1 INTRODUCTION

Clinical practice guidelines (CPGs) play a crucial role in establishing standardised diagnostic and treatment protocols established to treat patients by endorsing evidence-based medicine.^{1, 2} However, compiling evidence suggests that the financial conflicts of interest (COIs) between drug companies and the CPG authors potentially compromise the credibility of the guidelines.^3-13 These concerns jeopardise the trust in drug companies and draw attention.^{1, 2, 5, 14-18} Given the profound impact of CPGs on patients, clinicians and various stakeholders, and their perception as guiding principles for physicians,¹⁹ rigorous COI management strategies, encompassing minimisation of COIs among authors and guideline-producing societies, full disclosure of financial COIs and the appointment of COI-free CPG chairs, are indispensable. Such measures are imperative for cultivating reliable CPGs.^{2, 15, 20, 21}

Among several types of cancer, breast cancer is the most common cancer, with more than 2.3 million patients having newly diagnosed breast cancer and 685 000 deaths in 2020.²² In Japan, the number of patients with breast cancer was estimated at 97 142 in 2019, the most commonly diagnosed cancer among females.²³ There have been remarkable advancements in breast cancer treatments as well as increased prevalence of early diagnosis.^24-26 Recent research in the UK showed that the 5-year mortality rate for breast cancer significantly decreased from 14.4% during 1993−1999 to 4.9% during 2010−2015.²⁷ Similarly, the 5-year survival rate increased from 84.6% in 1993−1996 to 92.4% in 2009−2011 in Japan.^{23, 28, 29}

Furthermore, the field of breast cancer treatment has undergone a significant paradigm shift in the last decade with the introduction of breakthrough drugs such as human epidermal growth factor receptor 2 (HER2) inhibitors, poly(ADP-ribose) polymerase inhibitors and immunotherapies. Alongside the introduction of these novel drugs, the global market for breast cancer drugs has been growing substantially, reaching around $26.4 billion in 2022. However, limited head-to-head evidence regarding the safety and effectiveness of these novel drugs^30-33 has led to fierce competition among manufacturers and increased marketing activities for physicians.^34-36 A previous study reported that 78.2% of oncology CPG authors received personal payments for lecturing, consulting and drafting fees from drug companies in Japan in 2016.³⁷ Considering these fierce marketing activities by the drug companies, we hypothesise that the CPG authors for breast cancer would have financial interactions with drug companies in Japan.

2 METHODS

3 RESULTS

3.3 Undeclared and under-declared financial conflicts of interest

Our analysis revealed that 31 (20.8%) authors disclosed financial COIs with companies for at least COI category. Of 31 authors who disclosed their COIs, 25 (80.6%) declared financial COIs for receiving lecturing and consulting payments.

Of a total of $11 119 367 payments for lecturing, consulting and writing made to the authors between 2019 and 2020, $4 372 931 (39.3%) payments exceeded the declaration threshold set by the JSBC (Figure 1), while the remaining 60.7% ($6.7 million) were less than the declaration thresholds. Of the payments exceeding the thresholds, 86.4% ($3.8 million) were correctly declared by 16 authors. However, nine authors received undeclared payments summing $594 615, with median payments of $6109 per author.

4 DISCUSSION

This analysis of payment information publicly reported by major drug companies found that the JBCS2022 authors received over $3.8 million from these companies for the 5-year period from 2016 to 2020. More than three-quarters of the JBCS2022 authors had financial interactions with drug companies, particularly those manufacturing novel breast cancer drugs in Japan. Furthermore, substantial values of personal payments were compensated to the JBCS2022 chairpersons and leading authors. While most authors received personal payments below the declaration thresholds of the Japanese Society of Breast Cancer, nine authors had undeclared COIs with drug companies, and more than 60% of payments were not disclosed by the authors in the JBCS2022 due to these thresholds. These study findings highlighted several deviations from current international COI standards in the JBCS2022.

