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‣ Avaliação do desenvolvimento de drogas em onco-hematologia : valor preditivo dos estudos de fase I e importância da incorporação da terapia personalizada; Evaluation of the drug development process in oncology-hematology : predictive value of phase I studies and importance of the incorporation of personalized therapy

Denis Leonardo Fontes Jardim
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/11/2014 Português
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Tradicionalmente, o modelo de desenvolvimento de drogas em onco-hematologia utiliza-se de estudos de fase I como a primeira etapa no desenvolvimento clínico de uma droga. Nesses estudos, procura-se estabelecer a dose recomendada de novos agentes e seu perfil de segurança inicial, sendo as toxicidades o principal desfecho a ser monitorado. Posteriormente, estudos de registro são conduzidos para a aprovação de novas medicações por agências regulatórias. A maioria das medicações foi historicamente desenvolvida para uma população não-selecionada de um subtipo tumoral. No entanto, recentemente, o conhecimento em onco-hematologia vem sofrendo profundas mudanças, principalmente com o advento de novas técnicas de biologia molecular que permitem um melhor conhecimento da biologia das neoplasias. Com isso, é crescente a percepção de que existem subpopulações de pacientes com alterações moleculares específicas que demandam estratégias direcionadas; também é crescente o número de novas drogas de alvo molecular em desenvolvimento. Nesse contexto, é pouco sabido se o modelo tradicional de desenvolvimento de drogas, historicamente utilizado para medicações citotóxicas e para populações não selecionadas, estaria adequado frente essas novas demandas. Neste projeto de doutorado...

‣ Fish drug analysis—Phish-pharm: A searchable database of pharmacokinetics data in fish

Reimschuessel, Renate; Stewart, Leslie; Squibb, Elizabeth; Hirokawa, Keiko; Brady, Tiffany; Brooks, Deborah; Shaikh, Badar; Hodsdon, Clifford
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Publicado em 22/09/2005 Português
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Information about drug residues and pharmacokinetic parameters in aquatic species is relatively sparse. In addition, it is difficult to rapidly compare data between studies due to differences in experimental conditions, such as water temperatures and salinity. To facilitate the study of aquatic species drug metabolism, we constructed a Fish Drug/Chemical Analysis Phish-Pharm (FDA-PP) database. This database consists of more than 400 articles that include data from 90 species (64 genera) of fish. Data fields include genus, species, water temperatures, the average animal weight, sample types analyzed, drug (or chemical) name, dosage, route of administration, metabolites identified, method of analysis, protein binding, clearance, volume of distribution in a central compartment (Vc) or volume of distribution at steady-state (Vd), and drug half-lives (t1/2). Additional fields list the citation, authors, title, and Internet links. The document will be periodically updated, and users are invited to submit additional data. Updates will be announced in future issues ofThe AAPS Journal. This database will be a valuable resource to investigators of drug metabolism in aquatic species as well as government and private organizations involved in the drug approval process for aquatic species.

‣ Post-Approval Drug Safety Surveillance

Gibbons, Robert D.; Amatya, Anup K.; Brown, C. Hendricks; Hur, Kwan; Marcus, Sue M.; Bhaumik, Dulal K.; Mann, J. John
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 21/04/2010 Português
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Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality.

‣ Price, Performance, and the FDA Approval Process: The Example of Home HIV Testing

Paltiel, A. David; Pollack, Harold A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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The Food and Drug Administration (FDA) is considering approval of an over-the-counter, rapid HIV test for home use. To support its decision, the FDA seeks evidence of the test’s performance. It has asked the manufacturer to conduct field studies of the test’s sensitivity and specificity when employed by untrained users. In this paper, we argue that additional information should be sought to evaluate the prevalence of undetected HIV in the end-user population. Our analytic framework produces the elementary but counterintuitive finding that the performance of the home HIV test – measured in terms of its ability to correctly detect the presence and absence of HIV infection among the people who purchase it – depends critically on the manufacturer’s retail price. This finding has profound implications for the FDA’s approval process.

‣ Will the Requirement by the US FDA to Simultaneously Co-Develop Companion Diagnostics (CDx) Delay the Approval of Receptor Tyrosine Kinase Inhibitors for RTK-Rearranged (ROS1-, RET-, AXL-, PDGFR-α-, NTRK1-) Non-Small Cell Lung Cancer Globally?

