Today, Real World Data (RWD) is a popular topic in many studies. In particular, it is anticipated to be a significant resource for addressing issues brought on by drug development costs, lengthy development times, and safety concerns. The Swedish healthcare Quality Registries (QR) are studied to contribute to the improvement of health care with individual-based clinical data. Recorded data is used for quality improvement, guidance compliance monitoring, and research. However, the workflow for such a framework that applies RWD which is patient-related data that came from various sources to the new drug development field is currently not well-defined. Thus the main aim of this project is to establish a strategy for integrating RWD with pharmaceutical modeling. To achieve this aim, QRs were examined through an ontological approach. The data and procedures necessary for modeling the development of new drugs, as well as the correspondence of the pieces offered by QR, were studied to assess the feasibility. The modeling of new drug development was studied for three applications: Adverse Drug Event (ADE), Computer-based Simulation (CBS), and drug repurposing, and the analysis of QRs was conducted on seven diseases. After in-depth analysis, although there were differences between the registries, it showed enough feasibility in terms of how much the data provided in the studies on drug repurposing and computer-based simulation satisfied the items required for new drug development. However, in the case of rare diseases, given the lack of an automated method, the ethical ambiguity, and the speed of the process, there still seems to be potential for improvement.  Many registries have begun to support research on the development of novel medications, such as by independently recording the features of drugs. These initiatives could enable the future potential of new Real World Evidence (RWE) such as in the field of proteomics and genomics discovery. / Idag är Real World Data (RWD) ett populärt ämne i många studier. I synnerhet förväntas det vara en betydande resurs för att ta itu med problem som orsakas av kostnader för läkemedelsutveckling, långa utvecklingstider och säkerhetsproblem. Kvalitetsregistren studeras för att bidra till att förbättra hälso- och sjukvården med individbaserade kliniska data. Registrerade data används för kvalitetsförbättring, övervakning av efterlevnad av riktlinjer och forskning. Arbetsflödet för ett sådant ramverk som tillämpar RWD som är patientrelaterad data som kom från olika källor till det nya läkemedelsutvecklingsområdet är dock för närvarande inte väldefinierat. Därför är huvudsyftet med detta projekt att upprätta en strategi för att integrera RWD med läkemedelsmodellering. För att uppnå detta mål undersöktes kvalitetsregister genom ett ontologiskt tillvägagångssätt. De data och procedurer som krävs för att modellera utvecklingen av nya läkemedel, såväl som överensstämmelsen mellan de bitar som erbjuds av kvalitetsregister, studerades för att bedöma genomförbarheten. Modelleringen av utvecklingen av nya läkemedel studerades för tre tillämpningar: skadlig läkemedelseffekt, datorbaserad simulering och återanvändning av läkemedel, och analys av kvalitetsregister genomfördes på sju sjukdomar. Efter en djupgående analys, även om det fanns skillnader mellan registren, visade den tillräcklig genomförbarhet när det gäller hur mycket data som tillhandahållits i studierna om läkemedelsåteranvändning och datorbaserad simulering uppfyllde de krav som krävdes för utveckling av nya läkemedel. Men när det gäller sällsynta sjukdomar, med tanke på avsaknaden av en automatiserad metod, den etiska oklarheten och processens snabbhet, verkar det fortfarande finnas potential för förbättringar. Många register har börjat stödja forskning om utveckling av nya mediciner, till exempel genom att oberoende registrera drogens egenskaper. Dessa initiative skulle kunna möjliggöra den framtida potentialen för nya verkliga bevis, såsom inom området för proteomik och genomik.

