FDA staff and industry, the proposed guidance increases the burden on patients and doctors to figure out which devices are safe and which are not.  This would clearly put U.S. patients at greater risk.

FDA has not demonstrated that its proposed changes to the third party review pathway of Class I and Class II devices will benefit patients.  By definition, 510(k) devices only rarely are substantially superior to recent predicates.  Speeding up the process of clearance is not demonstrated to benefit patients.  Moreover, with registries, NEST, and other planned efforts to improve post-market surveillance still far from effectively implemented, any loosening of 510(k) regulations is very premature.

Finally, we note that Commissioner Gottlieb responded to recent media criticism of CDRH regulations by promising improvements to the 510(k) pathway to ensure patient safety.  The third party review program clearly moves in the opposite direction, reducing patient safety, rather than protecting patients from potentially harmful devices.   We strongly oppose it for that reason.

 

References

  1. Zuckerman, D.M., Brown, P, and Nissen, S.E.  (2011) Medical Device Recalls and the FDA Approval Process, Archives of Internal Medicine, 117, 1006-11.
  2. Zuckerman D.M., Brown P., Nissen S.E. (2011). In Reply, Archives of Internal Medicine, 171(11), 1045.
  3. Zuckerman D.M., Brown P., Nissen S.E. (2011). In Reply, Archives of Internal Medicine, 171(21), 1963.
  4. Zuckerman, D., Booker, N, and Nagda, S. (2012) Public Health Implications of Difference in US and European Union Regulatory Policies for Breast Implants, Reproductive Health Matters, 20 (40),102-111.
  5. Zuckerman D.M., Brown P. & Das A. (2014) Lack of Publicly Available Scientific Evidence on the Safety and Effectiveness of Implanted Medical Devices,  JAMA Internal Medicine, 174(11): 1781-1787.

 

NCHR Testimony on the Opioid Buprenorphine/Samidorphan for Depression

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).

NCHR Testimony on the Opioid Buprenorphine/Samidorphan for Depression

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).

NCHR Testimony on the Opioid Sufentanil

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

 

NCHR Testimony of TIRF REMS

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.

 

NCHR, NWHN, and OBOS Comments to USPSTF on Behavioral Weight Loss Interventions

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

NCHR Comments to FDA on Nicotine Replacement Therapy (NRT) Product Uses and Labeling Changes

National Center for Health Research, February 15, 2018

February 15, 2018

Dockets Management Staff
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

National Center for Health Research’s Public Comment on NRT

[Docket no.FDA-2017-N-6529]

Thank you for the opportunity to provide comments on FDA’s evaluation of nicotine replacement therapy (NRT) products, including product labeling. The National Center for Health Research (NCHR) is a nonprofit research center focused on research, policies, and programs that affect public health. Our Center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from companies that make medical products, so we have no conflicts of interest.

According to the National Health Interview Survey (NHIS), our nation’s effort to reduce smoking has reached a plateau of around 15 percent of American adults1.  Based on early data from the the landmark 1994 Lancet meta-analysis, nicotine replacement (NRT) products are about 70% effective at achieving abstinence up to about 12 months2. However, it remains unclear whether individual achievement of abstinence is sustainable over time and whether long-term NRT use is more or less beneficial on an individual or population health level. We commend the FDA for addressing their role in developing strategies to evaluate NRT products and labeling. We agree that urgent action is necessary and the FDA should consider science-based approaches to reduce further harm from combustible tobacco products.

In consideration of the FDA’s request for public comment, we will focus our remarks on two specific questions–question 3 and question 6.

Questions 3: What data would be required to demonstrate health benefits of reduction in consumption of combustible tobacco products?   

According the U.S. Surgeon General3, we know that smoking contributes significantly to the development of cancer, including cancer of the mouth and throat, esophagus, trachea/bronchus/lung, stomach, liver, pancreas, kidney, cervix, bladder, and colon and rectum. Smoking also increases cancer mortality risk and other cause-specific mortality risk in patients with a history of cancer. We also know that smoking is linked to a number of serious chronic diseases including heart disease, stroke, chronic obstructive lung disease and asthma, diabetes, rheumatoid arthritis, blindness, reproductive defects, ectopic pregnancy, and immune dysfunction. Given the magnitude of harms, there is no doubt that reducing the use of combustible tobacco products is beneficial for individual and population health.

