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Appendix B The Clinical Trials Process The following is an excerpt from Chapter 1: Introduction of Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary (IOM, 2010a). The focus of the workshop was clinical trials—a type of clinical research that prospectively evaluates the risks and benefits of a drug, device, behavioral intervention, or other form of treatment. The materi - als and resources (human capital, financial support, patient participants, and institutional commitment) available to conduct such research can vary by research sponsor, disease area being studied, and type of research question being asked. Once a research question has been posed and the concept for a study has been defined, funding must be secured to continue the process. The study protocol, which is an extensive blueprint for the trial and how it will be conducted, is also required to be submitted to the relevant institutions and organizations that provide ethical and regulatory approval. All clinical trials are designed to answer one or more specific ques - tions. They can vary by the study population chosen (number of subjects, as well as criteria to enter the study) and the type of question(s) posed. For example, clinical trials to gain U.S. Food and Drug Administration (FDA) approval for a new drug are designed to show its safety and effi - cacy over the course of a few years. These trials seek to answer narrowly defined questions related to safety and efficacy in a carefully selected group of study participants most likely to experience the intended effects 99
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100 PUBLIC ENGAGEMENT AND CLINICAL TRIALS of the drug. Clinical trials conducted without the goal of regulatory approval (e.g., government sponsored) might test a drug or intervention in a diverse group of study participants, include a long time frame for follow-up of study subjects, and address a broader set of questions. The workshop examined a variety of clinical trials, including those sponsored by industry and government, but the focus was on large, multicenter trials. The clinical trials process for gaining regulatory approval of a new drug has traditionally been described in five discrete phases. Each phase seeks to answer a different set of questions. An increasing number of vol - unteers are included in each phase as the trial progresses and attempts to build a case that an experimental drug or treatment is safe and effective against the disease or condition it is intended to treat. Phase 0 trials are exploratory, first-in-human studies designed to determine whether a drug affects the human body as expected from earlier preclinical, animal studies. These trials involve a small number of people (10−15) who receive a low, nontherapeutic dose of the inves- tigational drug. These preliminary trials help companies rank a number of different drug candidates in their pipeline and make decisions about which candidates should be developed. Phase I clinical trials test an experimental drug or treatment for the first time in a small group of people (20−80) over the course of a few weeks or a month. Their goals are to assess the safety of the drug or treat - ment, find a safe dosage range, and identify any side effects. In phase II trials, a larger group of people (100−300) receives the experimental drug to determine whether it is effective and further evalu - ate its safety. These trials involve subjects with the target disease and usually last months. Once preliminary evidence from phase II reveals that a treatment is effective, phase III trials are designed to fully examine the risk/benefit profile of an experimental drug or treatment and test it over a longer period of time in a broader population (1,000−3,000). Because these trials are the last phase in the preapproval process, they are often referred to as “pivotal” trials. Phase IV, or post-marketing, trials take place after a drug has been approved. They provide additional evidence on the risks and benefits of the drug or treatment and how it can be used optimally.