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.


  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:
  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:
  4.  Honey K. Advances in Tobacco Control. CANCER RESEARCH Catalyst: The Official Blog of the American Association for Cancer Research. November 2017. Available online:
  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
  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.
  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: