Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer.
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Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In July 2000, a marketing application for first-line letrozole treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival. (+info)
End points in cancer clinical trials and the drug approval process.
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The sequencing of the human genome and the elucidation of many molecular pathways important in cancer cell proliferation, apoptosis, and metastasis have provided unprecedented opportunities for development of new agents to prevent and treat cancer. The types of molecules in development are increasingly varied and include small molecules, monoclonal antibodies, antisense oligonucleotides, and ribozymes. Thus, the variety of anticancer agents in clinical development is now greater than ever before, and the number of agents currently in clinical trial for various cancer indications is estimated to exceed 400. Many of these drugs would be expected to work in only narrowly defined patient populations that must be prospectively identified. Thus, the development of the therapeutic agent must often be linked to the development of a molecular diagnostic product. Drugs that produce primarily cytostatic effects might not be expected to produce regression of tumor masses; thus, evaluation of such agents would best be done in populations of patients with low tumor burdens but high risk of disease progression. As traditional clinical end points prove more difficult to apply in evaluation of molecularly targeted therapies, a great need exists to define and validate surrogate markers of effect and of benefit. New clinical trial designs and end points are necessary to permit more efficient evaluation of putative cancer treatments. This editorial will review commonly used clinical trial end points and describe their potential advantages and disadvantages to expedite the drug approval process required in the United States. (+info)
Soluble fiber intake at a dose approved by the US Food and Drug Administration for a claim of health benefits: serum lipid risk factors for cardiovascular disease assessed in a randomized controlled crossover trial.
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BACKGROUND: The US Food and Drug Administration (FDA) approved health claims for 2 dietary fibers, beta-glucan (0.75 g/serving) and psyllium (1.78 g/serving), on the assumption that 4 servings/d would reduce cardiovascular disease risk. OBJECTIVE: We assessed the efficacy of this dose of fibers in reducing serum lipid risk factors for cardiovascular disease. DESIGN: Sixty-eight hyperlipidemic adults consumed a test (high-fiber) and a control low-fat (25% of energy), low-cholesterol (<150 mg/d) diet for 1 mo each in a randomized crossover study. The high-fiber diet included 4 servings/d of foods containing beta-glucan or psyllium that delivered 8 g/d more soluble fiber than did similar, unsupplemented foods in the control diet. Fasting blood samples and blood pressure readings were obtained at baseline and weeks 2 and 4, and the subjects' weight was monitored weekly. RESULTS: Compared with the control diet, the high-fiber diet reduced total cholesterol (2.1 +/- 0.7%; P = 0.003), total:HDL cholesterol (2.9 +/- 0.8%; P = 0.001), LDL:HDL cholesterol (2.4 +/- 1.0%; P = 0.015), and apolipoprotein B:A-I (1.4 +/- 0.8%; P = 0.076). Applying the Framingham cardiovascular disease risk equation to the data confirmed a reduction in risk of 4.2 +/- 1.4% (P = 0.003). Small reductions in blood pressure were found after both diets. The subjects reported no significant differences in palatability or gastrointestinal symptoms between the diets. CONCLUSIONS: The reduction in serum lipid risk factors for cardiovascular disease supports the FDA's approval of a health claim for a dietary fiber intake of 4 servings/d. Although relatively small in terms of patient treatment, the reduction in cardiovascular disease risk is likely to be significant on a population basis. (+info)
Surrogate end points in heart failure.
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Because of the increasing number of pharmacologic strategies available for treatment of heart failure (HF), the time has come to reassess the adequacy of end points used to evaluate therapeutic efficacy. Interest in the use of surrogate end points in clinical studies is increasing. A surrogate end point is defined as a measurement that can substitute for a true end point for the purpose of comparing specific interventions or treatments in a clinical trial. A true end point is one that is of clinical importance to the patient (e.g., mortality or quality of life), whereas a surrogate end point is one biologically closer to the disease process (e.g., ejection fraction or left ventricular volume in HF). The prime motivation for the use of a surrogate end point concerns the possible reduction in sample size or trial duration. Such reductions have important cost implications and in some cases may influence trial feasibility. Another, perhaps more important, aspect of measuring surrogate end points is that they increase our understanding of the mechanism of action of drugs and thus may help physicians to take a more enlightened approach in managing their patients. In this article we have analyzed the possible potentials of the surrogate end points in clinical studies of patients with chronic HF. Other uses of possible surrogates are discussed, and the limitations in finding true surrogates are mentioned. At this time we conclude there is no well established surrogate in HF. (+info)
The Anthrax Vaccine Program: an analysis of the CDC's recommendations for vaccine use.
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The anthrax vaccine was never proved to be safe and effective. It is one cause of Gulf War illnesses, and recent vaccinees report symptoms resembling Gulf War illnesses. The vaccine's production has been substandard. Without adequate evaluation, the Food and Drug Administration recently approved (retrospectively) significant changes made to the vaccine's composition since 1990. The vaccine's mandatory use for inhalation anthrax is "off-label." A skewed review of the vaccine literature by the Centers for Disease Control and Prevention (CDC) led to remunerative collaborative research with the army, involving civilian volunteers. Despite acknowledging possible fetal harm, the CDC offered the vaccine to children and pregnant women. New trends could weaken prelicensure efficacy and safety review of medical products intended for biodefense and avoid manufacturer liability for their use. (+info)
Status of certain additional over-the-counter drug category II and III active ingredients. Final rule.
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The Food and Drug Administration (FDA) is issuing a final rule stating that a certain ingredient in over-the-counter (OTC) drug products is not generally recognized as safe and effective or is misbranded. FDA is issuing this final rule after considering the reports and recommendations of various OTC drug advisory review panels and public comments on proposed agency regulations. This final rule addresses the ingredient octoxynol 9, considered in the rulemaking for OTC vaginal contraceptive drug products. Based on the failure of interested parties to submit new data or information to FDA under the proposed regulation, the agency has determined that the presence of this active ingredient in an OTC drug product would result in that drug product not being generally recognized as safe and effective for its intended use or would result in misbranding. This final rule is part of FDA's ongoing OTC drug product review. (+info)
Status of certain additional over-the-counter drug category II and III active ingredients. Final rule.
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The Food and Drug Administration (FDA) is issuing a final rule stating that the stimulant laxative ingredients aloe (including aloe extract and aloe flower extract) and cascara sagrada (including casanthranol, cascara fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, and cascara sagrada fluidextract) in over-the- counter (OTC) drug products are not generally recognized as safe and effective or are misbranded. This final rule is part of FDA's ongoing OTC drug product review. (+info)
Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.
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PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application. (+info)