📡 AI Distillation ── 2026-06-23

## Generative AI (LLM) in Pharmaceutical Materials Review **Benefits** Accelerates cross-referencing of large document sets (package inserts, promotional materials, SmPC, regulatory guidance) and supports drafting, summarization, and contradiction detection. The US FDA introduced its internal generative AI system "Elsa" in 2025; the EMA's 2024 "AI Reflection Paper" anticipates use in documentation workflows. Well-suited to structured formats such as ICH M11. **Risks** Hallucination (fabricated citations, invented efficacy claims), biases inherited from training data, and lack of the traceability that PMDA/FDA require. In GxP documents, errors translate directly into patient risk and may violate the Pharmaceutical and Medical Device Act (薬機法) prohibition on misleading advertising and similar provisions under the Act against Unjustifiable Premiums and Misleading Representations. **Implementation considerations** - **Human-in-the-loop is mandatory** — AI output serves as a draft; pharmacovigilance and materials-review staff bear final responsibility (FDA risk-based credibility framework, 2025). - **Verification and validation** — Computer system validation aligned with GAMP 5 / 21 CFR Part 11; output must link to primary sources (RAG-based citations). - **Audit trail** — Log prompts, model version, and outputs. - **Data governance** — Prohibit sending patient data or unpublished data to external APIs; prefer closed or on-premises deployment. A risk-based approach that starts with low-risk tasks (search, summarization) and expands incrementally is the most practical path. **Key references** - FDA, "Considerations for the Use of AI to Support Regulatory Decision-Making for Drug and Biological Products" (Draft Guidance, 2025) - EMA, "Reflection Paper on the Use of AI in the Medicinal Product Lifecycle" (2024) - ICH M11 Guideline: Clinical Electronic Structured Harmonised Protocol (CeSHarP) (2024) - ISPE, GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems, 2nd ed. (2022) - WHO, "Regulatory Considerations on AI for Health" (2024) --- ※ The body is kept to approximately 560 characters. FDA "Elsa" and the EMA Reflection Paper are evolving rapidly; verify the latest versions before implementation.

## Generative AI (LLM) in Pharmaceutical Materials Review: Overview --- ### Benefits Automating document cross-checking and consistency verification can reduce review person-hours by up to 60–70% (Deloitte 2023 estimate). Supports multilingual translation and terminology standardization of package inserts and submission materials, and reduces inter-reviewer variability. Effective for checking consistency across CTD (Common Technical Document) modules and for early detection of duplication or contradictions. ### Key Risks ① Hallucination (factual errors) contaminating regulatory documents; ② leakage of confidential or personal data via API; ③ inability to explain the basis of outputs in GCP/GMP audits (black-box problem); ④ bias amplification from training-data skews. ### Implementation Considerations Confirm SaMD classification under the FDA "AI/ML Medical Device Software Action Plan" (January 2021) and the 2024 final guidance beforehand. Assess whether the EU AI Act (in force August 2024) classifies the application as High-Risk and draft a GAMP 5-compliant validation plan. Institutionalize a Human-in-the-loop arrangement whereby final decisions are made by qualified persons (QPs, etc.), and maintain a complete audit trail of output logs. Handle data only in on-premises environments or in cloud environments with a signed Business Associate Agreement (BAA). --- ### Key References - FDA (2021). *Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD) Action Plan*. U.S. Food & Drug Administration. - European Parliament (2024). *Regulation (EU) 2024/1689 — Artificial Intelligence Act*. Official Journal of the EU. - ICH (2023). *ICH E6(R3): Guideline for Good Clinical Practice*. International Council for Harmonisation. - ISPE (2022). *GAMP 5 (2nd ed.): A Risk-Based Approach to Compliant GxP Computerized Systems*. International Society for Pharmaceutical Engineering. - Meskó, B. & Topol, E. J. (2023). The imperative for regulatory oversight of large language models in healthcare. *npj Digital Medicine*, 6, 120.

## Pharmaceutical and Medical Device Act, Articles 66–68 (Prohibition of Misleading Advertising) **Regulatory Intent** The full name of the law is the "Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices" (薬機法). Articles 66–68 aim to protect the life and health of the public by preventing people from being induced to purchase or use products improperly through false or exaggerated information. Because the efficacy and safety of pharmaceuticals are highly technical and information asymmetry is substantial, the law imposes prior restraint on labeling and advertising. **Summary of Each Article** - **Article 66**: Prohibits advertising, description, or dissemination of false or exaggerated claims regarding efficacy, effects, or performance. Also covers representations that imply endorsement by physicians and similar persons, suggestions of induced abortion, and obscene content. Applies to "any person" (not limited to advertisers). - **Article 67**: Restricts advertising of pharmaceuticals and regenerative medicine products for specified diseases requiring physician supervision (e.g., cancer) to the general public, as designated by Cabinet Order. - **Article 68**: Prohibits advertising the name, efficacy, or effects of unapproved pharmaceuticals and medical devices (blocking promotion of products before approval). **Operational Rules** The practical standard is the Ministry of Health, Labour and Welfare notification "Standards for Appropriate Advertising of Pharmaceuticals, etc." (established 1980, fully revised 2017). In addition to corrective orders and criminal penalties, the 2019 amendment (effective 2021) introduced a **surcharge system**: violations of Article 66 carry a surcharge of, in principle, 4.5% of revenue from the relevant product during the violation period. Advertising is determined by three criteria: customer solicitation, specificity (reference to a particular product or person), and general dissemination. **Key References** - MHLW, "Standards for Appropriate Advertising of Pharmaceuticals, etc." (MHLW Notification No. 0929004, 2017 revision) - Pharmaceutical and Medical Device Act, Articles 66–68 and Article 75-5-2 (surcharge) - Director, Pharmaceutical Supervisory and Narcotics Division, MHLW Bureau of Pharmaceutical and Food Safety, *Explanation of and Notes on Standards for Appropriate Advertising of Pharmaceuticals, etc.* - Japan Pharmaceutical Manufacturers Association, "Code of Practice for Promotion of Prescription Drugs" - Yakuji Regulatory Research Group (ed.), *A Plain Guide to the Pharmaceutical and Medical Device Act* (Yakuji Nippo)

## Pharmaceutical and Medical Device Act Articles 66–68: Prohibition of Misleading Advertising **Regulatory Intent** To protect consumers' rational decision-making and prevent inappropriate use, delayed medical consultation, and health harm. Functions as the "trust infrastructure" of a market where information asymmetry is pronounced. **Role of Each Article** - **Article 66**: Comprehensive prohibition of false or exaggerated advertising, representations that imply guarantees, and advertisements suggesting induced abortion - **Article 67**: Advertising of pharmaceuticals for "specified diseases" (designated by Cabinet Order, e.g., cancer) to the general public is prohibited in principle (permitted in specialist journals for healthcare professionals) - **Article 68**: Full prohibition on advertising the efficacy or effects of unapproved products **Criteria for Determining "Advertising" (1971 Pharmaceutical Affairs Bureau Notification No. 476)** Three requirements must all be met: ① customer solicitation; ② reference to a specific product or person; ③ broad public dissemination. The criteria apply to SNS posts, word-of-mouth, and materials formatted as academic presentations used for promotional purposes. **Enforcement** The 2021 amendment introduced a **surcharge** (4.5% of revenue from the violation period) alongside a multi-layered sanctions system comprising administrative guidance, business suspension, and criminal penalties (imprisonment up to 2 years or a fine up to ¥2 million). --- **Key References** - MHLW Pharmaceutical Affairs Bureau Director Notification, "Standards for Appropriate Advertising of Pharmaceuticals, etc." October 9, 1980, No. 1339 (2017 revision) - MHLW Notification, "On Control of Unapproved/Unlicensed Pharmaceuticals," June 1971, No. 476 - Japan Pharmaceutical Manufacturers Association, *Guidelines on Sales Information Provision Activities for Prescription Drugs*, MHLW, 2018 - Yakuji Nippo (ed.), *Commentary on the Pharmaceutical and Medical Device Act* (latest edition) - Matsuda Y., "Significance and Challenges of the Surcharge System in Pharmaceutical Advertising Regulation," *Journal of Drug Information*, Vol. 23, No. 1, 2021

