Do dying patients have a moral claim to access experimental drugs when all else has failed? This question has been the focus of an active and evolving debate concerning the rights of terminally ill patients, the nature of the drug development process, and the scope of federal regulation, with supporters arguing that seriously ill patients should be able to decide for themselves whether and when to attempt experimental therapies and opponents arguing that the resulting state of affairs would be disastrous for patient safety and for the integrity of the drug development process. This thesis concerns the ethical considerations surrounding the provision of experimental drugs for treatmentoften termed compassionate use or expanded accessand argues that compelling ethical merits on both sides of the debate complicate the formation of satisfactory public policy. Although patient autonomy is often invoked to support liberal access to experimental drugs, the paucity of known information about investigational compounds as well as the unique vulnerability of the terminally ill patient call into question the wisdom of the unfettered exercise of autonomy in this context. Although equitable distribution of experimental drugs is often felt to be a concern, the meaning of equity in this context has not been clearly defined, and in fact several working concepts of equitable access may not be achievable or desirable. Although the financial burden on drug manufacturers is frequently recognized as a barrier to expanded access, the potential for expanded access programs to constitute a marketing strategy should be recognized, and the mixing of profit motives with altruistic ones brought to light. Parsing these and other ethical nuances points to certain ways in which policies governing expanded access can be refined to allow for access while maximizing patient protection and ensuring the generation of scientific knowledge. Physicians, as frequent mediators of requests for experimental drugs, should be knowledgeable of the ethical issues inherent and should help to ensure the judicious use of experimental therapies. Finally, general misconceptions about the benefits of experimental therapy, pervasive in our culture, heighten the contentiousness of this debate. A workable legislative solution should be accompanied by a thoughtful and deliberate effort to educate patients, their advocates, and broader society about the realistic pace of drug development and the limits of modern medicine. This thesis recognizes that individuals who seek expanded access often have valid moral claims to do so, but advocates a cautious attitude toward the dissemination of experimental drugs for treatment and maintains the importance of government and physician participation in adjudicating access.

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.

no / Alopecia areata is an immunologically mediated disease characterized by extreme variability not only in the time of initial onset of hair loss but in the duration, extent and pattern of hair loss during any given episode of active loss. These variables, as well as the unpredictable nature of spontaneous regrowth and lack of a uniform response to various therapies, has made clinical trials in alopecia areata difficult to plan and implement. In fact, there are currently no drugs FDA-approved specifically for the indication of alopecia areata. To help facilitate well-controlled clinical trials for alopecia areata, this National Alopecia Areata Foundation (NAAF) sponsored subgroup of investigators/clinicians experienced in clinical trials and/or in the clinical care of patients with alopecia areata has outlined some general principles and potential endpoints for clinical studies in alopecia areata. These guidelines build on the Alopecia Areata Investigational Assessment Guidelines published in 1991 which established baseline clinical staging and background information important to gather on any alopecia areata patient involved in clinical research.

Keywords: Non-inferiority Test, Bootstrap, Misclassification, Partially Validated Data. / Moreover, misclassification is frequently encountered in collecting ordinal categorical data. We also consider the non-inferiority test based on the data with misclassification. We have explored two different approaches. The first approach can be applied when misclassification probabilities are known or can be calibrated. The second approach deals with the case when we have partially validated data that provide the information on misclassification. The proposed approaches have wide applications that are not confined to tests in medical research. We design a substantive study to illustrate the practicality and applicability of the proposed approaches. / When a new treatment comes out, it is likely to find benefits of the new one, such as fewer side effects, greater convenience of employment, or lower cost in terms of money and time. Therefore, the more appropriate research question is whether the new one is non-inferior or equivalent to, but not necessarily superior to the reference treatment. Consequently, the non-inferiority test or equivalence test is widely used in medical research, which is oriented towards showing that the difference of effect between the two treatments probably lies in a tolerance interval with the pre-defined lower or upper bounds. In this thesis, we consider non-inferiority tests when the data are ordinal categorical. In particular, we are interested in correlated data. We will develop non-inferiority testing procedures for data that are obtained by the paired design and three-armed design. We take advantage of a latent normal distribution approach to model ordinal categorical data. / Han, Yuanyuan. / Adviser: Poon Wai-Yin. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 114-117). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

