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Biomedical subjects

W Maurer

Publications and source records attributed to W Maurer.

At least 19 recordsLinked to original sources
PubMed2005

Creative and innovative statistics in clinical research and development.

OBJECTIVES: The aim of this paper is to show that even in a highly regulated area such as clinical research and development in pharmaceutical industry, there are needs and ample opportunities for statisticians and other medical informatics professionals to further creatively develop and implement methods in order to support the collection, analysis and interpretation of clinical data. METHODS: The recently published "Critical Path" initiative of the US Food and Drug Administration discusses the decline in new drug submissions in the last decade and illustrates potential causes in the present clinical development process. Areas where statisticians can and have begun to look for new innovative ways to overcome these shortcomings are presented and examples of such novel approaches that have been developed by statistical methodologists in the pharmaceutical industry together with statisticians in academia are given. RESULTS: In Early Development, i.e., in the first studies in man with a new compound, a combination of Bayesian methods and modeling approaches is particularly promising to increase the efficiency of decision making whereas in later phases (IIb and III) a marriage of modeling and classical frequentist approaches together with novel adaptive designs is expected help to chose the right dose regimen and to perform the trials more efficiently in reduced time. CONCLUSIONS: The combination of known statistical methods and thinking and the development of new approaches are in line with the present paradigm of "learning and confirming" in regulated clinical development while increasing the efficiency of both.

Bayes Theorem↗
PubMed2004

Immunity against vaccine-preventable potentially neurotropic diseases in children treated for malignant brain tumours with HIT-91 chemo- and radiotherapy.

Following surgery, chemotherapy and/or irradiation, patients with malignant brain tumours are at risk of neurotropic diseases, although these are partly vaccine-preventable. In a retrospective, controlled, observational study, the impact of the German-Austrian chemo- and radiotherapy protocol (HIT-91) on antibody concentrations against vaccine-preventable diseases and on vaccination behaviour was analysed. A significant level of seronegativity for measles- and mumps-IgG, and a reduced protection induced by inactivated vaccines was observed after HIT-91 therapy. Failure of seroconversion following measles and mumps live vaccinations was assessed in the HIT-91-treated group and in a group with benign brain tumours (BBT). Analysis of cellular immunological parameters revealed significant aberrations in the HIT-91-treated group 36 months after completion of HIT-91 therapy. A retrospective analysis of the patient's vaccination history revealed an incorrect risk perception concerning the choice of vaccinations. We therefore recommend clinical vaccination with serosurveillance in patients who have undergone treatment for brain tumours.

Adolescent↗
PubMed2003

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.

Humans↗
PubMed2002

Reconsidering some aspects of the two-trials paradigm.

A common standard for the demonstration of efficacy in a clinical submission is a statistically significant outcome in at least two pivotal trials ("two-trials convention"). When the data structures in different trials are sufficiently similar to allow pooling of the data across trials for a combined analysis, we argue here that such an analysis is a more logical and efficient basis for a judgment regarding efficacy. Criteria for combined analyses may be established, which ensure the same false positive rate protection as the two-trials convention. A combined analysis will generally have much more power than the corresponding application of the two-trials approach that has the same false positive rate protection. In addition, we describe the behavior of modified versions of pure combined analysis, which incorporate a formal standard for reproducibility of trial results by limiting the larger of the individual trial p-values. These modifications are shown to maintain the desirable behavior of the pure combined analysis, namely, higher power compared to the two-trials convention.

Clinical Trials as Topic↗
PubMed2000

Vaccine nomenclature: the three-letter code. OMCL Vaccine Nomenclature Drafting Group.

With increasing worldwide use of combined vaccines a short and informative system of names or codes for vaccines is essential. In addition, within the EU eleven official languages exist and some more are used. Due to these facts an increasing risk of medication errors for vaccines is emerging. A three-letter code naming system was first developed as part of the Note for guidance on pharmaceutical and biological aspects of combined vaccines (CPMP/BWP/477/97), but was deleted there later. Then a second approach was initiated by the European OMCL Network in order to implement this three-letter code system in the common nomenclature guideline within the Ph. Eur. (Index of standard terms). Both activities have not been successful until now to implement this system. Therefore we now present the three-letter code system in order to initiate either its voluntary use by vaccine manufacturers or to accelerate the obligatory implementation within the EU legislative framework. This coding system is thought to be used in addition to the brand name of the vaccine on the label of the final vaccine container, in order to have a safe last minute check whether the appropriate antigens are given.

