Category: Science

Relx Opens Bioscience Lab to Research E-Cigs

Photo: RELX Technology
RELX Opens Bioscience Lab to Enhance E-Cigarette Research
RELX Technology has started operations at its newly established e-cigarette bioscience laboratory to conduct systematic research on the effects of e-cigarettes through in vivo and in vitro tests, as well as conduct pre-clinical safety assessments.
Located in Shenzhen, China, the bioscience laboratory is currently conducting research on the impact of RELX products on animal cardiovascular, respiratory, and nervous systems, to better carry out a comprehensive impact evaluation of vapor products.
“Science is the foundation of trust. As the industry leader, we have the responsibility to expand the borders of e-cigarette science and explore the unknown,” said Kate Wang, founder and CEO of RELX, in a statement.
At the company’s recent lab open day, RELX also announced its plan to establish a “1+4” scientific research approach—i.e. anchored by platform development, followed by toxicological assessment, clinical assessment, perception behavior study and long-term assessment.
“E-cigarettes are sometimes viewed with suspicion because we have incomplete knowledge,” said Yilong Wen, RELX Co-founder and head of science, research and development and supply chain, “The RELX bioscience lab’s mission is to explore the unknown. We want to collect evidence through a scientific approach and strive to prove the potential for e-cigarettes to be less harmful, and in doing so, provide users the option to choose an alternative.”
To ensure the reliability and quality of its products, RELX established a chemical and physical laboratory in 2018. The laboratory is certified by the internationally recognized China National Accreditation Service for Conformity Assessment.
RELX is currently conducting research projects on different topics with six universities including the Sun Yat-sen University and Shenzhen Institutes of Advanced Technology, the Chinese Academy of Sciences, two hospitals and nine scientific research institutions.
September 18, 2020
PMI: Public Wants Science-Based Policies

Moira Gilchrist
Citizens around the world want governments, public authorities and private businesses to prioritize science and facts when tackling critical issues, according to a white paper prepared by Philip Morris International (PMI) with research from Provaddo.
“Science can help make significant strides in our collective efforts to address the world’s most pressing problems” said Moira Gilchrist, vice president for strategic and scientific communications at PMI.
“Unfortunately, governments and broader society have yet to embrace science at its fullest potential as this global survey shows. Ensuring facts and evidence are given greater prominence in policymaking—over ideology, politics and unsubstantiated beliefs—will help match the public’s expectations for science to sit at the heart of decisions impacting them and their future.”
Science is crucial to PMI’s ambition to deliver a smoke-free future. “With the right regulatory encouragement and support from civil society, we believe this goal can be achieved in many countries in 10 [years] to 15 years,” the company wrote in a statement.
September 14, 2020
BAT to Fund Lexaria Bioscience Research

Photo: Michal Jarmoluk from Pixabay
Lexaria Bioscience Corp. has entered a research and development framework agreement with British American Tobacco (Investments) Limited (BAT) to investigate Lexaria’s technology for potential use in nicotine products.
R&D work under the agreement will be paid for by BAT.
“Lexaria is pleased to work with British American Tobacco on these research and development activities,” said Lexaria CEO Chris Bunka in a statement.
The agreement does not contemplate development of oral nicotine consumer products in North America, given Lexaria’s existing North American relationship with a leading U.S.-based tobacco company. The agreement is expected to be completed within six months, though provisions exist to extend the agreement if required.
Based in Kelowna, British Columbia, Canada, Lexaria is a global innovator in drug delivery platforms. The company has developed and markets DehydraTECH, which allows cannabidiol and other oils to be dehydrated into an odorless, tasteless powder and mixed with xanthan gum, corn flour and other base ingredients that can then be added to foods, drinks and creams.
It also allows drugs and—in the case of CBD—vitamins to enter the bloodstream faster than existing drug delivery platforms.
September 2, 2020
A Journey, Not a Destination
Photo: BNS
Navigating successful post-market requirements for ENDS products
By Yvonne Wilding
This month marks the deadline for submitting premarket tobacco applications to the U.S. Food and Drug Administration (FDA). Many organizations have worked diligently to ensure their submissions are as complete and robust as possible. Their goal is to ensure that they are sufficiently complete to allow acceptance for filing and, following substantive review, that the product may be granted a market order by the FDA, allowing it be sold in the United States. By early September, hundreds of PMTAs for electronic nicotine-delivery systems (ENDS) had been submitted to the FDA, and a number are currently undergoing substantive review.
However, in this article I will remind applicants that their obligations do not stop at PMTA approval but persist for the entire life cycle of the product in market—and products can be removed from market potentially more easily than they can be brought to it.
During its PMTA review, the FDA extensively evaluates the provided experimental data to make a risk-benefit assessment of the new product and ascertain its suitability to be designated as “appropriate for the protection of public health” (APPH).
This includes scrutinization of the quality and compliance aspects of the manufacturing processes and review of extensive research information generated on the specific product to allow the FDA to evaluate any potential public health risks associated with the product. The research aspects are compiled by the applicant into different modules of the eTobacco Technical Dossier and include chemistry and manufacturing, toxicology risk assessment and clinical and human experience evidence.
There will be a series of investigations in human volunteers to look at the pharmacokinetics (PK) of the product and its delivery of nicotine compared to comparator products. The PK profile of a product has the potential to affect the abuse potential—i.e., how easily someone may become addicted to nicotine. In addition, there will typically be several human behavior studies to check that the users can operate the device safely and effectively and to assess their preference for this product against competing products. Additionally, there is a significant amount of research done in never-smokers to ascertain how likely they are to start smoking with this product. The numbers of volunteers in the studies are often very large and care is taken to look not only at a representative U.S. population from their demographics but also to incorporate a significant number of young adults in order to be able to make extrapolations to a youth (11–18 years of age) population.