Retrospective analysis of the data indicates that reduction in smoking from 1964 to 2012 averted about 8 million premature smoking-related deaths from all causes4.  Modeling analysis of the short term impacts of smoking with respect to cardiovascular events demonstrate that a one-time 1% decrease in smoking prevalence prevents about 1000 heart attacks and about 500 strokes per year5. Since heart attacks are the leading cause of death and strokes cause substantial disability, these reductions are significant. Short-term impact, such as those seen in the cardiovascular modeling study, can be studied prospectively in identified patient populations. For example, smoking cessation is built into the algorithm for perioperative cardiovascular risk reduction, which may represent an ideal population to follow prospectively in order to gather meaningful data on cardiovascular morbidity and mortality.

However, assessing long-term risk reduction may prove more difficult.  For example, there is a substantial lag in the cumulative effect of tobacco exposure and development of cancers. It will likely take decades to see the full health benefits of tobacco reduction and/or cessation. Therefore, prospective studies are limited in their feasibility for answering the question at hand.

Questions 6: …FDA has recommended the labeling on OTC NRT products be modified to include the following: “If you feel you need to use [the NRT product] for a longer period to keep from smoking, talk to your health care provider.” What is the impact of longer term NRT treatment? What is the impact on likelihood of cessation or relapse prevention? What data would support an affirmative recommendation to use approved OTC NRT products for durations that exceed those currently included…or would support a chronic or maintenance drug treatment indication for such products?

Early studies of NRT products estimate that they are about 70% effective at achieving abstinence up to about 12 months. However, it remains unclear whether maintenance use of NRT products provides added benefit, or whether it increases or decreases potential harm. A 2015 study in JAMA6, comparing standard NRT therapy (8 weeks), extended therapy (24 weeks), and maintenance therapy (52 weeks), concluded that maintenance NRT use did not provide additional benefit. While NRT therapy was shown to delay time to relapse, other research indicates that continued use of NRT products after relapse did not predict a return to abstinence7. Additional data from randomized trials are needed to establish effectiveness and safety of long-term NRT use.

Moreover, long-term exposure to nicotine in NRT products may pose serious harms. A 2017 systematic review found that most studies have assessed relatively short-term exposure to NRT (about 12 weeks or fewer)8. However, the systematic review identified a UK epidemiological study which estimated a small, but significant absolute risk of 3 cases of respiratory abnormalities in 1000 live births8,9.  Such a risk must be considered for labeling regarding use by women who are pregnant or could become pregnant. In addition, a historical cohort from the UK10 found that nicotine exposure from NRT was significantly associated with higher risk of heart disease or stroke and decreased survival over a 52-week follow-up period.

Given the insufficient evidence supporting long-term or chronic use and lack of evidence ensuring safe long-term use of NRT products, we strongly oppose the proposed label modification. In addition, healthcare providers have limited experience in the use of NRT. National data indicate that health care providers assess smoking about two-thirds of the time, but recommend drug therapy less than 2% of the time11. Therefore, more data are needed on providers’ knowledge and perceptions of NRT products to determine why they so rarely recommend them and how guidance from healthcare professionals regarding NRT could be improved. In order for healthcare providers to have an educated and informed discussion with patients about long-term use of NRT, more evidence is needed to determine whether the benefits of long-term NRT outweigh potential harms.    

Thank you for the opportunity to share our perspective.

Footnotes:

