EVALUATING EMERGING TOBACCO PRODUCTS AND THEIR … · tobacco products, including machine-made...

EVALUATING EMERGING TOBACCO PRODUCTS AND THEIR POTENTIAL IMPACT ON PUBLIC HEALTH:Developing Evidence for Products Introduced after February 15, 2007February 4, 2020

Erika L. Pfaunmiller, Ph.D.Manager, Technical Sales

YOUR PARTNER IN TOBACCO RESEARCH

TABLE OF CONTENTS

Introduction ............................................................................................................................3

FDA Requirements for Tobacco Products: Premarket Tobacco Applications.....................3

Challenges in Tobacco Product Clinical Studies: Scientific and Operational ....................4

Clinical Study Objectives: Measuring Exposure, Use, and Abuse Potential ......................4

Clinical Studies: Design and Execution ................................................................................4

Subject Recruitment: Unique Challenges ............................................................................5

Facility Requirements: Specialized Clinical Facilities ..........................................................5

Bioanalytical Data: Meeting Evolving Regulatory Expectations ..........................................6

Recommendations for Sponsors: Work with an Experienced Partner ...............................7

Conclusion ..............................................................................................................................7

References..............................................................................................................................8

© 2020 Frontage Laboratories, Inc.VISIT US AT: frontagelab.com2.


IntroductionDecades of studies have conclusively demonstrated that smoking combustible cigarettes, as well as second-hand smoke, are major causes of global morbidity and mortality from a constellation of conditions, including but not limited to chronic disorders such as pulmonary and cardiovascular disease, and multiple types of cancer.1

The most effective approach to harm reduction is smoking cessation. However, the addictive nature of nicotine and the behavioral aspects of smoking make this a challenging process. There is therefore a significant need to develop and regulate products such as e-cigarettes, that could potentially serve as reduced-risk alternatives.

In May 2016, the US Food and Drug Administration (FDA) finalized a rule regulating electronic nicotine delivery systems (ENDS), authority it was given under the Family Smoking Prevention and Tobacco Control Act that was signed into law in June 2009. The FDA oversees all tobacco products, including machine-made cigarettes, roll-your-own cigarettes, cigars, pipes, snuff, chewing tobacco, gum, dissolvable products, and ENDS. It is important to note that ENDS products that advertise claims of supporting smoking cessation or of any other health benefit are more strictly regulated as a drug or medical device.

Under the ruling, all new tobacco products introduced after February 15, 2007 must submit a Premarket Tobacco Product Application (PMTA) by May 2020 or withdraw from the market.2 “New” products include those previously marketed for which some aspect has changed i.e., “any modification including a change in design, any component, any part, or any constituent, including a smoke constituent, or in the content, delivery or form of nicotine, or any other additive or ingredient”3. The review process gives the FDA the ability to evaluate important factors such as ingredients, product design and health risks, as well as their appeal to youth and non-users. Applicants must demonstrate that the product is “appropriate for the protection of public health.”

For all parties concerned, the approval process is still nascent, and certain aspects of the PMTA guidance are open to interpretation. Furthermore, execution and data analysis of clinical studies of tobacco products pose unique challenges. It is therefore in the sponsors’ best interest to work closely with an experienced partner to design and

execute the studies, and perform the required bioanalytical services to produce the evidence needed by the FDA to perform a complete review.

In this paper we provide background on clinical studies in the US for new tobacco products and delineate how the appropriate testing facilities, equipment, and experienced staff are essential to generating high quality data.

FDA Requirements for Tobacco Products: Premarket Tobacco Applications There are multiple pathways through which sponsors of tobacco products may submit applications to the FDA division of Center for Tobacco Products (CTP) for approval. Here, we focus on the clinical study requirements to support a PMTA. The PMTA process is a primary pathway for new tobacco products and doesn’t require comparison to a predicate tobacco product.4

In a PMTA, applicants must demonstrate that the product is appropriate for the protection of the public health. In order to reach such a conclusion and to authorize marketing, the FDA considers, among other things:

• Risks and benefits to the population as a whole, including people who would use the proposed new tobacco product (including youth) as well as nonusers;

• Whether people who currently use any tobacco product would be more or less likely to stop using such products if the proposed new tobacco product were available;

• Whether people who currently do not use any tobacco products would be more or less likely to begin using tobacco products if the new product were available; and

• The methods, facilities, and controls used to manufacture, process, and package the new tobacco product.5

