📡 AI Distill ── 2026-06-28

Below is a summary of key points when applying generative AI (LLMs) in pharmaceutical and promotional material review. ## Benefits Primary screening in review workflows can be accelerated. AI assists with flagging potential deviations against the Sales Information Provision Activity Guidelines (MHLW notification, 2018; in effect April 2019) and the Standards for Proper Advertising of Pharmaceuticals (revised 2017), cross-checking against the approved scope of indications and efficacy (Pharmaceutical and Medical Device Act (薬機法) Article 66: misleading advertising / Article 68: unapproved-product advertising), and searching past review cases. Variability between reviewers is reduced, and explainability is improved through citation of applicable provisions. ## Risks The greatest concern is hallucination — fabricated citations and misidentified article numbers. Interpretation of the Pharmaceutical and Medical Device Act (薬機法) and GVP is context-dependent; relying solely on an LLM can produce false approvals or missed violations (false negatives). Additional challenges include bias from training data, information leakage when confidential materials are entered as prompts, and opacity of reasoning (accountability under GxP). ## Implementation Considerations LLMs should be limited to an advisory role; final decisions must rest with human reviewers (human-in-the-loop). Use RAG to ground outputs in the company's own SOPs and original regulatory texts, and always include relevant provisions and citations. Ensure validation (CSV/GAMP5, 21 CFR Part 11, data integrity ALCOA+) and audit trails. Design for zero tolerance of false negatives, and carefully review data handling agreements before using external APIs. ## Key References - Ministry of Health, Labour and Welfare (MHLW), "Guidelines on Sales Information Provision Activities for Prescription Drugs" (2018) - Standards for Proper Advertising of Pharmaceuticals (MHLW, Pharmaceutical Compliance Division Chief notification, revised 2017) - ISPE GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems, 2nd ed. (2022) - FDA "Artificial Intelligence in Drug Manufacturing" (Discussion Paper, 2023) - EMA "Reflection paper on the use of AI in the medicinal product lifecycle" (2024) (approx. 590 characters)

## Applying Generative AI in Pharmaceutical and Material Review: Benefits, Risks, and Considerations ### Benefits - **Speed and coverage**: Automates primary screening for compliance with Pharmaceutical and Medical Device Act (薬機法) Article 66 (misleading advertising) and Article 68 (unapproved-product advertising), reducing the burden on reviewers. - **Consistency**: Reduces variation caused by human error. Cross-referencing against MHLW Pharmaceutical Compliance Division Chief notifications and the Standards for Proper Advertising can be standardized. - **Knowledge accumulation**: Integrating past deviation cases (equivalent to MHLW monitoring project reports) via RAG enables rapid precedent lookup. ### Risks - **Hallucination**: Misquotation of article numbers and approved indications. LLMs can generate plausible-sounding but incorrect responses. - **Lag in tracking regulatory changes**: Knowledge cutoffs in training data may cause the model to miss the latest notifications. - **Blurred accountability**: Risk that the final approver shifts responsibility by claiming "the AI said it was fine" — a serious issue in the GxP context. - **Confidential information leakage**: Information leakage when unapproved indications or clinical data are entered into cloud-based LLMs. ### Implementation Considerations - AI determinations should be limited to **primary screening**, with a dual-review structure requiring final judgment by pharmacists or medical information personnel (MR-certified, etc.). - Use retrieval-augmented generation (RAG) to keep regulatory and notification databases current and mitigate the cutoff problem. - Mandate logging of reasoning (audit trails) and establish validation procedures aligned with the spirit of GMP/GVP. - Reference the EU AI Act (2023) high-risk AI provisions and confirm the classification for medical and regulatory use in advance. --- ### Key References - MHLW, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (2019, Bureau of Pharmaceutical and Food Safety) - European Commission, *EU Artificial Intelligence Act* (Regulation 2024/1689, 2024) - FDA, *Artificial Intelligence and Machine Learning in Software as a Medical Device* (2021) - Murdoch B. et al., "Privacy and Artificial Intelligence: Challenges for Protecting Health Information in a New Era." *BMC Medical Ethics* 22, 122 (2021) - MHLW, "Sales Information Provision Activity Monitoring Project" Report (FY2022 edition, Pharmaceutical Compliance Division)

Articles 66–68 of the Pharmaceutical and Medical Device Act (薬機法) regulate "advertising" of pharmaceuticals and other products, with the aim of preventing companies' promotional activities from distorting the judgment of patients and healthcare professionals. **Article 66 (Prohibition of misleading advertising, etc.)** prohibits the advertisement, description, or dissemination of false or exaggerated claims — whether explicit or implied — regarding the name, manufacturing method, efficacy, effectiveness, or performance of pharmaceuticals, medical devices, and similar products. Expressions that create the false impression that a physician has endorsed the efficacy, or content that implies abortion or is obscene, are also prohibited. A key feature is that this provision applies to any person. **Article 67** restricts by cabinet order the advertising of pharmaceuticals for specific diseases such as cancer to audiences other than healthcare professionals, thereby preventing misuse based on laypersons' self-judgment. **Article 68 (Prohibition of advertising unapproved pharmaceuticals, etc.)** prohibits advertising the efficacy, effectiveness, or other attributes of unapproved pharmaceuticals and medical devices. The provision cuts off demand stimulation before safety and efficacy have been confirmed by the national authority. (Note: information-provision obligations are covered separately under the Article 68-2 series.) In practice, the Standards for Proper Advertising of Pharmaceuticals (established in 1980, comprehensively revised in 2017, issued as a notification by the Chief of the MHLW Pharmaceutical Compliance Division) provides concrete judgment criteria and restrains expressions that guarantee maximum efficacy or assert comparative superiority. Violations are subject to corrective orders (Article 72-5), surcharges (introduced by the 2019 amendment, Article 75-5-2), and criminal penalties. Industry self-regulation (JPMA Code, Promotional Code for Prescription Drugs) also serves a complementary role. **Key References** - Pharmaceutical and Medical Device Act (薬機法) Articles 66–68, Article 75-5-2 - MHLW, "Standards for Proper Advertising of Pharmaceuticals" (revised September 29, 2017, Yakuseihatsu 0929 No. 4) - MHLW, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (2018) - Japan Pharmaceutical Manufacturers Association (JPMA), "Promotional Code" - Commentary on the 2019 Pharmaceutical and Medical Device Act amendment (introduction of surcharge system)

## Regulatory Purpose and Operation of Pharmaceutical and Medical Device Act (薬機法) Articles 66–68 ### Purpose The three articles each cover a distinct category of advertising violation: "false," "exaggerated," and "unapproved." They are a public health regulation designed to prevent health harm arising from patients and consumers making self-directed decisions based on incorrect pharmaceutical information; they were carried over from the former Pharmaceutical Affairs Act in the 2014 revision. ### Division of Scope | Article | Prohibited Category | Key Requirement | |------|---------|---------| | **Art. 66** | Misleading advertising | Describing or disseminating "false or exaggerated" claims regarding efficacy, effectiveness, or safety | | **Art. 67** | Advertising restrictions for specific-disease drugs | Prohibition of consumer-directed advertising for cabinet-order-designated diseases such as cancer and diabetes | | **Art. 68** | Prohibition of advertising unapproved products | Prohibition of advertising the name, manufacturing method, efficacy, or performance of items lacking approval or certification | ### Operational Core The MHLW Pharmaceutical Compliance Division Chief notification (2021 revised edition of the "Standards for Proper Advertising of Pharmaceuticals") provides practical standards. The three requirements for an act to constitute "advertising" are: (1) customer inducement, (2) specificity, and (3) recognizability (accumulated through case law and administrative interpretation since the 1971 notification). It has been clarified since 2021 that social media posts and influencer content are also subject to these rules. Violations are subject to corrective orders and surcharges imposed by prefectures (4.5% of sales, applying to Article 66 violations, introduced by the amendment that took effect in August 2021). --- **Key References** - MHLW, "Standards for Proper Advertising of Pharmaceuticals" (1980 Notification No. 10, revised 2021) - MHLW Bureau of Pharmaceutical and Food Safety, "Advertising Regulation under the Pharmaceutical and Medical Device Act" (2021) - Pharmaceutical Affairs Law Study Group, *Commentary on the Pharmaceutical Affairs Act*, Yakuji Nippo (latest edition) - Miyazawa Toshiya, "Legal Structure of Pharmaceutical Advertising Regulation," *Yakuji* Vol. 63 (2021) - PMDA, "Q&A on Advertising Regulations for Pharmaceuticals and Medical Devices" (2022)

