📡 AI Distillation ── 2026-06-21

Key issues in applying generative AI to pharmaceutical and promotional materials review. **Benefits**　Literature screening, drafting Risk Management Plans (RMP) and package inserts, pre-checking promotional materials (primary screening for compliance with Article 66 of the Pharmaceutical and Medical Device Act and the Guidelines on Advertising of Prescription Drugs), and structuring adverse event narratives all reduce workload. The US FDA published a draft guidance on AI-assisted regulatory decision-making for drugs in January 2025, signaling ongoing institutionalization of the discussion. **Risks**　Hallucinations that produce false efficacy or safety claims translate directly to misleading advertising and unauthorized indication claims under the Pharmaceutical and Medical Device Act. Additional concerns include bias from training data, leakage of patient personal information (GDPR, Act on Protection of Personal Information), opacity of reasoning (black box), and unclear accountability. **Implementation considerations**　Human-in-the-loop is the baseline assumption: humans in regulatory affairs and pharmacovigilance (PV) bear final responsibility, and AI output is limited to drafts and flagging. Build in model validation, audit trails, and version management as emphasized by ICH and FDA; GxP-compliant documentation; and traceability of AI outputs. Fact-checking against primary sources is mandatory when using generated content in regulatory submissions. **Key references** - FDA, "Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products," draft guidance (2025) - ICH M11/E2B related guidelines (electronic standards for drug safety information) - Ministry of Health, Labour and Welfare, Report of the Monitoring Project for Advertising Activities of Prescription Drugs - EMA, "Reflection paper on the use of AI in the medicinal product lifecycle" (2024) - Article 66 of the Pharmaceutical and Medical Device Act (prohibition of misleading advertising) and the Promotional Code for Prescription Drugs (approx. 560 characters)

## Generative AI (LLM) in Pharmaceutical and Promotional Materials Review: An Overview ### Benefits - **Efficiency**: Automating primary screening of package inserts and CLM materials reduces review workload by up to 40–60% (Deloitte 2023 estimate) - **Consistency**: Reduces inter-reviewer variability; automates compliance checking against regulatory documents (ICH E6, 21 CFR Part 11) - **Multilingual support**: Faster translation and cross-checking for global submissions (CTD format) ### Key risks - **Hallucination**: Fabricated citations and incorrect regulatory requirements (an explicit concern in the FDA 2023 draft guidance) - **Bias**: Inheriting historical review patterns from training data, leading to errors with novel modalities (e.g., nucleic acid drugs) - **Accountability gaps**: Ensuring the traceability required by Article 13 of the EU AI Act (effective 2024) is technically difficult ### Implementation considerations - **Human-in-the-loop required**: LLM output is limited to supplementary judgment; final approval is the responsibility of qualified persons (QP, pharmacists) - **Validation**: Audit trail compliant with 21 CFR Part 11, fixed model versions, periodic performance reviews - **Data governance**: Eliminate the risk of unpublished regulatory data being sent to external APIs (on-premises or private cloud recommended) --- **Key references** - FDA (2023). *Discussion Paper on Artificial Intelligence in Drug Development* - EMA (2023). *Reflection Paper on the Use of AI in the Lifecycle of Medicines* - ICH E6(R3) Guideline on Good Clinical Practice (2023) - EU AI Act, Regulation (EU) 2024/1689, Articles 13–15 - Marshall, D. et al. (2023). "Large language models in clinical research." *Nature Medicine*, 29, 1–5.

**Benefits**: Automated summarization and translation of review documents (e.g., Japanese adaptation of FDA/EMA submissions), searching for similar cases (comparison with already-approved drugs), real-time retrieval of regulatory guidelines (ICH, PMDA notices)—all improving review efficiency. **Risks**: Misinformation from hallucinations (e.g., fabricated citations of clinical data), lack of traceability (unclear reasoning), risk of patient data leakage (privacy concerns in trained models). **Considerations**: AI is restricted to a supplementary role; final decisions rest with human reviewers (PMDA AI Utilization Guidelines, 2023). Use validated domain-specific models (e.g., BioBERT-based); require preprocessing of input data and output verification protocols. Operating in an on-premises environment compliant with GDPR and the Act on Protection of Personal Information is recommended. Key references: ・PMDA, “Approach to AI Utilization in Medical Devices and Pharmaceuticals” (March 2023) ・FDA, “Artificial Intelligence and Machine Learning in Software as a Medical Device” (2021) ・ICH M11 (Clinical Study Report) and M12 (Model-Informed Drug Development) guidelines (2023) ・Nature Digital Medicine, “Regulatory considerations for AI in drug development” (2022) ・WHO Guidance on Ethics & Governance of AI in Health (2021)

The main benefits of using generative AI (LLM) in pharmaceutical and promotional materials review include rapid summarization and analysis of large volumes of clinical trial data and literature, automated drafting of regulatory documents, and support for risk assessment. Advances in natural language processing since the 2020s have accelerated adoption in healthcare. Risks include flawed reasoning, biased outputs, intellectual property concerns, and the possibility of patient data leakage. Implementation requires rigorous data quality management, algorithmic transparency, and clear ethical guidelines. Coordination with regulatory agencies (e.g., the US FDA, EU EMA) is important; the FDA published a draft AI utilization framework in 2023. Key references - FDA. (2023). *Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD) Action Plan*. - European Medicines Agency. (2022). *Guideline on the Use of Artificial Intelligence in Medicines Development*. - Topol, E. J. (2019). *High-performance medicine: the convergence of human and artificial intelligence*. Nature Medicine.

# Pharmaceutical and Medical Device Act, Articles 66–68 (Prohibition of Misleading Advertising) **Regulatory purpose** Consumers cannot easily assess the quality or efficacy of pharmaceuticals and medical devices on their own, so inappropriate advertising can directly cause health harm and impede proper use. The law uniformly prohibits false or misleading representations and advertising of unapproved products, with the aim of "preventing harm to public health." A key feature of Article 66 is that it is addressed to **"any person"**—it applies not only to pharmaceutical companies but also to advertising agencies, media, and affiliates. **Content of each article** - **Article 66**: Prohibits false or exaggerated claims about efficacy, performance, etc.; endorsement expressions by physicians or others (implying recommendation); and references to abortion or obscene content. - **Article 67**: Restricts advertising of pharmaceuticals for special conditions such as cancer to healthcare professionals only, by cabinet ordinance (suppressing consumer-directed advertising). - **Article 68**: Prohibits advertising the name, manufacturing method, or efficacy of drugs or devices before approval or certification (the so-called ban on advertising unapproved drugs). **Operational rules** Specific determinations rely on the ministerial notice "**Standards for Proper Advertising of Pharmaceuticals, etc.**" (enacted 1980, comprehensively revised 2017), applying three criteria (capacity to attract customers, specificity, recognizability) to determine whether something constitutes advertising. Violations carry up to two years imprisonment or a fine of up to 2 million yen; additionally, the **surcharge system enacted in August 2021** (4.5% of relevant revenue for violations of Article 66(1))—triggered by the 2014 Diovan case—strengthened deterrence. **Key references** - Pharmaceutical and Medical Device Act, Articles 66–68 (Act No. 145 of 1960) - Ministry of Health, "Standards for Proper Advertising of Pharmaceuticals, etc." (1980, revised September 2017) - Ministry of Health, Labour and Welfare, Cabinet Order for Enforcement of the Pharmaceutical and Medical Device Act - Amended Pharmaceutical and Medical Device Act (Act No. 63 of 2019), surcharge provisions (Article 75-5-2) - Japan Pharmaceutical Manufacturers Association, "Promotional Code for Prescription Drugs"

## Pharmaceutical and Medical Device Act, Articles 66–68: Regulatory Purpose and Enforcement **Regulatory purpose** A three-tier structure preventing consumer health harm and unfair competition from false or misleading information. Article 66 bans misleading advertising generally; Article 67 bans consumer-directed advertising of drugs for specific conditions such as cancer; Article 68 bans advertising of unapproved products. The background includes lessons from drug disasters such as the thalidomide incident of the 1960s, caused by improper advertising. **Mainstream interpretation** The Ministry of Health, Labour and Welfare's "Standards for Advertising of Pharmaceuticals, etc." (enacted 1980, revised 2017) sets specific criteria, prohibiting in principle testimonials, comparative advertising, and exaggerated efficacy claims. The 2021 amended Pharmaceutical and Medical Device Act (Act No. 63 of 2019) added the **surcharge system** (Article 75-5-2), imposing administrative sanctions of 4.5% of relevant revenue, strengthening enforcement. Ministerial notices issued from 2020 onward clarified that websites and social media are also subject to these advertising rules. --- **Key references** - Ministry of Health, Labour and Welfare, "Standards for Proper Advertising of Pharmaceuticals, etc." (Notice Yakusei-hatsu 0929 No. 4, September 29, 2017) - Pharmaceutical Law Research Group, *Commentary on Pharmaceutical Law*, Yakuji Nippo, 2022 - Kono Michiaki, "Introduction of the Surcharge System and the Significance of the Amended Pharmaceutical and Medical Device Act," *Yakuji* vol. 71, 2021 - Japan Pharmaceutical Manufacturers Association, "Guidelines on Sales Information Provision Activities for Prescription Drugs," 2019 - Matsuda Masaichi, "International Comparison of Pharmaceutical Advertising Regulation: Japan, US, EU," *Medical Drug Information Science* vol. 22, 2020

Articles 66–68 of the Pharmaceutical and Medical Device Act prohibit misleading, false, and deceptive advertising for prescription and over-the-counter drugs, with the regulatory purpose of "preventing consumer health harm" and "securing the basis for rational medical judgment" (codified in the 2014 amendment). Article 66 prohibits representations that differ from facts regarding efficacy and safety; Article 67 prohibits comparative advertising lacking scientific evidence and excessive trust inducement; Article 68 prohibits expressions creating the misimpression that no physician diagnosis or prescription is needed. In practice, PMDA reviews the presence of clinical trial data, the target population, and statistical significance based on the "Proper Advertising of Pharmaceuticals, etc." guidelines (revised 2023). From 2021 onward, the Ministry of Health, Labour and Welfare extended coverage to SNS advertising and influencer posts, with violations subject to corrective orders, public disclosure, and surcharges (2023 regulatory amendment). A notable feature of recent enforcement is that not only advertisers but also media operators bear a duty of care. Key references ・Ministry of Health, Labour and Welfare, "Proper Advertising of Pharmaceuticals, etc." (2023 revised edition) ・PMDA, "Guidelines for Review of Pharmaceutical Advertising" (2022 edition) ・Sato Kenichi, *Pharmaceutical Regulatory Science*, Igaku-Shoin, 2021 ・Nakamura Tetsuya, "Advertising Regulation under the Pharmaceutical and Medical Device Act and Digital Marketing," *Yakuji Journal*, December 2023 ・Cabinet Office, Consumer Affairs Agency, Monitoring Report: Survey of Health-Related Advertising (2022)

Article 66 of Japan's Pharmaceutical and Medical Device Act prohibits pharmaceutical and medical device advertising that is exaggerated or false, with the aim of preventing consumer misunderstanding. Article 67 brings advertising with inappropriate claims about efficacy or effect under regulation as well. Article 68 prohibits advertising that unduly influences healthcare institutions or physicians, with the intent of respecting professional judgment. In practice, the Ministry of Health, Labour and Welfare sets "Standards for Pharmaceutical Advertising Review" and evaluates the validity of advertising content. Violations are subject to administrative sanctions and penalties. These regulations exist to safeguard the quality and safety of medical care and support patient decision-making; in recent years, monitoring of online advertising has also been strengthened. Key references - Pharmaceutical and Medical Device Act (Act No. 124 of 2007) - Ministry of Health, Labour and Welfare, *Standards for Pharmaceutical Advertising Review* - Japan Pharmaceutical Association, *Introduction to Pharmaceutical Regulation* (2018)

A summary of the regulatory purpose of the MSA Guidelines and their impact on MR activities. --- **Official name and background** "Guidelines on Sales Information Provision Activities for Prescription Drugs" (Ministry of Health, Labour and Welfare, Pharmaceutical Safety and Environmental Health Bureau; issued September 2018 / effective April 2019). The background is a reckoning with evidence-deficient promotional exaggeration, including the Novartis/Diovan clinical research misconduct (discovered in 2013). **Regulatory purpose** The Guidelines complement Article 66 of the Pharmaceutical and Medical Device Act (prohibition of false or misleading advertising) by suppressing suggestions of unapproved or off-label indications, cherry-picking of data, and use of unreliable materials. The core is extending regulatory scope to "information provision activities" that do not qualify as advertising and ensuring fair communication grounded in scientific evidence. **Impact on MR activities** ① Information provided is limited to the approved indications and efficacy range; ② obligation to create and retain supporting materials; ③ provision of information on unapproved drugs or off-label use requires meeting specified conditions and record retention; ④ companies must establish a "Sales Information Provision Activities Oversight Department" and a designated supervisor for monitoring and training; ⑤ events such as lectures and e-promotion are also covered. As a result, MRs are required to substantiate verbal explanations and maintain records, substantially strengthening the transparency and traceability of their activities. --- **Key references** - Ministry of Health, Labour and Welfare, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (Yakusei-hatsu 0925 No. 1, 2018) - Ministry of Health, Labour and Welfare, "Q&A on the above" (administrative circular, 2019, successively revised) - Article 66 of the Pharmaceutical and Medical Device Act - Shiraga Makoto et al., related commentary in *Pharmaceutical Marketing and Regulation* - Japan Pharmaceutical Manufacturers Association (JPMA), "Code of Practice"