在各大藥廠明星藥品專利到期、新藥開發數量銳減的當下，全球首例植物新藥MediGene Veregen™ 的核准上市為製藥產業帶來新的希望，雖然製藥價值鏈與商品化模式已為人所熟知，但針對植物新藥特殊性所架構之商品化模式還是一個全新的議題，為了架構一個適合台灣中小型藥廠的植物新藥開發模式，本研究嘗試以技術層面為根基，從法規面、產品面與產業面深入探討MediGene Veregen™ 關鍵的成功因素，從中獲取值得台灣藥廠參考的經驗，同時考量台灣植物新藥開發的大環境限制因素，包括法規與健保，給予台灣藥廠一些植物新藥商品化策略建議。 本研究之架構以實務觀點出發，首先整理參考文獻以探討植物新藥包含的範圍與藥品開發流程，幫助藥廠了解植物新藥商品化需要具備的條件與資訊；接著針對台灣與美國在植物新藥方面審查上市之法規、流程與審核成果進行研究，結果顯示目前台灣有兩種植物新藥審查系統「中藥新藥」與「植物抽取新藥」，對廠商而言並不如美國單一系統來得便利；再者藉由探討植物新藥的價值鏈結構、法規結構、產品結構與產業結構，試圖架構植物新藥商品化模式；接下來以兩家新藥開發廠商為例進行實際個案研究，一家為成功推出植物新藥商品的德國藥廠MediGene AG，一家為台灣藥廠中天生技/合一生技，主要藉由分析MediGene Veregen™ 商品化過程的關鍵成功因素，比較中天生技/合一生技WH-1商品化模式的異同，探討是否有足以借鏡與改進之處。最後，歸納整理上述的研究做出結論，並且對於台灣藥廠提出策略建議，希望能對於台灣新藥開發公司有實質上的幫助。 / While the star drug patents of each big pharmaceutical company are expired one after another and the quantity of their newly developed drugs sharply declines in these years, MediGene Veregen™, the first botanical new drug in the world, enters the market and therefore brings a new hope for the pharmaceutical industry. Although the value chain and the commercialization model of pharmaceutical industry have been known and researched a lot, the specific construction of commercialization model for botanical drugs is still a brand new subject. In older to construct the model that is suitable for Taiwanese middle and small pharmaceutical companies for the process from development to commercialization of botanical new drugs, this research, based on the technical analysis, attempts to discuss the key success factors of MediGene Veregen™ through analyzing the aspects of the laws, regulations, industry and product itself. With the case study about the environmental limited factors of new drug development in Taiwan, including the laws and regulations as well as the health insurance, this research tries to offer Taiwan pharmaceutical companies some strategic suggestions for the development and commercialization of botanical new drugs. The structure of this research is based on the practical viewpoints. First, we reorganize the reference in order to define the scope of botanical new drugs and the processes of drug development. It can help pharmaceutical companies understand the conditions and information needed for botanical new drug commercialization. Then, our studies focus on the laws and regulations in Taiwan and the United States, as well as the application processes and approvals for botanical new drugs. The results show that there are two evaluation systems in Taiwan for botanical new drug applications. For those pharmaceutical companies, the dual system is not as convenient as the sole evaluation system in the States. Furthermore; based on the discussion on the structure of the value chain, laws, regulations, product and industry, this paper makes an attempt to construct a better commercialization model of botanical new drugs. Next, two pharmaceutical companies are chosen as case study in this paper. One is a German pharmaceutical company, MediGene AG, which launched the first botanical new drug. The other is a Taiwan pharmaceutical company, MicroBio Co., Ltd/Oneness Bio-Tech Co., Ltd. By analyzing the key success factors in the commercialization process of MediGene Veregen™ and comparing its commercialization model with MicroBio Co., Ltd/Oneness Bio-Tech Co. WH-1, we try to get any valuable idea and insight. Finally, our conclusion and strategic suggestions may have solid help for Taiwan botanical new drug pharmaceutical companies.