A summary of the Sales Information Provision Activity Guidelines (販提G) in 600 characters or fewer: --- **Regulatory Purpose** The full title is "Guidelines on Sales Information Provision Activities for Prescription Drugs." Issued in September 2018 as a notification from the Director-General of the MHLW Bureau of Pharmaceutical and Food Safety, and in effect from April 2019. The background is the 2013 Novartis Diovan (valsartan) clinical research data manipulation scandal, which brought the collusion between company promotion and research, and the distortion of evidence, into the public spotlight. The core of the guidelines is that they supplement Pharmaceutical and Medical Device Act (薬機法) Articles 66 (misleading advertising) and 68 (advertising of unapproved drugs), and bring all "information provision activities" — which blur the line between advertising and non-advertising — under regulatory scope. The aim is to prevent exaggeration of efficacy or safety without evidence, implied promotion of unapproved or off-label uses, and deviations carried out through hard-to-document means such as oral explanations and slides. **Impact on MR Activities** (1) Prohibition of scientifically unfounded comparisons and exaggerations; information is limited to the approved scope. (2) Documentation obligation — materials provided and content of explanations must be retained and made verifiable. (3) Establishment of an internal "review and oversight division" and organizational control through the Sales Information Provision Activity Supervisory Committee. (4) Oral explanations relying on individual MR discretion are restricted; activities shift to a basis of head-office-approved materials. (5) Violations are captured by MHLW's monitoring and surveillance program (case reports with company names anonymized). As a result, the MR role has shifted from "the person who sells" to "the person who accurately conveys appropriate information." **Key References** - MHLW Bureau of Pharmaceutical and Food Safety Director-General notification, "Guidelines on Sales Information Provision Activities for Prescription Drugs" (Yakuseihatsu 0925 No. 1, September 25, 2018) - MHLW, "Q&A on the Sales Information Provision Activity Guidelines" (2019 onward, with successive revisions) - MHLW, "Sales Information Provision Activity Monitoring Project Reports" (annual) - Pharmaceutical and Medical Device Act (薬機法) Articles 66 and 68 - Shirai Masaki et al., commentary related to *The Diovan Case and the Clinical Research Act* (2014 onward)

## Sales Information Provision Activity Guidelines: Regulatory Purpose and Impact on MR Activities ### Regulatory Purpose Issued in September 2018 as a notification from the Director-General of the MHLW Bureau of Pharmaceutical and Food Safety. The background is the collapse of trust in pharmaceutical information triggered by the Novartis valsartan clinical data misconduct case (2013). The core concern is "distortion of scientific evidence in favor of sales promotion," and the guidelines explicitly prohibit the implied suggestion of off-label indications and the circulation of materials that exaggerate efficacy. An operational notification issued under the name of the Pharmaceutical Compliance Division Chief provides detailed practical standards. ### Key Changes in MR Activities **Clarification of the obligation to provide appropriate information**: MRs may provide only information based on the latest package insert and Risk Management Plan (RMP). Comparative superiority claims lacking scientific basis are prohibited. **Stricter material review**: The establishment of an internal review system (multi-professional review involving medical, pharmaceutical, regulatory, and legal functions) was effectively mandated, along with post-distribution monitoring. **Visibility of deviation cases**: From FY2019 onward, MHLW has published company-specific deviation cases through the Sales Information Provision Activity Monitoring Program. As the risk of administrative guidance became concrete, corporate investment in compliance accelerated. --- **Key References** - MHLW, "Guidelines on Sales Information Provision Activities for Prescription Drugs," Yakuseihatsu 0925 No. 1 (September 25, 2018) - MHLW, "Sales Information Provision Activity Monitoring Project Reports," annual editions (2020–) - Japan Pharmaceutical Manufacturers Association (JPMA), "Explanatory Commentary on Standards for Proper Advertising of Prescription Drugs" (revised 2023) - Pharmaceutical and Medical Device Act (薬機法) Article 68 (prohibition of advertising unapproved drugs) and Article 66 (prohibition of misleading advertising) - Yamaguchi Toru et al., "International Comparison of Pharmaceutical Information Provision Regulations," *Drug Information Journal*, 2020;22(1)

The trajectory from the Nuremberg Code to the Declaration of Helsinki is a history in which the focus of research-subject protection shifted from "individual consent" to "institutional prior review." ## Current State (approx. 590 characters) The **Nuremberg Code** (1947) emerged from the verdicts of the Doctors' Trial, which judged Nazi human experimentation, and placed "the voluntary consent of the human subject is absolutely essential" as its first principle. However, the ten items were produced by a tribunal rather than by physicians, and their binding force on clinical medicine was limited. The World Medical Association (WMA) reframed these principles as a self-regulatory norm for physicians in the **Declaration of Helsinki** (adopted at the 18th WMA General Assembly in Helsinki, 1964). It distinguished between therapeutic and non-therapeutic research and, while premising that human experimentation is indispensable to medical progress, gave priority to subject welfare over scientific or social benefit. Subsequent revisions established the current framework. The **1975 Tokyo revision** introduced prior review by independent ethics committees (IRBs/research ethics committees) and research protocols, shifting from after-the-fact conscience to advance institutional review. The **2000 Edinburgh revision** strengthened restrictions on placebo use and disclosure of conflicts of interest. The **2008 Seoul revision** and **2013 Fortaleza revision** added provisions on post-trial access guarantees, mandatory publication of results and database registration, compensation for harm, and the use of biological specimens and data. The current state rests on three pillars: (1) informed consent, (2) independent ethics review, and (3) risk-benefit assessment. These connect to the 1979 **Belmont Report** (respect for persons, beneficence, justice), the CIOMS Guidelines, and ICH-GCP (1996), and have been translated into national law (in Japan, the Ethical Guidelines for Medical and Biological Research Involving Human Subjects). Protection of vulnerable populations and the fairness of global clinical trials are current points of debate. ## Key References - World Medical Association, *Declaration of Helsinki* (2013, Fortaleza revision) - *The Nuremberg Code* (1947), in *Trials of War Criminals before the Nuremberg Military Tribunals* - National Commission, *The Belmont Report* (1979) - CIOMS, *International Ethical Guidelines for Health-related Research Involving Humans* (2016) - Ezekiel J. Emanuel 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 **Turning point: 1947** The Nuremberg Code was established in the wake of the Nazi Doctors' Trial. It explicitly stated that "voluntary consent is absolutely essential," establishing the prototype of subject protection. **Institutionalization: 1964** The World Medical Association adopted the Declaration of Helsinki. Informed consent, prior review by independent ethics committees, and special consideration for vulnerable populations were codified. **Current state (2013, 7th revision)** - Conditions for placebo-controlled trials tightened (in principle prohibited when an effective treatment exists) - Post-trial access guarantees for research participants made mandatory - Transparency requirements for registration and publication of results strengthened - Implemented in international regulation through alignment with ICH-GCP (E6 guideline) The three principles — respect for persons, beneficence, and justice — established in the Belmont Report (1979) function as the common foundation of current regulation and have been codified in national GCP regulations in each country (in Japan, the GCP Ordinance, 1997). --- **Key References** - Nuremberg Military Tribunals (1947). *Trials of War Criminals Before the Nuremberg Military Tribunals*, Vol. 2 (The Medical Case). - World Medical Association (2013). Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. *JAMA*, 310(20), 2191–2194. - National Commission for the Protection of Human Subjects (1979). *The Belmont Report*. DHEW Publication No. (OS) 78-0012. - ICH (2016). *Guideline for Good Clinical Practice E6(R2)*. International Council for Harmonisation. - MHLW (1997). Ministerial Ordinance on Standards for the Conduct of Clinical Trials on Pharmaceutical Products (GCP Ordinance), Ministry of Health and Welfare Ordinance No. 28 of 1997.