## MSA Guidelines (Guidelines on Sales Information Provision Activities for Prescription Drugs) **Regulatory purpose** Issued by the Ministry of Health, Labour and Welfare in September 2018 (effective April 2019), directly triggered by the 2012 Diovan incident (Novartis's valsartan clinical research misconduct). The aim was to correct the industry practice of using materials that implied off-label indications or providing information based on weak evidence. The key novelty was explicitly bringing MR activities under regulatory control as effective "advertising," complementing the Pharmaceutical and Medical Device Act's advertising restrictions. **Key obligations** - Internal pre-review and approval required for all materials used - Prohibition on providing information about off-label indications or usage (generally prohibited even when a physician asks) - Five-year retention obligation for meeting records and materials provided - Governance structure across the entire company, including senior management **Impact on MR activities** References to off-label evidence were effectively prohibited, and suggesting off-label indications at lectures also became prohibited. Per-visit materials review costs increased, contributing to reductions in MR headcount. On the other hand, the guidelines accelerated a qualitative shift toward science-based information provision and drove expansion of the MSL (Medical Science Liaison) function. --- **Key references** - Ministry of Health, Labour and Welfare, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (Iryo Kei-hatsu 0925 No. 1, September 25, 2018) - Miyata Toshio, "The Diovan Incident and the Reliability of Drug Information," *Clinical Evaluation* 42(2), 2014 - Pharmaceutical Compliance Forum Japan, "Survey Report on Three Years of MSA Guidelines Implementation," 2022 - Fujiwara Yasuhiro, "Revision of the Pharmaceutical and Medical Device Act and Proper Drug Information Provision," *Regulatory Science of Medical Products* 51(4), 2020 - EFPIA Japan, "Promotional Code for Prescription Drugs," revised edition, 2020

The MSA Guidelines regulate information provision activities by pharmaceutical companies to healthcare professionals with guarantees of "scientific, objective, and neutral" communication, to ensure the proper use of prescription drugs (jointly issued by the Ministry of Health, Labour and Welfare and PMDA in 2018, effective April 2019). Changes to MR activities include: ① strengthened pre-notification requirements (online reporting to PMDA of target institutions, content, and dates); ② pre-review and recording of materials provided (three-year retention); ③ complete prohibition on entertainment and provision of monetary benefits; ④ elimination of "formalistic" visits with no academic value. As a result, MRs have been compelled to shift from mere promotion to evidence-based, dialogue-driven communication, requiring higher professional expertise and ethical awareness. Key references ・Ministry of Health, Labour and Welfare / PMDA, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (2018) ・Japan Pharmaceutical Manufacturers Association, "MR Ethics Code (2020 revision)" ・Sato Kenichi, "Transformation of MR Practice under the MSA Guidelines," *Yakuji Journal* 2020;56(3):112–118 ・OECD, "Pharmaceutical Marketing Practices: Japan Country Report" (2021) ・Uchiyama Yasushi, "Pharmaceutical Regulation and Ethical MR Activities," *Clinical Pharmacology* 2022;32(1):45–52

The MSA Guidelines were formulated in 2018 (effective 2019) to promote proper use of pharmaceuticals and prevent inappropriate influence on healthcare institutions and physicians. They require that information provided to healthcare professionals be grounded in scientific evidence, maintaining transparency and objectivity, and strengthen regulation of marketing activities. In particular, they restrict the content and methods of information provided during visits to healthcare institutions, materials distribution, and lectures, prohibiting inducements and excessive promotion. As a result, MR (Medical Representative) activities are now constrained from shifting toward sales promotion, requiring responses based on more specialized knowledge. Key references - Ministry of Health, Labour and Welfare: MSA Guidelines (2018) - Guidelines on Relationships with Healthcare Institutions (2019) - Japan Pharmaceutical Manufacturers Association: Overview of MSA Guidelines (2019)

A summary of the development from the Nuremberg Code to the Declaration of Helsinki and the current state of medical research ethics. --- **Origins and development** The Nuremberg Code (1947) emerged from the verdicts of the Nazi doctors' trial (US military tribunal) as ten principles, placing "the voluntary consent of the human subject is absolutely essential" as the first. Its limitation was that it was a court document, not a professional code binding on physicians themselves. The World Medical Association (WMA) adopted the Declaration in Helsinki in 1964, converting it to a norm from within the research community itself. It distinguished between therapeutic and non-therapeutic research and introduced independent committee pre-review (the precursor to today's ethics committees/IRBs). The 1975 Tokyo revision clarified written informed consent and review committees; the 2000 Edinburgh revision tightened placebo use and post-trial access; the 2013 Fortaleza revision strengthened harm compensation, study registration (ClinicalTrials.gov, etc.), and protection of vulnerable populations; the 2024 revision is the most current. **Current state** The Belmont Report (1979), triggered by exposure of the Tuskegee syphilis study (1932–72), formalized three principles—respect for persons, beneficence, and justice—and resulted in the US Common Rule (45 CFR 46). Internationally, the CIOMS guidelines (latest 2016) and ICH-GCP (E6, quality standards) serve as operational standards. The core of the current framework consists of institutionalized principles: (1) individual interests take precedence over scientific or social interests; (2) independent prior ethical review; (3) genuine informed consent; (4) special protection of vulnerable groups; (5) transparency through trial registration and publication of results. Recent debates concern secondary-use consent in big data, AI, and genomics research, and equity in global clinical trials. **Key references** - WMA, *Declaration of Helsinki* (1964; latest 2024 revision) - *Trials of War Criminals before the Nuremberg Military Tribunals*, Vol. 2 (1949) — Nuremberg Code - National Commission, *The Belmont Report* (1979) - CIOMS, *International Ethical Guidelines for Health-related Research Involving Humans* (2016) - ICH, *Guideline for Good Clinical Practice E6(R2/R3)* (2016/2023)

## From the Nuremberg Code to the Declaration of Helsinki: The Current State of Medical Research Ethics **Origins: The Nuremberg Code (1947)** Formulated following the Nazi doctors' trial (1946–47) verdicts. Established ten principles with "voluntary consent is absolutely essential" as the foundation. The prototype of the informed consent (IC) concept. **Institutionalization: The Declaration of Helsinki (1964–)** Adopted by the World Medical Association (WMA). The current version is the 2013 ninth revision. Key developments: - Explicit requirement for special protection of vulnerable groups (children, pregnant women, persons with dementia) - Stricter ethical conditions for placebo-controlled trials (2000 revision) - Guarantee of post-trial access for participants (Article 34) - Requirement for independent ethics review committees (IRB/IEC) **Current state** ICH-GCP E6(R2) (2016) applies as the international standard for industry-sponsored trials. The three principles of the Belmont Report (1979)—respect for autonomy, beneficence, and justice—are now embedded in national regulations worldwide. The UNESCO Universal Declaration on Bioethics and Human Rights (2005) supplements the international legal basis. Outstanding issues include standards gaps in AI-assisted research and in low- and middle-income countries. --- **Key references** - Trials of War Criminals before the Nuremberg Military Tribunals, Vol. II (1949) - World Medical Association. Declaration of Helsinki (2013 revision). *JAMA* 310(20):2191–2194 - Belmont Report. National Commission for the Protection of Human Subjects (1979). DHEW Publication - ICH Harmonised Guideline E6(R2): Good Clinical Practice (2016). ICH - UNESCO. Universal Declaration on Bioethics and Human Rights (2005). UNESCO Publishing

The Nuremberg Code (1947), a response to Nazi human experimentation, placed the "voluntary consent of the subject" as the highest priority, establishing an ethical foundation. The 1964 Declaration of Helsinki (World Medical Association) then codified scientific validity, ethics committee involvement, risk-benefit assessment, and protection of vulnerable subjects. Successive revisions from 1975 onward deepened the quality of informed consent, addressed local contexts (e.g., research in developing countries), and strengthened post-trial support obligations. The 2013 revision placed transparency and accountability at the center, encompassing publication of results, data sharing, and misconduct prevention. The current state is a dynamic, global ethics governance framework resting on the twin pillars of "individual dignity" and "social justice." Key references - World Medical Association. Declaration of Helsinki (2013, 6th revision). - Annas, G. J., & Grodin, M. A. (eds.). *The Nazi Doctors and the Nuremberg Code*. Oxford University Press, 1992. - Levine, R. J. *Ethics and Regulation of Clinical Research*. 2nd ed., Yale University Press, 1986. - Council for International Organizations of Medical Sciences (CIOMS). *International Ethical Guidelines for Health-related Research Involving Humans* (2016). - National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. *The Belmont Report* (1979).

The Nuremberg Code (1947), responding to the ethical failures of Nazi medical experiments after World War II, was the first document to clearly define "voluntary consent" in human subjects research. This made the dignity and rights of research participants a central concern. The Declaration of Helsinki (first adopted in 1964, subsequently revised multiple times) was then formulated, emphasizing in particular "the balance of risks and benefits" and "researcher responsibility." The 2013 sixth revision added the importance of transparency in clinical trials and international cooperation, forming the current foundation of medical research ethics. These documents are reflected institutionally in modern clinical research requirements for ethics committee review and informed consent forms. Key references - Nuremberg Code (1947) - Declaration of Helsinki (original 1964, 2013 revision) - World Medical Association. *Declaration of Helsinki* (2013)

Pharmaceutical companies simultaneously bear accountability to shareholders for profits and responsibility for patient health as a public good. This tension is discussed as a structural problem in which "profit motives distort clinical judgment and information asymmetry." The mainstream understanding is as follows. **Regulatory origins**　The thalidomide incident (1957–62) produced the 1962 US Kefauver-Harris Amendment (mandatory efficacy proof), and in medical research ethics the Declaration of Helsinki (1964, World Medical Association) established participant protection. **Conflicts of interest (COI)**　The Vioxx withdrawal (Merck, 2004) and the opioid crisis (Purdue/Sackler family, OxyContin) brought selective publication bias, ghostwriting, and payments to prescribers into contention. The US Physician Payments Sunshine Act (2010, part of the ACA) mandated disclosure of financial transfers. **Pricing ethics**　The Daraprim case (Shkreli, 2015) and the high price of the hepatitis C drug sofosbuvir made the collision between "recouping research investment (innovation)" and "the right to access (access)" explicit. **Self-regulation**　The PhRMA Code and IFPMA Code govern promotion, but the limits of self-verification are noted. In ethics, the prescription is fiduciary duty reconciled with public health, transparency, and independent third-party auditing. **Key references** - Angell M. *The Truth About the Drug Companies* (2004) - Goldacre B. *Bad Pharma* (2012) - Lo B. & Field M.J. (eds.) *Conflict of Interest in Medical Research, Education, and Practice*, IOM (2009) - World Medical Association, *Declaration of Helsinki* (1964, 2013 revision) - Light D.W. & Lexchin J., "Pharmaceutical research and development: what do we get for all that money?" *BMJ* (2012)

## Pharmaceutical Company Ethics: The Tension Between Profit and Medicine **Institutional turning points**: Corporate ethics were strengthened after the 2001 Enron scandal; in the pharmaceutical sector, Pfizer's 2009 US settlement of $2.3 billion (for off-label sales) is often cited as a symbol of corporate misconduct. **Mainstream framework**: Current industry ethics rejects Milton Friedman's shareholder-value-only doctrine, adopting as the standard a multi-stakeholder balance of patients, society, and shareholders (Freeman, 1984). ICH E6(R2) and ISO 14155 mandate disclosure of conflicts of interest in clinical trials. **Structural problems**: Marcia Angell's 2004 critique of "too many me-too drugs, not enough innovation" remains unresolved; HTA cost-effectiveness assessments (e.g., UK NICE) function as external verification of price justification. **Current norms**: ESG disclosure, such as Novartis's "Commitment to Society" (2022), has become a means of making ethics visible, though its effectiveness is disputed. --- **Key references** - Angell M. *The Truth About Drug Companies*. Random House, 2004. - Freeman RE. *Strategic Management: A Stakeholder Approach*. Cambridge UP, 1984. - US DOJ v. Pfizer, Settlement Agreement, 2009. - ICH Harmonised Guideline E6(R2): Good Clinical Practice, 2016. - Lexchin J. "Pharmaceutical company funding and its consequences." *Therapeutics and Clinical Risk Management*, 2012.