Terminology as Topic↗
PubMed1999

Vitamin B6 biosynthesis: formation of pyridoxine 5'-phosphate from 4-(phosphohydroxy)-L-threonine and 1-deoxy-D-xylulose-5-phosphate by PdxA and PdxJ protein.

In Escherichia coli the coenzyme pyridoxal 5'-phosphate (PLP) is synthesised de novo by a pathway that is thought to involve the condensation of 4-(phosphohydroxy)-L-threonine and 1-deoxy-D-xylulose, catalysed by the enzymes PdxA and PdxJ, to form either pyridoxine (vitamin B6) or pyridoxine 5'-phosphate (PNP). Here we show that incubation of PdxJ with PdxA, 4-(phosphohydroxy)-L-threonine, NAD and 1-deoxy-D-xylulose-5-phosphate, but not 1-deoxy-D-xylulose, results in the formation of PNP. The PNP formed was characterised by (i) cochromatography with an authentic standard, (ii) conversion to pyridoxine by alkaline phosphatase treatment, and (iii) UV and fluorescence spectroscopy. Furthermore, when [2-(14)C]1-deoxy-D-xylulose-5-phosphate was used as a substrate, the radioactivity was incorporated into PNP. These results clarify the previously unknown role of PdxJ in the de novo PLP biosynthetic pathway. The sugar used as substrate by PdxJ is 1-deoxy-D-xylulose-5-phosphate rather than the previously assumed 1-deoxy-D-xylulose. The first vitamin B6 vitamer synthesised is PNP, and not pyridoxine.

Alkaline Phosphatase↗
PubMed1999

Characterization of recombinant Arabidopsis thaliana threonine synthase.

Threonine synthase (TS) catalyses the last step in the biosynthesis of threonine, the pyridoxal 5'-phosphate dependent conversion of L-homoserine phosphate (HSerP) into L-threonine and inorganic phosphate. Recombinant Arabidopsis thaliana TS (aTS) was characterized to compare a higher plant TS with its counterparts from Escherichia coli and yeast. This comparison revealed several unique properties of aTS: (a) aTS is a regulatory enzyme whose activity was increased up to 85-fold by S-adenosyl-L-methionine (SAM) and specifically inhibited by AMP; (b) HSerP analogues shown previously to be potent inhibitors of E. coli TS failed to inhibit aTS; and (c) aTS was a dimer, while the E. coli and yeast enzymes are monomers. The N-terminal region of aTS is essential for its regulatory properties and protects against inhibition by HSerP analogues, as an aTS devoid of 77 N-terminal residues was neither activated by SAM nor inhibited by AMP, but was inhibited by HSerP analogues. The C-terminal region of aTS seems to be involved in dimer formation, as the N-terminally truncated aTS was also found to be a dimer. These conclusions are supported by a multiple amino-acid sequence alignment, which revealed the existence of two TS subfamilies. aTS was classified as a member of subfamily 1 and its N-terminus is at least 35 residues longer than those of any nonplant TS. Monomeric E. coli and yeast TS are members of subfamily 2, characterized by C-termini extending about 50 residues over those of subfamily 1 members. As a first step towards a better understanding of the properties of aTS, the enzyme was crystallized by the sitting drop vapour diffusion method. The crystals diffracted to beyond 0.28 nm resolution and belonged to the space group P222 (unit cell parameters: a = 6.16 nm, b = 10.54 nm, c = 14.63 nm, alpha = beta = gamma = 90 degrees).

Amino Acid Sequence↗
PubMed1998

Testing strategies in multi-dose experiments including active control.

