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Biomedical subjects

J Röhmel

Publications and source records attributed to J Röhmel.

At least 19 recordsLinked to original sources
PubMed2005

[Biometrical methods for the proof of efficacy in regulatory submissions. Non-inferiority in clinical studies].

The increasing number of approved efficacious therapies for various indications raises the question of whether the inclusion of a placebo group is still justified. In addition, pharmaceutical companies and regulatory agencies acknowledge that it may be sufficient to prove that a new therapy is comparable to an approved reference therapy regarding efficacy and safety in some situations. This becomes especially striking for the approval to market a generic drug. Another, perhaps even more important example is the increasing resistance of bacteria which calls for new antibiotics based on new therapeutic principles without having the claim for better efficacy. In these situations, a comparable efficacy would constitute progress. In the present paper, we discuss the numerous methodological challenges and approaches to overcome these problems that occur when it is not possible or even not wanted to use the classic approach of a randomized placebo-controlled superiority trial. Here, the field of medical biometry, which has proved in the last 25 years to be an integral part of the development of new drugs, demonstrates its suitability as a flexible and scientifically based means to fulfil the requirements resulting from clinical practice. Starting from the fact that statistical methods are not able to prove "equality" of two treatments, "shifted" hypotheses are considered and their importance for the different study designs is discussed. We show how the classic hypotheses known from placebo-controlled clinical trials can be embedded in this concept. The implications of this approach for the analysis and interpretation of study results is further discussed. The relevant guidelines of the European and US regulatory agencies are taken into account.

Biometry↗
PubMed2002

[Statistical principles of "good clinical practice" in veterinary medicine--a position paper for planning, implementation and evaluation of empirical studies].

The complexity of the design, conduct, analysis and evaluation of empirical studies necessitates a high degree of interdisciplinary collaboration in all areas of research. In order to make sure that no essential harmonisation is missed among the plenitude of processes, it has become common to provide direction on the essential operating procedures in so called "Good ... Practice" guidelines in recent years. In pharmaceutical research on human medicinal products guidelines on Good Clinical Practice have been an integral part of research and development in industry, academia, and the regulatory authorities for a long time. On the other hand, in the development and registration of pharmaceuticals for veterinary use such procedures are not yet established to this extent in Germany. Notwithstanding there being a lot of regulations on specialised subjects. This paper tries to summarise the current state of the discussion and to give an overview on the important points in the design, conduct, analysis and reporting of veterinary clinical studies mainly from an biometrical point of view.

Animals↗
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↗
PubMed1995

An adaptive method for establishing a dose-response relationship.

A multistage sampling method is proposed in dose-response trials, where dose adaptions can be performed in the preplanned adaptive interim analyses. The overall test for proving a dose-response relationship is performed by Fisher's product criterion for the p-values from the separate tests of a dose effect in the disjoint samples at the different stages. Based on these p-values decision boundaries for early stopping with the rejection of the global null hypothesis of no existing dose-response relationship are introduced. The power of the adaptive two-stage procedure using a particular adaptation rule is compared with the power of the test for a linear trend under analysis of variance assumptions in extensive simulations. The bias in estimation is also quantified. This procedure could be used for establishing a dose-response relationship without including a placebo treatment.

Antihypertensive Agents↗
PubMed1993

Clinical and statistical issues in therapeutic equivalence trials.

Absolute proof of efficacy can only be given by placebo controlled trials. It is, however, important to classify a drug within the spectrum of existing therapeutic alternatives and, where effective treatment is available, it may be imperative due to ethical considerations to demonstrate that one drug is as effective as another. The issue of therapeutic equivalence trials is discussed along the lines of the important items which should be defined in the protocol: a) the target parameter, which is the primary endpoint of the trial, b) the reference drug, which should be selected with respect to efficacy (superior to others), and safety (largest amount of data), c) the acceptance range, which depends on the primary endpoint, and its implication for the clinical endpoints of morbidity and mortality (the conventional acceptance range for bioequivalence trials does not apply), and d) the statistical procedures, which must take into consideration the unsuitability of the conventional power approach for confirming equivalence. In an equivalence trial, compared to those that are placebo-controlled, the proof that one drug is as effective as another relies much more upon the quality of conduct of the study according to Good Clinical Practice.

Clinical Trials as Topic↗
PubMed1990

Cigarette smoking, gastric acidity and peptic ulceration. What are the relationships?