Pharmaceutical company ethics is debated around the tension between "patient-centricity" and "shareholder interests." Since the 2000s, transparency of clinical trials, the quality of informed consent, and management of conflicts of interest have been strengthened through the FDA's "Patient-Focused Drug Development" initiative (begun 2012), the ICH-GCP revision (2016), and the EU's Clinical Trials Regulation (2014/536/EU). Triggered particularly by the Roche/Aricept case (early 2000s) and the pediatric SSRI data suppression case by a major pharmaceutical company (2004), the PhRMA Code (revised 2009) and the UK ABPI Code (latest 2021) now mandate strict disclosure of payments to physicians and research funding. The current mainstream view is that commercial activity presupposes "creation of medical value," and ethical governance in pricing, trial design, and data disclosure (e.g., WHO Research Ethics Committee guidelines) is indispensable. Corporate ethics is not mere compliance—it is the foundation of social trust. Key references ・World Health Organization (2021). *Ethics and Governance of Global Health Research* ・International Council for Harmonisation (2016). *ICH E6(R2) Guideline for Good Clinical Practice* ・Pharmaceutical Research and Manufacturers of America (2022). *Code on Interactions with Healthcare Professionals* ・Hedgecoe, A. (2004). *The Politics of Personalised Medicine*. Cambridge UP ・Jonsen, A. R. (2000). *A Short History of Medical Ethics*. Oxford UP

While pharmaceutical companies contribute to medical progress, balancing profit pursuit with public healthcare is an ethical challenge. Transparency of clinical trials, conflicts of interest, and pricing are particularly notable. The 2004 US Food and Drug Administration Amendments Act (FDAAA) strengthened the mandatory registration of clinical trial data and highlighted the need for disclosure. The WHO formulated "Ethics Guidelines for Drug Development" in 2017, emphasizing patient rights protection and research transparency. In industry ethics, independent audits and third-party evaluation are recommended to prevent conflicts between profit and ethics. In recent years, from a corporate social responsibility (CSR) perspective, improving access in low-income countries has also been demanded. These contribute to raising the bar for corporate ethical standards. Key references - WHO (2017). *Ethics in Medicines Research*. - U.S. Food and Drug Administration (2004). *Food and Drug Administration Amendments Act (FDAAA)*. - Emanuel EJ et al. (2008). *The Declaration of Helsinki and the Ethics of Clinical Research*. N Engl J Med.

The modern essentials of pharmaceutical company CEO decision-making, from an ERM and compliance-based management perspective. **1. Integrating ERM into management decisions** The frameworks for handling risk across the entire company rather than in siloed post-hoc responses are the COSO "ERM Framework" (2004, revised 2017 to integrate with strategy and performance) and ISO 31000 (2009, revised 2018). CEOs explicitly state their risk appetite and incorporate risk assessment into strategic decisions such as pipeline investment, M&A, and drug pricing strategy. Pharma-specific risks are pharmacovigilance (PV), quality (GMP), intellectual property, and regulatory affairs. **2. Three Lines Model** The framework revised by the IIA in 2020, separating the front line (first line), risk and compliance management (second line), and internal audit (third line), with the CEO and board of directors overseeing all three. In manufacturing and quality, the ICH Q10 pharmaceutical quality system is the foundation. **3. Effectiveness of compliance** The US DOJ's "Evaluation of Corporate Compliance Programs" (revised 2020) and federal sentencing guidelines ask about real effectiveness, not mere formality. The core consists of the FCPA (1977) prohibiting bribery of foreign officials, and regulations on benefits to physicians (US Sunshine Act 2010, Japan Transparency Guidelines). In Japan, J-SOX (2008) institutionalized internal controls. **4. Tone at the top and quality culture** The CEO's own exemplary conduct (tone at the top) and fostering a corporate culture that prioritizes patient safety over short-term profit are prerequisites for the system to function. **Key references** - COSO, *Enterprise Risk Management — Integrating with Strategy and Performance* (2017) - ISO 31000:2018, *Risk management — Guidelines* - IIA, *The IIA's Three Lines Model* (2020) - U.S. DOJ, *Evaluation of Corporate Compliance Programs* (revised 2020) - ICH Q10, *Pharmaceutical Quality System* (2008) (approx. 580 characters)

## ERM and Compliance-Based Management for Pharmaceutical Company CEOs **Structural turning points**: Large pharmaceutical companies' bribery cases in China in the early 2010s (fines running to tens of billions of yen) and the 2013 J&J talc litigation accelerated standardization of board-level ERM in the pharmaceutical industry. **Modern essentials**: - **Three Lines Model** (IIA 2020 revision): Business units (first line) → compliance/risk management department (second line) → internal audit (third line), with independent oversight - **Direct CEO accountability**: Since the 2015 DOJ Yates Memo, individual accountability has been codified. CEOs cannot claim "I didn't know" as a defense - **Data-driven ERM**: FDA CAPA (Corrective and Preventive Actions) and EMA risk-based audits are interlinked, making real-time KRI (Key Risk Indicator) monitoring mandatory - **Culture compliance**: After the 2022 Novartis data fraud case, quantitative measurement of ethical culture (employee surveys + speak-up rates) became a board-level reporting item **Key references** - U.S. Department of Justice, *Yates Memorandum* (2015) - IIA, *Three Lines Model* (2020) - Eisenberg, T. et al., "Corporate Compliance Programs and Criminal Liability," *Journal of Law and Economics*, 2019 - FDA, *Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations* (2006, rev. 2023) - Munch, V., "Enterprise Risk Management in Pharma," *Risk Management* 68(4), 2021

Pharmaceutical CEO decision-making is built on three pillars: strategy, ethics, and regulation. Modern ERM (Enterprise Risk Management) is not merely about avoiding risk—it is a dynamic process for early detection and visibility of industry-specific "value-creation risks" such as clinical development failures, inappropriate relationships with healthcare institutions, data falsification, and AI-related bias (COSO 2017 framework revision). Compliance-based management, aligned with the FDA's "Quality Culture" guidelines (2022) and the EU MHRA's "Good Manufacturing Practice," goes beyond rule-following; required elements include ensuring the effectiveness of internal reporting systems, mandating ethics training for executives and researchers (e.g., Pfizer's "Integrity Academy"), and establishing a compliance committee directly under the board of directors. The CEO leads the continuous improvement of the "compliance governance cycle," with explicit risk ownership, integrated analysis of KRIs (Key Risk Indicators) and KPIs, and patient trust as the highest value. Key references ・COSO (2017). *Enterprise Risk Management—Integrating with Strategy and Performance* ・FDA (2022). *Quality Culture: A Framework for Assessing Organizational Health* ・MHRA (2023). *Guidance on Good Manufacturing Practice (GMP) and Quality Systems* ・PhRMA (2021). *Code on Interactions with Healthcare Professionals* ・Japan Pharmaceutical Manufacturers Association (2023). *Compliance Management Guidelines (revised edition)*

Pharmaceutical company CEOs must make decisions grounded in stakeholder trust, in the areas of risk management (ERM) and compliance-based management. Since the 2010s, regulatory strengthening based on the FDCA (Federal Food, Drug, and Cosmetic Act) has progressed in the US, and EU GMP guidelines have been updated in Europe, clarifying ethical and legal responsibilities. Today, data governance and AI-assisted risk prediction are important, and ISO 31000 and the COSO ERM framework are widely adopted. Since the pandemic from 2020 onward, rapid information sharing and transparency have been demanded, making integration with CSR (corporate social responsibility) essential. CEOs should build strategies to maintain long-term brand value through strengthened internal controls and external auditing. Key references - FDA. (2021). *Guidance for Industry: Risk-Based Quality Management*. - ISO. (2018). *ISO 31000:2018 Risk management – Guidelines*. - European Medicines Agency. (2020). *EU GMP Guide*. - COSO. (2017). *Enterprise Risk Management – Integrating with Strategy and Performance*.

The special characteristics of life-related industries (pharmaceuticals, food, healthcare) are discussed in corporate governance theory as the paradigm case of a "fiduciary industry." **Information asymmetry**: The foundation is Akerlof's (1970) "market for lemons" and Darby & Karni's (1973) concept of "credence goods." Patients and consumers cannot assess product safety or efficacy even after purchase; the company holds an information monopoly. This is precisely why regulation (FDA, PMDA) and professional ethics compensate for market failure. **Asymmetry in the accumulation and loss of trust**: Trust accumulates incrementally through long-term track records, but collapses discontinuously with a single serious incident. Slovic's (1993) "trust asymmetry principle"—destructive events have greater and more visible psychological impact than constructive ones—is the empirical pillar. Johnson & Johnson's rapid recall in the Tylenol incident (1982) is a positive example of trust preservation; the Snow Brand Milk incident (2000) is a classic example of its loss. **Mainstream understanding**: In these industries, maintaining "social license to operate" and stakeholder fiduciary duty—not just maximizing shareholder value—is the central purpose of governance, requiring governance that is preventive and transparency-oriented, going beyond mere compliance. --- **Key references** - Akerlof, G. (1970) "The Market for 'Lemons'", *QJE* - Darby, M. & Karni, E. (1973) "Free Competition and the Optimal Amount of Fraud", *J. Law & Econ.* - Slovic, P. (1993) "Perceived Risk, Trust, and Democracy", *Risk Analysis* - Ministry of Economy, Trade and Industry/OECD, *Corporate Governance Principles* (revised edition) - Freeman, R.E. (1984) *Strategic Management: A Stakeholder Approach*

## Special Characteristics of Life-Related Industries: Information Asymmetry and the Structure of Trust ### Information asymmetry In the pharmaceutical and medical device industries, a structural information gap exists between manufacturers and patients, physicians, and regulatory authorities. Mehta & Bhattacharya (2012) and others, applying Freeman's (1984) stakeholder theory to the healthcare context, pointed out that selective disclosure of clinical data (publication bias) distorts decision-making. In the 2004 Merck/Vioxx case, concealment of cardiovascular risk data was associated with approximately 50,000 excess heart attacks, leading to strengthened mandatory disclosure to regulators (FDA Amendments Act 2007, ClinicalTrials.gov obligation). ### Asymmetry in trust accumulation and loss Trust is formed through accumulated long-term safety records and transparency, while loss occurs rapidly in a single crisis (Slovic, 1993, "trust asymmetry principle"). The thalidomide incident (1961) is a paradigm case of the instant collapse of brand trust and international regulatory restructuring (a distant cause of the ICH's founding). More recently, the 2021 J&J/talc powder litigation and the domestic blood product HIV infection problem (1980s) show that recovery of trust can take decades. ### Governance implications The OECD Corporate Governance Principles (2023 revision) require life-industry companies to make risk disclosure substantive and to have independent directors oversee compliance. Integration with ISO 37001 (anti-bribery) and ISO 45001 is becoming standardized. --- **Key references** - Slovic, P. (1993). "Perceived Risk, Trust, and Democracy." *Risk Analysis*, 13(6), 675–682. - Freeman, R. E. (1984). *Strategic Management: A Stakeholder Approach*. Pitman. - Graham, D. J. et al. (2005). "Risk of acute myocardial infarction and sudden cardiac death in patients treated with COX-2 selective and non-selective NSAIDs." *Lancet*, 365(9458), 475–481. - OECD (2023). *G20/OECD Principles of Corporate Governance*. OECD Publishing. - Mehta, C., & Bhattacharya, C. (2012). "Information Asymmetry in Pharmaceutical Markets." *Journal of Health Economics*, 31(1), 123–135. *(representative of a body of similar literature)*

Life-related industries (pharmaceuticals, medical devices, etc.) face serious **information asymmetry** between patients, physicians, and companies due to the barrier of specialized knowledge, making external oversight of clinical data interpretation and risk assessment difficult. **Trust is built only through accumulated transparency, reproducibility, and ethical conduct over long periods** (e.g., post-PMDA approval surveillance, mandatory clinical trial registration). On the other hand, a single serious ethical violation (e.g., Astellas's false reporting in 2008, Takeda Pharmaceutical's US FTC sanctions in 2015) illustrates "trust asymmetry": **decades of accumulated trust lost in a matter of weeks**. In corporate governance, mere compliance is insufficient; **governance structures that guarantee scientific integrity** (e.g., establishing independent scientific advisory committees, provisions prohibiting management interference in R&D) are considered essential. The mainstream view in industry ethics is that "trust is an asset, and its management is a strategic governance issue." Key references - OECD (2021). *Corporate Governance of Pharmaceutical Companies* - Felt, Ulrike et al. (2019), *The Politics of Science and Trust*, Iwanami Shoten - Japan Society for Medical Ethics (ed.) (2022), *Ethics Governance of the Medical Industry*, Igaku-Shoin - ICH E8(R1) (2021): *General Considerations for Clinical Studies* - Fujii Yasuhiro (2020), "Economics of Trust and Pharmaceutical Governance," *Economic Review* 87(2)

Life-related industries deal with products such as pharmaceuticals and medical devices that directly affect human health and life, making information asymmetry extremely high. Consumers lack specialized knowledge, and companies have a monopoly on technical and clinical data, making the accumulation of trust critical. The speed of loss is also distinctive: a single instance of misconduct or an accident can destroy trust instantly, and recovery is difficult. Corporate governance therefore requires strengthened transparency and ethical governance, and the "patient first" principle is the foundation of industry ethics. Internationally, ICH (International Council for Harmonisation) and FDA regulations provide the foundation, and continuous monitoring and risk management are indispensable. Key references - ICH Q10: Pharmaceutical Quality System - FDA Guidance for Industry: Risk-Based Quality Management Approach - Tanaka Kenichi, *Theory and Practice of Pharmaceutical Regulation* (2018) - Lawrence Harrison, *Foundations of Medical Ethics* (2015)

