Applied Biostatistics for the Health Sciences. Richard J. Rossi

drug on human cells and animals in a laboratory setting. If the initial laboratory research indicates that the drug may be beneficial to humans, the next step is to submit a new drug application (NDA) to the FDA. The NDA will contain information on the drug, the results of all prior test data on the drug, and descriptions of the manufacturing process used to make the drug. The FDA will then determine whether the drug is safe and effective for its proposed use(s), whether the benefits of the drug outweigh its risks, whether the drug’s proposed labeling is appropriate, and, if not, what the drug’s appropriate labeling is, and whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity. Supervised clinical trials represent the final testing ground for a new drug, and the results of the clinical trials will be used in the final approval or disapproval of a new drug.

      1.3.1 Safety and Ethical Considerations in a Clinical Trial

      Every well-designed clinical trial will have a predetermined research protocol that outlines exactly how the clinical trial will be conducted. The clinical trial protocol will describe what will be done in the trial, the rules for determining who can participate, the specific research questions being investigated, the schedule of tests, procedures, medications, and dosages used in the trial, and the length of the trial. During the clinical trial, the participants are closely monitored by the research staff to determine the safety and effectiveness of their treatment. In fact, the ethical treatment and safety of the participants are carefully controlled in clinical trials performed in the United States.

In general, a clinical trial run in the United States must be preapproved by an independent committee of physicians, biostatisticians, and members of the community, which makes sure that the risks to the participants in the study are small and are worth the potential benefits of the new drug or treatment. Many, if not most, externally funded or university-based clinical trials must be reviewed and approved by an Institutional Review Board (IRB) associated with the funding agency. The IRB has the power to decide how often to review the clinical trial, and once started whether the clinical trial should continue as initially planned or modifications need to be made to the research protocol. Furthermore, the IRB may end a clinical trial when a researcher is not following the prescribed protocol, the trial is unsafe, or there is clear and strong evidence that the new drug or treatment is effective.

      1.3.2 Types of Clinical Trials

      Clinical trials can generally be classified as one of the following types of trials:

       Treatment trials that are clinical trials designed to test experimental treatments, new drugs, or new medical approaches or technology.

       Prevention trials that are clinical trials designed to investigate ways to prevent diseases or prevent the recurrence of a disease.

       Screening trials that are clinical trials designed to determine the best way to detect certain diseases or health conditions early on.

       Diagnostic trials that are clinical trials designed to determine tests or procedures that can be used for diagnosing a particular disease or condition.

       Quality-of-life trials that are clinical trials designed to explore ways to improve the comfort and quality of life for individuals with a chronic or terminal disease or condition.

       Genetic trials that are clinical trials designed to investigate the role genetics plays in the detection, diagnosis, or response to a drug or treatment.

      Pharmaceutical companies commonly use treatment trials in the development and evaluation of new drugs, epidemiologists generally use prevention, screening, and diagnostic trials in their studies of diseases, public health officials often use quality-of-life trials, and geneticists often use genetic trials for studying tissue or blood samples from families or large groups of people to understand the role of genes in the development of a disease.

      The results of a clinical trial are generally published in peer-reviewed scientific or medical journals. The peer-review process is carried out by experts who critically review a research report before it is published. In particular, the peer reviewers are charged with examining the research protocol, analysis, and conclusions drawn in a research report to ensure the integrity and quality of the research that is published. Following the publication of the results of a clinical trial or biomedical research study, further information is generally obtained as new studies are carried out independently by other researchers. The follow-up research is generally designed to validate or expand the previously published results.

      1.3.3 The Phases of a Clinical Trial

      Clinical research is often conducted in a series of steps, called phases. Because a new drug, medicine, or treatment must be safe, effective, and manufactured at a consistent quality, a series of rigorous clinical trials are usually required before the drug, medicine, or treatment can be made available to the general public. In the United States the FDA regulates and oversees the testing and approval of new drugs as well as dietary supplements, cosmetics, medical devices, blood products, and the content of health claims on food labels. The approval of a new drug by the FDA requires extensive testing and evaluation of the drug through a series of four clinical trials, which are referred to as phase I, II, III, and IV trials.

Each of the four phases is designed with a different purpose and to provide the necessary information to help biomedical researchers answer several different questions about a new drug, treatment, or biomedical procedure. After a clinical trial is completed, the researchers use biostatistical methods to analyze the data collected during the trial and make decisions and draw conclusions about the meaning of their findings and whether further studies are needed. After each phase in the study of a new drug or treatment, the research team must decide whether to proceed to the next phase or stop the investigation of the drug/treatment. Formal approval of a new drug or biomedical procedure generally cannot be made until a phase III trial is completed and there is strong evidence that the drug/treatment is safe and effective.

      The purpose of a phase I clinical trial is to investigate the safety, efficacy, and side effects of a new drug or treatment. Phase I trials usually involve a small number of subjects and take place at a single or only a few different locations. In a drug trial, the goal of a phase I trial is often to investigate the metabolic and pharmacologic actions of the drug, the efficacy of the drug, and the side effects associated with different dosages of the drug. Phase I drug trials are also referred to as dose finding trials.

      When the results of a phase I trial suggest that a treatment or drug appears to have promise, the treatment or drug is generally next studied in a phase II trial. In phase II clinical trials, the drug or treatment being studied is evaluated on a larger group of subjects to further investigate its effectiveness and safety. In general, the goal of a phase II trial is to study the feasibility and level of activity of the drug or treatment. Thus, phase II trials are designed to provide more information about the effective dosage of a drug, the severity of the side effects, and how to manage the side effects. Phase II trials are also referred to as safety and efficacy trials and usually involve more subjects than phase I trials.

      When the preliminary results of a new drug or treatment from a phase II trial suggest the drug or treatment will be effective and safe, a phase III trial is designed to gather additional information that can be used in evaluating the overall benefit–risk relationship of the drug. Phase III trials are usually designed to compare the new drug/treatment with standard or commonly used drugs/treatments, to confirm its effectiveness, to further monitor side effects, and to determine how the new drug or treatment can be safely used. Phase III trials generally are large trials and may enroll subjects at a wide variety of locations. Phase III trials are also referred to as comparative treatment efficacy trials.

      Finally, when a new drug or treatment has been examined in phase I, II, and III trials and has been approved for the general public, a phase IV trial is usually initiated. A phase IV trial is a postmarketing study designed to obtain additional information on the