O constante crescimento mundial da Pesquisa Clínica no desenvolvimento de novas drogas foi responsável pelo aumento do interesse em traçar as atividades desenvolvidas pelas Autoridades Regulatórias. Os dados foram obtidos através de revisão bibliográfica sistemática, destacando o tempo de aprovação dos protocolos clínicos e as normatizações vigentes: no Brasil, Estados Unidos da América, União Europeia, Canadá e Japão. Além disso, observou-se a atuação de profissionais experientes na realização de atividades no Comitê de Ética para Análise de Projetos de Pesquisa (CAPPesq) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Com isso, foi possível identificar as diferenças significantes em relação à legislação e ao sistema regulatório dos países em questão. Deficiências no sistema regulatório brasileiro responsáveis pela demora no tempo de aprovação foram constatadas. Com a identificação destes fatores, foram elaboradas sugestões relacionadas à qualificação dos profissionais atuantes, organização das atividades desempenhadas pelas Autoridades Regulatórias e possíveis alterações administrativas. A diferente atuação das autoridades analisadas pode servir como fonte de aprimoramento do sistema regulatório nacional e, consequentemente, aprimorar o processo para aprovação e realização de protocolos clínicos com medicamentos testados no Brasil. / The world-wide Clinical Research for new drug development growth was responsible for the increase of interest in following the regulatory authorities activities. Data were collected through a systematic literature review.The main facts observed were clinical protocols time approval and guidelines in Brazil, United States of America, European Union, Canada and Japan. In addition, it was observed the activities realized by experienced professionals of the IRB of the University of São Paulo School of Medicine. Significant legislation and regulatory system differences between the countries were identified. Some deficiencies at Brazilian regulatory system, suggestions regarding the acting professionals qualification, organization of the regulatory authorities activities and possible administrative changes were discussed. The different performance of the regulatory authorities can serve as a source to upgrade the national regulatory system and consequently lead to improvements in process of approval and realization of clinical protocol with drugs tested in Brazil.

O constante crescimento mundial da Pesquisa Clínica no desenvolvimento de novas drogas foi responsável pelo aumento do interesse em traçar as atividades desenvolvidas pelas Autoridades Regulatórias. Os dados foram obtidos através de revisão bibliográfica sistemática, destacando o tempo de aprovação dos protocolos clínicos e as normatizações vigentes: no Brasil, Estados Unidos da América, União Europeia, Canadá e Japão. Além disso, observou-se a atuação de profissionais experientes na realização de atividades no Comitê de Ética para Análise de Projetos de Pesquisa (CAPPesq) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Com isso, foi possível identificar as diferenças significantes em relação à legislação e ao sistema regulatório dos países em questão. Deficiências no sistema regulatório brasileiro responsáveis pela demora no tempo de aprovação foram constatadas. Com a identificação destes fatores, foram elaboradas sugestões relacionadas à qualificação dos profissionais atuantes, organização das atividades desempenhadas pelas Autoridades Regulatórias e possíveis alterações administrativas. A diferente atuação das autoridades analisadas pode servir como fonte de aprimoramento do sistema regulatório nacional e, consequentemente, aprimorar o processo para aprovação e realização de protocolos clínicos com medicamentos testados no Brasil. / The world-wide Clinical Research for new drug development growth was responsible for the increase of interest in following the regulatory authorities activities. Data were collected through a systematic literature review.The main facts observed were clinical protocols time approval and guidelines in Brazil, United States of America, European Union, Canada and Japan. In addition, it was observed the activities realized by experienced professionals of the IRB of the University of São Paulo School of Medicine. Significant legislation and regulatory system differences between the countries were identified. Some deficiencies at Brazilian regulatory system, suggestions regarding the acting professionals qualification, organization of the regulatory authorities activities and possible administrative changes were discussed. The different performance of the regulatory authorities can serve as a source to upgrade the national regulatory system and consequently lead to improvements in process of approval and realization of clinical protocol with drugs tested in Brazil.