Pharmaceutical company ethics centers on the structural tension of "being a for-profit enterprise while handling human life and health." In the mainstream understanding, pharmaceuticals differ from ordinary commodities in that information asymmetry lies on the demand side — patients lack specialist knowledge, making market mechanisms function poorly (the health economics insight of Kenneth Arrow, 1963). This creates a collision between profit maximization and the public nature of healthcare. Historically, the 1962 Kefauver-Harris Amendment — enacted in response to the thalidomide disaster — mandated proof of efficacy, cementing the recognition that corporate self-regulation alone is insufficient. Since the 1990s, the management of conflicts of interest (COI) has become the central issue, with progress on transparency in payments to physicians (US Physician Payments Sunshine Act, 2010), clinical trial registration (mandatory on ClinicalTrials.gov from 2007), and regulation of ghostwriting and selective publication (publication bias). Within the framework of industrial ethics, Beauchamp and Childress's four principles of bioethics (autonomy, non-maleficence, beneficence, justice) are applied to corporate activities, with "justice (access and pricing)" being a particularly prominent issue. High drug prices, access in developing countries (2001 Doha Declaration and TRIPS), and the profitability of rare diseases are representative examples. The current consensus points toward combining self-regulation (IFPMA Code) with legal enforcement and transparency, and managing — rather than eliminating — conflicts of interest. The reconciliation of profit and medicine is understood as the "institutionalization of trust" through regulation, disclosure, and third-party verification. **Key References** - Beauchamp TL, Childress JF, *Principles of Biomedical Ethics* (8th ed., 2019) - Arrow KJ, "Uncertainty and the Welfare Economics of Medical Care" (1963) - Angell M, *The Truth About the Drug Companies* (2004) - IFPMA, "Code of Practice" (revised 2019) - US Physician Payments Sunshine Act (2010)

## Pharmaceutical Company Ethics: The Tension Between Profit and Medicine **Core structural tension** Pharmaceutical companies simultaneously bear fiduciary duties to shareholders and therapeutic obligations to patients. This dual responsibility was made explicit by the obligation to prove efficacy and safety in advance — an obligation institutionalized by the US Kefauver-Harris Amendment following the 1962 thalidomide disaster. **Principal ethical disputes** - **Access and pricing**: In the 2001 South Africa HIV drug lawsuit, 39 Big Pharma companies effectively conceded. The discrepancy with the WHO Essential Medicines Programme (established 1977) persists to this day. - **Selective publication of research**: In 2012, GlaxoSmithKline settled for $3 billion over the concealment of pediatric depression trial data for Paxil. The *BMJ* and others documented this as a systemic problem of publication bias. - **Disease creation**: Moynihan et al. coined the term "disease mongering" (2002); the market expansion for sexual dysfunction and attention deficit disorder are typical examples. - **Conflicts of interest**: Multiple RCTs have confirmed that honoraria and lecture fees paid to physicians influence prescribing behavior. The US Sunshine Act mandated disclosure in 2013. **Current mainstream understanding** "Procedural fairness in research ethics" alone — built on an extension of Bradford Hill's criteria for causation — is insufficient. The consensus in industrial ethics research (Angell 2004; Light & Lexchin 2012) holds that substantive ethical evaluation including **distributive justice (who can access medications)** is necessary. --- **Key References** - Angell, M. (2004). *The Truth About the Drug Companies*. Random House - Light, D.W. & Lexchin, J.R. (2012). Pharmaceutical research and development: what do we get for all that money? *BMJ*, 345, e4348 - Moynihan, R. & Cassels, A. (2005). *Selling Sickness*. Nation Books - US Dept. of Justice (2012). GlaxoSmithKline Settlement Press Release (USD $3 billion settlement) - WHO (2023). *Essential Medicines List*, 23rd edition

The decision-making structure of pharmaceutical CEOs has shifted — following a series of scandals since the 2000s (Merck's voluntary Vioxx recall in 2004, the GSK $3 billion settlement in 2012) — from reactive response to enterprise risk management (ERM). The essentials can be condensed into three points. First, **integrated risk recognition**. Built on the COSO-ERM framework (established 2004, revised 2017), risks in development, manufacturing, regulatory affairs, and promotion are embedded in the corporate value-creation process rather than separated from financial metrics. The modern hallmark is treating risk as a strategic variable rather than something to be avoided. Second, **structural internalization of compliance**. In the United States, the 1991 Federal Sentencing Guidelines and the 2003 OIG Compliance Guidance require "effective programs," and Corporate Integrity Agreements (CIAs) — which extend liability for violations to individual executives — have become standard. CEOs are expected to set the "tone at the top," and the standard design gives the independent Chief Compliance Officer (CCO) a direct reporting line to the board of directors. Third, **self-governance against psychological and behavioral biases**. Confronting the structural reality that conflicts of interest, groupthink, and optimism bias lead to the undervaluing of safety signals, companies monitor decision-making through multiple layers: whistleblower protection, a speak-up culture, and the three-lines-of-defense model. In Japan, the JPMA "Corporate Conduct Charter" and "Code of Practice" provide the regulatory framework. In short, the essentials lie in integrating risk into value creation (ERM), ensuring compliance through systems (independent CCO, three lines of defense), and compensating for the weaknesses of human judgment through structural design. **Key References** - COSO, *Enterprise Risk Management — Integrating with Strategy and Performance* (2017) - U.S. DOJ/OIG, *Compliance Program Guidance for Pharmaceutical Manufacturers* (2003) - D. Kahneman, *Thinking, Fast and Slow* (2011) - Japan Pharmaceutical Manufacturers Association (JPMA), *Code of Practice* (2013, with ongoing revisions) - M. Bazerman & A. Tenbrunsel, *Blind Spots* (2011)

## Pharmaceutical Company CEO Risk Management and Compliance-Based Management **Structural features** The modern pharmaceutical CEO operates on the premise of the "three-lines-of-defense model." Business units (first line), risk and compliance functions (second line), and internal audit (third line) are functionally separated, and the CEO embodies the tone at the top at the apex. **Institutional foundations of ERM** The COSO ERM 2017 revision is established as the industry standard. Pfizer, J&J, and Novartis have placed **risk committees** directly under the board of directors and disclose material risks quarterly. FDA's 21 CFR Part 11 and ICH Q10 also serve as reference frameworks for internal controls. **Turning points in compliance** The 2013 GlaxoSmithKline (GSK) China bribery case (fine of approximately CNY 3 billion) and J&J's 2012 Risperdal improper promotion settlement (approximately USD $2.2 billion) provided the impetus for the entire industry to **embed compliance into revenue processes**. Since then, an independent reporting line for the Chief Compliance Officer (CCO) has become standard. **Modern essentials** - Integration of supply chain and cyber risks into ERM - Alignment with ESG disclosure obligations (EU CSRD, scope expanded in 2024) - Development of ethical AI utilization guidelines (clinical trial data analysis domain) --- **Key References** - COSO, *Enterprise Risk Management — Integrating with Strategy and Performance* (2017) - FDA, *Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations* (2006) - U.S. DOJ, *GlaxoSmithKline LLC Plea Agreement* (2012) — legal document for the $3 billion settlement - Kaplan, R.S. & Mikes, A., "Managing Risks: A New Framework," *Harvard Business Review* (May 2012) - PhRMA, *Code on Interactions with Healthcare Professionals* (revised 2019)

The distinctive features of life-related industries (pharmaceuticals, healthcare, food) are framed in corporate governance theory as a "fiduciary structure." **Information asymmetry** — As formulated by Kenneth Arrow (1963, "Uncertainty and the Welfare Economics of Medical Care"), the supply side monopolizes specialized knowledge and safety data, and patients and consumers cannot evaluate quality in advance. Because market self-regulation fails, external regulation (FDA/PMDA, GMP/GCP, Pharmaceutical and Medical Device Act (薬機法)) and professional ethics provide a complement. This corresponds to the concept of "credence goods." **The slowness of trust accumulation** — Evaluating safety and efficacy requires long-term clinical trials and post-marketing surveillance (pharmacovigilance), and trust forms only over time. This is a textbook example of the "social license to operate" described by OECD Corporate Governance Principles and stakeholder theory (Freeman 1984). **The speed with which it is lost** — Because of the asymmetry, a single instance of concealment or falsification collapses trust instantly. As demonstrated by thalidomide (around 1960, Frances Kelsey), the Diovan data misconduct (2013, Novartis), and the Vioxx recall (2004, Merck), the damage is irreversible and spreads across the entire company and industry. The mainstream understanding holds that in such industries, "governance that does not damage trust" — incorporating regulatory compliance, transparency, and data integrity (ALCOA principles) — is a precondition for long-term corporate value, more important than short-term optimization of shareholder value. **Key References** - Arrow, K. J. (1963). "Uncertainty and the Welfare Economics of Medical Care," *American Economic Review* - Freeman, R. E. (1984). *Strategic Management: A Stakeholder Approach* - OECD (2023). *G20/OECD Principles of Corporate Governance* - Akerlof, G. (1970). "The Market for Lemons," *QJE* (information asymmetry) - Japan Pharmaceutical Manufacturers Association (JPMA), *Corporate Conduct Charter and Compliance Program Guidelines* (approx. 560 characters)