  1. Jamal A, Phillips E, Gentzke AS, et al. Current Cigarette Smoking Among Adults — United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:53–59. DOI: http://dx.doi.org/10.15585/mmwr.mm6702a1
  2.    Silagy C. et al. Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. The Lancet. 1994; 343:139-142.
  3.    U.S. Surgeon General. The Health Consequences of Smoking—50 Years of Progress. 2014. Available online: www.surgeongeneral.gov/library/reports.
  4.  Honey K. Advances in Tobacco Control. CANCER RESEARCH Catalyst: The Official Blog of the American Association for Cancer Research. November 2017. Available online: http://blog.aacr.org/advances-in-tobacco-control/
  5. James M. Lightwood and Stanton A. Glantz. Short-term Economic and Health Benefits of Smoking Cessation. Circulation. 1997;96:1089-1096, originally published August 19, 1997 https://doi.org/10.1161/01.CIR.96.4.1089
  6. Schnoll RA, Goelz PM, Veluz-Wilkins A, Blazekovic S, Powers L, Leone FT, Gariti P, Wileyto EP, Hitsman B. Long-term Nicotine Replacement Therapy:A Randomized Clinical Trial. JAMA Intern Med. 2015;175(4):504–511. doi:10.1001/jamainternmed.2014.8313
  7.    Hughes JR. et al. Effectiveness of continuing nicotine replacement after a lapse: A randomized trial. Addictive Behaviors. 2018;76: 68-81
  8. Lee, P.N. & Fariss, M.W. A systematic review of possible serious adverse health effects of nicotine replacement therapy. Arch Toxicol. 2017;91: 1565. https://doi.org/10.1007/s00204-016-1856-y
  9. Dhalwani NN. et al. Nicotine replacement therapy in pregnancy and major congenital anomalies in offspring. Pediatrics. 2015;135(5):859-67. doi: 10.1542/peds.2014-2560.
  10.    Dollerup J, Vestbo J, Murray-Thomas T, et al. Cardiovascular risks in smokers treated with nicotine replacement therapy: a historical cohort study. Clinical Epidemiology. 2017;9:231-243. doi:10.2147/CLEP.S127775.
  11.    Thorndike AN. et al. The Treatment of Smoking by US Physicians During Ambulatory Visits: 1994–2003. American Journal of Public Health (AJPH). Published Online: October 10, 2011. Available online: http://ajph.aphapublications.org/doi/abs/10.2105/AJPH.2006.092577

NCHR Comments on the USPSTF’s Evidence Review and Draft Recommendation Statement for Behavioral Counseling for Skin Cancer Prevention

National Center for Health Research: November 6, 2017

Thank you for the opportunity to express our views about the USPSTF’s evidence review and draft recommendation statement on behavioral counseling interventions for skin cancer prevention. The National Center for Health Research is a nonprofit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work.

Skin cancer prevention is a very important public health issue, and the public needs better information. The USPSTF previously cited evidence linking UV radiation exposure to an increased risk for melanoma later in life for children, and to a lesser extent, adults. Encouraging healthy sun-related behaviors that prevent UV exposure, and ultimately skin cancer, would save lives.

We support the efforts of the U.S. Preventive Services Task Force (USPSTF) to re-evaluate its recommendations in light of new research regarding behavioral counseling interventions to prevent skin cancer. We have a few comments regarding the draft recommendations:

#1: Based on new studies of children younger than 10 years old, we agree that there is sufficient evidence for USPSTF to expand their “B” grade recommendation for fair-skinned individuals from 10-24 years to 6 months-24 years.

#2: We agree with a “C” grade recommendation for fair-skinned adults older than 24 instead of an “I” grade. This means that discussion about behavioral counseling will be left to doctors and patients to decide based on doctors’ professional judgment and patients’ preferences. Some studies indicated that adults benefited from behavioral counseling interventions, particularly for interventions that were longer and more involved (e.g. sun protection-focused text messages over 12 months vs. single behavioral counseling session).

#3: We concur with maintaining an “I” grade for skin self-examination as the review team did not find any eligible studies to evaluate.

#4: Available data present challenges to making recommendations. For example, studies were not sufficiently long-term to study the incidence of skin cancer outcomes. Two adult studies followed patients for 24 months, but most studies only followed patients for 3-13 months. We agree that, ideally, additional studies are needed to assess skin cancer outcomes over a much longer period of time. We also recognize that it is not feasible to study the impact of these interventions long-term and agree with the USPSTF’s focus on reviewing behavioral counseling interventions aimed at promoting sun-protective behaviors that prevent individuals’ exposure to UV radiation in the short-term.

#5: Future reviews and recommendations should expand the recommendations to include people who do not have fair skin and light-colored hair and eyes. Although white people have the highest risk of melanoma and were overwhelmingly represented in this review, researchers noted that it is unknown whether these findings also apply to people of color, who die at higher rates from skin cancer. In addition, it would be beneficial to know if the benefits and risks were similar between men and women and for those who have family members who developed skin cancer.

#6: Studies are needed to determine which, if any, primary care-related interventions are effective for which demographic subgroups. Researchers concluded that successful behavioral counseling interventions were typically multi-component, including varying combinations of intervention components such as in-person counseling, print media, and sun protection aids like sunscreen.

In conclusion, we support USPSTF’s draft recommendations for behavioral counseling interventions to prevent skin cancer as well as their broader 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 provision of additional recommendations about more specific behavioral interventions to prevent skin cancer for individuals in various subgroups.