The FDA’s evaluation includes review of a tobacco product’s components, ingredients, additives and health risks, as well as how the product is manufactured, packaged and labeled.6

EVALUATING EMERGING TOBACCO PRODUCTS AND THEIR POTENTIAL IMPACT ON PUBLIC HEALTH:Developing Evidence for Products Introduced after February 15, 2007

© 2020 Frontage Laboratories, Inc.VISIT US AT: frontagelab.com3.YOUR PARTNER IN TOBACCO RESEARCH

Challenges in Tobacco Product Clinical Studies: Scientific and Operational While there are components in common, clinical studies for tobacco products do differ from those for pharmaceutical products. The development program for tobacco products does not, for example, progress from Phase I to II to III; however, the research encompasses both pre-clinical and clinical studies, which may be conducted in parallel. Here, we focus exclusively on clinical studies.

Clinical studies for tobacco products must, like pharmaceutical products, be conducted following Good Clinical Practices (GCPs), comply with all regulatory guidelines, and abide by all Health Insurance Portability and Accountability Act (HIPAA) regulations. They should therefore be conducted by an organization with history and expertise in clinical development.

Clinical studies of tobacco products are unique in the spectrum of study endpoints and design, subject recruitment challenges, requirements for specialized research facilities and staff training, and the complexity of the bioanalyses. Each of these challenges is discussed in more detail below.

Clinical Study Objectives: Measuring Exposure, Use, and Abuse Potential Data from clinical studies for tobacco products should determine likely patterns of human abuse and exposure. A clinical study which includes measuring exposure and health effects (i.e., early indicators of disease or injury) is a valuable preliminary step in determining a product’s potential for reducing individual risk.7

Evaluating changes in product use and behavior involves assessing the potential for abuse, defined by FDA as “the ability to produce psychoactive effects, which is viewed as correlated with, or predictive of, its intentional use...repeatedly, or even once.”8 Clinical assessment strategies include measuring phenomena which may themselves influence exposure and thus individual risk, including patterns of use (such as changes in quantity, frequency of use, and combined use of ENDS with other new tobacco products or conventional products); puffing style (topography); subjective responses (such as sensory perceptions of flavor and nicotine dosing effects); and risk perceptions.

Other research considerations may include individual characteristics of the tobacco user (e.g., age, gender, race/ethnicity, sensory preferences, and metabolic and genetic factors), tobacco use history and current status (type, duration and amount of use, and degree of dependence), and intentions regarding future use or quitting.

The clinical study design, including selection of measures of exposure or health effects are important components of the overall the evaluation of tobacco products. (See Figure 1.)

Clinical Studies: Design and Execution Clinical studies that investigate tobacco products in preparation for a PMTA submission vary considerably in their endpoints, number of subjects, duration, and basic design. Generally, in a clinical study of tobacco products, sponsors can expect to measure:

• Pharmacokinetics (PK) via blood draws and/or urine samples from subjects;

• Biomarkers of exposure and/or of potential harm;

• Subjective effects/abuse liability, that is the potential for addiction, abuse or misuse of the product and the exposure to nicotine during product use; and

• Subjects’ behavior/pattern of use through topography.


Non-Clinical HealthRisk Information

Toxicology Studiesand Analysis of

Constituents(Components,Ingredients,

Additivesand Flavors)

ConsumerPerception

andIntentions

Likelihoodof

Initiationand

Cessationby BothUsers &

Non-Users

ProductUse

Patterns

LabelingComprehensionand Actual Use

HumanFactors

AbuseLiability

Biomarkersof harm

andbiomarkersof exposure

HealthOutcomes

Non-clinical Human Subject Studies

Human Health Impact Information

Comprehensive overview of PMTA

Figure 1:

POTENTIAL MEASURES IN STUDIES OF TOBACCO PRODUCTS


It is common for clinical studies conducted to support PMTA submissions for ENDS or “new tobacco entities” to have a comparator arm of a combustible cigarette to substantiate any intended statement that the product affords a sustained reduction in human exposure to cigarette smoke toxicants, as assessed by measuring biomarkers of exposure. This data may support the claim that the “new” tobacco product is appropriate for the protection of public health, which is a key requirement for PMTAs.

Clinical studies evaluating tobacco products can be conducted using either a confinement or an ambulatory design, depending upon the study endpoint(s). Confinement studies provide the subject with the product either in a controlled sequence (defined use sequence within a certain period of time) or in a sequence in which the subject determines the rate of use within a period of time (commonly referred to as ad libitum use) while confined for a defined number of overnight stays at the research facility. In ambulatory studies, subjects use their assigned product(s) in the at-home setting and make repeated visits to the clinic, often reporting their outcomes via a paper or electronic diary.