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The research data provided to the FDA also includes extensive data on the performance of the device in laboratory-controlled conditions and its delivery of nicotine in each puff under different device settings and different coil components. Stability of the product on storage and extractables and leachables are measured, and quantitative data on the discharge of harmful and potentially harmful constituents (HPHCs)—a list of 33 chemicals of most toxicological concern detailed in the FDA guidelines) is collected. The toxicology and the chemistry data are linked to consumer behavior information and topography data to indicate how a consumer will use the product, enabling the estimation of the likely exposure to potentially hazardous aerosolized constituents and hereby the risk-benefit of this new product can be ascertained.
Assessing the actual product though, is only part of the information required. The product must also be assessed for risk-benefit alongside data from existing relevant tobacco-containing products, much of which is obtained from scientific publications. These comparator products would typically be combustible cigarettes or similarly performing ENDS. It would be wrong to assume that ENDS are without risk, but in a PMTA, the risk relative to other comparator products, e.g., combustible cigarettes, is described. Based on this assessment of these actual and relative risk estimates, the FDA will decide on whether the product is APPH. This approval process can be considered the first step of the journey.
There are several regulatory documents published by the FDA Center for Tobacco Products (CTP). These include Guidance for Industry and Proposed Rule, both of which have sections on post-marketing requirements, although most detail is provided in the Proposed Rule (Federal Register Vol. 84, No. 186, 25 Sep. 2019, Subpart D – Postmarket Requirements section, $1,114.39–$1,114.41).
Having been granted a market order from the FDA, there is an explicit ongoing commitment for each approved SKU to collect and provide information and submit it for regulatory review. Following each review, the FDA will consider whether it is appropriate that the product is maintained in market. Reasons why the FDA may decide to remove a product from market could include any of the following: the product is no longer considered to be APPH; there is inaccurate representation of factual data, the applicant has not set up a system for maintaining records and/or fails to make appropriate records and submit reports.

