A Ministry of Health, Labour and Welfare investigation into the alleged manipulation of data in post-marketing trials of Novartis (Switzerland)'s hypertension drug Divoan (valsartan) is under way, with calls for clinical trial guidelines to be tightened in Japan as a consequence.
IHS Global Insight perspective | |
Significance | Japan's Ministry of Health, Labour and Welfare (MHLW) has opened an investigation into the suspected post-marketing studies of Novartis (Switzerland)'s hypertension drug Diovan (valsartan), with tighter clinical trial guidelines one of the potential preventive measures being considered. |
Implications | Separately, the Japanese Society of Hypertension's draft guidelines on hypertension treatment have removed references to the KYOTO Heart and JIKEI studies. Those guidelines also see beta blockers demoted from the recommended first-line treatment choices for the first time. |
Outlook | Although Diovan may lose its position as Japan's second-bestselling drug, with eight hospitals stating they will not prescribe the drug given the plentiful alternatives, there is ongoing debate in Japan regarding the relationships between pharmaceutical companies, doctors, and research institutes. |
Japan's Ministry of Health, Labour and Welfare (MHLW) has opened its own investigation into Switzerland-based firm Novartis's post-marketing trials of hypertension drug Diovan (valsartan) held in Japan after two university-led investigations last month uncovered data manipulation that led to the retraction of two of those studies: the KYOTO Heart and JIKEI studies (see Japan: 15 July 2013: Japanese university claims researchers "manipulated" data during Diovan trial). As reported by Pharma Japan, the MHLW is first considering the investigations of the two universities, Kyoto Prefectural University of Medicine and Jikei University School of Medicine, and the response of Novartis before considering preventive measures, with no specific timeline outlined. It is expected that the committee will try to interview a former Novartis employer, known to have worked on the KYOTO and JIKEI studies but without declaring any conflict of interest (see Japan: 24 May 2013: Novartis comments on employee participation in independent clinical trial in Japan). Three other universities are carrying out ongoing investigations into other Diovan trials that the former employee participated in, namely: the VART, SMART, and NAGOYA Heart Study trials.
Draft hypertension guidelines released
In publishing its draft treatment guidelines for hypertension last week, an update to the 2009 guidelines, the Japanese Hypertension Society noted that it will not reference the suspect KYOTO and JIKEI studies in the new document, while previous citations of the JIKEI study in the 2009 guidelines will be removed. As reported by Pharma Japan, the society stressed that individual clinical trials do not influence clinical guidance decisions.
The new draft guidelines include calcium-channel blockers (CCBs), angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and diuretics as first-line recommended drugs, as reported by Pharma Japan. Beta blockers are removed as a first-line treatment option, and relegated to a fourth-line choice.
Outlook and implications
Diovan looks certain to lose its spot as the second-bestselling drug in Japan, with a considerable media and public backlash over the suspected clinical trial data manipulation. Eight local hospitals have stated they would not be prescribing the drug, a Tokyo hospital director stating: "It's morally problematic to keep using a drug that's faced questions on effects that have been its feature," as quoted by The Wall Street Journal. The drug earned JPY108.3 billion (USD1.05 billion) in revenues during 2012, with Japan the source of around 25% of Diovan's global sales.
None of the five suspect trials were cited during approval applications in any market, and the studies' retractions have not required any label change in terms of the drug's indications. The US FDA has stated it has "no new safety concerns with this drug", noting that millions of people have been prescribed Diovan over 15 years, and it has "a well-established safety and efficacy profile", as quoted by The Wall Street Journal. But the backlash has arisen because those studies were used to promote Diovan as beneficial in reducing the risk of strokes and heart failure, in addition to treating hypertension, giving the drug an advantage in the competitive ARB market, with at least six other ARB alternatives available in Japan. Novartis maintains that other global studies support the findings of the KYOTO and JIKEI studies in terms of prevention of heart attack and strokes, and denies that there was any "willful manipulation or falsification" of data.
More broadly, the MHLW is likely to introduce more carefully defined ethical guidelines for clinical trials in Japan, particularly post-marketing studies, with Iwao Kuwajima, head of the Japanese Organisation of Clinical Research Evaluation and Review, of the opinion that Japan's research reputation has been damaged. Post-marketing trials held in Japan are more often open, rather than double-blind, compared to Europe or the United States, meaning investigators know whether a patient is being prescribed placebo or not, and there are fewer legal restrictions on trials that are not being used for the purposes of new drug applications. The health ministry may also pay closer attention to rules governing corporate financial aid for clinical research, while doctors' clinical research activities may also become more proscribed. Drug companies in Japan last month began publishing details of payments made to doctors and research institutes under a new voluntary transparency code introduced by the Japan Pharmaceutical Manufacturers Association prior to the Diovan scandal (see Japan: 24 July 2013: Pfizer reveals USD239 mil. in payments to doctors, medical institutions in Japan during FY 2012 under new guidelines). Pharma firms' relationships with academic institutions will be scrutinised to a greater extent than previously.
The Japan Hypertension Society treatment guidelines will not be formally introduced until 2014. Of note is the lag between the guidelines in Japan and Western countries, with beta blockers removed as a first-line treatment from the UK NHS guidelines as early as 2006.