Novartis is maintaining its distance over claims of data manipulation in a Japanese post-marketing trial of the company’s antihypertensive valsartan (Diovan) in angina and stroke.
The investigator-initiated trial (IIT) of valsartan conducted by a research team at Kyoto Prefectural University of Medicine was led a former professor whose published papers on valsartan were withdrawn from medical journals after questions were raised over the validity of the findings.
The so-called Kyoto Heart Study, which the university now acknowledges was subject to data manipulation, also involved statistical analysis by a former Novartis employee who took part in other IITs of valsartan at Japanese universities – all without disclosing any affiliation with the company.
It is this aspect of the case that Novartis addressed in a statement released the day after Kyoto Prefectural University of Medicine disclosed the results of its investigation into the valsartan study led by Hiroaki Matsubara, the former professor in its department of cardiovascular and internal medicine who resigned from his post last February.
A lawyer for Matsubara has denied that his client was involved in any data manipulation.
Novartis has similarly distanced itself from any involvement. Media reports cite the company’s Japanese subsidiary as saying that no “intentional data manipulation has been confirmed”.
The company is also reported to have denied it refused a request from Kyoto Prefectural University of Medicine to interview the former employee involved in the valsartan studies. The ex-employee was contacted but declined to be questioned by the university, Novartis explained.
Meanwhile, the university itself says it cannot determine who may have manipulated the Kyoto Heart Study data, due to conflicting accounts.
Not for registration
Novartis has stressed that none of the valsartan IITs in which its employee or employees had an undisclosed involvement was used for registration purposes.
Consequently, “these trials do not have any impact on the information contained in the package insert for valsartan in any country worldwide”.
That does not take into account, though, any boost to sales of Diovan (which is now off-patent) or impact on treatment guidelines in Japan that may have followed the publication and dissemination of results from the IITs at Kyoto and other Japanese universities.
The efficacy and safety of valsartan in its primary indication of lowering blood pressure have not been called into question.
Conflict of interest
In its official statement, Novartis noted that in April 2013 it launched a third-party investigation into “allegations of an undisclosed conflict of interest (COI) related to Japanese post-registration valsartan investigator initiated trials (IITs)”.
The conflict of interest occurred when “former Novartis employees were not appropriately involved in valsartan IITs and were not appropriately disclosed in the trial publications”, the company explained.
At the time these studies were initiated, though (between 2001 and 2004), there were no specific guidelines for COI in investigator-initiated trials, the company maintained.
As a result, the former employees and their managers “misunderstood the appropriate level of involvement in IITs of employees of a pharmaceutical company”, it stated. “However, there are now COI guidelines for IITs in place across the industry which are followed by all Novartis Pharma Japan employees.”
Moreover, the company said, “preventive and corrective measures” have been implemented to address the causes identified in the third-party investigation of the valsartan IITs, “demonstrating our social and ethical accountability”.
According to the investigation by Kyoto Prefectural University of Medicine, the medical records of 34 of the 3,000 or so patients who took part in the Kyoto Heart Study made false statements as to whether or not these patients had previously experienced a stroke.
This undermined the study’s conclusion that valsartan was more effective than other antihypertensives at warding off angina and strokes.
The other Japanese universities at which the former Novartis employee had an undisclosed involvement in valsartan IITs are reportedly conducting their own investigations to determine whether the resulting data may be suspect.