1. FDA CTP updated their Tobacco Product Applications: Metrics & Reporting website through March 31, 2024.

2. FDA updated its Import alert 98-06 on May 23, 2024 for “New tobacco products that do not have the required FDA marketing authorization”

3. FOIA requests were updated for May 2024. There were 9 new nicotine and tobacco-related FOIA requests and 15 closed-out FOIA requests.

4. The PMTA marketing denial orders (MDOs) for JUUL Labs, Inc. issued on June 23, 2022 were rescinded by FDA on June 6, 2024, almost two years after the initial decision.

FDA Center for Tobacco Products updated their 'Tobacco Product Applications: Metrics & Reporting' website for review and actions through March 31, 2024.

FY 2024 Total-to-Date (October 2023-March 2024) data for ENDS PMTAs:
➢ 29,984 Accepted
➢ 6,454 Refuse-to-Accept (RTA)
➢ 582 Total Applications Received
➢ 0 Filed
➢ 0 Refuse-to-File (RTF)
➢ 0 Deficiency letters issued
➢ 0 Marketing Granted Orders issued
➢ 22,369 Marketing Denial Orders issued

There were almost 30K ENDS PMTAs accepted during this 6-month reporting period, indicating that there were a significant number of applications submitted during previous reporting periods that are working their way through the PMTA review process. Only 582 new tobacco product applications were received during this time which seems to indicate a focus on “first in, first reviewed” criteria as outlined in the recently released June 2022 CTP memo - Process for implementing new Acceptance and Filing Reviews for premarket tobacco product applications (PMTAs) based on new requirements under 21 CFR 1114

FDA updated its 98-06 import alert which represents the Agency's current guidance to FDA field personnel regarding the manufacturer(s) and/or products(s) at issue. Import Alert Name: "Detention Without Physical Examination (DWPE) of New Tobacco Products Without Required Marketing Authorization" The update to the “red list” includes several electronic nicotine delivery systems components/parts with product names such as Juicy Bar Brand Products and MR FOG Max Pro. The red list designation allows detainment of these tobacco products without physical examination upon import to the U.S.

Freedom of Information Act (FOIA) requests related to nicotine and tobacco were released for May 2024. Of the 15 FOIA relevant requests that were closed out in May, the consequential Technical Project Lead (TPL) memos requested were all withdrawn closed w/o charges. New requests (9) included several from tobacco manufacturers looking for information related to application content and decision summaries.

An interesting article was released related to FOIA requests in the nicotine industry - FOIAengine: Hundreds of FOIA Requests Signaled Challenge to FDA. It is unclear whether a meaningful amount of these FOIA requests have ever been filled and closed out. The current FOIA turnaround time is at least 6 months from request to close out but certain requests can be out for years. For example, a Campaign for Tobacco Free Kids FOIA request for ‘Requesting copies of all marketing denial orders (MDOs) issued to e-cigarette manufacturers’ submitted in June 2021 was withdrawn and closed without charges after almost 1100 days.

The JUUL PMTA MDOs were rescinded on June 6, 2024. PMTAs will go back into substantive (scientific) review at FDA CTP. This announcement comes almost two years after the MDOs were issued on June 23, 2022. A timeline of events:

➢ JUUL submitted PMTAs to FDA for the JUUL Device and JUULpods on July 30, 2020.

➢ MDOs were issued by FDA on June 23, 2022.

➢ On July 5, 2022, the FDA administratively stayed the MDOs after determining that certain scientific issues warranted additional review. This allowed the JUUL products to remain on the U.S. market.

➢ On July 29, 2022 JUUL Labs submitted a 10.75 appeal to FDA requesting several relief items including a supervisory review of the MDO and related deficiencies.

➢ On June 6, 2024 FDA rescinded the MDOs including a reasoning for the rescission.

In other JUUL news, on May 30, 2024 almost 400K JUUL Labs documents were released to the UCSF Industry Documents Library. These are internal JUUL documents released as a part of a settlement with the state of North Carolina in 2021 and include social media monitoring presentations and other strategic documents.

