June 11, 2019 FDA Releases Final Guidance for Premarket Tobacco Product Applications for ENDS

https://www.fda.gov/news-events/press-announcements/fda-finalizes-guidance-premarket-tobacco-product-applications-electronic-nicotine-delivery-systems

Introduction

On June 11th, 2019, FDA released the final guidance for Premarket Tobacco Product Applications (PMTA) for Electronic Nicotine Delivery Systems (ENDS). This comes about a month off the heels of federal judge Grimm’s order for FDA to speed up its review of e-cigarettes, and siding with Public Health Groups such as the Campaign for Tobacco-Free Kids, American Academy of Pediatrics, etc..

This was originally meant to be a high level summary, but after going through the 52 pages of information in the guidance document, this became more of a Cliff notes version. So, from 52 pages, I’ve condensed it down to about 9 pages.

High Level Summary

Products to which PMTA ENDS guidance applies to

E-liquids, E-cigarettes and ENDS products that package e-liquid and e-cigarettes together.

DOES NOT apply to the following categories of products:

• Products with a cessation claim, those would be considered as NRT and under CDER review.
• Unfinished Tobacco Products: “an e-liquid that is sold or distributed for further manufacturing into a finished ENDS product is not itself a finished tobacco product and, at this time, FDA does not intend to enforce against such e-liquids that are sold or distributed without a marketing order.”
• E-liquids containing zero nicotine that (1) are not made or derived from tobacco, and (2) “not intended or reasonably expected to be mixed with liquid nicotine or other materials made or derived from tobacco”

Individual or multiple products can be submitted in same PMTA, but FDA will review products separately. As such, it is important to lay out the product specific information in a format that is easy and clear to find.

Public Health Considerations

The standard is to show that the new tobacco product is appropriate for the protection of public health (APPH). Basically, determination of the risks and benefits to the population as a whole (users and nonusers of the product) using valid scientific evidence (Published literature, Nonclinical studies and “appropriate” Bridging studies).

*Interesting to note, is FDA’s statement regarding not absolutely requiring long term studies (FDA defines long term studies as “those studies conducted over six months or longer”). Examples of long term studies mentioned include carcinogenicity bioassays and clinical studies spanning more than 6 months (short term clinical studies can be bridged to the literature, or nonclinical in vitro assays).

Comparison Products

FDA suggests making comparisons to other tobacco products.

• Products within the same category and subcategory. FDA provides an example such as other e-liquids being used as comparator in an e-liquid PMTA. Closed e-cigarette devices should evaluate other similar product currently marketed, and same for open tank systems. Comparator products should be selected that match the candidate PMTA product in terms of materials used, ingredients in e-liquid, design, composition, heating source, etc.
• Products within different categories (i.e. cigarettes, heat not burn products) that are intended to be used via similar route of administration.

Summary of All Research Information Included in PMTA

Scientific Studies

1. Product Analysis and Manufacturing. This includes lab accreditation, method validation, CMC, product shelf life stability and product design hazards. In addition, FDA “recommends a comparison to other e-liquids with similar nicotine content, flavors, and other ingredients, used in the same manner and under similar conditions.” and “manufacturers of e-liquids test the constituent delivery in an e-cigarette that is designed to deliver low levels of aerosol (such as open refillable cigarette-like systems) as well as in an e-cigarette that is designed to deliver higher levels of aerosol with varying temperatures and voltage (such as a tank or mod system)”.

 The FDA list of constituents or “chemicals for analysis in e-liquids or aerosols, or both, as  appropriate” for PMTA candidate product(s) has been revised in the final guidance, from 29 to 33 constituents. They have removed 8 chemicals (ammonia, anabasine, 4-aminobiphenyl, 1-aminonapthalene, 2-aminonapthalene, benzo-A-pyrene, 1,3-butadiene, and isoprene) and added an additional 12 new chemicals (benzyl acetate, buteraldehyde, ethyl acetate, etyl acetoacetate, furfural, glycerol, glycidol, isoamyl acetate, isobutyl acetate, methyl acetate, N-butanol, propionic acid, and propylene oxide). FDA also mentions that additional flavorants be measured if they “can be respiratory irritants such as benzaldehyde, vanillin and cinnamaldehyde”.  FDA recommends that pH of the e-liquid and aerosol should also be measured.

  2. Nonclinical and Human Subjects Studies that must be provided (but not limited to):

1. 1. Studies assessing constituents of tobacco, aerosol
   2. Toxicology
   3. Consumer exposure
   4. Consumer use profiles
   5. Consumer risk perception

Important to note, FDA recommends including “documentation of all actions taken to ensure the reliability of the study, such as appropriate good laboratory practices found in 21 CFR part 58”.

Nonclinical Health Risk Information:

1. Toxicology data from the published literature
2. Analysis of constituents under intense and non-intense conditions
3. In vitro Toxicology (genotoxicity studies, cytotoxicity studies; recommend ICH S2(R1) and OECD protocol/guidelines)
4. Computational modeling of toxicants in product (for toxicity estimates)
5. In vivo Toxicology studies (“to address unique issues that can’t be addressed by alternative approaches”)

FDA suggests that “a thorough literature review, including publicly available toxicology databases, can provide valuable information on the toxicity of the ingredients in the e-liquid and aerosol by the expected route of exposure and level of exposure.” Following were recommendations listed by FDA.