The influence of cigarette smoking on intragastric acidity was assessed in duodenal ulcer patients in symptomatic remission and in healthy volunteers in a retrospective study. Continuous 24-hr pH recordings in 150 nonsmokers and 174 smokers receiving placebo treatment were compared. Daytime intragastric acidity was higher in smokers with a median pH (interquartile range) of 1.56 (1.34-1.80) than in nonsmokers, who had a median pH of 1.70 (1.45-1.97) (P less than 0.001). There was no difference in 24-hr and nighttime median pH between the two groups. The small difference in daytime intragastric acidity in smokers and nonsmokers is unlikely to account for the increased prevalence of peptic ulcer disease in smokers. The analysis of smoking status in duodenal ulcer patients and healthy controls and males and females supports the general trend towards higher daytime acidity in smokers. Again, no differences in pH during the 24-hr or night period were found between the groups. The epidemiological and clinical correlation between smoking and duodenal ulcer disease is not adequately explained by increased intragastric acidity.

Circadian Rhythm↗
PubMed1990

[Antisecretory effect of the H2-histamine receptor antagonist ranitidine in water-soluble tablets and film-coated tablets. Results of a randomized, placebo-controlled crossover study in humans].

This clinico-pharmacological trial aimed to prove equivalence between the known film-coated tablets of ranitidine (Sostril Filmtabletten) and the novel dispersible tablets for the preparation of a drinkable solution (Sostril Aquatabs) on a pharmacodynamic level. Therefore, the influence of single oral doses of the two ranitidine preparations (2 X 150 mg p.e.m. each) and placebo on the gastric hydrogen ion concentration was studied in 12 healthy volunteers using a randomized cross-over design. pH-values of the gastric juice were measured and recorded continuously for 24 h. Median pH-values for the entire study period were 2.20, 2.15 and 1.40 for dispersible tablets, filmcoated tablets and placebo, respectively. During the night-time median pH-values of 3.45 for both ranitidine preparations and 1.40 for placebo were calculated. From these results it can be concluded that the novel dispersible tablets are equivalent to the ranitidine filmcoated tablets with regard to their pharmacodynamic potency.

Adult↗
PubMed1988

Day-to-day variation of 24-hour intragastric acidity.

Twenty-four-hour intragastric acidity was measured continuously using an intragastric electrode in 13 normal volunteers studied four times. Subjects were studied twice in the hospital and twice as outpatients. The dietary conditions were strictly controlled and the replicate studies were compared to assess the variability of such recordings of acidity. The accuracy of the technique was assessed, and a detection limit for differences was calculated for commonly used time periods. Over 24 h, during the night, during the day, and during the evening the technique is able to detect consistent changes of pH of greater than 0.1 units. During separate 5-min periods the limits of detection were considerably greater. This study demonstrates the variability of 24-h intragastric acidity and confirms that continuous monitoring is able to detect important changes of acidity under both hospitalized and ambulant conditions.

Adult↗
PubMed1988

The effects of roxatidine acetate (HOE-760) on 24-hour intragastric acidity in healthy volunteers: comparison with ranitidine and placebo.

In a series of double-blind randomized studies in normal volunteers using continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, decreased median 24 h gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate, 150 mg at bedtime, raised median 24 pH of the same 17 subjects to 2.4 and nocturnal pH to 5.9. In another series of experiments, 150 mg roxatidine acetate at bedtime was as effective as ranitidine 300 mg nocte raising median nocturnal pH (14 volunteers) from 1.4 to 6.65 compared to 6.7, respectively. However, when drugs were taken after the evening meal (post cenam nocte, pcn) roxatidine acetate 150 mg was less potent than ranitidine 300 mg with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg pcn raised the pH to 4.9 suggesting that roxatidine is 1-2 times as potent as ranitidine, on a milligram-for-milligram basis.

Adolescent↗
PubMed1988

Pattern of 24 hour intragastric acidity in active duodenal ulcer disease and in healthy controls.

Twenty four hour intragastric acidity was measured by continuous recording using intragastric combined glass electrodes in 46 duodenal ulcer patients within 48 hours of endoscopic confirmation of active ulceration. Acidity during predefined time periods was compared with that measured in 40 healthy controls without gastrointestinal disease: it was significantly higher in duodenal ulcer patients at all times, but 25% of ulcer patients had median 24 hour acidity within the interquartile range of the normal group. During the evening (18,00 to 22,00 h) ulcer patients had considerable acidity with a median of 39.8 (63.1-31.6) mmol/l (interquartile range) compared with 5.6 (22.3-0.4) mmol/l of controls. It is suggested that antisecretory treatment be directed to decrease this period of unbuffered acidity, as well as during the night, which is presently considered of prime importance.

