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Biomedical subjects

Benjamin Djulbegovic

Publications and source records attributed to Benjamin Djulbegovic.

At least 37 records · Page 2Linked to original sources
PubMed2005

Use of re-randomized data in meta-analysis.

BACKGROUND: Outcomes collected in randomized clinical trials are observations of random variables that should be independent and identically distributed. However, in some trials, the patients are randomized more than once thus violating both of these assumptions. The probability of an event is not always the same when a patient is re-randomized; there is probably a non-zero covariance coming from observations on the same patient. This is of particular importance to the meta-analysts. METHODS: We developed a method to estimate the relative error in the risk differences with and without re-randomization of the patients. The relative error can be estimated by an expression depending on the percentage of the patients who were re-randomized, multipliers (how many times more likely it is to repeat an event) for the probability of reoccurrences, and the ratio of the total events reported and the initial number of patients entering the trial. RESULTS: We illustrate our methods using two randomized trials testing growth factors in febrile neutropenia. We showed that under some circumstances the relative error of taking into account re-randomized patients was sufficiently small to allow using the results in the meta-analysis. Our findings indicate that if the study in question is of similar size to other studies included in the meta-analysis, the error introduced by re-randomization will only minimally affect meta-analytic summary point estimate. We also show that in our model the risk ratio remains constant during the re-randomization, and therefore, if a meta-analyst is concerned about the effect of re-randomization on the meta-analysis, one way to sidestep the issue and still obtain reliable results is to use risk ratio as the measure of interest. CONCLUSION: Our method should be helpful in the understanding of the results of clinical trials and particularly helpful to the meta-analysts to assess if re-randomized patient data can be used in their analyses.

Colony-Stimulating Factors↗
PubMed2005

Estimating the mean and variance from the median, range, and the size of a sample.

BACKGROUND: Usually the researchers performing meta-analysis of continuous outcomes from clinical trials need their mean value and the variance (or standard deviation) in order to pool data. However, sometimes the published reports of clinical trials only report the median, range and the size of the trial. METHODS: In this article we use simple and elementary inequalities and approximations in order to estimate the mean and the variance for such trials. Our estimation is distribution-free, i.e., it makes no assumption on the distribution of the underlying data. RESULTS: We found two simple formulas that estimate the mean using the values of the median (m), low and high end of the range (a and b, respectively), and n (the sample size). Using simulations, we show that median can be used to estimate mean when the sample size is larger than 25. For smaller samples our new formula, devised in this paper, should be used. We also estimated the variance of an unknown sample using the median, low and high end of the range, and the sample size. Our estimate is performing as the best estimate in our simulations for very small samples (n < or = 15). For moderately sized samples (15 < n < or = 70), our simulations show that the formula range/4 is the best estimator for the standard deviation (variance). For large samples (n > 70), the formula range/6 gives the best estimator for the standard deviation (variance). We also include an illustrative example of the potential value of our method using reports from the Cochrane review on the role of erythropoietin in anemia due to malignancy. CONCLUSION: Using these formulas, we hope to help meta-analysts use clinical trials in their analysis even when not all of the information is available and/or reported.

Analysis of Variance↗
PubMed2005

Evaluation of new treatments in radiation oncology: are they better than standard treatments?

CONTEXT: The superiority of innovative over standard treatments is not known. To describe accurately the outcomes of innovations that are tested in randomized controlled trials (RCTs) 3 factors have to be considered: publication rate, quality of trials, and the choice of the adequate comparator intervention. OBJECTIVE: To determine the success rate of innovative treatments by assessing preferences between experimental and standard treatments according to original investigators' conclusions, determining the proportion of RCTs that achieved primary outcomes' statistical significance, and performing meta-analysis to examine if the summary point estimate favored innovative vs standard treatments. DATA SOURCES: Randomized controlled trials conducted by the Radiation Therapy Oncology Group (RTOG). STUDY SELECTION: All completed phase 3 trials conducted by the RTOG since its creation in 1968 until 2002. For multiple publications of the same study, we used the one with the most complete primary outcomes and with the longest follow-up information. DATA EXTRACTION: We used the US National Cancer Institute definition of completed studies to determine the publication rate. We extracted data related to publication status, methodological quality, and treatment comparisons. One investigator extracted the data from all studies and 2 independent investigators extracted randomly about 50% of the data. Disagreements were resolved by consensus during a meeting. DATA SYNTHESIS: Data on 12,734 patients from 57 trials were evaluated. The publication rate was 95%. The quality of trials was high. We found no evidence of inappropriateness of the choice of comparator. Although the investigators judged that standard treatments were preferred in 71% of the comparisons, when data were meta-analyzed innovations were as likely as standard treatments to be successful (odds ratio for survival, 1.01; 99% confidence interval, 0.96-1.07; P = .5). In contrast, treatment-related mortality was worse with innovations (odds ratio, 1.76; 99% confidence interval, 1.01-3.07; P = .008). We found no predictable pattern of treatment successes in oncology: sometimes innovative treatments are better than the standard ones and vice versa; in most cases there were no substantive differences between experimental and conventional treatments. CONCLUSION: The finding that the results in individual trials cannot be predicted in advance indicates that the system and rationale for RCTs is well preserved and that successful interventions can only be identified after an RCT is completed.

