FDA Releases More Positive Results for IQOS; British Medical Association Supports E-Cigs

I earlier reported (here) that Stanton Glantz, a University of California, San Francisco professor, urged the FDA to deny Philip Morris International’s application to market its IQOS heat-not-burn cigarette as a modified risk tobacco product, based on his comparison of lab results for IQOS users versus continuing smokers.  I noted that Glantz ignored data for IQOS users versus complete quitters, although that statistical comparison was not in the documents released by the FDA.

Additional data released by the FDA yesterday shows that PMI had submitted considerably more information from its Japanese study.  PMI reported data on exposure to carcinogens, carbon monoxide and nicotine, and, importantly, analyses for all of these results, including IQOS versus smoking, and IQOS versus quitting.

The following table shows all results after three months.  Differences in the table are described positively with respect to health (e.g., IQOS significantly lower).  “NS” indicates no significant difference between groups for that test.  The primary carcinogens are listed, with lengthy chemical metabolites abbreviated in parentheses.  

IQOS users were not significantly different than quitters with respect to inflammation, oxidative stress, blood pressure, lung function and carbon monoxide levels.  Compared with continuing smokers, IQOS users had significantly lower levels of 15 out of 16 carcinogen markers after 90 days of use.  There were no differences between IQOS and quitting for 13 of 16 markers.

My previous blog post was based on partial results released by FDA.  The agency’s latest release provides further evidence that toxin levels three months after switching to IQOS look more like complete quitting.

No one is claiming that IQOS is perfectly safe.  However, exposure to toxic agents among IQOS users is substantially lower than exposure among smokers, and very close to that associated with complete quitting.

In breaking news, the British Medical Association Board of Science has just issued a positive report on e-cigarettes (here).  Their findings, which likely apply to IQOS, appear below verbatim.

Is it safe to use an e-cigarette in the long-term?

In the absence of long-term studies it is not possible to be certain about the long-term health risks, but there is growing consensus that use of e-cigarettes is significantly safer than smoking.

Unlike cigarette smoking, e-cigarette use does not expose users to the products of combustion, and most of the toxicants causing smoking-related disease are absent or significantly reduced in e-cigarette vapour.

Indications to date are that complete switching can lead to improvements in the levels of toxins and carcinogens in urine similar to that in smokers who switch completely to NRT (nicotine replacement therapies).

Comparison of Laboratory Values: IQOS Users Versus Continuing Smokers and Versus Complete Quitters After 3 Months
Lab Marker	IQOS Versus Smoking	IQOS Versus Complete Quitting*
Inflammation
White blood cell count	IQOS significantly lower	NS
C-reactive protein	NS	NS
Soluble ICAM	IQOS significantly lower	NS
Fibrinogen	NS	NS
Oxidative Stress
Prostaglandin F2 alpha	IQOS significantly lower	NS
11-DTX-B2	NS	NS
Cholesterol, Triglycerides
High density lipoprotein	IQOS significantly higher	NS
Low density lipoprotein	NS	NS
Total cholesterol	NS	NS
Triglycerides	NS	IQOS significantly lower
Blood pressure
Systolic	NS	NS
Diastolic	NS	NS
Lung function
Forced expiratory vol, 1 sec.	NS	NS
Carbon monoxide	IQOS significantly lower	NS
Carboxyhemoglobin	IQOS significantly lower	NS
Nicotine	NS*	IQOS significantly higher
Carcinogens**
Nicotine-derived nitrosamine ketone (NNK)	IQOS significantly lower	Quitting significantly lower
Butadiene (MHBMA)	IQOS significantly lower	NS
Acrolein (3-HPMA)	IQOS significantly lower	Quitting significantly lower
Acrolein (HMPMA)	IQOS significantly lower	NS
Benzene (S-PMA)	IQOS significantly lower	NS
Polycyclic aromatic hydrocarbons (1-OHP)	IQOS significantly lower	NS
Polycyclic aromatic hydrocarbons (CYP 1A2)	IQOS significantly lower	NS
N-nitrosonornicotine	IQOS significantly lower	Quitting significantly lower
4-aminobiphenyl	IQOS significantly lower	NS
1-aminonaphthalene	IQOS significantly lower	NS
2-aminonaphthalene	IQOS significantly lower	NS
o-toluidine	IQOS significantly lower	NS
Acrylonitrile (CEMA)	IQOS significantly lower	NS
Styrene (HEMA)	IQOS significantly lower	NS
Benzo(a)pyrene	IQOS significantly lower	NS
Toluene (S-BMA)	NS	NS

NS, No significant difference

* IQOS results in nicotine levels that are similar to smoking

** carcinogen (chemical metabolites)

Tobacco Harm Reduction Is Science, Not Conspiracy

Technology newsmonger The Verge should stick to covering cell phones and earbuds.  Last week it published a fantastical tale of e-cigarette intrigue, suggesting the existence of an international tobacco and vaping industry conspiracy.  The article by Liza Gross (here), richly sourced, linked my work to this imagined scheme.

