New tobacco products are being developed to provide an alternative to conventional tobacco products: Electronic Nicotine Delivery Systems (ENDS), leaf-free oral products, and heat not burn are prime examples. Cardno ChemRisk scientists are well positioned to address regulatory challenges related to reduced harm nicotine products. Clients get convenient, one-stop access to a team of respected experts dedicated to understanding and resolving the issues surrounding alternative nicotine products. Our mission is to provide clients with innovative risk assessment services and solutions that maximize the technological advancements of these products, while minimizing the risk to humans and the environment. We have extensive experience supporting clients’ regulatory needs involving nonclinical, clinical, and behavioral evaluation of nicotine products. 

Nicotine Regulatory and Premarket Application (PMTA) Support Services


Company and Team Overview

ChemRisk scientists take an integrated, multi-disciplinary, and collaborative approach to evaluating the public health impacts of nicotine products for Premarket Tobacco Application (PMTA) submissions for the U.S. Food and Drug Administration (FDA), as well as international regulatory submissions outside the U.S.

Our experts have pioneered and helped popularize many of the approaches used in the risk assessment field, both in the U.S. and abroad. We have presented more than 1,000 papers at scientific conferences and published greater than 600 papers in scientific peer-reviewed journals.  Cardno ChemRisk professionals have a longstanding reputation for thorough scientific analysis, which is frequently referenced in regulatory decision-making and scientific proceedings.

Cardno ChemRisk has experience serving as an interface between industry and regulators. We have significant familiarity with the kinds of information that regulators use to drive decision making and can often predict probable science-driven regulatory outcomes.  Our experience both responding to and predicting regulatory action distinguishes us from our competitors.

Cardno ChemRisk has supported numerous PMTAs for open and closed system electronic nicotine delivery systems (ENDS), oral nicotine products, and e-liquid products, which has ranged from providing targeted nonclinical or clinical support to leading and executing entire comprehensive PMTA research programs.

Expertise and Experience

Our team of scientists, who support regulatory nicotine and ENDS work, have expertise in toxicology, exposure assessment, human health and environmental risk assessment, environmental fate and transport modeling, biostatistics, analytical chemistry, product testing, aerosol science, microbiology, epidemiology, clinical research, behavioral research, surveillance studies, database development, systematic literature reviews, and physiologically based pharmacokinetic (PBPK) modeling.

Our experts have presented and published on a broad range of toxicology, chemistry, clinical, and health risk related topics.

See List of Presentations and Publications ➞

Our experts have supported regulatory submissions for:

  • FDA Center for Tobacco Products (CTP)
  • Medicines and Healthcare products Regulatory Agency (MHRA)
  • National Institutes of Health (NIH) National Institute of Drug Abuse (NIDA)

Nicotine Regulatory Support Services

Navigate on this page to:

-Research and Development and Product Stewardship
-Product Testing and Chemistry Research
-Toxicology Research
-Microbial Research
-Human Health Risk Assessment

 

-Clinical Research
-Behavioral Research
-Systematic Literature Review
-Environmental Assessment
-Regulatory Submission Authoring and Support


Research and Development and Product Stewardship

Overview:

  • Product stewardship involves the science required to design, produce, and manage products throughout their lifecycle that protects people and the planet.
  • Product stewardship is multifaceted with research and development of innovative products founded on science-based evaluations to inform human and environmental health risk.
  • The benchmark of appropriateness for the protection of public health (APPH) in the context of the PMTA will continually evolve and require a product stewardship approach for product sustainability.

Expertise:

  • Cardno ChemRisk scientists are well versed in the integrated scientific approach needed to design products with public health, product stewardship, and environmental, social, and governance in mind.
  • Our scientists have supported industry to design and execute comprehensive product stewardship programs that are founded in quality science, integrated with product innovation, and combined with stakeholder engagement.

Services:

  • Product stewardship program development and management
  • Research program development
  • Ingredient hazard, toxicology and risk evaluation
  • Product performance testing design
  • Product quality, specification, and stability evaluation
  • Product exposure and human health risk assessment
  • Product environmental assessment
  • State-of-the-science and art analyses
  • Systematic literature reviews
  • Stakeholder engagement

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Product Testing and Chemistry Research

Overview:

  • Product testing and characterization is the foundation for evaluating product quality and stability, consumer exposures, human health risk, and the potential for abuse liability. Testing of harmful and potentially harmful constituents (HPHCs) and leachables in the product and in aerosol of electronic vapor products (EVPs) over the anticipated shelf-life is a critical component of the PMTA.

