Pooled Analysis Of Clinical Trials Research Articles

FDA Orders New Guides for ADHD Prescriptions

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessFDA Orders New Guides for ADHD PrescriptionsJim RosackJim RosackSearch for more papers by this authorPublished Online:16 Mar 2007https://doi.org/10.1176/pn.42.6.0001aMedications prescribed to treat attention-deficit/hyperactivity disorder (ADHD) must be accompanied by a patient medication guide, the U.S. Food and Drug Administration (FDA) said last month. The announcement came a year after two advisory committees urged the agency to provide more complete and clear information on the benefits and risks of taking medications most commonly prescribed to treat ADHD (Psychiatric News, April 21, 2006).There are 14 amphetamine and methylphenidate preparations and one nonstimulant medication, atomoxetine, approved for the treatment of ADHD. Draft medication guides (“med guides”) for each of the medications are now posted on the FDA's Web site (see the link at end of article). They are aimed at prescribers, adult patients, and the parents or caregivers of children taking the medications.The final med guides should be available in pharmacies within the next three to four months, according to Thomas Laughren, M.D., director of the FDA's Division of Psychiatry Products.The language in the draft med guides was written by FDA staff. FDA officials have requested that each manufacturer review the drafts, and companies often suggest changes. The final content is negotiated between the FDA and the manufacturers of each medication.The med guides use lay language to point out two specific areas of concern associated with taking stimulant medications: the potential for an increased risk of serious cardiovascular adverse events, including heart attack, stroke, and sudden death; and the potential for an increased risk of adverse psychiatric events such as the worsening of existing symptoms or the development of treatment-emergent mania, delusions, or hallucinations.In a box at the beginning of each med guide is the question, “What is the most important information I should know about [medication name]?” For the amphetamines and methylphenidate preparations, the box notes that spontaneous reports have occurred with patients taking stimulant medications, concerning “heart-related problems” and “mental (psychiatric) problems.”The box goes on to warn that sudden death, heart attacks, strokes, and increases in heart rate and blood pressure have all been reported. Patients and parents are urged to discuss with their doctor any heart problems that they, the child, or their immediate relatives have and are told that their doctor should check for heart problems before starting the medication.In addition, patients and parents are instructed to call their doctor immediately if “any signs of heart problems such as chest pain, shortness of breath, or fainting” develop while taking the ADHD medication. Similarly, they should be on the lookout for “new or worse behavior and thought problems, new or worse bipolar illness, or new or worse aggressive behavior or hostility.” Parents are specifically told to watch for “new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious), or new manic symptoms” in children and teenagers.The med guide for atomoxetine carries the same warnings about“ heart-related problems” and “new mental (psychiatric) problems in children and teenagers”; however, these warnings come much later in the med guide. Because atomoxetine is a dual reuptake inhibitor (serotonin/norepinephrine reuptake inhibitor, or SNRI) rather than a stimulant, the most prominent warning, listed at the beginning of the atomoxetine med guide, concerns “suicidal thoughts and actions in children and teenagers.”The FDa's Laughren told reporters at a press briefing last month that the agency decided to follow the advice of its Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee, even though there is no documented direct link between the medications and the spontaneous adverse events of cardiovascular or psychiatric problems.Laughren noted that the advisory committees reviewed reports of cardiovascular events associated with patients who took ADHD medications. There were 39 deaths and 54 reports of “serious but nonfatal” cardiac events. The information “arose entirely from spontaneous reports [through the agency's MedWatch drug surveillance system].” Many of the cases, he noted, involved young patients with unknown cardiac disease or congenital defects or patients taking multiple medications.“While the possibility exists,” Laughren said, “that these events are related to the underlying cardiovascular disease and not the drug, [the advisory committees] advised us to go ahead and alert the public to the possibility that the drug might have had a role.”Evidence of a “causal link” between the ADHD medications and psychiatric adverse events “is stronger than for the cardiovascular events,” said Laughren. He noted that reports of treatment-emergent mania or psychotic symptoms arose not just from MedWatch, but also from a pooled analysis of clinical-trials data.More information and links to the draft med guides are posted at<www.fda.gov/cder/drug/infopage/ADHD/default.htm>.▪ ISSUES NewArchived

Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials

Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.

