Health
Scientists describe problems in Philip Morris e-cigarette experiments
Part 3: Former employees and contractors have detailed irregularities in the clinical experiments that underpin Philip Morris International’s application to the FDA for approval of its iQOS smoking device. The agency is expected to decide by next year on whether the tobacco giant can sell its new product in the U.S.
https://www.reuters.com/investigates/special-report/tobacco-iqos-science/
TOKYO/NEUCHATEL, Switzerland – The U.S. Food and Drug Administration is weighing whether to approve a potentially path-breaking smoking device by Philip Morris International Inc. With a decision expected next year, former employees and contractors have described to Reuters a number of irregularities involving clinical trials that underpin the tobacco giant’s application to the agency.
By heating tobacco instead of burning it, the company says the device, known as iQOS, avoids subjecting smokers to the same levels of carcinogens and other toxic substances found in a regular cigarette. The company has spent more than $3 billion developing new smoking platforms like iQOS. As part of that initiative, Philip Morris has published extensive scientific findings, based in part on clinical studies.
Tamara Koval, who worked at the company from 2012 to 2014 and helped coordinate clinical trials for the device, questioned the quality of some of the researchers and sites contracted to carry out those experiments. Koval was a co-author of the company’s protocol used to run the studies globally. When she highlighted an irregularity in one of the studies, Koval said, Philip Morris excluded her from meetings.
Reuters also found irregularities during interviews with some of the principal investigators contracted to conduct the trials for the company. One principal investigator said he knew nothing about tobacco. Philip Morris had to jettison the experiment that investigator performed after it emerged he hadn’t followed a basic procedure for obtaining informed consent from participants during clinical trials.
A second investigator submitted urine samples that exceeded what a human being is capable of, according to two former company employees, and then initially refused to acknowledge there was a problem. A third said he doesn’t hold such company-sponsored clinical trials in high regard, describing them as “dirty” because their purpose is more commercial than scientific.
After reviewing Reuters’ findings, Philip Morris said in a statement that “all studies were conducted by suitably qualified and trained Principal Investigators.” The company said it understands that “FDA inspectors have already audited some facilities” involved in the trials. Philip Morris also said it had taken steps to address “any reported irregularity in our studies.”
“Our policies encourage speaking up about suspected violations of law or our policies and we do not tolerate retaliation against those who speak up,” the company said.
In addition to former Philip Morris employees involved with the iQOS program, Reuters interviewed six of the 11 principal investigators who were responsible for five of eight clinical trials the company submitted to the FDA. Reuters also reviewed hundreds of pages of publicly available Philip Morris study reports and FDA filings.
That reporting identified shortcomings in the training and professionalism of some of the lead investigators, as well as their knowledge of the study results.
A group of tobacco research and policy experts reviewed detailed summaries of Reuters’ reporting and Philip Morris’ response. The experts, including a former head of the FDA and two former scientific advisers for the agency, said those findings raise concerns about Philip Morris’ clinical trial program.
“Taken as a whole, it’s clear they do not have the sophistication to carry out adequate and well-controlled clinical trials,” said David Kessler, the FDA’s commissioner from 1990 to 1997, referring to the company. “I am not inferring any malicious intent here, just that they lack sophistication, because this is not their bread and butter.”
If the FDA has already audited some of the trial sites used by Philip Morris, the agency “should carefully review its audits and possibly expand them,” said Kessler, a former dean of the medical school at Yale University.
Tom Eissenberg, who served on the FDA’s tobacco products scientific advisory committee until earlier this year, said: “The FDA should audit.”
Reuters did not find any evidence that the outcome of the experiments presented by the company to the FDA was manipulated or falsified.
The new insights into the company’s clinical trial program for iQOS come at a crucial time for Philip Morris. The world’s largest publicly traded tobacco company by market value and maker of Marlboro cigarettes has applied to the U.S. FDA to be able to sell iQOS in America, and also for permission to market it as a modified-risk tobacco product. That designation could mean that Philip Morris is allowed to market iQOS as presenting less harm or risk of disease to users than traditional tobacco.
For now, the FDA is evaluating the company’s studies. Reuters outlined its findings about the iQOS trials to the agency. The FDA said it cannot comment on a pending application.