To generate a quantitative measure of the subject’s usage behavior, computerized devices can be affixed to the cigarette or ENDS. The resulting puff topography includes the number of puffs, puff duration (milliseconds), puff volume (milliliters), and inter-puff interval (seconds). The subjective effects of the product are usually measured via multiple choice or visual analog scale questionnaires.

Collection of PK samples typically requires collection of serial blood samples and/or urine segments to measure nicotine levels. Due to the rapid time to maximum blood concentration, 10-12 blood samples are generally collected within approximately 4 hours after product use, requiring an in-dwelling catheter to meet collection timepoints within minutes of each other and experienced phlebotomists. Sample processing requires a high-speed centrifuge and calibrated freezers that reach at least -70°C. Typically 24-hour urine collections are utilized to measure urine levels of nicotine as well as other tobacco-specific biomarkers.

Subject Recruitment: Unique ChallengesA robust subject database of tobacco product users is supported by access to a diverse population that includes current tobacco

users, ex-users, and never users (those who’ve used tobacco products less than approximately 100 times in a lifetime). Ideally the database is organized by subject product use preferences for easy search capability, including length of time of use, flavor preference if applicable, and dual vs. solo use.

Differences among subjects may lead to variability in responses to product administration. The demographic profile of subjects and even geographic location may play a role in product exposure, how a product is used or how safe it may be. For this reason, the diversity in clinical trial populations can be critical to public health and well-being through increased representation.9

Facility Requirements: Specialized Clinical FacilitiesConfinement studies must be performed in specialized clinical research facilities where smoking is carefully controlled and monitored. See Figure 2.


Figure 2:


The clinical research facility should be designed to control secondary exposure to tobacco products and minimize contamination from nicotine. The ideal facility will have separate, dedicated smoking rooms with controlled airflow, using for example the simple principle of displacement whereby air introduced through floor outlets rises as it warms and is exhausted near the ceiling. All furniture should have non-absorbent fabric that is easy to clean. Subjects and staff should be provided with scrubs or other easily laundered clothing, that are cleaned each day to limit nicotine contamination.

Separate dispensing rooms and the requirement that clinical research staff administer tobacco product and/or subjects sign-in/out tobacco products (either the empty pod with the device, or the cigarette butt) are necessary for product accountability, which is a GCP requirement for any clinical study.

As expected, confinement studies can only be conducted in a clinical research facility with the appropriate accommodations, including bed space, dedicated restrooms/showers, capability to serve meals, recreation areas and overnight staff.

Bioanalytical Data: Meeting Evolving Regulatory Expectations Study endpoints in clinical studies of tobacco products may include PK, and/or changes in biomarkers of exposure and biomarkers of biological effect. If biomarkers are to be analyzed, it is important to understand the range of options and the applicability of each. (See sidebar, “Suitable Biomarkers.”)

While the FDA expects meaningful data, the agency has not specified which biomarkers and methods are required; only that bioanalytical methods must be validated and compliant with FDA guidelines. It is therefore important to work with a clinical research partner that is familiar with the options, understands FDA expectations, and has experience in method development/validation, and assay execution.

The Cooperation Center for Scientific Research Relative to Tobacco (CORESTA) was formed to help interpret the FDA’s position and to define standards for the tobacco industry. One objective of CORESTA is to provide an authoritative source of publicly available, credible science, and best practices related to tobacco and its derived products, and to develop methods for physical or chemical

measurements. This group, which includes Frontage as an active member, is working to establish standards for the list of specific biomarkers to be analyzed as part of tobacco-specific regulatory submissions.