Adolescent↗
PubMed1988

Continuous intravenous infusions of famotidine maintain high intragastric pH in duodenal ulcer.

Three double blind crossover studies were carried out to assess the ability of primed infusions of famotidine to raise intragastric pH over 24 hours in 12 duodenal ulcer patients. pH was measured continuously using intragastric electrodes and solid state recording devices. The studies compared the effects of placebo, famotidine 10 mg bolus injection iv followed by continuous infusions of 3.2 mg/h and 4 mg/h in random order. Gastric acidity decreased significantly with both dose regimens (p less than 0.0005) but the effects of either dosage were similar. During fasting median pH rose from 1.35 to 7.1 and 7.05 respectively. During the day, when standard meals were taken, median pH rose from 1.30 to 4.3 and 3.65 respectively. Despite continuous infusions the H2-antagonist was less effective during this time. The latter finding raises questions about gastric secretory control during the day when food is eaten.

Adult↗
PubMed1988

The effects of roxatidine acetate on 24-hour intragastric acidity. Investigations in healthy volunteers and comparison with ranitidine and placebo.

In a series of double-blind randomised studies in normal volunteers with continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine acetate, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate 75 mg twice daily decreased median 24-hour gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate 150 mg at bedtime raised median 24-hour pH in the same 17 subjects to 2.4 and nocturnal pH to 5.9. In the second experiment, in 14 volunteers, roxatidine acetate 150 mg at bedtime was as effective as ranitidine 300 mg at night, raising median nocturnal pH from 1.4 to 6.65 compared to 6.7 for ranitidine. However, when drugs were taken after the evening meal (post cenam nocte; PCN) roxatidine acetate 150 mg was less potent than ranitidine 300 mg, with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg PCN produced the greatest rise of pH, to 4.9, suggesting that the true potency ratio of the 2 drugs is between 1 and 2.

Adolescent↗
PubMed1988

Early evening ranitidine administration promotes faster duodenal ulcer healing.

In a prospective double-blind clinical trial, 141 patients with endoscopically diagnosed duodenal ulcer were randomly assigned to treatment with ranitidine 300 mg, taken either at 6 PM or at 10 PM. After 2 wk of treatment, 52 of 70 patients (74%) in the 6 PM treatment group had healed, compared with 32 of 64 patients (50%) taking ranitidine at 10 PM (p less than 0.01). After 4 wk, the cumulative healing rates were 100% and 94%, respectively, for the 6 PM and 10 PM treatment regimens. These results suggest that ranitidine, taken as a single daily 300-mg dose at 6 PM after dinner, provides more rapid duodenal ulcer healing than the same dose of the drug taken at 10 PM.

Adolescent↗
PubMed1987

Comparison of ranitidine 300 mg twice daily, 300 mg at night and placebo on 24-hour intragastric acidity of duodenal ulcer patients.

Continuous measurement of 24-hour intragastric acidity was performed in 12 duodenal ulcer patients in remission during treatment with placebo, ranitidine 300 mg nocte and ranitidine 300 mg b.d. Median 24-hour acidity was 79.4 mmol litre-1 during placebo treatment; it decreased to 28.2 mmol litre-1 during treatment with ranitidine 300 mg nocte and to 3.6 mmol litre-1 during treatment with ranitidine 300 mg b.d. The two regimens decreased intragastric acidity to a similar degree during the night, but significantly greater inhibition of daytime and 24-hour acidity followed use of ranitidine 300 mg b.d.

Adult↗
PubMed1987

Single dose treatment with H2 receptor antagonists: is bedtime administration too late?

Using ambulatory ph-metry, intragastric acidity was measured over three separate 24 hour periods in each of 12 healthy volunteers receiving either (a) placebo (1800 h and 2200 h), (b) 300 mg ranitidine (1800 h) and placebo (2200 h), or (c) placebo (1800 h) and 300 mg ranitidine (2200 h). Ranitidine was significantly more effective in decreasing 24 h median intragastric acidity when the drug was administered at 1800 h rather than at 2200 h. Median pH (and interquartile range) was 1.45 (1.4-1.7) on placebo, 2.55 (2.05-3.2) on ranitidine given at 2200 h and 3.35 (2.5-3.85) on ranitidine given at 1800 h (p less than 0.004). The total duration of highly acidic electrode readings (pH less than 1.5) over a 24 h period was reduced significantly by administering the H2-receptor antagonist at 1800 h compared with the later administration. It is suggested that treatment of duodenal ulcers by single administration of ranitidine in the early evening should be evaluated by clinical trial.

Adult↗