Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.

Many factors determine whether and when a class of therapeutic agents will be successfully developed and brought to market, and historians of science, entrepreneurs, drug developers, and clinicians should be interested in accounts of both successes and failures. Successes induce many participants and observers to document them, whereas failed efforts are often lost to history, in part because involved parties are typically unmotivated to document their failures. The GLP-1 class of drugs for diabetes and obesity have emerged over the past decade as clinical and financial blockbusters, perhaps soon becoming the highest single source of revenue for the pharmaceutical industry (Berk 2023). In that context, it is instructive to tell the story of the first commercial effort to develop this class of drugs for metabolic disease, and how, despite remarkable early success, the work was abandoned in 1990. Told by a key participant in the effort, this story documents history that would otherwise be lost and suggests a number of lessons about drug development that remain relevant today.

Opposed to Pain: Antikamnia Chemical Company.

The Antikamnia (AK) Chemical Company founded in 1890, which eventually was renamed The Antikamnia Remedy Company in 1819, was an important medicine company that thrived prior to passage of the 1906 Food and Drug act using smart worldwide marketing. As dangerous as the AK products were, success continued after 1906 by pursuing methods to flout regulations and stick to the marketing methods and legal maneuvering that kept AK sales strong. This article describes the tumultuous history of one of the most successful drug companies between 1890 and well into the 1920s.

[The participation of the USSR in development of penicillin industry in the Eastern Europe].

The article considers on the basis of analysis of archival documents issue of rendering assistance by the Soviet Union to the countries of Eastern Europe to organize production of penicillin. It is established that by the mid of 1950s, modern powerful plants were launched in Bulgaria, Romania and Czechoslovakia by the forces of Soviet engineers . Their construction was carried out on preferential terms for countries-customers. The mutually beneficial cooperation in sphere of production of antibiotics carried out and with other countries of this region. It is demonstrated that the USSR, performing task of enormous humanitarian significance in conditions of the Cold War, simultaneously implemented another goal - formation of loyalty of population of these countries and organization of coalition of friendly states on its Western borders.

The Origins of "Confidential Commercial Information" at the FDA.

This Viewpoint reviews regulations regarding FDA's handing of confidential commercial information, explains how these regulations serve as a barrier to disclosure of information in the interest of public health, and suggests how information could be carefully shared to improve health outcomes and advance research.

Premios Nobel Chain y Schatz evalúan la producción de penicilina en Chile en los años sesenta / Nobel Prize winners Chain and Schwartz evaluate the production of penicillin in Chile in the sixties

En los años sesenta el antiguo Instituto Bacteriológico de Chile obtuvo de la Universidad de Chile la ayuda de Albert Schatz, descubridor de la estreptomicina, para mejorar su producción de penicilina. Esta asesoría no fue aprovechada y la situación empeoró, hasta la llegada de Mario Miranda como Director, quien trajo a Sir Ernst Chain, Premio Nobel por el desarrollo de la penicilina, para que hiciese una evaluación de la planta de producción antes de decidir su cierre. El autor de estas líneas, quien puso fin a la producción en 1973, relata las visitas y las conclusiones de ambos asesores.

In the sixties the ancient Bacteriological Institute of Chile obtained from the University of Chile the transfer of Albert Schatz, discoverer of streptomycin, to improve its penicillin production. This advisory was wasted and the situation worsened until the arrival of Mario Miranda as the new Director, who brought Sir Ernst Chain, Nobel Prize for the development of penicillin, to make an evaluation of the production plant before deciding to continue or close it. The author of these lines, who ended production in 1973, recounts the visits and the conclusions of both advisors.

Russell Earl Marker and the Beginning of the Steroidal Pharmaceutical Industry.

A biographical essay is presented on the chemical research of Russell E. Marker (1902-1995). The biography begins in 1925 with Marker's decision to forgo a Ph.D. in chemistry because he did not wish to complete the course requirements at the University of Maryland. Marker then took a position at the Ethyl Gasoline Company where he helped develop the octane rating for gasoline. He then moved to the Rockefeller Institute where he studied the Walden inversion, and then to Penn State College where his already prolific publication record soared to even greater heights. In the 1930s, Marker became fascinated with steroids and their potential as pharmaceuticals and collected specimens from plants in the southwest US and Mexico, discovering many sources of steroidal sapogenins. With his students at Penn State College, where he rose to full professor, he discovered the structure of these sapogenins and invented the "Marker degradation" that converted diosgenin and other sapogenins into progesterone. Together with Emeric Somlo and Federico Lehmann, he co-founded Syntex and began the manufacture of progesterone. Shortly thereafter, he left Syntex, began another pharmaceutical company in Mexico, then quit chemistry altogether. A discussion of Marker's legacies and the ironies in his professional career is provided.

