Puntos claveEnglish 中文 (chinese)
¿Cuál es la magnitud de los pagos de las empresas farmacéuticas a los autores que escribieron los cinco artículos retractados sobre los ensayos clínicos sobre valsartán después de la revelación del escándalo en el 2013?
Un análisis transversal retrospectivo que utiliza los datos de las empresas farmacéuticas en el 2016 demostró que 29 de 50 autores (58 %) asociados con los 5 artículos recibieron pagos de las empresas farmacéuticas, y el 10 % de los autores recibieron el pago en yenes japoneses de más de ¥5 millones. El pago total al autor correspondiente de estos 5 artículos representó el 43,4 % del total de los pagos.
Los hallazgos del estudio sugieren que quienes practicaron los ensayos clínicos recibieron grandes pagos de la industria farmacéutica, incluso después del escándalo sin precedentes.
Financial relationships between pharmaceutical companies and physicians can bias the conduct, findings, and reporting of clinical trials. In Japan, the valsartan scandal was a significant event: all 5 key articles on the valsartan clinical trials were retracted after the revelation of data falsification. Consequently, the Japan Pharmaceutical Manufacturers Association issued transparency guidelines, and pharmaceutical payments have been publicly disclosed since 2013. However, the distribution of payments from pharmaceutical companies among authors involved in the valsartan scandal after its revelation has not been studied to date.
To identify the characteristics and distribution of payments from pharmaceutical companies to researchers involved in the valsartan scandal in Japan by using a comprehensive payment database.
Design, Setting, and Participants
This retrospective cross-sectional study, conducted from January 1, 2016, through September 30, 2017, used information on payments from 78 pharmaceutical companies to 50 authors of 5 articles retracted after the valsartan scandal: the Kyoto Heart Study, Jikei Heart Study, SMART (Shiga Microalbuminuria Reduction Trial), VART (Valsartan Amlodipine Randomized Trial), and Nagoya Heart Study. Payments from companies to physicians were analyzed during the period from January 1, 2016, to September 30, 2017.
Main Outcomes and Measures
The main outcomes were the amount and proportion of payments made by pharmaceutical companies to authors, and the forms of these payments.
Of 50 eligible authors, 29 (58%) received payments from pharmaceutical companies in 2016. The payments in the Japanese yen totaled ¥64 188 393 (US $564 858) and the mean (SD) payment was more than ¥1 283 768 (¥2 999 919) (US $11 297 [$26 399]). Five authors (10%) received more than ¥5 million (US $44 000) and 3 authors (6%) received more than ¥10 million (US $88 000). The total payments to the corresponding author of each article was ¥27 826 374 (US $244 872), accounting for 43.4% of the total payments. Regarding forms of the payments, lecture fees accounted for 81.3% of the total payment (¥54 182 972 [US $476 810]).
Conclusions and Relevance
Many authors involved in the valsartan scandal received payments from the pharmaceutical industry. Although whether such payments to these authors have decreased since the scandal is unclear, the findings appear to demonstrate that their financial relationships with the industry are still prominent. The findings of the study appear to support the need to encourage more transparency in such relationships because misconduct can occur within unclear relationships.
Financial relationships between pharmaceutical companies and physicians can bias the conduct, findings, and reporting of clinical trials.1 This problem is well illustrated in the misconduct in Japanese clinical trials of valsartan (hereafter, the valsartan scandal), an angiotensin receptor blocker manufactured by Novartis.2 With financial and personnel support from Novartis, 5 Japanese medical schools conducted the clinical trials of valsartan in the 2000s, namely, the Kyoto Heart Study (Kyoto Prefectural Medical University),3 Jikei Heart Study (Jikei University of Medicine),4 Shiga Microalbuminuria Reduction Trial (SMART) (Shiga University of Medical Science),5 Valsartan Amlodipine Randomized Trial (VART) (Chiba University),6 and Nagoya Heart Study (Nagoya University)7 (Table 1). Their findings were published in international medical journals: the Jikei Heart Study was published in The Lancet in 2007,4 and the Kyoto Heart Study was published in European Heart Journal in 2009.3 However, these 5 primary and 3 associated studies, including a subanalysis of the Kyoto Heart Study, were retracted after the revelation of the originally unmentioned involvement of a Novartis employee (statistician) in these studies, and numerous instances of data fabrication.