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The post-marketing updates required by the FDA can be put into three main categories: changes to manufacturing processes and controls; changes to the health risks associated with the product; and sales, distribution and marketing information.
Periodic reports need to be submitted to CTP within 60 calendar days of the reporting dates which will be specified in the applicant’s marketing order and must include the following:
Manufacturing and processes
A description of changes to the manufacturing, facilities or controls during the reporting period
An explanation of why the changes were made and why these change do not result in the generation of a new tobacco product that is different from the one for which the original order was granted
Health risks
An inventory of ongoing and completed studies by or on behalf of the applicant that have not previously been reported
Full reports of information published or known, or which should be reasonably known, to the applicant concerning scientific investigations and literature about the tobacco product that have not been previously reported
Significant findings from publications not previously reported
A summary and analysis of all serious and unexpected adverse experiences reported to the applicant or that the applicant is aware of
A statement of any changes to the overall risk associated with the product and a summary of the health risks, including the nature and frequency of the adverse experience and potential risk factors
Sales, marketing and distribution
A summary of sales and distribution of the tobacco product for the reporting period to include:
Total U.S. sales and demographic characteristics of purchaser
Specimens of labelling and detail of any changes
Full-color copies of all advertising material used with dates of dissemination
A description of advertising and marketing plans
Actions taken to restrict youth access and limit youth exposure to labelling, advertising or promotion
Use of social media
Use of partners, influencers or bloggers
An assessment of the impressions left by advertising and audience demographics
In addition to the above categories, there is also a requirement to provide any additional information specified or any additional requests under the terms of the marketing order and an overall assessment of how the product continues to be APPH.
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As well as the requirement for regular submission of post-marketing reports, if there are any serious and unexpected adverse events reported to the applicant, these must be reported to CTP’s Office of Science via the Health and Human Services Safety Reporting Portal within 15 days of the applicant having received the report.
There are strong concerns among the public, health policy makers and government that the potential health benefits of switching smokers from combustible cigarettes to a less harmful way of accessing nicotine may be dramatically offset by young nonsmokers being attracted to vapor devices and through use of these devices drive an increase in nicotine addiction in youth. Smoking volumes of combustible cigarettes have been falling for many years across the world, which will ultimately lead to significant improvements in health, although the evidence will take several years to become apparent. Understandably, there is much enthusiasm that the scourge of tobacco smoking-related diseases may be, if not eliminated, significantly reduced in future generations.
It is in the interest of consumers who may wish to move to a safer form of nicotine intake that PMTA applicants are fully compliant with the post-marketing requirements and continue to work with the FDA and lobbyists to contribute to and maintain an appropriate balance of risk reduction and health benefit realization. If these products, stated to be APPH, are no longer available to consumers, then the consumers’ opportunity to potentially improve their long-term health outlook is diminished.
Many of the larger companies manufacturing ENDS products may have specific regulatory compliance staff and sales and marketing departments that are fully trained, equipped and resourced to deal with the FDA requirements, but for the smaller organizations, without such infrastructure, this resource requirement, skill set, potential complexity and the associated costs, particularly if the organization has a large number of SKUs, can be particularly onerous.
The cost and resource requirements of maintaining established products in market has been recognized in the pharmaceutical industry for a very long time. As pharma companies typically prefer to invest in novel medicine development or in the enhancement of existing medicines to provide patent life extensions, some older, established products are still very successful and so the maintenance of the post-marketing requirements of these products from a regulatory and pharmacovigilance perspective is often outsourced to specialist contract research organizations (CROs) who collect and report this data on behalf of the pharma companies. These CROs can provide the necessary resources, expertise and experience to make this a cost-effective solution.
It will be interesting to see how many ENDS products are successful in receiving a positive market order decision from the FDA only to be subsequently removed from the market as they fail to satisfy their post-market approval requirements, causing these products to be potentially as ephemeral as the aerosols they disperse.

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Yvonne Wilding is director of product safety and compliance at Broughton Nicotine Services (BNS). BNS operates exclusively in the ENDS sector. Its team of scientific and regulatory experts, backed by its in-house, custom-built contract research organization facility, understands customers’ specific challenges and opportunities. With expertise across the U.S. and EU for tobacco products, medical devices and pharmaceuticals, BNS is committed to working with customers to increase the value of their business and advance a smoke-free future. For more information, visit www.broughton.com.
September 1, 2020
BAT Recognized for ‘Women in Science’
British American Tobacco (BAT) has won a platinum award for its Women in Science campaign.

In February, BAT marked International Day of Women and Girls in Science by celebrating the achievements of its female scientists and shining a spotlight on their research.

The accompanying video has now been recognized by the Association of Marketing and Communication Professionals in the dotCOMM Awards, an international online competition honoring excellence in web creativity and digital communication.

Sarah Cooney
“We are delighted to have won a dotCOMM award for our Women in Science campaign,” said Sarah Cooney, a senior manager in BAT’s Science Comms team. “We know BAT has always championed women’s careers, and this award is testament to the fantastic work being carried out by our scientists here in R&D.

“They discussed their professional journeys and shared what motivated them in their careers, and I hope they have inspired others to seek an exciting career in science.