The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Similar to last year, 2021 will be remembered for the COVID-19 pandemic. Although five vaccines have been approved by the two most important drug regulatory agencies, namely the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the pandemic has still not been brought under control. However, despite the context of a global pandemic, 2021 has been an excellent year with respect to drug approvals by the FDA. In 2021, 50 drugs have been authorized, making it the fourth-best year after 2018 (59 drugs) and 1996 and 2020 (53 each). Regarding biologics, 2021 has been the third-best year to date, with 14 approvals, and it has also witnessed the authorization of 36 small molecules. Of note, nine peptides, eight monoclonal antibodies, two antibody-drug conjugates, and two oligonucleotides have been approved this year. From them, five of the molecules are pegylated and three of them highly pegylated. The presence of nitrogen aromatic heterocycles and/or fluorine atoms are once again predominant among the so-called small molecules. This report analyzes the 50 new drugs approved in 2021 from a chemical perspective, as it did for those authorized in the previous five years. On the basis of chemical structure alone, the drugs that received approval in 2021 are classified as the following: biologics (antibodies, antibody-drug conjugates, enzymes, and pegylated proteins); TIDES (peptide and oligonucleotides); combined drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

Denaturing and Native Mass Spectrometric Analytics for Biotherapeutic Drug Discovery Research: Historical, Current, and Future Personal Perspectives.

Mass spectrometry (MS) plays a key role throughout all stages of drug development and is now as ubiquitous as other analytical techniques such as surface plasmon resonance, nuclear magnetic resonance, and supercritical fluid chromatography, among others. Herein, we aim to discuss the history of MS, both electrospray and matrix-assisted laser desorption ionization, specifically for the analysis of antibodies, evolving through to denaturing and native-MS analysis of newer biologic moieties such as antibody-drug conjugates, multispecific antibodies, and interfering nucleic acid-based therapies. We discuss challenging therapeutic target characterization such as membrane protein receptors. Importantly, we compare and contrast the MS and hyphenated analytical chromatographic methods used to characterize these therapeutic modalities and targets within biopharmaceutical research and highlight the importance of appropriate MS deconvolution software and its essential contribution to project progression. Finally, we describe emerging applications and MS technologies that are still predominantly within either a development or academic stage of use but are poised to have significant impact on future drug development within the biopharmaceutic industry once matured. The views reflected herein are personal and are not meant to be an exhaustive list of all relevant MS performed within biopharmaceutical research but are what we feel have been historically, are currently, and will be in the future the most impactful for the drug development process.

Adolf Thierry and the first pharmaceutical factory in Southeast Europe.

The paper explores the beginnings of pharmaceutical industry development in Croatia and the establishment of the first pharmaceutical factory in Southeast Europe. Adolf Thierry de Chateauvieux (St. Pölten, 1854 - Pregrada, 1920), a nobleman hailing from France, immigrated to Croatia at the end of the 19 th century. He bought the Angjelu cuvaru ( Guardian Angel ) pharmacy (1892) in the small town of Pregrada and established the first pharmaceutical factory (1894) in this part of Europe. The factory had an equipped laboratory, a production facility, a storage room for raw materials and balsams, a room for packaging and shipping finished products and a commercial office. Production was mainly based on herbal remedies. The most famous were Thierry's Balsam and Thierry's Centifolia Ointment, both registered and patented in London (1900). By virtue of Adolf Thierry's entrepreneurial spirit and skilful product advertisement, his medicinal preparations were distributed across Europe, America, India and Africa, a testament to which is the well-preserved and researched documentation.

The discovery of insulin revisited: lessons for the modern era.

2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin's discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin's role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry's role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.

Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors.

INTRODUCTION: Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature. METHODS: We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration "Drug Alerts and Statements" repository. We categorized reports into errors of "contamination," suprapotency," and "subpotency." Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available. RESULTS: We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm. DISCUSSION: Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors. CONCLUSION: In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.

Pharmacy in Latvia during the occupation regime of Nazi Germany (1941-1945).

The study covers the period of World War II after shift of occupational powers in Latvia when Soviet occupation was replaced by the occupation regime of Nazi Germany in the summer of 1941 and retained until first half of 1945. Due to this shift gradually Latvia, Lithuania, Estonia and Belarus were merged into a single administrative area and designated as "Ostland". Soviet officials left the pharmaceutical industry, which they had tried to apply to the communist ideology from June 1940 to June 1941 creating confusion and chaos. The renewed Pharmacy Board of Latvia had to deal with the restoration of supervision and a partial return from the communist to the capitalist regime. The research provides an insight to adaptation and development of the pharmaceutical industry in Latvia during Nazi Germany occupation regime, highlighting as essential indicators the administrative operation of Pharmacy Board of Latvia and its cooperation with German authorities, the availability of medicines, process of reprivatisation of pharmacies and changes in the number of pharmaceutical employees. The research issue raised is topical, since it is this period that reflects the industry's ability to adapt and perform work in fundamentally different and severe circumstances, which include both resource deficits and the transition from one regime to another. The collected evidence shows the efforts to stabilize the pharmaceutical industry in many terms. One example was the attemptions to ensure the rational dispensing of medical products to the pharmacies and hospitals, with the greatest degree of austerity, because the supply and consumption of medication was extremely complex issue throughout the war.

