No abstract

Treatment effect has declined over time in MDD trials, and there has been a high failure rate for these trials during the entire period, but the reasons for these findings remain elusive. Baseline disease severity seems to be a more important factor in study outcome than study duration, dosing regimen, sample size, time when studies were conducted, and regions where data were generated. Close attention is needed to a variety of factors in the design and conduct of these studies, including patient population, diagnostic considerations, patient assessment, and clinical practice differences. These considerations become increasingly important as globalization of clinical trials continues to increase.

Purpose: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non^small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Experimental Design: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Results: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. Conclusions: On November18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.Lung cancer is the leading cause of cancer death in both men and women in the United States (1). Initial therapy for advanced non -small lung cancer (NSCLC) is systemic chemotherapy with a two-drug combination regimen that often includes a platinum. Docetaxel and pemetrexed are approved by the Food and Drug Administration (FDA) for use as the second-line chemotherapy. Recently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was granted FDA-accelerated approval under subpart H for treatment of advanced NSCLC after failure of both platinum-based and docetaxel chemotherapy, based on a response rate of f10% in single-arm clinical trials. Erlotinib (T arceva, OSI Pharmaceuticals, Melville, NY) inhibits EGFR tyrosine kinase autophosphorylation by inhibition of the intracellular domain. Studies in cell lines and enzyme assays have both shown that erlotinib inhibits EGFR at concentrations significantly lower than those needed to inhibit c-src and v-abl. Whereas erlotinib was more selective for EGFR tyrosine kinase than it was for several other tyrosine kinases tested, several other tyrosine kinases in the same family as EGFR were not tested. Although erlotinib seems rather selective for EGFR, insufficient data exist to make a definitive decision regarding selectivity (2 -4). Chemistry and ToxicologyErlotinib hydrochloride is a quin...