Dr Sharon Goodall.
Dr. Sharon Goodall joined British American Tobacco (BAT) in 2009, taking on a number of successive roles in both product development and scientific research. She originally graduated with a B.Sc. in biomedical science and a Ph.D. in food science and engineering. More recently, Goodall was head of vapor product development at BAT’s US subsidiary, followed by becoming group head of new sciences, curating BAT’s “Beyond Nicotine” scientific research strategy. At present, Goodall is group head of regulatory science at BAT’s global r&d hub in Southampton, UK, where she currently leads the scientific substantiation of BAT’s tobacco harm reduction strategy. Sharon is a mother of two children under five, an outdoor enthusiast, and ex-soldier who — pre-Covid — like many others, enjoyed traveling.
In order to be recognized as MRTPs, products must undergo extensive testing to provide robust evidence to the US regulator, the Food and Drug Administration (FDA), to demonstrate that their consumption indeed bears a lowered health risk compared to conventional tobacco products. Among many other parameters, the studies often use biomarkers as a “surrogate endpoint” or way of showing their potential.
Tobacco Asia (TA): Dr. Goodall, what are “bio-markers”, generally speaking?
Dr. Sharon Goodall (SG): A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, a toxicological condition, or a disease. A biomarker can be used to establish how a human body reacts to exposure to certain toxicants or potentially health-impairing sub-stances, for instance those contained in a tobacco product.
The [US] FDA has described a biomarker as a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic intervention. There are many different biomarkers which can be used to assess various clinical and toxicological parameters, such as safety, diagnostic, prognostic, risk, predictive, monitoring, response.
TA: Which biomarker types are important in the context of BAT’s research? How are they defined and how do they differ from one another?
SG: There are three biomarker types that we generally use in our research:
Biomarkers of Exposure (BoEs) are defined as a tobacco constituent or metabolite that is measured in a biological fluid or breath in human subjects participating in clinical studies, or in [human] tissue - such as cells analyzed in vitro - that has the potential to interact with a biological macromolecule. Within our studies we normally measure priority harmful and potentially harmful constituents [HPHCs] that have been identified in tobacco and tobacco smoke associated with potential smoking related disease development. In the case of [BAT’s] reduced risk products [RRPs] these have on average 90% lower toxicant emissions and, therefore, when a smoker switches to these products completely we see a significant reduction in these BoEs in the blood, urine, and breath of study participants.
Biomarkers of Potential Harm [BoPHs] are biomarkers associated with the effects of exposure to tobacco smoke constituents on the human body. These are generally early responses associated with disease development, including oxidative stress and inflammation, as well as responses associated with disease pathways or conditions, for example the development of atherosclerosis or hypertension. In the case of our RRPs, the expectation is that these [biomarkers] are changed in a beneficial manner in subjects switching completely to these products from smoking combustible cigarettes. For instance, we saw a fractional increase of exhaled nitric oxide in those who switched to a RRP. The blood clotting factor Thromboxane also decreased, as measured by 11-DTXB2, in those who completely switched. In both cases, these measures trend towards levels seen in never-smokers and quitters, and dem-onstrate the potential positive impact of smokers switching completely to a RRP. However, it should be noted that smoking is not the only factor that affects the levels of these biomarkers. Lifestyle factors such as fitness, diet, illness, and environmental exposures can also have an effect.
Thirdly, we use Biomarkers of Compliance, which monitor [the] product use status in our studies. In the case of the 12-month study of [BAT’s RRP] glo, the cyanoethyl valine hemoglobin biomarker [CEVal] was used to monitor whether subjects in the glo or smoking cessation arms of the study were compliant and had not used combustible cigarettes. The rationale for this is that CEVal is formed from exposure to acrylonitrile, which is a component of cigarette smoke and rarely found elsewhere, including in the aerosol generated from glo. Therefore, if CEVal did not reduce in those in the smoking cessation and glo arms [branches] of the study, this would indicate par-ticipants had used combustible cigarettes.
TA: Please describe a typical lab study set-up involving volunteer participants and the groups into which these participants would be divided.
SG: All of our clinical studies are conducted to the highest possible standards and follow good clinical practice guidelines. Before starting any study, we gain ethical approval, and all subjects must have signed an informed consent form for the study before screening and enrolment commences. All studies are run by independent clinics, which operate to these high standards, in-cluding approval and supervision from a qualified institutional review board.
For our BoPH clinical study, we have four study “arms”: one in which current smokers continue to smoke as normal; a second in which current smokers switch completely to the study RRP; a third in which current smokers stopped smoking completely; and a fourth in which subjects who had never smoked continue not to smoke or use any nicotine or tobacco products.
This was followed by a randomization of smokers to either continue to smoke or switch to the RRP being tested. For the smoking cessation arm, we tend to recruit volunteers that wish to stop smoking and offer counselling as well as nicotine replacement therapy as required for the study period. Finally, the never-smokers within the study will continue not to use any nicotine or tobacco products for the [entire] study period. Volunteers from all arms will be asked to give monthly blood, urine, and breath samples, the final time-point being at the end of the study period.
