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As the U.S. Food and Drug Administration considers whether to approve the innovative Iqos smoking device, made by Philip Morris International Inc., researchers have raised concerns about studies submitted to the authority, half of which were conducted in Japan.

With a decision expected this year, former employees and contractors have described 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 its Iqos device 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. The eight clinical experiments that Philip Morris submitted to the FDA were conducted between 2013 and 2015. Four of the studies were done in Japan.

Tamara Koval, who worked at the company from 2012 to 2014 and helped coordinate clinical trials for the device, has 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 for trial subjects that exceeded the volume a human being is capable of producing, 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 6 of the 11 principal investigators who were responsible for 5 of 8 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.

Marketed as lower risk

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. The device is now sold in more than two dozen nations after it was first launched in Japan and Italy in late 2014.

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 were 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 trial participants were smokers using urine tests.

Asked about the tests, Sugimoto said he thought they would prevent nonsmokers 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 scientific advisory committee for tobacco products 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.

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 noncompliance 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.

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.

Concerns over study methods

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.

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 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.”

The business of tobacco

In Tokyo’s upscale Ginza shopping district, around the corner from the sparkling storefronts of Tiffany & Co Ltd. and Cartier SA, shoppers searching for a new device called Iqos can buy it in a boutique.

The store combines a high-tech aesthetic with the feel of an exclusive club: The young woman at the door says a members-only smoking lounge is upstairs.

In Japan, Philip Morris blitzed officials with the science of Iqos to persuade them to classify the device in a way that would lead to a lower tax rate than cigarettes. Other traditional cigarette companies, notably British American Tobacco PLC and Japan Tobacco Inc., have launched similar devices. None has reported anything close to the global sales of Iqos.

The company chose Japan as its first Iqos market, launching in late 2014. If the company could achieve its goals in “priority” markets like Japan, it would provide “good reference points to other countries,” said the 2014 Philip Morris presentation on reduced-risk products like Iqos.

At first business lagged but by early 2016 the buzz surrounding Iqos in Japan was growing, thanks in part to a group of Japanese entertainers. That April, six popular Japanese comedians were on a national TV show when the presenters began to talk about smoking. One of the comedians, Terumoto Goto — a household name — held up a red Iqos. “It doesn’t release smoke,” he explained. “It’s like steam coming out of my mouth.” The five men sitting around him on the TV set held up Iqos units as well.

Goto said he bought an Iqos because his wife wouldn’t let him smoke cigarettes inside their house and the neighbors didn’t like him standing around and smoking outside. Toshiyuki Itakura, just behind Goto, chimed in about smoking the device in public: “There doesn’t seem to be any harm.”

Searches on Google for the Japanese word for Iqos spiked that day.

The talent agency that represents Goto and Itakura, Yoshimoto Kogyo Co. Ltd., said in a statement: “Our company received absolutely no payment from Philip Morris or affiliated companies” for the appearance. The network that carried the show, TV Asahi Corp., said it did not consult with the tobacco company beforehand.

Away from the public eye, Philip Morris employees equipped with pages of scientific findings were lobbying government officials in Japan. They hoped to convince regulators to tax Iqos at a lower rate than cigarettes and exempt it from ordinances that ban smoking in public places and restaurants.

Koki Okamoto, a member of the Tokyo Metropolitan Assembly, said Tokyo’s planned public smoking regulations almost certainly will exempt Iqos. “My personal view, as a lawyer, is that there will be reluctance to apply penalties to something without scientific evidence on health hazards,” said Okamoto.

Philip Morris says its Iqos tobacco inserts made up 11.9 percent of the Japanese tobacco market in the third quarter, up from 3.5 percent a year ago. That growth took on additional significance for company revenue in light of the lower tax rates. The Iqos kit retails for about ¥11,000, roughly $100. The company said that cigarettes in Japan are taxed at 60 percent, while the Iqos tobacco inserts — priced about the same as a pack of Marlboros — are at 51 percent.

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