For questions or more information, please contact Megan Polanin, PhD, at mp@center4research.org.

NCHR Letter to the DC City Council on Artificial Turf

National Center for Health Research: October 26, 2017

Dear Council Members,

I am writing to respond to the request for additional information from Councilwoman Cheh as follow-up to my statement and the written materials I provided at the October 13 roundtable on artificial turf.

As the president of the National Center for Health Research, I expressed my strong concerns about the safety of the synthetic turf that the city has used and is continuing to use.  As a scientist who has worked on health policy issues for more than 30 years, I don’t shock easily.  However, the fact that school athletic fields and playgrounds are exposing D.C. children on a daily basis to chemicals and materials that are known to increase obesity; contribute to early puberty; cause attention problems such as ADD; harbor deadly bacteria; and exacerbate asthma is very disturbing.  Surely these are exactly the types of health problems that the D.C. government should be doing its best to reduce, not increase.

Federal agencies were investigating the safety of these products during the Obama Administration and were close to completion when the Trump Administration took over the two federal agencies involved, the Environmental Protection Agency and the Consumer Product Safety Commission.  Despite claims to the contrary at the October roundtable, neither agency has concluded that artificial turf is safe.  However, it is clear that we can’t depend on the Trump Administration to scrutinize the science regarding these products in a way that will be credible, and that means more work for the rest of us who care about children’s safety.

Envirofill and Other Hot Artificial Turf

As noted at the roundtable, all types of turf have risks and benefits, including natural grass.  However, some materials are well known to have substantial risks.  For example, DCPS is installed synthetic turf with Envirofill at Janney Elementary.  Although it is advertised as “cooler” and safer than older types of artificial turf, on a recent 64 degree afternoon, the temperature at the new Janney Envirofill field was 136 degrees, compared to 89 degrees on the grass.  And 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 is contained 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; here’s a screen grab from a November 2016 Patriots vs. Seahawks game, which shows how the silica sand infill is kicked up when players dive on a synthetic surface with silica sand infill.

In addition, the Envirofill pellets are coated with an antibacterial called Microban, which is a trade name for triclosan.  Triclosan is registered as a pesticide with the EPA and last year the FDA banned triclosan from soaps because manufacturers were not able to prove that it is safe for long-term use, since research shows a link to liver and inhalation toxicity and hormone disruption.  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.

I recently gave a guest lecture at a local college and when I asked if anyone had experience with artificial turf, two young women had stories to share.  They described playing on an artificial turf field on a sunny day, where they could actually see the heat waves rising off the field that had a strong chemical odor.

Councilwoman Cheh asked me to provide scientific evidence to back up my statements.  In addition to the links provided above regarding triclosan and silica, I want to describe the data regarding carcinogens and hormone disrupting chemicals that can cause obesity, early puberty, and attention deficits.

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 that there is “no evidence that children are harmed” or “no evidence that the fields cause cancer.”  That is often misunderstood as meaning that the products are safe or are proven to not cause harm. Neither is true.

It took decades to prove that smoking can cause cancer, a fact that everyone now agrees is true.  As each type of artificial turf is replaced by a new type of artificial turf, it will be equally difficult to prove that these different types of fields cause specific children to develop cancer, obesity, early puberty, or ADD.  For that reason, we need to focus on what is known about the materials the fields are made of and what the implications are for children’s health.

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).  The latter conducted three laboratory studies to investigate the potential health risks to children from playground surfaces made from recycled tires. One study evaluated the level of chemicals released and the other two studies looked at the risk of injury from falls.

The OEHHA studies showed that the children would be exposed to five chemicals, including four PAHs, one of which, chrysene,” was high enough to possibly increase the chances of a child developing cancer.[1]

Out of the 32 playgrounds studied, only 10 met that state’s standard for “head impact safety” to reduce brain injury and other serious harm in children who fall while playing. All five surfaces made of wood chips met the safety standard.[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]

Less is known about the materials that are used in PIP and other rubber products; some are recycled tire materials and some are “virgin rubber” but all are made from synthetic rubber, which is a petroleum based product.  This week I visited a playground at Chevy Chase Recreation Center.  Although the playground seems to be a relatively new solid rubber surface, there are several areas that are already broken, with dark crumb rubber and other very small colorful particles clearly showing. Some of the particles look like they could be from plants, but you can’t crush or tear them as you can with plant material.  Children can pick up those particles intentionally or unintentionally; little children are likely to eat it or get it in their mouths, shoes, or clothes, and children of any age will certainly get it on their skin.  As noted above, the evidence is clear that these rubber particles are dangerous.

