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The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation.

ABSTRACT: In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations.We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as "Project MIX." Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect.The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes.

SUBMITTER: Wertz MS

PROVIDER: S-EPMC3243707 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation.

Wertz Marcia S MS Kyriss Thomas T Paranjape Suman S Glantz Stanton A SA

PLoS medicine 20111220 12

<h4>Background</h4>In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations.<h4>Methods and fin ...[more]

PMID: 22205885

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Project description:BackgroundSpurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco "harm reduction," leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine how the tobacco industry organized to try to influence the IOM committee that prepared the report.Methods and findingsWe analyzed previously secret tobacco industry documents in the University of California, San Francisco Legacy Tobacco Documents Library, and IOM public access files. (A limitation of this method includes the fact that the tobacco companies have withheld some possibly relevant documents.) Tobacco companies considered the IOM report to have high-stakes regulatory implications. They developed and implemented strategies with consulting and legal firms to access the IOM proceedings. When the IOM study staff invited the companies to provide information on exposure and disease markers, clinical trial design for safety and efficacy, and implications for initiation and cessation, tobacco company lawyers, consultants, and in-house regulatory staff shaped presentations from company scientists. Although the available evidence does not permit drawing cause-and-effect conclusions, and the IOM may have come to the same conclusions without the influence of the tobacco industry, the companies were pleased with the final report, particularly the recommendations for a tiered claims system (with separate tiers for exposure and risk, which they believed would ease the process of qualifying for a claim) and license to sell products comparable to existing conventional cigarettes ("substantial equivalence") without prior regulatory approval. Some principles from the IOM report, including elements of the substantial equivalence recommendation, appear in the 2009 Family Smoking Prevention and Tobacco Control Act.ConclusionsTobacco companies strategically interacted with the IOM to win several favored scientific and regulatory recommendations.

Project description:BACKGROUND: Previous studies have documented strategies to promote off-label use of drugs using journal publications and other means. Few studies have presented internal company communications that discussed financial reasons for manipulating the scholarly record related to off-label indications. The objective of this study was to build on previous studies to illustrate implementation of a publication strategy by the drug manufacturer for four off-label uses of gabapentin (Neurontin, Pfizer, Inc.): migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. METHODS: We included in this study internal company documents, email correspondence, memoranda, study protocols and reports that were made publicly available in 2008 as part of litigation brought by consumers and health insurers against Pfizer for fraudulent sales practices in its marketing of gabapentin (see http://pacer.mad.uscourts.gov/dc/cgi-bin/recentops.pl?filename=saris/pdf/ucl%20opinion.pdf for the Court's findings).We reviewed documents pertaining to 20 clinical trials, 12 of which were published. We categorized our observations related to reporting biases and linked them with topics covered in internal documents, that is, deciding what should and should not be published and how to spin the study findings (re-framing study results to explain away unfavorable findings or to emphasize favorable findings); and where and when findings should be published and by whom. RESULTS: We present extracts from internal company marketing assessments recommending that Pfizer and Parke-Davis (Pfizer acquired Parke-Davis in 2000) adopt a publication strategy to conduct trials and disseminate trial findings for unapproved uses rather than an indication strategy to obtain regulatory approval. We show internal company email correspondence and documents revealing how publication content was influenced and spin was applied; how the company selected where trial findings would be presented or published; how publication of study results was delayed; and the role of ghost authorship. CONCLUSIONS: Taken together, the extracts we present from internal company documents illustrate implementation of a strategy at odds with unbiased study conduct and dissemination. Our findings suggest that Pfizer and Parke-Davis's publication strategy had the potential to distort the scientific literature, and thus misinform healthcare decision-makers.

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The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation.

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The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation.

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