Philip Morris says the device, which heats small tobacco inserts, is meant for smokers who would not otherwise quit. Its chief executive officer, Andre Calantzopoulos, has told investors and media alike that he intends to one day replace cigarettes with products like iQOS. So far, iQOS makes up a fraction of the company’s $75 billion revenues and Philip Morris continues to market conventional cigarettes across the globe.
Internal Philip Morris documents reviewed by Reuters show the significance of iQOS goes beyond its profit potential. The device is now sold in more than two dozen nations after it was first launched in Japan and Italy during late 2014.
The company has a 10-year plan for what it calls “normalization” of the tobacco industry, according to a 2014 strategy document. The industry has been shunned over the past two decades for producing and marketing products that kill people and previously lying about it. Under a section on “strategies and actions” to achieve that goal, the document lists, among other things, new smoking devices such as iQOS and the scientific research involved in developing them.
Told about that document, Philip Morris said: “The suggestion that the purpose of our development of IQOS and our scientific research program is to ‘normalize’ the tobacco industry is false.”
That previously undisclosed document and others can be found in a searchable repository published by Reuters, The Philip Morris Files.
As part of its submission to the U.S. FDA, the company said the results of its research showed the device significantly reduced the level of certain harmful substances that users were exposed to compared with cigarettes, and satisfied their nicotine cravings. “In fact the level of reduction is so considerable, it approaches 95% of the levels measured in smokers who quit altogether,” the company said in a statement to Reuters.
Taken along with the company’s laboratory studies, Philip Morris said, the research program “in its entirety demonstrates that IQOS is likely to reduce the risk of smoking related diseases.”
Philip Morris is responsible for the majority of the science that has been published about iQOS. “Those who criticize us should probably look at our science,” said Tommaso Di Giovanni, a company spokesman, during a tour of Philip Morris’ research and development headquarters in March.
The eight clinical experiments that Philip Morris submitted to the FDA were conducted between 2013 and 2015. For one study, scientists in Texas and Florida did not respond to messages left by Reuters. Other scientists, in Belfast and Tokyo, declined to talk. Half of the eight studies were done in Japan.
FDA guidelines for conducting clinical studies say a trial should adhere to standards such as Good Clinical Practice. That best-practices document says investigators “should be qualified by training and experience and should have adequate resources” to properly conduct a trial.
Masayuki Sugimoto, the principal investigator who oversaw testing at one facility used by Philip Morris to conduct a trial, said his Tokyo clinic is “heavily in the red.”
Sugimoto said he generally has little confidence that all the participants in experiments like the one he ran for Philip Morris on nicotine tell the truth about their smoking history – that is, whether they smoke.
Speaking about the final study report from the Philip Morris trial, Sugimoto said in an interview that he generally doesn’t have time to read such things in detail. He said he probably signed a document indicating he had received the final report. Sugimoto gestured with his thumb and forefinger to indicate a thick document: “I just don’t read them.”
Philip Morris said that it “did not receive any such comments or statements from the PI,” or principal investigator. Sugimoto’s study, it said, was completed “without any issues.” The company said the study data was reviewed and discussed with the investigator throughout the trial.
The Japanese company hired to monitor studies in the country, CMIC Holdings Co Ltd, said in a statement that researchers confirmed that trial participants were smokers by using urine tests.
Asked about the tests, Sugimoto said he thought they would prevent non-smokers from joining the trial but added, “I don’t know whether they were done that rigorously.”
Told of Sugimoto’s doubts about the honesty of study participants, Eissenberg, who served on the FDA’s tobacco products scientific advisory committee from 2011 to 2017, said “it raises a great deal of concern.”
A principal investigator “is required to make sure that the participants meet the inclusion-exclusion criteria that are in the protocol,” said Eissenberg. He was referring to the fact that clinical trial subjects’ backgrounds – such as whether they are smokers – should meet the parameters of the experiment for the data to be valid. “And a PI should have confidence in that,” he said.
SIGNED DOCUMENT: Masahiro Endo, one of the principal investigators on the iQOS clinical trials, signed off on the study report for the experiments he conducted. In an interview with Reuters, he initially said he was not aware of the results of the trials.
At another laboratory in Japan, issues with how the study was carried out were so acute that data from 56 participants was thrown out, raising questions about the competence of the principal investigator. Philip Morris halted the study at that location.