## The Distinctive Features of Life-Related Industries: Mainstream Understanding in Governance and Ethics **Information asymmetry** — As Kenneth Arrow formalized in the healthcare market in 1963, the supply side (pharmaceutical and medical device companies) holds an overwhelming monopoly on quality and risk information. Structural asymmetry exists not only between patients and physicians, but also between companies and regulatory authorities — this asymmetry is the institutional rationale for disclosure obligations and post-marketing surveillance (PMS). **Trust accumulation** is long-term and cumulative. As Freeman's (1984) stakeholder theory shows, the relational capital built with patients, healthcare professionals, and regulators forms the actual substance of corporate value. The accumulation of approvals, safety records, and academic contributions functions as the "collateral" for trust. **The speed with which trust is lost** is asymmetrically fast. As Barber (1983) points out in his theory of trust, trust is constructed through repeated confirmation of expectations, but a single incident is enough to destroy it. The 2004 Vioxx market withdrawal (Merck) and the 2012 Kaketsuken misconduct (Japan) are textbook examples of decades of accumulation collapsing within months. The EU's 2010 GVP regulatory strengthening stands in the same context. In contemporary corporate governance theory, the mainstream direction — as reflected in the 2018 Corporate Governance Code revision — is to incorporate these factors into board-level accountability as "non-financial risks," with trust capital being increasingly made explicit under the S (social) axis of ESG disclosure. --- **Key References** - Arrow, K.J. (1963). "Uncertainty and the Welfare Economics of Medical Care." *American Economic Review*, 53(5). - Freeman, R.E. (1984). *Strategic Management: A Stakeholder Approach*. Pitman. - Barber, B. (1983). *The Logic and Limits of Trust*. Rutgers University Press. - EMA (2010). *Guideline on Good Pharmacovigilance Practices (GVP)*. EMA/541760/2011. - Financial Services Agency (2018). *Corporate Governance Code (Revised Edition)*.

Freud, Jung, and Adler all proposed frameworks — each from a different angle — for how human beings understand themselves, during the 1900s to 1930s. **Freud** (Sigmund Freud, 1856–1939) founded psychoanalysis and conceived of self-understanding as "making the unconscious conscious." He set out the topographic model of conscious, preconscious, and unconscious, and later the structural model of id, ego, and superego (1923, *The Ego and the Id*), placing the verbal articulation of repressed infantile drives and conflicts through free association and dream analysis at the core of therapy and self-insight. **Jung** (Carl Gustav Jung, 1875–1961) broke from Freud around 1913 and founded analytical psychology. In addition to the personal unconscious, he posited a collective unconscious shared by all humanity, along with archetypes (persona, anima/animus, shadow, etc.), and defined self-understanding as the lifelong process of integrating consciousness with the unconscious — "individuation." His typology of introversion/extraversion became the source of later personality type systems (such as the MBTI). **Adler** (Alfred Adler, 1870–1937) founded individual psychology. Viewing human beings as an indivisible whole, he understood self-understanding through "compensation for inferiority feelings," "lifestyle," "teleology," and "social interest." His emphasis on purpose over cause is a defining characteristic. In terms of influence on modern psychology: Freud's concept of the unconscious persists in dynamic psychotherapy and cultural theory; Jung's typology informs personality assessments; and Adler's teleological approach and emphasis on interpersonal relationships connects to cognitive behavioral therapy, positive psychology, and recent popular psychology (*The Courage to Be Disliked*). All three have been criticized for limited empirical support, yet they laid the foundations for introspection and clinical psychology. **Key References** - Freud, S., *The Ego and the Id* (1923) - Jung, C. G., *Psychological Types* (1921) - Adler, A., *Understanding Human Nature* (1927) - Ellenberger, H. F., *The Discovery of the Unconscious* (1970) - Gay, P., *Freud: A Life for Our Time* (1988)

## The "Self-Understanding" Frameworks of Three Major Psychologists and Their Modern Influence **Freud (1856–1939)** proposed the three-layer structure of unconscious, preconscious, and conscious, along with the id-ego-superego model. He defined self-understanding as "making repressed drives conscious" and operationalized introspection through free association. In contemporary psychology his ideas are carried forward in the "schema" concept of cognitive behavioral therapy (CBT) and neuropsychoanalysis (Solms, 2021). **Jung (1875–1961)** introduced the collective unconscious and archetypes (shadow, anima/animus, Self), and positioned the "individuation process" as a lifelong, developmentally oriented form of self-realization. He influenced contemporary narrative therapy and personality typology (the theoretical ancestor of the MBTI), and also became a foundation of transpersonal psychology. **Adler (1870–1937)** centered his account on "compensation for inferiority feelings" and "social interest," arguing for self-understanding through teleological and subjective meaning-making. His work connects directly to contemporary positive psychology (Seligman), Acceptance and Commitment Therapy (ACT), and the coaching domain. What the three have in common is the systematization of introspection and its connection to therapeutic application. Contemporary psychology has refined these ideas empirically and inherited them critically. --- **Key References** - Freud, S. (1923). *Das Ich und das Es*. Internationaler Psychoanalytischer Verlag. - Jung, C. G. (1959). *The Archetypes and the Collective Unconscious* (CW 9i). Princeton UP. - Adler, A. (1927). *Menschenkenntnis*. Hirzel. - Solms, M. (2021). *The Hidden Spring: A Journey to the Source of Consciousness*. Profile Books. - Ansbacher, H. L., & Ansbacher, R. R. (Eds.) (1956). *The Individual Psychology of Alfred Adler*. Basic Books.

The Dunning-Kruger effect originates from a 1999 study by Justin Kruger and David Dunning at Cornell University. In tests of logic, grammar, and humor, they observed that lower-performing participants tended to overestimate their own performance while higher-performing participants slightly underestimated theirs. At the core is the "metacognitive blind spot" — the "dual burden" hypothesis, which holds that the ability required to perform a task is the same ability required to accurately evaluate one's own performance. In other words, a person who is poor at something lacks the very criteria needed to recognize that fact. However, in the current mainstream understanding, this classical interpretation has been substantially revised. First, statistical criticism: Edward Nuhfer and Gilles Gignac & Marcin Zajenkowski showed that a considerable portion of the observed pattern can be explained by regression to the mean and measurement error, and that the same characteristic graph pattern emerges even from random data. Second, there is confusion with the "better-than-average effect" (self-enhancement bias): the overestimation by lower performers reflects not only a metacognitive deficit, but also the general tendency for everyone to rate themselves above average. The current standard is a cautious interpretation: (1) the effect is real but the effect size is smaller than originally claimed; (2) metacognitive deficiency is only one contributing factor, confounded by regression effects, self-enhancement motivation, and task difficulty. The finding that even low performers improve their self-assessments with specific feedback and training has high replicability and remains as an educational implication. Key References - Kruger, J. & Dunning, D. (1999). "Unskilled and Unaware of It." *J. Pers. Soc. Psychol.* - Dunning, D. (2011). "The Dunning–Kruger Effect." *Adv. Exp. Soc. Psychol.* - Gignac, G. & Zajenkowski, M. (2020). "The Dunning-Kruger effect is (mostly) a statistical artefact." *Intelligence.* - Nuhfer, E. et al. (2017). "How Random Noise … Mimics the Dunning-Kruger Effect." *Numeracy.* - Krueger, J. & Mueller, R. A. (2002). "Unskilled, unaware, or both?" *J. Pers. Soc. Psychol.*

## The Dunning-Kruger Effect and the Metacognitive Blind Spot Published in 1999 by David Dunning and Justin Kruger of Cornell University in the *Journal of Personality and Social Psychology*, the study experimentally demonstrated that people with lower ability tend to overestimate their own performance. The root cause is **metacognitive deficiency** — because the ability to evaluate a particular skill overlaps with the skill itself, those who are unskilled cannot recognize their own lack of skill. Re-examinations in the 2020s have seen Nuhfer et al. (2016) and Krüger & Heck (2020) argue that the effect is "merely a statistical artifact (regression to the mean)." On the other hand, Ehrlinger et al. (2008) confirmed the effect in replications with different tasks, and the current understanding has been refined to "an ability × task-context-dependent phenomenon." The metacognitive blind spot refers to the tendency to underestimate one's own reasoning biases relative to others (Scopelliti et al., 2015). **External feedback** and **elaborative retrieval** are considered effective for achieving accurate self-evaluation. --- **Key References** - Kruger, J. & Dunning, D. (1999). *Unskilled and unaware of it.* JPSP, 77(6), 1121–1134. - Ehrlinger, J. et al. (2008). *Why the unskilled are unaware.* Organizational Behavior and Human Decision Processes, 105(1), 98–121. - Nuhfer, E. et al. (2016). *Random number simulations reveal how random noise affects the measurements.* Numeracy, 9(1). - Krüger, T. & Heck, D.W. (2020). *Putting the Dunning–Kruger effect "to the test".* Intelligence, 80, 101452. - Scopelliti, I. et al. (2015). *Bias blind spot: Structure, measurement, and consequences.* Management Science, 61(10), 2468–2486.

