Now, however, questions have been raised about another clinical trial, the Jikei Heart Trial, which was published in the Lancet in 2007. (Matsubara was not involved in this trial.) Novartis , which manufactures valsartan (Diovan), the drug studied in both trials, has announced that it is investigating both trials in response to new allegations that a Novartis employee worked on the trials without any disclosure of his company affiliation.
The Novartis employee, Nobuo Shirahashi, was listed as a member of the statistical analysis organization for both the Kyoto Heart Study and the Jikei study. In both cases his only listed affiliation is Osaka City University. Novartis, in a statement, said it “takes these allegations very seriously and has launched a comprehensive investigation with independent third party experts to review these allegations.”
Novartis said that the trials were not used “for registration purposes.” Novartis also said that both Kyoto and Jikei were “investigator initiated trials” which are, ostensibly, “conceived, designed and conducted by independent steering committees of physicians.”
Questions about the statistics used in both trials were raised last year in a letter to the Lancet by Yoshiki Yui concerning the Jikei study. According to Yui, “the mean and SD of achieved systolic blood pressure (SBP) between the valsartan group and the group assigned conventional treatment without angiotensin-receptor blockers (ARBs) is the same. This finding seems strange to me.” Yui said the probability of this occurrence is extremely unlikely. “To my knowledge, of the many hypertensive trials… the mean and SD of achieved SBP is equal in both study groups only in the Jikei Heart Study and the Kyoto Heart Study.” Yui pointed to further statistical anomalies in the two trials, including this:
In the Jikei Heart Study, the coincidence of identical means and SDs for achieved SBP suggests that the normal distribution of the two groups is the same, because the normal distribution is determined by mean and SD; this is very odd. In other words, a randomised but heterogeneous population becomes homogeneous after a 3-year drug intervention. This ought to be the other way round.
There has been recent media coverage on the Kyoto Heart(1) and Jikei Heart(2) trials, which were Japanese post registration investigator initiated Valsartan trials. Investigator initiated trials are conceived, designed and conducted by independent steering committees of physicians.
There have been allegations of an undisclosed conflict of interest related to the Kyoto Heart and Jikei Heart trials. The conflict of interest allegations include a Novartis employee who was allegedly involved in the trials and who was not disclosed as a Novartis employee.
Novartis takes these allegations very seriously and has launched a comprehensive investigation with independent third party experts to review these allegations.
At Novartis, we expect all employees to follow the Novartis Code of Conduct, which sets out principles for ethical behavior, professionalism and good business practice and forms an integral part of the terms of employment of all associates of Novartis Group companies.
The results of the Kyoto Heart and Jikei Heart trials were not used by Novartis for registration purposes.
Valsartan has a proven safety and efficacy profile and has been prescribed to millions of patients worldwide. Valsartan has been approved and marketed worldwide for over 15 years. There are multiple major morbidity and mortality clinical trials conducted outside of Japan, including Val-HeFT(3) and VALIANT(4), which have demonstrated the benefits of valsartan beyond its proven blood pressure-lowering efficacy. Valsartan is the only ARBapproved in the US and EU for treatment of both post-MI and heart failure patients.
Sawada T, Yamada H, Dahlöf B, Matsubara H; KYOTO HEART Study Group. Retraction of: Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J. 2013 Apr;34(14):1023.
Mochizuki S, Dahlöf B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S, Tajima N; Jikei Heart Study group. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2007 Apr 28;369(9571):1431-9.
Cohn JN, and Tognoni G. for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75.
Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003 Nov 13;349(20):1893-906.