FDA should prioritize direct measures of health and behavioral effects over indirect measures or assumptions in making regulatory decisions

We submitted this comment to the FDA on August 25, 2023. The Regulations.gov tracking number is llr-bc0j-aik8. A PDF copy is available for download here.

FDA should prioritize direct measures of health and behavioral effects over indirect measures or assumptions in making regulatory decisions

Docket No. FDA–2023–N–2873

 Developing FDA’s Center for Tobacco Products’ Strategic Plan

Stanton A. Glantz, PhD, Pamela M. Ling, MD, MPH; Nhung Nguyen, PhD;
Lauren Kass Lempert, JD, MPH; Andre Luiz Oliveira da Silva, MsC, PhD; Jennifer Fung, PhD;
Wendy Max, PhD; Suzaynn F. Schick, PhD; Bonnie Halpern-Felsher, PhD; Sabrina Islam, PhD;
Vira Pravosud, PhD; Hai-Yen Sung, PhD; Janet Wojcicki, PhD, MPH; Karla Llanes, PhD

UCSF TCORS

August 25, 2023

FDA announced[1] a Public Meeting and Listening Session and an opportunity to submit written public comments to obtain feedback on five proposed goals it is using to develop a strategic plan for FDA’s Center for Tobacco Products’ (CTP) comprehensive Strategic Plan. In particular, CTP asked, “What are three specific actions CTP could take in the next 5 years that would have the most impact in significantly reducing tobacco-related death and disease?” One of these three specific actions should be to establish a policy of prioritizing direct measures of health and behavioral effects over indirect measures or assumptions whenever possible when making regulatory decisions.

            This principle particularly applies to the following strategic goals 1, 2, and 4:

1. Develop, Advance, and Communicate Comprehensive and Impactful Tobacco Regulations and Guidance.

2. Ensure Timely, Clear, and Consistent Product Application Review to Protect Public Health.  

4. Improve Public Health by Enhancing Knowledge and Understanding of CTP Tobacco Product Regulation and the Risks Associated with Tobacco Product Use.

Since at least 1972, tobacco companies have promoted four premises: (1) reduced toxicity indicates reduced risk; (2) collaboration with the tobacco industry will not undermine tobacco control; (3) nicotine addiction is unavoidable; (4) to curtail cigarette use, solutions must be consumer-approved (i.e., profitable), as exemplified in efforts to influence the British Independent Scientific Committee on Smoking and Health.[2]  Companies often worked through scientists with undisclosed connections to industry to promote the industry view of harm reduction, as exemplified in an unsigned editorial in The Lancet authored by Michael Russell endorsing RJ Reynolds’ Premier heated tobacco product for harm reduction.[3]  Tobacco companies also had some success in lobbying the Institute of Medicine to recommend a tiered claims system (with separate tiers for exposure and risk, which they believed would ease the process of qualifying for a claim) in its 2001 FDA-commissioned report Clearing the Smoke,[4] which, in turn, influenced the 2009 Family Smoking Prevention and Tobacco Control Act.[5]

The essential argument for focusing on biomarkers was that because new products would not have been in widespread use long enough for health effects to be manifest at the individual or population levels, assessment of these products would have to be limited to biomarker analysis and short-term toxicology studies rather than human evidence.  FDA has de facto adopted this position in its marketing authorizations for Philip Morris’ IQOS[6] heated tobacco product and RJ Reynolds’ Vuse Solo[7] e-cigarette.

            The theoretical problem that real-world human evidence is not available does not apply to e-cigarettes. Because of the combined effect of the delay in FDA issuing the Deeming Rule taking authority over e-cigarettes until 2016, FDA’s enforcement discretion decision to delay the requirement for e-cigarettes to submit premarket applications, and FDA allowing e-cigarettes to remain on the market while it processed PMTAs, e-cigarettes have been on the market and used by consumers for 17 years (since 2006).

            Even following Philip Morris’ recommendation to the Institute of Medicine Clearing the Smoke committee to wait 5 years before starting to consider epidemiology studies,[8] this is more than enough time to obtain and consider epidemiological evidence. 

Moving beyond a focus on biomarkers is particularly important because e-cigarette aerosol contains thousands of chemicals,[9] which may pose different, even new, risks than cigarettes. By limiting discussion to a few toxicants (generally based on combusted cigarette smoke), FDA could be missing important health effects.  In addition, directly observed disease patterns in people are a more direct assessment of health and behavioral effects of e-cigarettes than biomarkers.

As summarized in a public comment submitted regarding FDA’s proposed menthol product standard for cigarettes,[10] there is a large epidemiological literature on health effects of e-cigarettes as actually used in the general population.  This literature shows elevated risks for cardiovascular, pulmonary, and oral diseases.  In contrast to studies focusing on biomarkers, the direct human epidemiology shows that risks for e-cigarettes for cardiovascular and oral diseases are similar to cigarettes and while lower than smoking for pulmonary disease, e-cigarette risks are much larger than FDA has assumed.  Dual use or use of both cigarettes and e-cigarettes (versus exclusive use of either product) is associated with increased odds of disease across all outcomes that were examined.

Likewise, there is a large literature on effects of e-cigarette use on smoking behavior in both youth and adults that is inconsistent with the FDA’s assumption that e-cigarettes promote “switching completely” in a way that would reduce harm.

There is also a large epidemiological literature on the relationship between e-cigarette use and cigarette smoking behavior that shows that, as consumer products, e-cigarette use is not associated with smoking cessation[11]^{, [12], [13], [14]} and that youth who initiate nicotine use with e-cigarettes have increased odds of smoking cigarettes.[15]

            To implement the policy of prioritizing direct measures of health and behavioral effects over indirect measures or assumptions whenever possible when making regulatory and other decisions:

• FDA should make decisions about risks of e-cigarettes and other established products based on documented effects on disease in the population, not just short-term measures of a limited number of cigarette-based biomarkers.

• FDA should heed its own meta-analysis[16] and stop assuming that reducing, but not stopping, cigarette smoking substantially reduces risks until such time as it presents strong population-based evidence to the contrary.

• FDA should prioritize the effects of dual and poly product use in regulatory and public communication decision making.

• FDA should complete and publish its own assessment of the epidemiological evidence of disease risk associated with e-cigarette use compared to cigarette use and dual use in the general population.

• FDA should stop making regulatory and public communication decisions on the assumption that e-cigarettes as consumer products help people stop smoking until there is strong population-based evidence that this assumption is correct.

• FDA should complete and publish its own assessment of the relationship between e-cigarette and other tobacco use among youth and young adults, particularly the extent to which e-cigarettes are attracting youth at low risk of nicotine initiation with cigarettes and the extent to which youth who initiate nicotine use with e-cigarettes move to or add cigarettes or other tobacco products.

The FDA should also prioritize direct human evidence when assessing the risks of other new products to the extent possible.