Biomedical subjects
FDA
Publications and source records attributed to FDA.
Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes.
PURPOSE: This article summarizes data submitted to the U.S. Food and Drug Administration for marketing approval of azacitidine as injectable suspension (Vidaza, Pharmion Corporation, Boulder, CO) for treatment of patients with myelodysplastic syndrome. EXPERIMENTAL DESIGN: In one phase 3 controlled trial, 191 study subjects were randomized to treatment with azacitidine or to observation; an additional 120 patients were treated with azacitidine in two phase 2 single arm studies. The primary efficacy end point was the overall response rate, defined as complete or partial normalization of peripheral blood counts and bone marrow blast percentages for at least 4 weeks. RESULTS: In the controlled trial, the overall response rate was 15.7% in the azacitidine treatment group; there were no responders in the observation group (P < 0.0001). Response rates were similar in the two single arm studies. During response patients stopped being red cell or platelet transfusion dependent. Median duration of responses was at least 9 months. An additional 19% of azacitidine-treated patients had less than partial responses, most becoming transfusion independent. The most common adverse events attributed to azacitidine were gastrointestinal, hematologic, local (injection site), and constitutional. There were no azacitidine-related deaths. CONCLUSIONS: On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Full prescribing information is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome.
Evaluation of blend uniformity and content uniformity based on 2003 stratified sampling guidance and 1999 blend uniformity analysis guidance: product A.
In August 1999 the FDA issued a Draft Abbreviated New Drug Application (ANDA) Guidance for Industry titled "ANDA's: Blend Uniformity Analysis" that detailed blend uniformity sampling and acceptance criteria for the determination of final blend uniformity for generic drug products. Although this guidance was written specifically to address ANDA's, the guidance was also adopted as standard practice in the development of NDA's (New Drug Applications). The proposed release criteria established for blend uniformity were to be used in addition to, and independent from, the USP finished product uniformity release requirements. Based on the Blend Uniformity Guidance, batches that failed to meet the blend uniformity acceptance criteria should be rejected regardless of the products ability to demonstrate final product uniformity. In March 2002, the Product Quality Research Institute (PQRI) issued a proposal to the FDA with respect to both ANDA's and NDA's recommending the use of stratified sampling for final blend and in-process dosage units. The proposal recommended the use of final blend uniformity and dosage unit uniformity to demonstrate overall batch uniformity, with the possibility of using dosage unit uniformity in lieu of blend uniformity during routine commercial production. Consequently, in October 2003, the FDA issued a Draft Guidance for Industry titled "Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling Assessment" that detailed the criteria for the use of stratified sampling and acceptance criteria to demonstrate batch uniformity. In response to the PQRI proposal, Endo Pharmaceuticals conducted an impact evaluation of the proposed PQRI sampling procedures and acceptance criteria on a product-by-product basis as compared to the 1999 Draft Guidance and current USP requirements. The evaluation of Product A demonstrates the benefit of implementing the 2003 Guidance for products that demonstrate questionable blend uniformity but acceptable finished product uniformity.