SATURNINO P. JAVIER, MD, FPCP, FPCC, FACC
Dr. Saturnino P. Javier is an interventional cardiologist at Makati Medical Center and Asian Hospital and Medical Center. He is a past president of the Philippine Heart Association (PHA) and past editor of PHA’s Newsbriefs
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Just a couple of years ago, the health research system of Japan suffered a major blow when several reputable medical journals retracted the publication of several large scale post-marketing studies undertaken by Japanese investigators in several universities – namely Jikei University School of Medicine, Chiba University, Shiga University of Medical Science, Kyoto Prefectural Universityof Medicine and Nagoya University. The trials involved the antihypertensive agent valsartan (marketed as Diovan) manufactured by Novartis Pharma.
In 2013, The Lancet retracted the JIKEI HEART Study (Seibu Mochizuki et al) because of ethical issues related to conflict of interest as well as to the integrity and credibility of trial data. Initially published in The Lancet in April 2007, the study showed the benefit of valsartan in preventing more cardiovascular events when combined with the conventional treatment for hypertension, coronary artery disease and heart failure. Earlier, the Kyoto Heart Study, another valsartan study which was published in the European Heart Journal in 2009 was retracted in February 2013.
The scale of the scandal prompted the Japanese Health Ministry to undertake its own investigation. A parallel investigating committee from Jikei University expressed concern over the reliability of the blood pressure data – citing that “the data were intentionally altered…… during their statistical analyses.” In addition, the statistician, Nobuo Shirahashi, was employed by Novartis Pharma Japan – a fact that was not disclosed early on – as this denotes a veritable conflict of interest. In light of these findings, The Lancet indicated that there was sufficient doubt as to the integrity of the JIKEI HEART Study as well as the undisclosed involvement of a company statistician.
Belatedly as it might seem, I wrote the medical director of Novartis Healthcare Philippines Inc., Dr. Francis Domingo, to learn more about the controversial retraction of a pivotal trial, as well as the fate of its principal investigator, Dr. Seibu Mochizuki.Hiroaki Matsubara, the author of the Kyoto Heart Study had earlier resigned from his position as professor at the Kyoto University.
My interest in the JIKEI issue comes from four diverse persuasions—as head of the Makati Medical Center Institutional Review Board (the research ethics committee which regularly evaluates research protocols involving humans), as a previous member of the Novartis speakers’ bureau which regularly conducted lecture circuits for many healthcare professionals in the country, as a trial investigator for serelaxin (another product of Novartis intended for acute heart failure) and as an ordinary cardiology practitioner who regularly uses valsartan on a number of hypertensive patients. With all these backgrounds, I felt I had every right to learn more about the drug, the controversy, the company response, the authors’ fate and future directions.
In his brief response to my communication, Dr. Domingo maintained that the JIKEI Heart Study was an independent investigator-initiated trial funded by the JIKEI University School of Medicine, with an unrestricted grant from Novarits Pharma KK, Japan. He stressed that apart from the grant, Novartis had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript or the decision to sustain the data for publication. He stressed that Novartis takes this issue seriously and that it expects all its employees to follow the Novartis Code of Conduct which embodies the principles of ethical behavior, professionalism and good business practice. He ended by stating that Novartis is committed to the high standards of ethical business conduct and regulatory compliance in all aspects of its work.
What I would have wanted to find in his response are more than company values and principles. There are many questions one can raise in this scenario – what sanctions (if ever) were meted on Mochizuki et al, what measures were taken to prevent a similar incident, what was the impact of the retraction on Japan’s research climate, and most importantly, what steps did Novartis undertake to caution or alert speakers and others who depended on those trial data in their lecture circuits – not only in the Philippines but elsewhere.
Fortunately for valsartan, the product had numerous other trials to support its efficacy and safety in hypertension and hypertensive cardiovascular disease. In fact, valsartan remains an agent with its own niche for hypertension control today.
The entire brouhaha ultimately highlights the essence and impact of research ethics in the conduct of studies today. It essentially mandates vigilance on everyone’s part – regulatory agencies, principal investigators, sponsors, ethics review committees, trial monitors and contract research organizations to ensure that the principles of the Declaration of Helsinki and the International Conference on Harmonization- Good Clinical Practice (ICH-GCP) are upheld and promoted.
September 2017 Health and Lifestyle