Ou, Sai-Hong Ignatius; Soo, Ross A.; Kubo, Akihito; Kawaguchi, Tomoya; Ahn, Myung-Ju
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 01/04/2014 Português
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The discovery of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) in 2007 and the approval of crizotinib for the treatment of advanced ALK-rearranged NSCLC in 2011 represents a landmark in the development of targeted oncology therapy. The approval of crizotinib was accompanied simultaneously by the approval of the Vysis (Abbott Molecular) break-apart fluorescence in situ hybridization (FISH) test as the companion diagnostic (CDx) test to detect ALK rearrangement. Pfizer, the manufacturer of crizotinib, sponsored the screening of thousands of patients and the standardization of the ALK FISH test as part of the approval process for crizotinib, a first in class ALK inhibitor. Many pharmaceutical companies are now using the Food and Drug Administration (FDA)-approved ALK FISH assay to enroll patients onto trials for their own respective ALK inhibitors. In essence they are “piggybacking” on the FDA-approved ALK FISH assay without having to pay for the development of a CDx, nor screening for ALK-rearranged NSCLC patients in the protocols because screening for ALK rearrangement is now the standard of care in NSCLC after the approval of crizotinib. Since 2007, rearrangement in more receptor tyrosine kinases (RTKs) such as ROS1...

‣ Accelerated Approval and Breakthrough Therapy Designation: Oncology Drug Development on Speed?

Yao, James C.; Meric-Bernstam, Funda; Lee, J. Jack; Eckhardt, S. Gail
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Recent advances in biotechnology have led to discoveries resulting in major improvements in the therapy of refractory malignancies, although most advanced cancers remain incurable. Thus, there is global consensus around the need to streamline the drug approval process for effective agents. Accelerated approval and Breakthrough Therapy Designation hold the promise of making new treatments available sooner through the use of smaller studies employing intermediate endpoints. Here we consider the inherent limitations of smaller studies and discuss strategies for hastening oncology drug development while maintaining high efficacy standards.

‣ Clinical Trial 2.0: Can Health 2.0 Transform the FDA Drug Approval Process?

Atanassova, Mira
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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Historically, patient activism has played a great part in shaping the drug approval process. Today, aided by developing web technologies, patients are once again seeking increased involvement in their medical care. Their desire to be involved is manifesting in the development of patient-run clinical trials, where patients, with the aid of online health-oriented social networks, are testing the safety and effectiveness of new drugs. While these trials are not currently recognized as valid, scientifically rigorous endeavors and are not accepted by the FDA as evidence of the safety and effectiveness of new drugs, small changes in trial structure can make these patient initiatives a meaningful part of the drug development process. This paper examines the structure and challenges of patient-run clinical trials in the context of the drug development and approval process and suggests an point-of-care design alternative as a way to address the concerns aroused by such patient-led studies. Ultimately, the paper concludes that the enormous social value of such studies should not be ignored, and that the medical, scientific, and regulatory communities should work with patients in helping them designing reliable studies responsive to their needs that can become a meaningful part of the drug development and approval process.

‣ FDA’s Proposed Regulations to Expand Access to Investigational Drugs For Treatment Use: The Status Quo in the Guise of Reform

Rossen, Benjamin
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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On December 14, 2006, FDA proposed two new regulations in the Federal Register amending current regulations governing expanded access to investigational drugs for treatment use and charging for investigational drugs. The proposal comes at a time when FDA has been under new pressure to provide seriously ill patients with early access to investigational drugs outside the framework of clinical trials. In recent years, patient advocacy groups have filed citizen petitions with FDA asking the agency to provide specific criteria for obtaining access or to create an early approval mechanism to provide access. Further, FDA has seen proposed federal legislation intended to ensure early patient access to investigational treatments and nearly lost a lawsuit in federal court in which terminally ill patients sought a fundamental right of access to investigational therapies under the Due Process Clause of the Constitution. The proposed regulations seek to assuage patient activists, physicians, drug sponsors, and other critics who contend that FDA must strike an appropriate balance between allowing patient access to promising treatments while protecting against undue risks and safeguarding the clinical trials process. Although FDA heralded the announcement of the rules as a key step forward to improving patient access...

