Several post-marketing clinical trials of the blockbuster blood pressure drug Diovan may have been run by employees of the drug’s manufacturer Novartis.
While the firm is not naming the employees or the trials by name, one is believed to relate to the cardiologist Hiroaki Matsubara, a former Kyoto Prefectural University researcher, who has had a number of his Diovan studies retracted in Japan, the US and Europe.
Another large trial, the Jikei Heart Trial, also came under scrutiny when it was revealed that a Novartis employee, Nobuo Shirahashi, was involved with both studies, but his only listed affiliation was Osaka City University.
Novartis originally said Shirahashi had ‘an adjunct position’ at the University and, “being famous in the statistician community, merely gave advice on what type of statistical analysis to use”.
But in March Japanese newspaper The Mainichi reported that Novartis invested ¥100 million in the University’s research. Novartis admits in its statement “one of our former employees [presumably Shirahashi] had varying levels of involvement in five investigator initiated valsartan trials in Japan”.
Novartis went on: “There have been allegations of an undisclosed conflict of interest related to five Japanese post-registration investigator initiated valsartan [Diovan] trials.
“The conflict of interest allegations include two former Novartis employees who were allegedly involved in the trials and who were not appropriately disclosed in the trial publications as Novartis employees.”
Spate of retractions
In December 2012, the Japanese Circulation Society retracted two of Matsubara’s papers, citing ‘serious errors in data analysis’ in both.
A 2012 paper claimed that Diovan helped diabetics to avoid heart disease; the other, published in 2011, claimed benefits for high-risk hypertensive patients.
There have also been five retractions of Matsubara’s Diovan studies by the American Heart Association, and the major Kyoto Heart Study was also retracted from the European Heart Journal.
The statement formally apologises for Novartis’ earlier defence of the Kyoto Heart Study, saying its position “was based on what it believed at the time,” implying that its defence of the study was wrong.
Matsubara has stood by his conclusions, saying that the errors were accidental, and a Kyoto Prefectural University committee in January found no signs of misconduct.
But the once prominent cardiologist unexpectedly resigned from his post at the University in February, fuelling speculation that he was working in some capacity for Novartis. The University is now investigating these claims for a second time now that he has left his academic post.
Novartis said it will not be naming those alleged to be involved at this time.
The Swiss firm has maintained its distance from the research since the first spate of retractions last year, but pressure on the company has been ramped up in recent months, prompting its new statement.
It goes on: “Their [the Novartis staff] affiliation should have been reported accurately,” but added that some of the physicians involved “were aware of their employment by Novartis”.
It adds that their involvement has not led to any ‘inappropriate conclusions’ in these studies, adding that as the studies were post registration, they had no bearing on marketing approvals.
But the trials may have artificially increased the marketing share of the drug, given that they were seemingly independent and all had positive results, something that could be used by Novartis sales reps to convince doctors it was the right drug to prescribe for their patients.
Novartis says it takes these allegations ‘very seriously’ and after pressure from groups such as Retraction Watch, the firm launched an investigation in April using what it calls ‘external specialists’.
It says this review is focusing on allegations related to Diovan investigator initiated trials started in Japan between 2001 and 2004. “Novartis will take appropriate corrective actions in light of the investigation,” it added.
Sales of the drug hit ¥119.2 billion (US$1.3 billion) in 2011, making it the top-selling drug for Novartis’s Japanese subsidiary and the third-best-selling drug in Japan.
Globally the drug brought in $5.7 billion in 2011 before losing its patents in major markets, including the US, last year.