Philip Morris has smoking device problems during clinical trials — FDA
TOKYO/NEUCHATEL, SWITZERLAND — The US Food and Drug Administration (FDA) 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 coauthor of the company’s protocol used to run the studies globally. When she highlighted an irregularity in one of the studies, Mr. 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 Mr. 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 US 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 US 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.”
Mr. 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, Mr. 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. Mr. Sugimoto gestured with his thumb and forefinger to indicate a thick document: “I just don’t read them.” —