## Critical Reassessment of Self-Esteem and Related Concepts Baumeister, Campbell, Krueger, and Vohs (2003) scrutinized thousands of studies and concluded that high self-esteem is **not the cause but the consequence (a correlation)** of academic achievement, occupational success, and positive interpersonal relationships. Educational policies following California's 1986 "Task Force to Promote Self-Esteem" (unconditional praise) showed little effect, and the authors noted that elevated self-esteem can in some cases be linked to narcissism and aggression (defensive violence when threatened). After this, interventions aimed directly at boosting "self-evaluation as a feeling" were reassessed. What emerged as an alternative was Bandura's **self-efficacy (1977/1997)** — a domain-specific judgment that one "can perform a specific task." Rather than global self-worth, it focuses on perceived capability, and is a stronger predictor of behavior. Neff's **self-compassion (2003)**, by contrast with self-esteem's dependence on comparison with others and conditions of success (which make it unstable), provides stable self-acceptance through self-kindness, common humanity, and mindfulness even in failure. Because it requires neither comparison nor a sense of superiority, it is also less prone to connection with aggression. In summary: self-efficacy = "Can I do this?" (capability expectation); self-esteem = "Am I worthwhile?" (evaluation); self-compassion = "How do I treat myself when I fail?" (acceptance). The latter two are weakly correlated but conceptually independent, and in recent years self-efficacy and self-compassion are considered more adaptive than unstable self-esteem. **Key References** - Baumeister, R.F., Campbell, J.D., Krueger, J.I., & Vohs, K.D. (2003). *Psychological Science in the Public Interest*, 4(1). - Bandura, A. (1997). *Self-Efficacy: The Exercise of Control*. Freeman. - Neff, K.D. (2003). *Self and Identity*, 2(2), 85–101. - Neff, K.D. & Vonk, R. (2009). *Journal of Personality*, 77(1).

Baumeister et al. (2003, *Psychological Science in the Public Interest*) concluded that self-esteem interventions have virtually no effect on academic performance, occupational outcomes, interpersonal relationships, or health, fundamentally shaking the "self-esteem boom" of the 1970s–90s. Evidence accumulated that high self-esteem correlates with narcissism, aggression, and unrealistic optimism, and the causal direction was repeatedly shown to be reversed (success leads to high self-esteem, not the other way around). In response to this critique, two alternative constructs emerged. **Self-efficacy (Bandura, 1977–)** is "the belief that one can perform a specific task." It is task-specific, a strong predictor of behavior, and is distinct from the global sense of worth in self-esteem. Intervention effects are also more replicable. **Self-compassion (Neff, 2003–)** consists of three components — self-kindness, common humanity, and mindfulness — and avoids the problem in self-esteem of easily falling into "conditional value through comparison with others." Neff & Vonk (2009) showed that self-compassion is superior to self-esteem in emotional stability and avoidance of narcissism. Leary et al. (2007) confirmed similar advantages within the sociometer theory framework. The current mainstream has shifted from interventions targeting self-esteem to **strengthening self-efficacy through acquisition of concrete skills** and **the practice of self-compassion in the face of failure**. --- **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. - 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. - Leary, M. R. et al. (2007). Self-compassion and reactions to unpleasant self-relevant events. *Journal of Personality and Social Psychology, 92*(5), 887–904.

A genealogical account of the structure of self-criticism (excessive self-blame) through five theories. **Freud (1923, *The Ego and the Id*) — the superego**: The earliest theoretical formulation of self-criticism. The psychic agency formed by the internalization of parental prohibitions during the Oedipal period punishes the ego as "conscience," and the resulting tension becomes guilt. He located the source of criticism in developmental history and the unconscious. **Horney (1950, *Neurosis and Human Growth*) — "the tyranny of the should"**: An idealized self-image tyrannically dominates the actual self with imperatives about how one "should" be. She reframed Freud's internal agency as a self-alienation arising from interpersonal anxiety. **Ellis (from 1955, REBT) — irrational beliefs**: Formulated irrational beliefs centered on "must/should" thinking as the cognitive cause of emotional disturbance (ABC theory). He derived self-downing from irrational absolute demands. **Beck (from the 1960s, cognitive therapy) — cognitive distortions**: Systematized the "negative automatic thoughts" of depression. He operationally described how systematic distortions such as all-or-nothing thinking, overgeneralization, and personalization produce self-criticism, making them testable. **Brown (from 2006, shame research)**: Distinguished between guilt (evaluation of an act) and shame (denial of one's worth as a person). Through qualitative research, she showed that shame is the emotional core of chronic self-criticism, and that empathy and connection serve as the antidote. The genealogy traces a shift from introspective and speculative accounts to empirical and intervention-ready descriptions: unconscious agency (Freud) → interpersonal alienation (Horney) → verbal irrational beliefs (Ellis) → operationalization of cognitive distortions (Beck) → shame as emotion (Brown). **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. (1979). *Cognitive Therapy of Depression*. - Brown, B. (2012). *Daring Greatly*.

## The Structure of Self-Criticism: Theoretical Genealogy **Freud (1923)** — the superego formulated the prototype of self-criticism as the internalization of parental and social prohibitions. The stronger the punitive superego, the deeper the neurotic guilt. **Horney (1950)** reinterpreted this as the "tyranny of the should." She pointed out that the compulsive pursuit of an idealized self-image corrodes the authentic self. **Ellis (1955, founder of REBT)** operationalized this within the framework of "irrational beliefs." He organized it as the proposition that absolute imperatives such as "I must be perfect" and "if I am not approved of, I am worthless" drive self-criticism. **Beck (1960s, cognitive therapy)** refined this into measurable "cognitive distortions." He showed that at the level of automatic thoughts and schemas, "all-or-nothing thinking" and "overgeneralization" structure self-criticism. **Brown (2010s)** examined these in an integrated manner through shame research. She demonstrated empirically that "shame" is an attack on the self as such and has neurologically and socially distinct functions from guilt (criticism of an action). --- **Key References** - Freud, S. (1923). *The Ego and the Id*. Hogarth Press. - 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. - Brown, B. (2010). *The Gifts of Imperfection*. Hazelden.