**Guidelines on Sales Information Provision Activities (販提G): Regulatory Intent and Impact on MR Activities** The full title is "Guidelines on Sales Information Provision Activities for Prescription Drugs." Issued as an MHLW Pharmaceutical and Food Safety Bureau Director notification on September 25, 2018, effective April 1, 2019 (partially revised with Q&A in 2021). **Regulatory Intent** The trigger was a series of clinical research data manipulation and misleading promotion cases, most notably the Diovan (valsartan) scandal (ディオバン事件). As administrative guidance complementing Articles 66 (prohibition of false/exaggerated advertising) and 68 (prohibition of advertising unapproved drugs) of the Pharmaceutical and Medical Device Act, the guidelines require companies to provide fair and accurate evidence-based information. The key innovation is broadening the scope beyond advertising to cover all forms of information provision — oral explanations, SNS, lectures, and slides — under the umbrella of "sales information provision activities." **Impact on MR Activities** 1. **Prohibition of off-label claims**: Implying efficacy or safety beyond what is stated in approved labeling, the package insert, or review reports is prohibited. 2. **Restriction of unapproved/off-label information**: Prohibited in principle; permitted only when healthcare professionals request it, subject to procedural requirements and record-keeping. 3. **Organizational controls**: Companies must establish a supervisory function for sales information provision activities, conduct prior review of materials, create and retain records of activities, and maintain a monitoring system. 4. **Disclosure of conflicts of interest** and elimination of false or exaggerated representations. As a result, MRs have been compelled to shift from the role of "salesperson" to that of information provider presenting verifiable evidence. **Key References** - MHLW, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (MHLW Bureau Director Notification, September 25, 2018) - MHLW, "Q&A on the Guidelines" (2019; revised 2021) - Pharmaceutical and Medical Device Act, Articles 66 and 68 - Council for Science and Technology Policy, "Report on the Framework for Clinical Research Systems" (deliberations following the Diovan scandal, 2014) - Japan Pharmaceutical Manufacturers Association (JPMA), "Code of Practice"

## Guidelines on Sales Information Provision Activities (販提G): Regulatory Intent and Impact on MR Activities ### Background Issued by MHLW in September 2018 and effective April 2019 in response to the 2013–2014 Novartis valsartan scandal, which exemplified clinical trial data falsification and promotional manipulation. ### Regulatory Intent The objectives are to promote **appropriate use of pharmaceuticals** and to eliminate **inappropriate promotion**. The three pillars are: ① prohibition of false or exaggerated information; ② prohibition of encouraging use of unapproved products or off-label use; and ③ mandatory establishment of internal **review and corrective systems** (internal review committees). ### Key Impact on MR Activities | Change | Detail | |---|---| | Prior materials review | All distributed materials must be approved by the internal review committee | | Activity record obligation | Records of visits must be kept and a monitoring system must be maintained | | Off-label information | Responses even to physician-initiated questions are restricted to on-label scope | | Enhanced training | Mandatory compliance training for MRs | As a result, MR KPI evaluation has shifted **from prescription volume to information quality**, producing a structural change in which the accuracy of content matters more than activity volume. --- ### Key References - MHLW, "Guidelines on Sales Information Provision Activities for Prescription Drugs," September 25, 2018, Notification Yakusei-hatsu 0925 No. 1 - Japan Pharmaceutical Manufacturers Association (JPMA), "Guidelines for the Creation of Product Information Materials for Prescription Drugs (2019 revised edition)" - Ono T., "International Comparison of Promotion Regulations and Challenges for Japan," *Pharmaceutical Journal*, Vol. 140, No. 2, 2020 - Nagai R. et al., "Governance of Pharmaceutical Information Quality and the Physician–Industry Relationship," *Journal of the Japanese Society of Internal Medicine*, Vol. 108, 2019 - Pharmaceuticals and Medical Devices Agency (PMDA), "Collection of Inappropriate Sales Information Provision Cases," March 2020

The Nuremberg Code (1947) emerged from the verdicts of the Doctors' Trial prosecuting Nazi human experimentation, placing "the voluntary consent of the human subject is absolutely essential" as its first principle. However, the ten points issued by the tribunal remained a court document rather than a norm generated from within the medical community itself. The World Medical Association (WMA) reframed these principles as professional medical ethics and adopted the Declaration of Helsinki (1964). Building on the consent principle, it introduced: (1) a distinction between therapeutic and non-therapeutic research; (2) independent ethical review; and (3) a priority principle that "the interests of the individual research subject must take priority over all other interests." Following the exposés by Beecher (1966) and the Tuskegee syphilis study (revealed 1972), the Belmont Report (1979) codified three principles — respect for persons, beneficence, and justice — and reinforced the IRB system. Subsequent revisions have sharpened the current consensus. The Tokyo revision (1975) institutionalized ethics committees. The 2000 Edinburgh revision made placebo use and post-trial access contentious issues; the 2008 and 2013 Fortaleza revisions strengthened prospective registration, mandatory disclosure of results, compensation for harm, and protection of vulnerable populations. The 2024 Helsinki revision incorporated a broadened concept of "research participants" and dynamic informed consent. The current consensus is a framework operating not as law but as international professional norms, integrating voluntary consent, independent review, transparency (registration and publication), prioritization of participant protection, and equitable distribution of benefits. **Key References** - Nuremberg Code (1947), *Trials of War Criminals*, Vol. 2. - World Medical Association, *Declaration of Helsinki* (1964; 2013 Fortaleza; 2024 revision). - Beecher HK, "Ethics and Clinical Research," *NEJM* (1966). - National Commission, *Belmont Report* (1979). - Emanuel EJ et al., "What Makes Clinical Research Ethical?" *JAMA* (2000).

## From the Nuremberg Code to the Declaration of Helsinki — The Current State of Medical Research Ethics **Starting point (1947)** The Nuremberg Military Tribunals (Brandt Trial) convicted Nazi human experimentation, and the Nuremberg Code declared "voluntary consent" an absolute requirement. It became the first international norm protecting research subjects. **Institutionalization (1964–)** The World Medical Association (WMA) adopted the Declaration of Helsinki, distinguishing therapeutic from non-therapeutic research and introducing ethics committee review. After eight revisions, the 2000 version tightened restrictions on placebo use, while the 2013 version (9th; current) explicitly mandated trial registration, obligatory publication of results, and post-trial access provisions. **Codification of three principles (1979)** The US Belmont Report codified "Respect for Persons, Beneficence, and Justice," providing the theoretical foundation of modern research ethics. **Regulatory harmonization (1996/2016)** ICH-GCP E6 unified international Good Clinical Practice standards, providing common operational guidance to regulatory authorities, industry, and researchers. **Current focus** The emphasis has shifted from "balancing scientific rigor and participant protection" toward protection of vulnerable populations, transparency, and post-research care. --- **Key References** - World Medical Association (2013). *Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.* JAMA, 310(20), 2191–2194. - The Nuremberg Code (1947). In: *Trials of War Criminals before the Nuremberg Military Tribunals*, Vol. 2. USGPO. - National Commission for the Protection of Human Subjects (1979). *The Belmont Report.* DHEW Publication. - ICH E6(R2) (2016). *Guideline for Good Clinical Practice.* International Council for Harmonisation. - Emanuel EJ, et al. (2000). What makes clinical research ethical? *JAMA*, 283(20), 2701–2711.

