Ultimate Fate of Oncology Drugs Approved by the US Food and Drug Administration Without a Randomized Trial
ABSTRACT To approve a new anticancer drug, the US Food and Drug Administration often requires randomized trials. However, several oncology drugs have been approved on the basis of objective end points without a randomized trial. We reviewed the long-term safety and efficacy of such agents.
We searched the Web site of the US Food and Drug Administration's Center for Drug Evaluation and Research and MEDLINE for initial applications of investigational anticancer drugs from 1973 through 2006.
Overall, 68 oncology drugs, excluding hormone therapy and supportive care, were approved, including 31 without a randomized trial. For these 31 drugs, a median of two clinical trials (range, one to seven) and 79 patients (range, 40 to 413) were used per approval. Objective response was the most common end point used for approval; median response rate was 33% (range, 11% to 90%). Thirty drugs are still fully approved. United States marketing authorization for one drug, gefitinib (an epidermal growth factor receptor [EGFR] inhibitor), was rescinded after a randomized trial showed no survival improvement; however, this trial was performed in unselected patients, and it was subsequently demonstrated that patients with EGFR mutation are more likely to respond. Nineteen of the 31 drugs have additional uses (per National Comprehensive Cancer Network or National Cancer Institute Physician Data Query guidelines), and subsequent formal US Food and Drug Administration approvals were obtained for 11 of these (range, one to 18 new indications). No drug has demonstrated safety concerns.
Nonrandomized clinical trials with definitive end points can yield US Food and Drug Administration approvals, and these drugs have a reassuring record of long-term safety and efficacy.
- SourceAvailable from: Tania CrombetAdvances in Cancer Therapy, 11/2011; , ISBN: 978-953-307-703-1
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ABSTRACT: The new complexes of 4-methylesculetin (H2mesc), [Zn2(bpy)2(mesc)2], [Zn(PPh3)2(mesc)], Na2[MoO2(mesc)2], (PPh4)2[Mo2O5(mesc)2], [Pd(bpy)(mesc)], [Pd(phen)(mesc)], [Pd(PPh3)2(mesc)], [Pt(PPh3)2(mesc)] and [Ag(bpy)2]. (bpy)H2mesc(NO3), are reported. The complexes were characterized on the bases of elemental analysis, spectroscopic (IR, UV–Vis, mass, 1H, 13C and 31P NMR) and physical (conductivity and thermal) techniques. The ligand (mesc2−) behaves in a binegative bidentate fashion, chelating the metal ions through the deprotonated hydroxy oxygen atoms, except in case of Ag(I), where it was found outside the coordination sphere of the complex. The X-ray crystal structure of [Zn2(bpy)2(mesc)2] has been determined. The bond length of Zn–O(7) is shorter than Zn–O(6). A theoretical study on H2mesc and its dianion mesc−2 was undertaken through computational conformational analysis, indicating the higher basicity of O(7) with respect to O(6). H2mesc and the complexes have been tested as anti-neoplastic agents against human prostate cancer (DU 145) and human breast cancer (MDA-MB231) cell lines.Inorganica Chimica Acta 06/2014; 423:132. DOI:10.1016/j.ica.2014.05.048 · 2.04 Impact Factor
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ABSTRACT: Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two-stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two-stage design proposed by Chang et al. (Biometrics 1987; 43:865-874). However, the new design allows the use of mid-course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.Pharmaceutical Statistics 05/2012; 11(3). DOI:10.1002/pst.541 · 1.10 Impact Factor