After numerous renewals and reignitions since the initiation of the "War on Cancer" more than five decades ago, the recent reignition of "Moonshot to Cure Cancer" points to the systemic persistence of cancer as a major cause of loss of life and livelihood. Literature points to the diminishing returns of cancer research through time, as well as heterogeneities in cancer research centers' innovation strategies. This dissertation focuses on the strategic decision by cancer research centers to invest their resources in conducting early phases of clinical trials on new candidate drugs/treatments (resembling exploration) or late phases of clinical trials that push established candidates towards acquiring FDA approvals (resembling exploitation). The extensive clinical trials data suggests that cancer research centers are not only different in their emphasis on exploratory trials, but also in how their emphasis is changing over time. This research studies the dynamics of this heterogeneity in cancer research centers' innovation strategies, how experiential learning and capability development interact to cause dynamics of divergence among learning agents, and how the heterogeneity among cancer research centers' innovation strategies is affected by the dynamics of learning from experience and capability development. The findings of this dissertation shows that endogenous heterogeneities can arise from the process of learning from experience and accumulation of capabilities. It is also shown that depending on the sensitivity of the outcome of decisions to the accumulated capabilities, such endogenous heterogeneities can be value-creating and thus, justified. Empirical analysis of cancer clinical trials data shows that cancer research centers learn from success and failure of their previous trials to adopt more/less explorative tendencies. It also demonstrates that cancer research centers with a history of preferring exploratory or FDA trials have the tendency to increase their preference and become more specialized in one specific type (endogenous specialization). These behavioral aspects of the cancer research centers' innovation strategies provide some of the tools necessary to model the behavior of the cancer research efforts from a holistic viewpoint. / Doctor of Philosophy / The "Moonshot to Cure Cancer" was renewed most recently in September 2022. However, renewal and reignition of this national collective effort is nothing new; this effort started as "War on Cancer" in 1971 and has been reignited numerous times. After more than 50 years of our collective battle to cure cancer, it claims almost 600,000 lives annually and remains as the second leading cause of death in the US. There are a wide variety of cancer research centers from all around the world contributing to this collective effort and they make considerably different decisions regarding their investment in research. There is evidence suggesting that some of the research centers' investment decisions are not optimal and can be improved. It has been shown that systems such as patent regulations can be revised to encourage such improved decisions among cancer research centers. This dissertation focuses on the process of clinical trials for new drugs/treatments for cancer. New drugs/treatments have to pass different phases of trials to ensure that they are safe and effective before they can acquire FDA approvals. Cancer research centers decide whether to invest in early phases of clinical trials for new drug/treatment candidates or invest in late phases of trials for candidates that have already passed the early phases. The clinical trials data show that there has been a sharp rise in number of early phases of trials on new drugs/treatments; however, the same rise cannot be seen in the late phases of trials resulting in approvals. It can also be seen that different research centers put different levels of emphasis on initiating early phases of trials for new drugs/treatments (exploration). In this dissertation, the hypothesis is that this ongoing dilemma that cancer research centers face to invest on how much emphasis to put on exploration in their clinical trials is affected by learning from experience. To test this hypothesis, a mathematical model is used to show differences in decisions can be causes solely by learning from experience, when the decision maker is learning "what to do" from success/failure of previous efforts and learning "how to do it" from practicing and accumulating the required skills. Then, the hypothesis is formally tested using the clinical trials data. The results show that cancer research centers learn from the success and failure of their previous exploratory trials when deciding on their emphasis on exploration. Also, they accumulate skills, resources, and capabilities relevant to the type of research the conduct more often and specialize in either of late- or early-phases of trials. The findings of this dissertation show that learning from experience can cause in differences in decisions. It also finds evidence that cancer research centers learn to place different levels of emphasis on exploration in their clinical trials. These findings can later be used in models of the cancer research ecosystem to study how funding structures and policies can be changed to improve the outcomes of our collective effort to cure cancer.

