Zometa

Some basic issues relevant for demonstration of superior efficacy 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 efficacy 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.

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(R); Novartis Pharma AG, Basel, Switzerland) is a new, highly potent heterocyclic nitrogen containing bisphosphonate that has an imidazole-- ring 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 countries. 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.

CONCLUSION

In order to provide evidence of efficacy, results must be substantiated. There are good arguments in favor of one well-conducted between-treatment comparison over two comparisons with a prespecified value derived from historical results. In the development of drugs in rare indications, efforts should also be undertaken to make a valid treatment comparison possible. Formal plans for pooled analyses can be useful in clinical drug development. The possibility of superiority should be accounted for in noninferiority studies. The superior efficacy of zoledronic acid doses of 4 and 8 mg compared to pamidronate 90 mg has been convincingly demonstrated.

Acknowledgments-The author thanks Gerd Rosenkranz, Joanne Machalaba, and an anonymous referee for helpful comments on an earlier version.

REFERENCES

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2. Mundy GR. Hypercalcemia of malignancy. Am J Med. 1997;103:134-145.

3. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19:558-567.

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8. US Department of Health and Human Services, FDA CDER and CBER. Guidance for industry: Providing clinical evidence of effectiveness for human drug

and biological products. Rockville, MD: Food and Drug Administration; May 1998.

9. Committee for Proprietary Medicinal Products (CPMP). CPMP/EWP/482/99 Final. Points to consider on switching between superiority and non-inferiority. Brussels, Belgium: Committee for Proprietary Medicinal Products; July 27, 2000.

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ERHARD QUEBE-FEHLING, PHD

Senior Statistician, Biostatistics Oncology, Novartis Pharma AG, Basel, Switzerland

Reprint address: Erhard Quebe-Fehling, PhD, Novartis Pharma AG, WSJ-27.4.089, 4002 Basel, Switzerland. E-mail: erhard.quebe-fehling@pharma.novartis.com.

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