A proposal for a new PhD level curriculum on quantitative methods for drug development.

This paper provides an overview of "Improving Design, Evaluation and Analysis of early drug development Studies" (IDEAS), a European Commission-funded network bringing together leading academic institutions and small- to large-sized pharmaceutical companies to train a cohort of graduate-level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early-stage researchers for 36 months. IDEAS training activities are composed of a well-rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development.

Evaluation of an integrated care program for schizophrenia: concept and study design.

Concept and design of an independent scientific evaluation of different pathways of care for schizophrenia patients in Germany with respect to effectiveness and efficiency are presented. In this prospective, observational study, schizophrenia patients receiving an integrated care treatment, the intervention group (IG), are compared with patients under routine care conditions treated by the same physician (first control group, CG 1). A second control group (CG 2) of patients treated by office-based psychiatrists not participating in the integrated care program will be recruited and their data compared with the two other groups. The total amount of psychiatric hospital days after 12 months is defined as primary outcome parameter. Secondary outcome parameters comprise the frequency of psychiatric inpatient readmissions, severity of schizophrenia symptoms, remission rates and quality of life. Patients undergo assessments at baseline, month 6 and 12 using standardized and experimental questionnaires. Routine data of a regional German social health insurance fund complement information on included patients. Additionally, a cost-effectiveness and cost-utility analysis will be performed. Until now, 137 psychiatrists included 980 patients in the integrated care project in Lower Saxony, Germany, and 47 psychiatrists (IG and both CGs) are willing to participate in the independent evaluation. For the first time, a prospective observational controlled evaluation study of a countrywide integrated care project planning to recruit 500 schizophrenia patients has started using comprehensive assessments as well as routine data of a social health insurance fund.

Informative simultaneous confidence intervals in hierarchical testing.

BACKGROUND AND OBJECTIVES: In clinical trials involving multiple tests it is often difficult to obtain informative simultaneous confidence intervals (SCIs). In particular in hierarchical testing, no quantification of effects is possible for the first tested (and most important) hypothesis after its rejection. Our goal is a construction of SCIs that are always informative. METHODS: We present an approach where the level is split after rejection of each hypothesis to obtain an informative confidence bound. The splitting weights are continuous functions of the parameters. Our method is realizable by a simple algorithm and is illustrated by an intuitive graphical representation. RESULTS: We show theoretically and by an example that the new SCIs always provide information when a hypothesis is rejected. The power to reject the first hypothesis is not smaller than for the classical fixed-sequence procedure. The price for the extra information is a small power loss in the hypotheses proceeding the most important one. CONCLUSIONS: Given the substantial gain in information, a small loss of power for the non-primary hypotheses seems often acceptable. Especially in the context of non-inferiority trials, this method is a useful alternative. The flexibility in the choice of the weight functions makes the procedure attractive for applications.

Multiple tests of cost-effectiveness angles.

Cost-effectiveness angles are an attractive measure of performance when comparing effects and costs of health-care therapies because they have a clear interpretation and are well suited for statistical inference. In clinical trials, a common setup is the comparison of multiple new therapies with a single control. If cost-effectiveness angles are calculated for each comparison, multiplicity issues should be taken into account when quantifying uncertainty of the point estimates. Therefore, this paper proposes a parametric test for multiple cost-effectiveness angles that guarantees strong family-wise error rate control. The idea is to replace the test of m cost-effectiveness angles as a union-intersection test of 3m linear hypotheses. Considering the correlation structure of the individual test statistics for the linear hypotheses leads to a maximum-type test for the intersection hypothesis. Inverting these test decisions then gives simultaneous CIs of cost-effectiveness angles with the appropriate coverage probabilities.

23-Gauge versus 20-gauge system for pars plana vitrectomy: a prospective randomised clinical trial.

AIM: To compare the sutureless 23-gauge system with a standard 20-gauge system in pars plana vitrectomy. METHODS: 60 patients in two randomised groups were included in this prospective clinical trial. Pars plana vitrectomy with either 23- or 20-gauge instruments was performed. The main outcome measures were postoperative conjunctival injection and pain. Secondary outcome parameters were time of surgery, intraocular pressure, visual acuity and complications. RESULTS: Conjunctival injection (p = 0.0003) and postoperative pain (p = 0.01) were significantly reduced following 23-gauge vitrectomy compared with the 20-gauge procedure. Opening (p = 0.006) and closure times (p<0.00001) were significantly shorter, and vitrectomy time (p = 0.001) significantly longer in the 23-gauge system compared with 20-gauge vitrectomy. However, retinal manipulation and overall surgery times did not differ significantly between both groups. The same applies for eye pressure, distance and reading acuity. Regarding complications, two choroidal haemorrhages and one flat serous choroidal detachment occurred in the 23-gauge group. CONCLUSION: The 23-gauge system for pars plana vitrectomy offers significantly higher patient comfort during the early postoperative period. Time of surgery is almost equal--a shorter time for wound closure is neutralised by a longer vitrectomy time in the 23-gauge group.

