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Investigator Initiated Trials in Japan

July 1, 2014 08:45 CET

Novartis responds to Tokyo District Prosecutor's Office investigation

Novartis Pharmaceuticals said today that although NPKK has not yet received official notification, NPKK understands that the Tokyo District Prosecutor’s Office (TPO) has publicly disclosed that it will proceed with charges against a single former employee, Shirahashi, regarding the publication of an article containing manipulated data related to a sub- analysis of the Kyoto Heart Study in violation of Japan’s Pharmaceutical Affairs Law.

Novartis Pharmaceuticals has also learned that the Tokyo District Prosecutor’s Office (TPO) has publicly disclosed that it will proceed with charges against NPKK in Japan. The charges against NPKK are in connection with the actions of the single former employee, Shirahashi.

Under the dual liability characteristic of the Japan legal system, the charges allege that NPKK carries responsibility for failing to oversee an employee. The charge carries with it a maximum fine of 2 million Yen (USD 19,710).

NPKK understands that the TPO has also re-arrested Shirahashi for further investigation. NPKK will co-operate with authorities in the ongoing investigation.

The company said it will review the contents of the charges against NPKK in further detail once it receives official notification from the TPO.

“Novartis and NPKK have already undertaken decisive action to address problems with the company’s Investigator-Initiated Trial (IIT) research programs in Japan,” said David Epstein, Global Division Head of Novartis Pharmaceuticals. “We are committed to changing the culture at NPKK and demonstrating ethical leadership among pharmaceutical companies in Japan.”

In April, Novartis announced several measures designed to identify and correct all issues with IITs in Japan, including the replacement of the NPKK senior management team, a comprehensive third-party review of the company’s IITs, and ongoing remedial training to ensure compliance with the company’s Code of Conduct. The company also said it expects to soon issue new global guidelines on IITs.

Novartis said it remains fully committed to Japan and bringing breakthrough medicines to Japanese patients in the areas of cancer, multiple sclerosis, respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD), ophthalmology, skin diseases and heart failure.

Previous updates

  • June 13, 2014 18:45 CET

    Novartis is aware of actions taken by the authorities in Japan this week including the arrest of a former associate and visit by the Public Prosecutors Office to the Novartis office in Tokyo. We are also working with the Ministry of Health, Labor and Welfare (MHLW) on issues relating to delayed reporting of individual case safety reports. We are cooperating fully with the authorities on all matters.

    These events are all related to previously acknowledged problems with a number of Investigator Initiated Trial (IIT) programs in Japan. Novartis takes these issues extremely seriously and has already implemented wide-ranging measures to identify and address problems. These include replacement of our senior management team in Japan, third party review of all our IIT programs in the country and remedial training for Novartis Japan associates.

    We recognize the culture at Novartis Japan needs to change and are committed to upholding high standards of ethical business conduct. Novartis does not tolerate unethical behavior by its associates in any country and takes necessary steps to ensure compliance with the company’s Code of Conduct and all applicable laws.

  • April 3, 2014 11:00 CET

    Novartis announced on April 3 a set of wide-ranging measures to identify and address problems with the company’s Investigator-Initiated Trial (IIT) research programs in Japan. The announcement follows the release of the findings of the independent panel of experts commissioned by Novartis and NPKK to investigate the Company’s involvement in the SIGN trial. Novartis said that based on a preliminary review of the report, it was very concerned about possible breaches of patient confidentiality and instances of document destruction.

    Among the measures were the appointments of new senior executives at Novartis Japan (NPKK) including: Dirk Kosche as Head of Novartis Pharmaceuticals and Francis Bouchard as Head of Oncology. Novartis Group also announced Michael Ferris as Country President for Japan.

    “We need to build a new Novartis Pharma in Japan with a fresh team of experienced executives who will be accountable for operating the business in a fully compliant and ethical manner,” said David Epstein, Division Head, Novartis Pharmaceuticals. “Together with our NPKK associates, the new team will work to fulfill our responsibility to Japanese society, and through our ongoing scientific research, Novartis will continue to introduce innovative medicines that make a real difference to patients in Japan.”

    Additionally, the Company announced a broad third-party internal review of IITs, which was initiated in early February after concerns were raised about the involvement of NPKK associates in Tokyo University Hospital’s SIGN IIT.  The company said that it fully expects that in the course of this ongoing review other IIT issues will come to light which will be addressed. The internal review is expected to be completed by the summer and a summary of the main findings and response by Novartis will be made public. In the meantime, the Company is placing a temporary moratorium on all IIT funding in Japan.