The domestic effect of the valsartan scandal was significant. The Ministry of Health, Labour and Welfare criminally charged Novartis and its employee for using fabricated results of the Kyoto Heart Study and Jikei Heart Study in their advertisement for valsartan in November 2014. They were later acquitted on charges of fraudulent and exaggerated advertising. Japan’s new Clinical Research Act, enforced in April 2018, legally defines the term clinical research as clinical trials designed to establish the efficacy of drugs or medical devices. However, this new legal definition is not consistent with the global consensus on clinical research, which covers a wider range of studies, including observational studies. As of March 2019, the case against Novartis is being heard by the Japanese Supreme Court. A series of illegal activities was also covered in international media outlets, including the Wall Street Journal and The New York Times. Consequently, a new law was enforced in April 2018 to regulate clinical research.
In 2011, the Japan Pharmaceutical Manufacturers Association (JPMA) published transparency guidelines requiring disclosure of all payments to authors for lectures, writing, and consulting, to be published with individuals’ names and affiliations.8 Thus, the 71 companies belonging to the JPMA voluntarily began publishing their data on payments to authors since 2013. However, JPMA’s platform for such disclosure is not user friendly and has been inconsistent from company to company. For example, most companies publish their data in the form of images, which makes it difficult to aggregate the data. Moreover, to use a company’s data, an individual must be registered on the company’s website. Such conditions hampered analysis of payments to individual physicians. Although the valsartan scandal should have made the financial relationships between pharmaceutical companies and physicians more subtle, overall, they remained prolific; total payments by the 10 companies with the highest total disbursements to physicians have decreased only slightly, from the Japanese yen of ¥12.9 billion (US $113 million) in 2012 to ¥11.4 billion (US $100 million) in 2016.9 It is thus important to clarify the financial relationships among relevant stakeholders after the valsartan scandal, including the individuals and institutions involved in the valsartan scandal. However, to date, little research has been conducted in this area. The aim of this study is to identify the characteristics and distribution of pharmaceutical companies’ payments to valsartan scandal researchers after the scandal, using a comprehensive payment database for Japan constructed by our team for fiscal year 2016.
Study Design, Participants, and Setting
The participants in our study were the authors of the aforementioned 5 key articles that were retracted after the valsartan scandal: the Kyoto Heart Study,3 the Jikei Heart Study,4 SMART,5 VART,6 and the Nagoya Heart Study7 (Table 1). Valsartan was manufactured by Novartis and approved in the Japanese national health insurance system in November 2000. In 2012, annual domestic sales of valsartan peaked, reaching ¥140 billion (US $1232 million). This study was approved retrospectively by the Institutional Review Board of the Medical Governance Research Institute. The Institutional Review Board waived the need for informed consent from study participants because all the descriptive data collected were publicly available. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We collected payment data from the disclosures of all 78 companies. These companies are categorized into 71 active JPMA members, 6 subsidiaries of these companies, and 1 past member. For most of these companies, the most recent data are from 2016; moreover, each company updates its payment data and deletes old data annually. The companies included in this study, as well as the starting and ending dates of their payment data, are listed in eTable in the Supplement.
We obtained each company’s payment data and generated a unified single database from them, as follows. First, because no data were published in the form of a spreadsheet, data with character codes were converted into a spreadsheet format. Second, data with no character code were converted into text files using an optical character reader. Third, for data protected against facsimile or reproduction, we used FullShot, version 10 software (Inbit Inc) to scan the data and convert the resultant images into text files. Finally, we confirmed that the transformed data were accurately converted by comparing them with the original data. Our database included physicians’ names, their main institutions, payments received, the form of payments, and the total amount of payments. The form of payment was categorized into the following 4 types: payment for lecture, payment for writing, consulting fees, and others. The data did not include research payments, honoraria, and meal benefits.