A summary of the genealogy connecting Buddhist thought and contemporary psychotherapy. --- ## The Influence of the Middle Way, Emptiness, and Dependent Origination on MBSR and ACT Jon Kabat-Zinn founded MBSR in 1979 at the University of Massachusetts Medical Center. He studied Zen (Rinzai and Soto) and Theravada Vipassana, and secularized the Buddhist concept of right mindfulness (sati), redefining it as "non-judgmental, present-moment attention." Here, Nāgārjuna's (2nd–3rd century) emptiness (śūnyatā) and dependent origination (pratītyasamutpāda) support the attitude of observing thoughts and emotions as dependently arisen phenomena that arise and cease, rather than as fixed entities. The Middle Way (Madhyamā Pratipad), which rejects both indulgence and asceticism, overlaps with MBSR's fundamental stance of observing experience without either suppression or absorption. ACT (Steven C. Hayes, from the 1980s) is grounded in Relational Frame Theory, but "defusion" and "self-as-context" are Nāgārjunian in that they dismantle the reification of self and thought through the logic of emptiness. "Acceptance" can be understood as the clinical translation of the Middle Way's stance of non-avoidance and non-attachment. Both therapies secularized and operationalized Buddhist liberation doctrine, converting it into evidence-based interventions. (approx. 540 characters) **Key References** - Kabat-Zinn, J. (1990). *Full Catastrophe Living* - Hayes, S.C., Strosahl & Wilson (1999/2012). *Acceptance and Commitment Therapy* - Garfield, J.L. (1995). *The Fundamental Wisdom of the Middle Way* (annotated translation of Nāgārjuna's *Mūlamadhyamakakārikā*) - Gethin, R. (1998). *The Foundations of Buddhism* - Williams & Kabat-Zinn (eds.) (2013). *Mindfulness: Diverse Perspectives on its Meaning, Origins and Applications*

## Buddhist Philosophy and Its Influence on MBSR and ACT **The core of the Middle Way, emptiness, and dependent origination** In the *Mūlamadhyamakakārikā*, Nāgārjuna (2nd–3rd century) argued that phenomena have no fixed, independent existence (emptiness/śūnyatā) and arise through mutual interdependence (dependent origination/pratītyasamutpāda). The Middle Way is the epistemological stance of departing from the two extremes of "permanence" and "annihilation." **MBSR (1979, Kabat-Zinn)** "Non-judgmental attention to the present moment" secularizes the dependent origination insight that "the self is relational and fluid." The dismantling of a fixed self-conception is considered the mechanism for relief from chronic pain and stress. **ACT (Hayes, 1990s)** "Defusion" and "Self-as-Context" correspond to an operational definition of emptiness. The point of not identifying thoughts and emotions as fixed entities is structurally aligned with Nāgārjuna's concept of "no-self-nature" (asvabhāva). Hayes explicitly acknowledges Buddhist influence. --- **Key References** - Nāgārjuna (c.150–250 CE). *Mūlamadhyamakakārikā* (Jay Garfield tr., 1995) - Kabat-Zinn, J. (1990). *Full Catastrophe Living*. Delacorte Press. - Hayes, S.C., Strosahl, K., & Wilson, K.G. (1999). *Acceptance and Commitment Therapy*. Guilford Press. - Williams, J.M.G., & Kabat-Zinn, J. (2011). Mindfulness: Diverse perspectives. *Contemporary Buddhism*, 12(1), 1–18. - Garfield, J.L. (2015). *Engaging Buddhism: Why It Matters to Philosophy*. Oxford University Press.

## Core Concepts of Adlerian Psychology and Its Reassessment in Japan The **separation of tasks** (German: Aufgabentrennung) refers to the attitude of distinguishing between one's own tasks and others' tasks, using the criterion of who ultimately bears the consequences of a given choice. It argues for "not living to meet others' expectations" and that "how one is evaluated by others is others' task," teaching liberation from the need for approval. **Social interest** (German: Gemeinschaftsgefühl; English: social interest) is the concept that Alfred Adler (1870–1937) placed as the culmination of individual psychology (Individualpsychologie). It refers to the sense of viewing others as comrades and finding one's place (sense of belonging) in contribution to the community. It is organized as a trinity of "self-acceptance, trust in others, and contribution to others." The separation of tasks is the starting point; social interest is the destination. Ichiro Kishimi and Fumitake Koga's *The Courage to Be Disliked* (Diamond Publishing, 2013), which simplified these concepts in the form of a dialogue between a philosopher and a young man, became a bestseller in Japan with over two million copies sold. A sequel, *The Courage to Be Happy*, was published in 2016. By contrasting Adler's teleology against Freud's causal theory, and through stimulating propositions such as "all problems are interpersonal problems" and "the denial of trauma," the book drove Adler's reassessment. However, academic circles have also raised criticisms regarding the interpretation of original texts and the oversimplification of "denial of trauma." Adler had long been called "the forgotten giant," but this book was the decisive turning point in his restoration in Japan. **Key References** - Kishimi, I. & Koga, F., *The Courage to Be Disliked*, Diamond Publishing, 2013 - Kishimi, I. & Koga, F., *The Courage to Be Happy*, Diamond Publishing, 2016 - Adler, A. (tr. Kishimi, I.), *Lectures on Individual Psychology*, Arte, 1996 - Noda, T., *Speaking on Adlerian Psychology*, Sogensha - Ansbacher, H. L. & Ansbacher, R. R., *The Individual Psychology of Alfred Adler*, 1956

## Reassessment of Adlerian Psychology Alfred Adler (1870–1937) was a founder of depth psychology alongside Freud and Jung. The two central concepts of individual psychology are the "separation of tasks" and "social interest" (Gemeinschaftsgefühl). The **separation of tasks** is a practical principle of asking "whose task is this?" and concentrating on one's own tasks without intervening in others'. It holds that the majority of interpersonal conflict stems from the "mixing of tasks." **Social interest** is the sense of belonging to and desire to contribute to humanity and the universe as a whole, and is considered an indicator of psychological health. The separation of tasks is the prerequisite for social interest — there is no genuine cooperation without independence. In 2013, Ichiro Kishimi and Fumitake Koga's *The Courage to Be Disliked* (Diamond Publishing) became a bestseller with over two million copies sold, and Adler was rediscovered in Japan as "the third psychologist." Its spread in the self-help context reflects a natural fit with Japanese society's strong needs for approval and conformity pressure. At the same time, criticisms from academic psychology — "thin empirical support" and "limits of clinical application" — remain persistent. --- **Key References** - Adler, A. (1927). *Menschenkenntnis*. Hirzel. (Japanese translation: *Ningen Chino Shinrigaku*) - Adler, A. (1933). *Der Sinn des Lebens*. Passer. (Japanese translation: *Jinsei no Imi no Shinrigaku*) - Kishimi, I. & Koga, F. (2013). *The Courage to Be Disliked*. Diamond Publishing. - Mosak, H. H., & Maniacci, M. (1999). *A Primer of Adlerian Psychology*. Brunner/Mazel. - Maeda, S. (1985). "Clinical significance of individual psychology." *Japanese Journal of Clinical Psychology*, 3(1).

A summary of the regulatory and institutional lessons of the 1937 Sulfanilamide Elixir Disaster: --- In the autumn of 1937, S.E. Massengill Company of Tennessee used the highly toxic solvent diethylene glycol (an antifreeze component) — at the direction of chemist Harold Watkins — to create a palatable liquid formulation of the antibacterial drug sulfanilamide. Released without safety testing, it killed an estimated 105 people, primarily children, from renal failure. The Pure Food and Drugs Act of 1906 could only regulate adulteration and mislabeling; the company could only be prosecuted on the grounds that the product labeled "elixir" was not in fact a true ethanol solution (a labeling violation). The FDA had no legal authority to require pre-market safety data. This disaster was the decisive impetus for the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938. The core lesson was the institutionalization of the concept of "placing the burden of pre-market safety proof on the manufacturer." New drugs were required to submit safety data to the FDA before marketing (the prototype of the NDA), and governmental prior review was codified for the first time. This is positioned as the starting point of the pre-market regulatory paradigm, which continued through the 1962 Kefauver-Harris Amendment (requiring proof of efficacy and GMP) enacted in response to the thalidomide disaster. The case also demonstrated the necessity of toxicity evaluation of the complete formulation, including excipients and solvents. **Key References** - Wax, P.M. "Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug and Cosmetic Act." *Annals of Internal Medicine*, 1995. - Ballentine, C. "Sulfanilamide Disaster." *FDA Consumer*, 1981. - U.S. FDA, historical materials on the enactment of the Federal Food, Drug, and Cosmetic Act of 1938. - Carpenter, D. *Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA*. Princeton University Press, 2010. - Hilts, P.J. *Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation*. 2003.