I have always been entirely transparent about my research sponsors.   
I have publicly reported that my research at the University of Alabama at Birmingham, from 1999 to 2005, and since at the University of Louisville, has been supported by unrestricted grants to those institutions. The funds are managed according to the institutions’ policies to assure that grantors have no influence on my research products or activities. 

Since my first publication in tobacco harm reduction (THR) in 1994, I have been interested in all THR products, regardless of manufacturer.  The Verge cited an “unsolicited” email from me to claim a connection to Reynolds, the marketer of Eclipse, but I had submitted my note via a blind "Talk to RJR" email account, as I had no relationship with anyone at the company.  The purpose of my email was to challenge Reynolds for positioning Eclipse as a lower risk product for smokers.  I objected that it was not lower risk, but rather “a tobacco product which delivers only xx% of (specific toxins) when compared with currently available products because the tobacco is heated rather than burned.”  I was correcting Reynolds, suggesting they make a reduced exposure claim rather than a reduced risk claim.  Note that when Congress gave the FDA regulatory authority over tobacco nine years later, it included both reduced risk and reduced exposure as pathways for Modified Risk Tobacco Product approval by FDA for product claims by tobacco manufacturers.

As a result of my email to Reynolds, the company provided a senior scientist to give a well- received public seminar at the UAB School of Public Health describing the company’s research and resulting peer-reviewed articles on Eclipse (here). 

Elsewhere in its story, The Verge used half-truths to besmirch me and others with regards to contact with tobacco companies.  For 23 years I have worked with a wide range of organizations interested in tobacco harm reduction.  I generated peer-reviewed articles and other reports as a scientific advisor for the American Council for Science and Health, and as a fellow of the Heartland and R Street Institutes, all without financial remuneration.  These activities fall within my responsibilities as Professor of Medicine and Endowed Chair of Tobacco Harm Reduction Research at the University of Louisville.

The dictionary defines “verge” as the edge, rim, or margin of something.  Ms. Gross’s article espouses a conspiracy theory that, in my case, is well beyond the margin of accuracy.  Had the author contacted me, I would have provided the Tobacco Truth.

Smoke But No Fire: IQOS Opponent Misrepresents 3-Month Studies to FDA

Stanton Glantz, a University of California, San Francisco professor, this week urged the FDA to “…deny [Philip Morris Intermational’s] application to market IQOS [its heat-not-burn cigarette] 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.”

Glantz’s declaration is based on his review of lab results from two groups of smokers three months after (1) continuing to smoke or (2) switching to IQOS.  The studies, from Japan and the U.S., were submitted by PMI in its application (available at the FDA website here ).

It is well known that individuals’ lab results do not improve instantly upon smoking cessation.  The PMI submission clearly indicated that many of the subjects’ lab values are not expected to change for 6-12 months or longer after quitting. 
Beyond that, Glantz completely ignored a third PMI study group: smokers who had quit completely for three months. 

In this post I present the comparison that Glantz emphasized – IQOS users versus continuing smokers – but I add an equally important comparison that Glantz ignored – IQOS users versus complete quitters.  Because the U.S. study had too few subjects in the latter group  (n=9) for stable comparisons, I will focus on the Japan study, which involved 70 IQOS users, 41 continuing smokers and 37 complete quitters.  I will also note one omission in Glantz’s comparison.

The comparisons of IQOS and continued smoking in the table below were calculated by PMI and presented in its application.  PMI also calculated differences for IQOS versus quitting, but I could not find them in the material released so far by the FDA.  So those comparisons in the table are from my assessment of point estimates and confidence intervals from the submission.  All differences in the table are described positively with respect to health (e.g. IQOS significantly lower).  “NS” indicates no significant difference between groups for that test.

Comparison of Laboratory Values After 3 Months: IQOS Users Versus Continuing Smokers and Versus Complete Quitters in Japan
Lab Marker	IQOS Versus Smoking	IQOS Versus Complete Quitting*
Inflammation
White blood cell count	IQOS significantly lower**	NS
C-reactive protein	NS	NS
Soluble ICAM	IQOS significantly lower	NS
Fibrinogen	NS	NS
Oxidative Stress
Prostaglandin F2 alpha	IQOS significantly lower	IQOS possibly lower
11-DTX-B2	NS	Quitting possibly lower
Cholesterol, Triglycerides
High density lipoprotein	IQOS significantly higher	NS
Low density lipoprotein	NS	NS
Total cholesterol	NS	NS
Triglycerides	NS	IQOS possibly lower
Blood pressure
Systolic	NS	NS
Systolic	NS	NS
Lung function
Forced expiratory vol, 1 sec.	NS	NS

NS, No significant difference

* My assessment based on point estimates and confidence intervals in submission  
** Omitted by Glantz

The PMI calculations show that IQOS users had four statistically significant favorable comparisons at 3 months compared with smokers.  Other results show no differences.  My assessment of IQOS users versus complete quitters reveals no significant differences for ten lab results.  There were only two possibly significant results favoring IQOS and one favoring complete quitting. 

In summary, the results at three months do not prove anything definitive, which was emphasized in PMI’s application.  These results were not used by PMI to support any positive claims about IQOS; they should not have been used by Professor Glantz to make any counter claims.