The high prevalence (77.2%) of financial ties to drug companies for non-research purposes among the authors in this study aligns with many previous studies in Japan, albeit with higher percentages.^{3-9, 13, 41, 42, 44-48} This could indicate a vulnerability to financial COI among the influential breast cancer experts in Japan. For example, the author previously reported that the proportions of authors accepting payments from drug companies were 66.0% in obstetrics and gynecology,¹³ 88% in nephrology,⁵ 88.2% in gastroenterology,^{3, 45} 88.6% in urology,⁴⁶ 90.6% in dermatology,⁴⁷ 91.3%–100% in rheumatology,^{4, 41} 87.0%–91.9% in infectious diseases,^{6, 44} 94.4% in cardiology,⁴⁸ 94.6% in hematology,⁹ 95.6% in a diabetes CPG,⁴² 96.3% in otolaryngology⁷ and 100% in a CPG for hepatitis C treatment.⁸

Meanwhile, previous studies in other high-income countries, such as the United States, the UK and Canada, reported lower fraction of COIs for CPG authors than did those among the breast cancer CPG authors in this study.^{11, 49-55} Desai et al. reported that 45.6% (224 out of 491 authors) of National Comprehensive Cancer Network (NCCN) CPG authors were financially ties to health care companies, including both pharmaceutical and medical device companies, in the United States in 2020.⁵⁶ Of 47 authors of the NCCN breast cancer CPGs, 19 (40.4%) authors, had financial COIs with health care companies.⁵⁶ However, this is a result of ongoing efforts by many medical professional societies in these countries to properly manage financial COIs among CPG authors. In 2016, Mitchell et al. reported that 86% of NCCN CPG authors received payments from health care industry.⁵⁷

The finding that the majority of JBCS2022 authors received personal payments from drug companies over the study period represents a clear deviation from international COI standards. The National Academy of Medicine and the Guidelines International Network, a group of guideline-producing organisations from 47 countries, strongly recommend that the majority of authors should not have any financial COIs.^{1, 2} Additionally, Lenzer et al. stated that multiple CPG authors with financial COIs was one of the eight indicators that should raise substantial skepticism among CPG readers.¹⁵ Nevertheless, we previously reported that the majority of CPG authors across specialties in Japan received personal payments from drug companies.^{3-10, 41, 45-47, 58, 59} Moreover, previous research has demonstrated the correlation between COIs among guideline developers and recommendations favouring drug companies.⁶⁰ For example, the Surviving Sepsis Campaign reportedly received funding from drug companies, raising concerns about the potential influence of financial interests on guideline recommendations.^{14, 61, 62} Thus, the financial relationships between the drug industry and professional medical societies, which have played essential roles in creating CPGs and educating physicians in Japan, could endanger the integrity and trust of the public, patients and physicians in clinical recommendations and professional activities of professional medical societies.^63-65

Additionally, the significant disparity between the median and average payments per author suggested that a small fraction of JBCS2022 authors received disproportionately large payments. Notably, the JBCS2022 chairperson and leaders of its subcommittees received considerably higher personal payments than other authors. This practice of assigning chairpersons with substantial COIs deviates from international standards.^{1, 2, 15} Given the influential role of CPG chairpersons in guideline development and recommendation formulation, it is imperative to appoint experts free from any COIs to these positions, as is the practice in many international medical societies.^{16, 17, 66}

One of the fundamental principles in managing the financial COIs of health care professionals, including CPG authors, is ensuring complete transparency in the financial relationships between health care companies and CPG authors.^{2, 5, 67-69} However, this study revealed that the JBCS required JBCS2022 authors to declare their financial COIs only if they exceeded certain monetary thresholds (more than $4682 per year per company for lecturing and writing payments). These thresholds resulted in a significant under-declaration of COIs among the CPG authors. A literature review by Ngo-Metzger et al. reported that, as of 2012, half of the COI policies mandated that CPG authors declare all financial COIs, irrespective of monetary value.¹⁷ Following these findings, the US Preventive Services Task Force revised their COI policies in 2015, shifting from requiring declarations only for COIs exceeding $10 000 per year to mandating the disclosure of all financial COIs, regardless of amount.¹⁷ The JBCS2022's numerous deviations from international COI management standards highlight the immediate need for more transparency and rigorous COI management in JBCS guidelines.