Suitable Biomarkers

A biomarker of exposure is the presence of a quantifiable constituent as a direct result of an external exposure. Examples, all of which can be measured in blood, plasma, serum or urine, include:

• Nicotine, Cotinine and Trans-3’-hydroxycotinine

• Total NNN and Total NNAL

• CEMA, 3-HPMA, 3-HMPMA

• AAMA and GAMA

• 1-aminonaphthalene, 2-aminonaphthalene and 4- aminobiphenyl

• NAT and NAB

A biomarker of biological effect (BOBE), also called a biomarker of potential harm, is “a significant, objective, measurable alteration in a biological sample after smoking a tobacco product that is known to be on a pathway predictive of pathological change, or a surrogate for that pathway, which is altered in a proportion of smokers and is reversible on cessation of smoking.”10



Examples of BOBE include:

• Oxidative stress (8-epi-prostaglandin F2 alpha in human urine)

• Cardiovascular disease (11-dehydro thromboxane B2 in human urine)

• Inflammation (fibrinogen in human plasma)

There are a number of factors that must be taken into account when selecting BOBEs, including the relationship of the biomarker to a tobacco-related disease, the ability to indicate physiological/biochemical changes at an early stage of the disease process, and the involvement in the pathological pathway.11

Recommendations for Sponsors: Work with an Experienced PartnerAs the FDA’s data requirements for PMTAs are evolving, sponsors can improve their chance of approval by partnering with a full-service clinical research partner that has experience in:

• Designing tobacco studies, including helping to determine the appropriate endpoints;

• Executing and managing the studies, with the appropriate facilities and experienced research personnel;

• Performing the wide range of bioanalytical services that may be required for different studies;

• Interpreting and reporting the data; and

• Balancing data requirements with the logistical complexities inherent to tobacco product clinical studies.

Conclusion Sponsors of all “new” tobacco products introduced after February 15, 2007 must submit a PMTA to the FDA by May 2020, or withdraw their product from the market. For all parties concerned, the approval process is still in its infancy, and certain aspects of the PMTA guidance are open to interpretation. It is, therefore, critical for sponsors to work closely with an experienced clinical research partner that is familiar with the FDA’s processes, has a history of successfully conducting clinical studies that evaluate both pharmaceutical and tobacco products, has appropriate clinical facilities, experienced research personnel and access to eligible study subjects, and can develop, validate, and execute the necessary bioanalytical methods.

New Jersey as a Research-Friendly Locale

Since the passage of New Jersey’s Smoke-Free Air Act of 2006, smoking in enclosed indoor spaces is prohibited in the state as part of the effort to eliminate one of the New Jersey’s most significant public health threats, to reduce smoking-related illnesses, and to save lives. For a decade there were no exceptions, even for research facilities. However, in 2016 a change in the law allowed smoking in clinical research facilities under the supervision of an Institutional Review Board (IRB). The location of Frontage’s purpose-built facility takes advantage of New Jersey’s interest in advancing public health and of ready access to subjects with a wide range of demographics.


Frontage Laboratories, Inc. is a CRO that provides integrated, science-driven, product development services throughout the drug discovery and development process to enable pharmaceutical and biotechnology companies to achieve their development goals. Comprehensive services include drug metabolism and pharmacokinetics, analytical testing and formulation development, preclinical and clinical trial material manufacturing, bioanalysis, preclinical safety and toxicology assessment and early phase clinical studies. Frontage has enabled many biotechnology companies and leading pharmaceutical companies of varying sizes to advance a myriad of molecules through development and file regulatory submissions in the United States, China and other countries.

© 2020 Frontage Laboratories, Inc.VISIT US AT: frontagelab.com8.

References1. US Department of Health and Human Services (2014) The health consequences of smoking: 50 years of progress: A report of the

Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health,

https://www.ncbi.nlm.nih.gov/books/NBK179276/?report=reader

2. May 2020 is the deadline as of this publication, but it is subject to possible change.

3. Content and Format of Substantial Equivalence Reports; Food and Drug Administration Actions on Substantial Equivalence Reports, Federal Register, April 2, 2019.

4. https://www.fda.gov/media/104674/download

5. Guidance for Industry: Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems, FDA, June 2019.

6. https://www.fda.gov/news-events/press-announcements/fda-permits-sale-two-new-reduced-nicotine-cigarettes-through-premarket- tobacco-product-application

7. Hanson, K. et al., Measures for assessing subjective effects of potential reduced-exposure products, Cancer Epidemiol. Biomarkers Prev. 18, 3209-3224, 2009.

8. https://www.safetypharmacology.org/AM2012/am12presentations/Klein_PD_AbuseLiability.pdf

9. https://www.fda.gov/consumers/consumer-updates/fda-encourages-more-participation-diversity-clinical-trials

10. Gregg, E.O. et al, An approach to the validation of biomarkers of harm for use in a tobacco context, Regul. Toxicol. Pharmacol. 44, 262-277, 2006.

11. Scherer, G., Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: A literature review, Regul.Toxicol. Pharmacol. 94, 203-233, 2018.



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