A medicina clínica apresentou a partir dos anos 1960 uma certa inflexão em seus mecanismos internos de produzir conhecimento, assim como em sua forma de aplicar esses conhecimentos na prática. A principal diferença em relação ao passado foi que, a partir dessa época, os problemas de natureza clínica, como diagnóstico diferencial, terapêutica e estimativa de prognóstico, passaram a ser processados predominantemente por instrumentos de análise padronizados e, principalmente, submetidos ao escrutínio de uma razão empírico-matemática. A entidade paciente deixou de ser um ente emissor de sintomas e sinais que são processados por um médico, para ser uma nova entidade em que esses signos, previamente estabelecidos e validados pelos estudos clínicos e pela razão matemática, são encaixados pelos médicos nas manifestações dos pacientes. Na mesma época em que esse processo ocorreu o mundo ocidental vivia um período de crise que se caracterizava por um baixo crescimento econômico e por um questionamento por parte da sociedade dos princípios normativos, tanto éticos quanto morais, que regiam sua forma de viver. Nos Estados Unidos, a partir de 1962 passou a ser uma exigência legal que toda droga nova, antes de ser comercializada, deveria provar, através de testes científicos, que ela tinha eficácia terapêutica, que de fato funcionava na patologia que se propunha tratar. A metodologia para promover esse tipo de demonstração foi construída a partir dessa exigência. As regras de prova científica de eficácia foram construídas a partir dessa demanda legal, e são chamadas genericamente de Epidemiologia Clínica. Vários agentes participaram ativamente do processo de definição das regras do método científico que foram então, a partir dessa data, implementadas e sedimentadas. Destacam-se nesse debate, a comunidade acadêmica, a sociedade civil, os economistas, os advogados e juizes, os agentes do governo, e, finalmente, a indústria farmacêutica. Essa última assumiu uma posição de destaque, secretariando, e, de certa forma impondo uma agenda de discussão. O motivo por detrás dessa atitude foi uma profunda crise de legitimidade das regras de operação do negócio farmacêutico em dois de seus principais componentes: os desenvolvimentos tecnológicos, responsáveis pelas inovações na área terapêutica, e, a garantia de um mercado historicamente monopolístico, legitimada pela instituição secular da lei de patentes. Ambos esses institutos passaram, nas décadas de 1960 e 1970, por um conturbado processo de rediscussão de seus fundamentos. Defende-se que essa função de secretariar a discussão por parte da indústria farmacêutica teve um papel de destaque na construção das regras de cientificidade que passaram, desde então, a regular o ato médico. A implementação, aceitação e sedimentação como princípio normativo de prova de verdade dessa metodologia científica, sobretudo na comunidade médica, ocorreu de uma forma muito particular. Discute-se nesse trabalho a história dessa implementação sob duas perspectivas: a história oficial conforme descrita pelo Departamento de História do Food and Drug Administration (FDA, Agência Federal Norte-americana), e, alternativamente, através de uma análise dos discursos proferidos por personagens que direta e efetivamente participaram dessa discussão. Médicos, farmacologistas, advogados, legisladores, economistas, profissionais da indústria farmacêutica e agentes do governo emitiram e discutiram opiniões, e estas foram registradas e publicadas. Esse material compõe a matéria prima em cima da qual trabalha-se no sentido de compor uma história que acaba por ter alguns pontos diferenciais em relação à versão oficial. Em torno desses pontos procura-se produzir um discurso sobre a relação entre ciência, lei, economia, e, prática médica. A dimensão científica dessa história se mistura intensamente com outros aspectos igualmente importantes como: debates legislativos, interesses econômicos de segmentos privados, papel do Estado na regulação econômica, confiabilidade na neutralidade das publicações científicas, participação do mundo acadêmico no desenvolvimento tecnológico de um país, etc.. Defendese que a fusão desses discursos em um formato consensual construiu uma situação em que a referida dimensão técnico-científica passou a ter uma importância relativamente maior do que as outras como instrumento de legitimação da verdade em medicina na sociedade, e que esse fato teve algumas importantes conseqüências práticas, destacando-se: um processo progressivo de desumanização do atendimento médico e a produção de um sistema de barreiras que dificultam o exercício de uma critica eficiente e positiva por parte dos profissionais ligados à pratica médica. Por último, em torno do conceito de humanismo, abordado particularmente dentro da tradição filosófica ocidental, discute-se o quanto essa hipertrofia da dimensão técnica e suas conseqüências práticas, podem ser questionadas em seus fundamentos epistemológicos visando a reconstrução de uma prática médica mais humana e emancipadora. / Since 1960 Clinical Medicine suffered a kind of inflection in its internal mechanisms of producing theoretical knowledge, as well as in the way that this knowledge is applied in practical life. The most important difference in relation to the past was that problems of clinical nature like, differential diagnosis, therapeutical decisions, and prognosis estimation, started to be predominantly processed by standardized analytical instruments, and most important, they were always previously submitted to an empirical-mathematical reasoning. Individual patients were no longer a being that reported signs and symptoms that were processed by a physician, they started to be a new entity in which these signs, previously established and validated by clinical studies have to be necessarily engrafted by the physicians in patients manifestations. At the same time that this process occurred, western world was living an important critical period, characterized by a very slow economic growth, and by a reevaluation of its ethical and moral values. After 1962, in the United States, it became obligatory to prove, through empirical scientific evidence that a new drug was effective, before marketing and sales authorization was issued to a company who wanted to launch the drug. The scientific method designed to prove efficacy of a drug was actually developed after this legal demand. This method is called generically Clinical Epidemiology. Several actors participated in the discussion of the rules of this method. Medical Schools, government representatives, pharmaceutical industry can be cited; the latter played a very special role, since it acted as a secretary of the whole process. The reason behind this was that, at those times, the two major pillars of the pharmaceutical business, innovation capacity and patent law, were being severely criticized, and proposals for changing the way this things were being conducted in American society were about to become a reality. We defend the position that the attitude of the pharmaceutical business representatives, were crucial for the establishment of the scientific rules that were considered consensual, and that these rules, for many reasons, started to be the paradigm of medical reasoning and individual decision in medical problems. Implementation, acceptance, and maintenance of this new clinical scientific method that was born after the legal demand for prove of efficacy of a new drug, particularly in medical community, occurred in a very particular way. We discuss the history of this process under two separate perspectives: the official history, as described by History Department of the Food and Drug Administration, and alternatively, through an analysis of the speeches of persons who actually participated directly in this discussion. Physicians, pharmacologists, lawyers, legislators, economists, pharmaceutical industry representatives, government members and politicians, all these groups, emitted their opinions and these were registered and published. This is the row material that was used to composite a new story of the whole process, and the result of this work is somehow different from the official history reported before. The scientific dimension of this story is mixed up with other important aspects like: legislative debates, private economical interests, the role of the State in regulating the economy, academic participation in decisions related to economic growth of a country, etcWe try to prove that the intersection of all these interests in a consensual framework built up a situation in which the previously referred technical-scientific dimension started to have a relatively bigger importance in relation to the other aspects as an instrument to legitimate what is truth (or what is false) in clinical medicine, to the whole body of the society. This fact brought two important practical consequences: a progressive reduction in other human aspects of clinical medicine apart from technology, and, the development of a system of barriers that jeopardize the possibility of a critical attitude towards the scientific method from those who practice medicine. Around the concept of humanism, studied particularly inside western philosophical tradition, we discuss how much this so called hypertrophy of the technical-scientific dimension and its practical consequences can be scrutinized and questioned in its epistemological foundations in order to rebuild a new medicine more human and critical.