有鑑於生物科技成為科技趨勢，以及其創造出的龐大價值，近年來台灣也開始大力推動生技產業的發展。產業是企業的組合，企業的成長與否正是驅動產業生態變化的主要原因。本研究主要探討台灣生技藥物研發公司的創業過程，希望透過研究成果對台灣生技公司的發展有所貢獻。 　　本研究的研究架構以Timmons Model做為主軸，以機會、資源、團隊做為主要的研究構面，先對個案公司進行靜態的研究構面探討，然後分析其發展的動態平衡過程。 / Because biotechnology sets a trend and creates great value, Taiwan government tries to develop his own biotechnology industry. However, an industry will bloom if most of companies related to the industry are operated well. The objective of this study is to observe and analyze the entrepreneurial process of biomedical R&D companies in Taiwan. 　　The research bases on Timmons Model that was developed by Timmons for analyzing an entrepreneurial process of a company and consists of three driving forces, opportunity, resource, and team. Every entrepreneurial process of companies in the thesis is observed first according to the three driving forces. Then it is analyzed by using the idea of constant balancing.

生技產業為我國未來六大明星產業之一，除政府成立生技創投基金，民間企業也陸續加入這波生技投資行列，如永豐餘集團旗下的上智生技創投，與潤泰集團旗下的鑽石生技投資。以籌資來源而言，又分為借款融資關係(負債端)的外部資金，以及股東投資關係(權益端)的自有資金兩種，對於公司經營各有優缺點，亦應取得平衡。唯目前多數為權益端的資金投入，尤其以該產業中風險最高的新藥研發公司為例，仍普遍高達95%以上的股東權益比率。顯示其籌資來源有限，且難以吸引負債端的投資者參與。而這樣的資金來源比例，除不符合企業融資順位理論於公司成長階段的籌資策略與負債權益比率，權益端資金多以短期獲得高利潤為目的，以資金性質亦不適合占資產達95%以上之比例。 以目前負債端籌資管道，新藥研發公司多數利用台灣中小企業信用保證基金直保部或經濟部促進產業創新或研究發展貸款計畫專案申請，唯融資額度上限遠不足以支付藥物開發費用，且非一般負債端直接經由銀行評估取得融資之方式。綜觀國際業態，單一全新藥物開發至上市平均需約USD8億元(約NTD240億元)不等，而台灣公司的研發策略多數為分段發展或老藥新用(藥物重新定位)策略，但仍有高度資金需求。唯銀行、負債端投資者普遍缺乏投入該產業的意願，主要顧慮為具冗長的產品研發週期業態、高度不確定性的產品上市審查、長期臨床試驗伴隨的高額成本。此外，對於資金專注研發之新藥研發公司，亦面臨擔保品不足之問題。而實務上，負債端資金提供者如銀行，對於複雜的生技領域與新藥研發公司業態不甚了解，為降低融資意願的另一主因。 故本研究旨在建立一套適用於新藥研發公司之一般性價值評估方式，解決此雙方認知差異問題，以增加更多元的籌資管道。其中，本文參考其他國家評估方法，選擇其中針對技術型公司、發展久遠的韓國技術信用保證基金KOTEC評估模式，導入台灣微脂體、基亞生物科技、賽德醫藥科技3間新藥研發公司個案作一評估。並於最後研究結論，經由分析比較個案公司間歷年經營狀況，得出公司整體與個別質、量性指標項目量化的相對分數，以台灣微脂體分數157分最高，基亞生技次之。本研究亦參考個案評估狀況，得出該類公司較佳的一般性經營策略結論，發現公司創立早期可先以開發週期短、風險較低的老藥新用開發以代替副業產生短期營收的效用，同時累積本業開發經驗，待時機成熟再轉入全新藥物開發為一攻守兼具的經營模式，以供新藥研發公司參考。此外，本研究屬於探索性研究，僅於評估新藥研發公司分數階段，尚未轉換為公司融資評等。該部分尚待具一定案源量後，以統計模型將評估分數與還款違約率關聯性做一分析，方能計算融資評等。而建立內部評等模型、資訊系統對台灣銀行規模而言，為一額外高昂成本，亦建議可效法韓國由政府主導為可行方式之一。 / The biotechnology industry is one of the six future stars of the industries in Taiwan. The government established Biotechnology Venture Capital (BVC), and the more and more private companies joined the procession of biotech investments, such as the two famous biotech funds, Taiwan Global BioFund (TGB) and Diamond BioFund Inc.. According to sources of funding, we can divided them into two groups: one is the loan of external funds (liability side), and the other is the shareholder investment of internal funds (equity side), both of them have different advantages and disadvantages for the company, and the company should strike a balance between these advantages and disadvantages. However, the majority of the funds are invested from the equity side, especially the new drug development companies, which are the highest risk types in the industry, and most of their equity ratio is higher than 95 %. This information indicates the limited sources of funding, and the difficulty to attract liability side’s investors to participate. That proportion of funding sources doesn’t comply with the company’s financing strategy and debt to equity ratio in the growth stage of the enterprise life cycle in the pecking order theory, and equity side’s funds are not suitable for accounting for more than 95% of assets in balance sheet because most of them want to get high profits in the short-term. Currently, major new drug development companies usually apply for loans from the Direct Guarantee Dept. of the Small & Medium Enterprise Credit Guarantee