A panel of the health and welfare ministry on Sept. 30 issued an interim report on the manipulation of clinical research data for Novartis Pharma K.K.’s high blood pressure drug Diovan, a trade name for Valsartan.
The report pointed out the possibility that the company’s use of scientific papers that mentioned advantageous points of Diovan on the basis of the clinical research data could constitute an “extravagant advertisement” in violation of the Pharmaceutical Affairs Law.
It is still not clear who manipulated the data for what purposes. The interim report is far from unraveling the truth. Because the incident has cast a cloud over the credibility of clinical research in Japan, the panel should continue its investigation in a thorough manner.
Diovan was developed in the 1990s, and its sales in Japan started in 2000. Since it was hoped that the drug would be effective not only in lowering blood pressure but also in preventing angina pectoris and strokes, clinical research involving up to 3,000 patients was carried out.
Research teams at Kyoto Prefectural University of Medicine, Jikei University School of Medicine, Chiba University, Nagoya University and Shiga University of Medical Science separately started clinical research on the drug from 2002 to 2004. Their research results were published in reputable medical journals in Europe and the United States from 2007 to 2012. Some of their findings were quoted in a guideline for the Japanese Society of Hypertension.
After a third-party doctor posed questions about the research results, it was found that the data had been manipulated by research teams at Kyoto Prefectural University of Medicine and Jikei University School of Medicine.
Papers written by these teams showed that Diovan was particularly effective in preventing angina pectoris and strokes when compared with other high blood pressure drugs. But one paper after another written by the teams was withdrawn starting in late 2012.
It was found that a Novartis employee (who quit the company in May 2013) became involved in research conducted by each of the five university teams; he analyzed the data. The employee introduced himself only as a part-time lecturer at Osaka City University.
It was also found that Novartis donated a total of ¥1,132.9 million to the teams of the five universities. Of the sum, some ¥380 million went to the team at Kyoto Prefectural University of Medicine and some ¥190 million to the team at Jikei University School of Medicine. The panel said that although it is not clear who manipulated the research data gathered by the teams of either university and for what purposes, both universities and Novartis should bear the responsibility.
It is not unreasonable to presume that in making the donations to the research teams, Novartis sought to benefit from the clinical research. The panel expressed the view that the Novartis employee was not involved in the research as an individual but that Novartis was involved as a company.
As the panel pointed out, the five universities lacked awareness of the importance of resolving conflicts of interest. The panel said that neither the universities nor Novartis were organized to grasp and manage conflicts of interest. Pharmaceutical companies should set up sections to deal with the problem independently of sales sections, as the panel suggested.
The panel pointed out basic problems with the research. It said that data management was inappropriate, that team leaders’ handling of the matters was unsatisfactory, that ethics committees of the universities did not work properly and that the research teams did not have sufficient awareness of the need to protect patients who had taken part in the clinical research. It is deplorable that the teams have disposed of materials connected with their research.
Novartis used the results of the clinical research done by the teams at Kyoto Prefectural University of Medicine and Jikei University School of Medicine to help promote sales of Diovan. In and after 2006, the company quoted the teams’ papers about 700 times in pamphlets and lecture meetings aimed at doctors.
Five years after sales started in 2000, Diovan’s annual sales topped ¥100 billion. The drug was prescribed to several million patients a year. In 2009, sales reached a peak of ¥140 billion. There are years in which the sales of Diovan accounted for nearly half of Novartis’ sales.
The panel said it’s possible that the use of the research results by the company could constitute an extravagant advertisement, therefore it called on the government to carry out on-the-spot inspections.
Under the Pharmaceutical Affairs Law, government authorities have only limited powers of inspection. For example, they may not forcibly enter and inspect the places concerned and may not confiscate materials, although those who refuse to cooperate can be fined.
When companies are inspected, authorities may not interrogate employees. The health and welfare ministry should strongly persuade the company to accept inspections by the ministry. It also should consider revising not only the guidelines concerning advertisements and sales promotions by pharmaceutical companies but also the Pharmaceutical Affairs Law.
It is clear that the desire of university professors to build their research reputations and the effort of a pharmaceutical company to use research results to promote product sales fed one another.
This incident not only caused anxiety for patients but also damaged trust in Japan’s clinical research. At present, clinical research before sales of a drug are approved is under legal controls. The government should strongly consider legally controlling clinical research after sales of the drug start. Pharmaceutical companies should stop involving their employees in research conducted by doctors and place limits on the amount of their donations to universities.