A Case Study Demonstrating Superiority of a New Compound over the Gold Standard
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Drug Infomation loumal. Vol. 35, pp. 1173-1178, 2001 F’rinted in the USA. All rights reserved.
A CASE STUDY DEMONSTRATING SUPERIORITY OF A NEW COMPOUND OVER THE GOLD STANDARD ERHARD QUEBE-FEHLING, PHD Senior Statistician, Biostatistics Oncology, Novartis Pharma AG, Basel, Switzerland
Some basic issues relevant for demonstration of superior eflcacy are discussed with the case of the development of zoledronic acid 4 and 8 mg in hypercalcemia of malignancy. Topics such as number of studies, significance level, consistency of results across subgroups, and choice of primary eflcacy variable are addressed. Two calibration studies using a comparison with a prespecified value as a criterion for efficacy are compared with one between-treatment pooled analysis. A further point is the switch from noninferiority to superiority. Some lessons for statistics can be drawn from the case study. Key Words: Evidence of efficacy; Calibration study; One pivotal study; Replication; Switching from noninferiority to superiority
INTRODUCTION/BACKGROUND THIS PAPER DISCUSSES some basic aspects of providing evidence of efficacy with the example of the zoledronic acid development for hypercalcemia of malignancy (also “tumor-induced hypercalcemia”). Hypercalcemia of malignancy is the most common life-threatening metabolic complication of malignancy, affecting approximately 10% to 20% of patients with advanced cancer (1). Tumor cells secrete factors that stimulate excessive bone resorption and release of calcium from the bone matrix and also increase renal reabsorption of calcium, resulting in increased serum calcium levels. The severity is dependent on the level of calcium in the serum. This is, in practice, generally measured by albumin-corrected serum calcium.
Reprint address: Erhard Quebe-Fehling, PhD, Novartis Pharma AG, WSJ-27.4.089, 4002 Basel, Switzerland. E-mail: [email protected].
In a review of hypercalcemia of malignancy, pamidronate was referred to as the “mainstay of treatment” (2) since the time the drug was approved by the Food and Drug Administration (FDA) in the United States. It was subsequently also approved in many other countries. Zoledronic acid (ZOMETA@; Novartis Pharma AG, Basel, Switzerland) is a new, highly potent heterocyclic nitrogen containing bisphosphonate that has an imidazolering side chain. Major et al. said, “It has been shown in preclinical studies to be more potent than currently available bisphosphonates, including pamidronate” (3). In 1999, the zoledronic acid development for hypercalcemia of malignancy was principally concluded. Approvals were granted in the European Union and in a number of other counmes. Results were published (3). Development and results are outlined in the next section. This example will now be used to discuss principal questions for providing evidence of efficacy in retrospect.
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ZOLEDRONIC ACID DEVELOPMENT IN HYPERCALCEMIA OF MALIGNANCY Original
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