Challenging a dogma--surgery yields superior long-term results for T1a squamous cell carcinoma of the glottic larynx compared to radiotherapy.

AIMS: The aim of this study was to compare laser surgery, conventional endoscopic surgery and radiotherapy in the treatment of early T1a glottic cancer. METHODS: We conducted a retrospective analysis of patients with early vocal cord cancer (who underwent either conventional surgery via endoscopy or laryngofissur, or primary radiotherapy) at the Medical University of Vienna. By univariate and multivariate Cox regression models the influence of treatment and other parameters on survival and locoregional control were analysed. RESULTS: 337 Patients were analyzed with a mean follow-up period of 133.8 months. Overall survival rates where similar in all three treatment groups. Five-year, 10-year and 15-year estimates of disease specific survival for laser-treated patients were 100%, for conventional surgery were 100%, 98% and 98%, and for radiotherapy were 96%, 92% and 91%, respectively. Locoregional recurrences were observed after laser surgery in 10%, after conventional surgery in 13% and after radiotherapy in 30% of the patients treated. According to the log-rank test, time to relapse was significantly shorter for irradiated patients compared to patients who underwent surgery (p < 0.0001). Mortality caused by the laryngeal tumour was significantly higher in the radiotherapy group (p = 0.003). CONCLUSION: Patients undergoing laser or conventional surgery have a significantly lower incidence of locoregional recurrences and longer disease-free intervals when compared to patients treated by radiotherapy.

Prospective analysis of factors related to migraine attacks: the PAMINA study.

Migraine is related to numerous factors such as hormones, stress or nutrition, but information about their actual importance is limited. Therefore, we analysed prospectively a wide spectrum of factors related to headache in migraineurs. We examined 327 migraineurs recruited via newspapers who kept a comprehensive diary for 3 months. Statistical analysis comprising 28 325 patient days and 116 dichotomous variables was based on the interval between two successive headache attacks. We calculated univariate Cox regression analyses and included covariables with a P-value of <0.05 in two stepwise multivariate Cox regression analyses, the first accounting for a correlation of the event times within a subject, the second stratified by the number of headache-free intervals. We performed similar analyses for the occurrence of migraine attacks and for the persistence of headache and migraine. Menstruation had the most prominent effect, increasing the hazard of occurrence or persistence of headache and migraine by up to 96%. All other factors changed the hazard by <35%. The two days before menstruation and muscle tension in the neck, psychic tension, tiredness, noise and odours on days before headache onset increased the hazard of headache or migraine, whereas days off, a divorced marriage, relaxation after stress, and consumption of beer decreased the hazard. In addition, three meteorological factors increased and two others decreased the hazard. In conclusion, menstruation is most important in increasing the risk of occurrence and persistence of headache and migraine. Other factors increase the risk less markedly or decrease the risk.

Optical coherence tomography guided retreatment of photodynamic therapy.

AIM: To evaluate the results of a retreatment modality of photodynamic therapy (PDT) based on optical coherence tomography (OCT) and fluorescein angiography (FA). To quantify the effect of PDT with the help of measurement of the retinal thickness. METHODS: Eyes with predominantly classic subfoveal choroidal neovascularisation (CNV) due to age related macular degeneration were included. PDT was performed every three months, when needed. OCT, FA, and measures of distance acuity were performed at baseline, after 6 weeks, 3 months, and from then on every 3 months. A control group of a consecutive series of eyes that had been retreated based only on FA results was installed. RESULTS: Forty eyes of 38 patients were included. The average age was 73 years. The maximum retinal thickness decreased from 404 mum at baseline to 281.6 mum at month 12. Furthermore there was a significant decrease of retinal thickness in both subgroups. The number of retreatments was reduced, when activity was diagnosed using OCT and FA. (2.4 v 4.0). The distance acuity correlated significantly with the maximum retinal thickness (p=0.0042). CONCLUSION: Information about the activity of a neovascular lesion can be obtained with the help of OCT. The retreatment modalities can be optimised by using OCT and FA and the number of retreatments can be reduced.

Sequential tests for noninferiority and superiority.

