“All studies were conducted by suitably qualified and trained Principal Investigators.”

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.”

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 was 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 that trial participants were smokers by using urine tests.

Asked about the tests, Sugimoto said he thought they would prevent non-smokers 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 tobacco products scientific advisory committee 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 non-compliance 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.

Philip Morris confirmed to Reuters that “informed consent was not obtained prior to execution of a study procedure” – specifically, the collection of urine samples. The problem was identified by CMIC, the contract research group, during a routine monitoring visit, Philip Morris said. A subsequent round of audits, it added, “led to prompt discontinuation of the study at the Seishukai Clinic.” The incident, the company said, was properly logged in the study report and the submission to the FDA.

“It suggests the investigator had no idea, did not understand or just didn’t care what his responsibilities were in conducting the study,” said Greg Koski, a former director of the U.S. federal Office for Human Research Protections, which advocates for research subjects. “This is such a flagrant violation, that investigator shouldn’t be doing clinical studies.”

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.

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.

“It seems like the investigator here is in the role of a technician, not as a principal investigator,” said Kessler, the former FDA commissioner.

Kessler said it’s hard to understand how such investigators could have signed off on the clinical study report “when they clearly were not versed in the study results.”

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” – good clinical practices – “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.”

In Poland, some urine samples collected as part of one Philip Morris clinical study exceeded the limits of what a human being is capable of producing in a single day, according to Koval and Lad, the former clinical data manager.

Lad, who worked at Philip Morris from 2012 to 2015, said he didn’t think anything “malicious” had happened. Maybe urine samples were swapped or there was a mistake with the containers used to collect the urine, he said.

But when the principal investigator for the Polish site was asked about the results, she would not admit there was a problem, Lad and Koval said. Instead, they said, the scientist explained that the test subjects were large Polish men.

Philip Morris said that “a few participants” in an early stage of the trial “produced unusually large volumes of urine.” Because medical tests showed no problems with the subjects, the company said, the investigator did not initially consider the samples to be “adverse events.”

After discussion with the medical monitors of the study as well as Philip Morris, the investigator “ultimately decided to mark these incidences as adverse events,” the company said. An investigation at the site confirmed that researchers had followed study protocol and good clinical practices, the company said.

The principal investigator running the study in Poland for Philip Morris, Katarzyna Jarus-Dziedzic, declined to discuss what happened with the urine case at her site, citing confidentiality.

Koval said that after she raised concerns about the Polish study with Philip Morris executives in Switzerland she was excluded from meetings.

Philip Morris said in a statement that Koval was “part of the team” that followed up on the urine samples. In fact, the company said, she was “an active member” of the group that finalized the data set from the studies for further analysis.

Koval confirmed that she was part of the team and involved with the data set. But she stood by her account that she was shut out of conversations and meetings about the urine samples.

In 2014, Philip Morris terminated her contract, Koval said. She said she returned to the pharmaceutical industry a few months later and now works for Swiss drugs giant Novartis AG.

After leaving Philip Morris, Koval was given a certificate of service that said, “Tamara drove clinical program development activities.” It said she had demonstrated “professionalism” and “unwavering commitment” in her work.

Additional reporting by Ari Rabinovitch in Jerusalem, Joe Brock in Johannesburg, Anna Koper in Warsaw, Amanda Ferguson in Belfast, Hyunjoo Jin in Seoul and Kate Kelland in London.

No more harmful than coffee When Hans-Joerg Urban joined Philip Morris International Inc’s research headquarters as a scientist in 2005, he said a senior executive laid out the tobacco giant’s vision for the future: to create cigarettes no more harmful than a simple cup of coffee. About a decade later that quest culminated in the iQOS, a device that heats tobacco but does not burn it. Philip Morris says the lack of combustion means smokers are exposed to far lower levels of toxic emissions than with regular cigarettes. “The ultimate result of this is reduced tobacco related harm and diseases,” the company said in a statement. The world’s largest publicly traded tobacco company by market value has applied to the U.S. Food and Drug Administration to market iQOS as less harmful than cigarettes. But four scientists and researchers who worked for the company on the iQOS program told Reuters that while Philip Morris was able to prove the lower amounts of exposure to harmful substances, that doesn’t necessarily mean that using the device is less likely to result in disease than regular cigarettes. “Exposure is not directly linked to the risk of having a disease,” said Urban, a scientist who worked at Philip Morris until 2010 analyzing data from clinical and laboratory experiments. “The diseases are much too complicated.” Dorothy Hatsukami, a former member of the FDA’s tobacco products scientific advisory committee, agrees. “At this point, research is still too nascent to say with certainty that reduced exposure translates into reduced risk,” she said. Philip Morris is seeking FDA approval to market iQOS under two different standards. It has applied for approval as a device that reduces exposure to harmful substances. It has also applied on a second track with a higher bar – to get approval to market it as carrying reduced risk of tobacco-related disease. The first option, a special provision for companies that are unable to meet the threshold of reduced risk, comes with a restriction. Consumers cannot be “misled into believing” the product is less harmful than other tobacco products, FDA regulations say. If the FDA approves the application, that would raise the possibility of Philip Morris International’s former parent company and U.S. partner, Altria Group Inc, capturing market share in a nation where overall cigarette sales plummeted more than 30 percent between 2005 and 2016. Kishor Lad, a clinical data manager at the company between 2012 and 2015, said to prove the product presents less risk of tobacco-related disease, the company would need to conduct large clinical trials over several years to show that people who used iQOS lived longer than people who smoked cigarettes. Philip Morris said it disagrees. Under U.S. regulations, the company said, the FDA “does not require premarket epidemiological data as a condition of marketing authorization.” Lad added that it’s not correct to say that “if you’re less exposed to these harmful substances then, sort of, it’s less harmful for you.”

The Philip Morris Files By Tom Lasseter, Paritosh Bansal, Thomas Wilson, Ami Miyazaki, Duff Wilson and Aditya Kalra Picture Editor: Thomas White Graphics: Chris Inton Design: Jeff Magness Edited by Peter Hirschberg