In the company’s study documentation released by the FDA, Philip Morris recorded the reason for discarding the data as non-compliance with good clinical practices, specifically “failure of the site to meet sample collection procedures and data recording procedures.”
Kishor Lad, who was Philip Morris’ data manager on the study, said the site crossed a line of what’s allowed during such trials: It collected samples before getting informed consent forms signed by the volunteers. “Completely a no-no in the GCP world,” Lad said, using the acronym for good clinical practice.
Philip Morris confirmed to Reuters that “informed consent was not obtained prior to execution of a study procedure” – specifically, the collection of urine samples. The problem was identified by CMIC, the contract research group, during a routine monitoring visit, Philip Morris said. A subsequent round of audits, it added, “led to prompt discontinuation of the study at the Seishukai Clinic.” The incident, the company said, was properly logged in the study report and the submission to the FDA.
“It suggests the investigator had no idea, did not understand or just didn’t care what his responsibilities were in conducting the study,” said Greg Koski, a former director of the U.S. federal Office for Human Research Protections, which advocates for research subjects. “This is such a flagrant violation, that investigator shouldn’t be doing clinical studies.”
Mamoru Oki was the principal investigator at the time at the facility, the Seishukai Clinic in Tokyo. Reached by phone, Oki said: “My specialty is urology and I don’t know anything about tobacco, so I cannot talk.”
Told of that remark, Philip Morris said: “Dr. Oki was qualified and trained specifically on the product.”
Dorothy Hatsukami, a member of the FDA’s tobacco products scientific advisory committee from 2010 to 2013, said a principal investigator’s professed lack of knowledge about tobacco is not ideal.
“For any tobacco-related clinical trial, an investigator with a background in tobacco product research would have better qualifications to evaluate the study results than a novice,” she said.
The study continued at a parallel site, the Tokyo Heart Center.
During an interview at the center, principal investigator Masahiro Endo said repeatedly that he had no idea what the results were from his study.
“We did medically safe and accurate blood samples, but were not told the results. So even if we are asked questions, we won’t be able to answer,” he said. “We were paid, it ended there.”
But in a statement signed last year and submitted by Philip Morris to the FDA, Endo said he had read the clinical study report from the company and confirmed “that to the best of my knowledge it accurately describes the conduct and results of the study.” Principal investigators in all of the Philip Morris clinical trials signed the same statement.
A day after speaking with Reuters, Endo sent an email clarifying that after checking his records he saw that he’d signed a receipt saying he received a report on the results and acknowledging that he’d be listed as the principal investigator. He had spoken during the interview “with a fuzzy memory,” Endo said.
Clinical trial experts interviewed by Reuters said it’s not uncommon for principal investigators to be unaware of test results sent to a third party specialty laboratory for analysis. But they also emphasized that if companies want better science, they need the investigators to be more involved with all aspects of a study.
“It seems like the investigator here is in the role of a technician, not as a principal investigator,” said Kessler, the former FDA commissioner.
Kessler said it’s hard to understand how such investigators could have signed off on the clinical study report “when they clearly were not versed in the study results.”
Other principal investigators described their work differently.
Fumimasa Nobuoka, a principal investigator on one of the trials in Japan, said he read the Philip Morris study report: “I thought it was well done, well written.”
James Borders, who was the principal investigator for a study held in Lexington, Kentucky, said the experiments in his trial were done ethically and followed sound scientific practice.
Borders, who became chief medical officer at the Baptist Health Lexington hospital, said such studies help consumers make an informed decision. His decision to be involved with the study, he said, hinged on the proposition that a device like iQOS could be the “lesser of two evils.”
Philip Morris said that while it sponsored the clinical trials, the experiments were “performed by reputable research facilities” and monitored by contract research organizations – companies used to oversee such studies. It hired U.S.-based Covance Inc to serve as its global contract research organization, according to an internal Philip Morris 2013 assessment plan. Covance, a unit of Laboratory Corporation of America Holdings, declined to comment.
CMIC, the company hired to monitor the Japan studies, said in a statement: “All the clinical trials you referred to were conducted in accordance with GCP guidelines” – good clinical practices – “and we believe that the results of the trials are scientifically trustworthy.”
As part of her job coordinating between Philip Morris and those contracted to run its clinical trials, Koval, the former company scientist, conducted medical safety training across the world for principal investigators and others involved with the iQOS studies.