Expertise:

  • Cardno ChemRisk scientists are trained in analytical chemistry, aerosol science, consumer product safety, data analysis, inhalation toxicology, exposure science, and human health risk assessment.
  • Our team of scientists take an integrated approach of product testing study design to fully inform:
    • Product design, stability, and performance
    • Product human health risk assessments
    • Toxicology and clinical study design
    • Data and weight of evidence integration
    • Scientifically robust bridging strategies

Services:

  • Study design, laboratory management, data analysis, and synthesis of findings of nonclinical research, including:
    • Liquid and aerosol physicochemistry
    • Product performance
    • Product storage and stability
    • Extractable and leachable studies
  • Database development for integration of product testing data, toxicology information, and health-based guidance values to inform health risk
  • Product stability and specifications analysis
  • Systematic literature reviews
  • Regulatory submission authoring

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Toxicology Research

Overview:

  • Toxicological assessment of HPHCs, extractables and leachables, product and flavorant ingredients, and overall product mixtures is a critical component of the PMTA for evaluating consumer exposure, human health risk, and product APPH.

Expertise:

  • Our trained toxicologists and Diplomates of the American Board of Toxicology (DABT) provide leading toxicological evaluation of a broad range of nicotine products.
  • Our scientists have designed and delivered learning courses for industry and regulators on topics of hazard characterization, dose-response, dosimetry, computational modeling, application of in vitro methods, and derivation of health-based guidance values for risk assessment.
  • Cardno ChemRisk toxicologists are proficient in toxicological evaluation of ingredients to inform on product design, product testing, bridging strategies, and assessment of human health risk.

Services:

  • Study design, laboratory management, data analysis, and synthesis of findings of nonclinical research, including in vitro toxicity testing and in vivo inhalation studies
  • Hazard evaluation, computational modeling (quantitative structure activity relationship modeling – QSAR), and toxicology read-across of product ingredients, HPHCs, extractables/leachables, and target/untargeted chemicals
  • Product database development for integration of hazard characterization, toxicology information, product testing data, and health-based guidance values to inform health risk
  • In vitro in vivo extrapolation (IVIVE) for application of hazard characterization and risk assessment
  • Derivation of health-based guidance values
  • Toxicological profiles
  • Systematic literature reviews
  • Toxicology and risk assessment learning courses
  • Regulatory submission authoring

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Microbial Research

Overview:

  • Microorganisms and associated toxins may be introduced at multiple stages in the production of the tobacco crop, or the production of e-liquid ingredients. Microbial contaminants can consist of a variety of fungi, bacteria, yeast, and mold, and associated toxins (e.g., endotoxins, mycotoxins, and β-glucans). With product age, bacteria and fungi may also produce tobacco-specific nitrosamines (TSNAs).
  • Product stewardship, implementation of Hazard Analysis and Critical Control Plans (HACCP), and a strong quality control plan can help reduce the potential for microbial contamination in tobacco products. Because microorganisms and associated toxins are ubiquitous in our natural environment, microbial testing is a critical component of assuring product quality and consistency over the product lifecycle.

Expertise:

  • Our scientists are skilled in microbial sampling, characterization, identification, and hazard analysis and have conducted multiple microbial risk assessments.
  • Cardno ChemRisk experts have conducted comprehensive literature reviews on microbial contamination in tobacco products and the efficacy of anti-microbial preservatives.
  • Cardno ChemRisk scientists prepare HACCPs, conduct facility inspections and audits, and conduct critical review and root cause analysis (RCA) to identify causes of microbial contamination and development of mitigation measures.

Services:

  • Study design, laboratory management, data analysis, and synthesis of findings of hazard identification and risk assessment
  • Systematic literature reviews
  • Facility compliance audits and inspections
  • Product stewardship and HACCP
  • Regulatory submission authoring

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Human Health Risk Assessment

Overview:

  • Risk assessment is the process by which consumer physicochemical exposures can be placed into context of health risk.
  • Risk assessments of product ingredients, HPHCs, leachable compounds, and microbial organisms and associated toxins are key to evaluating whether a product is APPH or can support a modified risk claim, which are key requirements of the PMTA and Modified Risk Tobacco Product Application (MRTPA) process.