## Regulatory and Institutional Lessons of the 1937 Sulfanilamide Elixir Disaster After S.E. Massengill Company marketed a liquid formulation using diethylene glycol as the solvent, 107 people died in the United States. The Pure Food and Drugs Act of 1906 did not require prior review of efficacy or safety, and the manufacturer had not conducted animal toxicity studies. This disaster was the direct legislative impetus for the **Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938**. The obligation to prove pre-market safety for new drugs was codified into law for the first time. The prototype of the New Drug Application (NDA) system to the FDA was established here, giving rise to the fundamental principle of modern regulation: "scientific safety review before market entry." The lessons can be summarized in three points: (1) reactive regulation cannot prevent deaths (the necessity of prior review); (2) toxicity evaluation of the entire formulation — including solvents and excipients — is indispensable; (3) regulatory gaps cannot be left to market self-regulation and must be remedied through legislation. --- **Key References** - Ballentine C. "Sulfanilamide disaster." *FDA Consumer*, 1981. - Wax PM. "Elixirs, diluents, and the passage of the 1938 Federal Food, Drug, and Cosmetic Act." *Ann Intern Med*, 1995; 122(6):456–461. - FDA. *From Test Tube to Patient: Improving Health Through Human Drugs*, 4th ed. 1999. - Jackson CO. *Food and Drug Legislation in the New Deal*. Princeton UP, 1970.

## Institutional Lessons of the Thalidomide Disaster and Frances Kelsey's Role **Overview of the disaster**: In 1957, West German firm Grünenthal marketed the sedative and morning-sickness drug "Contergan" (thalidomide). Sold in approximately 46 countries worldwide, it caused an estimated 10,000 or more children to be born with limb malformations (phocomelia). In 1961, West German pediatrician Widukind Lenz and Australian obstetrician William McBride independently identified the teratogenicity, leading to the product's withdrawal. **Kelsey's role**: Frances Oldham Kelsey, an FDA medical reviewer, repeatedly withheld approval for "Kevadon" — the name under which Richardson-Merrell applied for US approval in 1960 — citing insufficient safety data, particularly regarding peripheral neuritis and fetal effects. This spared the United States from large-scale harm. President J.F. Kennedy awarded her the President's Award for Distinguished Federal Civilian Service in 1962. **Institutional lessons**: The disaster prompted the **Kefauver-Harris Amendment** to be enacted in the United States in 1962. It added the scientific proof of "efficacy," informed consent, and proper clinical trials (the forerunner of GCP) as requirements for approval. This became the starting point for the mandatory teratogenicity testing and post-marketing surveillance (pharmacovigilance) systems adopted in countries worldwide. **Key References** - Lenz W. "A short history of thalidomide embryopathy." *Teratology* (1988) - McBride WG. Teratogenicity report. *Lancet* (1961) - U.S. Kefauver-Harris Amendment (1962), FDA official historical materials - Kelsey FO-related archives, FDA History Office - Stephens T, Brynner R. *Dark Remedy: The Impact of Thalidomide* (2001)

## The Thalidomide Disaster and Frances Kelsey's Role **Factual background** In 1957, West German firm Grünenthal began marketing the sedative thalidomide. Approximately 10,000 children with limb reduction defects (phocomelia) were born in Europe and Japan. In Japan, the drug continued to be sold until 1962, compounding the harm. **Kelsey's decision** FDA reviewer Frances Oldham Kelsey repeatedly refused the US approval application from pharmaceutical company Richardson-Merrell in 1960, citing reports of peripheral neuropathy and insufficient teratogenicity data. This decision prevented large-scale harm within the United States. In 1962, President Kennedy awarded her the President's Award for Distinguished Federal Civilian Service. **Institutional lessons** This event was the direct impetus for the Kefauver-Harris Amendment in the United States in 1962. The law established — ahead of the rest of the world — the mandatory requirement of "prior proof of efficacy" and randomized controlled trials. "Teratogenicity screening" also became a mandatory requirement in new drug review, forming the prototype of the current ICH S5 guideline. --- **Key References** - Stephens, T. & Brynner, R. (2001). *Dark Remedy: The Impact of Thalidomide*. Perseus Publishing. - Kefauver-Harris Drug Amendments (1962). Public Law 87-781, U.S. Congress. - FDA (2010). "Frances Kelsey: FDA Medical Reviewer Leaves Her Mark on History." *FDA Consumer Health Information*. - Vargesson, N. (2015). "Thalidomide-induced teratogenesis: History and mechanisms." *Birth Defects Research Part C*, 105(2), 140–156. - 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 the PMS System **SMON (Subacute Myelo-Optico-Neuropathy)** was a drug disaster in which the intestinal drug clioquinol (clioquinol) caused lower-body numbness, gait disturbance, and visual impairment, occurring frequently from the late 1950s onward, with a cumulative total of approximately 11,000 recognized cases. In 1970, Tadao Tsubaki of Niigata University proposed the clioquinol causation hypothesis, and in the same year the Ministry of Health and Welfare suspended the sale of clioquinol preparations. **The regulatory impact** can be summarized in the following points. 1. **The 1979 revision of the Pharmaceutical Affairs Act** — Directly prompted by the settlements and verdicts in the SMON litigation, this revision explicitly added the assurance of pharmaceutical efficacy and safety as a statutory purpose, and introduced re-examination and re-evaluation systems. This became the legal starting point for the PMS concept of "continuing to monitor safety even after approval." 2. **Establishment of the Drug Side Effects Damage Relief Fund (now PMDA)** (1979) — A pioneering global system for providing administrative relief to victims without fault. 3. Subsequently, the system developed from **GPMSP (1993, standards for post-marketing surveys) → GVP/GPSP (revised Pharmaceutical Affairs Act, 2005)**, systematizing post-marketing use-results surveys, adverse drug reaction reporting, and periodic safety update reports (PSUR). In short, the SMON disaster institutionalized the recognition that "safety cannot be guaranteed by approval-stage review alone," and is regarded as the origin of pharmacovigilance (PV) in Japan. **Key References** - Tsubaki T. (1970). Epidemiological study of SMON and clioquinol. *Nippon Iji Shinpo* (Japan Medical Journal) - Ministry of Health and Welfare, *SMON Research Group Report* (1972) - Materials related to the Pharmaceutical Affairs Act revision (Law No. 56 of 1979) - Sato M. et al., *History of Drug Disasters and Pharmaceutical Safety Surveillance*. Nihon Hyoronsha. - PMDA, "History of the Adverse Drug Reaction Relief System"

## The SMON Disaster and Its Impact on Japan's PMS System **Overview of the disaster** SMON (Subacute Myelo-Optico-Neuropathy) was a drug disaster that affected approximately 11,000 patients in Japan during the 1960s. In 1970, Tadao Tsubaki and colleagues identified the intestinal drug clioquinol as the causative agent. The harm was concentrated in the years 1964–70. **Institutional turning points** 1. **1979 revision of the Pharmaceutical Affairs Act**: A "re-examination system" following manufacturing approval was newly established. Japan was the first country in the world to codify into law a mechanism for reassessing efficacy and safety 4–6 years after approval. 2. **Strengthening of adverse drug reaction reporting obligations**: Spontaneous reporting by manufacturers and medical institutions was mandated, and a 15-day/30-day reporting system to the Ministry of Health and Welfare (MHW) was established. 3. **GPMSP (1993) → GPSP (2004)**: Standards for the conduct of post-marketing surveys were codified by ministerial ordinance. The three pillars of use-results surveys, special surveys, and post-marketing clinical trials were clarified. 4. **From "negative proof" to "continuous monitoring"**: The previous stance of "waiting until a problem emerges" was replaced by a paradigm shift toward actively collecting data after approval. The 1979 SMON litigation settlement established "the three-party responsibility of the state, companies, and physicians," and became the opportunity to embed the rationale for PMS obligations falling to the regulator into the legal system. --- **Key References** - Tsubaki T. "Etiology of SMON." *Igaku no Ayumi* (Progress in Medicine), 1970. - Nakajima M. *The Invisible Disease — The History of SMON and Administrative Responsibility*. Bungei Shunju, 1978. - MHW notification, "Standards for Post-Marketing Surveys of Pharmaceuticals (GPMSP)," Ministry of Health and Welfare Ordinance No. 10 of 1993. - Narita M et al. "Post-marketing surveillance systems in Japan." *Pharmacoepidemiology and Drug Safety*, 2004. - Kato I. et al. "Legal liability in pharmaceutical administration — analysis of the SMON verdict." *Horitsu Jiho* (Law Times), 1979.