We identified payments from pharmaceutical companies for all the observed authors and formulated descriptive analyses of the characteristics and values of these payments. We further extracted the names of all individuals who received payments of ¥0.5 million, ¥5 million, ¥10 million, or more from any pharmaceutical company. The cutoff values of ¥0.5 million and ¥5 million are used by the Pharmaceutical Affairs and Food Sanitation Council of the Ministry of Health, Labour and Welfare to determine whether committee members should be granted voting rights; if a member receives a payment of ¥0.5 million or more and less than ¥5 million from a single pharmaceutical company, he or she is not granted voting rights in the committee; if a committee member receives a payment of ¥5 million or more from a single pharmaceutical company, he or she cannot be a committee member at all.
Analyzing the data for all 50 authors of the 5 studies (Table 2), we found that the payments totaled ¥64 188 393 (US $564 858) and the mean (SD) payment was more than ¥1 283 768 (¥2 999 919) (US $11 297 [$26 399]). Twenty-nine authors (58%) received at least 1 payment in 2016, 5 authors (10%) received more than ¥5 million (US $44 000), and 3 authors (6%) received more than ¥10 million (US $88 000). The total payment to the corresponding authors of each article was ¥27 826 374 (US $244 872), accounting for 43.4% of the total payments to all 50 authors. However, 2 of these 5 corresponding authors (40%) had already resigned from their post to take responsibility for the valsartan scandal, and, thus, hardly received any of the payments. Only 1 author received a payment from Novartis (¥111 370 [US $980]). According to the information disclosed by Novartis, the total value of the company’s payments to researchers decreased from ¥1558 million (US $13.7 million) in 2012 to ¥787 million (US $6.9 million) in 2016.10
Table 3 shows the payments to the authors by form or payment. Lecture fees accounted for as high as 84.4% of the total payments (¥54 182 972 [US $476 810]) to all 50 authors. The next highest amounts of payments were in the form of consulting fees, at 10.5% (¥6 730 730 [US $59 230]), and writing fees, at 3.8% (¥2 439 415 [US $21 467]).
We found that 58% of the physicians involved in the valsartan scandal received at least 1 pharmaceutical payment in 2016, with a mean payment value exceeding ¥1 283 768 (US $11 297). The corresponding authors of the 5 key articles received a total of ¥27 826 374 (US $244 872), accounting for 43.4% of the total payments in 2016, while 2 of the 5 authors (40%) had already resigned their post to take responsibility for the scandal and hardly received any of the payments.
This study has data limitations; thus, whether pharmaceutical payments to authors have changed since the valsartan scandal is unclear. However, this study clearly demonstrates that authors’ financial relationships with the pharmaceutical industry are still prominent. Only 1 author received payment from Novartis; therefore, it may be reasonable to assume that these authors had multiple payment sources other than Novartis. For example, 2 corresponding authors received more than ¥10 million in payments, and are currently professors at Nagoya University and University of Tokyo; the corresponding authors of the VART study (Chiba University) moved to the University of Tokyo in 2012. Both schools have been recognized as top medical schools in Japan, with notable traditions and contributions to the Japanese medical society. We speculate that the title of professor at these universities could be a lucrative facilitator through which companies can promote their products to general physicians; in turn, the professors also enjoy benefits of the roles provided by the companies, which enhance their reputation and income.
According to the information disclosed by Novartis, the total value of the company’s payments to researchers decreased from ¥1558 million (US $13.7 million) in 2012 to ¥787 million (US $6.9 million) in 201610; despite this reduction, the amount of payments could still be regarded as significant. This finding would indicate that Novartis has continuously provided payments to physicians and medical specialists other than those related to the valsartan scandal. As the company with the third largest pharmaceutical sales in the world,11 Novartis produces a diverse array of drugs, including agents for diabetes and anticancer drugs. Thus, even after the valsartan failure, which was significant, Novartis can still afford to make large payments to physicians in specialties other than hypertension.