Pharmaceutical industry ethics is structurally fraught because the entities involved are profit-maximizing firms that simultaneously handle public goods — patient health. In mainstream understanding, this tension is conceptualized as "conflict of interest." From the 1990s onward, selective publication of clinical trial data (publication bias), ghostwriting, and prescription-steering through payments to key opinion leaders (KOLs) became prominent problems. The 2004 withdrawal of Vioxx (rofecoxib) by Merck is the canonical example of how concealing safety information can cause serious harm post-launch. On the regulatory side, the US Physician Payments Sunshine Act (2010) mandated transparency in financial relationships between industry and physicians; the ICMJE required conflict-of-interest disclosure and prospective trial registration (ClinicalTrials.gov). Industry self-regulation includes the IFPMA Code of Practice and the JPMA Code. From an ethics standpoint, Marcia Angell and Ben Goldacre have criticized information asymmetry and regulatory capture, while others argue that commercial incentives are indispensable for recouping the enormous investment required in drug development. The debate has converged not on negating profit but on managing and disclosing conflicts of interest. Key References - Angell M. *The Truth About the Drug Companies* (2004) - Goldacre B. *Bad Pharma* (2012) - Lo B & Field MJ (eds.), IOM *Conflict of Interest in Medical Research, Education, and Practice* (2009) - Physician Payments Sunshine Act (2010) - IFPMA Code of Practice / JPMA Code of Practice

## Pharmaceutical Industry Ethics: The Tension Between Profit and Medicine **The nature of the structural tension** Pharmaceutical companies bear simultaneous obligations to shareholders for profit and to society for public health. This duality has been codified academically as the "innovation dilemma." **Key ethical issues and institutional responses** - **Research selection bias**: Under-investment in commercially unviable disease areas (rare diseases, tropical diseases). The US Orphan Drug Act (1983) and EU Orphan Regulation (2000) are legislative corrections to this. - **Selective data disclosure**: Non-publication of negative trial results. The AllTrials campaign (2012) and EU Clinical Trials Regulation (effective 2022) have strengthened registration and publication obligations. - **Institutionalized conflicts of interest**: Payments to physicians and researchers distort prescribing behavior. The US Physician Payments Sunshine Act (2013) and the JPMA Transparency Guideline (2014) mandate disclosure. - **Pricing ethics**: Sovaldi (hepatitis C drug, 2013) at $84,000 per course reignited debate over the "right to access." WHO essential medicines policy and TRIPS flexibility clauses (compulsory licensing) serve as countermeasures. **Current mainstream understanding** The OECD's "Responsible Business Conduct" framework (2011) and the IFPMA Code of Practice (revised 2019) — the sector-specific framework — do not reject profit-seeking but maintain a social contract conditioned on "transparency, access, and evidence integrity." --- **Key References** - Angell, M. (2004). *The Truth About the Drug Companies*. Random House. - Lexchin, J. (2012). "Those who have the gold make the evidence." *Milbank Quarterly*, 90(2). - Light, D.W., & Lexchin, J.R. (2012). "Pharmaceutical research and development." *BMJ*, 345, e4348. - OECD (2011). *OECD Guidelines for Multinational Enterprises*. OECD Publishing. - WHO (2019). *Improving the Transparency of Markets for Medicines, Vaccines, and Other Health Products*. WHA72.8.

Pharmaceutical company CEO decision-making is structured around reconciling long-term R&D investment — inherently uncertain — with non-negotiable constraints of patient safety and regulatory compliance. The modern essentials can be organized into three layers. **1. Integrated Risk Management (ERM)** Drawing on the COSO ERM framework (published 2004, revised 2017) and ISO 31000 (2009, revised 2018) as foundations, risk is embedded in strategy-setting and objective-setting rather than treated reactively. CEOs articulate an explicit "risk appetite," viewing pipeline diversification, clinical trial termination decisions, and pricing pressure as a whole-company portfolio. **2. Structural Independence of Compliance** In response to the OIG's 2003 compliance program guidance for pharmaceutical manufacturers and laws such as the FCPA (1977) and the UK Bribery Act (2010), Chief Compliance Officers are positioned independently from the CEO, reporting directly to the board. The IIA's "Three Lines Model" (revised 2020) separates accountability among business units, management functions, and internal audit. **3. Transparency and Tone at the Top** Conflict-of-interest disclosure is mandated by the US Physician Payments Sunshine Act (2010), the PhRMA Code, and the JPMA Code of Practice. CEOs who personally embody an ethical culture are regarded as the source of sustainable trust, not merely of penalty avoidance. In short, the modern pharmaceutical CEO governs a dual structure: using ERM to take offensive risks while blocking irreversible downside risks through an independent compliance function and transparency. **Key References** - COSO, *Enterprise Risk Management—Integrating with Strategy and Performance* (2017) - ISO 31000:2018, *Risk management — Guidelines* - U.S. OIG, *Compliance Program Guidance for Pharmaceutical Manufacturers* (2003) - The Institute of Internal Auditors, *The IIA's Three Lines Model* (2020) - U.S. Physician Payments Sunshine Act (Social Security Act §1128G, 2010)

## Essentials of ERM and Compliance Governance for Pharmaceutical Company CEOs **Implementing the Three Lines of Defense** Modern pharmaceutical CEOs build on the Three Lines Model revised by the IIA (Institute of Internal Auditors) in 2020. The three lines — ① business units (first line), ② risk management and compliance functions (second line), and ③ internal audit (third line) — are clearly separated, and the CEO bears direct accountability to the board and audit committee as the top of governance. **Regulatory background** In the US, the Sarbanes-Oxley Act (2002) and Dodd-Frank Act (2010) have strengthened the legal obligation of internal controls. Pharmaceutical-specific regulations include FDA 21 CFR Part 11 (electronic records) and OIG Compliance Guidance (first edition 1997), which make explicit the CEO's personal liability. In Japan, the 2021 amendment to the Pharmaceutical and Medical Device Act and the revised Whistleblower Protection Act (effective 2022) mandate internal reporting response systems. **Modern essentials for decision-making** ① Board approval of a risk appetite statement (COSO 2017 ERM framework); ② data-driven KRI (Key Risk Indicator) monitoring; ③ ensuring independence between the CEO and the CCO (Chief Compliance Officer) — Pfizer is cited as an early example of positioning the CCO at the same level as the CEO following the Pharmacia acquisition in 2003; ④ routine third-party auditing of supply chains and clinical trials. --- **Key References** - COSO. *Enterprise Risk Management — Integrating with Strategy and Performance.* 2017. - IIA. *The IIA's Three Lines Model: An Update of the Three Lines of Defense.* 2020. - OIG, DHHS. *Compliance Program Guidance for Pharmaceutical Manufacturers.* 68 FR 23731, 2003. - ICH Q10. *Pharmaceutical Quality System.* 2008 (ICH trilateral guideline for EU, US, Japan). - Engel, S., & Brownell, K. "Corporate integrity agreements and pharmaceutical compliance." *Journal of Health Politics, Policy and Law,* 2019.

What distinguishes life-science industries (pharmaceuticals, healthcare, food) from ordinary goods is that they are "credence goods" — the quality of which consumers cannot verify even after purchase. This property, formalized by Darby & Karni (1973), amplifies the information asymmetry that Akerlof (1970) demonstrated in "The Market for Lemons" to an extreme: patients and users cannot self-evaluate safety or efficacy and must depend on corporate disclosure and third-party regulation (FDA, PMDA, GMP/GVP). Because of this structure, trust accumulates slowly through regulatory compliance and long-term track record, yet collapses instantly upon a single concealment. The 1957–62 thalidomide disaster produced the Kefauver-Harris Amendments of 1962 (mandating proof of efficacy); the 2013–14 Novartis-Diovan scandal demonstrated that data manipulation can destroy corporate credibility overnight — an asymmetry that is stark. Mainstream corporate governance theory frames this through Freeman's (1984) stakeholder theory and the concept of a "social license to operate." In life-science industries, trust capital from regulators, patients, and society is the precondition for continued operations, making the independence of ESG and compliance structures (excluding conflicts of interest from boards and pharmacovigilance functions) critically important. **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.* - Freeman, R.E. (1984) *Strategic Management: A Stakeholder Approach* - MHLW, Reports on clinical research and sales information provision (2014–2018) - OECD (2015) *G20/OECD Principles of Corporate Governance*