Expertise:

  • Our experts have pioneered and helped popularize many of the approaches used in the risk assessment field, both in the U.S. and abroad.
  • Our scientists have published more than 600 papers in scientific peer-reviewed journals on various toxicology, exposure, and risk-related topics.
  • Our scientists have designed and delivered learning courses for industry and regulators on topics of hazard characterization, dose-response, dosimetry, computational modeling, application of in vitro methods, and derivation of health-based guidance values for risk assessment.

Services:

  • Product risk assessment (including ingredients, HPHCs, leachables and microbials)
  • Risk integration into specifications analysis
  • Hazard evaluation, computational modeling, and toxicology read-across
  • Consumer topography and exposure analysis
  • Product database development for integration of hazard characterization, toxicology information, product testing data, and health-based guidance values to inform health risk
  • In vitro in vivo extrapolation (IVIVE) for application of hazard characterization and risk assessment
  • Derivation of health-based guidance values
  • Toxicological profiles
  • Systematic literature reviews
  • Toxicology and risk assessment learning courses
  • Risk communication
  • Regulatory submission authoring

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Clinical Research

Overview:

  • Clinical research of nicotine products is a critical component of the PMTA and MRTPA process as it informs on abuse liability, consumer behaviors, human factors, and potential foreseeable product misuse.
  • Clinical research for PMTAs and MRTPAs involve studies on pharmacokinetics pharmacodynamics (PKPD), actual product use, smoking cessation, biomarkers of exposure/harm, and label comprehension.

Expertise:

  • Our experts are well versed in clinical research design, execution, and management and have provided clinical research oversight and analysis for numerous regulatory submissions to different agencies within the FDA, including the Center for Tobacco Products.

Services:

  • Study design, laboratory management, data analysis, and synthesis of findings of clinical research, including studies of PKPD, topography, label comprehension, biomarkers, gateway effects, and cessation/switching
  • Systematic literature reviews
  • PKPD data analysis and modeling
  • Regulatory submission authoring

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Behavioral Research

Overview:

  • Behavioral research of nicotine products is a critical component of the PMTA and MRTPA process as it informs on consumer behaviors and their perceptions and intentions of use, likelihood of use, awareness, dual and poly tobacco use, transitional patterns, and cessation.

Expertise:

  • Our experts have designed consumer surveys to evaluate the behavioral aspects of nicotine product use as it pertains to perceptions of initiation, use, appeal, and risk.
  • Our epidemiologists have designed studies to evaluate the gateway effects of ENDS to smoking.
  • Our experts are recognized leaders in sample design for weighted population surveys, which are important for applicability and extrapolation of behavioral research to the general population.

Services:

  • Study design, laboratory management, data analysis, and synthesis of findings of behavioral research
  • Systematic literature reviews
  • Data analysis and modeling
  • Regulatory submission authoring

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Systematic Literature Review

Overview:

  • Providing a synthesis of the published literature and the current state-of-the-science is a requirement of the FDA and is important for identifying opportunities for filling data gaps and bridging to existing data.

Expertise:

  • Our experts in toxicology, chemistry, epidemiology, and clinical and behavioral science are well versed in methods of systematic literature reviews for regulatory applications and have published numerous literature reviews in scientific journals and presented such work at professional national and international conferences.
  • Our scientists have conducted comprehensive literature reviews for FDA CTP submissions involving: in vivo/in vitro toxicology, clinical health, abuse liability and pharmacokinetics, initiation, cessation, transition, switching, topography, human factors, consumer perception, and nationally representative datasets [e.g. Population Assessment of Tobacco and Health (PATH); National Youth Tobacco Survey (NYTS)].

Services:

  • Systematic literature review and synthesis
  • Database development and management
  • Data gap and bridging analysis
  • Data analysis and modeling
  • Regulatory submission authoring

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Environmental Assessment

Overview:

  • The FDA established minimum threshold for accepting PMTA for FDA review. Under § 25.15(a) (21 CFR 25.15(a)), all submissions requesting FDA action require the submission of either a claim of categorical exclusion or an environmental assessment (EA). The omission of an EA in the PMTA could result in a refuse to accept (RTA) letter, or if the EA was not considered adequate, a refuse to file (RTF) letter.
  • The FDA has identified the absence, or an incomplete EA, as the leading cause of RTA or RTF letters for PMTAs.