• Description of search methodology
• All publications related to Tox evaluation of ingredients and the mixture of ingredients in e-liquid and aerosol produced (specifically oral, inhalation, dermal and ocular routes of exposure)
• Information concerning container extractables and leachables which could be transferred to e-liquid or aerosol
• Toxicological endpoints: cytotoxicity, genotoxicity, carcinogenicity and respiratory, cardiac, reproductive and developmental toxicity
• Exposure kinetics, metabolism and deposition and elimination profile of ingredients (should mimic highest consumer use scenario and one lower exposure level)
• Conclusion regarding toxicological concern of ingredients, constituents, flavors, humectants that will be delivered in the aerosol
• Info on physiochemical changes of the mixture of ingredients in product (due to temperature, wattage and or voltage changes)

”We recommend that you provide aerosolization properties of each of the ingredients (e.g. constituents, humectants, metals, flavors included), particle size of these ingredients in the product and deposition of these particles through inhalation.”

“In the absence of toxicological data for a particular toxicant of concern, we recommend that you consider computational modeling using surrogate chemical structures.”

Human Health Impact Information

FDA Recommends studies that identify (1) Biomarkers of Exposure (BOE), (2) Biomarkers of Potential Harm (BOPH) and (3) Health outcome measurements or endpoints in the following populations:

• Users who switch from other tobacco products to candidate PMTA product
• Tobacco users and nonusers who after using candidate PMTA product, switch to or switch back to higher risk products
• Tobacco users who use the candidate PMTA product versus quitting tobacco
• Tobacco users who use the candidate PMTA product versus FDA approved cessation medications
• Tobacco users who use the candidate PMTA product with other tobacco products
• Nonusers (youth, never users, former users) who may initiate or relapse tobacco with use of candidate PMTA product
• Nonusers who experience adverse health effects from candidate PMTA product

Studies that FDA suggests may be included to address above concerns:

1. Consumer Perceptions and Intentions. Should “include use intentions among current ENDS users, nonusers, and other tobacco product users, as well as reasons for use”.
2. Likelihood of initiation and cessation by users and nonusers of tobacco (published literature or applicant initiated studies). FDA states, “Although randomized clinical trials could address cessation behavior of users of tobacco products, FDA believes this would also be true for observational studies (perception, actual use, or both) examining cessation behaviors.”
3. Product Use Patterns. User topography, frequency of product use and use patterns over time. FDA suggests for products not previously on the market, that applicant conduct actual use studies. Marketing data or company research conducted can be used for previously marketed products.

* FDA also recommends sharing marketing plan or sales data for currently marketed products.

   4. Labeling Comprehension and Actual Use.

   5. Human Factors. Studies such as actual use studies, labeling comprehension, focus group studies and surveys that identify:

• Normal use and forseeable misuse
• Product user and nonusers
• Use environment
• Use-related hazards and estimated use error risk
• Risk controls
• Adverse experiences

   6. Abuse Liability. PK evaluations, addictiveness, abuse and misuse potential. Comparisons should be made to other ENDS products and cigarettes.

  7. Biomarkers of Potential Harm and Biomarkers of Exposure.

  8. Health Outcomes. Changes in physiological measurements (heart rate, and blood pressure), changes in lung, cardiac and metabolic function, adverse experiences (cough, throat irritation) and changes in lab values (complete blood count, markers of inflammation).

Additional information for E-liquid Products

In addition, FDA suggests that additional info in Product Analysis and Manufacturing section for e-liquid PMTAs.

1. Components, Ingredients and Additives. Provide adequate information to characterize ingredients in e-liquid and identify “characteristics in e-liquid that may impact constituents in the aerosol.” “FDA also recommends that you provide e-liquid design parameters that would be affected by, and that would affect, e-cigarette performance, such as e-liquid viscosity and boiling point.”
2. Flavors. FDA recommends scientific reviews of flavors in e-liquid in terms of toxicity and appeal (to youth and young adults).

Additional information for E-cigarettes

1. E-cigarette design factors.
2. Possible design parameters for subcategories of e-cigarette components and parts. (Batteries, Atomizers and other similar parts and software)

Additional Information Regarding Literature Reviews

While FDA states that literature reports may be acceptable to support a PMTA, they are considered a less robust form of support.

Literature reviews should identify the following:

• Search strategy
• Specific question addressed by literature
• Clearly identify all publications that address the specific question
• Funding source identification
• Study design and methods
• Characterization of study participants
• Year and geographical location of studies
• Strengths and limitations of study
• Interpretation of study findings
• Provide adequate justification for bridging data from category to candidate product
• Summary of the evidence from literature
• Documentation of how literature findings support (or do not) marketing of product would be appropriate for the protection of public health
• Bibliography and appendix with references publications
• Comparative assessments of health risks of candidate product compared with quitting tobacco, using other tobacco products and never use of tobacco

Additional Information Regarding Analysis of Published Literature and Public Databases

• Must provide critical study detaiis
• If primary data can’t be obtained, the recommendation is to obtain other relevant info such as protocol, records of trial conduct and procedures, subject data listings for key variables and documentation of statistical analysis
• Capture and document complete info for all adverse experiences and subject withdrawal from study

Additional Information Regarding Bridging

FDA states that bridging “may be feasible for a subset of products or for certain types of studies”.

1. They state, “For example, “X-flavor” e-liquids with nicotine concentrations ranging from 1 milligram to 24 mg/mL may not require unique studies for each nicotine concentration of the “X-flavor” products if data from a subset of nicotine concentrations (e.g., low, middle, high) of “X-flavor” products may be bridged to other concentrations of “X-flavor” products.”.
2. Information from earlier versions of ENDS products or similar products may be used for bridging studies
3. Bridging studies to other intended locations or regions where product will be used versus conducting new studies

Postmarket Requirements

FDA does not require a postmarketing plan in the PMTA. They state, a marketing order under 910(c)(1)(A)(i) of the Tobacco Act “may require that the sale and distribution of the tobacco product be restricted, but only to the extent that the sale and distribution of the tobacco product may be restricted under a regulation under 906(d).” Finally, under 910(f), FDA “may require that you establish and maintain certain postmarket records and make certain postmarket reports to FD