Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis.

BACKGROUND: Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe. METHODS: This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies. RESULTS: The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies. CONCLUSIONS: To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.

Structured Benefit-Risk Assessment Across the Product Lifecycle: Practical Considerations.

BACKGROUND: Assessing the benefit-risk profile of a medicinal product is a complex but fundamental activity that sponsors and regulators must perform throughout the product's lifecycle. In order to improve the transparency and consistency of the decision-making process, regulators and sponsors alike are increasingly applying a structured approach to benefit-risk assessment. However, to our knowledge, there has been little practical guidance in the published literature regarding how to embed such a process organizationally. This paper seeks to address this gap. METHODS: Using a case study approach, we describe (1) how to integrate a lifecycle approach to structured benefit-risk assessment within a biopharmaceutical company; (2) key issues to anticipate during implementation, and (3) best practices and lessons learned to date. RESULTS: Based on our experience, key prerequisites for successful implementation included the selection of a structured benefit-risk assessment (SBRA) framework; application of a "core" approach to conducting SBRA with an accompanying template; development of a supporting standard operating procedure; and cross-functional team training. Common implementation challenges encountered were (1) facilitating cross-functional team adoption of SBRA nomenclature and analytic methods, including the use of a value tree and effects table, and (2) applying the SBRA framework to different products with heterogeneous data sources. CONCLUSION: Conducting transparent, systematic benefit-risk evaluations is an emerging "best practice" for medicinal product lifecycle management. Our experience using such an approach resulted in improvements in the consistency, quality, conciseness and strategic value of our benefit-risk assessments, and increased transparency and harmonization in the communication of the product benefit-risk profile.