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.

How to produce 'marketable and profitable results for the company': from viral interference to Roferon A.

This paper looks at the commodification of interferon, marketed by Hoffmann La Roche (short: Roche) as Roferon A in 1986, as a case study that helps us understand the role of pharmaceutical industry in cancer research, the impact of molecular biology on cancer therapy, and the relationships between biotech start-ups and established pharmaceutical firms. Drawing extensively on materials from the Roche company archives, the paper traces interferon's trajectory from observed phenomenon (viral interference) to product (Roferon A). Roche embraced molecular biology in the late 1960s to prepare for the moment when the patents on some of its bestselling drugs were going to expire. The company funded two basic science institutes to gain direct access to talents and scientific leads. These investments, I argue, were crucial for Roche's success with recombinant interferon, along with more mundane, technical and regulatory know-how held at Roche's Nutley base. The paper analyses in some detail the development process following the initial success of cloning the interferon gene in collaboration with Genentech. It looks at the factors necessary to scale up the production sufficiently for clinical trials. Using Alfred Chandler's concept of 'organizational capabilities', I argue that the process is better described as 'mobilisation' than as 'translation'.

Rethinking the Belmont Report?

This article reflects on the relevance and applicability of the Belmont Report nearly four decades after its original publication. In an exploration of criticisms that have been raised in response to the report and of significant changes that have occurred within the context of biomedical research, five primary themes arise. These themes include the increasingly vague boundary between research and practice, unique harms to communities that are not addressed by the principle of respect for persons, and how growing complexity and commodification in research have shed light on the importance of transparency. The repercussions of Belmont's emphasis on the protection of vulnerable populations is also explored, as is the relationship between the report's ethical principles and their applications. It is concluded that while the Belmont Report was an impressive response to the ethical issues of its day, the field of research ethics involving human subjects may have outgrown it.

From academic laboratory to the market: Disclosed and undisclosed narratives of commercialization.

This paper examines how the Weizmann Institute of Science has been telling the story of the successful commercialization of a scientific invention, through its corporate communication channels, from the early 1970s to today. The paper aims to shed light on the transformation processes by which intellectual-property-based commercialization activities have become widely institutionalized in universities all over the world, and on the complexities, ambiguities and tensions surrounding this transition. We look at the story of the scientific invention of Copolymer-1 at the Weizmann Institute of Science and its licensing to Teva Pharmaceutical Industries, which subsequently developed the highly successful drug Copaxone for the treatment of multiple sclerosis. We argue that, in its tellings and retellings of the story of Copolymer-1, the Weizmann Institute has created narratives that serve to legitimize the institution of academic patenting in Israel.

The roots of modern oncology: from discovery of new antitumor anthracyclines to their clinical use.

In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a research agreement for the discovery and development up to clinical trials of new natural antitumor agents. This agreement can be considered as a pioneering and fruitful example of a translational discovery program with relevant transatlantic connections. Owing to an eclectic Streptomyces, found near Castel del Monte (Apulia), and to the skilled and motivated participants of both institutions, a new natural antitumor drug, daunomycin, was ready for clinical trials within 3 years. Patent interference by the Farmitalia French partner was overcome by the good quality of the Italian drug and by the cooperation between Prof. Di Marco, director of the Istituto Ricerche Farmitalia Research Laboratories for Microbiology and Chemotherapy, and Prof. Karnofsky, head of the Sloan-Kettering Cancer Institute of New York, leading to the first transatlantic clinical trials. The search for daunomycin's sister anthracyclines led to the discovery and development of adriamycin, one of the best drugs born in Milan. This was the second act prologue of the history of Italian antitumor discovery and clinical oncology, which started in July 1969 when Prof. Di Marco sent Prof. Bonadonna the first vials of adriamycin (doxorubicin) to be tested in clinical trials. This article reviews the Milan scene in the 1960s, a city admired and noted for the outstanding scientific achievements of its private and public institutions in drugs and industrial product discovery.

History of the Tinnitus Research Consortium.

This article describes the creation and accomplishments of the Tinnitus Research Consortium (TRC), founded and supported through philanthropy and intended to enrich the field of tinnitus research. Bringing together a group of distinguished auditory researchers, most of whom were not involved in tinnitus research, over the fifteen years of its life it developed novel research approaches and recruited a number of new investigators into the field. The purpose of this special issue is to highlight some of the significant accomplishments of the investigators supported by the TRC. This article is part of a Special Issue entitled "Tinnitus".

Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation--technological development issues.

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

[Chapter 3. Transitions in clinical trials and appropriate use of drugs in Japan (1980-2010)].

This paper reviews the status of clinical trials and appropriate use of drugs from historical perspectives in the last 30 years in Japan. Industry-sponsored clinical trials in Japan began being regulated under the revised Pharmaceutical Affairs Law in 1980. Japanese modifications were made to the ICH-GCP, which reached step 4 in May 1996, and a notification called the "New GCP" was issued in March 1997. This was fully implemented as of April 1998. The number of clinical trials, however, dropped sharply after 1998. Patients worldwide who have no drugs for their diseases are waiting for new medicines. Clinical trials must be held as part of a scientific and valid process. Physicians have a duty to use new medicines considering a balance of effectiveness and safety. In Japan, several "yakugai" cases were observed in the past. They were not only caused by the toxicological effects of drugs but were also due to social factors in drug use. Responding to these scandals, new regulations were developed and contributed to the appropriate use of drugs in Japan.

'Saving the lives of our dogs': the development of canine distemper vaccine in interwar Britain.

This paper examines the successful campaign in Britain to develop canine distemper vaccine between 1922 and 1933. The campaign mobilized disparate groups around the common cause of using modern science to save the nation's dogs from a deadly disease. Spearheaded by landed patricians associated with the country journal The Field, and funded by dog owners and associations, it relied on collaborations with veterinary professionals, government scientists, the Medical Research Council (MRC) and the commercial pharmaceutical house the Burroughs Wellcome Company (BWC). The social organization of the campaign reveals a number of important, yet previously unexplored, features of interwar science and medicine in Britain. It depended on a patronage system that drew upon a large base of influential benefactors and public subscriptions. Coordinated by the Field Distemper Fund, this system was characterized by close relationships between landed elites and their social networks with senior science administrators and researchers. Relations between experts and non-experts were crucial, with high levels of public engagement in all aspects of research and vaccine development. At the same time, experimental and commercial research supported under the campaign saw dynamic interactions between animal and human medicine, which shaped the organization of the MRC's research programme and demonstrated the value of close collaboration between veterinary and medical science, with the dog as a shared object and resource. Finally, the campaign made possible the translation of 'laboratory' findings into field conditions and commercial products. Rather than a unidirectional process, translation involved negotiations over the very boundaries of the 'laboratory' and the 'field', and what constituted a viable vaccine. This paper suggests that historians reconsider standard historical accounts of the nature of patronage, the role of animals, and the interests of landed elites in interwar British science and medicine.

A tale of two vaccines: lessons from polio that could inform the development of an HIV vaccine.

Two vaccine trials that were conducted 50 years apart are reviewed and compared: the 1954 field trial of the Salk inactivated polio vaccine and the RV144 HIV vaccine trial conducted in Thailand between 2003 and 2009. Despite the obvious differences in science and historical periods, several lessons were identified that could inform the future HIV vaccine effort. Those lessons are related to paradigm changes that occur when science progresses, the need to test scientific hypothesis in efficacy trials, the controversies surrounding those trials, the need for strong community and political support, the participation of government and nongovernment institutions, the balance between implementation of other preventive and therapeutic interventions, and the priority given by society to develop a vaccine. If we have the humility and courage to apply some of those lessons, we may be able accelerate the development of an urgently needed HIV vaccine.

How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years.

Phenobarbital (phenobarbitone) was first used as an antiepileptic drug 100 years ago, in 1912. This article tells the story of the discovery of its antiepileptic action, its early development, and the subsequent course of its clinical use over the 100-year period. The side effects, pharmacokinetics, and misuse of barbiturates are considered, along with the more recent clinical trials and the drug's current clinical utilization. The introduction of controlled drug regulations, the comparative cost of phenobarbital, and its inclusion on the World Health Organization (WHO) essential drug list are discussed. It is one of the few drugs on the formulary in 1912 that is still listed today, and remarkably its efficacy in epilepsy has not been significantly bettered. The current recommendation by the WHO is that phenobarbital should be offered as the first option for therapy for convulsive epilepsy in adults and children if availability can be ensured. This is rated as a strong recommendation because of the proven efficacy and low cost of phenobarbital, and despite its perceived side-effect profile and the practical problems of access. Whether this recommendation puts "a hierarchy on the brain," as has been suggested, is arguable. Much still needs to be learned about the drug's effects, and the issues raised by phenobarbital have lessons for all antiepileptic drug therapy.