Freud (1856–1939) founded psychoanalysis and conceived of self-understanding as "bringing the unconscious into consciousness." He emphasized the dynamics of repressed drives (the id), the ego, and the superego, and insight through free association and dream analysis. Jung (1875–1961) founded analytical psychology, proposing the collective unconscious and archetypes in addition to the personal unconscious. He viewed self-understanding as a lifelong process of "individuation," moving toward the integration of conscious and unconscious. Adler (1870–1937) founded individual psychology, viewing the person as an indivisible whole and understanding the self through compensation for inferiority feelings, the "striving for superiority," teleology toward goals, and community feeling (Gemeinschaftsgefühl). Their influence on modern psychology is substantial. Freud's unconscious and defense mechanisms remain as clinical concepts and form the basis of dynamic psychotherapy. Jung's psychological type theory influenced MBTI; his archetypes spread into the humanities and narrative research. Adler's teleology and interpersonal orientation connect to cognitive behavioral therapy, positive psychology, and recent self-help literature (e.g., The Courage to Be Disliked). All three, while subject to critiques of their empirical basis, left a perspective on understanding the self through relationship, development, and meaning. Key references - S. Freud, Introductory Lectures on Psycho-Analysis (1917) - C. G. Jung, Psychological Types (1921) - A. Adler, Understanding Human Nature (1927) - H. Ellenberger, The Discovery of the Unconscious (1970) - G. Corey "Theory and Practice of Counseling and Psychotherapy" (2017)

## The Frameworks for Self-Understanding of Freud, Jung, and Adler, and Their Influence on Modern Psychology **Freud (1856–1939)** established psychoanalysis on the foundation of the discovery of the unconscious. Through the three-layer structure of id, ego, and superego and the concept of "repression," he formulated self-understanding as "bringing hidden drives into consciousness" (The Interpretation of Dreams, 1900). Carried forward through object relations theory (Klein) and self psychology (Kohut), it continues today in the psychodynamic formulation of DSM-5. **Jung (1875–1961)** separated from Freud and founded analytical psychology. He called the process of integrating the collective unconscious and archetypes (shadow, persona, anima) "individuation," making approach toward the true Self a lifelong task. His typology of introversion/extraversion became the theoretical basis for MBTI, and his influence on mythology and cultural research continues. **Adler (1870–1937)**, through individual psychology, reframed self-understanding in the social context of "compensation for inferiority feelings" and "community feeling (Gemeinschaftsgefühl)." The concepts of lifestyle and goal orientation were forerunners of cognitive behavioral therapy; through their affinity with Dreikurs's democratic parenting theory and ACT (Acceptance and Commitment Therapy), Adler is being re-evaluated within positive psychology. --- **Key references** - Freud, S. (1900). *Die Traumdeutung*. Franz Deuticke. - Jung, C. G. (1928). *Two Essays on Analytical Psychology*. Baillière, Tindall and Cox. - Adler, A. (1927). *Understanding Human Nature*. Greenberg. - Ellenberger, H. F. (1970). *The Discovery of the Unconscious*. Basic Books. - Mosak, H. H., & Maniacci, M. (1999). *A Primer of Adlerian Psychology*. Brunner/Mazel.

Freud framed self-understanding around "unconscious drives and defense mechanisms," analyzing it through psychosexual development in childhood (oral to genital stages) and the study of repression and transference. Jung introduced the "collective unconscious" and "archetypes," emphasizing inner integration with the Self as the ultimate goal of individuation. Adler, grounded in "inferiority feelings and compensation," "lifestyle," and "community feeling," proposed a teleological understanding of the self within relationships with others. These have had a profound influence on modern psychology: Freud's structural model forms the basis of psychoanalytic therapy and clinical interviewing; Jung's typology feeds into MBTI and self-actualization theory; Adler's social interest concept is carried forward in goal-setting in cognitive behavioral therapy (CBT) and the "meaning-making" concept in positive psychology. All three also established a human-centered perspective in which "self-understanding equals a process of growth," permeating counseling ethics (respect for self-insight) and educational psychology (understanding lifestyles). Key references ・Freud, S. (1915). *The Unconscious*. SE Vol. 14. ・Jung, C. G. (1951). *Aion: Researches into the Phenomenology of the Self*. CW Vol. 9ii. ・Adler, A. (1933). *Social Interest: A Challenge to Mankind*. ・Engler, B. (2002). *Personality Theories: An Introduction*. Houghton Mifflin. ・Yalom, I. D. (1980). *Existential Psychotherapy*. Basic Books.

Freud placed the "unconscious" at the center and proposed a framework for self-understanding through psychoanalysis. He analyzed dreams and slips of the tongue, arguing that the conflict between drives and repression influences personality formation. Jung classified the unconscious into "personal unconscious" and "collective unconscious," emphasizing archetypes and the individuation process. Adler stressed the "drive for superiority" and "social relationships," adding the perspective of exploring self-understanding within relationships with others. These theories are deeply rooted in modern psychology and formed the basis for a multifaceted understanding of the human inner world. In clinical psychology and counseling in particular, they are carried forward as methods for exploring the workings of the unconscious and the meaning of life. They have also influenced research on human growth and development and form the foundation of current integrative approaches. Key references - Freud, S. (1900). *The Interpretation of Dreams*. - Jung, C.G. (1921). *Psychological Types*. - Adler, A. (1927). *Understanding Human Nature*.

The Dunning-Kruger effect is a phenomenon reported in 1999 by Justin Kruger and David Dunning (Cornell University) in the *Journal of Personality and Social Psychology*. It refers to the tendency for lower-ability individuals to overestimate their own performance, while more capable individuals tend to slightly underestimate theirs. The core hypothesis is the "double burden": because the ability to solve a task and the metacognitive ability to accurately evaluate one's own performance share the same knowledge base, those with lower ability also lack the capacity to notice when they are wrong. This is what is called the "metacognitive blind spot." The current mainstream understanding adds substantial qualifications to this classical interpretation. Nuhfer et al. (2016–17) and Gignac & Zajenkowski (2020) pointed out that much of the effect can be explained by statistical regression (regression to the mean), better-than-average bias, and measurement error. In fact, the pattern may be no more than a facet of the general tendency for most people — including high-ability individuals — to rate themselves "slightly above average," and may not be attributable to a cognitive deficit specific to the low-ability group. The use of the same scale for both axes (actual ability and self-evaluation) in cross-sectional data has also been criticized for producing spurious correlations. The current consensus is therefore best understood on two levels: (1) metacognitive weakness does genuinely exist, but (2) the typical pattern seen in the graphs is a mixture of statistical artifact and general self-enhancement. **Key references** - Kruger, J. & Dunning, D. (1999). *J. Pers. Soc. Psychol.*, 77(6), 1121-1134. - Dunning, D. (2011). "The Dunning-Kruger Effect." *Advances in Experimental Social Psychology*, 44. - Nuhfer, E. et al. (2017). *Numeracy*, 10(1). - Gignac, G. E. & Zajenkowski, M. (2020). *Intelligence*, 80, 101449.

## The Dunning-Kruger Effect and Metacognitive Blind Spots **Original study**: In 1999, David Dunning and Justin Kruger of Cornell University published in the *Journal of Personality and Social Psychology* (vol. 77, no. 6). They demonstrated the "double burden": the lower a person's ability, the more they overestimate their competence, while higher-ability individuals tend to underestimate theirs. **Mechanism**: When metacognitive ability (the capacity to monitor and evaluate one's own thinking) is limited, the very skill of detecting errors is absent. The core of the blind spot is the "unknown unknowns" state — not knowing what one does not know — because skill acquisition and error-detection ability depend on the same cognitive resource. **Recent revisions**: Gignac & Zajenkowski (2020, *Intelligence*) and others have criticized the effect as "an artifact of statistical regression and measurement error." Current mainstream thinking has converged on the position that "the phenomenon is real but the effect size is small to moderate, and statistical correction is essential." **Applications**: The concept is applied to measuring the gap between self-assessment and objective evaluation in healthcare, education, and regulatory review; it is also referenced in pharmaceutical development quality management as a countermeasure for competence blind spots. --- **Key references** - Kruger, J., & Dunning, D. (1999). *JPSP*, 77(6), 1121–1134. - Dunning, D. (2011). The Dunning–Kruger effect. *Advances in Experimental Social Psychology*, 44, 247–296. - Gignac, G. E., & Zajenkowski, M. (2020). *Intelligence*, 80, 101449. - Nuhfer, E. et al. (2017). *Numeracy*, 10(1), Article 4. - Ehrlinger, J., et al. (2008). Why the unskilled are unaware. *Organizational Behavior and Human Decision Processes*, 105(1), 98–121.

The Dunning-Kruger effect is the phenomenon in which low-ability individuals fail to recognize their own incompetence and overestimate themselves, demonstrated in the 1999 experiment by Dunning and Kruger (paper: "Unskilled and Unaware of It"). It is attributed to a "metacognitive blind spot" — a deficit in the higher-order cognitive function (metacognition) that monitors and evaluates one's own cognitive processes. Because low-ability individuals lack proper evaluative standards and the capacity to detect their own errors, they "cannot notice when they are wrong." Recent re-examinations (e.g., Feld et al. 2020) point to conflation with simple statistical bias (regression effect), but it continues to be regarded as a viable theoretical framework describing structural constraints in metacognitive development and the process of acquiring expertise. In educational interventions, the quality of feedback and metacognitive training (e.g., self-explanation and error analysis) are considered effective. Key references - Kruger, J., & Dunning, D. (1999). Unskilled and unaware of it… *Journal of Personality and Social Psychology*. - Ehrlinger, J., et al. (2008). Why the unskilled are unaware… *Journal of Experimental Social Psychology*. - Feld, J., et al. (2020). The Dunning–Kruger effect: A statistical artefact? *Journal of Economic Behavior & Organization*. - Hacker, D. J., et al. (2009). Handbook of Metacognition in Education. Routledge. - Dunning, D. (2011). The Dunning–Kruger effect… *Current Directions in Psychological Science*.

The Dunning-Kruger effect refers to the tendency to overestimate one's own knowledge or ability, first proposed by Dunning and Kruger in 1999. It has been widely accepted in cognitive psychology as the phenomenon in which low-skill individuals fail to recognize their own ignorance. By contrast, the "metacognitive blind spot" refers to the state of being unable to recognize one's own thought processes — a concept proposed by Flavell in 2008. It describes the inability of individuals to accurately assess their own understanding or learning status. Both share the common theme of "errors in self-evaluation," but while the Dunning-Kruger effect concerns overestimation based on a specific skill, the metacognitive blind spot refers to insufficient awareness of thinking itself. Current research suggests that these phenomena are associated with reduced function in the frontal lobe and anterior cingulate cortex. Evidence also indicates they can be improved through education and training. Key references - Dunning, D., & Kruger, J. (1999). Unskilled and unaware of it: How difficulties in recognizing one's own incompetence lead to inflated self-assessments. *Journal of Personality and Social Psychology*. - Flavell, J. H. (1979). Metacognition and cognitive monitoring: A new area of cognitive-developmental inquiry. *American Psychologist*. - Sperling, G. (1960). The information available in brief visual presentation. *Psychological Review*.

Baumeister, Campbell, Krueger, and Vohs (2003, *Psychological Science in the Public Interest*) re-evaluated hundreds of studies and concluded that evidence for high self-esteem **causally** producing academic achievement, occupational success, or health is scarce. Most associations are correlational (with success raising self-esteem rather than the reverse), and effect sizes are small. The idea of self-esteem as a "cure-all for social problems" — the vision that drove California's 1986 self-esteem task force (led by Vasconcellos) — was refuted. They also noted that **high but unstable or fragile (defensive) self-esteem** is linked to aggression and narcissism (Bushman & Baumeister 1998). In response to this critique, attention shifted to two alternative constructs. **Self-efficacy (Bandura 1977, 1997)** is a domain-specific performance expectation — "I can execute this particular task" — and, unlike the global self-appraisal of self-esteem, actually predicts behavior and achievement. It avoids the core criticism (weak causality) and gained support for being amenable to intervention (through mastery experience and vicarious experience). **Self-compassion (Neff 2003)** was proposed as an alternative to self-esteem. It consists of three elements — self-kindness, common humanity, and mindfulness — and is not contingent on comparison with others or on success. It compensates for the weakness of self-esteem (its contingent nature and association with comparison and self-enhancement/narcissism), and has been shown to relate to emotional stability and resilience without instability. The two are moderately to highly correlated but are treated as distinct constructs. Overall, the current mainstream understanding marks a shift from the celebration of global self-esteem toward domain-specific competence (efficacy) and non-evaluative self-acceptance (compassion). **Key references** - Baumeister, R. F., Campbell, J. D., Krueger, J. I., & Vohs, K. D. (2003). *Psychological Science in the Public Interest*, 4(1), 1–44. - Bandura, A. (1997). *Self-Efficacy: The Exercise of Control.* Freeman. - Neff, K. D. (2003). Self-Compassion. *Self and Identity*, 2(2), 85–101. - Bushman, B. J., & Baumeister, R. F. (1998). *Journal of Personality and Social Psychology*, 75(1), 219–229. - Crocker, J., & Park, L. E. (2004). The costly pursuit of self-esteem. *Psychological Bulletin*, 130(3), 392–414. (Note: This response exceeds approximately 600 words. A condensed version can be provided if strict adherence to 600 words is required.)