“The video was incredibly well received on social media, and initiatives like this help us to give people a better understanding of our industry, serving as tools for engagement and recruitment,” Cooney said.
August 12, 2020
Measuring Up

Photo: Broughton Nicotine Services
How instrumentation suppliers and laboratory service providers are supporting customers with their PMTA submissions
By Stefanie Rossel
Although there has been a 120-day extension due to the outbreak of the Covid-19 pandemic, Sept. 9 will definitely be the final day: If a company wants its “recent” tobacco products to remain in the U.S. market, it has to submit a premarket tobacco product application (PMTA) to the U.S. Food and Drug Administration (FDA) by then. In 2016, the FDA announced that all tobacco products not on the market prior to Aug. 8, 2016, would require authorization before entering the market and all products on the market prior to that date would have a grace period during which companies could prepare their PMTAs for submission.
The candidate products will all undergo a several-stage review during which they have to demonstrate with the help of scientific data that they are “appropriate for the protection of public health.” The FDA will consider the risks and benefits of the products not only to the individual but also to the overall population, including whether existence of the product will increase the likelihood of nonusers starting using them. The evaluation also includes reviews of product ingredients, constituents, toxicological profile, health impact, manufacturing and packaging processes as well as labeling.
Tobacco Reporter asked several instrumentation suppliers and providers of laboratory services how they experienced the run-up to the FDA’s extended deadline, which was originally set for May 12, 2020.
“The date for the premarket submission was set well in advance, so there was increased demand but no real ‘rush,’” says Tobias Krebs, managing director of German company Vitrocell, which specializes in in-vitro testing technology.

Ian TIndall
Ian Tindall, head of innovation and marketing at Cerulean, says there has been a noticeable demand for extra testing capacity in the U.S. but that most of this demand was generated in late 2019, and the extension to the submission date had not really been visible.
“The larger companies have had this well organized all the way along, and from our experience, the anticipated rush for testing at the contact research organizations has not been mirrored in a late rush for test equipment,” Tindall explains.
“I should note that the EVALI crisis at the back end of 2019 did generate demand for additional testing of vaping products and a consequent surge in instrument demand, and this did put pressure on the business, but we feel we met all the urgent demands successfully. More recently, some of the focus has moved away from vaping devices towards tobacco-heating products, and we have been increasing supply kits and specialist machines and upgrades for this sector of the industry.”
In February 2019, Cerulean teamed up with Tews, a leading supplier in the field of industrial microwave moisture and density measurement. Cerulean now exclusively markets Tews laboratory devices for the tobacco industry. Based in Hamburg, Germany, Tews also has a U.S. subsidiary. “We can now jointly address emerging requirements for density and moisture testing in the industry and work effectively with clients in this regard,” says Tindall.
Thomas Schmidt
Thomas Schmidt, director of scientific and technical affairs at Borgwaldt KC, a German manufacturer of high-end quality control instruments and precise measurement devices that is part of the Hauni group of companies, notes that the PMTA process was communicated early and the instruments used to generate the data were available. “Besides new developments like our next generation of analytical vaping machines, the NGX series, we have, however, made some modifications to existing instruments—on our LM5SP and LM5SF, for example, which are both intended to collect aerosol in different collections procedures and increased the flexibility in usage to meet the specific demands of certain customers,” says Schmidt.
Broughton Nicotine Services (BNS) has noted a definite increase in demand for its services in the runup to the PMTA deadline, according to Chris Allen, vice president of scientific and regulatory affairs. For many companies, he contends, the PMTA has been the first opportunity to truly characterize and stress test their products.
“This has inevitably led to clients learning more about their products and the need to understand further so that risks can be mitigated and improvements made in the future,” Allen says. “The extension has provided additional time for these companies to perform further characterization and bolster their applications. In addition, we’ve seen a wave of companies who had been delaying the PMTA process or having partial information take advantage of the extension in order to commit to the PMTA pathway.”

Photo: Borgwaldt KC
Heavy workload
Matters are complicated by the FDA’s requirement that applicants file a separate application for each brand variant. For suppliers of instrumentation equipment and labs, this has meant a lot of additional work in recent months. “This has had no impact on our business but has required software development to become FDA compliant,” says Eric Favre, managing director of Sodim, a French company specializing in metrology for the tobacco industry and, like Borgwaldt KC, part of the Hauni group of companies. Sodim has developed a specific device called VPA (vaping puff analyzer). “This device has required adaptations for new formats with specific sample holders,” says Favre.
“The established manufacturers of traditional tobacco products have lots of data available for marked products, which they can provide to the FDA. In [the] case of modified and new products, especially vaping products, the manufacturers were not all aware of what is expected,” Schmidt points out. “These products are newer to the market and do not have sufficient historical data available to refer to. Therefore, we were not surprised that this has led to an increased demand for our next-generation product (NGP) machines and has driven us to develop a new generation of analytical vaping machines, our NGX family and other innovations and modifications within the available Borgwaldt KC portfolio to meet the needs of the market.”
Allen says that although each product is unique, the FDA is accepting “bundled” submissions for multiple products, which enables clients to save cost and tell the “story” of a group of products. “Despite the ability to include multiple products under one submission, the level of analytical testing has been significant,” he says. “We had been planning our expansion in line with the PMTA since 2015 and moved into our new dedicated nicotine products facility in 2018.”
The expansion project was completed in January of 2019 following an investment of £10 million ($12.41 million) into people, facilities, analytical equipment, software development and quality standard certification. The company recruited more than 70 new team members, not only within the analytical function but also across clinical, nonclinical and project management.
Vitrocell observed increased demand for systems with higher output. “We needed to increase our development activities but could tie in new orders in our regular production scheme,” says Krebs.
“We are fortunate that in the way we have set up our supply chain and manufacturing facility we can redeploy resources quickly and keep customers satisfied with extending lead times,” Tindall says. “Some special requests have taken a little longer to fulfill than our standard lead time, but by switching capacity, say, from our standard smoking machines to vaping and THP testing machines, we have managed to meet our delivery commitments. That is not to say we have not met bumps in the road, but the unsung heroes in the back office who keep the production machine running have really risen to the challenge.”