    Novartis recognizes that the culture at NPPK needs to change and is committed to upholding high standards of ethical business conduct and to following all laws and regulations while strengthening its culture of performance with integrity.  Novartis does not tolerate unethical behavior by its associates in any country and takes necessary steps to ensure compliance with the Company’s Code of Conduct and all applicable laws.

  • January 9, 2014 11:00 CET

    Novartis is aware that a criminal charge has been filed against Novartis Pharma K.K. We are cooperating fully with the authorities.

    Novartis believes it is our responsibility to fully address the circumstances that led to the current investigation and have implemented a series of corrective measures to strengthen governance across the organization in Japan, ensuring that a repeat of the valsartan IIT issue cannot occur and ensuring adherence of Novartis Japan associates to the highest standards of ethics and compliance.

    Japan is, and will continue to be, a key place for Novartis to invest and grow. Novartis has been a major contributor to clinical research in Japan with investments of over 50 billion Japanese Yen since 2007. We currently fund research in Japan into breakthroughs for heart failure, cancer, psoriasis, and respiratory disease. From 2007 to 2012, Novartis has conducted 175 clinical studies in Japan with over 14,000 patients and has obtained 31 regulatory approvals, including 15 New Molecular Entities (NMEs) and 16 Label extensions for new clinical indications. Novartis regrets the inconvenience to patients, to healthcare professionals and to Japanese society that has been caused by the valsartan IIT issue in Japan.

  • October 3, 2013 15:45 CET

    Today Novartis held a press conference in Tokyo, Japan, in response to the release of an interim report on September 30 summarizing the findings of the Japanese Ministry of Health, Labor and Welfare (MHLW) Review Committee in its review of the involvement of Novartis Pharma Japan (NPKK) in Diovan investigator-initiated trials (IIT). The press conference was chaired by David Epstein, Division Head, Novartis Pharmaceuticals, who was joined by Eric Cornut, Chief Operating Officer, Novartis Pharmaceuticals, and Yoshiyasu Ninomiya, President & Representative Director of Novartis Pharma K.K.

    Following a careful review of the Committee’s interim report, Mr. Epstein announced immediate corrective actions. These include the expansion of Eric Cornut’s current role to include Chairman, Novartis Japan, and the establishment of a Compliance Advisory Board comprised of senior Novartis executives and external experts. Collectively, these actions will strengthen governance across the organization in Japan, ensuring that a repeat of the Diovan IIT issue cannot occur and ensuring adherence of Novartis Japan associates to the highest standards of ethics and compliance.

    Mr. Epstein also reaffirmed Novartis’ commitment to Japan and the seriousness with which Novartis takes allegations of conflict of interest and reliability of data, and committed again to working cooperatively with the MHLW to address and bring closure to this issue in Japan. He stated: “Novartis is fully prepared to take the measures necessary to rectify the situation. Novartis remains committed to Japan, and serving our patients in Japan is our top priority”.

    Japan is, and will continue to be, a key place for Novartis to invest and grow. Novartis has been a major contributor to clinical research in Japan with investments of over 50 billion Japanese Yen since 2007. We currently fund research in Japan into breakthroughs for heart failure, cancer, psoriasis, and respiratory disease. From 2007 to 2012, Novartis has conducted 175 clinical studies in Japan with over 14,000 patients and has obtained 31 regulatory approvals, including 15 New Molecular Entities (NMEs) and 16 Label extensions for new clinical indications.

    The results of the five Japanese post-registration investigator-initiated Diovan trials that are the subject of the MHLW investigation were not used by Novartis for registration purposes or labeling submissions. Therefore, these trials do not have any impact on the information contained in the package insert for Diovan in any country worldwide.

    Diovan has a proven safety and efficacy profile and has been prescribed to millions of patients worldwide. Diovan has been approved and marketed worldwide for over 15 years. There are multiple major morbidity and mortality clinical trials conducted around the World, including Val-HeFT1 and VALIANT2, which have demonstrated the benefits of Diovan beyond its proven blood pressure-lowering efficacy. Diovan is the only ARB approved in the US and EU for treatment of both post-MI and heart failure patients.

    Novartis regrets the inconvenience to patients, to healthcare professionals and to Japanese society that has been caused by the Diovan IIT issue in Japan.

    1. 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.
    2. 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.

  • October 1, 2013 10:00 CET

    On September 30, the Ministry of Health, Labor and Welfare (MHLW) Valsartan Study Committee held its third meeting and issued their interim report summarizing the Committee findings. This Committee report also addressed the involvement of Novartis Pharma K.K. (NPKK) in the Diovan investigator initiated trials (IITs).

