Biopharmaceutical statistics in a pharmaceutical regulated environment: past, present, and future.

The practice of statistics in the pharmaceutical industry has changed markedly over the last 25 years. This paper examines the evolution of clinical trial statistics in relationship to advances in statistical methodology and computational power as well as the changing regulatory environment. The current role of the biopharmaceutical statistician is assessed along with the drivers for future change.

Organization and analysis of safety data using a multivariate approach.

The collection of safety data is an important part of clinical trials. These safety data are often described and reported in great detail with expenditure of substantial effort and energy. Because of the wide variety of data that require scrutiny from the safety perspective, however, statistical comparisons of the safety profiles of different treatments often lack focus and structure and result in situations where the comparisons for each individual item lack power and thus are inconclusive. In this paper, we propose to organize the safety data into a more manageable form by consolidating them into a number of K classes characterized by body systems and determined in conjunction with the underlying disease as well as the treatments involved. Within each class, we propose assignment to each patient of an overall intensity grade based on all relevant information. The consolidation of the safety data as proposed provides an informative summary for the safety profile of each treatment. The analysis of such organized data concentrates on comparison of the mean intensity grades for different treatments within the K classes simultaneously with use of scores that reflect the acceptability of the various intensity levels to an individual. Furthermore, we demonstrate that the proposed multivariate comparison has much higher power than the univariate one to detect differences in certain cases. We provide examples to illustrate the proposed procedure.

Three measures for simultaneously evaluating benefits and risks using categorical data from clinical trials.

Randomized clinical trials are typically conducted to compare the efficacy (benefits) and side effects (risks) of two or more treatments. One can use results from such trials to decide on a preferable treatment that reflects one's own evaluation of the benefits and risks. To facilitate the necessary decision making, we propose in this paper three measures for simultaneously assessing benefits and risks. All three measures use weights that reflect the relative importance of the various treatment outcomes to an individual. Two of them carry the flavour of benefit/risk ratios, while the third generalizes Hilden's measure which incorporates patients' preferences. The proposed measures and procedures are illustrated using data from a phase III clinical trial of antihypertensive compounds.

Holter monitor ST segment evaluation in hospitalized patients with unstable angina.

The correlation of angina attacks with ST segment changes detected during ambulatory Holter monitoring was evaluated in patients with unstable angina. Forty hospitalized patients had one to three 24-hour Holter recordings each. Twenty-three patients had a cardiac catheterization, confirming significant coronary artery disease. The Holter recordings, scanned blindly by computer, were evaluated for ST segment shifts (defined as +/- 1.5 mm from baseline, lasting 60 seconds or longer). Angina attacks were carefully logged. Over the total forty patient experience, only 15 of 74 (20.3%) angina attacks had corresponding ST segment shifts on the Holter recordings. Nine of 34 (26.5%) angina attacks in the 23 patients who had a cardiac catheterization had corresponding ST segment shifts. A total of 159 ST segment shifts were recorded on these forty patients, but only 15 (9.4%) ST shifts corresponded to a time when the patients were actually experiencing angina attacks. The performance of the test procedure was quantified by use of Youden's J statistic. The aggregate J, over all patients, was 0.203 (J = 1.0 is perfect, J = 0.0 is useless). When consideration was restricted to patients with cardiac catheterization, the aggregate experience J was 0.263. Dealing with only the patients who had angina attacks during the monitoring, and computing the J statistic for each individual patient, the resulting mean J statistic was 0.146, with SEM = 0.0731. The Holter monitoring worked reasonably well in only 2 of the 14 patients who gave clear tests of the procedure. In an attempt to improve the performance of the procedure, 21 Holter recordings in eight patients were reread for ST segment shifts of only +/- 1 mm from baseline, lasting 30 seconds or longer. In these eight patients with rescanned Holter recordings, only five of 17 (29.4%) angina attacks resulted in an ST segment shift. In conclusion, ambulatory Holter recordings proved not to be a suitable method of documenting ST segment shifts during angina attacks in this study.

Some observations on the collection of medical event data.

A review of the philosophy, strategies, and methods for the collection of medical event (ME) information in clinical trials sponsored by the Research and Development Division of THe Upjohn Company is presented. Goals for collection of ME information for Phase I, II, and III trials are reviewed. Case report form and terminology issues are discussed, with particular emphasis placed on procedures that avoid premature decisions on ME causality and incomplete reporting of events. Procedures for separating the seriousness from the intensity of the MEs are reviewed. Analysis issues are considered insofar as they impact on data collection procedures and goals. Recommendations are made with respect to protocol content, data collection forms, and related analysis issues.

Serum FSH, LH and testosterone in the male rhesus following prostaglandin injection.

Adult male rhesus were treated with PGE2, PGF2 alpha or the 13,14-dihydro-15-keto metabolite of PGE2 in a randomized crossover design. Serum concentrations of FSH, LH and testosterone were determined and compared to the respective values in the same uninjected animals. No significant changes were noted in controls or following the metabolite injection. FSH increased gradually for 4 hours after metabolite treatment. In contrast, injection of PGF2 alpha was followed by an abrupt (within 15 minutes) increase in LH and testosterone. FSH increased gradually in 2 of 3 treated animals. Injection of PGE2 was followed by a similar abrupt increase in LH concentration. This was not always associated with a significant increase in testosterone or FSH. These results demonstrate that injections of PGE2 or PGF2 alpha can change serum gonadotropin and testosterone concentrations in male rhesus monkeys, and that the effects of these two prostaglandins are qualitatively different.

Vaginal prostaglandin E2 in the management of fetal intrauterine death.

The results of a multicentre clinical trial of prostaglandin E2 (PGE2) administered by the vaginal route in the management of intrauterine fetal death and missed abortion showed an overall efficacy of 97 per cent. The mean induction-abortion interval was 10.7 hours with a mean total dose of 60.4 mg of PGE2. Side effects were tolerated well and there was no evidence of significant alterations in hepatic or renal function.