Fund of Taiwan (Taiwan SMEG) or the Promote Industrial Innovation or R&D Loan Program of Industrial Development Bureau in Taiwan, but the amount of loan is insufficient to cover the costs for the new drug development, and this method is not a general way to obtain liability side’s financing from the bank’s direct evaluation. In the international situation, the progress from development to sale of a single new drug spends about US $800 million (about NT $24 billion) on average. Despite Taiwan's R&D strategies only cover the sectional development progress or the policy of the new usage of old drugs (drug repositioning), there is still a high degree of capital requirement. However, in the present, banks and other liability side’s investors still lack the will to invest in the new drug development companies. These investors concern about several major problems, including the lengthy product development cycle, high uncertainty of the product examination and approval, the high cost of long-term clinical trials in this industry. In addition, these companies are also faced with the problem of lacking collateral, because they invest much money in new drug R&D. On the other hand, liability side’s investors, such as banks, don’t understand the complex field of new drug development companies' business models, and this situation becomes another reason for reducing the financing will. Therefore, we should establish a general evaluation method applicable to new drug development companies, to solve the problem of cognitive differences between liability side’s investors and the borrowers, and expand the funding sources of these companies. This article refers to the actual evaluation method in other countries, chooses the most suitable and well developed evaluation model --- Korea Technology Finance Corporation (KOTEC)’s evaluation method for the technology-based company, and utilizes the method to evaluate three cases of the new drug development companies in Taiwan, including Taiwan Liposome Co., Medigen Biotechnology Crop., and CytoPharm, Inc.. In conclusion of the study, by analyzing and comparing the three companies’ operating situations in recent years, we can get relative quantified scores from the companies’ overall and individual qualitative, quantitative indicators, and the result is that Taiwan Liposome Co. gets the highest score, 157 points, then Medigen Biotechnology Crop. gets the middle one. This study also refers the case situations, to find a better general business strategy for such companies. We find that new drug development company in the early stage can focus on new usage development of old drugs ,which has advantages of short development cycle and lower risk, to replace the sideline that generates short-term revenue, and accumulate the experience of drug development. When the time is ripe, it can transfer to new drug development. This way is the general suggestion of both offensive and defensive business model for new drug development companies. In addition, this study is an exploratory research, which only focuses on the evaluation stage, and has not converted the result into a corporate financing credit rating. To calculate financing credit ratings, we require a lot of historical cases data to establish a statistical analysis model, and link evaluation scores with repayment default rates. The establishment of an internal rating model or information system incurs high additional costs for the size of the banks in Taiwan, so the recommended one of the possible ways is that we can follow the example led by the South Korea Government.