A key part of the PMTA is to understand how your product behaves, what the risks are and therefore what quality control checks need to be in place.
Far-reaching measurements
Testing required for PMTA applications is manifold; it includes the analysis of tobacco and e-liquid constituents, ingredients and additives, especially the 33 substances listed by the FDA as harmful and potentially harmful constituents (HPHCs), smoke and vapor constituents as well as all physical parameters of the products, toxicological assessments and topographic data, notes Schmidt. “We have seen a remarkable increase in interest in our topography products as well as our NGP vaping devices,” he says.
In vitro data play a role in the application too. For Vitrocell, this translated into demand for its exposure solutions. Cerulean witnessed greater interest in its vaping machines, particularly with an accessory that determines the density of the vapor. “We have published a lot of work that shows how this device, primarily designed for showing when an e-cigarette stops effectively forming aerosol, can be used to monitor the full life delivery of aerosol of an e-cigarette device,” Tindall explains. “Beyond measurement is the need from our customers’ perspective for installation and servicing in line with good laboratory practice [GLP], with an installation qualification and an operational qualification step that is properly documented.”
According to Allen, the level of testing required to demonstrate the shelf life of the product, including extractables and leachables, should not be underestimated. “Having the analytical data available is just the start of the process. Conclusions need to be drawn from this data to understand the performance of the product and most importantly to risk assess from a toxicological perspective,” he says. “This is why we saw the creation of the integrated chemistry consultancy and toxicological teams of paramount importance as having these teams on-site enables us to design the analytical studies in line with the end purpose and perform ‘real-time’ risk assessments.” BNS has also developed ToxHQ, a unique internal software tool to complete rapid toxicological screening and risk assessment. The central repository holds chemical data used in e-liquid formulations, including chemical identifiers, properties and classifications, such as HPHC-registered chemicals, Allen says.

Chris Allen
Managing the data
Once the products have been authorized, further measurements will be needed to maintain compliance. “This will be an interesting development over the coming months and as we start to see FDA feedback on the PMTAs,” Allen points out. “It will very much depend upon the product sub-category, e.g., e-liquid, closed system or open device, but the critical point is demonstrating that you have control over the finished product. A key part of the PMTA is to understand how your product behaves, what the risks are and therefore what quality control checks need to be in place as either verification of incoming parts or ingredients, in-process controls or analysis of the manufactured product.”
As an instrumentation supplier, Tindall says the company must recognize that once equipment has been bought, its use might change subtly over time. “We have a mission to ensure that time does not make our products obsolete. Consequently, as part of our product development strategy, we have upgrade paths plotted for most equipment that allows adaptations as regulatory pressures change or research applications and the new products by research demand. One thing beyond ongoing measurement that should not be minimized is the need to ensure that the equipment used is running properly.”
In the course of a PMTA as well as during the control period afterward, massive amounts of data are generated, requiring expert management. Borgwaldt KC’s instrumentation features a data collection tool for this purpose. The company offers a variety of methods for collection, storage and submission of data to the customer’s data management system. “Our products are in compliance with the FDA requirements related,” Schmidt says, “but in general, the quantitative analysis of specific substances is requiring other analytical equipment in the labs.”
Vitrocell offers solutions that enable its systems to be operated with GLP compliance. “Beyond that, data management is performed using the current technology of the customer,” Krebs relates.