During one study training session in Tokyo, Koval said, she realized some of the researchers could not speak English well and she was unable to communicate with them. Koval said she does not speak Japanese and there was no interpreter present.
“I was like, Jesus, what are we doing here?” she said. At dinner later, Koval said, she saw two of the men, and they were unable to describe in English what their jobs were.
When asked about Koval’s session, Philip Morris said it was a meeting with its contract research organization and others. It added that “all PIs and team members with active roles in the study were fluent in English.”
But Sugimoto, one of the Japanese principal investigators, told Reuters in an interview, “I can’t speak English.”
And Endo, another of the lead researchers, said that when Philip Morris executives visited his site someone was present who helped translate “questions like whether to cut the crusts off bread” when giving food to study subjects.
CMIC said, “All the principal investigators received adequate training in Japanese before the trial began.”
In Poland, some urine samples collected as part of one Philip Morris clinical study exceeded the limits of what a human being is capable of producing in a single day, according to Koval and Lad, the former clinical data manager.
Lad, who worked at Philip Morris from 2012 to 2015, said he didn’t think anything “malicious” had happened. Maybe urine samples were swapped or there was a mistake with the containers used to collect the urine, he said.
But when the principal investigator for the Polish site was asked about the results, she would not admit there was a problem, Lad and Koval said. Instead, they said, the scientist explained that the test subjects were large Polish men.
Philip Morris said that “a few participants” in an early stage of the trial “produced unusually large volumes of urine.” Because medical tests showed no problems with the subjects, the company said, the investigator did not initially consider the samples to be “adverse events.”
After discussion with the medical monitors of the study as well as Philip Morris, the investigator “ultimately decided to mark these incidences as adverse events,” the company said. An investigation at the site confirmed that researchers had followed study protocol and good clinical practices, the company said.
The principal investigator running the study in Poland for Philip Morris, Katarzyna Jarus-Dziedzic, declined to discuss what happened with the urine case at her site, citing confidentiality.
Koval said that after she raised concerns about the Polish study with Philip Morris executives in Switzerland she was excluded from meetings.
Philip Morris said in a statement that Koval was “part of the team” that followed up on the urine samples. In fact, the company said, she was “an active member” of the group that finalized the data set from the studies for further analysis.
Koval confirmed that she was part of the team and involved with the data set. But she stood by her account that she was shut out of conversations and meetings about the urine samples.
In 2014, Philip Morris terminated her contract, Koval said. She said she returned to the pharmaceutical industry a few months later and now works for Swiss drugs giant Novartis AG.
After leaving Philip Morris, Koval was given a certificate of service that said, “Tamara drove clinical program development activities.” It said she had demonstrated “professionalism” and “unwavering commitment” in her work.
No more harmful than coffee
By PARITOSH BANSAL, TOM LASSETER, DUFF WILSON and ADITYA KALRA
When Hans-Joerg Urban joined Philip Morris International Inc’s research headquarters as a scientist in 2005, he said a senior executive laid out the tobacco giant’s vision for the future: to create cigarettes no more harmful than a simple cup of coffee.
About a decade later that quest culminated in the iQOS, a device that heats tobacco but does not burn it. Philip Morris says the lack of combustion means smokers are exposed to far lower levels of toxic emissions than with regular cigarettes. “The ultimate result of this is reduced tobacco related harm and diseases,” the company said in a statement.
The world’s largest publicly traded tobacco company by market value has applied to the U.S. Food and Drug Administration to market iQOS as less harmful than cigarettes.
But four scientists and researchers who worked for the company on the iQOS program told Reuters that while Philip Morris was able to prove the lower amounts of exposure to harmful substances, that doesn’t necessarily mean that using the device is less likely to result in disease than regular cigarettes.
“Exposure is not directly linked to the risk of having a disease,” said Urban, a scientist who worked at Philip Morris until 2010 analyzing data from clinical and laboratory experiments. “The diseases are much too complicated.”
Dorothy Hatsukami, a former member of the FDA’s tobacco products scientific advisory committee, agrees. “At this point, research is still too nascent to say with certainty that reduced exposure translates into reduced risk,” she said.
Philip Morris is seeking FDA approval to market iQOS under two different standards. It has applied for approval as a device that reduces exposure to harmful substances. It has also applied on a second track with a higher bar – to get approval to market it as carrying reduced risk of tobacco-related disease. The first option, a special provision for companies that are unable to meet the threshold of reduced risk, comes with a restriction. Consumers cannot be “misled into believing” the product is less harmful than other tobacco products, FDA regulations say.
