Pooling, meta-analysis, and the evaluation of drug safety

BACKGROUND: The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. METHODS: We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1) a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2) an active reference drug in 2 larger trials of patients at low risk for this event. RESULTS: Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12]) compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. CONCLUSIONS: Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files

Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening

<p>Abstract</p> <p>Background</p> <p>Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care.</p> <p>Methods</p> <p>DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented.</p> <p>Results</p> <p>The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint.</p> <p>Conclusions</p> <p>These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00627783">NCT00627783</a></p

TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan–Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT

Molecular determinants of anti-EGFR sensitivity and resistance in metastatic colorectal cancer

Since 2004, the clinical impact of monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) on patients with metastatic colorectal cancer (MCRC) has been clearly established. The combination of these biological agents with conventional chemotherapy has led to a significant improvement in response rate, progression-free survival and overall survival in first-line as well as in second- or third-line treatment of MCRC. However, the high variability of response and outcome in MCRC patients treated with these anti-EGFR mAbs has highlighted the need of identifying clinical and/or molecular predictive markers to ensure appropriate use of targeted therapies. The presence of somatic KRAS mutations has been clearly identified as a predictive marker of resistance to anti-EGFR in MCRC, and the use of anti-EGFR mAbs is now restricted to patients with no detectable KRAS mutation. Several studies have indicated that amplification of EGFR, overexpression of the EGFR ligands and inactivation of the anti-oncogene TP53 are associated with sensitivity to anti-EGFR mAbs, whereas mutations of BRAF and PIK3CA and loss of PTEN expression are associated with resistance. Besides these somatic variations, germline polymorphisms such as those affecting genes involved in the EGFR pathway or within the immunoglobulin receptors may also modulate response to anti-EGFR mAbs. Until now, all these markers are not completely validated and only KRAS genotyping is mandatory in routine practice for use of the anti-EGFR mAbs in MCRC

Analyzing rockfall activity (1600–2002) in a protection forest—a case study using dendrogeomorphology

For the first time, dendrogeomorphology has been used to investigate spatial and temporal variations of rockfall activity in a protection forest. We report results of 564 cores from 135 severely injured Larix decidua Mill. trees on the west-facing Täschgufer slope, Swiss Alps. While trees sampled reached an age of 297 years on average, the oldest one attained breast height in AD 1318. For reasons of sample depth, the analysis was limited to the period 1600–2002. In total, we reconstructed 741 growth disturbances (GD) during the last four centuries. Impacts were most commonly found in trees located in the southern part of the slope, where GD recurred more than once per decade. In contrast, trees in the northern part were less frequently disturbed by rockfall and define recurrence intervals of more than 150 years.Throughout the last four centuries, rockfall has caused GD to the trees sampled on the Täschgufer slope, most frequently in the form of low magnitude–high frequency events. In addition, we identified one high magnitude–low frequency event in 1720, which displaced the forest fringe of the northern sector a considerable distance downslope and eliminated an entire forest stand. To analyze past rockfall activity, we introduce a “rate” defined as the number of impacts per meter width of all tree surfaces sampled per decade. Results clearly demonstrate that this rockfall “rate” continually decreased in both sectors after the large 1720 rockfall event. Significantly low rockfall “rates” can be observed during the 1850s, 1960s and 1970s in the northern and during the 1820s in the southern sector. In contrast, high rockfall “rates” were identified during the 1870s and 1990s in the northern, and during the 1770s in the southern sector.Reconstructed data further show that the forest recolonizing the southern sector after the 1720 event gradually improved its protective function, reducing “rates” by a factor of 13 between the 1740s and the 1990s. In the recent past, “rates” oscillated around 0.7 GD 1 meter width⁻¹ (10 years)⁻¹. In the well-established forest of the northern sector, the efficacy of the protective forest was temporarily reduced by the rockfalls in 1720, resulting in increased rockfall “rates”. Since then, the protective function of the forest stand has increased again, resulting in a rate of 0.4 GD 1 m width⁻¹ (10 years)⁻¹ during the late 20th century

Naturalistic decision making and emotion in refereeing: affect at the heart of judgment

International audienceIntroduction: This study examines emotions in decision making during sport refereeing. We study how emotions contribute to referees’ judgment acts. We seek to determine whether 1) a negative affect arises from the referees’ relationship to the unfolding game; 2) judgment acts are able to end this unsatisfactory situation. Method: We have investigated four games in a professional rugby championship. The game was filmed from the stands, the referee was equipped with a head-mounted camera, and a self-confrontation interview was realized. We analyzed the situations in which the referees reported negative affect. Results/discussion: In some cases, affective dissatisfaction was related to an abnormal situation. The referee showed what was abnormal and overcame his dissatisfaction through a judgment act. In other cases, affective dissatisfaction was related to a paradoxical situation. The return to a satisfactory state occurred when a norm became predominant to determine the normality/abnormality of the situation within its unfolding

NMR-based prediction of cardiovascular risk in diabetes.

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