Given such deep-rooted financial ties between pharmaceutical companies and researchers, the enforcement of the Clinical Trials Acts (rinsho-kenkyu-hou) in 2018 was unavoidable.12 Under the Clinical Trials Acts, both pharmaceutical companies and researchers are required to disclose financial relationships during clinical trials, and punishment has been introduced to regulate potentially similar crimes. The intention of this act in Japan, and of the adoption of Open Payments in the United States, is to ensure greater transparency and/or reduce payments that might otherwise facilitate research misconduct. However, although Open Payments has successfully encouraged transparency, pharmaceutical payments to researchers have not necessarily been reduced.13-15 Similarly, in Japan, open platforms such as Open Payments, which provide details of physicians’ financial relationships with the pharmaceutical industry, could promote transparency of such relationships; nevertheless, how to maintain fair relationships between researchers and pharmaceutical companies remains to be discussed. There is an urgent need to broaden this discussion in Japan.
Despite widespread criticism about conflicts of interest after the valsartan scandal, financial relationships between physicians and the pharmaceutical industry are still common and opaque. The existence of financial relationships between physicians and the pharmaceutical industry is not necessarily unfavorable by itself; however, it is important to encourage transparency in such relationships, and to accurately disclose payments as much as possible, because undisclosed relationships may potentially promote misconduct.
To our knowledge, this study is the first investigation of pharmaceutical payments for authors involved in the valsartan scandal in Japan. However, it has some limitations. First, this study focuses on payments only in 2016. Although we are interested in payments in previous years, because the authors may have received substantial payments before the valsartan scandal, there are no data accessible data before 2016, because each company updates its payment data and deletes old data annually. We used data from 2016, as these are the most recent data. Second, we collected payment data as published by all 71 companies of the JPMA; however, related data from non-JPMA pharmaceutical companies were not included.
Of the 50 authors involved in the valsartan scandal, 29 (58%) received pharmaceutical payments 4 years after the scandal was revealed. We believe that a more sophisticated disclosure of pharmaceutical payments is needed. Efforts on these lines may help reduce research misconduct in the future.
Accepted for Publication: March 22, 2019.
Published: May 17, 2019. doi:10.1001/jamanetworkopen.2019.3817
Correction: This article was corrected on July 19, 2019, to fix errors in the payments from some pharmaceutical companies.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Sawano T et al. JAMA Network Open.
Corresponding Author: Toyoaki Sawano, MD, Department of Surgery, Minamisoma Municipal General Hospital, 54-6 Takamicho 2 chome, Haramachi, Minamisoma, Fukushima 975-0033, Japan (firstname.lastname@example.org).
Author Contributions: Dr Sawano had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Sawano, Ozaki, Saito.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sawano.
Critical revision of the manuscript for important intellectual content: Ozaki, Saito, Shimada, Tanimoto.
Obtained funding: Ozaki.
Administrative, technical, or material support: Ozaki.
Supervision: Ozaki, Shimada, Tanimoto.
Conflict of Interest Disclosures: Dr Ozaki reported receiving personal fees from Medical Network Systems Inc outside the submitted work. Dr Saito reported receiving personal fees from TAIHO Pharmaceutical Co Ltd outside the submitted work. Dr Tanimoto reported receiving personal fees from Medical Network Systems Inc outside the submitted work. No other disclosures were reported.
Funding/Support: The Medical Governance Research Institute and the Waseda Chronicle provided financial support for this study.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the Waseda Chronicle for acquisition of the payment data and thank Editage (https://www.editage.jp/) for English-language editing. Editage was compensated for their contribution.
Additional Information: The Waseda Chronicle is a nonprofit organization engaged in journalism and is a member of the Global Investigative Journalism Network. The Medical Governance Research Institute is a nonprofit organization and has received donations from various people, industries, and organizations, which includes donations from Ain Pharmacies.
MJ, eds. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009.
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