If the FDA approves the application, that would raise the possibility of Philip Morris International’s former parent company and U.S. partner, Altria Group Inc, capturing market share in a nation where overall cigarette sales plummeted more than 30 percent between 2005 and 2016.
Kishor Lad, a clinical data manager at the company between 2012 and 2015, said to prove the product presents less risk of tobacco-related disease, the company would need to conduct large clinical trials over several years to show that people who used iQOS lived longer than people who smoked cigarettes.
Philip Morris said it disagrees. Under U.S. regulations, the company said, the FDA “does not require premarket epidemiological data as a condition of marketing authorization.”
Lad added that it’s not correct to say that “if you’re less exposed to these harmful substances then, sort of, it’s less harmful for you.”
A tax increase that’s proven to save lives
Disclosure statement
https://theconversation.com/a-tax-increase-thats-proven-to-save-lives-87908
Jeffrey Drope currently receives funding from the US National Institutes of Health, the Institute for Global Tobacco Control at the Johns Hopkins Bloomberg School of Public Health, and the World Health Organization. He is Vice President, Economic and Health Policy Research at the American Cancer Society.
Otis W. Brawley reports no external funding. He is the Chief Medical Officer, American Cancer Society.
Republish our articles for free, online or in print, under Creative Commons licence.
Shao Fei lights a cigarette on a Beijing street in 2015 as a co-worker looks on. Shao said at the time that higher taxes on cigarettes would lead him to stop smoking.
Reuters/Kim Kyung-Hoon
Lung cancer remains the world’s largest cancer killer, but the world is not doing all it can to curb it.
Tobacco use is the largest risk factor for lung cancer. It is also a risk factor for at least 11 other cancers, and the reason that a mind-numbing 1.5 million tobacco-related cancer deaths occur every year worldwide.
This is much more than a health crisis. The global estimate of health costs and lost productivity from smoking-related illnesses was enormous in 2016, estimated at 1.8 percent of the world’s annual gross domestic product.
Without urgent action, scholars predict there will be a billion tobacco-related deaths this century. The costs of treating smoking-related diseases will become an increasingly significant economic burden in many low- and middle-income countries over the next 20 years.
Currently, these countries account for about 40 percent of the overall global costs of tobacco and a growing share of global smoking prevalence. Economic growth in these countries coupled with aggressive marketing by tobacco companies is making things worse. These dynamics represent a clear threat to health and development.
We spend our lives studying, teaching about and promoting cancer control, and we can report there are proven tools at our disposal that can help the world avoid this catastrophe. Arguably, the single most effective tool, both in terms of cost and population-level effects, is tobacco taxation.
Tax – one of public health’s best tools
A large body of evidence demonstrates that applying excise taxes on tobacco products on a sustained basis so that people cannot afford them is currently the most effective policy instrument to discourage smoking. Effective taxes deter people and especially youth from starting to use tobacco and encourage current tobacco users to cut down or quit.
In fact, raising cigarette excise tax in each country by one international dollar – an international dollar in a particular country has the same purchasing power as a U.S. dollar in the U.S. – per 20-cigarette pack would lead to a decrease in daily smoking prevalence from 14.1 percent to 12.9 percent and 66 million fewer smokers in one year.
This also translates into 15 million fewer smoking-related deaths among adults over time.
Most of the world’s governments have signed the World Health Organization Framework Convention on Tobacco Control, the world’s first public health treaty under the WHO’s auspices. Most use the WHO’s associated MPOWER framework to help them translate this commitment into effective, actionable public health policies. Both recommend that raising the price of tobacco through higher taxes is an essential tool to reduce tobacco use.
But the 2017 WHO Report on the Global Tobacco Epidemic revealed that tobacco taxation is the least well-implemented major tobacco control measure. Only 10 percent of the world’s population lives in countries where tobacco taxes are sufficiently high to have a preventive impact on tobacco use.
Raising taxes on tobacco would curb smoking, studies show. Reuters/Regis Duvignau
In many countries, the tobacco industry and its surrogates have been spreading inaccurate data and specious arguments to discourage governments from increasing tobacco taxes. The companies have, for example, overinflated the threat of illicit trade in tobacco products.