The problem of simultaneous sequential tests for noninferiority and superiority of a treatment, as compared to an active control, is considered in terms of continuous hierarchical families of one-sided null hypotheses, in the framework of group sequential and adaptive two-stage designs. The crucial point is that the decision boundaries for the individual null hypotheses may vary over the parameter space. This allows one to construct designs where, e.g., a rigid stopping criterion is chosen, rejecting or accepting all individual null hypotheses simultaneously. Another possibility is to use monitoring type stopping boundaries, which leave some flexibility to the experimenter: he can decide, at the interim analysis, whether he is satisfied with the noninferiority margin achieved at this stage, or wants to go for more at the second stage. In the case where he proceeds to the second stage, he may perform midtrial design modifications (e.g., reassess the sample size). The proposed approach allows one to "spend," e.g., less of alpha for an early proof of noninferiority than for an early proof of superiority, and is illustrated by typical examples.

Flexible two-stage designs: an overview.

In this overview we introduce the basic ideas behind a new flexible approach in sequential designs. The different concepts based on two-stage combination tests and conditional error functions are brought together. We sketch the construction of p-values, confidence intervals, and median unbiased estimates. Finally, recursive combination tests are introduced which extend the flexibility to the choice of the number of interim analyses.

As to the clastogenic-, sister-chromatid exchange inducing-and cytotoxic activity of inosine triphosphate in cultures of human peripheral lymphocytes.

The influence of commercial inosine triphosphate (ITP) on the chromosome aberration rate, the mitotic rate, sister-chromatid exchange (SCE) frequency, and the proportion of first (X1), second (X2) and third (X3) division metaphases was investigated in 72h cultures of human peripheral lymphocytes. The blood donors had mild inactive arthrosis and a normal health check-up. All cultures of each volunteer were set-up simultaneously. In contrast to a previous report [Arch. Biochem. Biophys. 278 (1990) 238-244], it was demonstrated in two preliminary studies (number of subjects, n=5 each) that ITP at a final concentration of 100 microM does not induce chromosomal aberrations and, furthermore, that not ITP concentrations higher than 100 microM but ITP doses higher than 3.8mM prohibit culture growth. Based on these results, cultures with a final ITP concentration of 3.6mM (max.) and 1.8mM (max./2) were compared with control cultures (number of subjects n=10; three males and seven females, mean age x=57.6 years). Whereas no increase in the chromosomal breakage rate was observed in cultures with an ITP concentration of 1.8mM and only a marginally significant one (P=0.048) for 3.6mM ITP cultures, a highly significant induction of SCEs, not only at an ITP concentration of 3.6mM (P<0.0001) but also at 1.8mM (P<0.0001) was seen. The increase in the SCE frequency was not linear, but steeper from 0 to 1.8mM than from 1.8 to 3.6mM. Nevertheless, the difference between 1.8 and 3.6mM cultures was significant (P=0.027). The distribution of the number of SCEs per metaphase as well as the distribution of SCEs per chromosome correspond to the expected Poisson values. The investigation of the cytotoxic effect of the studied ITP concentrations revealed a highly significant reduction of the mitotic rate from 0 to 1.8mM as well as from 1.8 to 3.6mM in the aberration studies (all P values are equal to smallest possible one for a sample size of 10, namely, 0.002), and in the SCE studies there is a significant decrease in the X3 frequency when ITP is increased (0-1.8mM: P=0.0061 and 1.8-3.6mM: P<0.0001). The proportion of X1 within all X1 and X2 metaphases changes significantly only at the second dose step (0-1.8mM ITP: P=0.22 and 1.8-3.6mM ITP: P<0.0001). The results are discussed.

A cream containing the chelator DTPA (diethylenetriaminepenta-acetic acid) can prevent contact allergic reactions to metals.

Chelating agents in protective barrier creams have often been used in the prevention of allergic contact dermatitis to nickel. In a pilot study, we demonstrated the preventive effect of 10% diethylenetriaminepentaacetic acid (DTPA) in an oil-in-water emulsion in nickel-sensitized patients. Now we reproduced these results in a randomized, double-blind study. Additionally, we investigated the efficacy of the barrier cream in other clinically relevant metal allergies. Individuals sensitized to various metals had a significant decrease in positive patch test reactions after pre-treatment with the DTPA-cream: 2.5% nickel sulfate (24/28 positive without pre-treatment versus 1/28 with pre-treatment; p<0.0001), 5% nickel sulfate (30/32 versus 15/32; p=0.0003), 1% cobalt chloride (19/20 versus 6/20; p=0.001) and 5% copper sulfate (13/14 versus 5/14; p=0.02). However, the cream had no protective effect with 1% palladium chloride (17/23 versus 16/23) and with 0.5% potassium dichromate (9/13 versus 7/13). We conclude that the DTPA-cream clearly abrogates positive patch test reactions in nickel-, cobalt- and copper-sensitized subjects and that it may therefore be helpful in the management of allergic contact dermatitis.

The effect of remifentanil on the heat pain threshold in volunteers.