‣ Learning from Prozac: A Case Study on Reforming the FDA Drug Approval Process

Wood, Maria
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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The law, focused as it is on making final determinations and settling issues one way or another, continually lags behind science, which concentrates on an evolving understanding of various phenomena through constant enhancement of current understandings of existing realities. Thus, a drug approval process, which obviously deals with scientific issues of drug development, cannot always keep pace with scientific understandings of drug development. The law is flexible and capable of accommodating new understandings, though; therefore, consideration of the scientific issues involved in drug development and approval is appropriate and ought to be undertaken as much as possible in order to develop legal answers that are as accurate as they can be at any given time.

‣ Past, Present and Future in the Search for the Perfect Anti-epileptic Drug

Robinson, Kristin N.
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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This paper explores the development of anti-epileptic drugs, starting with the earliest forms of treatment, moving to the drugs currently in use and those recently approved by the FDA, and ending with the drugs (and devices!) that will likely be approved for use in the near future. It covers all aspects relating to such drugs, examining why the need for an effective drug is so significant, how a specific medication is chosen by a physician and his patient, the special considerations for anti-epileptic drug use in certain populations, the problems with the current approval process for anti-epileptic drugs by the FDA, and the scientific advances that have been and continue to be made in the search for a safe and effective anti-epileptic drug.

‣ Disclosure of the Dealings Between Drug Developing Companies and the FDA Under the Federal Securities Laws

Heinonen, Mikko
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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The purpose of this article is to highlight the main issues raised by the Food and Drug Administration’s (“FDAâ€) approval process relating to new drugs and the treatment of this process receives in the context of the Federal Securities Laws . The partial inspiration for this article has been the recent highly publicized case concerning ImClone Systems Incorporated – a case, which well exemplifies both the connection between the valuation of a biotech/medical company and the FDA’s approval process for new drugs, and also the huge effect of the approval process to the market’s valuation of the stock price.

‣ Is the FDA Sexist? Sex and the Drug Approval Process

Petrovic, Emily S.
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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This paper examines the role of sex in the drug approval process. Medical literature has explored in great depth the many ways in which men and women differ, sometimes dramatically, often in ways that are seemingly unrelated to the physical, anatomical distinctions between the two sexes. After years of intentionally excluding women from critical phases of clinical drug trials, the FDA formally reversed such policies in the 1990s. A number of prescription drugs recently removed from the market disproportionately harmed women as compared to men. Loopholes in the current system have perpetuated the drug approval process’s inadequate consideration for the needs of women, thereby subjecting them to a higher level of risk. Efforts to correct for the lack of drug trials aimed to ensure the safety and efficacy for pediatric patients are also reviewed to provide a contrast. While the intentional biases in the system have been addressed, the current drug approval process fails to provide women with the same degree of protection as it does men. A number of issues remain requiring additional study and consideration before a complete solution can be proposed.

‣ Improving the efficiency of the later stages of the drug development process : survey results from the industry, academia, and the FDA

Gottschalk, Adrian Hedley Benjamin, 1975-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 82 p.; 1198979 bytes; 1198715 bytes; application/pdf; application/pdf
Português
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Drug development in the United States is a lengthy and expensive endeavor. It is estimated that average development times range from eleven to fifteen years and exceed costs of one billion dollars. The development pathway includes basic scientific discovery, pre-clinical testing in animals, clinical development in humans, and an application process. The Food and Drug Administration is responsible for the oversight and approval of drugs going through this process. Numerous financial and economic studies have been conducted that show the benefits to accelerating the drug development process. In 1992, the United States Congress enacted the Prescription Drug User Fee Act I, which mandated faster response times from the FDA in return for user fee payments to the FDA by the drug developing companies. Data on approval times for new drugs indicate that this process was indeed shortened. In contrast, the average drug development process prior to the filing of an application has been increasing in cost and time. The first purpose of this research is to quantify the benefits of accelerated new drug application review time under the Prescription Drug User Fee Acts I and II. The second purpose of the research is to investigate what industry and the FDA can do together to reduce the development process time between the IND and NDA without compromising patient safety and welfare...