In reality, many of the countries with the highest tobacco taxes also have the lowest levels of illicit trade. Experience across many countries demonstrates that straightforward steps, such as programs that track and trace tobacco products and even modest law enforcement efforts to find and punish those trafficking in illicit trade, greatly mitigate any such challenges.
Success depends on support
As with many interventions, success depends upon visible and vocal support from a wide variety of actors, including health and political stakeholders. While some in the tobacco control community have advocated for tobacco taxation, many natural allies have remained relatively quiet.
Momentum is now growing and new coalitions are forming to promote tobacco taxation. For example, Prevent20 is a community of cancer organizations from around the world that supports and promotes the use of tobacco taxes as a key cancer prevention strategy. The coalition’s name reflects the grim statistic that 20 percent of all cancer deaths globally are caused by tobacco use.
In September, the Prevent20 Coalition signed an open letter to Dr. Tedros Adhanom Ghebreyesus, the new WHO director general, acknowledging and supporting his existing commitment to fighting the tobacco epidemic and encouraging him to redouble WHO efforts on global health and, specifically, on raising tobacco taxes.
It was particularly important for the health community to raise the issue of tobacco taxes while Dr. Tedros was attending the United Nations General Assembly meeting, where delegates debated and passed resolutions on issues including development, financing for development and health.
Under the Sustainable Development Goals, governments have committed to fully implement and enforce the WHO FCTC. They have also committed (in Target 3.4) to reduce premature mortality from noncommunicable diseases by one-third by 2030.
It is impossible to meet this target without serious reductions in tobacco use, a major risk factor for the four main noncommunicable diseases: cardiovascular disease, chronic respiratory disease and diabetes, as well as cancer.
WHO itself has called for a 30 percent relative reduction in adult smoking prevalence by 2025. If taxes were implemented adequately around the world to meet the target, governments could generate up to US$800 billion annually.
From a health and political perspective, there could be significant co-benefits – governments could reinvest revenue in priorities such as improving health systems as well as disease prevention and treatment. This would thereby deliver significant savings in future health care costs. Some countries already have turned tobacco taxes toward improving care, such as Costa Rica and the Philippines, where tobacco excise taxes are paying to extend health care to millions more people.
In global meetings, this potential for revenue generation has led governments to conclude that tobacco taxes should be leveraged as a domestic source of development financing – a strategy explicitly set out in the Addis Ababa Action Agenda. But politicians need to demonstrate the will to translate intent into action.
Cancer organizations are beginning to raise their voices to share accurate information about tobacco taxes and health, to debunk tobacco industry misinformation, encourage governments and their constituents to support higher tobacco taxes, and make it easier for governments to adopt and implement them.
Progress is not possible if we let the tobacco industry shape health policy, so the wider health and development community must join the cancer community in being visible and vocal advocates for high tobacco taxes.
UCSF public comment on PMI MRTP application: Evidence that IQOS hurts vascular fuction as much as a cigarette
Matthew Springer and his colleagues at UCSF have submitted this public comment to the FDA. The tracking number is 1k1-8zxa-mq9v and a PDF of the comment is available here
https://tobacco.ucsf.edu/ucsf-public-comment-pmi-mrtp-application-evidence-iqos-hurts-vascular-fuction-much-cigarette
The evidence PMI presents in its MRTP application for IQOS is misleading and does not support the conclusion that IQOS will not harm endothelial function; independent research done in a more relevant physiological model shows that IQOS harms endothelial function as much as conventional cigarettes
Matthew L. Springer, Ph.D., Pooneh Nabavizadeh, M.D., and Leila Mohammadi, M.D., Ph.D. Department of Medicine, Division of Cardiology
Cardiovascular Research Institute
UCSF Tobacco Center of Regulatory Science
University of California, San Francisco
Docket Number: FDA-2017-D-3001
November 20, 2017
Philip Morris Products S.A. (PMP S.A.) modified risk tobacco product (MRTP) applications1-3 for its heat-not-burn product IQOS (also designated iQOS and THS2.2) in the United States claim that IQOS does not adversely affect the functioning of the vascular endothelium. The endothelium consists of cells lining arteries that play an important role in controlling normal functioning of arteries (vascular function). Abnormal endothelial function increases the risk of heart disease and heart attacks. The evidence that PMI presents is misleading and does not support the conclusion that IQOS will not harm endothelial function. In addition, new independent research done in a more relevant physiological model shows that IQOS harms endothelial function as much as conventional cigarettes.
