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Risk Minimization Method Evaluation in Oncology

Title
Risk Minimization Method Evaluation in Oncology

Abstract
Purpose: Pemetrexed is licensed for use in mesothelioma and non-small-cell lung cancer. Early clinical development indicated that it causes cytotoxicity with dose (efficacy) limiting gastrointestinal (GI) and blood toxic effects. Use of folic acid and vitamin B12 reduced these toxicities. This study was undertaken to assess the effectiveness of a risk minimization program based on administration of folic acid and vitamin B12 to reduce the therapeutic toxicity of pemetrexed and physicians’ compliance with these measures. Methods: Lilly Safety Database was searched for reports of GI and blood toxicity associated with pemetrexed. The period of early development was compared with the subsequent period in which risk minimization measures were in place. Reports from the postmarketing period were assessed to determine the percentage reported with appropriate risk minimization supplemention. Results: The proportion of severe GI and blood toxicity in clinical trials was lower after the introduction of supplementation (67.3% vs 84.8%, P < 0.001). A reduction in toxicity was also seen in the individual MedDRA System Organ Classes: hematological toxicity (49.5% to 43%, P = 0.015) and GI toxicity (26.5% to 12.9%, P < 0.001). In the 4-year postmarketing period, compliance with the risk minimization program as assessed by the percentage of initial reports, which included details of appropriate supplementation, was stable at 70%. This rose to 97.7% on follow-up. Conclusion: Implementation of this risk minimization program demonstrated a significant reduction in adverse drug reaction reports of high-grade blood and GI toxicity together with a high level of compliance with supplementation treatment. It is feasible to verify the success of a risk minimization method by objective demonstration of a reduction in toxicity and, separately, to confirm physicians’ compliance with the risk minimization program.