Deep Dive - Creating a Knowledge Graph

Knowledge Graph: Premarket Tobacco Product Application (PMTA)

What is a knowledge graph? A knowledge graph, also known as a semantic network, represents a network of real-world entities—i.e. objects, events, situations, or concepts—and illustrates the relationship between them. This information is usually stored in a graph database and visualized as a graph structure, prompting the term knowledge “graph.” A knowledge graph is made up of three main components: nodes, edges, and labels. Any object, place, or person can be a node. An edge defines the relationship between the nodes. Knowledge graphs are powerful tools for managing and leveraging complex information, making them valuable in fields like regulatory science, where understanding the relationships between various data points is crucial.

1. Regulatory Framework

• FDA Center for Tobacco Products (CTP)

  • Tobacco Control Act

  • Deeming Rule

2. Application Components

• Product Description

  • Product Category (e.g., ENDS, HTPs, Smokeless)

  • Product Specifications

  • Manufacturing Process

• Health Risk Information

  • Harmful and Potentially Harmful Constituents (HPHCs)

  • Toxicological Data

  • Carcinogenicity Studies

• Behavioral and Clinical Studies

  • Human Health Impact

  • Abuse Liability Studies

  • Consumer Perception Studies

• Environmental Impact

  • Environmental Assessment (EA)

  • Environmental Impact Statement (EIS)

• Labeling and Marketing

  • Labeling Requirements

  • Marketing Plans

  • Youth Prevention Strategies

3. Review Process

• Initial Submission

  • Application Submission

  • Acceptance Review

• Substantive Review

  • Scientific Review

  • Deficiency Letters

  • Amendments and Responses

• Final Decision

  • Marketing Granted Order

  • Marketing Denial Order

  • Post-Market Surveillance

4. Scientific Disciplines Involved

• Chemistry

  • Product Composition

  • Chemical Analysis

• Toxicology

  • Toxicological Risk Assessment

  • Genetic Toxicology

• Engineering

  • Product Design

  • Manufacturing Controls

• Behavioral Science

  • Consumer Behavior

  • Usage Patterns

• Epidemiology

  • Population Health Impact

  • Longitudinal Studies

5. Data Standards and Tools

• Data Submission Standards

  • CDISC Standards

  • Electronic Common Technical Document (eCTD)

• Validation Tools

  • Product Form Validator Tool

  • Electronic Submissions Gateway (ESG)

6. Common Issues and Best Practices

• Common Deficiencies

  • Incomplete Data

  • Inadequate Risk Assessment

  • Insufficient Labeling Information

• Best Practices

  • Comprehensive Data Collection

  • Clear and Concise Documentation

  • Robust Scientific Justification

7. Stakeholders

• Manufacturers

  • Tobacco Companies

  • ENDS Manufacturers

• Regulators

  • FDA Reviewers

  • Scientific Advisory Committees

• Public Health Organizations

  • American Cancer Society

  • Campaign for Tobacco-Free Kids

• Consumers

  • Adult Smokers

  • Youth and Non-Smokers

8. Legal and Policy Considerations

• Litigation

  • Legal Challenges to PMTA Decisions

  • Compliance with Court Orders

• Policy Development

  • Regulatory Updates

  • Public Health Policies

This knowledge graph provides a comprehensive overview of the various topics associated with a PMTA, highlighting the interconnected nature of the regulatory framework, application components, review process, scientific disciplines involved, data standards and tools, common issues and best practices, stakeholders, and legal and policy considerations.

Resource Links

Chatbots

PMTA MGO Chatbot - This large language model (LLM) response agent was trained on several PMTA marketing granted orders and their respective technical project lead memos issued by FDA CTP. You can create prompts like “Walk through, step-by-step, the PMTA process from submission to postmarket reporting and provide specific actions related to each step of the review process.” This is very much a proof-of-concept exercise but responses are improving.

I am making available a strategic analysis of CTP Application Job Aids. This resource provides a step-by-step analysis of the job aids provided to FDA CTP reviewers assigned to premarket tobacco product applications (PTMA), exemption request (EX) and substantial equivalence (SE) applications submitted under sections 910(a), 905(j)(A)(3) or 905(j), respectively, of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The document includes the strategic analysis as well as the job aids.