This comment focuses on PMI’s assertion that IQOS aerosol exposure involves less cardiovascular risk than smoke exposure. PMI researchers have published studies that compare the effects of tobacco smoke and IQOS aerosol on various physiological systems at the cell, animal, and clinical levels (for example, Smith et al.4). The conclusions that they draw from these studies all point toward IQOS being substantially less harmful than cigarettes. However, some of the criteria used in these studies are incongruous with expected and established physiological assays.
In addition, PMI’s descriptions of their research findings in the MRTP application are worded to imply that IQOS is not harmful to vascular endothelial function known to be caused by tobacco smoke. However, this implication is unsupported because PMI has not performed the most physiologically relevant tests. PMI has not shown that IQOS aerosol exposure leads to less vascular endothelial dysfunction than cigarette smoke exposure.
Endothelial function assessed by arterial flow-mediated dilation (FMD) is a validated measure of cardiovascular health effects. FMD is the process by which arteries dilate (get larger) in response to increased blood flow.5, 6 The endo¬thel¬ial cells that line the arterial wall mediate blood flow to peripheral tissues and the heart by producing nitric oxide (NO) and other factors that lead to vasodilation. Endothelial cells sense increased blood flow because of increased friction of the liquid against the lining of the artery (shear stress) as blood flow velocity increases, and the cells respond by activating the enzyme endothelial nitric ox¬ide syn¬thase (eNOS), which creates NO, leading to FMD.
FMD is quantified by ultra¬sound in humans as the percent vasodilation of the arm’s brachial artery in res¬ponse to restoration of blood flow after transient occlusion.7 FMD is a well-established clinical prognostic indicator of endothelial function that is concordant with other measures of cardiovascular health such as risk of myocardial infarction.6-9 Brachial artery FMD correlates with endothelium-depen¬dent vasodilation of the coronary arteries10 and with a number of adverse cardiovascular outcomes including myocardial infarction and atherosclerosis11-13 that are increased by cigarette smoke. In a seminal pair of papers in the 1990s, David Celermajer and colleagues showed that both smoking and chronic exposure to secondhand smoke (SHS) impair FMD.14, 15 Juonala et al.16 reported that FMD was impaired in young adults whose parents were smokers 19-27 years earlier. Several groups including ours and our collabor¬ators have shown that a 30-minute exposure to SHS at real-world levels impairs FMD in humans.17-19 In a rat model of FMD, we have shown that exposure to realistic levels of sidestream smoke from tobacco cigarettes, filtered little cigars, and marijuana cigarettes with and without cannabinoids (but not exposure to clean air) impairs FMD, an effect that occurs after as little as one minute of exposure.20-22 In short, measurement of FMD is a common test to determine whether inhalation of aerosols leads to chronic or acute endothelial dysfunction, and FMD measurement is expected to be included in the basis of any claims that a tobacco product does not negatively impact endothelial function.
PMI’s studies of endothelial function are based on isolated cell properties in culture and on biomarkers, and do not directly test for endothelial dysfunction potentially caused by IQOS aerosol inhalation. PMI claims to have studied the relative effects of IQOS aerosol and cigarette smoke on mechanisms involved in endothelial function, with the conclusion that IQOS exposure is more benign than cigarette smoke exposure in this regard. Notably, PMI’s studies of endothelial functional properties are on the level of cell culture and address the integrity of endothelial cell monolayers and monocyte efflux as well as molecular changes.23, 24 Their rodent studies addressed long-term differences in atherosclerotic plaque. Their clinical investigations include measurements of soluble intercellular adhesion molecule-1 (sICAM-1) as a biomarker indicative of endothelial dysfunction.25 Importantly, neither their clinical nor animal studies include measurements of FMD.
Their published reports have been carefully worded to avoid saying that IQOS does not cause endothelial dysfunction, but the MRTP application makes the claim that the systems toxicology studies reported in the application “cover a variety of human-derived in vitro model systems comparing the impact of THS aerosol with that of cigarette smoke on vascular inflammation, endothelial dysfunction and airway epithelium toxicity” (PMP S.A. MRTP application Executive Summary, Section 2.7, page 11). The conclusion that IQOS aerosol induces less endothelial dysfunction is not supported by their studies.