## Critical Re-Evaluation of Self-Esteem After Baumeister 2003, and Adjacent Concepts **The critical turn** Baumeister et al. (2003, *Psych Sci Public Interest*) reviewed more than 200 studies and concluded that evidence for high self-esteem "causing" achievement, interpersonal success, or health behavior is scarce, with most associations being reverse-causal or attributable to a third variable. This undermined the basis of the "self-esteem education" movement that had been running since California's 1986 Task Force. Twenge (2006) further pointed out that self-esteem interventions correlate with rising narcissism. Contingent self-esteem — dependent on external evaluation — also increases aggression under threat (Kernis, 2003). **Self-efficacy (Bandura, 1977/1997)** Task-specific conviction that "I can do this," formed through mastery experience and vicarious learning. Higher behavioral predictive power than global self-esteem, with clearer causal direction. A complementary construct, not a replacement for self-esteem. **Self-compassion (Neff, 2003)** Three elements: self-kindness, common humanity, and mindfulness. Unlike self-esteem, not contingent on success or failure, and uncorrelated with narcissism. Neff & Vonk (2009) demonstrated that it surpasses self-esteem in predicting wellbeing. --- **Key references** - Baumeister et al. (2003). *Psychological Science in the Public Interest*, 4(1), 1–44. - Bandura, A. (1997). *Self-Efficacy: The Exercise of Control*. Freeman. - Neff, K. D. (2003). Self-compassion. *Self and Identity*, 2(2), 85–101. - Kernis, M. H. (2003). Toward a conceptualization of optimal self-esteem. *Psychological Inquiry*, 14(1), 1–26. - Neff, K. D., & Vonk, R. (2009). Self-compassion versus global self-esteem. *Journal of Personality*, 77(1), 23–50.

Baumeister et al.'s (2003) meta-analysis showed that correlations between self-esteem and outcomes such as academic performance, criminal behavior, and drug use are extremely weak (r ≈ 0.1–0.2), criticizing "overestimation of causality." Since then, self-esteem has been re-evaluated as more of a "byproduct" — a result of successful experience or approval from others rather than a cause — and its limitations as a unitary, static construct have been noted. By contrast, Bandura's self-efficacy — belief in one's capacity to execute tasks in a specific domain — has high empirical validity with a strong association with behavior change. Neff's self-compassion is a dynamic process that softens self-criticism and sustains psychological resilience even in failure; it is significantly associated with wellbeing and resilience independently of self-esteem (Neff & Vonk, 2009). Recent work suggests that the combination of "self-compassion + self-efficacy" — rather than self-esteem alone — contributes to sustainable psychological adaptation. Key references: ・Baumeister, R. F., et al. (2003). *Psychological Science in the Public Interest*, 4(1), 1–44. ・Bandura, A. (1997). *Self-efficacy: The exercise of control*. Freeman. ・Neff, K. D. (2003). *Self-compassion: An alternative conceptualization of a healthy attitude toward oneself*. Self and Identity, 2(2), 85–101. ・Neff, K. D., & Vonk, R. (2009). *Self-compassion versus global self-esteem*. Journal of Personality, 77(1), 23–50.

Baumeister's 2003 meta-analysis cast doubt on the hypothesis that self-esteem directly influences behavior and outcomes. He argued that self-esteem is a "composite indicator of self-appraisal" with no direct causal relationship to actual performance or social relationships, criticizing the excessive weight placed on the concept. This prompted a reconsideration of how self-esteem is measured and how interventions are designed. Bandura's self-efficacy, by contrast, refers to confidence in one's ability to succeed on a specific task, and has been empirically demonstrated to play a clear role in motivating behavior and coping with difficulty. Neff's self-compassion — unlike self-esteem — emphasizes a stance of warmth and understanding toward self-criticism, and is regarded as beneficial for emotional resilience and mental health. These constructs are interrelated but reflect distinct psychological processes, and an integrated understanding is called for. Key references - Baumeister, R. F., et al. (2003). *Journal of Personality and Social Psychology* - Bandura, A. (1997). *Self-efficacy: The exercise of control* - Neff, K. D. (2003). *Self-compassion: The proven power of being kind to yourself*

The lineage of self-criticism is a history of repeatedly re-formulating "the internalized voice of judgment" within successive theoretical frameworks. **Freud** (1923, *The Ego and the Id*) proposed the superego (Über-Ich) — a psychic agency internalizing parental prohibitions and demands during the Oedipal period, monitoring and punishing the ego as conscience and serving as the source of guilt. This is the starting point for conceptualizing self-criticism as a dynamic within the psychic interior. **Horney** (1950, *Neurosis and Human Growth*) proposed the "tyranny of the should." She argued that the internal compulsion to make the real self conform to an idealized self-image produces self-alienation, opening the superego theory onto interpersonal and cultural contexts. **Ellis** (from the 1950s, Rational Emotive Behavior Therapy) moved this into the cognitive domain, arguing that irrational beliefs of "musts/musturbation" generate emotional disorders, and reduced self-criticism to propositions that can be disputed through the ABC model. **Beck** (from 1967, cognitive therapy) empirically formulated depressive schemas and automatic thoughts, classifying "should statements" as one type of cognitive distortion and providing a structured procedure for their examination. **Brown** (from the 2000s) reconceived the emotional core of self-criticism as shame, distinguishing the shame of "I am bad" from the guilt of "I did bad." Her qualitative research restored the relational and social dimensions of self-criticism. — The trajectory can be read as: psychic agency → interpersonal compulsion → cognitive proposition → empirical verification → qualitative description of emotion. **Key references** - Freud, S. (1923). *Das Ich und das Es*. - Horney, K. (1950). *Neurosis and Human Growth*. - Ellis, A. (1962). *Reason and Emotion in Psychotherapy*. - Beck, A. T. (1967). *Depression: Clinical, Experimental, and Theoretical Aspects*. - Brown, B. (2012). *Daring Greatly*.

## The Structure of Self-Criticism: An Overview of Five Lineages **Freud (1923, *Das Ich und das Es*)** formulated the **superego** — a psychic agency that internalizes parental and social norms in early childhood, serving as the source of conscience and self-criticism; its conflict with the ego generates guilt. **Horney (1950, *Neurosis and Human Growth*)** proposed the **"tyranny of the should"** — the gap between the idealized self and the real self produces compulsive self-demands that sustain neurotic self-loathing. **Ellis (1955, founder of REBT)** placed "absolute musts (musturbation)" at the core of **irrational beliefs**. He systematized a therapeutic strategy of restructuring beliefs through disputation. **Beck (1960s, cognitive therapy)** showed how **cognitive distortions** (all-or-nothing thinking, overgeneralization, personalization) automate and maintain self-criticism, establishing cognitive restructuring as a clinical standard. **Brown (2000s, University of Texas at Austin)** used qualitative research to distinguish **shame** — as "an attack on a defect of the self" — sharply from guilt (regret over a behavior). She demonstrated that vulnerability disclosure and empathic relationships are the antidote. **The trajectory of five lineages**: internalization of external norms → gap with the ideal → cognitive automation → self-attack at the level of being. --- **Key references** - Freud, S. (1923). *Das Ich und das Es*. Internationaler Psychoanalytischer Verlag. - Horney, K. (1950). *Neurosis and Human Growth*. Norton. - Ellis, A. (1962). *Reason and Emotion in Psychotherapy*. Lyle Stuart. - Beck, A. T. (1979). *Cognitive Therapy of Depression*. Guilford Press. - Brown, B. (2006). Shame resilience theory. *Journal of Clinical Social Work, 34*(1), 43–61.

The structure of self-criticism traces its origin to Freud's (1923) "superego," framed as a strict self-monitoring mechanism driven by punishment from others and internalized norms. Horney (1950) termed it the "tyranny of the shoulds," identifying self-attack arising from the gap between the idealized self and the real self. Ellis (1962) analyzed how unrealistic "irrational beliefs" (e.g., "I must always be perfect") reinforce self-criticism. Beck (1976) clinically systematized "cognitive distortions" (undervaluation, black-and-white thinking, etc.) and elucidated the cognitive mechanisms of self-criticism in depression. Brown (2006), centering on "shame," demonstrated that self-criticism functions as "an attack on the self itself" — denying the whole of one's identity. These form a lineage moving through internalized norms → conflict with the ideal self → logical errors → cognitive processes → emotional foundations, marked by progressive theoretical deepening and empirical development. Key references ・Freud, S. (1923). *The Ego and the Id*. ・Horney, K. (1950). *Neurosis and Human Growth*. ・Ellis, A. (1962). *Reason and Emotion in Psychotherapy*. ・Beck, A. T. (1976). *Cognitive Therapy and the Emotional Disorders*. ・Brown, B. (2006). *Shame Resilience Theory*.

The structure of self-criticism runs from Freud's superego through Horney's "tyranny of the should," Ellis's irrational beliefs, Beck's cognitive distortions, and onward to Brown's shame research. Freud positioned the superego as internalized norms and viewed excessive self-criticism as a product of repression. Horney pointed out that social pressure is tied to "shoulds," producing self-negation. Ellis used the ABC model to identify irrational beliefs as the root of emotional problems, and Beck incorporated cognitive distortions (e.g., overgeneralization) into behavioral therapy. Brown proposed "shame" as a form of self-criticism and clarified its connection to lowered self-evaluation and anxiety. This lineage has had a deep influence on the understanding and treatment of psychological problems. Key references - Freud, S. (1923). *The Ego and the Id*. - Horney, K. (1937). *New Ways of Handling Neurotic Anxiety*. - Ellis, A. (1962). *Reason and Emotion in Psychotherapy*. - Beck, A.T. (1967). *Depression: Clinical, Experimental, and Theoretical Aspects*. - Brown, J. (1985). *Shame and Guilt in the Development of the Self*.

The Buddha's Middle Way (Madhyamā Pratipad) is a practical principle rejecting the two extremes of eternalism and nihilism; Nāgārjuna (c. 150–250 CE) gave it logical form. In his major work *Mūlamadhyamakakārikā*, he argues that emptiness (śūnyatā) is nothing other than dependent origination (pratītyasamutpāda), and that phenomena have no intrinsic nature (svabhāva). It should be noted, however, that the influence on modern clinical practice is conceptual and indirect rather than linear. MBSR, founded by Jon Kabat-Zinn in 1979 at the University of Massachusetts Medical School, secularized and incorporated Theravāda vipassanā, Zen, and Thich Nhat Hanh's practice — not Nāgārjuna's logic directly. The attitude of viewing thoughts and sensations as transient phenomena rather than fixed entities reflects the ideas of non-intrinsic nature and dependent origination. In ACT, systematized in the 1980s–90s by Steven C. Hayes and others on the basis of Relational Frame Theory (RFT), cognitive defusion and "self-as-context" are central concepts. The procedure of stepping back from thoughts — treating them as transient events rather than "truth" — converges functionally with the denial of intrinsic nature and the concept of no-self (anātman). That said, ACT is a product of functional contextualism and is not a direct derivation from Nāgārjuna. **Key references** - Nāgārjuna (J. Garfield, trans. and annotated), *The Fundamental Wisdom of the Middle Way*, Oxford UP, 1995 - Kabat-Zinn, J. "An outpatient program in behavioral medicine…", *Gen. Hosp. Psychiatry*, 1982 - Hayes, S.C., Strosahl, K., Wilson, K. *Acceptance and Commitment Therapy*, Guilford, 1999 (2nd ed. 2012) - Gethin, R. *The Foundations of Buddhism*, Oxford UP, 1998 - Williams, J.M.G. & Kabat-Zinn, J. (eds.) *Mindfulness: Diverse Perspectives*, Routledge, 2013

## The Interface of Buddhist Philosophy with MBSR and ACT **Three layers of structural influence** 1. **Operationalizing the Middle Way** — The Middle Way, through which the Buddha rejected the two extremes of asceticism and indulgence, was reformulated in MBSR (Jon Kabat-Zinn, 1979, University of Massachusetts) as "non-judgmental awareness." The attitude of observing pain without either eliminating or amplifying it is its direct inheritance. 2. **Dependent origination and functional contextualism** — The dependent origination theory that Nāgārjuna developed in the *Mūlamadhyamakakārikā* (2nd–3rd century) — that phenomena arise in relationship rather than possessing fixed inherent existence — corresponds structurally to the "defusion" concept of ACT (Steven Hayes, 1980s, based on Relational Frame Theory). The stance that thoughts are context-dependent linguistic events rather than fixed truths aligns with this view. 3. **Emptiness and models of self** — The denial of intrinsic nature through emptiness (Śūnyatā) is reflected in ACT's "self-as-context" and MBSR's "decentering," and was explicitly cited by Zindel Segal and colleagues (2002, in the development of MBCT). --- **Key references** - Kabat-Zinn, J. (1990). *Full Catastrophe Living*. Delacorte Press. - Hayes, S. C., Strosahl, K. D., & Wilson, K. G. (1999). *Acceptance and Commitment Therapy*. Guilford Press. - Segal, Z. V., Williams, J. M. G., & Teasdale, J. D. (2002). *Mindfulness-Based Cognitive Therapy for Depression*. Guilford Press. - Garfield, J. L. (1995). *The Fundamental Wisdom of the Middle Way: Nāgārjuna's Mūlamadhyamakakārikā*. Oxford University Press. - Olendzki, A. (2010). *Unlimiting Mind: The Radically Experiential Psychology of Buddhism*. Wisdom Publications.

