1. New CTP science policy memos released

2. ENDS PubMed literature surveillance and ClinicalTrial.gov surveillance

3. FDA announces proposed rule to require submission of tracking numbers for imports of e-cigarette products

4. The Fifth Circuit Court of Appeals recently vacated and remanded FDA marketing denial orders for five e-cigarette manufacturers.

   Deep Dive into CTP’s view of flavors in tobacco products

CTP Reviewer Memos Released

FDA Center for Tobacco Products released two reviewer memos used in the evaluation of recent ENDS PMTA authorizations.

June 03, 2024: Genotoxicity Hazard Identification and Carcinogenicity Tiering of Constituents in ENDS Premarket Tobacco Product Applications

• This memorandum outlines the framework for identifying genotoxic hazards and tiering the carcinogenic potential of constituents in ENDS (Page 26).

• It uses a tiered approach similar to those recommended by the EPA and IARC, with constituents placed into one of five tiers (Page 5).

• Tiers 1-3 are reserved for constituents evaluated by IARC or EPA and demonstrate carcinogenic potential (Page 5).

• Tier 1 constituents are identified as "carcinogenic to humans" with strong evidence of human carcinogenicity (Page 5).

• Tier 2 constituents are "likely to be carcinogenic to humans" but lack the evidence strength of Tier 1 (Page 5).

• Tier 4 classifications are based on genotoxicity assays with limited or conflicting results, which reduce certainty (Page 5).

• The memorandum emphasizes using a component-based approach for complex mixtures like ENDS (Page 2).

• The genotoxicity test batteries are designed to detect carcinogens that act through DNA damage mechanisms (Page 5).

June 03, 2024: Calculating Excess Lifetime Cancer Risk in ENDS Premarket Tobacco Product Applications

• The memorandum describes the process and methodology for calculating the Excess Lifetime Cancer Risk (ELCR) posed by ENDS constituents (Page 2).

• It is used as part of the workflow for evaluating cumulative cancer risk in tobacco product constituents (Page 26).

• The ELCR approach incorporates a tiering system to categorize constituents based on carcinogenic risk (Page 2).

• It is aimed at better assessing toxicological risks associated with ENDS, which lack long-term human epidemiological data (Page 5).

• The risk assessment for ENDS considers Tier 1-3 constituents to provide a comparison with marketed tobacco products (Page 5).

• Limitations include the dependency on the quality of scientific data and potential unknown pyrolysis products during aerosolization (Page 5).

• The approach allows for comparative cancer risk evaluations between new and existing products (Page 5).

Takeaway: Releasing scientific reviewer memos used in the evaluation of PMTAs is an important step toward transparency as noted in the Reagan-Udall report. Increased awareness of the FOIA process and how to use it to request important CTP documents will hopefully continue to improve scientific data exchange between CTP and its stakeholders. It is, however, confusing that the document releases are prefaced with disclaimers that this information should not be used as a tool, guide or manual for the preparation of PMTAs.

Recent ENDS Literature and Clinical Trials Review

Periodically reviewing ENDS-related publications and clinical trial information reveals current trends in the research.

ENDS Publications - Most recent 100 relevant publications at link

• Selya A, Hannon MJ, Shiffman S. Youth use of electronic nicotine delivery systems (ENDS) in the Population Assessment of Tobacco and Health (PATH) Wave 6: Impact of survey mode. Addict Behav. 2024 Aug 2;158:108124. doi: 10.1016/j.addbeh.2024.108124. Epub ahead of print. PMID: 39102771.

• Oldham MJ, Desai RW, Randazzo J, Walling BE, Lalonde G, Weil R. Evaluation of mixtures of flavor chemicals in a 90-day nose-only exposures in sprague-dawley rats. Hum Exp Toxicol. 2024 Jan-Dec;43:9603271241269022. doi: 10.1177/09603271241269022. PMID: 39101688.

ENDS Clinical Trials - Most recent 100 relevant trials at link

• Effects of E-cigarette Flavors on Youth TCORS 2.0

ClinicalTrials.gov ID NCT03634839

Sponsor: Yale University

• Menthol and Mint Experimental Tobacco Marketplace (ETM) Study

ClinicalTrials.gov ID NCT04879225

Sponsor: Wake Forest University Health Sciences

Takeaway: PATH wave data and TCORS-funded studies continue to be represented in the literature, which includes studies assessing impacts of flavor in tobacco products.