Clinical Trials, Phase III as Topic↗
PubMed2005

Erythropoietin use in oncology: a summary of the evidence and practice guidelines comparing efforts of the Cochrane Review group and Blue Cross/Blue Shield to set up the ASCO/ASH guidelines.

Clinical research evidence on outcomes of using epoetin (EPO) to treat or prevent anemia in oncology has recently been systematically synthesized to provide a scientific foundation for developing and implementing clinical practice guidelines. Two groups have distinguished themselves by their meticulous research methods, the Blue Cross and Blue Shield Association Technology Evaluation Center (BCBSA TEC) and the Cochrane Review Group (CRG), and have summarized existing research evidence on the role of EPO in anemia associated with cancer treatment. An ASH/ASCO (American Society of Hematology/American Society of Clinical Oncology) panel has used the BCBSA TEC review to develop practice guidelines on the use of EPO in patients with cancer. The ASH/ASCO guideline panel identified eight important clinical circumstances for which use of EPO in oncology might be considered and used the BCBSA TEC evidence review to formulate evidence-based guidelines that support use of EPO. Both BCBSA TEC and CRG found solid evidence exists to show that EPO improves hemoglobin levels and reduce the risk for transfusion. The ASH/ASCO panel concluded that best empirical evidence exists to support the use of EPO to correct anemia due to chemotherapy if Hgb</=10g/dl. In other clinical circumstances the ASH/ASCO panel made recommendations either by extrapolating evidence from similar settings or relied on expert opinion since sufficient evidence was lacking. Both BCBSA TEC and CRG also concluded that limited evidence exists that EPO improves symptoms, fatigue, or quality of life, particularly when anemia is less severe. The finding from these systematic reviews are also reflected in the opinion of the ASH/ASCO guidelines panel, which also concluded that better evidence is needed to support use of EPO in oncology under these circumstances. In this paper, the findings from the guidelines set by ASH/ASCO that were culled from systematic reviews by BCBSA TEC and the Cochrane Review are compared and contrasted.

Anemia↗
PubMed2004

Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma.

Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.

Adult↗
PubMed2004

Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group.

OBJECTIVE: To determine whether poor reporting of methods in randomised controlled trials reflects on poor methods. DESIGN: Observational study. SETTING: Reports of randomised controlled trials conducted by the Radiation Therapy Oncology Group since its establishment in 1968. PARTICIPANTS: The Radiation Therapy Oncology Group. Outcome measures Content of reports compared with the design features described in the protocols for all randomised controlled trials. RESULTS: The methodological quality of 56 randomised controlled trials was better than reported. Adequate allocation concealment was achieved in all trials but reported in only 42% of papers. An intention to treat analysis was done in 83% of trials but reported in only 69% of papers. The sample size calculation was performed in 76% of the studies, but reported in only 16% of papers. End points were clearly defined and alpha and beta errors were prespecified in 76% and 74% of the trials, respectively, but only reported in 10% of the papers. The one exception was the description of drop outs, where the frequency of reporting was similar to that contained in the original statistical files of the Radiation Therapy Oncology Group. CONCLUSIONS: The reporting of methodological aspects of randomised controlled trials does not necessarily reflect the conduct of the trial. Reviewing research protocols and contacting trialists for more information may improve quality assessment.

Clinical Trials, Phase III as Topic↗
PubMed2004

Where is the evidence?

Explore the source record for details and available documents.

Attitude of Health Personnel↗
PubMed2003

Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients.

PURPOSE: Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. PATIENTS AND METHODS: Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. RESULTS: Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. CONCLUSION: Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

Antifungal Agents↗
PubMed2003

Pharmaceutical industry sponsorship and research outcome and quality: systematic review.

OBJECTIVE: To investigate whether funding of drug studies by the pharmaceutical industry is associated with outcomes that are favourable to the funder and whether the methods of trials funded by pharmaceutical companies differ from the methods in trials with other sources of support. METHODS: Medline (January 1966 to December 2002) and Embase (January 1980 to December 2002) searches were supplemented with material identified in the references and in the authors' personal files. Data were independently abstracted by three of the authors and disagreements were resolved by consensus. RESULTS: 30 studies were included. Research funded by drug companies was less likely to be published than research funded by other sources. Studies sponsored by pharmaceutical companies were more likely to have outcomes favouring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons). None of the 13 studies that analysed methods reported that studies funded by industry was of poorer quality. CONCLUSION: Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.

Clinical Trials as Topic↗
PubMed2003

Choosing a control intervention for a randomised clinical trial.

BACKGROUND: Randomised controlled clinical trials are performed to resolve uncertainty concerning comparator interventions. Appropriate acknowledgment of uncertainty enables the concurrent achievement of two goals : the acquisition of valuable scientific knowledge and an optimum treatment choice for the patient-participant. The ethical recruitment of patients requires the presence of clinical equipoise. This involves the appropriate choice of a control intervention, particularly when unapproved drugs or innovative interventions are being evaluated. DISCUSSION: We argue that the choice of a control intervention should be supported by a systematic review of the relevant literature and, where necessary, solicitation of the informed beliefs of clinical experts through formal surveys and publication of the proposed trial's protocol. SUMMARY: When clinical equipoise is present, physicians may confidently propose trial enrollment to their eligible patients as an act of therapeutic beneficence.

Control Groups↗