MEDICINE AND COLONIAL PATENT LAW IN INDIA: A Study of Patent Medicines and the Indian Patents and Designs Act, 1911 in Early- Twentieth-Century India.

This paper investigates the history of drugs sold as "patent medicines" in India in the early twentieth century. The paper investigates their legitimacy as patenting of medicines was forbidden by the Indian Patents and Designs Act, 1911 (IPDA). The paper argues that the instrument of letters patents functioning as the prerogative of the Crown that gave monopolistic rights to grantees to sell any compound without having to disclose its constituents was the reason behind this seemingly conflicting historical relationship between the law and the market. Colonial law-making left sufficient space within the ambit of the IPDA for letters patents to have their ill effects. The colonial state made attempts to address this as a public health issue by incorporating concerns related to this class of medicines within regulations addressed to the drugs market in the 1930s. The currency of patent medicines in the market was further added to by Indian indigenous entrepreneurs fueled by cultural nationalism of Swadeshi ideology in Bengal in the early twentieth century. However, even such indigenous responses or attempts at hybridization of manufacturing and selling practices related to patent medicines were mostly informed by upper-caste/ upper-class interests and not so much by those of consumers of these medicines.

Developing Medical Affairs Leaders Who Create the Future.

Medical affairs has evolved over recent years from a support, to a partner, to a strategic leadership function. In the future, there will be significant changes in healthcare and pharmaceutical industries, and many of these will be due to technological advances and digitalisation. Medical affairs will be largely influenced by these developments in terms of partnerships with key stakeholders, embracing innovation and patient-centric healthcare, and demonstrating value for novel treatment options. In order to secure future success within their roles, medical affairs professionals will have to demonstrate specific capabilities founded on communications and behavioural change, business leadership acumen, knowledge acquisition and self-development, and the ability to generate real-world evidence from insights and expertise within data science and analytics. It will be our responsibility as medical affairs leaders to create this foundation for the leaders of tomorrow.

Syphilis and Pharmaceutical Industry Marketing Between the Two World Wars in Croatia.

Between the two World Wars, the pharmaceutical industry strengthened its influence within the Croatian medical community. Due to the scarcity of professional biomedical journals in the Croatian language, larger pharmaceutical companies started to publish free promotional journals, magazines, and booklets which quickly became popular. They thus succeeded in creating a broad network of opinion leaders by recruiting physicians as authors, primarily writing on their experiences with application of certain drugs. As a paradigmatic social disease of the interwar period, syphilis stimulated the development of various marketing strategies used by the industry in these publications.

["Rave" Factory at the Beginning of Chemical-Pharmaceutical Production Era in Croatia] / Tvornica "Rave" u ozracju pocetaka kemijsko-farmaceutske proizvodnje na podrucju Hrvatske

The paper presents the development and business of the chemical-pharmaceutical factory Rave PLC, founded in Zagreb in 1922. Based on archival and building documentation, professional and daily newspapers, and promotional material, the formation of the factory complex in the Zagreb industrial zone was reconstructed, its marketing strategy and its impact on the development of domestic drug production and hygiene and sanitary necessities were presented. As an important motive for its operations, the factory emphasized industrial independence, the national features of its business and the promotion of cooperation with young domestic industry. In accordance with the above-mentioned text, Rave PLC participates in the construction and development of domestic pharmaceutical production and market, encouraging the development of modern industry and struggle for more favourable conditions of its business. Its unprecedented history is an important segment of our pharmaceutical past, but also an indispensable element of knowing the industrial development of the wider region. This segment of the beginnings of pharmaceutical manufacturing is essential in knowing the origins of entrepreneurship in our region as a significant element in raising awareness of national production, development and identity.

Flu pandemic, world power, and contemporary capitalism: building a historical-critical perspective.

OBJECTIVES: To present a historical-critical analysis of the configuration process of the 2009-2010 flu pandemic in order to show the relationships between this process and the organization of world power, and to promote social and political mobilization. METHODS: Primary and secondary sources on the dynamics of the 2009-2010 flu pandemic were studied. The sources were validated by plausibility assessment and historiographical analysis. From a historical-territorial and critical approach, the relations between the world configuration of the pandemic and the economic, political, and ideological power relations of contemporary capitalism were identified. RESULTS: It is revealed that the expanding monopoly of the pig industry provided favorable conditions for the evolutionary explosion of the influenza A(H1N1) virus. The World Health Organization (WHO) made decisions that were inclined toward the economic interests of the pig and pharmaceutical industries within the framework of financial-cognitive capitalism. CONCLUSIONS: The modes of conduct of these institutions and companies materialized the world relations of economic, political, and ideological power of our time, which determined the configuration process of the pandemic. The worldwide spreading of the virus is barely a trail of the process.

Clinical trials and the origins of pharmaceutical fraud: Parke, Davis & Company, virtue epistemology, and the history of the fundamental antagonism.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. This new framework fundamentally altered the set of epistemic virtues-a phrase we draw from the philosophical field of virtue epistemology-considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place.