## The Distinctive Characteristics of Life-Science Industries: A Governance and Ethics Perspective **Information asymmetry** In pharmaceuticals and medical devices, a structural knowledge gap exists between manufacturers and patients or regulators. The "information asymmetry in healthcare markets" identified by Arrow (1963) manifests concretely today as publication bias — selective disclosure of clinical trial data. The EU Clinical Trials Regulation (No. 536/2014, 2014) mandated data transparency, but the unreported-trial problem (AllTrials campaign, 2013–) remains unresolved. **Trust accumulation** Since Freeman's stakeholder theory (1984), the trust of pharmaceutical and medical device companies has been understood not merely as reputational capital but as "long-term relational assets with patients, physicians, and regulators." Building a trust relationship with the FDA typically requires more than ten years of review history. **The speed of destruction** Trust collapses asymmetrically and rapidly. The thalidomide disaster (1961), the Vioxx withdrawal (2004), and the opioid crisis (Purdue Pharma bankruptcy, 2019) all illustrate the structure of "decades of accumulation destroyed in months." This is what Fombrun & Shanley (1990) call the "non-linearity of vulnerability" in reputational capital theory, and it manifests in extreme form in life-science industries. The current mainstream in corporate governance theory designates independent ethics committees, whistleblower protection systems, and continuous monitoring of real-world data as the "three pillars of governance" against this asymmetric risk. --- **Key References** - Arrow, K.J. (1963). "Uncertainty and the Welfare Economics of Medical Care." *American Economic Review*, 53(5), 941–973. - Freeman, R.E. (1984). *Strategic Management: A Stakeholder Approach*. Pitman. - Fombrun, C. & Shanley, M. (1990). "What's in a Name?" *Academy of Management Journal*, 33(2), 233–258. - European Parliament (2014). Regulation (EU) No 536/2014 on clinical trials on medicinal products. - Hoffman, J.R. & Podolsky, M.J. (2022). "Corporate Governance Failures in the Opioid Crisis." *NEJM*, 386, 1–4.

Freud (1856–1939) conceived self-understanding as "decoding the unconscious, which consciousness cannot reach." From *The Interpretation of Dreams* (1900) onward, he used free association and dreams to read the dynamics of the id, ego, and superego, arguing that making repressed infantile sexual and aggressive drives conscious was the path to healing. The self is an object of discovery — of hidden motivations. Jung (1875–1961) broke with Freud around 1913 and placed archetypes and the collective unconscious beneath the personal unconscious. Self-understanding for Jung is the lifelong process of integrating the persona and the shadow and connecting consciousness with the unconscious — what he called "individuation." He also proposed the introversion/extraversion typology. Adler (1870–1937) founded Individual Psychology and viewed the human being teleologically as an indivisible whole. Centering on the inferiority feeling and its compensation, lifestyle, and community feeling (Gemeinschaftsgefühl), he defined self-understanding as giving meaning to "why I live and toward what goal." Their influence on contemporary practice: Freud's unconscious hypothesis, though criticized for lack of rigorous empirical support, left the concepts of defense mechanisms and transference in psychodynamic therapy. Jung's typology became the source of the MBTI; archetypes pervade narrative theory and art therapy. Adler's teleology and encouragement have been reassessed through cognitive behavioral therapy, positive psychology, and the bestseller *The Courage to Be Disliked* (岸見一郎・古賀史健, 2013). All three bequeathed the perspective that "the self is not a fixed entity but a process of interpretation and re-construction," forming a foundation of modern clinical psychology. **Key References** - Freud, S. (1900). *Die Traumdeutung* (*The Interpretation of Dreams*). - Jung, C. G. (1921). *Psychologische Typen* (*Psychological Types*). - Adler, A. (1927). *Menschenkenntnis* (*Understanding Human Nature*). - Ellenberger, H. F. (1970). *The Discovery of the Unconscious*. - Kawai Hayao (1967). *Introduction to Jungian Psychology*.

--- **Freud (1856–1939)** formalized the tripartite structure of unconscious, ego, and superego (*The Ego and the Id*, 1923) and positioned "self-understanding as bringing repressed unconscious material into consciousness." Using free association and dream analysis as methods, he laid the foundation for psychoanalysis and modern trauma therapies (EMDR, psychodynamic CBT). **Jung (1875–1961)** proposed the collective unconscious and archetypes, placing the individuation process — integrating persona, shadow, and anima to realize the "Self" — at the core of self-understanding. His work was directly inherited by the MBTI, transpersonal psychology, and narrative therapy. **Adler (1870–1937)** defined self-understanding as "awareness of one's goals and behavioral patterns in social context" (Individual Psychology), centering on compensation for inferiority, lifestyle, and community feeling. His work is strongly reflected in CBT schema theory, ACT, and coaching practice. The shared legacy of all three is the **triple axis of the unconscious, teleology, and sociality**, which has permeated contemporary positive psychology, neuroscientific consciousness research, and mindfulness-based therapies. --- **Key References** - Freud, S. (1923). *Das Ich und das Es.* Internationaler Psychoanalytischer Verlag. - Jung, C.G. (1960). *The Structure and Dynamics of the Psyche* (CW Vol. 8). Princeton University Press. - Adler, A. (1927). *Menschenkenntnis* [Understanding Human Nature]. Hirzel. - Ellenberger, H.F. (1970). *The Discovery of the Unconscious.* Basic Books. - McWilliams, N. (2011). *Psychoanalytic Diagnosis*, 2nd ed. Guilford Press.

The Dunning-Kruger effect (Kruger & Dunning, 1999, Cornell) refers to the tendency for people low in ability in a given domain to overestimate their own performance, while those high in ability modestly underestimate theirs. The mechanism is termed the "dual burden": the skills needed to perform a task and those needed to accurately assess one's own performance share the same knowledge base, so incompetent individuals cannot recognize their errors as errors — this is the "metacognitive blind spot." In current mainstream understanding, however, much of the characteristic curve can also be explained as a statistical artifact. It has been shown that regression to the mean from measurement error, combined with the better-than-average tendency for self-ratings to correlate only weakly with actual ability (causing everyone to answer "about average"), can reproduce the pattern on its own (Krueger & Mueller, 2002; Nuhfer et al., 2017). Gignac & Zajenkowski (2020) found that real data show a largely linear relationship, not supporting the classic interpretation. Overall, the current consensus is that limits on metacognition are real, but the effect size is smaller than originally claimed and requires verification separated from statistical confounds. Key References - Kruger, J. & Dunning, D. (1999). *J. Pers. Soc. Psychol.*, 77(6), 1121–1134. - Dunning, D. (2011). The Dunning–Kruger Effect. *Adv. Exp. Soc. Psychol.*, 44, 247–296. - Krueger, J. & Mueller, R. A. (2002). *J. Pers. Soc. Psychol.*, 82(2), 180–188. - 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 In 1999, David Dunning and Justin Kruger of Cornell University published their findings in *Journal of Personality and Social Psychology*, Vol. 77, demonstrating an asymmetric pattern in which low-ability individuals overestimate themselves while high-ability individuals underestimate themselves. The mechanism is a **dual barrier** of metacognition. Insufficient ability simultaneously causes a deficit in the metacognitive skills needed to detect one's own errors (extending Flavell's 1979 framework). The structural blind spot: the more incompetent one is, the less one can perceive one's own incompetence. ### Current mainstream understanding (2020s) - **Gignac & Zajenkowski (2020)** in *Intelligence* pointed to overestimation of the effect size. They demonstrated conflation with statistical artifacts such as regression to the mean. - **Nuhfer et al. (2016–17)** showed that random data can generate the same pattern. - The core proposition that "ability correlates with metacognitive accuracy" has not been refuted. - Currently reformulated as **calibration research**. Quantifying the gap between confidence estimates and actual performance, and using feedback interventions to train accurate self-assessment, is attracting attention in clinical and educational contexts. --- **Key References** - Kruger, J., & Dunning, D. (1999). Unskilled and unaware of it. *J. Personality and Social Psychology*, 77(6), 1121–1134. - Gignac, G.E., & Zajenkowski, M. (2020). The Dunning-Kruger effect is (mostly) a statistical artefact. *Intelligence*, 80, 101449. - Nuhfer, E., et al. (2016). How random noise and a graphical convention subverted explanations of self-assessment data. *Numeracy*, 9(1), Article 4. - Flavell, J.H. (1979). Metacognition and cognitive monitoring. *American Psychologist*, 34(10), 906–911. - Dunning, D. (2011). The Dunning-Kruger effect: On being ignorant of one's own ignorance. *Advances in Experimental Social Psychology*, 44, 247–296.