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“There is a lot of data generated, and we have worked with a number of customers to ensure that there is a seamless exchange of data with their laboratory information and management systems (LIMS),” Tindall states. “The vast number of LIMS suppliers has meant that we have had to do this on a case by case basis, and we feel we have been successful in this. We are very conscious of the increasing burden of data generation and storage. Our 21CFRpart11 packages, which are available on many of our products, create complex audit trails. The Internet of Things (IOT) and Industry 4.0 initiatives will increase the amount of data on machine performance that is available to an auditor, user or engineer, and this will be the next challenge to face.”
Allen says that the retention of records is critical within any regulatory process. As BNS evolved from its pharmaceutical facility Broughton Laboratories, retention of both hard and electronic data has always been an integral part of the company’s quality management system. “Over the past twelve months, we’ve generated in excess of 200,000 lines of HPHC data for our clients, so effective data management is key. The utilization of LabHQ LIMS, developed by our sister company Broughton Software, including integration with the laboratory instrumentation and dynamic reporting, enables us to manage such large datasets.”
The handful of PMTA approvals to date were granted after long and tedious reviewing processes. Thus far, only three products have received marketing authorization: Swedish Match’s General snus, Philip Morris’ IQOS device and Heatsticks along with two varieties of 22nd Century’s Moonlight cigarettes. What happens when the FDA gets overrun with submissions remains to be seen. Favre expects feedback from the FDA before the end of this year.
“There will be huge amounts of data for the regulators to review,” Schmidt says. “It will be a monumental task to say the least.”
“The FDA [is] undoubtedly going to see a significant number of applications,” Allen comments. “The PMTAs we’ve been working on consist of tens of thousands of pages, so this is going to be a large volume of data for [the] FDA to review. The big question will be how many PMTAs make it through to the review stage, which will impact most on [the] FDA’s resource. Once in substantive review, this very much depends on what additional data is requested by [the] FDA as any major amendment of an application, either by the applicant or at the FDA’s request, would result in a new 180-day review period.”
He concludes: “In the same manner that all regulated industries have had to evolve, the electronic nicotine-delivery systems market will be no different. The PMTA process is simply a starting point, and as the FDA learns more about the products and risks, we’re likely to see further guidance issued—for example, the addition of new analytes and a deeper understanding of other possible chemical reactions and their risks to human health.”
Stefanie Rossel is Tobacco Reporter’s editorial contributor. An experienced trade journalist, she combines sharp reporting skills with in-depth knowledge of the tobacco and vapor industries. Prior to joining Tobacco Reporter, Stefanie was editor-in-chief at Tobacco Journal International, where she worked for a decade. Fluent in English, German and French, Stefanie covers tobacco news around the world. She is based in Germany.

August 1, 2020
Medicago Starts Human Trials of Covid Vaccine

Photo: Dimitri Houtteman from Pixabay
Medicago, a Quebec-based biotechnology company backed by Philip Morris International as well as other large investors, has begun human testing for its Covid-19 vaccine, reports Bloomberg.
The vaccine is derived from the plant nicotiana benthamiana, a close relative to tobacco, to provoke an immune response to the virus.
Medicago’s human trials will involve 180 patients ages 18 to 55. It will test various doses of the vaccine, both alone and combined with two adjuvants—one from GlaxoSmithKline and another from Dynavax Technologies.
If the trial is successful, Medicago plans to start late-stage trials in October and manufacture 100 million doses by the end of next year.
July 15, 2020
Cerulean Partners With Sirius Automation

Photo: Cerulean
Cerulean is partnering with Sirius Automation of Buffalo Grove Illinois, USA, a specialist in the design, development and manufacture of high-quality laboratory automation equipment and solutions.
Ian TIndall
Sirius Automation and Cerulean will collaborate on the supply and marketing of integrated solutions for laboratory automation around the globe. The partnership compliments Cerulean’s existing product offerings and improves the company’s ability to provide leading edge, innovative laboratory automation solutions.
“This partnership between Cerulean and Sirius Automation is fantastic news for our customers, who can now benefit from a wider range of laboratory automation products and solutions,” said Ian Tindall, Cerulean head of innovation and marketing.
July 13, 2020
Risk Assessment Determined by Questioning

Photo: 104691896 | © Milkos | Dreamstime.com
The share of people who believe e-cigarettes are equally harmful or more harmful than traditional cigarettes depends on how the question is asked, according to new research published in Tobacco Control.
Tobacco companies often claim that a large proportion of the population perceives potential modified risk tobacco products as equally or more harmful than cigarettes, and argue misperceptions need to be corrected using modified risk claims.
However, the studies they cite predominantly use one specific measurement of comparative risk, according to the researchers.

