What Constitutes Appropriate for the Protection of Public Health (APPH) Evidence?

October 22, 2024

The term "Appropriate for the Protection of Public Health," commonly abbreviated as APPH, is a cornerstone of the FDA's process for regulating tobacco products. It signifies the standard that a new tobacco product must meet to receive marketing authorization. Using FDA CTP meeting information, specifically the 2019 and 2023 CTP PMTA meeting transcripts, this exercise offers insights into how various scientific disciplines within the FDA evaluate the APPH standard in the context of Premarket Tobacco Product Applications (PMTAs).

What Does APPH Mean?

• A Population-Level Focus: APPH emphasizes evaluating the impact of a new tobacco product on the entire US population, including both current tobacco users and nonusers. This means considering potential risks and benefits to public health as a whole.

• Legal Foundation: The APPH standard originates from Section 910(c)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the Tobacco Control Act of 2009. This legal framework guides the FDA's review process.

• Multiple Lines of Evidence: The FDA considers various types of scientific data to determine if a product meets the APPH standard. These include studies on individual health risks, population health risks, consumer perception, and abuse liability.

Role of Scientific Disciplines in Evaluating APPH for PMTAs:

The sources reveal how different scientific disciplines within the FDA contribute to the APPH evaluation:

Chemistry:

• Quantifying HPHCs: Chemistry plays a crucial role in identifying and measuring the levels of harmful and potentially harmful constituents (HPHCs) in new tobacco products. This data informs the assessment of potential health risks associated with product use.

• Comparing to Existing Products: Chemistry compares the HPHC yields of a new product to those of existing tobacco products in the same category and at least one different category. This comparative analysis helps to determine if the new product presents similar or different levels of risk.

• Normalizing HPHC Data: To ensure accurate comparisons between different types of tobacco products, chemistry develops methods to normalize HPHC yields, taking into account factors like product use patterns. This normalization process facilitates meaningful comparisons between products like cigarettes, smokeless tobacco, and ENDS.

• Evaluating Manufacturing: Chemistry assesses the manufacturing process of the new product to determine if it consistently produces products of the intended quality and composition. This evaluation involves scrutinizing all steps, from raw material receipt to finished product storage, and analyzing the controls in place to ensure product consistency.

Toxicology:

• Assessing Health Risks: Toxicology examines the potential for both cancer and non-cancer health risks from the product's constituents. This evaluation includes reviewing studies on genotoxicity, carcinogenicity, and other toxicological endpoints.

• Ingredient Changes: Toxicology carefully evaluates the impact of ingredient modifications in a new product compared to existing products. The focus is on understanding how these changes might affect the overall toxicity profile.

• Excess Lifetime Cancer Risk (ELCR): Toxicology employs ELCR calculations to quantitatively assess the potential for cancer risk from exposure to the product's constituents over a lifetime. This assessment utilizes established toxicity reference values, as outlined in FDA guidance documents, to inform the evaluation of potential carcinogenic risks.

Behavioral and Clinical Pharmacology (BCP):

• Nicotine Yield and Abuse Liability: BCP assesses the nicotine yield of a new product and compares it to existing products to evaluate its potential for abuse liability. This analysis focuses on understanding how nicotine delivery might influence user dependence and addictive potential.

• Clinical Biomarkers of Exposure (BOE): BCP reviews clinical BOE data to determine the levels of nicotine and other HPHCs that users are exposed to when using the new product. This information provides real-world insights into potential health risks.

Social Science:

• Consumer Perception: Social science investigates how consumers understand and perceive a new product, including its potential risks and benefits. This understanding is crucial for evaluating how the product might influence initiation, cessation, and switching patterns among different population groups.

• Impact on Tobacco Use Behaviors: Social science evaluates how the introduction of a new product might affect overall tobacco use behaviors in the population. This includes assessing potential changes in initiation, cessation, and product switching patterns.

• Non-users on APPH evaluations: There are several product characteristics that could influence initiation rates among non-users: Flavors: Flavored tobacco products, particularly those with flavors that appeal to youth, are recognized as a significant risk factor for initiation. Marketing and Perception: How a product is marketed and perceived by consumers can also influence initiation. For example, if a new product is perceived as less harmful or more socially acceptable, it could lead to increased experimentation and uptake among non-users.

Epidemiology:

• Real-world Health Outcomes: Epidemiology assesses observational studies that examine the health risks associated with using a new product in real-world settings. This provides evidence on the potential impact of the product on public health.

• Population Health Impact Models: Epidemiology scrutinizes the validity of data, assumptions, and results used in PHI models that project the potential long-term effects of a new product on population health.

The Collaborative Nature of APPH Review:

Multidisciplinary Perspective: The APPH determination for a PMTA is not made by any single discipline alone. Rather, it relies on the integration of evidence from all the scientific disciplines involved.

Information Sharing: To ensure a comprehensive and cohesive review, frequent communication and information sharing occur between the different disciplines. This includes small group meetings to discuss specific scientific issues and ensure alignment in findings and conclusions.

Key Takeaways:

APPH is Central to FDA Tobacco Regulation: The APPH standard plays a critical role in the FDA's mission to protect public health by ensuring that new tobacco products do not pose undue risks.

Scientific Rigor is Essential: The FDA relies on a robust, multidisciplinary scientific review process to evaluate APPH, drawing upon expertise from various fields.

The FDA Continues to Evolve: As the science of tobacco harm reduction advances, the FDA continuously refines its processes and guidance for assessing APPH to make the most informed decisions possible.