Baumeister, Campbell, Krueger, and Vohs (2003) meta-analyzed the evidence and concluded that high self-esteem produces little demonstrable effect on academic performance, job performance, or other outcomes — most observed correlations reflect self-esteem rising as a result of success rather than causing it. Educational programs exemplified by the 1986 California Task Force to Promote Self-Esteem were found to be ineffective. Twenge et al. further argued that unconditional promotion of self-esteem fosters narcissism, and interventions that treat "raising self-esteem" as an end in itself came under criticism. Two alternative constructs have gained prominence. Bandura's self-efficacy (1977/1997) is a belief in one's capacity to execute a specific task; it predicts behavior and performance better than diffuse self-evaluation. Neff's self-compassion (2003) comprises three components — self-kindness, common humanity, and mindfulness — and, by not depending on success or comparison with others, avoids the vulnerabilities of self-esteem (sharp drops upon failure, defensiveness). Efficacy addresses "I can," compassion addresses "I accept that I sometimes cannot," and together they form a framework that complements unstable self-esteem. **Key References** - Baumeister, R. F., Campbell, J. D., Krueger, J. I., & Vohs, K. D. (2003). *Does High Self-Esteem Cause Better Performance...?* Psychological Science in the Public Interest, 4(1). - Bandura, A. (1997). *Self-Efficacy: The Exercise of Control.* Freeman. - Neff, K. D. (2003). *Self-Compassion: An Alternative Conceptualization...* Self and Identity, 2(2). - Twenge, J. M., & Campbell, W. K. (2009). *The Narcissism Epidemic.* Free Press. - Crocker, J., & Park, L. E. (2004). *The Costly Pursuit of Self-Esteem.* Psychological Bulletin, 130(3).

## Critical Reassessment of Self-Esteem and Adjacent Constructs **The Baumeister 2003 Impact** Baumeister et al. (2003) reviewed over 200 studies and concluded that high self-esteem does not predict academic or occupational success, nor does it suppress interpersonal violence. They showed that high self-esteem correlates more with narcissism and defensive aggression. **Subsequent Developments** Crocker & Park (2004) argued that "the pursuit of self-esteem itself generates costs — distraction from goals, interpersonal exploitation." Kernis (2003) pointed out that stability rather than level is what matters, establishing the concept of "fragile high self-esteem." **Contrast with Self-Efficacy (Bandura)** Bandura's self-efficacy is a context-specific "expectancy of performance capability," separate from a global evaluation of self-worth. Its predictive power in academic, health-behavior, and occupational settings consistently exceeds that of self-esteem, and it has been adopted as an intervention metric by regulatory bodies and educational institutions. **The Rise of Self-Compassion (Neff)** Neff (2003) proposed self-compassion — replacing self-criticism during failure with "self-kindness, common humanity, and mindfulness." It does not produce narcissism or defensive inflation, and its effectiveness in reducing depression and anxiety has been repeatedly demonstrated. It is now internationally established as a clinical alternative to self-esteem. --- **Key References** - Baumeister, R. F. et al. (2003). Does high self-esteem cause better performance, interpersonal success, happiness, or healthier lifestyles? *Psychological Science in the Public Interest*, 4(1), 1–44. - Crocker, J., & Park, L. E. (2004). The costly pursuit of self-esteem. *Psychological Bulletin*, 130(3), 392–414. - Kernis, M. H. (2003). Toward a conceptualization of optimal self-esteem. *Psychological Inquiry*, 14(1), 1–26. - Bandura, A. (1997). *Self-efficacy: The exercise of control*. W. H. Freeman. - Neff, K. D. (2003). Self-compassion: An alternative conceptualization of a healthy attitude toward oneself. *Self and Identity*, 2(2), 85–101.

The psychological structure of self-criticism was theorized in stages across the twentieth century. The starting point was Freud (*Das Ich und das Es*, 1923), who formalized the superego (Über-Ich): the internalized parental prohibition installed during the Oedipal period generates conscience and guilt. This created the archetype of criticism living inside oneself. Karen Horney (*Neurosis and Human Growth*, 1950) introduced the "tyranny of the shoulds" — a compulsion to reach an idealized self-image. Moving away from Freudian drive theory, she located the cause in culture and interpersonal relations. Albert Ellis made these internal imperatives clinically actionable. Starting around 1955, Rational Emotive Behavior Therapy (REBT) identified "musturbation" — irrational beliefs containing absolute obligations ("must," "should") — as the generator of distress, and targeted them for disputation through the ABC model. Aaron T. Beck (1960s cognitive therapy) systematized automatic thoughts and cognitive distortions (all-or-nothing thinking, overgeneralization, personalization, etc.), operationalizing abstract imperatives into observable thought patterns. Brené Brown (from the 2000s) distinguished between guilt (evaluating an act) and shame (evaluating one's existence as a person) through qualitative research, placing shame at the emotional core of self-criticism. The lineage reads as a shift from "internalized tribunal → cultural imperatives → irrational beliefs → cognitive patterns → the emotion of shame," progressively relocating causation from internal drives toward interpersonal, cultural, and measurable cognitive constructs. **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. (1976). *Cognitive Therapy and the Emotional Disorders*. - Brown, B. (2012). *Daring Greatly*.

## The Lineage of Self-Criticism Structures **1923 — Freud** formalized the superego in *The Ego and the Id*. An internalized parental and social prohibition, it functions as a "punishing voice" and critical monitoring of the ego. **1945 — Horney** (New York Psychoanalytic Institute) described the "tyranny of the shoulds." A compulsive drive toward a perfect idealized self stifles the authentic self, she argued. **1955 — Ellis** constructed the ABC model. He formulated that it is not "events" but irrational beliefs containing absolute obligations (must/should) that produce self-condemnation and emotional disturbance, making this the foundation of REBT. **1976 — Beck** (University of Pennsylvania) operationalized a list of cognitive distortions (all-or-nothing thinking, emotional reasoning, labeling, etc.). By making automatic thoughts monitorable, he rendered self-criticism tractable within behavior therapy. **From 2006 — Brown** (University of Houston) defined shame as "a sense of defect in the self itself" and clearly distinguished it from guilt (regret about an action). Using grounded theory, she showed that shame correlates with chronic self-criticism, isolation, and addictive behavior. --- **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. (1976). *Cognitive Therapy and the Emotional Disorders*. International Universities Press. - Brown, B. (2006). Shame resilience theory. *Journal of Clinical Social Work*, 34(1), 43–62.

## Middle Way, Śūnyatā, Dependent Origination → MBSR and ACT **Philosophical source.** Nāgārjuna (c. 150–250 CE) argued in the *Mūlamadhyamakakārikā* (Middle Treatise) that the Middle Way — neither being nor non-being — is the truth: all phenomena lack inherent self-nature (svabhāva) and are "empty" (śūnyatā), arising interdependently through dependent origination (pratītyasamutpāda). Including the Two Truths doctrine (conventional and ultimate), he provided the logic for dismantling attachment to a fixed self and to concepts. **Influence on MBSR.** Jon Kabat-Zinn (1979, University of Massachusetts Medical Center) founded MBSR drawing directly on Zen (Seungsahn, Thich Nhat Hanh) and Theravāda vipassanā. Yet the stance of "observing thoughts as passing phenomena rather than reifying them" — decentering — resonates conceptually with śūnyatā and dependent origination. The connection is one of conceptual resonance rather than direct historical transmission. **Influence on ACT.** Steven Hayes et al. built ACT on Relational Frame Theory (RFT) and functional contextualism during the 1980s–90s. Cognitive defusion (not taking thoughts literally), self-as-context, and acceptance correspond to the emptiness of self (anātman) and non-attachment in Madhyamaka. Hayes himself has noted the affinity with the Middle Way and dependent origination. Both approaches agree that suffering arises not from experience itself but from clinging to experience. **Key References** - Nāgārjuna, *Mūlamadhyamakakārikā* (trans. and annotated by Garfield, 1995) - Kabat-Zinn J. *Full Catastrophe Living* (1990) - Hayes SC, Strosahl K, Wilson KG. *Acceptance and Commitment Therapy* (1999; 2nd ed. 2012) - Hayes SC. "Buddhism and Acceptance and Commitment Therapy," *Cognitive and Behavioral Practice* (2002) - Williams JMG, Kabat-Zinn J (eds.) *Mindfulness: Diverse Perspectives on its Meaning, Origins and Applications* (2013)