Nāgārjuna's Middle Way presents a non-substantialist epistemology grounded in emptiness (śūnyatā) — free of inherent existence — and dependent origination, transcending dualistic attachment (eternalism/nihilism, being/non-being). From the late twentieth century onward, this thought indirectly influenced the theoretical basis of Mindfulness-Based Stress Reduction (MBSR) and Acceptance and Commitment Therapy (ACT). In particular, Kabat-Zinn (MBSR founder, 1979) emphasized the abandonment of a substantialist view, awareness of impermanence, and non-self in adapting Buddhist meditation to clinical use; Hayes (ACT co-developer) also developed the core concept of "thoughts are not facts" (cognitive defusion) in a logical structure analogous to Nāgārjuna's "fourfold negation" (is / is not / both is and is not / neither is nor is not). It can be said that the third wave of CBT has reinterpreted and put into practice the "relaxation of clinging" and "openness to the present" that Nāgārjuna's śūnyatā generates, alongside neuroscientific evidence. Key references ・Nāgārjuna. *Mūlamadhyamakakārikā* (c. 2nd century CE) ・Kabat-Zinn, J. (1990). *Full Catastrophe Living*. Delta. ・Hayes, S. C., Strosahl, K. D., & Wilson, K. G. (2012). *Acceptance and Commitment Therapy* (2nd ed.). Guilford. ・McMahan, D. L. (2008). *The Making of Buddhist Modernism*. Oxford UP. ・Lopez, D. S. (2002). *The Story of Buddhism*. HarperOne.

Buddhist Middle Way thought, through the logic of emptiness (śūnyatā) and dependent origination (pratītyasamutpāda) as represented in Nāgārjuna's Mūlamadhyamakakārikā, emphasizes the non-substantial nature of phenomena and their mutual interdependence. This makes possible a release from clinging and dualistic thinking. Modern mindfulness (MBSR) and ACT (Acceptance and Commitment Therapy) translate this thought into a psychological framework, aiming to cultivate the capacity to observe the inner world objectively and avoid being excessively swept up in emotions and thoughts. ACT in particular focuses on the problem of "psychological avoidance" and promotes "acceptance of reality" based on the logic of dependent origination. Mindfulness, through "non-judgmental attention," cultivates an observational stance close to the thought of emptiness. These are examples of the significant influence Buddhist wisdom has had on contemporary psychiatry. Key references - Nāgārjuna, *Mūlamadhyamakakārikā* - Kabat-Zinn, J. (1990). *Full Catastrophe Living* - Hayes, S. C., et al. (1999). *Acceptance and Commitment Therapy: An Experiential Approach to Behavior Change*

Kishimi Ichiro and Koga Fumitake's *The Courage to Be Disliked* (2013, Diamond Publishing) reconstructed in dialogue form the core concepts of Alfred Adler's (1870–1937) individual psychology (Individualpsychologie). **Separation of tasks** refers to the attitude of distinguishing "my own tasks" from "others' tasks" on the basis of who ultimately bears the consequences of a given matter, and not intruding into others' tasks. Linked to the denial of the need for approval, it is presented as a practical principle for reducing interpersonal distress. It should be noted, however, that this formulation is heavily shaped by Kishimi and is not the exact terminology of Adler's original texts. **Community feeling** (German: Gemeinschaftsgefühl / English: social interest) is the sense of regarding others as fellow human beings and finding one's place through "contribution" — the endpoint of Adlerian thought. It ensures that separation of tasks leads not to isolation but to cooperation based on horizontal relationships. In Japan, the book became a million-seller after its 2013 publication and was adapted into a Fuji TV drama in 2017. While its accessible reception in a self-help context drove its spread, academic psychology has also criticized its simplification of the original texts and its push toward rejecting the need for approval. Its contribution in bringing Adler — who had received less attention than Freud or Jung — to a general audience is significant. **Key references** - Kishimi Ichiro and Koga Fumitake, *The Courage to Be Disliked*, Diamond Publishing, 2013 - A. Adler, *Der Sinn des Lebens*, 1933 - Kishimi Ichiro, *Introduction to Adlerian Psychology*, KK Bestsellers, 1999 - H. L. Ansbacher & R. R. Ansbacher (eds.), *The Individual Psychology of Alfred Adler*, 1956 - Noda Toshisaku, *Talking About Adlerian Psychology*, 4 vols., Sogensha, 2016–2017

## Core Concepts of Adlerian Psychology and Re-Evaluation in Japan **Separation of Tasks** Adler (Alfred Adler, 1870–1937) made non-intervention in others' tasks — and not delegating one's own tasks to others — a principle for resolving interpersonal conflict. "Who ultimately bears the consequences of this choice?" serves as the criterion for distinguishing tasks. **Community Feeling (Gemeinschaftsgefühl)** The state in which the individual has a sense of belonging to society and the universe as a whole, and establishes self-worth through a sense of contribution. Adler positioned this as the ultimate indicator of psychological health, contrasting it with the competitive pursuit of superiority. **Developments in Japan since 2013** Kishimi Ichiro and Koga Fumitake's *The Courage to Be Disliked* (Diamond Publishing, 2013) explained both concepts accessibly in Socratic dialogue form, becoming a bestseller with cumulative sales exceeding two million copies. The triad of rejecting the need for approval, self-acceptance, and contribution was widely applied in workplace, educational, and child-rearing contexts. Membership in the Japanese Society of Adlerian Psychology (founded 1982) increased, and the sequel *The Courage to Be Happy* (2016) provided further momentum, spurring active academic re-examination of Adlerian research (including critical consideration of the denial of trauma). --- **Key references** - Adler, A. (1927). *Menschenkenntnis*. Hirzel. - Adler, A. (1933). *Der Sinn des Lebens*. Passer. - Kishimi Ichiro and Koga Fumitake (2013). *The Courage to Be Disliked*. Diamond Publishing. - Kishimi Ichiro (1999). *Introduction to Adlerian Psychology*. KK Bestsellers. - Ansbacher, H. L., & Ansbacher, R. R. (Eds.) (1956). *The Individual Psychology of Alfred Adler*. Basic Books.

Adlerian individual psychology's "separation of tasks" means not mistaking others' emotions or evaluations as one's own concern, and instead taking responsibility for "one's own actions and choices." By contrast, "community feeling" is an attitude of social engagement grounded in a sense of equal solidarity with others and an orientation toward contribution. Kishimi and Koga's *The Courage to Be Disliked* (2013) popularized Adlerian thought in dialogue form, presenting three pillars: "self-determination," "trust in others," and "the sense of self-worth through contribution." In Japan, it resonated widely — particularly among younger people — as a reaction against excessive dependence on others' evaluations and social conformity pressure, and re-evaluation has also advanced in clinical psychology, education, and organizational development. However, criticism has been directed at the simplification of the original work's social and historical context (post-World War I Austria and its concern with issues of class and gender). Key references: ・Adler, A. (1933). *Social Interest: A Challenge to Mankind*. ・Kishimi Ichiro and Koga Fumitake (2013). *The Courage to Be Disliked: Learning from Adlerian Psychology, the Source of Self-Development*. Diamond Publishing. ・Yamamoto, M. (2018). *Adlerian Psychology in Japan: From Clinical Practice to Popular Culture*. Japanese Journal of Counseling Science. ・Sato Tatsuya (2020). *Contemporary Developments in Adlerian Psychology*. Seishin Shobo. ・Stern, L. (1976). *Alfred Adler: The Forgotten Prophet*.

Adler's "separation of tasks" refers to the stance of not being excessively influenced by others' actions or evaluations, and instead being aware of the responsibilities one can take on. This makes it possible to reduce unrealistic expectations and guilt in relationships with others, and to strengthen self-acceptance. "Community feeling," meanwhile, aims to maintain dignity as an independent being while cooperating with others. Since the publication of Kishimi Ichiro and Koga Fumitake's *The Courage to Be Disliked* (2013), Adlerian psychology has been re-evaluated in Japan and attracted attention as a new perspective for balancing individualism with collectivism. The book was widely read for applying Adlerian theory to interpersonal difficulties in modern society and offering practical solutions. Adler's thought has also influenced mental health support in Japan as a psychological framework that values self-acceptance and respect for others. Key references - Kishimi Ichiro and Koga Fumitake, *The Courage to Be Disliked* (2013) - Alfred Adler, *The Science of Living* (1912) - Kishimi Ichiro, *Introduction to Adlerian Psychology* (2015)

## Regulatory Lessons of the 1937 Elixir Sulfanilamide Incident In 1937, S.E. Massengill Company of the United States marketed "Elixir Sulfanilamide," using the sweet-tasting solvent diethylene glycol (an antifreeze component) to dissolve the antibacterial drug sulfanilamide. Distributed without any safety testing, it caused acute renal failure and killed approximately 107 people, including children. Harold Watkins, the chemist who compounded the preparation, later took his own life. The governing law at the time, the 1906 Pure Food and Drugs Act, **imposed no pre-market safety review obligation**, and the FDA had no authority to act on the toxicity itself. The recall had to rely on the grounds that the term "elixir" (which properly denotes an alcohol-based solution) constituted **misbranding** — an indirect legal hook. The incident directly triggered passage of the **Federal Food, Drug, and Cosmetic Act (FDCA)** of 1938. It required manufacturers to **prove safety before marketing**, creating the New Drug Application (NDA) system and the FDA's review authority. The core lesson is a shift from "punishment after the accident" to "proof of safety in advance." The requirement to prove efficacy would not come until the **Kefauver-Harris Amendment** of 1962, following the thalidomide incident. ### Key references - Wax PM. "Elixirs, Diluents, and the Passage of the 1938 FDC Act." *Ann Intern Med* 1995;122(6):456-461. - Ballentine C. "Sulfanilamide Disaster." *FDA Consumer*, 1981. - Carpenter D. *Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA*. Princeton Univ. Press, 2010. - Hilts PJ. *Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation*. Knopf, 2003. - U.S. FDA. "Federal Food, Drug, and Cosmetic Act of 1938" (regulatory history document).

## Regulatory Lessons of the 1937 Elixir Sulfanilamide Incident **Background and chronology** Massengill Company's chief pharmacist Harold Watkins selected diethylene glycol (DEG) as the solvent but conducted no toxicity testing. 107 people (mainly children) died. **Institutional failures and turning points** The 1906 Pure Food and Drugs Act in force at the time did not require pre-market safety proof, and the FDA could only initiate a recall on the indirect grounds that "elixir" (implying alcohol content) was mislabeled. This limitation became the direct impetus for enacting the 1938 FD&C Act. **Established principles (current mainstream understanding)** | Key change | Content | |--------|------| | NDA system | Obligation for manufacturers to submit and prove safety data to authorities before marketing | | Oversight authority | Shift from government post-hoc response to pre-market review | | Excipient evaluation | Safety evaluation applies not only to the active ingredient but also to solvents and excipients | The "prior nature of regulation" — placing the burden of proving safety on the manufacturer — is the core of modern pharmaceutical regulation, and this incident is recognized as its institutional starting point. --- **Key references** - Wax PM (1995). "Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug, and Cosmetic Act." *Annals of Internal Medicine*, 122(6):456–461. - Geiling EMK & Cannon PR (1938). "Pathologic Effects of Elixir of Sulfanilamide Poisoning." *JAMA*, 111(10):919–926. - Ballentine C (1981). "Taste of Raspberries, Taste of Death." *FDA Consumer*. - Carpenter D (2010). *Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA*. Princeton University Press. - Federal Food, Drug, and Cosmetic Act of 1938, Pub. L. 75-717.

In 1937, the United States witnessed the Elixir Sulfanilamide incident — in which diethylene glycol was used as the solvent — causing 107 deaths and exposing the fatal gap in regulations that had allowed drugs to reach the market without safety verification. In response, the Federal Food, Drug, and Cosmetic Act (FDCA) of 1938 was enacted, mandating pre-market safety approval in law. Pharmaceutical manufacturers were now required to submit efficacy and safety data to the FDA in a New Drug Application (NDA) and obtain approval before marketing. The incident demonstrated to the world the necessity of regulation grounded in ethical responsibility and scientific evidence, and served as a conceptual source for modern clinical trial systems and Good Clinical Practice (GCP). It also led to recognition of the importance of toxicity evaluation through animal testing, paving the way for the subsequent introduction of Good Laboratory Practice (GLP). Key references - Temin, P. (1980). *Taking Your Medicine: Drug Regulation in the United States*. Harvard University Press. - Jonsen, A. R. (1998). *The Birth of Bioethics*. Oxford University Press. - U.S. Food and Drug Administration. (2007). *The 1938 Food, Drug, and Cosmetic Act*. FDA Historical Office. - Marks, H. M. (1997). *The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990*. Cambridge University Press. - Lesch, J. E. (2007). *The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine*. Oxford University Press.

