Introduction 1

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Introduction

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1.1. Why a Book about Clinical Trials in Osteoporosis?

There have been many books published about the design, conduct, and analysis of clinical trials. Why are osteoporosis trials a special case that deserve a book of their own? There are three main reasons. First, most diseases have a well-understood definition and aetiology. Osteoporosis is a disease that is understood by those work- ing within the subspecialty, but currently there is no definition that is agreeable to both medical and scientific communities and its aetiology is poorly understood. It is within this framework that the pharmaceutical industry is trying to develop new treatments for the so-called “silent epidemic”.

In layman’s terms, the disease of osteoporosis is defined as “brittle bones occurring in the elderly that could lead to fractures.” The classical definition was

“a bony fracture caused by minimal trauma owing to a loss in bone mineral.”

A published consensus definition states that osteoporosis is “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.”

The National Institutes of Health (NIH) Consensus Conference Statement on Osteoporosis Prevention, Diagnosis, and Therapy states that

“osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.”

The World Health Organization (WHO) operationally defines osteoporosis as “bone density 2.5 standard devia- tions (SDs) below the mean for young white adult women at lumbar spine, femoral neck, or forearm”.

It is now recommended that the diagnostic use of this definition is restricted to bone density of the femur.

Although it is not clear how to apply this in men and children, it is recommended that the same diagnostic thresholds can be used in men.

The NIH statement recognises that “bone strength reflects the integration of two main features: bone density and bone quality. Currently, there is no accurate measure of overall bone strength. Bone mineral density (BMD) is frequently used as a proxy measure and accounts for approximately 70% of bone strength.” Thus, osteoporosis has become a disease that is characterized by measurement of BMD.

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The endpoint of many clinical trials is BMD, either used as a primary endpoint in its own right or used as a surrogate marker for fracture risk.

Regulatory authorities tend to consider osteoporosis in terms of fracture when it comes to licensing new treatments for the management of the disease, and, increasingly, BMD for the prevention of osteoporosis. It is, therefore, imperative that the researcher understands which definition of the disease they are using and what the endpoint or hypothesis they are trying to evaluate is before they embark on a research programme.

Second, because osteoporosis is a disease that is diagnosed using a measurement of BMD and is monitored over many years using such measurements, there are a range of technical issues to ensure the quality and consistency of BMD measure- ments that must be considered. Several of these relate to the choice of equipment, standardization, and quality control before a trial begins, in addition to technical issues that must be considered throughout the life of the study.

Third, osteoporosis trials are often long-term trials carried out in normal, asymptomatic women, in whom proven drugs for the treatment and prevention of osteoporosis are already licensed. This is particularly true of clinical trials in women who are close to the menopause. This presents ethical issues because the latest version of the Declaration of Helsinki (Finland), produced in Edinburgh (UK) in 2000, specifically states that placebo control in the presence of a proven treat- ment is unethical.

This conflicts with the requirements of the US Food and Drug Administration (FDA), which still requires placebo control for licensing purposes.

These women are also unlikely to gain any direct benefit from a short-term trial, which raises other ethical issues. Postmenopausal women (aged 55 to 65 years) are unlikely to have any long-term reduction in fracture risk if the fracture does not occur until they are aged 80 years. Any protective effect of treatment will have worn off. What happens at the end of the study? Will treatment still be available to subjects if a proven treatment effect is demonstrated?

In summary, the definition of osteoporosis is not universally agreed, it is a dis- ease defined by a measurement of BMD and often clinical trials are carried out in normal, asymptomatic women. For researchers entering into this therapeutic area, it seems to be initially confusing and technically challenging. On this basis, osteo- porosis clinical trials deserve a book that provides an introduction to the novice and clearly explains the design and implementation of these trials. This is not designed to be an in-depth book for the expert, but nowhere else is this overview currently available in an easy-to-find manner.

1.2. How this Book Works

The aim of this book is to lead the researcher through all the stages of a clinical trial. Section 1 covers study design (Chapter 2) and the pretrial phase, including ethical considerations specific to osteoporosis trials (Chapter 3) and the standard- ization and pretrial quality control required to ensure consistent measurement of BMD (Chapter 4).

2 Colin G. Miller and Derek Pearson

Section 2 looks at the day-to-day running of the trial. Chapter 5 gives a rundown of the current regulatory framework, the organization of the trial by the sponsor, and the requirements for audit. The administrative organization of the trial is covered in Chapter 6.The endpoints in most osteoporosis trials rely on BMD measurements and morphometric measurements of vertebral height to detect vertebral fractures mor- phometric X-ray analysis (MXA). Good subject positioning, an understanding of the limitations of dual-energy X-ray absorptiometry (DXA) measurements, and review of DXA results are vital. These are covered in Chapter 7. At any point in the trial, participating centres could find themselves the subject of audit by the sponsor or reg- ulatory authorities. Quality control of the equipment and biochemical markers of bone turnover is covered in Chapter 8. Several useful tools for monitoring quality control data are discussed.

Section 3 covers data analysis and presentation. Chapter 9 is a guide to writing a paper for a peer-reviewed journal to a standard that will ensure that readers will gain full benefit from your trial and the results will be easily included into subsequent metaanalysis. Sample data are given in Appendix B to enable the reader to check the worked examples in the text. The sample data are from a small placebo-controlled, double-blind study looking at the use of calcitonin in postmenopausal women. The primary endpoint is BMD, which is measured using DXA at the lumbar spine.

Secondary endpoints include measuring ultrasound transmission through the heel (ultrasonometry or quantitative ultrasound [QUS]). Data for BMD and QUS are given in the appendix. Other aspects of this trial are considered at other points in the book (e.g. study design in Chapter 2 and ethical considerations and written, informed consent in Chapter 3).

Section 4 gives background information on current and future therapies for osteoporosis (Chapter 10) and considers what the ideal treatment for osteoporosis might be (Chapter 11). Help in selecting the best equipment for measuring BMD is given in Chapter 12, whereas Chapter 13 reviews the wide range of biochemi- cal markers of bone turnover. The final chapter (Chapter 14) looks to the future to consider where clinical trials in osteoporosis might be leading.

We have attempted to use standard terminology throughout the book. This includes the sponsor (usually a pharmaceutical company that is funding the research) and the clinical research organization (CRO), which is a company responsible for administering the trial, quality assurance of the data, analysing the data, and producing the final report. In addition, sponsors often appoint an independent company to act as a quality assurance (QA) centre to review and analyse BMD results. A clinical research associate (CRA) is the representative of the sponsor or CRO who liaises between the CRO and each site participating in the trial. The investigator is the researcher at the local site who has responsi- bility for recruiting research subjects and running the study locally. We have chosen to refer to those taking part in osteoporosis clinical trials as “subjects”

rather than “patients” for the reason that many of them are not ill, but are nor- mal women and men. The drug under investigation is usually under develop- ment by the sponsor and is known throughout the book as the “new molecular entity” (NME).

1. Introduction 3

Most chapters contain many references to other source material. These enable the reader to learn about any of the issues covered in the book in greater depth. As always, there are many abbreviations in the book, but a full glossary is given in Appendix A.

References

1. Christiansen, C. (1993). Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94:646–50.

2. National Institutes of Health Consensus Development Conference Statement: Osteoporosis Prevention, Diagnosis, and Therapy March 27–29, 2000 (http://consensus.nih.gov/2000/

2000Osteoporosis111html.htm accessed 13/11/06).

3. Kanis, J.A. (1994). Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. Geneva: World Health Organization.

4. Kanis, J.A. and Gluer, C.C. (2000). An update on the diagnosis and assessment of osteo- porosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 11:192–202.

5. Selby, P.L., Davies, M. and Adams, J.E. (2000). Do men and women fracture bones at similar bone densities? Osteoporos Int 11:153–7.

6. Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and revised by the 52nd World Medical Assembly, Edinburgh, Scotland, 2000 (http://

www.wma.net/e/policy/b3.htm accessed 13/11/06).

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