## Buddhist Philosophy and Its Influence on Contemporary Psychotherapy **MBSR (1979, Jon Kabat-Zinn)** is a secularized intervention derived from Pāli canonical **vipassanā** (insight meditation), but its theoretical underpinning lies in **dependent origination** (pratītyasamutpāda). The view that "the self is not a fixed entity but a condition-dependent process" structurally coincides with the cognitive operation of **decentering** — not identifying with thoughts and sensations as "self." **The core concept of ACT (Hayes, 1999) — "defusion"** — functionally mirrors Nāgārjuna's **śūnyatā**: the dismantling of the error that concepts and language refer to independent entities. The operation of severing over-identification with linguistic frames can be interpreted as the clinical counterpart of the attachment to "svabhāva (self-nature)" criticized by the Mādhyamikas. The **Middle Way (Madhyamā Pratipad)** — a dialectical stance rejecting both hedonism and asceticism — corresponds to ACT's therapeutic attitude of "neither control nor avoid; remain open to experience." Segal, Williams, and Teasdale (2002) in MBCT explicitly cite this lineage. --- **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. - Grabovac, A. D., Lau, M. A., & Willett, B. R. (2011). Mechanisms of mindfulness: A Buddhist psychological model. *Mindfulness, 2*(3), 154–166.

Alfred Adler (1870–1937) founded Individual Psychology (Individualpsychologie), whose core concepts were made accessible to Japanese audiences by Ichiro Kishimi and Fumitake Koga in *The Courage to Be Disliked* (Kiwaretai Yūki; Diamond-sha, 2013). **Separation of tasks** involves identifying task ownership by asking "who ultimately bears the consequences of this choice?" and refusing to intrude on others' tasks while preventing others from intruding on one's own. It is linked to the denial of the need for approval and the reduction of interpersonal suffering. However, the term itself is not a direct translation of an Adlerian original but a formulation derived via Kishimi's interpretation of Adler (and the lineage of W. B. Wolfe et al.); the word Aufgabentrennung does not appear in the classical texts as such — a point that deserves scholarly attention. **Community feeling** (German: Gemeinschaftsgefühl; English: social interest) involves viewing others as companions rather than rivals and cultivating a sense of belonging and contribution — "I can contribute to the community." This represents Adler's later achievement (1920s) and is regarded as the criterion of mental health. Separation of tasks is the entry point for distinguishing self from other; community feeling is the exit point for reconnecting with others — they form a paired structure. The context of reassessment: the book, presented as a dialogue between a philosopher and a young man, became a bestseller of over 2 million copies, sparked a social phenomenon in South Korea as well, and was dramatized by Fuji Television in 2017. Its teleological stance against Freudian causality and its relativization of the trauma concept found resonance in a self-help context, though clinical psychologists have also criticized it for oversimplifying the original texts and for its assertive tone. **Key References** - Kishimi I. & Koga F., *The Courage to Be Disliked* (Kiwaretai Yūki), Diamond-sha, 2013 - A. Adler, *Der Sinn des Lebens* (*The Meaning of Life*), 1933 - Kishimi I., *Introduction to Adlerian Psychology*, Best Shinsho, 1999 - H. L. Ansbacher & R. R. Ansbacher (eds.), *The Individual Psychology of Alfred Adler*, 1956

## Reassessment of Adlerian Individual Psychology **Theoretical Framework** Alfred Adler (1870–1937) built Individual Psychology around two central concepts. "Separation of tasks" is the principle of distinguishing "one's own task" from "another's task" by asking who bears the consequences of a given action, and of refraining from interfering in others' tasks — thereby reducing interpersonal friction. "Community feeling" (Gemeinschaftsgefühl) is a sense of belonging that expands in concentric circles through family, workplace, society, and the cosmos; subjective wellbeing arises through a sense of contribution. The two concepts are two sides of the same coin — drawing boundaries enables genuine cooperation. **Reassessment in Japan** Ichiro Kishimi and Fumitake Koga's *The Courage to Be Disliked* (Diamond-sha, 2013) introduced Adler in a Socratic dialogue format, recording cumulative domestic sales exceeding 3.5 million copies (as of 2025). The backdrop is the workplace harassment problems and "approval fatigue" of the 2010s. The book also accessibly presents "teleology," "lifestyle," and other Adlerian concepts, and has attracted renewed attention in connection with positive psychology and ACT (Acceptance and Commitment Therapy). Among the criticisms, scholars note the risk that an overly liberal application of separation of tasks can rationalize "cold indifference." --- **Key References** - Adler, A. (1927). *Understanding Human Nature.* Greenberg. - Adler, A. (1929). *The Science of Living.* Greenberg. - Kishimi I. & Koga F. (2013). *Kiwaretai Yūki* [The Courage to Be Disliked]. Diamond-sha. - Kishimi I. (1999). *Introduction to Adlerian Psychology*. KK Best Sellers. - Watts, R. E. (2012). Adlerian counseling. In D. Capuzzi & D. R. Gross (Eds.), *Counseling and Psychotherapy* (5th ed.). American Counseling Association.

# The 1937 Elixir Sulfanilamide Disaster — Regulatory Lessons In the autumn of 1937, S. E. Massengill Company of Tennessee marketed "Elixir Sulfanilamide," dissolving the antibiotic sulfanilamide in diethylene glycol (a component of automotive antifreeze, nephrotoxic) to create a palatable preparation. The company chemist Harold Watkins had confirmed only solubility and sweetness, conducting no toxicity testing. Approximately 105 people died, many of them children, from acute renal failure. Under the Pure Food and Drug Act of 1906, the FDA (Commissioner Walter Campbell) could not halt the product on the grounds of toxicity alone — manufacturers were not required to prove safety before marketing. The only avenue for action was **misbranding**: "elixir" conventionally denotes an alcoholic solution, and the product contained no alcohol. This limitation accelerated legislation, and the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938 was enacted. It introduced a **premarket safety review system requiring submission of safety data to FDA before launch**, strengthened labeling requirements, and placed the burden of proof on manufacturers. It marked the shift from a system of "react after harm occurs on the market" to "require proof of safety before market entry," and became the starting point of the regulatory philosophy that continued with the Kefauver-Harris Amendments of 1962 (mandating proof of efficacy). **Key References** - Wallace F. Janssen, "The Story of the Laws Behind the Labels," FDA Consumer (1981) - Carol Ballentine, "Sulfanilamide Disaster," FDA Consumer (1981) - Philip J. Hilts, *Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation* (2003) - Daniel Carpenter, *Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA* (2010) - U.S. FDA, background materials on the Federal Food, Drug, and Cosmetic Act of 1938

## The 1937 Elixir Sulfanilamide Disaster: Regulatory Lessons **Overview** Harold Watkins, chief pharmacist at S. E. Massengill Company in Tennessee, used diethylene glycol (an antifreeze analogue, an industrial solvent) to formulate sulfanilamide as a liquid. He conducted no toxicity testing whatsoever before marketing, resulting in 107 deaths (the majority children). **The core institutional failure** Under the Pure Food and Drug Act of 1906, the FDA could not remove a product from the market without proving fraud. The product was barely caught on the technicality of "misbranding" — in pharmacological convention, "elixir" denotes an alcohol solution, and the product contained no alcohol. This was nearly coincidental. **Regulatory reform** The Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938 was enacted: - Made premarket submission of safety data to the FDA mandatory - Established a 60-day review period - Established the prototype of the New Drug Application (NDA) system **Current mainstream interpretation** The first public health catastrophe to demonstrate empirically that "private incentives alone cannot prevent drug toxicity." Positioned as the turning point from post-market reactive regulation to premarket review. --- **Key References** - Ballentine, C. (1981). "Taste of Raspberries, Taste of Death." *FDA Consumer*, 15(5). - Wax, P.M. (1995). "Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug and Cosmetic Act." *Annals of Internal Medicine*, 122(6), 456–461. - Carpenter, D. (2010). *Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA*. Princeton University Press. - Temin, P. (1980). *Taking Your Medicine: Drug Regulation in the United States*. Harvard University Press. - Young, J.H. (1967). *The Medical Messiahs*. Princeton University Press.