Pharmaceuticals have benefitted countless lives. New therapies are being developed every day—many prove effective, but many do not. In order to ensure only safe and effective drugs enter the market, the United States' Food and Drug Administration (FDA) approves each treatment based on data garnered from clinical trials. Clinical trials take time, however, and investigational new drugs (INDs) can demonstrate signs of efficacy long before approval. These cases introduce a fundamental question: should the government limit patient access to a drug that has yet to be proven safe and effective? Or do patients have the right to freedom from governmental intervention in their medical decision-making? In this paper, the history of IND regulation will be explored, followed by an examination of the freedom to access from constitutional, ethical, and infrastructural perspectives. Changes to the current system will then be proposed.

A medicina clínica apresentou a partir dos anos 1960 uma certa inflexão em seus mecanismos internos de produzir conhecimento, assim como em sua forma de aplicar esses conhecimentos na prática. A principal diferença em relação ao passado foi que, a partir dessa época, os problemas de natureza clínica, como diagnóstico diferencial, terapêutica e estimativa de prognóstico, passaram a ser processados predominantemente por instrumentos de análise padronizados e, principalmente, submetidos ao escrutínio de uma razão empírico-matemática. A entidade paciente deixou de ser um ente emissor de sintomas e sinais que são processados por um médico, para ser uma nova entidade em que esses signos, previamente estabelecidos e validados pelos estudos clínicos e pela razão matemática, são encaixados pelos médicos nas manifestações dos pacientes. Na mesma época em que esse processo ocorreu o mundo ocidental vivia um período de crise que se caracterizava por um baixo crescimento econômico e por um questionamento por parte da sociedade dos princípios normativos, tanto éticos quanto morais, que regiam sua forma de viver. Nos Estados Unidos, a partir de 1962 passou a ser uma exigência legal que toda droga nova, antes de ser comercializada, deveria provar, através de testes científicos, que ela tinha eficácia terapêutica, que de fato funcionava na patologia que se propunha tratar. A metodologia para promover esse tipo de demonstração foi construída a partir dessa exigência. As regras de prova científica de eficácia foram construídas a partir dessa demanda legal, e são chamadas genericamente de Epidemiologia Clínica. Vários agentes participaram ativamente do processo de definição das regras do método científico que foram então, a partir dessa data, implementadas e sedimentadas. Destacam-se nesse debate, a comunidade acadêmica, a sociedade civil, os economistas, os advogados e juizes, os agentes do governo, e, finalmente, a indústria farmacêutica. Essa última assumiu uma posição de destaque, secretariando, e, de certa forma impondo uma agenda de discussão. O motivo por detrás dessa atitude foi uma profunda crise de legitimidade das regras de operação do negócio farmacêutico em dois de seus principais componentes: os desenvolvimentos tecnológicos, responsáveis pelas inovações na área terapêutica, e, a garantia de um mercado historicamente monopolístico, legitimada pela instituição secular da lei de patentes. Ambos esses institutos passaram, nas décadas de 1960 e 1970, por um conturbado processo de rediscussão de seus fundamentos. Defende-se que essa função de secretariar a discussão por parte da indústria farmacêutica teve um papel de destaque na construção das regras de cientificidade que passaram, desde então, a regular o ato médico. A implementação, aceitação e sedimentação como princípio normativo de prova de verdade dessa metodologia científica, sobretudo na comunidade médica, ocorreu de uma forma muito particular. Discute-se nesse trabalho a história dessa implementação sob duas perspectivas: a história oficial conforme descrita pelo Departamento de História do Food and Drug Administration (FDA, Agência Federal Norte-americana), e, alternativamente, através de uma análise dos discursos proferidos por personagens que direta e efetivamente participaram dessa discussão. Médicos, farmacologistas, advogados, legisladores, economistas, profissionais da indústria farmacêutica e agentes do governo emitiram e discutiram opiniões, e estas foram registradas e publicadas. Esse material compõe a matéria prima em cima da qual trabalha-se no sentido de compor uma história que acaba por ter alguns pontos diferenciais em relação à versão oficial. Em torno desses pontos procura-se produzir um discurso sobre a relação entre ciência, lei, economia, e, prática médica. A dimensão científica dessa história se mistura intensamente com outros aspectos igualmente importantes como: debates legislativos, interesses econômicos de segmentos privados, papel do Estado na regulação econômica, confiabilidade na neutralidade das publicações científicas, participação do mundo acadêmico no desenvolvimento tecnológico de um país, etc.. Defendese que a fusão desses discursos em um formato consensual construiu uma situação em que a referida dimensão técnico-científica passou a ter uma