Surgimiento, evolución y principales resultados del Centro Nacional Coordinador de Ensayos Clínicos / Emergence, development and main results of the National Coordinating Center of Clinical Trials

En la década de los 90, el desarrollo acelerado de la Industria Médico Farmacéutica cubana impuso la necesidad de crear estructuras que garantizaran la evaluación clínica de productos para su introducción a la práctica médica y posterior comercialización. Uno de los centros fundados para contribuir con estos fines fue el Centro Nacional Coordinador de Ensayos Clínicos. El presente trabajo recoge en síntesis las razones que motivaron la creación del centro y muestra, brevemente, su desarrollo organizacional por más de 17 años. Describe, además, los principales componentes del sistema de diseño y conducción de ensayos clínicos; así como los aportes más significativos de cada uno de ellos para el cumplimiento de sus objetivos como centro

The fast development of the Cuban pharmaceutical industry in the 90ïs prompted the creation of structures to assure the clinical evaluation of products for their introduction into the medical practice and their further marketing. The National Coordinating Center of Clinical Trials was one of the most important centers founded to accomplish these objectives. The present paper showed in short the reasons behind the emergence of this center and its organizational development for more than 17 years. It also described the main components of the design and the conduction of clinical trials as well as their most significant contributions to fulfill the set objectives

A magic bullet for the "African" mother? Neo-Imperial reproductive futurism and the pharmaceutical "solution" to the HIV/AIDS Crisis.

On the basis of a close reading of popular and medical texts which address a debate over the ethics of clinical drug trials funded by the United States and designed mainly for sub-Saharan Africa, I argue that international public health discourse about infant HIV infection in that region reflects and legitimates a neo-imperialist, anti-reproductive justice ideology. Participants share a fetal-centered logic that US-funded biomedicine must shoulder the burden of rescuing sub-Saharan Africa from itself by using the bodies of HIV-positive pregnant women to transmit biomedicine's magic bullet­antiretroviral drugs­to the next generation. The survival of the fetus, disguised as the well-being of the HIV-positive woman and accomplished by the magic of biomedical research, becomes the survival of a region otherwise doomed by its present state of economic, political, and medical incapacity. This version of what queer theorist Lee Edelman (2004, No Future: Queer Theory and the Death Drive) calls "reproductive futurism" redounds to the benefit of the more explicitly women-hating and nationalist ideologies of still-powerful right-wing movements against reproductive and sexual rights.

The therapeutic test: an ancient malady in the 21st century.

The response to treatment was the diagnostic mainstay in ancient times when diseases were poorly understood. Now that the bases of most diseases are known, appropriate diagnostic means are available. However, many physicians still rely on therapeutic tests to establish diagnoses. Since most illnesses are self-limited and because of the placebo effect, many physicians and patients attribute the improvement to the medication and believe that the correct diagnosis was made. However, inappropriate therapeutic tests often lead to diagnostic delays, rapid emergence of antibiotic-resistant bacterial pathogens, increased risks of adverse drug reactions, and unnecessary expenses. To reduce the frequency of unwarranted therapeutic tests, health-care professionals and educators must take steps to rectify the problem.

Profitable failure: antidepressant drugs and the triumph of flawed experiments.

Drawing on an analysis of Irving Kirsch and colleagues' controversial 2008 article in "PLoS [Public Library of Science] Magazine" on the efficacy of SSRI antidepressant drugs such as Prozac, I examine flaws within the methodologies of randomized controlled trials (RCTs) that have made it difficult for regulators, clinicians and patients to determine the therapeutic value of this class of drug. I then argue, drawing analogies to work by Pierre Bourdieu and Michael Power, that it is the very limitations of RCTs -- their inadequacies in producing reliable evidence of clinical effects -- that help to strengthen assumptions of their superiority as methodological tools. Finally, I suggest that the case of RCTs helps to explore the question of why failure is often useful in consolidating the authority of those who have presided over that failure, and why systems widely recognized to be ineffective tend to assume greater authority at the very moment when people speak of their malfunction.