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There are four key uses for medical imaging: screening, diagnosis or prognosis, monitoring the natural history of the disease, and monitoring therapeutic intervention. There are eight key metrics when evaluating a biomarker or imaging technique which has to be put into context with the key use of the system. This chapter will describe these key metrics in this context with particular emphasis of the use in clinical trials.

The term blinded read or independent read is used in literature to define a process by which medical images are read by an independent radiologist or team of radiologists and or physicians. There are three major kinds of blinded read: eligibility, safety, and efficacy, of which each of these is managed in a different manner. This chapter presents the various methodologies that are employed in blinded reads across phases of trials and between different therapeutic areas.

Medical imaging is now utilized extensively in clinical trials for eligibility, efficacy, and safety evaluations. The uses of imaging span from a qualitative assessment of disease findings to quantitative assessments, each resting on diagnosis of the condition or change in the severity of the condition. This introductory chapter is designed for the novice with a limited or no background in radiological techniques and aims to briefly review the different imaging techniques, technology, terminology, and optimal imaging uses.

The diagnosis and treatment of osteoporosis is still a relatively young science. Although Albright first described osteoporosis in 1947,1 it is only since the late 1980s and early 1990s that we have had the instruments available for the diagnosis and then treatment of this disease. As for any medical area in its infancy, we can, therefore, expect a significant number of changes in the coming years, as a result of more comprehensive understanding of bone physiology and elucidation of the genetic factors leading to increased risk factors.

When your clinical centre has been notified that you have been selected as a site for a new clinical trial in osteoporosis, you can be assured that the sponsor has made an assessment of the subject population and facilities available. It is now up to the investigator, site administrator, and staff to prove the sponsor made the right decision in placing the study at their site. Because delays in study start-up can cause a sponsor to lose millions of dollars, it is imperative to get the study up and running as soon as possible. During this process, the emphasis is on speed and accuracy. Always remember that there are many qualified sites able and willing to take on this project should your commitment falter. You can congratulate yourself that you have been chosen to participate, but the site must be organized to get to work on the project quickly!

There is a standard set of start-up, ongoing monitoring, and close-out requirements and procedures for all clinical trials. These generic requirements are discussed in other books and are not the remit of this book. However, because of the nature of this therapeutic area, it is important to consider the particular extras and details that have to be evaluated, and this chapter provides an overview of these items. The sponsor needs to be aware of these items in a timely manner — all too often the novice will overlook an important detail until it becomes a critical issue. This chapter will help ensure these kinds of errors are avoided.

It is the design of your study that will give it credence in the wider scientific community. If it is clear from the dissemination of the study that there has not been a clear hypothesis, endpoints are inappropriate, and the study design is inadequate, it is unlikely that the outcome of the study will be used to contribute to the process of regulatory approval, or form part of a metaanalysis. It is important to get the design right from the start. The time taken will be very worthwhile. The purpose of this chapter is to give an overview of the following: 1. Phase I to IV studies and different trial types 2. Endpoints 3. Study design, size, and power 4. The effect of antiresorptive therapies versus true anabolic therapies on trial design 5. Inclusion and exclusion criteria 6. Study protocols and documentation 7. Sampling and randomization 8. Design of data collection. The chapter will also discuss the advantages of true clinical and health-status outcomes compared with the more common use of surrogate outcomes.

Medical instruments can be used in one of four primary ways: for screening, diagnosis, prognosis, and monitoring the natural history of the disease or therapeutic intervention. Good quantitative endpoints in clinical trials are usually obtained from instruments measuring a physiological parameter that is relevant to the anticipated effect of the molecular entity under investigation, and nowhere is this more apparent than in the field of osteoporosis. The surrogate endpoint of choice, bone mineral density (BMD), is in fact a recognised diagnostic endpoint in its own right in that the World Health Organization (WHO) criterion for defining osteoporosis in an individual is a BMD that is >2.5 standard deviations (SD) below peak bone mass. However, in the arena of clinical trials the choice of endpoint is not as simple as this (see Section 2.3).

Study Design and the Pretrial Phase.- Study Design and Endpoints.- Ethical Considerations.- Standardization and Pretrial Quality Control.- Performing the Trial.- Organization of the Clinical Trial by the Sponsor.- Local Site Organization.- Clinical Trial Quality Assurance.- Laboratory and Instrument Quality Control.- Data Analysis and Presentation.- Data Analysis and Presentation: Writing a Paper for Publication.- Background.- Current Therapies for Osteoporosis.- The Ideal Drug for Treatment of Osteoporosis.- Instrument Measurements in Osteoporosis Clinical Trials: Evaluating the Endpoints.- Biochemical Markers of Bone Turnover.- Future Therapies and Clinical Trials.