importância relativamente maior do que as outras como instrumento de legitimação da verdade em medicina na sociedade, e que esse fato teve algumas importantes conseqüências práticas, destacando-se: um processo progressivo de desumanização do atendimento médico e a produção de um sistema de barreiras que dificultam o exercício de uma critica eficiente e positiva por parte dos profissionais ligados à pratica médica. Por último, em torno do conceito de humanismo, abordado particularmente dentro da tradição filosófica ocidental, discute-se o quanto essa hipertrofia da dimensão técnica e suas conseqüências práticas, podem ser questionadas em seus fundamentos epistemológicos visando a reconstrução de uma prática médica mais humana e emancipadora. / Since 1960 Clinical Medicine suffered a kind of inflection in its internal mechanisms of producing theoretical knowledge, as well as in the way that this knowledge is applied in practical life. The most important difference in relation to the past was that problems of clinical nature like, differential diagnosis, therapeutical decisions, and prognosis estimation, started to be predominantly processed by standardized analytical instruments, and most important, they were always previously submitted to an empirical-mathematical reasoning. Individual patients were no longer a being that reported signs and symptoms that were processed by a physician, they started to be a new entity in which these signs, previously established and validated by clinical studies have to be necessarily engrafted by the physicians in patients manifestations. At the same time that this process occurred, western world was living an important critical period, characterized by a very slow economic growth, and by a reevaluation of its ethical and moral values. After 1962, in the United States, it became obligatory to prove, through empirical scientific evidence that a new drug was effective, before marketing and sales authorization was issued to a company who wanted to launch the drug. The scientific method designed to prove efficacy of a drug was actually developed after this legal demand. This method is called generically Clinical Epidemiology. Several actors participated in the discussion of the rules of this method. Medical Schools, government representatives, pharmaceutical industry can be cited; the latter played a very special role, since it acted as a secretary of the whole process. The reason behind this was that, at those times, the two major pillars of the pharmaceutical business, innovation capacity and patent law, were being severely criticized, and proposals for changing the way this things were being conducted in American society were about to become a reality. We defend the position that the attitude of the pharmaceutical business representatives, were crucial for the establishment of the scientific rules that were considered consensual, and that these rules, for many reasons, started to be the paradigm of medical reasoning and individual decision in medical problems. Implementation, acceptance, and maintenance of this new clinical scientific method that was born after the legal demand for prove of efficacy of a new drug, particularly in medical community, occurred in a very particular way. We discuss the history of this process under two separate perspectives: the official history, as described by History Department of the Food and Drug Administration, and alternatively, through an analysis of the speeches of persons who actually participated directly in this discussion. Physicians, pharmacologists, lawyers, legislators, economists, pharmaceutical industry representatives, government members and politicians, all these groups, emitted their opinions and these were registered and published. This is the row material that was used to composite a new story of the whole process, and the result of this work is somehow different from the official history reported before. The scientific dimension of this story is mixed up with other important aspects like: legislative debates, private economical interests, the role of the State in regulating the economy, academic participation in decisions related to economic growth of a country, etcWe try to prove that the intersection of all these interests in a consensual framework built up a situation in which the previously referred technical-scientific dimension started to have a relatively bigger importance in relation to the other aspects as an instrument to legitimate what is truth (or what is false) in clinical medicine, to the whole body of the society. This fact brought two important practical consequences: a progressive reduction in other human aspects of clinical medicine apart from technology, and, the development of a system of barriers that jeopardize the possibility of a critical attitude towards the scientific method from those who practice medicine. Around the concept of humanism, studied particularly inside western philosophical tradition, we discuss how much this so called hypertrophy of the technical-scientific dimension and its practical consequences can be scrutinized and questioned in its epistemological foundations in order to rebuild a new medicine more human and critical.