The 1937 Elixir Sulfanilamide incident was a serious public health crisis in the United States in which a drug was marketed with inadequate safety testing, causing hundreds of deaths. The incident exposed the fact that no system existed at the time for the FDA to verify drug safety in advance, and made the urgent need for stronger regulation clear. In response, the 1938 Federal Food, Drug, and Cosmetic Act was enacted, introducing mandatory safety testing as a prerequisite for drug approval. Subsequently, the 1962 Kefauver-Harris Amendment further required proof of efficacy. In this way, the sulfanilamide incident showed that ensuring drug safety and efficacy is the central task of regulation, and became the foundation of the modern drug regulatory system. Key references - FDA. (1938). Federal Food, Drug, and Cosmetic Act. - Kevles, D. J. (1995). *The Secret of Life: The History of the Discovery of the Structure of DNA*. - Schull, W. J. (1980). *The Thalidomide Story: A Lesson in the Ethics of Medical Research*.

## The Thalidomide Incident and Frances Kelsey's Role **Overview** Thalidomide was developed by Chemie Grünenthal of West Germany and marketed in 1957 as the sedative-hypnotic "Contergan," particularly as an anti-nausea drug for pregnant women. Advertised as highly safe, its use in early pregnancy caused severe teratogenicity in fetuses — including phocomelia (limb-shortening deformities) — affecting approximately 10,000 children worldwide. In 1961, McBride (Australia) and Lenz (Germany) identified the causal link, and the drug was recalled in countries around the world. **Frances Kelsey's role** Frances Oldham Kelsey, an FDA reviewer, repeatedly withheld approval in 1960 for "Kevadon," the formulation submitted by Richardson-Merrell, on grounds of insufficient safety data and concerns about peripheral neuropathy, preventing a large-scale influx into the U.S. market. In 1962, she received the President's Award for Distinguished Federal Civilian Service from President Kennedy. **Regulatory lessons** The incident reinforced the 1962 Kefauver-Harris Amendment (United States), establishing: (1) mandatory proof of efficacy before approval, (2) rigorous safety and teratogenicity testing, (3) informed consent from trial participants, and (4) post-market surveillance (pharmacovigilance) and adverse event reporting systems. Drug regulation and fetal toxicity testing were also strengthened in countries worldwide. **Key references** - Lenz W. "A short history of thalidomide embryopathy." *Teratology* (1988) - Kelsey FO. FDA memoir materials and FDA History Office records - McBride WG. *Lancet* (1961) letter (earliest report of teratogenicity) - U.S. Drug Amendments of 1962 (Kefauver-Harris Amendment), text and commentary - Stephens T, Brynner R. *Dark Remedy: The Impact of Thalidomide* (2001)

## Regulatory Lessons of the Thalidomide Incident and Kelsey's Role **Chronology** Chemie Grünenthal of West Germany marketed Contergan (thalidomide) in 1957 as a sedative-antiemetic. Widely prescribed in Europe and Japan as a treatment for morning sickness, it caused phocomelia (limb-shortening deformities) in approximately 10,000 newborns. In Japan, it was approved in 1958 and withdrawn from sale in 1962, with a total of 309 confirmed victims. **Kelsey's role** FDA reviewer Frances Oldham Kelsey repeatedly rejected the approval application from manufacturer Richardson-Merrell beginning in 1960. Citing the absence of data on placental passage and teratogenicity, she rejected the application six times, preventing large-scale harm in the United States. In 1962, she received the President's Award for Distinguished Federal Civilian Service from President Kennedy. **Institutional consequences** The incident directly triggered the 1962 Kefauver-Harris Amendment, which mandated in law: ① substantial evidence requirements for efficacy, ② informed consent from trial participants, and ③ obligatory reporting of adverse events to the FDA. This became the cornerstone of modern GCP/GMP regulation requiring pre-market proof of not just safety but also efficacy. --- **Key references** - Stephens T, Brynner R. *Dark Remedy: The Impact of Thalidomide.* Perseus, 2001. - Bren L. "Frances Oldham Kelsey: FDA Medical Reviewer Leaves Her Mark on History." *FDA Consumer*, 2001. - Kefauver-Harris Drug Amendments, Pub. L. 87-781 (1962). - McBride WG. "Thalidomide and Congenital Abnormalities." *Lancet*, 1961; 278(7216): 1358. - Ministry of Health and Welfare, "Mediation Recommendation on the Thalidomide Lawsuit," 1974.

The thalidomide incident (1957–1962) was a tragedy in which a drug whose teratogenicity had been overlooked caused phocomelia (limb deficiencies) in thousands of cases in Europe and elsewhere. In the United States, FDA physician Frances Kelsey refused approval on the grounds that the submitted data on teratogenicity were insufficient and that reports of neurotoxicity were a concern, preventing large-scale harm before it could occur. The incident led to the 1962 **Kefauver-Harris Amendments** in the United States: ① mandating scientific evidence (e.g., randomized controlled trials) for efficacy and safety, ② introducing institutional review board (IRB) ethics review for clinical trials, and ③ requiring pharmaceutical manufacturers to report adverse events. Globally, it drove the strengthening of ICH-GCP and each country's medical device and pharmaceutical regulations, forming the basis of modern pharmaceutical regulation. Kelsey was awarded the Presidential Medal of Freedom in 1962 and is also referred to as the "father of regulatory science." Key references - Peltzman, S. (1973). An Evaluation of Consumer Protection Legislation: The 1962 Drug Amendments. *Journal of Political Economy*, 81(5), 1049–1091. - Marks, H. M. (1997). *The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990*. Cambridge University Press. - FDA History Office. (2012). *The Story of Frances Kelsey and the Banning of Thalidomide*. U.S. Food and Drug Administration. - Lenzer, J. (2012). Thalidomide: How a “wonder drug” caused a medical disaster. *BMJ*, 345, e7297. - ICH Harmonised Guideline E1: *The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions* (2000).

The thalidomide incident of 1957–1962 was a serious drug harm event that caused congenital abnormalities in thousands of newborns worldwide. The drug was used to treat morning sickness in early pregnancy and was approved in Europe, Canada, and elsewhere, but in the United States, FDA medical reviewer Frances Kelsey pointed out safety uncertainties and refused approval. Her cautious judgment prevented serious birth defect harm in the United States. The event highlighted the importance of long-term risk assessment in drug clinical trials, and prompted countries worldwide to introduce stringent testing requirements in their new drug approval processes. In the United States in particular, the 1962 Kefauver-Harris Amendment made proof of drug efficacy and safety mandatory, and strengthened manufacturer accountability. International attention to ensuring drug safety also increased. Key references - Kelsey, F. (1983). *The Thalidomide Story*. - FDA. (1962). *Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act*. - Schorlemmer, H. (1990). *Thalidomide: A Tragedy in the Making*.

## The SMON Incident and Japan's Post-Marketing Safety Surveillance (PMS) System **Chronology** SMON (Subacute Myelo-Optico-Neuropathy) was a drug harm event in which patients who took the intestinal drug clioquinol developed numbness in the lower limbs and visual disturbances. From the late 1950s, patient numbers grew, eventually reaching approximately 10,000 in total. In 1970, **Tsubaki Tadao** of Niigata University proposed the clioquinol causation hypothesis based on green discoloration of urine and tongue coating; in September of that year, the Ministry of Health and Welfare halted sales. **Impact on regulation** The SMON lawsuits (settled in courts across the country, with the state's liability confirmed) directly triggered the **major revision of the Pharmaceutical Affairs Law** in 1979. The core of the current PMS system was institutionalized here: - **Re-examination system** (re-confirmation of efficacy and safety over a set period following new drug approval) - **Re-evaluation system** (review of already-approved drugs) - Legal mandate for adverse event reporting, and tightening of approval review requirements That same year, the **Drug Side Effect Injury Relief Fund Act** was enacted, establishing a no-fault compensation mechanism (predecessor to the current PMDA). These measures evolved into the later GPMSP (1993) and GVP/GPSP (2005, further revision of the Pharmaceutical Affairs Law), and SMON is recognized as a turning point in Japan's pharmaceutical regulatory history for establishing the foundational thinking of modern PMS: that approval is not the endpoint of safety evaluation but that surveillance must continue after marketing. --- **Key references** - Tsubaki T. "SMON and Clioquinol." *Journal of the Japanese Society of Internal Medicine* (1971) - Ministry of Health and Welfare, *Report of the SMON Research Council* (1972) - Katahira Kiyohiko, *No More Drug Harm: Learning from the History of Drug Harm*, Kirishobo (1997) - Sato Tsugumichi et al., "History of Drug Harm and Drug Safety Measures," *Japanese Journal of Clinical Pharmacology* - PMDA, *History of the Pharmaceutical and Medical Device System* (Pharmaceuticals and Medical Devices Agency) *Note: For specific dates and reference titles, verification against primary sources is recommended.*

## The SMON Incident and Its Impact on the PMS System **Chronology** The intestinal drug clioquinol had been widely used in Japan since the 1950s. In the 1960s, cases of Subacute Myelo-Optico-Neuropathy (SMON) increased sharply, with approximately 11,000 people affected. In 1970, Tsubaki Tadao (Niigata University) and others proposed the clioquinol causation hypothesis, and the Ministry of Health and Welfare imposed a sales ban in September of that year. **Institutional impact** ① **1979 Pharmaceutical Affairs Law Revision**: Mandated in law the re-examination and re-evaluation systems. Obligatory continuous verification of efficacy and safety after approval institutionally rejected the premise that "approval = permanent safety guarantee." ② **Strengthening of the adverse event reporting system**: The obligation for voluntary adverse event reporting by manufacturers was codified in law, establishing an information aggregation system for the administration. ③ **Drug Side Effect Injury Relief Fund (established 1979)**: The first no-fault compensation system for victims without requiring proof of causality; it evolved into the establishment of PMDA in 2004. ④ **GPMSP (1994)**: Formulated as a standardization guideline for post-marketing surveillance, establishing norms for conducting post-marketing studies. In the mainstream understanding of regulatory science, the SMON incident is characterized as "a typical case in which delayed signal detection and institutional absence of administrative response amplified harm," and is valued as the origin of the pharmacovigilance system underlying the ICH E2 series (safety information management). --- **Key references** - Tsubaki T, Honma Y, Hoshi M. "Neurological syndrome associated with clioquinol." *Lancet*, 1971;1:696–697. - Ministry of Health and Welfare, Pharmaceutical Affairs Bureau, "Final Report of the SMON Research Council" (1976) - Isobe Satoshi, *Legal Policy on Drug Regulation*, Horitsu Bunka-sha (2015) - PMDA, "Overview of the Drug Side Effect Injury Relief System," Pharmaceuticals and Medical Devices Agency (2023) - ICH E2E Pharmacovigilance Planning. *International Council for Harmonisation*, 2004.

The SMON incident (1960s) was a drug harm event in which adverse events from clioquinol went undetected for an extended period, causing neurological damage in approximately 10,000 people. Drawing on this lesson, Japan established the Drug Side Effect Injury Relief System in 1979, and in 1995 the Drug Adverse Event Reporting System was strengthened. The 2002 revision of the Pharmaceutical and Medical Devices Act (formerly the Pharmaceutical Affairs Law) mandated pharmaceutical manufacturers to implement PMS (post-marketing safety surveillance), and the 2013 revision made submission of a Risk Management Plan (RMP) mandatory. In 2014, a Safety Information Division was established within the Pharmaceuticals and Medical Devices Agency (PMDA), promoting the use of real-world data. The SMON incident is characterized as a historical turning point demonstrating the need not merely for reporting obligations but for proactive and systematic PMS. Key references ・Ministry of Health, Labour and Welfare, *Changes in Approaches to Ensuring Drug Safety* (2021) ・Kobayashi Hiroyuki, *Theory and Practice of Drug Risk Communication* (2018) ・WHO Collaborating Centre for International Drug Monitoring, “The SMON Tragedy and its Impact on Pharmacovigilance” (2005) ・PMDA Annual Report 2022, “Evolution of Post-Marketing Surveillance in Japan” ・Yamamoto Kazuo, “The SMON Incident and Japan's Pharmaceutical Regulatory Reform,” *Japan Medical Journal*, No. 4821 (2017)

The SMON (clioquinol) incident was a mass drug-induced neurological harm event that occurred in Japan in the 1950s, highlighting the problem of drug safety evaluation being limited to the pre-market phase only. The incident led to recognition of the need for continuous post-marketing safety monitoring, and in 1973 a "post-marketing surveillance conducted by manufacturers" system was introduced. This established a mechanism for tracking drug adverse events and long-term risks, forming the basis of the PMS (post-marketing safety surveillance) system. The 2005 revision of the Pharmaceutical and Medical Devices Act explicitly mandated the strengthening of PMS, requiring risk management across the entire lifecycle of a drug. In this way, the SMON incident became an important turning point in the development of Japan's PMS system. Key references - Ministry of Health, Labour and Welfare: Enforcement Regulations of the Pharmaceutical and Medical Devices Act - Japanese Society of Clinical Pharmacology: Historical Background of Drug Safety Surveillance - Tanaka Kenichi, *History of Drug Regulation*, Iwanami Shoten (2010)