‣ Assessing personalized medicines in Australia: A national framework for reviewing codependent technologies

Merlin, T.; Farah, C.; Schubert, C.; Mitchell, A.; Hiller, J.; Ryan, P.
Fonte: Hanley & Belfus Inc Publicador: Hanley & Belfus Inc
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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BACKGROUND: Since the mapping of the human genome in 2003, the development of biomarker targeted therapy and clinical adoption of "personalized medicine" has accelerated. Models for insurance subsidy of biomarker/test/drug packages ("codependent technologies" or technologies that work better together) are not well developed. Our aim was to create a framework to assess the safety, effectiveness, and cost-effectiveness of these technologies for a national coverage or reimbursement decision. METHODS: We extracted information from assessments of recent Australian reimbursement applications that concerned genetic tests and treatments to identify items and evidence gaps considered important to the decision-making process. Relevant international regulatory and reimbursement guidance documents were also reviewed. Items addressing causality theory were included to help explain the relationship between biomarker and treatment. The framework was reviewed by policy makers and technical experts, prior to a public consultation process. RESULTS: The framework consists of 5 components--context, clinical benefit, evidence translation, cost-effectiveness, and financial impact--and a checklist of 79 items. To determine whether the biomarker test, the drug...

‣ The accelerated approval process in oncology : an examination of the conversion rate of approved therapies to full approval

Kim, Jean Jinsun
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 82 leaves; 6601439 bytes; 6603691 bytes; application/pdf; application/pdf
Português
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In 1992, Accelerated Approval, or Subpart H approval, was added to the NDA regulations so promising products that provide a meaningful therapeutic benefit for serious or life-threatening diseases could be introduced to the market sooner, particularly for diseases or conditions where there was a great unmet medical need. Accelerated Approval is based on either a surrogate endpoint that is reasonably likely to predict clinical benefit or a clinical endpoint other than survival or irreversible morbidity. After approval, the sponsor is required to perform post-marketing studies to demonstrate clinical benefit. Since the FDA expanded the use of the Accelerated Approval regulatory path to include oncology drugs in 1995, thirty drugs (both small molecule as well as biologics) have been granted accelerated approval in oncology. However, from various reports in the literature and the FDA site, it appears that only a small fraction of these approvals (four to six) have been converted into regular approvals, based on the demonstration of clinical benefit in the post-marketing studies that support the benefit seen in the pivotal studies.; (cont.) In my research, I examined the basis of approval for six drugs that were converted to full approval and compared this group to the seven drugs that received accelerated approval before 2000 but as yet have not converted to full approval. The six drugs that were converted to full approval...

‣ REFORMING DRUG APPROVAL IN THE UNITED STATES: MEASURES NECESSARY TO ALLEVIATE THE CASH CRUNCH FACED BY SMALL BIOTECHNOLOGY COMPANIES

McWilliams, Douglas E.
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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Over the past decade, the infant biotechnology industry, led by small biotechnology companies, has produced numerous breakthrough drugs which have saved lives, reduced suffering and cut the cost of health care. Given that the biopharmaceutical industry has only been in existence for a little over 20 years, biotechnology holds enormous potential for the advancement of medical treatments. Unfortunately, even with biotechnology, as with the more traditional methods of drug development, the government mandated testing and approval of new therapeutic products takes a considerable amount of time and costs an exorbitant amount of money. The United States has the most demanding drug approval process in the world. Under the current Food and Drug Administration's drug approval process, the time required to gain approval for new drugs averages between 10 to 12 years and the cost approximates $350 million. In addition, the Food and Drug Administration (FDA) has come under attack as taking too conservative of an approach to approving beneficial new drugs. The purpose of this paper is to analyze the effects of this costly drug approval process on small biotechnology companies, to determine the effects of a decline in small biotechnology companies on the United States and to analyze current proposals to change the current Food and Drug Administration's drug approval process to ensure the survival of small biotechnology companies. Part II of this paper identifies the various stages of the drug approval process. Part III explores the policy behind the FDA's extensive drug approval process. Part IV examines the adverse affects of the drug approval process on small biotechnology companies. Part V analyzes the effect of a declining biotechnology industry on the United States. Part VI addresses current proposals to change the FDA drug approval process focusing on their ability to help small biotechnology companies.