Rather than provide a lengthy description of all the studies showing the impact of hormone-disrupting chemicals (also called endocrine disrupting chemicals or EDCs), I will assume you know that the evidence is clear about those chemicals being in rubber and plastic and causing health problems.  Scientists at the NIH environmental institute, which is called the National Institute of Environmental Health Sciences, have concluded that unlike most other chemicals,  hormone-disrupting chemicals can be dangerous at very low levels as well as at higher levels, and the exposures can be even more 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 ages 3 and younger.  Like playgrounds and artificial turf fields, these products were sold in the U.S. for many years prior to the ban, because the companies were not required to prove that the products were safe.

Instead of focusing on those studies, here is just one recent scientific study on the health risks of synthetic rubber.  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]

That article lists numerous EDCs found in rubber products and warns that “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.”

Dangers of Hard Fields and Playgrounds

I want to briefly mention safety issues pertaining to Gmax scores.  As you know, a Gmax score over 200 is considered extremely dangerous and is considered by industry to pose a death risk.  The synthetic turf industry and ASTM suggest that scores should be below 165 to ensure safety comparable to a grass field.  At the roundtable it was mentioned that grass fields can also get extremely hard, which is true.  However, 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.  Moreover, averaging Gmax scores for a field is an inappropriate way to determine safety.  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.

Conclusions

I have appreciated the opportunity to meet with several Councilmembers’ staff and I commend the Council for banning crumb rubber during FY 2018.  Unfortunately, however, Envirofill, “poured in place” rubber (PIP), EPDM, and all the other synthetic materials currently on the market all have petroleum based materials and therefore share some of the same health risks.  While the companies that sell these products claim they are safe and meet federal safety standards, there are currently no federal safety tests required to prove that these products are safe.  In many cases, the materials used are not public, making independent research difficult to conduct. None of these products are proven to be as safe as natural grass in well-constructed fields such as the Maryland Soccerplex. Although a well-respected grass expert offered a free consultation on how to install well-engineered grass designed to withstand rain and play, DGS did not respond to his offer.

I have also attached an annotated bibliography of numerous relevant scientific articles on artificial turf that will help you see that there is growing evidence of the harm of these synthetic materials on fields and playgrounds.  This is just a sample of studies, and there are many more, so let me know if you’d like additional information.

I am one of many parents and scientists in D.C. that are very concerned about the impact of these artificial fields and playgrounds on our children.  It is clear that city officials have assumed these products are safe because the salespeople told them they were safe.  Unfortunately, there is clear scientific evidence that these materials are potentially harmful, and the only question is how harmful are they and how much exposure is likely to be harmful?  Our children deserve better.

Sincerely,

Diana Zuckerman, PhD

President

  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/

NCHR Comments on the USPSTF’s Draft Recommendation Statement, Evidence Review, and Modeling Report on Cervical Cancer Screening

National Center for Health Research: October 9, 2017

Thank you for the opportunity to express our views on the U.S. Preventive Services Task Force (USPSTF) draft recommendation statement, evidence review, and modeling report for cervical cancer screening. The National Center for Health Research is a nonprofit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work.

We agree that this is the right time for the U.S. Preventive Services Task Force to re-evaluate its cervical cancer screening recommendations, due to new research studies and decision modeling analysis. In 2012, the USPSTF recommended starting screening at age 21 and stopping at age 65. Women could get a Pap every 3 years, or starting at age 30, women could get both a Pap and HPV test (co-test) every 5 years. Based on the USPSTF’s review, we agree with maintaining most of the 2012 recommendations, but have significant concerns about changes USPSTF has proposed.

We are very concerned about the proposed grade “A” recommendation to exclusively screen women with the HPV test every 5 years starting at age 30. As the Task Force recognized, clinical trial evidence to support primary HPV screening as a preferred screening strategy is inadequate. There is also a lack of well-designed and implemented clinical trials comparing co-testing and primary HPV screening. The pivotal ATHENA trial, the U.S. prospective study supporting the efficacy of primary HPV screening, had significant shortcomings and does not provide clear and substantial evidence that primary HPV testing reduces cancer incidence or mortality. The Task Force appropriately classified this study as “poor quality” and excluded it from the draft evidence review. However, some medical societies are still quoting it.