Inferential test strategies for multi-arm trials are adapted or proposed for the special situation when more than one dose of a test treatment, placebo and active control(s) are compared. This includes between doses, dose-placebo and dose-active-control comparisons. The procedures refer to situations when detailed comparisons make sense only if the sensitivity of the trial has been shown, for example, if a dose-response relationship or a difference between active control and placebo has been established. Split strategies, hierarchical (assuming an order restriction among doses) or linked procedures are introduced. In linked procedures, equivalence to the active control will be established only if the dose is also shown to be effective as compared to placebo. All the inferential procedures control the experimentwise error rate in the strong sense for the respective sets of null hypotheses considered.

Alkylating Agents↗
PubMed1997

Remifentanil compared with alfentanil for ambulatory surgery using total intravenous anesthesia. The Remifentanil/Alfentanil Outpatient TIVA Group.

The purpose of this study was to test the hypothesis that using a 1:4 ratio of remifentanil to alfentanil, a remifentanil infusion would provide better suppression of intraoperative responses and comparable recovery profiles after ambulatory laparoscopic surgery than an alfentanil infusion, as part of total intravenous anesthesia. Two hundred ASA physical status I, II, or III adult patients participated in this multicenter, double-blind, parallel group study. Patients were randomly assigned 2:1 to either the remifentanil-propofol or alfentanil-propofol regimens. The anesthesia sequence was propofol (2 mg/kg intravenously [IV] followed by 150 micrograms.kg-1.min-1), and either remifentanil (1 microgram/kg IV followed by 0.5 microgram.kg-1.min-1)of alfentanil (20 micrograms/kg IV followed by 2 micrograms.kg-1.min-1), and vecuronium. After trocar insertion, infusion rates were decreased (propofol to 75 micrograms.kg-1.min-1; remifentanil to 0.25 microgram.kg-1.min-1; alfentanil to 1 microgram.kg-1.min-1). Alfentanil and propofol were discontinued at 10 and 5 min, respectively, before the anticipated end of surgery (last surgical suture); remifentanil was discontinued at the end of surgery. Recovery times were calculated from the end of surgery. The median duration of surgery was similar between groups (39 min for remifentanil versus 34 min for alfentanil). A smaller proportion of remifentanil patients than alfentanil patients had any intraoperative responses (53% vs 71%, P = 0.029), had responses to trocar insertion (11% vs 32%, P < 0.001), or required dosage adjustments during maintenance (24% vs 41%, P < 0.05). Early awakening times were similar. Remifentanil patients qualified for Phase 1 discharge later and were given postoperative analgesics sooner than alfentanil patients (P < 0.05). Actual discharge times from the ambulatory center were similar between groups (174 min for remifentanil versus 204 min for alfentanil) (P = 0.06). In conclusion, remifentanil can be used for maintenance of anesthesia in a 1:4 ratio compared with alfentanil, for total IV anesthesia in ambulatory surgery. This dose of remifentanil provides more effective suppression of intraoperative responses and does not result in prolonged awakening.

Adult↗
PubMed1997

Remifentanil versus remifentanil/midazolam for ambulatory surgery during monitored anesthesia care.

BACKGROUND: This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting. METHODS: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter, double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 microgram/kg, given over 30 s followed by a continuous infusion of 0.1 microgram.kg-1.min-1 (remifentanil), remifentanil, 0.5 microgram/kg, given over 30 s followed by a continuous infusion of 0.05 microgram.kg-1.min-1 (remifentanil+midazolam). Five minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or midazolam, 1 mg, (remifentanil+midazolam). If patients were not oversedated, a second dose of placebo or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin closure. RESULTS: At the time of the local anesthetic, most patients in the remifentanil and remifentanil+midazolam groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively). The final mean (+/-SD) remifentanil infusion rates were 0.12 +/- 0.05 microgram.kg-1.min-1 (remifentanil) and 0.07 +/- 0.03 microgram.kg-1.min-1 (remifentanil+midazolam). Fewer patients in the remifentanil+midazolam group experienced nauses compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four patients (5%) in the remifentanil group and two patients (2%) in the remifentanil+midazolam group experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/ min). CONCLUSIONS: Remifentanil alone or combined with midazolam provided adequate analgesia and maintained adequate respiration at the doses reported. The low dose of remifentanil combined with 2 mg midazolam, compared with remifentanil alone, resulted in fewer side effects, slightly greater sedation, and less anxiety.

Adult↗