    Novartis takes allegations of conflict of interest (COI) and reliability of data very seriously. We believe it is our responsibility to fully address the circumstances that led to the current investigation. We are committed to working cooperatively with the MHLW to address this and other concerns raised in the interim report including questions related to Diovan advertising and the impact of the advertising on the financing of health insurance.

    NPKK will further enhance its corporate governance system to prevent a recurrence of this issue. They have already taken preventative steps to reinforce our commitment to corporate social responsibility including implementing new standard operating procedures and mandatory training for employees.

    Japan is, and will continue to be, a key place for Novartis to invest and grow. We have been a major contributor to clinical research in Japan with investments of over 50 billion Japanese Yen since 2007. Novartis currently funds research into breakthroughs for heart failure, cancer, psoriasis, and respiratory disease in Japan. From 2007 to 2012, Novartis has conducted 175 clinical studies in Japan with over 14,000 patients and has obtained 31 regulatory approvals, including 15 New Molecular Entities (NMEs) and 16 Label extensions for new clinical indications.

    Novartis regrets the inconvenience to patients, healthcare professionals and the Japanese society that has been caused by the Diovan IITs in Japan.

  • September 27, 2013 20:00 CET

    On September 26, David Epstein, Division Head of Novartis Pharmaceuticals, met with Mr. Norihisa Tamura, the Minister of Health, Labor and Welfare of Japan following an invitation by the Minister. Novartis expressed its regret for the inconvenience caused by the valsartan investigator initiated trails (IITs) in Japan and expressed its continued willingness to address and overcome this issue in Japan.

    Novartis is aware of recent media reports concerning the investigation by the MHLW into the Japanese IITs. To date, the MHLW has not published the interim report related to their investigation. Novartis will not speculate on outcomes until we receive official notification from the MHLW.

    Novartis takes allegations of conflict of interest (COI) and reliability of data very seriously. In April, we launched an investigation using third party experts to investigate these allegations. The investigation has now been completed and confirmed there was an undisclosed COI but did not discover any evidence of willful manipulation or falsification of data in these studies.

    Novartis Pharma K.K. (NPKK), Japan has taken preventive and corrective measures to address the causes identified in the third party investigation, including redesigning the standard operating procedures for IITs and retraining employees on COI guidelines and process for IITs.

    Novartis remains committed to conducting clinical research in Japan and bringing new medicines to patients in Japan, in accordance with applicable laws and regulations while following the highest standards of ethical business conduct in all aspects of our work.

  • September 06, 2013 08:00 CET

    Novartis has learned today that the primary manuscript for the Jikei Heart study1 has been retracted by the Lancet. The reasons given for the retraction include a conflict of interest (COI) that was not disclosed, and concerns over the reliability of the blood pressure data reported in the paper.

    The Jikei Heart study was not used for registration purposes or labeling submissions. Therefore, this retraction does not have any impact on the information contained in the package insert for valsartan in any country worldwide. Valsartan has a proven safety and efficacy profile and has been prescribed to millions of patients worldwide. There are major morbidity and mortality clinical trials conducted outside of Japan, including Val-HeFT2 and VALIANT3, which have demonstrated the benefits of valsartan beyond its proven blood pressure-lowering efficacy.

    Novartis is aware that other valsartan studies are also under review by the universities where the research was conducted and further updates are expected.

    Novartis takes allegations of conflict of interest and reliability of data very seriously. In April, we launched an investigation using third party experts to investigate these allegations. The investigation was recently completed and confirmed there was an undisclosed COI but did not discover any evidence of willful manipulation or falsification of data in these studies.

    Novartis Pharma K.K. (NPKK), Japan has taken preventive and corrective measures to address the causes identified in the third party investigation, including redesigning the SOP for IITs and retraining employees on Conflict of Interest guidelines and process for IITs.

    These valsartan investigator initiated trials (IITs) were initiated between 2001 and 2004, during a time when large scale physician-led clinical research in Japan was in its early days. As a result, there was limited understanding about IITs among investigators and pharmaceutical companies. The recent discussions regarding the valsartan IITs in Japan have therefore highlighted that this issue is broader than the specific cases involving NPKK.

    Since the time of these studies, NPKK has applied international best-in-class guidelines and practices to subsequent clinical research carried out by NPKK in Japan. Furthermore, Novartis would like to, with the authorities and other stakeholders, contribute to raising awareness of the rules and procedures that would ensure the ongoing quality of physician-led research in Japan.

    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. Novartis is committed to high standards of ethical business conduct and regulatory compliance in all aspects of its work.

    1. 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.
    2. 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.
    3. 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.

For more information on the Novartis Code of Conduct, visit: