Clinical Study Requirements

6.21.5.2.1 Phase I studies

These should be conducted using standard protocols to determine drug safety, tolerability, and pharmacokinetics. The existence of assays for various surrogate markers of bone formation and resorption makes it possible to leverage phase I studies to obtain valuable information on NCE pharmacology in human subjects. These surrogate markers provide a sensitive and dynamic indication of the nature, size, and duration of the biologic response to the tested drug, as demonstrated in the study of an OPG construct.54 Measurement of telopeptides of collagen type I in serum or urine provides a clear measurement of antiresorptive effects of an NCE and measurement of bone-specific alkaline phosphatase or procollagen peptides gives a clear indication of changes in bone formation.

6.21.5.2.2 Phase II studies

Phase II studies extend safety data, confirm biological activity of the NCE in humans, and define dose and dosing frequency for phase III trials. For osteoporosis NCEs, phase II trials are typically 1 year in duration and utilize BMD measurement as the primary clinical endpoint. Surrogate markers of bone remodeling can also be used as these give excellent information to assess dose responses, maintenance of pharmacological action, and mechanism of action. Bone biopsy and histomorphometry provide information regarding NCE mechanism of action and maintenance or improvement in bone quality.

6.21.5.2.3 Phase III studies

FDA guidelines recommend a 3-year phase III trial with reduction in fracture incidence as the primary endpoint. There is an option for a BMD endpoint if the preclinical studies support maintenance or improvement of bone quality.

However, given the competitive market for osteoporosis drugs that already show fracture benefit, commercial considerations likely make the generation of data demonstrating fracture benefit an imperative. It is possible that shorter trials showing fracture benefit will be accepted, as was the case with teriparatide. All subjects should receive calcium and vitamin D supplementation, with a total calcium intake of 1500 mg being maintained. Trials are double-blinded placebo or active-controlled randomized trials. Currently osteoporosis NCE trials are typically placebo-controlled. However, the ethics of conducting a placebo rather than active NCE as comparator is coming under increased discussion. Very large and expensive trials would be required to gain acceptable confidence intervals for noninferiority in fracture benefit in an active-controlled trial. Alternatives are to continue with placebo-controlled studies but to exclude patients at high fracture risk and/or to allow shorter trials demonstrating fracture benefit after 1-2 years.

The simplest fractures in which to show benefit are vertebral fractures. These are commonly defined radiologically as deformations leading to a 20% reduction in the height of lumbar vertebrae. These occur with sufficient frequency (5/100 patient-years) in patients with low BMD and at least one prevalent fracture to allow trials of 1000-2000 subjects. Hip fractures are much more clinically important as they are associated with much greater morbidity and mortality. Reduction in hip fracture incidence was demonstrated for alendronate and risedronate, though the number of trial participants required was around 5000, as the frequency is about 0.8/100 patient-years in patients with one prevalent fracture.55

Secondary endpoints for the phase III osteoporosis trials are BMD, effects on surrogate markers of bone remodeling, and bone quality as assessed by histomorphometry. An ideal profile of a successful osteoporosis NCE will show increases in BMD in the lumbar vertebrae and in the femoral neck and reduction in both vertebral and hip fracture incidence. Due to the excellent safety profiles of approved osteoporosis treatments, a high standard for safety and tolerability will be applied to new drug applications in this area.

6.21.5.3 Clinical Issues in Developing Drugs to Treat Skeletal Effects of Metastatic Bone Disease

Metastatic bone disease is associated with significant morbidity: bone pain, fracture, and hypercalcemia are common. Bisphosphonates (Figures 5 and 6) have demonstrated that treatment of these patients with antiresorptives is of clinical benefit. As in the development of NCEs for osteoporosis, use of surrogate markers of bone resorption allows the leveraging of phase I and II trials to determine optimum dosing and dosing frequency accurately. More aggressive disease needs higher NCE doses for the effective suppression of bone resorption and clinical benefit in inhibiting skeletal events.

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