PMI’s Own Data on Biomarkers of Potential Harm in Americans Show that IQOS is Not Detectably Different from Conventional Cigs

November 13, 2017

Stanton A. Glantz, PhD

I just submitted this public comment to the FDA on PMI's Modified Risk Tobacco Product application for IQOS.  The tracking number is 1k1-8zrx-juh9 and a PDF of the comment is avaiable here.
PMI’s Own Data on Biomarkers of Potential Harm in Americans Show that
IQOS is Not Detectably Different from Conventional Cigarettes,
so FDA Must Deny PMI’s Modified Risk Claims
Stanton A. Glantz, PhD
Professor of Medicine
Principal Investigator, UCSF Tobacco Center of Regulatory Science
University of California San Francisco
Docket Number: FDA-2017-D-3001
November 13, 2017
In its application PMI presents data that it represents as showing that IQOS produces lower levels of toxic chemicals than conventional cigarettes and lower toxicological effects in animal studies.  PMI also presents data on 24 biomarkers of potential harm in human users derived from two of their “Reduced Exposure” studies: ZRHR-REXA-07-JP in Japan, and ZRHM-REXA-08-US in the U.S.  These biomarkers include measures of inflammation, oxidative stress, cholesterol and triglycerides, blood pressure, and lung function. 
            These human data are the most important information in the application because they represent direct evidence on how IQOS affects people.   As summarized in Table 1 (page 3 of this comment) based on details in section of the PMI MRTP application, there is no statistically detectable difference between IQOS and conventional cigarettes for 23 of these 24 biomarkers in Americans in PMI’s studies.  This is indicated by the fact that 23 of the 95% confidence intervals include zero (i.e., no statistically significant difference). 
            Moreover, when using the conventional 95% confidence standard for statistical hypothesis testing, one would expect 5% of the tests to yield false positives.  Five percent of 24 tests is 1.2 tests, which means that one would expect 1 or 2 false positive results. PMI had one positive result (Soluble ICAM), which is what one would expect by chance.
            Overall, PMI’s own data supports the conclusion that IQOS is no different from conventional cigarettes in terms of effects on these biomarkers of potential harm in American people.
            These results are more important than all the preclinical data (aerosol toxicity and animal studies) because they represent real people smoking the actual IQOS product.
            It is also important to note that PMI did not do any of these conventional statistical tests which are routine for such scientific analysis.  Rather they simply emphasize the direction of changes while ignoring the fact that these differences are within what would be expected based on simple randomness.  No tobacco company would tolerate such assertions made by the FDA or other public health authorities.  FDA should not tolerate it coming from a tobacco company.
            The results reported in PMI’s application for Japan are slightly more positive for IQOS, with 3 of 13 biomarkers showing differences from conventional cigarettes (where one would expect 1 false positive by chance).  These results are not strong enough to warrant drawing a conclusion of modified risk.  More important, the US results are more relevant to Americans because of potential biological differences in response between Japanese and US people.
            These conclusions are based on taking PMI’s results at face value.  Although PMI summarized the results of the ZRHR-REXA-07-JP and XZRHM-REXA-08-US Clinical Risk Endpoint (CRE) studies in Module 6.1.4 CRE, the actual studies themselves have not yet been released.  Because the FDA has not yet released these and other PMI clinical studies in Module 7, it is impossible to comment on what pro-IQOS biases may have been built into the study design. 
            Section 911(g)(1) of the Tobacco Control Act states that FDA may issue an order authorizing marketing of a modified risk product “only if … the applicant has demonstrated that the product, as it is actually used by consumers, will significantly reduce harm and the risk of tobacco-related disease to individual users.” PMI has failed to meet this statutory requirement. FDA must deny PMI’s application to market IQOS as a modified risk tobacco product because PMI’s own data fails to support a modified risk claim in people who are actually using the product.
            (Table 1 is viewable in the PDF of the comment available here.)



Dr Glantz,
The clinical studies you mention also contained an arm in which smokers quit smoking completely. Just for context, do you happen to know how many of the 24 biomarkers in table 1 improved significantly when smokers quit smoking completely?
Jonathan Foulds PhD


... because the FDA has not yet made the details of the experiments available for public comment.
The law requires that IQOS be assessed as actually used.  Presumably that is what PMI did in their studies.

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