FMD in rats exposed to undiluted IQOS aerosol is impaired to the same extent as in rats exposed to cigarette smoke. Our work26, 27 demonstrated that ten 5-second exposures of rats to IQOS aerosol over a 5 minute period substantially impaired FMD to the same extent as similar exposure to cigarette smoke. Our exposure conditions were designed to approximate the use of a single IQOS HeatStick, with identical exposure conditions for the cigarette exposures. To confirm that our exposure conditions were relevant to real-world use, we measured blood levels of nicotine immediately after and 20 minutes after the end of the brief exposure, and determined that the nicotine concentrations after one complete cigarette exposure period were comparable to the blood levels in humans after smoking a single cigarette.
This validated our conditions for inhalation of undiluted cigarette smoke by the rats, and by extension, the relevance of our comparable conditions for inhalation of IQOS aerosol.
These results were presented on November 14, 2017 at the American Heart Association annual Scientific Sessions. Their press release containing a more detailed description of these findings (attachment #1), as well as the poster presentation itself (attachment #2), are appended at the end of this comment after the references.
Conclusion. Unless PMI is able to provide results from humans or living animals showing that IQOS aerosol exposure leads to less vascular endothelial dysfunction than cigarette smoke exposure, PMI’s MRTP application should not claim nor imply that IQOS carries reduced risk for vascular endothelial function.
REFERENCES
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ATTACHMENT #1: AHA PRESS RELEASE
Heat-not-burn tobacco products may be ‘not so hot’ at protecting blood vessel function
Tuesday News Tip Poster Presentation T1051 Session: AT.APS.28.
Embargoed until time 12 p.m. PT/ 3 p.m. ET, Tuesday, Nov. 14, 2017
This news tip contains updated study information not reflected in the abstract.
ANAHEIM, California, Nov. 14, 2017 — Heat-not-burn devices may eliminate users’ exposure to tobacco smoke, but the vapor they produce has the same negative impact on blood vessel function as smoking, according to a preliminary animal study presented at the American Heart Association’s Scientific Sessions 2017, a premier global exchange of the latest advances in cardiovascular science for researchers and clinicians.
Heat-not-burn products are not new, but have been recently updated and test marketed in several countries outside the United States with greater success. Despite tobacco industry claims of heat-not-burn products being less harmful than regular cigarettes, the health effects of the devices are still unproven, according to researchers.
Heat-not-burn devices raise the temperature of tobacco enough to release nicotine-containing vapor but not enough to burn, avoiding smoke exposure. To test the devices’ ability to reduce harm, researchers assessed whether exposure to the vapor affects the ability of rats’ blood vessels to widen when there is increased blood flow – a measure of blood vessel health that is impaired with exposure to smoke from cigarettes, small cigars and marijuana.
Researchers found:
• After ten 15-second exposures over five minutes to the vapor from iQOS, a heat-not-burn device that has been test-marketed in several countries, blood vessel function decreased by 58 percent.
• Similarly, after ten 5-second exposures over five minutes to iQOS vapor, blood vessel function decreased by a similar amount, 60 percent.
• The reduction was comparable to that induced by cigarette smoke (57 percent for the 15-second exposures, 62 percent for the 5-second exposures).
• Exposure to clean air had no impact on blood vessel dilation.
• The amount of nicotine in the rats’ blood after exposure to cigarette smoke was similar to the amount in blood after humans have smoked one cigarette, confirming that the exposure conditions were relevant to the real world. However, the amount of nicotine in the blood after exposure to iQOS vapor was substantially higher (70.3 nanogram/milliliter for iQOS, 15.0 nanogram/milliliter for cigarettes).
Using heat-not-burn products may not avoid the adverse cardiovascular effects of smoking cigarettes.
The research was conducted by Pooneh Nabavizadeh, M.D. in a group led by Matthew L. Springer, Ph.D. Other contributors were Jiangtao Liu, M.D., Sharina Ibrahim, B.Sc. and Ronak Derakhshandeh, M.S.
The study was funded by the National Heart, Lung, and Blood Institute at the National Institutes of Health and the U.S. Food and Drug Administration Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the FDA.
Presentation Location: Basic Science Section, Science and Technology Hall