Remifentanil offers a wide range of clinical uses and has been successfully combined with general anesthetics. However, there are few human experimental studies demonstrating the analgesic property of remifentanil. It was our aim to determine the analgesic effect of remifentanil with regard to dose-dependent increments in a human model of heat pain threshold assessment. Twenty healthy volunteers were randomized in a double-blinded cross-over design to receive an infusion of remifentanil or saline. The stepped infusion was increased every 5 min by 0.01 microg. kg(-1). min(-1) up to 0.17 microg. kg(-1). min(-1)and terminated in case of defined safety limits. Thermal sensory testing of the heat pain threshold was performed every 5 min at the left forearm. The dose-response relationship and the effective dose for at least 50% of the subjects (ED(50)) were determined. Remifentanil led to a clear dose-dependent increase of the heat pain threshold differing significantly from placebo (P < 0.0007). The ED(50) of remifentanil equals 0.05 microg. kg(-1). min(-1) (first quartile 0.025 microg. kg(-1). min(-1) and third quartile 0.06 microg. kg(-1). min(-1)) in this experimental setting. In conclusion, an opioid-mediated analgesic effect of remifentanil was determined in a human heat pain threshold model. The dose of 0.05 microg. kg(-1). min(-1) is an effective and safe increment in healthy volunteers.

Bronchoplastic procedures in malignant and nonmalignant disease: multivariable analysis of 144 cases.

OBJECTIVES: We sought to analyze the experience with bronchoplastic procedures over a 7-year period and to determine putative prognostic factors for survival. METHODS: From 1991 to 1997, 144 bronchoplastic procedures were performed for non-small cell lung cancer (n = 123), small cell lung cancer (n = 5), carcinoid tumor (n = 10), and metastases of extrathoracic malignant tumors (n = 6). There were 111 sleeve lobectomies, 17 bilobectomies, 4 lobectomies with carinal resection, 8 sleeve pneumonectomies, and 4 bronchotomies without parenchymal resection. Multivariable analysis included risk factors, such as age, sex, type of bronchoplastic procedure (bronchotomy, lobectomy, bilobectomy, or pneumonectomy), additional angioplasty, TNM staging, histology, radicality of resection, respiratory risk (forced expiratory volume in 1 second, percent predicted < 60), cardiovascular risk, and adjuvant therapy. RESULTS: Overall 1- and 3-year survival was 72% and 52%, respectively. The overall 30-day mortality was 8.3% (5.4% for single sleeve lobectomies). Multivariable analysis demonstrated 4 risk factors for survival. High tumor stage, type of bronchoplastic procedure, impaired lung function, and presence of cardiovascular risk were associated with a poor outcome. Univariate analysis showed reduced survival in patients with sleeve pneumonectomies (1-year survival, 25%). CONCLUSIONS: Bronchoplastic procedures for central tumors and sleeve pneumonectomies are associated with poor survival. Careful selection of these patients, as well as of patients with impaired lung function and cardiovascular risk factors, is mandatory.

Gastric emptying in Type II (non-insulin-dependent) diabetes mellitus before and after therapy readjustment: no influence of actual blood glucose concentration.

AIMS/HYPOTHESIS: Hyperglycaemia that is induced short-term slows gastric emptying in healthy subjects and patients with diabetes mellitus. Little information is available on the impact of longer-lasting, naturally occurring blood glucose increases and their reduction to euglycaemic values. We studied the relation between gastric emptying and pre-prandial and postprandial blood glucose concentrations in patients with Type II (non-insulin-dependent) diabetes mellitus and secondary failure to respond to oral hypoglycaemic treatment (a) before readjusting hypoglycaemic therapy and (b) 1 week thereafter. METHODS: We studied 9 female and 1 male patient (age 60-78 years, BMI 21.9-32.5 kg/m2, diabetes duration 3-33 years, HbA1c 8.8-13.2%). Gastric emptying of a radiolabelled semisolid 1168 kJ meal was recorded scintigraphically. RESULTS: Blood glucose concentration pre-prandial and postprandial was considerably lower subsequent to than before therapy readjustment in all patients (fasting, 7.9 mmol/l+/-1.5 SD vs 11.7+/-1.7 mmol/l; 60 min postprandial, 11.7+/-2.0 vs 15.4+/-2.2 mmol/l). By contrast, gastric emptying was unchanged (residual radioactivity in stomach 50 min postprandial 65.7+/-14.1% vs 66.5+/-12.9%). There was no relation between emptying and either fasting blood glucose concentration or its postprandial increase. CONCLUSION/INTERPRETATION: The data do not support a major impact of actual, longer-lasting, naturally occurring blood glucose concentrations upon the rate of gastric emptying in patients with Type II diabetes.