Japan's HIV-tainted blood products disaster saw the continued use of unheated blood coagulation factor concentrates throughout the early 1980s, despite warnings of HIV contamination risk, resulting in approximately 1,800 hemophilia patients — roughly 40% of all hemophilia patients — becoming infected, with many dying. The lessons of these structural failures are as follows. First, liability for inaction. Even though heated preparations had been approved in the United States in 1983 and the risk was internationally known, the Ministry of Health and Welfare's (then) AIDS Research Group (chaired by Hideyuki Abe) and the regulatory authority delayed the recall and transition to heated products. The stance of "waiting for definitive proof" without adopting the precautionary principle allowed the harm to spread. Second, conflicts of interest and expert capture. Pharmaceutical companies (Midori Juji and others), researchers, and government authorities were closely intertwined, and decisions were made in the absence of patient representation. The "Gunji Documents" (discovered in 1996) confirmed that authorities had been aware of the risks. Third, diffusion of responsibility and inability to assign accountability. Multiple actors were involved, and "organized irresponsibility" arose in which no one bore final responsibility. In current theories of administrative accountability, this is understood not as a collection of individual negligence but as a deficit of institutional accountability (accountability) in system design. The lessons established include: (1) institutionalization of the precautionary principle; (2) transparency and public disclosure in pharmaceutical administration; (3) conflict-of-interest management; and (4) patient participation (drug disaster education, establishment of PMDA in 2004). The "Vow Monument" erected after the 1996 settlement has become a symbol of prevention of recurrence. **Key References** - HIV-tainted blood products case: Tokyo/Osaka HIV litigation settlement confirmation (1996) - Ministry of Health and Welfare, "Survey Report on HIV Infection through Blood Products" (related to the Gunji Documents, 1996) - Muto K. et al., essays in medical ethics related to *Why Drug Disasters Don't Disappear* - Japan Association for Bioethics, ed., *Bioethics* (chapters on the precautionary principle and conflicts of interest) - Kurihara C. "Drug disasters and the precautionary principle." *Rinshohyoka* (Clinical Evaluation)

## Structural Failures of Japan's HIV-Tainted Blood Products Disaster and Modern Lessons **The skeleton of the case** In the 1980s, under a structure of "regulatory capture" formed by the Ministry of Health and Welfare, Midori Juji, and Teikyo University, the transition to heated preparations was delayed by approximately two years. Approximately 1,800 hemophilia patients were infected with HIV, and physicians and officials including Akihito Matsumura and Hideyuki Abe were subsequently criminally prosecuted for professional negligence causing death (indicted in 1996). **Mainstream academic interpretation** | Layer of failure | Content | |--------|------| | Epistemological failure | The 1983 US CDC warning was minimized as "external pressure," and uncertainty was invoked as justification for inaction | | Institutional failure | The revolving door between the Pharmaceutical Affairs Bureau and the pharmaceutical industry, combined with non-public committee proceedings, eliminated accountability | | Ethical failure | "Medical paternalism" suppressed patients' right to know and the principle of informed consent | **Formulation in contemporary ethics and theories of administrative accountability** Onishi (2010) positions this case as a textbook example of "organized ignorance" — a structure in which, while aware of the risk, the collective pretended "not to know," inviting diffusion of responsibility. The 1996 settlement and the Minister of Health's apology were turning points from accountability for outcomes to accountability for process, providing the institutional foundation for independent review by PMDA and mandatory transparency of post-marketing safety information. --- **Key References** - Feldman EA & Bayer R (eds.), *Blood Feuds: AIDS, Blood, and the Politics of Medical Disaster*, Oxford UP, 1999 - Kurioka M. "The HIV-tainted blood products trial and medical malpractice jurisprudence." *Horitsu Jiho* (Law Times), Vol. 68, No. 12, 1996. - Onishi N, "Organized Ignorance and the Japanese HIV-tainted Blood Scandal," *Social Science & Medicine*, 71(9), 2010 - Ministry of Health, Labour and Welfare, "Final Report of the Emergency Comprehensive Measures Research Project for HIV-infected Persons," 1997 - Terao Y. "Accountability and information disclosure in pharmaceutical administration." *Jurist*, No. 1189, 2000.

## The State's Information Management Responsibility in Japan's Tainted Fibrinogen Blood Product Disaster In the matter of fibrinogen preparations (formerly Midori Juji, now Mitsubishi Tanabe Pharma) and hepatitis C virus infection, the mainstream understanding in medical policy history holds that the core of the state's (Ministry of Health and Welfare / Ministry of Health, Labour and Welfare) responsibility lies in "inaction — knowing of the hazard, yet failing to exercise regulatory authority and communicate the information." The fibrinogen preparation was approved in Japan in 1964, but the FDA revoked its approval in the United States in 1977 due to hepatitis risk. In 1987, a cluster infection was reported at an obstetric practice in Aomori Prefecture (the so-called "Aomori case"), and the state is said to have had the means to recognize the danger no later than that year. However, guidance on transitioning to heated preparations and recalling unheated stock was delayed, allowing harm to expand. The decisive point of contention was the "list of 418" problem. Although submitted by the company in 2002, it came to light in 2007 that the Ministry of Health, Labour and Welfare had failed to notify individual patients of their infection, and the revelation drew intense public criticism. This became the symbol of information management responsibility. Rulings in courts across Japan — including the Osaka District Court (2006) — recognized the responsibility of both the state and the company, and in 2008 the **Tainted Fibrinogen Blood Product Victims Relief Special Measures Law** (private member's legislation, Fukuda Yasuo Cabinet) was enacted, with Minister of Health Yoichi Masuzoe reaching a basic agreement with plaintiffs. In the same year, the **Hepatitis C Tainted Blood Products Verification and Review Committee** was established for the prevention of recurrence of drug disasters; its 2010 final recommendation identified "structural deficiencies in the system for collecting, evaluating, and communicating adverse drug reaction and infection information" and recommended the establishment of a third-party monitoring organization. The mainstream understanding positions this not as individual negligence but as a failure of information governance — a deficit in the institutional design for delivering safety information to victims. ### Key References - Committee on the Investigation of the Tainted Fibrinogen Blood Product Case and the Review of Pharmaceutical Administration for Prevention of Recurrence, *Final Recommendations* (2010) - Tainted Fibrinogen Blood Product Victims Relief Special Measures Law (Law No. 2 of 2008) - Osaka District Court judgment, June 21, 2006 (hepatitis C drug disaster litigation) - Ministry of Health, Labour and Welfare, *Report on Fibrinogen Preparations etc. (related to the so-called list of 418)* (2007) - National Hepatitis C Drug Disaster Litigation Plaintiffs and Defense Team, eds., *History of the Hepatitis C Drug Disaster Trial*. Nihon Hyoronsha, 2012.

## The State's Information Management Responsibility in Japan's Tainted Fibrinogen Blood Product Disaster In the 1980s, the Ministry of Health and Welfare (then) recognized the risk of hepatitis C infection through fibrinogen preparations but delayed the revocation of manufacturing approval. Despite receiving the FDA's recommendation against use in 1987, the preparations continued to be used in Japan until 1994. The mainstream assessment in policy history positions the state's responsibility as "information concealment through inaction." Specifically: (1) the Ministry of Health and Welfare knew of the list of infected individuals but failed to notify victims (discovered in Osaka HIV litigation documents in 2002); (2) structural collusion between pharmaceutical administration and the pharmaceutical industry (so-called "revolving door" personnel practices) undermined transparency; and (3) even after the 2002 revelations, a nationwide investigation was deferred, delaying confirmation of the full scale of the harm. The enactment of the "Tainted Fibrinogen Blood Product Victims Relief Special Measures Law" in 2008 and the Prime Minister's apology are regarded as the turning point at which the state explicitly acknowledged the failure of information management. Research by Fukushima Masanori and others positions this case as a textbook example of "regulatory capture." --- **Key References** - Hanai J. "Structure and policy implications of the hepatitis C drug disaster litigation." *Healthcare and Society*, 17(3), 2007. - National Defense Team for Hepatitis C Drug Disaster Litigation, eds., *History of the Hepatitis C Drug Disaster Trial*. Nihon Hyoronsha, 2010. - Fukushima M. "Drug disasters and regulatory failure." *Japanese Journal of Clinical Pharmacology and Therapeutics*, 40(5), 2009. - Ministry of Health, Labour and Welfare, "Final Recommendations of the Committee on the Investigation of the Tainted Fibrinogen Blood Product Case and the Review of Pharmaceutical Administration for Prevention of Recurrence," 2010. - Abraham, J. *Science, Politics and the Pharmaceutical Industry*, UCL Press, 1995 (theoretical basis for regulatory capture)