Smoking is addictive and causes a number of serious diseases, such as cardiovascular disease, lung cancer, and chronic obstructive pulmonary disease (COPD). Despite existing strategies to reduce smoking-related harm (i.e., preventing initiation and promoting cessation of smoking), it is estimated that more than one billion people worldwide will continue to smoke in the foreseeable future (Eriksen et al., 2015).
More recently, Tobacco Harm Reduction has emerged as an additional approach to address the health risks of smoking (World Health Organization (WHO) study group on tobacco product regulation, 2008; Zeller et al., 2009). Tobacco Harm Reduction was defined by the U.S. Institute of Medicine (IOM) as “decreasing total morbidity and mortality, without the complete elimination of tobacco and nicotine use.” The IOM referred to “potentially reduced-exposure products (PREPs) as having reductions in exposure to one or more tobacco toxicants” (Institute of Medicine, 2001). Tobacco Harm Reduction is based on encouraging smokers to switch to less harmful products that emit significantly lower levels of toxicants while providing levels of nicotine comparable to cigarettes. The U.S. Family Smoking Prevention and Tobacco Control Act embraces the concept of Tobacco Harm Reduction and defines a modified risk tobacco product (MRTP) as any tobacco product that is sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products (Food and Drug Administration (FDA), 2009).
Candidate MRTPs include products such as e-cigarettes and heat-not-burn products as well as other smokeless tobacco products
Effective Tobacco Harm Reduction requires that a significant number of smokers adopt available MRTPs, meaning that MRTPs must be designed to minimize product risk while maximizing product acceptance by smokers. Therefore, an effective MRTP must meet two conditions:  it must significantly reduce the risk of disease compared with cigarettes, and  it must be acceptable to smokers and encourage them to switch while neither appealing to non-smokers nor being perceived as an alternative to quitting (Institute of Medicine, 2001).
To address a range of consumer needs and thereby ensure the broadest possible adoption of reduced-risk alternatives, the industry is developing a portfolio of products, including heated tobacco products (i.e., heat-not-burn products), e-vapor products (i.e., e-cigarettes), oral tobacco, and nicotine products.
Evaluating candidate and potential MRTPs for their potential to significantly reduce smoking-related disease and death requires a robust, science-based assessment framework (Kozlowski and Abrams, 2016; Morven Dialogues, 2015), implemented by companies in the industry (Murphy et al., 2017; Smith et al., 2016a). As a result, numerous studies conducted with
Recently, several independent reports and studies reviewing the available science on heated tobacco and e-vapor products have been published:
In our view, while evidence regarding the harm reduction potential of candidate MRTPs has accumulated rapidly in the scientific literature, it is essential to share the scientific basis of product assessment and the available methods as well as the data and results of assessment studies to enable their independent review and analysis.
Since the report by Begley et al. showing that many key cancer studies could not be reproduced, attention has been drawn to scientific reproducibility issues (Begley and Ellis, 2012). Peer review, which plays a major role in scientific quality control, has revealed its limits, and several studies have highlighted possible reasons why much peer-reviewed scientific literature is not reproducible (Begley and Ioannidis, 2015; Couchman, 2014; Drubin, 2015; Frye et al., 2015; Gaudart et al., 2014; Iorns and Chong, 2014). The key contributing factors include inappropriate study designs, lack of validation of reagents, inadequate documentation of methods and datasets, and insufficient sharing of data and methods with the community, which are essential for an experiment’s analysis or replication.
Consequently, this “crisis in science” calls for a significant shift to better practices (e.g., (McNutt, 2014)) desired by scientists, funders, and regulatory agencies (in addition to the general public). Such a change should allow meaningful meta-analyses, hypotheses formulation, and the development of robust scientific methods. For scientists to further advance science, the following points should be considered (Freedman et al., 2017):
Beyond the experiments and how they are reported, disclosing potential conflicts of interest (COI) adequately and giving the proper credit to researchers are critical. Although industry-funded research is often met with skepticism, research that is industry-funded should be identified as such. A number of publications presented data suggesting fact that industry funding increases the likelihood that researchers will produce pro-industry conclusions and suppress the publication of negative findings (Babor and Miller, 2014). However, one may also consider the fact that drugs entering industry-sponsored clinical trials may have been more thoroughly vetted and are therefore more likely to be safe and effective, as compared with drugs entering academic trials (Del Parigi, 2012). In a perspective article, Barton and colleagues reported that they could not find any data showing that financial conflict of interest actually leads to a decrease in scientific quality (Barton et al., 2014).
Processes and/or platforms such as INTERVALS that encourage transparent sharing of data in a way that allows easy review and understanding will facilitate
The quantitative assessment of the risk reduction potential of candidate and potential MRTPs involves (i) the use and/or development of state-of-the-art methods in regulatory and systems toxicology, (ii) a deep knowledge of the mechanisms that lead to smoking-related diseases, and (iii) expertise in the design and conduct of clinical studies aimed at substantiating reduced exposure and risk in adult smokers.