TA: What criteria are employed when putting together the volunteer groups? For example, are they selected by age brackets or whether (or not) they are active smokers?
SG: All of our studies adhere to protocols that define inclusion and exclusion criteria. This nor-mally requires participants to be healthy and have no underlying conditions. We also aim to have the [study] arms balanced as much as possible, including age and gender balance, to support direct comparisons and population generalization. Active smokers only are recruited for switching to the RRP, smoking cessation, and continuing-to-smoke arms. It would be unethical to enroll anyone who is not a current tobacco or nicotine consumer into our studies and ask them to use any products containing tobacco or nicotine.
[The volunteers’] compliance with all study instructions is key. For instance, participants are asked to switch to the study RRP and those in the smoking cessation arms should not smoke any combustible cigarettes for the whole study period. To monitor this we use the CEVal biomarker that I already described.
TA: What particular expectations do you have in such studies?
SG: Typically, the same biomarkers are used for all study arms [within any given study] to allow for a direct comparison. We’d expect from these studies that smokers and never-smokers will show little change in their biomarkers at the end of the study period, with smokers having higher levels of BoEs and less favorable levels for the BoPHs compared to never-smokers. On the other hand, the arm switching [to a RRP] along with the cessation arm should show significant reductions [i.e. change from baseline] in BoE lev-els. We know from other data that [RRPs] have on average 90% lower toxicant emissions than [combustible] cigarettes. As for BoPH, we expect favorable changes, which could be an increase – for example in HDL cholesterol - or a decrease, for instance in the white blood cell count.
TA: What are the most commonly used control products in such studies?
SG: In these studies, the control products are combustible cigarettes, where generally partici-pants continue to smoke their own brand products and purchase these themselves as normal. However, studies often include a never-smoked group, whose members also act as a control. There also is the cessation group, which acts as yet another comparator, or control.
TA: How are the various biomarkers typically validated and why is that validation so crucially important?
SG: It is important because it helps define the analytical methods to assess these biomarkers in studies. Validation generally follows FDA and European Medicines Agency guidelines. Reaching scientific consensus regarding the validity, specificity, and sensitivity of particular biomarkers helps to ensure that the scientific community uses robust methods with reproducible results.
The other side to validation or qualification is the extent to which any particular BoPH is shown to be associated with clinical manifestations of disease. BoPHs are early changes which can be detectable in healthy smokers a number of years before the associated diseases are diagnosable. For this, we look at disease mechanisms or path-ways that are associated with and predictive of later clinical presentation, and we have published research pertaining to some of these, including the development of high blood pressure that is a risk factor for heart disease. As BoPHs are early changes associated with disease development, it is important that these changes can be influenced through either reversal or halt in progression, which is what we are looking for when smokers switch from cigarettes to an alternative or quit smoking.
In addition, it is important that we also understand the impact of other factors on biomarkers. For example, some BoEs are affected by environmental exposures. So we need an understanding of how such potentially confounding variables may be eliminated in a study. For some of the BoPH biomarkers measured, lifestyle factors such as diet and a sedentary lifestyle can have a significant impact on disease development. Thus, this knowledge needs to be factored into our study design to reduce or manage these variables.
TA: What is “real world evidence”? How does it come into play in RRP or MRTP research and why is needed to effectively validate biomarkers?
SG: Real world evidence is data generated in circumstances that are as close to “normal life” as possible. Often used for post-marketing surveillance, these studies try to assess the impact of a product when used in the real world with minimal intervention, which can over time differ from a controlled study setting. This can be an important way of understanding how products are used and it provides important insights into consumer behavior and real-world impact.
TA: What is population modeling? How does it come into play in RRP research and how is real world evidence used to validate population modeling?
SG: Population modelling is very important. It uses available health and consumer behavior data from previous years to create algorithmic models to predict the possible public health impact of the introduction of particular alternative products by using a variety of assumptions based on available scientific evidence to map out likely scenarios and impact. In the absence of epidemiological data, which can take up to 30 years to generate, this can be a very powerful tool to demonstrate the potential long-term impact of a reduced-risk product. Regulators and public health authorities have increasingly recognized the key role played by population modeling studies.
TA: And a final question. We sometimes read about “combustible reduced toxicant prototype” – or “RTP” - in older BAT studies. Is that the actual product whose reduced health risk was assessed during the course of a study?
SG: That term, RTP, has now become obsolete. It was used for the first- and second-generation combustible reduced toxicant products studied in 2008/09 and 2012. These consisted of experimental, novel designs for combustible cigarettes that followed on decades of research aimed at trying to make conventional cigarettes less risky. But a decision was taken not to pursue this approach due to lack of meaningful progress soon after 2012, and we invested in the development of a portfolio of alternative tobacco and nicotine products, including vapor, heated tobacco, and modern oral products. We continue to perform extensive research and development to generate new evidence to scientifically substantiate the reduced-risk potential of each of our [RRP] flagship brands: Vuse, glo, and Velo. We have invested more than £1billion since 2017 into research and development of these products and continue to conduct cutting-edge research so that we can deliver on our purpose of building “A Better Tomorrow.”