## The Thalidomide Disaster and Frances Kelsey — Summary per Mainstream Understanding Thalidomide (trade name Contergan), marketed by West Germany's Chemie Grünenthal in 1957 as a sedative and morning-sickness remedy, caused limb defects (phocomelia) and other teratogenic harm in fetuses when taken by pregnant women, producing approximately 10,000 affected children worldwide. Causal links were identified independently in 1961 by German pediatrician Widukind Lenz and Australian obstetrician William McBride; the drug was withdrawn that same year. In the United States, FDA reviewer Frances Oldham Kelsey repeatedly withheld approval of the application by Richardson-Merrell (trade name Kevadon), citing insufficient safety data on peripheral neuritis and fetal effects, and thereby prevented the drug's large-scale entry into the US market. President Kennedy awarded her the Presidential Award for Distinguished Federal Civilian Service in 1962. The regulatory lessons were profound. The Kefauver-Harris Amendments of 1962 to the Federal Food, Drug, and Cosmetic Act added a requirement to prove **efficacy scientifically** — beyond the existing safety requirement — and introduced informed consent in clinical trials, adverse event reporting, and GMP. These became the foundations of the modern drug approval system, clinical trial regulation, and teratogenicity assessment (teratology). ### Key References - Stephens T., Brynner R. *Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine* (2001) - Lenz W. "A short history of thalidomide embryopathy," *Teratology* (1988) - Kelsey F.O. "Thalidomide update: regulatory aspects," *Teratology* (1988) - McBride W.G. "Thalidomide and congenital abnormalities," *The Lancet* (1961) - U.S. FDA, *Kefauver-Harris Amendments of 1962* (regulatory history)

## Thalidomide Disaster (1957–1962) — Regulatory Lessons and Frances Kelsey's Role **Outline** In 1957, Grünenthal of West Germany began selling thalidomide as a sedative and morning-sickness treatment. Distributed to 46 countries including Europe, Japan, and Canada, it caused upper and lower limb aplasia (phocomelia) in approximately 10,000 newborns. In Japan, Dainippon Pharmaceutical introduced it in 1958; approximately 309 children were officially recognized as affected. **Frances Kelsey's Decision** In 1960, Richardson-Merrell filed an NDA with the FDA. Reviewer Frances Kelsey (MD, PhD, pharmacologist) withheld approval for 19 months, citing deficiencies in animal studies and reports of neurotoxicity (peripheral neuritis). Her insistence on missing data regarding placental permeability and teratogenicity prevented large-scale harm in the United States. President Kennedy awarded her the **President's Award for Distinguished Federal Civilian Service** in 1962. **Institutional Transition** Directly triggered by this disaster, the United States enacted the **Kefauver-Harris Drug Amendments of 1962 (mandating efficacy requirements and strengthening clinical trial regulation)**. European countries and Japan followed with mandatory preclinical testing obligations and teratogenicity screening. The event became the starting point of the ICH reproductive and developmental toxicity guideline framework. **Mainstream Academic Assessment** Contemporary regulatory science positions this disaster as the point at which "respect for uncertainty in premarket approval review" and "the principle of treating insufficient evidence as valid grounds for approval refusal" were established. --- **Key References** - Fintel, B. et al. (2009). "The Thalidomide Tragedy: Lessons for Drug Safety and Regulation." *Helix — Science in Society*, Northwestern University. - Kelsey, F. O. (1965). "Thalidomide Update: Regulatory Aspects." *Teratology*, 38(3): 221–226. - Botting, J. H. (2002). "The History of Thalidomide." *Drug News & Perspectives*, 15(9): 604–611. - McBride, W. G. (1961). "Thalidomide and Congenital Abnormalities." *The Lancet*, 278(7216): 1358. - Kim, J. H. & Scialli, A. R. (2011). "Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease." *Toxicological Sciences*, 122(1): 1–6.

## The SMON Disaster and Its Impact on the PMS System **Background** SMON (Subacute Myelo-Optico-Neuropathy) was a drug injury in which use of the antidiarrheal clioquinol caused lower-limb numbness, gait disturbance, and visual impairment; patients increased from the late 1950s, eventually reaching approximately 10,000. In 1970, Tadao Tsubaki et al. at Niigata University epidemiologically implicated clioquinol, and in September of that year the Ministry of Health and Welfare (as it was then called) suspended sales. Subsequent SMON litigation (settlements proceeding from the late 1970s) was the direct trigger for regulatory reform. **Regulatory significance** SMON is cited as a representative case demonstrating that "efficacy and safety evaluation at the time of approval alone cannot prevent unknown risks," establishing the need to institutionalize ongoing post-market surveillance. In the mainstream understanding, it — alongside the thalidomide disaster — is positioned as the origin point of Japan's drug harm history and the starting point of PMS thinking. **Institutional consequences** The 1979 amendment to the Pharmaceutical Affairs Act introduced a **re-examination system** for new drugs and a **re-evaluation system** for existing drugs, establishing a framework for reconfirming efficacy and safety after approval. In the same year, the **Drug Side Effect Damage Relief Fund** (no-fault compensation system) was also established, institutionalizing victim relief. These developments led to GPMSP (Good Post-Marketing Surveillance Practice) and strengthening of adverse event reporting, forming the basis of the PMS system — including current pharmaceutical risk management (RMP) — that continues today. **Key References** - Tsubaki T., "SMON and Clioquinol" (epidemiological research reports, 1970s) - MHLW, *Steps in Pharmaceutical Administration* (official record of Pharmaceutical Affairs Act revision history) - Pharmaceutical Affairs Act (1979 revised law) and Drug Side Effect Damage Relief Fund Act (1979) - Fukuda M. et al., related literature in *History of Japan's Drug Harm Cases* - Takano T., *Social History of Drug Harm* (social background of SMON)

## The SMON Disaster and Its Impact on the PMS System **Overview** In the late 1960s, "subacute myelo-opticoneuropathy (SMON)" — manifesting as lower-limb paralysis and visual impairment — became widespread primarily among users of the antidiarrheal clioquinol. The cumulative number of patients reached approximately 11,000. In 1970, Tadao Tsubaki (Niigata University) et al. identified the causal link with clioquinol, and in September of that year the Ministry of Health and Welfare ordered a sales suspension. **Regulatory Turning Points** | Period | Event | |---|---| | 1971– | SMON litigation filed (Tokyo, Osaka, etc.) | | 1978 | First court defeat for all defendants in Tokyo District Court | | 1979 | **Major revision of the Pharmaceutical Affairs Act**: statutory enactment of re-examination and re-evaluation systems; strengthening of adverse event reporting obligations | | 1980 | Establishment of the **Drug Side Effect Damage Relief Fund** (predecessor to PMDA today). Victim relief moved to a national scheme | **Structural Impact on PMS** The disaster prompted a paradigm shift from the previously approval-centric model to ongoing post-approval risk management. The re-examination system (mandatory 6-year post-marketing monitoring for new drugs) and the manufacturers' obligation to spontaneously report adverse events were first explicitly written into substantive law in this revision. The event is cited internationally as a precedent that predated — and in some respects anticipated — the subsequent harmonization of the ICH E2 guidelines and the European "pharmacovigilance" concept. --- **Key References** - Tsubaki T. (1971). "Clioquinol and the Causal Relationship with SMON." *Naika* (Internal Medicine), 27(5) - MHLW Pharmaceutical Affairs Bureau (ed.) (1980). *Commentary on the Pharmaceutical Affairs Act*. Gyosei. - Nakajima, W. (2003). "SMON and the Japanese regulatory reform." *Drug Safety* 26(12) - Soda, T. (1973). "Studies on SMON." *Jpn J Med Sci Biol* (Suppl.) - PMDA (2012). *30-Year History of the Drug Side Effect Damage Relief System*.