Toxicity testing is at a turning point now that long-range strategic planning is in progress to update and improve testing procedures for potential stressors. The U.S. Environmental Protection Agency (EPA) commissioned the U.S. National Research Council (NRC) to develop a vision for toxicity testing in the 21st century (Committee on Toxicity Testing and Assessment of Environmental Agents, 2007; Krewski et al., 2010; Thomas et al., 2013) to base the new toxicology primarily on Pathways of Toxicity (PoT) (Basketter et al., 2012). The report by the NRC envisions a shift away from traditional toxicity testing and toward a focused effort to explore and understand the signaling pathways perturbed by biologically active substances or their metabolites that have the potential to cause adverse health effects in humans. This understanding should allow researchers to:
Systems toxicology (Sturla et al., 2014), or
The identification of pathways of toxicity is imperative in order to understand the mode of action of a given stimulus and to group together different stimuli based on the toxicity pathways they perturb. The first component of the vision focuses on pathway identification, which is preferably derived from studies performed in human cells or cell lines using omics assays. The second component of the vision involves targeted testing of the identified pathways in whole animals and clinical samples to further explain toxicity pathway data. This two-component toxicity testing paradigm, combined with chemical characterization and dose-response extrapolation, delivers a much broader understanding of the potential toxicity associated with a biologically active substance. Systems biology plays an important role in this paradigm, consolidating large amounts of information that can be probed to reveal key cellular pathways perturbed by various stimuli (Sturla et al., 2014). Of importance, moving to mechanism-based assessment comes with its own challenges and requires new ways to assess literature data (Smith et al., 2016b; U.S. EPA (U.S. Environmental Protection Agency), 2014).
Importantly, omics technologies used to characterize the effect of different exposures molecularly also allow detailed descriptions of what each individual is exposed to (i.e., the exposome). For example, the EXPOsOMICS consortium (Vineis et al., 2017) aims at characterizing the external and internal exposome in relation to air pollution and water contaminants (Turner et al., 2018). Methods developed in this field are relevant to Tobacco Harm Reduction science, and vice versa, so a conversation between the relevant stakeholders through community platforms, such as INTERVALS, is highly relevant.
Furthermore, 21st century toxicology has identified the promise of new technologies and the need for large-scale efforts. Aligned with the 3Rs strategy — which states that animal use in scientific research should be reduced, refined, and replaced — in vitro studies using relevant test systems and systems biology approaches offer new prospects in the field of human toxicology (Daneshian et al., 2011). It is important that synergies are established between different laboratories to ensure that the best possible methods are developed and validated for regulatory consideration.
In drug development and toxicological risk assessment, compound testing usually starts
In vitro models capture events efficiently at molecular, cellular, and, at best, tissue levels and can be used to study transport rates across epithelia, toxicity, and mechanism of action (Fernandes and Vanbever, 2009). However, the fourth level of biological organization, which includes the physiological functions of an organism, can only be mimicked in the whole animal (Barré-Sinoussi and Montagutelli, 2015; Choy et al., 2016).
In addition to physiology, the organ of a living animal has advantages over in vitro models, especially in
Therefore, despite criticism, animal models continue to serve an important role in human disease research and toxicological assessment (Denayer et al., 2014; Simmons, 2008; Vandamme, 2014). However, considering the genetic differences between species, it is crucial to gain a detailed understanding of the similarities and differences between the experimental test system and the human disease or mechanism(s) that it is intended to model. Inter-species comparisons conducted solely at the molecular level are generally
Philip Morris International R&D initiated the creation of INTERVALS with the intention to build an online platform enabling independent, third-party collaboration and data analysis by sharing protocols, tools, and data from assessment studies proactively. The site and associated data warehouse are developed in collaboration with Emakina and Douglas Connect GmbH.
In order to address concerns of reproducibility, INTERVALS was built using the latest standards in data sharing and reproducible research to gather all relevant information regarding the design and conduct of studies, as well as their results and data files, in a single place. This should enable easy review of the methods and results as well as reuse of the data and generation of new hypotheses.
Historically, the name INTERVALS corresponded to INhalation Toxicology rEpositoRy for noVel tobAcco & aLternative productS. While setting up the platform, we realized it had the potential to go beyond inhalation toxicology assessment and to also include clinical study designs and results or other population studies. The name remains relevant, as it also highlights the fact that the platform is intended to share the scientific assessment of products positioned in the interval between continuous cigarette smoking and smoking cessation transparently.
Candidate and potential MRTPs are largely developed and, so far, assessed by tobacco companies. In order to establish the validity of the findings, and in line with the possible ways Bauchner and colleagues described to restore industry’s credibility (Bauchner and Fontanarosa, 2013), the INTERVALS platform will (i) provide public access to the data of industry-sponsored research, (ii) enable academic scientists to (re)analyze the data, and (iii) report the contributions and identities of all persons involved. Moreover, to ensure the scientific integrity of the platform, an independent editorial board will ensure that the platform remains focused on protocols and data relevant to MRTP assessment. The INTERVALS platform aims to complement rather than replace the publication and peer review systems. Most studies published on INTERVALS will likely be published in scientific journals. The INTERVALS platform will allow researchers to find all relevant information, (more) detailed protocols, and, most importantly, interoperable data files in a single platform to allow independent reanalysis of key findings, meta-analyses, and efficient data reuse. It will also encourage communication by enabling constructive feedback on studies and protocols and will foster education by providing reference texts and media on diverse topics relevant to MRTP assessment.
The scientific community is invited to use the platform to learn about and/or share their own results and data sets generated with potential and candidate MRTPs, such as heat-not-burn and electronic cigarettes, so that the INTERVALS platform becomes a comprehensive data repository. The portal allows users to browse the data by product, study, diseases, and pathways or endpoints and obtain relevant information related to study design, methods, and, most importantly, results from preclinical as well as clinical studies.
The INTERVALS platform, specifically the protocols section, also aims to facilitate alignment of best experimental practices and promote understanding of best methodologies for assessment of these novel products.
The INTERVALS platform has been designed to be easy to use and enable easy retrieval of relevant information. It is built to become a community platform; therefore, feedback is very important, and we invite you to contact us to share any comments you may have. We hope that INTERVALS will foster a much-needed collaboration between scientists in academia, industry working groups, and regulatory bodies so that MRTPs fulfill their potential for Tobacco Harm Reduction.
An independent editorial board will be assembled to review datasets and studies suitable for publication on INTERVALS, as per COPE guidelines for Editors.