Furthermore, the substantial financial relationships between the JBCS2022 authors and drug companies might cast doubt on the credibility of some JBCS2022 recommendations for breast cancer. Chugai Pharmaceutical contributed $795 542 to more than half of the JBCS2022 authors. For instance, the JBCS2022 strongly recommended the use of atezolizumab (Tecentriq from Chugai Pharmaceutical) with nab-paclitaxel (Abraxane from Taiho Pharmaceutical) for advanced or metastatic PD-L1-positive triple-negative breast cancer (TNBC) patients,³⁹ based on the IMpassion130 trial, which demonstrated an improvement in overall survival in a subgroup analysis of PD-L1-positive patients.^{70, 71} However, the IMpassion131 trial, a confirmatory phase 3 randomised controlled trial evaluating the efficacy of atezolizumab with paclitaxel compared to paclitaxel alone in PD-L1-positive TNBC patients, found no significant difference in either progression-free survival or overall survival.⁷² Following these negative results from the IMpassion131 trial, the approval of atezolizumab and nab-paclitaxel for metastatic TNBC patients with PD-L1-positive tumours was voluntarily withdrawn by the manufacturer in the United States in 2021.⁷³ Similarly, atezolizumab was removed from the French early access program in 2020, which allowed patients to access drugs before full approval.⁷⁴ Moreover, despite all eight clinical trials^75-81 reviewed in the JBCS2022 failing to show significant benefits in overall survival, the JBCS2022 recommended bevacizumab (Avastin from Chugai Pharmaceutical) as a first-line treatment for HER2-negative metastatic or recurrent breast cancer.³⁹ Contrary to the JBCS2022 recommendation, the US Food and Drug Administration (FDA) withdrew approval for bevacizumab for metastatic HER2-negative breast cancer treatment in 2011 due to its high risk of severe adverse events and low efficacy.⁸² Notably, the JBCS2022 did not mention these withdrawals by the FDA. Although the withdrawals of these drugs for breast cancer treatment in the United States have sparked controversy within the academic community worldwide, and the judgments by the FDA may not always be appropriate in other countries with differing patient backgrounds, the substantial financial ties between JBCS2022 authors and the manufacturer call into question the objectivity of these JBCS2022 recommendations including the strong recommendation for the use of atezolizumab. As the developer of the publicly accessible payment database themselves emphasised,⁸³ legally binding policies and consensual governance must be achieved to formulate harmonised physician, patients and industrial relationship, such as creation of legally binding and government-run payment database and utilisation of this payment database by medical professional societies and CPG authors to verify their COI declaration and disclosure. In fact, this approach has already been adopted by several medical professional societies in the United States, including the American Society of Clinical Oncology, one of the most influential oncology societies.^{5, 84}

5 CONCLUSIONS

In conclusion, we observed that there were the extensive financial interactions between authors of the Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer and drug companies. The JBCS2022 chairpersons received much larger payments than those to other authors from drug companies producing breast cancer drugs, some of which were not recommended in other countries. Furthermore, due to the less transparent COI management strategies, the majority of financial COIs with the drug companies were under-declared by the authors. These findings call for immediate policy reforms to promote transparency, integrity and credibility of breast cancer practice guidelines in Japan. Such improvements in COI management are essential to protect the objectivity of CPG recommendations and to maintain the confidence of both the health care providers managing and treating breast cancer in accordance with JBCS2022 and the patients receiving the treatments.

AUTHOR CONTRIBUTIONS

Conceptualisation, methodology, resources, software, formal analysis, investigation, writing—original draft, writing—review and editing, visualisation and study administration: Anju Murayama. Conceptualisation, methodology, resource, software, formal analysis and writing—review and editing: Kenichi Higuchi. Conceptualisation, writing—original draft and writing—review and editing: Keerthana R. Byreddy. Conceptualisation, methodology, resources, investigation and writing—review and editing: Kugo Hinari. Conceptualisation, methodology, resource, formal analysis, investigation, writing—original draft and writing—review and editing: Yuki Senoo.

CONFLICT OF INTEREST STATEMENT

The authors declare they have no conflicts of interest.

ETHICS STATEMENT

As this study was a retrospective analysis of publicly available data and met the definition of non-human subjects research, no institutional board review or approval was required according to the Japanese Ministry of Health, Labor and Welfare's Ethical Guidelines for Medical and Health Research Involving Human Subjects.

DECLARATION OF GENERATIVE AI IN SCIENTIFIC WRITING

During the preparation of this work, the authors used ChatGPT version 4.0 to check and correct grammatical and spelling errors. After using this tool, the authors carefully reviewed and edited the content as needed and take full responsibility for the content of the publication.