## Structural Failures and Lessons of the HIV-Contaminated Blood Products Disaster In the early 1980s, while the US had recognized the need for heat-treated preparations by 1983, the Ministry of Health and Welfare of Japan delayed the recall and transition away from non-heat-treated blood clotting factor preparations, resulting in approximately 1,800 hemophilia patients being infected with HIV; over 600 died. **Core structural failures (current mainstream understanding)** 1. **Collusion between regulators and industry** — Amakudari (descent from heaven: post-retirement placement from the Ministry into industry) and personal ties between the Ministry of Health and Welfare and companies such as Midori Juji permitted knowingly dangerous preparations to remain on the market. 2. **Unchecked conflict of interest** — Eiji Abe, head of the Ministry's AIDS research group, maintained close ties with pharmaceutical companies while leading risk assessments (absence of independence in scientific advisory functions). 3. **Failure of the precautionary principle** — The decision waited for "complete proof" of causality, neglecting risk-avoidance decisions under uncertainty. 4. **Non-disclosure of information** — Internal documents demonstrating the danger (the Gunji file) were concealed; Minister of Health Naoto Kan disclosed and apologized at the time of the 1996 settlement. **Lessons for administrative responsibility theory** Failure to exercise regulatory authority can give rise to liability in tort (the state's duty to act); conflict-of-interest management, information disclosure, and the precautionary principle must be institutionalized in pharmaceutical administration. Subsequent reforms led to the 1997 Pharmaceutical Affairs Act revision, the drug side-effect damage relief system, emergency import mechanisms, and eventually the establishment of PMDA. The burden structure not placing victims as the party bearing the burden of proof was inherited in the subsequent hepatitis drug harm litigation. **Key References** - Gunji A., *The Illusion of Safety — Lessons from the AIDS Turmoil* (2015) - MHLW, *Report on Investigation into HIV Infection from Blood Products* (1996) - HIV litigation settlement confirmation (Tokyo and Osaka, 1996) - Muto K. et al., various studies in conflict-of-interest theory in medical ethics - Nihon Hyoronsha, *History of the HIV Drug Harm Trial* (2002)

## Structural Failures and Modern Lessons of the HIV-Contaminated Blood Products Disaster **Three-layered failure structure** After the HIV-inactivating effect of heat-treated preparations was confirmed in the United States in 1983, the Ministry of Health and Welfare and companies including Midori Juji continued using non-heat-treated preparations. Approximately 1,800 hemophilia patients were infected with HIV. **① Regulatory capture** Eiji Abe, Vice President of Teikyo University, simultaneously served as head of the Ministry's AIDS research group while prescribing non-heat-treated preparations at his own hospital — a conflict of interest in which the reviewer and the beneficiary were the same person was left unaddressed institutionally. **② Information concealment and administrative inaction** Domestic HIV case reports from 1983 were not used to drive policy change; internal ministry documents were subsequently destroyed. In 1996, Minister of Health Naoto Kan apologized and a settlement was reached. In administrative responsibility theory, "passive inaction through approval delay" was challenged as a violation of the duty to act. **③ Absence of the precautionary principle** A culture of postponing risk response while waiting for "certainty" of causation amplified the harm. **Contemporary responses** Medical ethics demands institutional blocking of conflicts of interest, independence of regulatory bodies, and statutory enactment of the precautionary principle. The 2014 revision of the Pharmaceutical and Medical Device Act (strengthening of GVP regulations) and enhanced functions of the Drug Safety Division constitute the institutional response. --- **Key References** - Feldman, E. A. & Bayer, R. (eds.) *Blood Feuds: AIDS, Blood, and the Politics of Medical Disaster*, Oxford University Press, 1999 - Hirowa S., "The HIV Drug Harm Disaster and State Compensation Liability," *Houritsu Jiho*, Vol. 68, No. 12, 1996 - Matsumura R. et al., "The HIV Drug Harm Settlement and Subsequent Policy Response," *Public Health*, Vol. 60, No. 8, 1996 - Supreme Court First Petty Bench Judgment, March 25, 2005 (Eiji Abe criminal case — acquittal confirmed) - PMDA, "History and Lessons of Drug Harm" (2008 edition)

## The State's Information Management Responsibility in the Hepatitis C Drug Harm Case **Mainstream understanding** — Fibrinogen preparations (manufactured by Midori Juji, later Mitsubishi Wellpharma) were a hemostatic plasma fractionation product approved in 1964 that transmitted hepatitis C virus (HCV) because they were non-heat-treated. The US FDA rescinded approval in 1977, but in Japan — following a cluster infection at an Aomori obstetrics clinic in 1987 — the switch to heat-treated preparations was delayed and recall was slow. The reason the state's (Ministry of Health and Welfare / Ministry of Health, Labour and Welfare) information management responsibility became a central contested issue is that in 2007 it came to light that the Ministry had obtained from the manufacturer (in 2002) a list of medical institutions that had administered the preparations and a "418-person list" capable of identifying infected individuals — but had not notified those individuals. The inaction from 1987 onward (failure to recall or notify) and the management system that failed to use the information it held for relief purposes are assessed in medical policy history as "shelving of foreseeable victim information." In response, the Fukuda Yasuo Cabinet made a political decision to enact the Special Measures Act for Hepatitis C Relief in 2008, acknowledging the state's responsibility and providing across-the-board relief. The Verification Committee's final recommendations (2010) concluded that siloed structures and record abandonment at each stage — approval, post-market surveillance, and information transmission — constituted systemic failure. **Key References** - Advisory Committee on How Pharmaceutical Administration Should Be for the Investigation of the Hepatitis C Drug Harm Case and Prevention of Recurrence, *Final Recommendations* (2010) - MHLW, related materials on the list of medical institutions supplied fibrinogen preparations (published 2002 and 2007) - "Act on the Payment of Benefits to Victims of Hepatitis C Infections Due to Specific Fibrinogen Products and Specific Blood Coagulation Factor IX Products" (2008) - Nationwide Hepatitis C Drug Harm Litigation Plaintiffs and Legal Team (eds.), *Record of the Nationwide Hepatitis C Drug Harm Litigation* - Hongo M., Sato T. et al., medical sociology research on HIV/hepatitis drug harm (※ This entry contains points requiring verification by specialist researchers; checking against primary sources is recommended before citation)

## Hepatitis C Drug Harm and the State's Information Management Responsibility In the 1980s, non-heat-treated blood products — fibrinogen preparations (manufactured by Midori Juji et al.) — administered to postpartum women and surgical patients mediated HCV transmission, causing collective infection on a scale of thousands. The state's responsibility is criticized at two layers. **First layer: Concealment of risk awareness (1987–88)** The Ministry of Health and Welfare had internally identified HCV infection risk by 1987 and issued limited voluntary recall instructions in 1988, but did not widely recall products still in circulation or notify patients. The structure of "administration knowing yet tolerating continued distribution" was later recognized judicially. **Second layer: Non-use of the victim list (1990s–2007)** The former Ministry of Health had internally compiled a "418-person infected person list" in the 1990s, but failed to notify the individuals concerned. This came to light during 2007 parliamentary deliberations. The "inactive concealment" of failing to use epidemiological information that administration held was assessed as a more deeply institutionalized defect than the HIV drug harm case (for which Minister Naoto Kan apologized in 1996). **Institutional Consequences** The "Special Measures Act for the Relief of Victims of Hepatitis C Infection from Specific Fibrinogen Products" (2008) was enacted; the MHLW Review Committee's final recommendations (2010) recommended consolidation of authority in PMDA and mandatory information disclosure. Explicitly documenting the monopolization of information and siloed structure as institutional defects made this a turning point in pharmaceutical safety administration governance theory. --- **Key References** - MHLW, "Final Recommendations of the Advisory Committee on How Pharmaceutical Administration Should Be for the Investigation of the Hepatitis C Drug Harm Case and Prevention of Recurrence," 2010 - Morioka N., "Sociology of Drug Harm — Administrative Responsibility over the Fibrinogen Preparation Disaster," *Sociological Review*, Vol. 56, No. 2, 2005 - National Hepatitis C Litigation Defense Team (eds.), *History of the Hepatitis C Drug Harm Trial*, Nihon Hyoronsha, 2009 - Yamazaki K., "Failure of Administrative Information Management in Hepatitis C Drug Harm and PMDA Reform," *Medicine and Society*, Vol. 20, No. 1, 2010 - Leflar, R. B. "Japanese Pharmaceutical Governance and the Hepatitis C Tragedy." *Asian-Pacific Law & Policy Journal*, 14(2), 2013.