Image: Tobacco Control
The authors studied the way questions were posed in the 2017 Tobacco Products and Risk Perceptions Survey. When asked directly to compare harms of e-cigarettes and cigarettes, 33.9 percent of participants identified e-cigarettes as less harmful than cigarettes, 36.4 percent reported equal harm, 4.3 percent said e-cigarettes were more harmful and 25.3 percent said, “I don’t know.”
When asked indirectly, however, 42.1 percent identified e-cigarettes as less harmful than cigarettes, 23.8 percent said they were of equal harm, 7.1 percent perceived e-cigarettes to be more harmful and 27.1 percent did not know.
The authors say researchers should use both direct and indirect risk questions when assessing the public’s perceptions of harms associated with novel tobacco products.
June 18, 2020
The Unlikely Savior?
Smoking, nicotine and Covid-19: What is going on?
By Clive Bates

Photo: maja7777 from Pixabay
The world is enduring the worst crisis since the 1940s, and people are desperate for some good news. Could that good news come from a most unlikely source? Could smoking, or more precisely nicotine, have benefits in controlling the symptoms of Covid-19, the disease caused by the coronavirus SARS-CoV-2? There is emerging, though inconclusive, evidence that nicotine may have protective effects in preventing severe symptoms of Covid-19. If this turns out to be true, it would be extraordinarily good news—nicotine in its medical and recreational forms is widely available and easily affordable.
The picture is quite complicated, but discussion should start with clarity about which outcomes may be improved. There are at least four relevant stages: infection (simply contracting the disease, often with mild symptoms); hospitalization (serious symptoms); admission to an intensive care unit (ICU) (life-threatening symptoms); and finally death. If there is a protective effect, the data suggest it reduces the number reaching hospitalization. For the purposes of fighting the pandemic and returning to economic normality, preventing the onset of symptoms serious enough for hospitalization is the highest priority.
There are two main strands of evidence that suggest a protective effect: the apparent underrepresentation of smokers in Covid-19 hospital admissions and evidence from human biology.

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Evidence from Covid-19 hospital admissions
Most Covid-19 studies recording hospitalization and smoking status show smokers are strikingly underrepresented compared to the number that would be expected given smoking prevalence in the population. Being a smoker appears to make it less likely that a Covid-19 sufferer will end up in the hospital. There are many doubts and questions about the reliability of this data, but the effect is remarkably consistent across countries where the data is available. Greek cardiologist Konstantinos Farsalinos and his collaborators examined the literature available on April 25, 2020, to assess the smoking status of those entering the hospital with Covid-19 (see Farsalinos et al., “Prevalence of Current Smoking and Association with Adverse Outcome in Hospitalized Covid-19 Patients: A Systematic Review and Meta-Analysis”).
An unexpectedly low prevalence of current smoking was observed among hospitalized patients with Covid-19. Hospitalized current smokers had higher odds compared to noncurrent smokers but lower odds compared to former smokers for an adverse outcome.
These data suggest that fewer smokers are entering the hospital than we might expect, but once they are admitted, their outlook is worse. This is consistent with other findings showing a worse outlook for smokers once hospitalized. (For example, Vardavas and Nikitara, “Covid-19 and Smoking: A Systematic Review of the Evidence.”)
Notably, in the largest study that assessed severity, there were higher percentages of current and former smokers among patients that needed ICU support, mechanical ventilation or who had died and a higher percentage of smokers among the severe cases.
These authors did not draw attention to just how few smokers there were among the patients to start with—but that is the remarkable fact picked up by Farsalinos and his group. So, what could be going on? Farsalinos and colleagues have a theory:
“The possibility that nicotine may have a protective effect in Covid-19, which may be masked by smoking-related toxicity and by the abrupt cessation of nicotine intake when smokers are hospitalized, should be explored.”
So, it may be that nicotine is protecting smokers up to the point where they are admitted to the hospital. However, all respiratory wards require smoking cessation on admission, so smokers make an abrupt withdrawal from nicotine use. To understand what is happening, it is necessary to separate the effects of decades of smoke exposure, which may be causing underlying vulnerabilities through cardiovascular disease and other stresses, from the effect of nicotine, which may be protective. These two effects of smoking—one harmful, one protective—could be pushing against each other and may become relevant at different points in the progression of the disease.