Expertise:

  • Our scientists have leveraged over 50 years of experience preparing NEPA EAs across a broad range of industries into EAs tailored specifically for the FDA PMTA.
  • Cardno ChemRisk experts have developed innovative methodologies for screening ingredients of complex mixtures (e.g., e-liquids) for identifying constituents warranting a closer examination, as well as calculating Expected Introduction Concentrations (EICs) and Expected Environmental Concentrations (EECs) for chemicals released into the environment during manufacture, use, and disposal of products.
  • Our experts are familiar with the FDA EA requirements relating to confidential information, supply chain, nicotine sourcing, and other critical components of an EA.

Services:

  • Supply chain assessment including interviews
  • EIC and EEC assessments
  • Environmental Assessment including confidential appendices
  • Dossier authoring
  • Facility inspections and compliance audits

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Regulatory Submission Authoring and Support

Overview:

  • Regulatory submissions to the FDA CTP follow a prescribed structure, however synthesis of the research takes an integrated, collaborative, and comprehensive scientific approach among various subject matter experts.

Expertise:

  • Our experts in toxicology, chemistry, epidemiology, and clinical and behavioral science have designed and provided targeted nonclinical, clinical and behavioral research support, as well as served as Principal Investigators in leading, managing, and authoring entire comprehensive PMTA research programs.

Services:

  • Oversight, management, analysis, and authoring of synthesized research findings from nonclinical, clinical, and behavioral studies
  • Coordination and management of publishing and submission
  • Regulatory agency interactions

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Presentations and Publications


Select presentations and publications authored by our scientists include:

  • Parker, J., A.K. Madl, A.D.G Jones, D.J. Lauer, R.K. Brewster, and C. Boles.   Microorganisms and associated toxins in cigarettes, ENDS, and other tobacco-related products: Current state-of-the-science and applications for microbial risk assessment.  Tobacco Science Research Conference, August 29-31, 2021, Boston, MA.
  • Massarsky, A., A. Bonin, Y. Atalay, N. Binczewski, A. Madl, A. Jones. Ecotoxicological screening assessment of e-liquid mixtures using ecological structure relationships (ECOSAR). Virtual poster presentation at the 2021 SETAC Annual Meeting, November 14-18 2021.
  • de Gandiaga, E., A. Hazell, A. Sharma, M. Donnell, A. Massarsky, A. Schulte, A. Bernal, and A.K. Madl. 2021. Exposure and human health risk of metals from electronic nicotine delivery systems. Abstract #2608. Virtual Poster Presentation at the 2021 Society of Toxicology (SOT) Annual Meeting. March 12-26.
  • O’Neill, H.C., M.J. Vincent, A.A. Han, S.E. Brown, A.M. Hazell, M.L. Kreider, and A.K. Madl. Hazard and risk banding framework for prioritization and bridging of e-liquids for toxicity testing. Abstract #2609. Virtual Poster Presentation at the 2021 Society of Toxicology (SOT) Annual Meeting. March 12-26.
  • More, S.L., S.A. Thornton, J.R. Maskrey, A. Sharma, E. de Gandiaga, T.J. Cheng, E.S. Fung, A.J. Bernal, and A.K. Madl. 2020. PBPK modeling characterization of potential acute impairment effects from inhalation of ethanol during e-cigarette use. Inhal Tox. 32(1):14-23.
  • Madl, A.K., Unice, J.R. Maskrey, and A. Bernal. 2019.  Nicotine profile across a range of e-cigarette user conditions: Validation of a pharmacokinetic model. Poster presented at the annual meeting of the Society for Research on Nicotine & Tobacco, February 20-23, 2019, San Francisco, CA.
  • Bernal, A., E. de Gandiaga, T. Cheng, A. Sharma, A. Schulte, and A.K. Madl. 2019. E-cigarette topography: State-of-the-science analysis and considerations for human health risk assessment. Poster presented at the annual meeting of the Society for Research on Nicotine & Tobacco, February 20-23, 2019, San Francisco, CA.
  • de Gandiaga, E., A. Bernal, T. Cheng, A. Schulte, and A.K. Madl. 2019. Aldehyde concentrations produced across different generations of electronic cigarettes meta-analysis and risk assessment of aerosol concentrations. Poster presented at the annual meeting of the Society for Research on Nicotine & Tobacco, February 20-23, 2019, San Francisco, CA.