Due to lack of available evidence, the Task Force relied heavily on mathematical models to arrive at the grade “A” recommendation. While mathematical models that incorporate real world data help to support available evidence, they are hypothetical, and conclusions must still be weighed against evidence from clinical trials and observational studies. This definitely is well below the standard of an “A” recommendation; in fact, we believe screening based exclusively on HPV tests should not be recommended.

Based on the USPSTF’s decision modeling analysis, primary HPV testing potentially confers a slightly higher mortality benefit (approximately 10 life-years per 1000 women) compared to cytology alone, but it requires significantly more colposcopies to be done for each possible cancer averted (766 vs. 39). Moreover, the models demonstrate that primary HPV testing and co-testing prevent approximately the same amount of deaths, but co-testing would require more total tests (19,806 vs. 12,151). However, models are necessarily based on assumptions that are not necessarily accurate.  The conclusions from these models are not based on research conducted on actual patients.

In addition, while the USPSTF depended on the draft modeling report to conclude that primary HPV screening may provide more benefits than harms, other recent modeling analyses by Felix et al., concluded that screening by co-testing may be superior to screening by HPV test alone. Therefore, the totality of the evidence does not support eliminating co-testing as an acceptable strategy.

We therefore conclude that the Task Force’s grade “A” recommendation assigned to primary HPV screening is inappropriate, because it is primarily based on modeling analysis and not clinical trials or real-world data. This grade “A” would certainly mislead physicians and women to believe that there is incontrovertible evidence to support an HPV testing-only screening strategy rather than co-testing or Pap smear only testing. Since the recommendation is that women can select a Pap smear every 3 years or the HPV test every 5 years, many women will likely choose the less frequent screening option, not realizing that they will be at increased risk of needing additional, more invasive testing with the HPV test only screening.

The seven cited randomized clinical trials are difficult to interpret. First, the studies cannot be assumed to be representative of women in the U.S. since they were conducted primarily in European countries with national screening programs and more standardized triage strategies. Second, the studies were extremely heterogeneous in terms of test technology, screening intervals, and follow-up protocols. Third, the study results were mixed. For instance, the NTCC phase II trial found that hrHPV test alone had a higher CIN3 detection rate only in the first screening round, and actually had a lower rate of detection in the second round. The Task Force’s review contends that the “cumulative rate was still double.” However, it is possible  that detection rates of CIN3 declined in the second screening round because the lesions regressed due to HPV clearance.  Thus, perhaps the colposcopies triggered by HPV positivity in the first screening round were unnecessary. Bottom line: these data are inconclusive. Last, the studies included surrogate endpoints for cancer incidence and mortality, such as CIN2 or CIN3 detection. These endpoints are likely not the most meaningful outcomes for women, since CIN2/3 lesions do not always progress to cervical cancer and sometimes regress instead.  There are several other determinants of disease trajectory that may differ among women in different countries.

While we understand why the USPSTF advises women to “discuss with their provider which testing strategy is best for them” it is obvious that this advice will not necessarily provide excellent guidance for the average patient.  Many providers will not realize that population-based studies and well-conducted clinical trials do not substantially support primary HPV as a preferred testing strategy. Instead, providers are likely to depend on the USPSTF recommendation or those of medical societies, rather than careful scrutiny of the data.  Furthermore, the triage strategy for a positive HPV test is not standardized; it varies from cytology test, HPV genotype test, or direct colposcopy. Such a decision would depend on organized follow-up and would necessitate an informed discussion, which may not be possible in a single office visit. As suggested in the ARTISTIC subsample, a positive HPV test is likely to cause anxiety, and many patients will undergo colposcopy they would not have been needed had they been screened with a Pap smear instead.

In conclusion, we agree with maintaining much of the 2012 recommendations, but we strongly disagree with the proposed “A” rating for HPV testing alone, and urge that the USPSTF reconsider the shortcomings of the evidence and revise their recommendation to give preference to co-testing and Pap smears alone, rather than stand-alone HPV testing.

Thank you for the opportunity to comment on this most important issue which will have an impact on the lives of many adult women on a national level.

For questions or more information, please contact Danielle Shapiro, MD, MPH at ds@center4research.org.

References:

Felix, JC., et. al. The Clinical and Economic Benefits of Co-Testing Versus Primary HPV Testing for Cervical Cancer Screening: A Modeling Analysis. J Women’s Health. 2016; 25(6):606-16

Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. October 2017. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2