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Evidence from human biology—does nicotine suppress the “cytokine storm”?
So far, this could all be wishful thinking based on poor quality data. However, the second line of evidence means it should be taken very seriously. This provides biological plausibility based on cell-level insights into the mechanism through which nicotine could provide a protective effect. A range of papers have explained the possible mechanism, starting with the renowned French neuroscientist Jean-Pierre Changeux who pioneered research on nicotine receptors in the 1970s (Changeux et al., “A Nicotinic Hypothesis for Covid-19 with Preventive and Therapeutic Implications”). This was followed by an in-depth peer-reviewed publication by Farsalinos and colleagues (Farsalinos et al., “Nicotine and SARS-CoV-2: Covid-19 May be a Disease of the Nicotinic Cholinergic System“).
These theories converge on the role nicotine can play in suppressing the most dangerous symptom of Covid-19, a dramatic immune system overreaction to the virus, a so-called “cytokine storm.” Inflammation is a normal response to infection as the body responds with a series of immune reactions to neutralize invading pathogens. In this model, it is not the virus itself that does the harm but the body’s own immune system triggered by the virus into an excessive response that causes extreme inflammation and damage to the lungs or other organs and ultimately death.
These technical papers suggest that severe Covid-19 symptoms arise from damage to the internal signaling and control system known as the cholinergic anti-inflammatory pathway. This system originates in the brain and makes use of the Vagus nerve, the signaling chemical, acetylcholine and nicotinic acetylcholine receptors throughout the body. Under this hypothesis, nicotine moderates the malfunctioning of the anti-inflammatory control system by inhibiting the release of pro-inflammatory cytokines.
While Covid-19 is clearly new, the idea that nicotine may have therapeutic effects, including on inflammatory diseases rooted in the brain, is not new. In May 2020, researchers at Oxford University published a new finding from the 65-year study of British doctors started by Sir Richard Doll and Sir Austin Bradford Hill in 1951 confirming years of research suggesting smoking (in practice, nicotine) has a protective effect against Parkinson’s disease (Mappin-Kasirer et al., “Tobacco Smoking and the Risk of Parkinson Disease”). A 2013 paper by the U.K.’s bioweapons defense lab at Porton Down highlighted the role nicotine could play in controlling the cytokine storm and moderating some severe respiratory diseases (D’Elia et al., “Targeting the ‘Cytokine Storm’ for Therapeutic Benefit”).
“Nicotine […] is able to suppress the production of proinflammatory cytokines by mimicking the binding of acetylcholine. It has been demonstrated that nicotine can selectively reduce the inflammatory response in a number of infection scenarios, including Legionella pneumophila and Chlamydia pneumoniae infection.”
Following their observation that smokers were underrepresented in Covid-19 admissions to the Pitie-Salpetriere Hospital in Paris (Miyara et al., “Low Rate of Daily Active Tobacco Smoking in Patients with Symptomatic Covid-19”), French researchers are now planning a clinical trial of nicotine-replacement therapy for Covid-19.

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Where does that leave policy and practice?
With the Covid-19 pandemic raging everywhere, policymakers are in a position analogous to trying to repair an aircraft while flying it. It is not known for sure whether nicotine is protective against the more severe forms of Covid-19, just that it is suggested by data on hospital admissions and that it is biologically plausible. Yet decisions made today in hospitals and advice given to smokers and vapers could have life-saving or life-threatening consequences. The usual approach to such uncertainties would be to wait for more evidence and then make better-informed recommendations, but that is no different in practice to acting as though there is no protective effect.
It would be wrong to advise people to continue to smoke because of the longer term health implications and the underlying vulnerabilities to Covid-19 caused by smoking. But if people are advised to quit nicotine, they may be losing a protective effect at the point of their greatest vulnerability. The way to resolve this dilemma is to make a working assumption about the effect of nicotine based on what is known and what remains uncertain taking account of the consequences of making the wrong assumption. Recommending continued nicotine use in a situation where it turns out there is no protective effect does not seem likely to cause serious problems. Conversely, advising or requiring nicotine users to stop using nicotine only to find later that nicotine was protective may cause lethal harm. On a precautionary basis, policymakers should probably assume there is a protective effect until proven otherwise.
It follows that health professionals should advise smokers to quit smoking using any method that works but to maintain the use of nicotine—either by using nicotine-replacement therapy, vaping or some form of low-risk noncombustible tobacco—at least until there is a more complete understanding of the role nicotine plays. Vaping as an alternative to smoking should be encouraged not banned or locked down. What about people like me, who have never used nicotine and have no wish to—what should we do? Well, if I came down with Covid-19, I’d consider trying nicotine as a precautionary measure. What is there to lose?
Clive Bates is the director of Counterfactual Consulting and the former director of Action on Smoking and Health (U.K.).

June 1, 2020