Contract Research Organization (CRO) industry has been a fast growingservice sector within the pharmaceutical and biotechnology industry since the early 1980’s. Aiming at assisting its clients in obtaining product registration and market approval from the health authorities (i.e. Food and Drug Administration of the US and Department of Health of Taiwan), CRO’s provide extensive consultations as well as clinical research and management services, covering both pre-clinical and clinical arenas. In recent years, global CRO’s have been expanding towards the Southeastern Asian (thereafter “SEA”) region targeting, Singapore, Taiwan, Hong Kong, China, and South Korea. While most of the empirical research on market entry mode has targeted the manufacturing industries, more recent studies have been completed on service sectors targeting advertising and financing industries. Since the history of CRO is relatively short, limited study has been performed on this industry, especially on the international entry patterns and behaviors for the CRO industry. This research document examines the current environments of CRO industry in Taiwan and Singapore and the factors influencing international company’s decisions on the entry mode. A recommendation of the best options to enter Taiwan and Singapore for the international CRO’s is presented. The paper concludes with findings as well as recommendations for further investigation directions.

Magister Pharmaceuticae - Mpharm / The aim of this study was to determine quality control specifications needed for a dossier and an investigator's brochure of A. afra capsules, which can be used to motivate the registration and clinical testing of A. afra capsules in chronic asthma. The specific objectives were: (1) to establish the minimum product quality requirements for registration of A. afra capsules, (2) to prepare and pharmaceutically characterize a capsule product of A. afra freeze dried aqueous extract (FDAE) suitable for registration, and (3) to identify pharmaceutical product quality aspects of an investigator's brochure (IB) that would be appropriate for use in motivating a clinical trial of A. afra capsules in chronic asthma.

Independent from initial severity, many patients develop persistent symptoms after infection with SARS-CoV-2, described as long COVID syndrome. Most of these patients are treated by general practitioners (GPs). As evidence-based treatment recommendations are still sparse, GPs must make their therapy decisions under uncertainty. We investigated (1) the most frequently observed long COVID symptoms in general practices and (2) GPs' applied treatment and rehabilitation plans for these symptoms. In total, 143 German GPs participated in an online-based survey between 05/2021 and 07/2021. We found that each GP practice was treating on average 12 patients with long COVID symptoms. Most frequently seen symptoms were fatigue and reduced performance. Current therapy options were rated as poor and loss of smell and taste, fatigue, or lack of concentration were perceived to be especially difficult to treat. The use of drug and non-drug therapies and specialist referrals focused primarily on physiological and less on psychosomatic/psychological rehabilitation and followed guidelines of similar conditions. Our results provide first insights into how GPs approach a newly emerging condition in the absence of guidelines, evidence-based recommendations, or approved therapies, and might inform about GP preparedness in future pandemics. Our results also emphasize a gap between the current knowledge of the long COVID manifestation and knowledge about effective rehabilitation.