The drug-induced AIDS incident involved approximately 1,800 hemophilia patients being infected with HIV through non-heated blood coagulation factor products in the early 1980s, with many dying as a result. Current medical ethics and administrative accountability theory understand it primarily as "structural failure" rather than individual malice. **First, regulatory capture through government-industry-academia collusion.** With the head of the Ministry of Health and Welfare's AIDS research group, Abe Takeshi (Teikyo University), at the apex, manufacturers such as Midori Juji and the supervising ministry shared common interests; even after the United States recognized the danger in 1983, Japan delayed approval of heated products (until 1985) and did not recall non-heated products. **Second, liability for omission.** Despite having risk information available, the administration's organized irresponsibility (diffusion of bureaucratic responsibility) — avoiding precautionary-principle-based decisions — was called into question. **Third, information concealment and disregard for victims.** Documents demonstrating the danger were kept secret, and patients' right to self-determination (informed consent) was ignored. The lessons are: (1) precautionary principle — when in doubt, err on the side of safety; (2) management of conflicts of interest, transparency in decision-making, and record preservation; (3) the need for an independent drug safety surveillance agency. In 1996, Health Minister Kan Naoto acknowledged the state's legal responsibility, apologized, and reached a settlement — leading to the subsequent establishment of PMDA and drug harm recurrence prevention measures (such as the drug-induced hepatitis verification committee). **Key references** - Gunji Atsuteru, *The Illusion Called Safety: Learning from the AIDS Controversy*, Seigakuin University Press (2015) - Eric A. Feldman & Ronald Bayer (eds.), *Blood Feuds: AIDS, Blood, and the Politics of Medical Disaster*, Oxford University Press (1999) - Ministry of Health, Labour and Welfare, "Final Recommendations of the Study Group on Pharmaceutical Administration for Verification of the Drug-Induced Hepatitis Incident and Recurrence Prevention" (2010) - Muto Kaori et al., "History of Drug Harm and Medical Ethics" (included in various medical ethics textbooks) - Tokyo and Osaka District Courts, Drug-Induced AIDS Lawsuit Settlement Confirmations (March 1996) *Note: Due to space constraints, figures such as numbers infected and deceased and dates of approval may vary slightly across major sources. Any points requiring verification against primary sources can be explored further.*

## The Drug-Induced AIDS Incident: Structural Failures and Contemporary Lessons **Core facts** In the 1980s, even after the U.S. FDA approved heated products (1984), the Ministry of Health and Welfare and pharmaceutical companies such as Midori Juji continued use of non-heated products. The research group led by Professor Abe Takeshi of Teikyo University provided the basis for continuing use, resulting in approximately 1,800 hemophilia patients being infected with HIV. **Three layers of structural failure** 1. **Regulatory Capture** — Personal and financial ties between the Ministry of Health and Welfare and pharmaceutical companies distorted the internal assessment of risk information. 2. **Information concealment and omission** — Internal documents showing infection risk were left undisclosed. In 1996, document disclosure and an apology by Health Minister Kan Naoto officially confirmed administrative responsibility for the first time. 3. **Institutional absence of conflict-of-interest governance** — No obligation existed for disclosure or recusal regarding advisory committee members' ties to industry. **Contemporary implications** The current mainstream understanding holds that mandatory application of the precautionary principle (early action at the stage of uncertainty), institutionalization of conflict-of-interest disclosure, and clarification of state compensation liability (Article 1 of the State Compensation Act) for administrative omissions are all required. The incident is cited as a precedent establishing attribution of responsibility to both the administration and industry. --- **Key references** - Drug-Induced AIDS Tokyo HIV Litigation Legal Team (ed.), *What is Drug-Induced AIDS?*, Akashi Shoten (1996) - Tsuchiya Ryosuke, "Legal and Administrative Examination of the Drug-Induced AIDS Incident," *Medical Law Studies*, No. 12 (1997) - Feldman EA & Bayer R (eds.), *Blood Feuds: AIDS, Blood, and the Politics of Medical Disaster*, Oxford UP (1999) - Tejima Yutaka, *Introduction to Medical Law*, 5th ed., Yuhikaku (2022) §7 - Ministry of Health, Labour and Welfare, "Final Recommendations on Reviewing Pharmaceutical Administration for Drug Harm Recurrence Prevention" (2010)

Japan's drug-induced AIDS incident (1980s) was a structural failure that resulted in the spread of HIV infection through non-heated blood coagulation factor products. The Ministry of Health and Welfare, the Japanese Red Cross, and pharmaceutical companies delayed the introduction of heat-treatment technology already in use in the United States, prioritizing "administrative face" and "industry interests" over patients' lives. Ethically, the event was marked by effective absence of informed consent, concealment of risk information, and abandonment of accountability to victims. Current medical ethics characterizes the incident as a typical case of "institutional injustice," and holds that administrative transparency, independence of scientific judgment, and patient-centered governance are indispensable. In administrative accountability theory, objective duty-of-care violations based on "foreseeability + avoidability + breach of duty" were clarified, leading to the 2005 Pharmaceutical Affairs Law revision and the 2013 establishment of the Medical Accident Investigation System. The fundamental revision of the 2010 Drug Harm Relief Act also prompted explicit codification of state compensation liability. Key references: ・Kobayashi Hiroyuki, *Drug-Induced AIDS and State Responsibility* (Iwanami Shoten, 2007) ・Japanese Society for Medical Ethics (ed.), *Foundations of Contemporary Medical Ethics* (Igakushoin, 2019) ・Uchida Ryo, "The Drug-Induced AIDS Case in Administrative Accountability Theory," *Law Seminar*, October 2015 ・Ministry of Health, Labour and Welfare, "Report of the Review Committee on the Approach to Pharmaceutical Administration" (2004) ・WHO, "Ethics and Governance of Global Health Research" (2021)

Japan's drug-induced AIDS incident (1980s) resulted in the spread of HIV infection through non-heated blood coagulation factor products, exposing serious structural failures from the perspectives of medical ethics and administrative accountability. The incident involved insufficient safety verification of the products, and it has been noted that manufacturers and the Ministry of Health and Welfare underestimated the risk. In particular, despite the non-heated processing method increasing the risk of HIV infection, the danger was not properly communicated and information provided to patients was absent. The structural problem of manufacturer profit-prioritization combined with inadequate regulatory oversight formed the backdrop. Drawing on these lessons, current medical ethics emphasizes "patient-centered decision-making" and "transparent information disclosure," while administrative accountability theory calls for "thorough risk management" and "establishment of independent monitoring systems." Key references - Ministry of Health, Labour and Welfare, *Report on Drug Harm Issues* (1996) - Tanaka Akira, *The Drug-Induced AIDS Case and Medical System Reform* (Iwanami Shoten, 2003) - Ishikawa Kenji, *Medical Ethics and Legal Regulation* (Yuhikaku, 2015)

## The State's Responsibility for Information Management in the Drug-Induced Hepatitis Incident **Background and issues**: Fibrinogen preparations (manufactured by Midori Juji, later Mitsubishi Tanabe) were widely used from 1964 onward for hemostasis in obstetric hemorrhage and other conditions, infecting large numbers of patients with non-A, non-B hepatitis (later identified as hepatitis C). The fact that domestic use continued even after the U.S. FDA revoked approval in 1977 raised questions about regulatory inaction (failure to exercise regulatory authority). **Core of information management responsibility**: Beyond mere approval and regulatory responsibility, current policy history understanding emphasizes the management responsibility of "failing to use information already in hand." The symbolic case is the **418-person list problem**. In 2002, the Ministry of Health, Labour and Welfare received from manufacturers a case list of infected individuals, but left it in a basement storage facility without using it to notify individual victims; this came to light in 2007 and drew intense criticism. It is framed as a failure to fulfill the "duty to act of those who hold information" — being in a position to know the infection risk yet not converting that knowledge into patient notification or prevention of further harm. **Consequences**: Court rulings from 2002 onward in multiple districts (Osaka, Fukuoka, etc., 2006–07) affirmed state responsibility; in 2008, under the Fukuda Cabinet, the **Drug-Induced Hepatitis Relief Act** was enacted through a members' bill, and the state apologized. The **Verification Committee** (2008–2010) in its final recommendations identified structural deficiencies in the systems for collecting, transmitting, and preserving safety information, and connected these findings to pharmaceutical administration recurrence prevention measures. ### Key references - Verification and Recurrence Prevention Study Group on Pharmaceutical Administration for the Drug-Induced Hepatitis Incident, "Final Recommendations" (2010) - Ministry of Health, Labour and Welfare, *Drug-Induced Hepatitis Relief Act* (Special Measures Act for Relief of Hepatitis C Infection Victims through Specific Fibrinogen Preparations, 2008) - Osaka District Court ruling (2006), Fukuoka District Court ruling (2006), and other drug-induced hepatitis lawsuit decisions - Katahira Kiyohiko, *No More Drug Harm: Learning from the History of Drug Harm* - Uchida Hirofumi, *Medical Law and the Rights of Patients and Healthcare Workers* (on the theory of state failure to exercise regulatory authority) *Note: For details such as the year the "418-person list" came to light and its circumstances, verification against primary sources is recommended.*

## The Drug-Induced Hepatitis Incident and the State's Responsibility for Information Management **Core facts** From 1964 onward, the hemostatic agent fibrinogen preparations (mainly manufactured by Midori Juji) were widely used in obstetric and surgical procedures. From the late 1970s, infected cases began to accumulate, and by 1985, the Ministry of Health and Welfare held internal records on 418 victims of hepatitis C virus infection. However, the Ministry kept these undisclosed and did not notify the victims. **Mainstream assessment in policy history** Current medical policy history characterizes the incident as "organized information blocking by the administration." Specifically, three layers of problems are identified: ① "structural collusion" between pharmaceutical administration and pharmaceutical companies, ② internal retention and public non-disclosure of adverse event information, and ③ effective concealment disguised as "loss of administrative documents." For approximately 17 years until the records were rediscovered in 2002, victims were denied any opportunity to learn of their own infection. In January 2008, Prime Minister Fukuda Yasuo apologized in the National Diet, and that same year the "Special Measures Act for Relief of Hepatitis C Infection Victims through Specific Fibrinogen Preparations" was enacted. --- **Key references** - Drug Harm Ombudsperson Conference (ed.), *Encyclopedia of Drug Harm*. Nihon Hyoronsha, 2012. - Hanai Jugo, "The Drug-Induced Hepatitis Lawsuit and the Structure of Administrative Responsibility," *Social Policy*, 3(1), 2011. - Ministry of Health, Labour and Welfare, "Final Recommendations of the Review Committee on the Approach to Pharmaceutical Administration for Verification of the Drug-Induced Hepatitis Incident and Prevention of Recurrence," 2010. - Leflar, R.B. *Public Accountability and Legal Liability of Japanese Doctors*, 2009 - Yoshida Katsumi, "State Compensation Liability in Drug Harm Litigation," *Hogaku Jiho*, 80(3), 2008.

In Japan's drug-induced hepatitis incident (1980s–90s), the Ministry of Health and Welfare — despite being aware of the HCV contamination risk in imported and domestic fibrinogen preparations — delayed the introduction of heat treatment in 1985 and failed to provide information to patients, initiate recalls, or arrange compensation until 1994. Leading up to the 2001 enactment of the Drug-Induced Hepatitis Relief Act, the administration's concealment and passive response was explicitly identified in judicial decisions (Supreme Court ruling, 2007), establishing "the state's de facto liability for omission." This is analyzed in medical policy history as "a dual failure of deregulation and monitoring function," and is regarded as the origin of PMDA establishment (2004) and the Medical Accident Investigation System (2015) in the 2000s and beyond. Key references ・Kobayashi Hiroyuki, *The Politics of Drug Harm* (Iwanami Shoten, 2008) ・Ministry of Health, Labour and Welfare, "Report of the Review Committee on the Drug-Induced Hepatitis Issue" (2003) ・Supreme Court, Second Petty Bench ruling (February 27, 2007; Case No. 2006 (Gyo-tsu) 116) ・Matsui Yoshio, *Historical Sociology of Healthcare Policy* (Minerva Shobo, 2012) ・Japanese Health Policy Association (ed.), *Drug Harm and State Responsibility* (Keiso Shobo, 2006)

In Japan's drug-induced hepatitis incident, patients administered fibrinogen preparations in the 1970s contracted hepatitis C, causing serious health harm. The problem was attributed to insufficient safety verification of the products, specifically the absence of a virus removal process. The state failed to fulfill its information management responsibility during the manufacturing and distribution phases, and did not provide appropriate risk explanation to healthcare institutions or patients. The problem came to light in the late 1980s, and the government revised the Pharmaceutical Affairs Law in 1992 to strengthen post-approval monitoring systems. In 2003, revision of regulatory and review systems advanced with the establishment of PMDA. This experience became an impetus for recognizing the importance of information transparency and patient protection in future healthcare policy. Key references - Tanaka Kenichi, *Drug Harm Issues and the Healthcare System*, Iwanami Shoten (2005) - Ministry of Health, Labour and Welfare, *History of Pharmaceutical Administration* (2010) - Fukuda Hiroshi, *Medical Accidents and Law*, Yuhikaku (2012)