Psychological factors as a predictor of treatment response in patients with heartburn: A pooled analysis of clinical trials

Objective. A pooled analysis, using data from three prospective, randomized, double-blind, placebo-controlled, clinical studies, was undertaken to determine the relationship between well-being and subsequent clinical response to acid suppressant therapy in 1887 adult patients with reflux symptoms (with/without endoscopically verified erosive esophagitis). Material and methods. Well-being was assessed at study entry using the Psychological General Well-Being (PGWB) Index. Patients were assessed for complete relief of heartburn (absence of symptoms in the preceding 7 days) after 4 weeks’ treatment (omeprazole 10 or 20 mg once daily; ranitidine 150 mg twice daily). Results. Multiple logistic regression analysis identified baseline PGWB Index total score and anxiety score as independent prognostic indicators of treatment response in endoscopy-positive patients (n=1333). Thus, the likelihood of achieving complete heartburn relief was impaired by high baseline levels of anxiety or a low total well-being score. In the endoscopy-negative group, high levels of depression and low vitality scores affected treatment response adversely. Furthermore, age (for endoscopy-positive patients only) and body mass index (for endoscopy-negative patients only) showed an association with treatment outcome. Gender seemed to have no prognostic value on treatment outcome. Conclusions. Patient well-being may be a useful prognostic indicator in patients presenting with reflux symptoms, with a high level of anxiety predicating against a response to acid suppressant therapy, particularly in those with normal endoscopic findings.

Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials

Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according to the standard therapy. Although there is evidence that elderly patients benefit from adjuvant (radio-) chemotherapy to the same extent as younger patients, no large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. We carried out a retrospective analysis using source data of 3825 patients who received 5-fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of > or = 70 years. We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (CI) 9.7-11.8] and in younger patients (11.3 months, 95% CI 10.9-11.7; P = 0.31). Response rate did not differ between age groups > or = 70 and <70 years (23.9% and 21.1%; respectively; P = 0.14). Progression-free survival was marginally prolonged in elderly patients (5.5 months, 95% CI 5.2-5.8; compared with 5.3 months, 95% CI 5.1-5.5; P = 0.01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression-free survival compared with bolus 5-FU. 'Fit' elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.

Efficacy of bolus and infusional 5-FU in elderly and non-elderly patients with metastatic colorectal cancer - a pooled analysis of clinical trials

8045 Background: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according the standard therapy, although they benefit to the same extent from adjuvant (radio-) chemotherapy as younger patients. No large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. Methods: We carried out a retrospective analysis using source data of 3,825 patients who received 5-FU containing treatment in 22 European trials and identified 629 patients with an age of ≥ 70 years. Results: An equal overall survival was observed in elderly patients (10.8 months, 95 % CI 9.7–11.8) and in younger patients (11.3 months, 95 % CI 10.9–11.7, p = .31). Response rate did not differ between the age groups ≥ 70 and < 70 years (20.8 % and 17.6 %, p = .14). Progression free survival was marginally prolonged in elderly patients (5.5 months, 95 % CI 5.2–5.8 and 5.3 months, 95 % CI 5.1–5.5, p = .01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression free survival compared to bolus 5-FU. The Cox- regression analysis showed no influence of age on OS. Conclusions: We conclude that “fit” elderly patients (fulfilling standard inclusion criteria of clinical trials) benefit to the same extent from palliative chemotherapy with 5-FU. Infusional 5-FU is more effective in elderly as in younger patients. Standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials. No significant financial relationships to disclose.

Efficacy of bolus and infusional 5-FU in elderly and non-elderly patients with metastatic colorectal cancer - a pooled analysis of clinical trials

Efficacy of bolus and infusional 5-FU in elderly and non-elderly patients with metastatic colorectal cancer - a pooled analysis of clinical trials

Candesartan cilexetil: an update of its use in essential hypertension.

Candesartan cilexetil is converted to the angiotensin II receptor antagonist candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of candesartan to the angiotensin II type 1 (AT(1)) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic BP and diastolic BP are achieved with a once-daily dosage of candesartan cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, candesartan cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day candesartan cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, candesartan cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of candesartan cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with candesartan cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with candesartan cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with candesartan cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of candesartan cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity. Candesartan cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that candesartan cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, candesartan cilexetil is a useful therapeutic option in the management of patients with hypertension.