‣ Harmonizing Pharmaceutical Regulation Among the United States, the European Union, and Japan: The ICH Initiative

Fayad, Nihal
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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The United States, the European Union and Japan comprise 75% of the world's pharmaceutical market and generate 90% of all pharmaceutical research. Recognizing the need for and benefits of harmonized testing standards the United States, the European Union and Japan formed a joint initiative between the industry and regulators called the International Conference on Harmonization (ICH). The ICH initiative has been underway for over a decade now. This paper will examine the disparate pharmaceutical regulatory regimes of the U.S., the EU, and Japan and will explore the ICH effort and its progress thus far. Part I of this paper overviews the current regulation of new pharmaceuticals in the United States, the European Union, and Japan. Based on these overviews, it will be apparent that the regulatory agencies of these three regions have already made some progress in harmonizing international standards. Part II explores the forces at work behind harmonization and discusses the potential benefits of pharmaceutical harmonization. Part III explains the ICH initiative including the mechanics of the ICH process and its implementation in the three ICH regions. Part IV of the paper addresses problems inherent in, and barriers to the achievement of the goals of the ICH. Finally...

‣ A History of Accelerated Approval: Overcoming the FDA's Bureaucratic Barriers in order to Expedite Desperately Needed Drugs to Critically Ill Patients

Stahl, Jacob
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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After the passage in 1962 of the Kefauver-Harris Drug Amendments that mandated that the FDA grant premarket approval for all drugs and added a requirement that drug manufacturers demonstrate the efficacy of their products, the drug approval process dramatically slowed for the next two decades. Only after a combination of sustained criticism by free market advocates and dramatic lobbying efforts and protests by AIDS activists desperate for any drug that might prolong their lives did the FDA relent and implement the accelerated approval program. The FDA can grant accelerated approval for drugs designed to treat life-threatening diseases for which no approved treatments currently exist based upon data from surrogate endpoints (laboratory markers), so long as the endpoints are reasonably believed to predict clinical benefit. This paper examines the history of accelerated approval, and in particular its application to AIDS and cancer drugs. Additionally, it explores critiques of the program from clinical academicians and consumer advocates, and replies from its defenders including the pharmaceutical industry, patient advocates and free market economists. It concludes with recommendations on how to reinvigorate the process in order to expedite the development of cancer drugs.

‣ Protecting the Ignorant, the Unthinking and the Credulous: Are the FDA's Efforts to Accelerate the Drug Approval Process Compromising Public Safety?

Katz, Gail
Fonte: Harvard University Publicador: Harvard University
Tipo: Paper (for course/seminar/workshop)
Português
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Recently, five approved prescription drugs were recalled in a one-year period after the Food and Drug Administration (FDA or the agency) deemed them to be too unsafe for patient use. Notorious among them was fenfluramine (Pondimin), the "fen" half of "fen-phen," a drug used to promote weight loss in patients. The list also includes Seldane, a popular antihistamine as well as Redux, Posicor, and the pain medication Duract. All had side effects not detected in clinical trials. This unusually high rate of withdrawals in such a short period of time sparked the most recent round of debate over the ever-controversial topic of the FDA drug approval process.

‣ Essays on the pharmaceutical industry

Chen, Xiaobo
Fonte: University of Delaware Publicador: University of Delaware
Tipo: Tese de Doutorado
Português
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Arnold, Michael A.; Essay 1: Strategic buying to keep competition in the market. I introduce a two-period dynamic model where a retailer transacts with two firms which produce a homogeneous product with different marginal costs. In this model, the firm with higher marginal cost would exit the market if price is below marginal cost. If the weak firm exits, the buyer faces a monopolist in the second period. To prevent this outcome, the buyer may intentionally purchase from the weak firm to keep it in the market. This behavior is called strategic buying. I analyze the conditions under which strategic buying will occur and responses of each firm to this strategic buying. Essay 2: Empirical study: the effects of announcements during the drug approval process on the stock valuation of the corresponding pharmaceutical firms. The purpose of this essay is to investigate which announcements during the new drug approval process impact the valuation of the related pharmaceutical company's stock using an event-study method over the period from 2004 to 2011. The results reveal extension of FDA review deadline, issuance of a complete response letter from the FDA, and approval of the first-time generics have negative influence on the stock price; public disclosure of advisory committee recommendation and approval of a new drug have significant positive impact on the related firm's stock returns; submission of a new drug application (NDA)...