Paradigm shifts in clinical trials enabled by information technology.

The use of the world wide web for clinical trials changes the processes of performing clinical research in several fundamental ways. Greatly improved security, monitoring capability, and accuracy and timeliness of study conduct can be achieved while lowering cost. Data quality is enhanced while co-ordinating centre effort is reduced. The web provides a natural environment for linking the various components of clinical research, leading to new levels of simplicity and efficiency. It also enhances opportunities for recruitment of study investigators and patients. Other information technology tools and databases can be used to assist in this regard as well. Web-based trials change the relationship of the investigator site to the study and the site to the co-ordinating centre. Different roles and responsibilities lead to simplified processes and more and higher quality data. Many standard co-ordinating centre activities, such as randomization, protocol implementation and amending, document tracking, adverse event reporting, site monitoring, report generation and data analysis are all fundamentally changed in a web-based trial. Opportunities are enhanced to identify potential investigators and support their successful study conduct. As the role of investigator sites is changed in web-based research, more primary care medical providers can be attracted to research, providing more typical patients to studies than those sometimes available through more traditional research sites, especially those at academic study sites. Other activities can now be co-ordinated electronically with the advent of the web. The Institutional Review Board (IRB) can use online tools to control investigator participation, resulting in improved study efficiency and patient safety. A web-based research pharmacy provides tremendous efficiencies in managing and distributing study medications. Financial payments to the sites can be performed and recorded electronically, or even administered based on timeliness and quality of the data. Our early experience with web-based trials indicates that there can be tremendous gains in study efficiency and accuracy by restructuring processes, roles and responsibilities through a comprehensive centralized, web-based trial. The future appears bright for web-based clinical trials.

Detecting dose response with contrasts.

Analyses of dose response studies should separate the question of the existence of a dose response relationship from questions of functional form and finding the optimal dose. A well-chosen contrast among the estimated effects of the studied doses can make a powerful test for detecting the existence of a dose response relationship. A contrast-based test attains its greatest power when the pattern of the coefficients has the same shape as the true dose response relationship. However, it loses power when the contrast shape and the true dose response shape are not similar. Thus, a primary test based on a single contrast is often risky. Two (or more) appropriately chosen contrasts can assure sufficient power to justify the cost of a multiplicity adjustment. An example shows the success of a two-contrast procedure in detecting dose response, which had frustrated several standard procedures.

Randomization tests for assessing the equality of area under curves for studies using destructive sampling.

Testing the equality of the area under a curve (AUC) for different dose groups is frequently done in pharmacokinetic research. Equality of AUCs is one indicator of bioequivalence. When the experimental unit must be sacrificed to obtain a response, AUC can be simply estimated using a linear combination of response means at various time points. The distribution of this estimator is simply obtained using standard statistical theory, and statistical hypothesis tests are easily constructed. These tests assume a normal distribution of responses at each time point (or at least large enough samples to assure that the mean response is normally distributed). The applicability of this test to cases of non-normal response distributions when small numbers of observations are sampled at each time point is questionable. Randomization tests are suggested for this problem. These tests provide a valuable alternative to this normal-theory test. Discussion of the assessment of dose proportionality is also presented.

Factorial dose-response studies using frequency and magnitude of dose.

In the early stages of traditional drug development, the frequency of dosing (e.g., QD, BID, etc.) is typically determined by the pharmacokinetic properties of a compound. After an appropriate dose frequency is chosen, the magnitude of dose is then evaluated via parallel-group dose-response trials. For some drugs, however, blood levels at any given time may not be accurate predictors of clinical response, or the drug may not be absorbed systemically. In those instances, we propose the use of a factorial dose-response trial that simultaneously evaluates frequency of dosing and magnitude of dose. We consider this approach to selecting an appropriate dosing regimen to be more scientifically founded and more cost-effective, than independent evaluation of dose and frequency through separate clinical trials. Some design considerations and statistical analysis strategies for these factorial trials are presented in this paper.

Dose response studies. I. Some design considerations.

A critical aspect of biomedical research is the characterization of the dose response relationship of a compound. This is true in laboratory experiments and clinical trials and pertains to efficacy, safety, and the resulting benefit/risk ratio. Presented here is Part I of this article, which deals with some clinical trial design issues surrounding dose response studies. Some additional comments are made about trials for identifying the minimum effective dose, randomized concentration controlled trials, and the use of one-sided hypotheses in designing such trials. Part II is a separate paper reviewing some analysis strategies for dose response studies.

Dose response studies. II. Analysis and interpretation.

The primary focus of this paper is to examine analysis strategies for parallel, randomized dose response studies with particular emphasis on identifying the minimum effective dose. Such studies have become a standard for drug development in the pharmaceutical industry. Particular attention is paid to ANOVA followed by multiple comparison procedures with some additional discussion of the utility or regression models. When there are three or fewer dose groups and a placebo in a study, ANOVA techniques are preferred; with a larger number of dose groups, regression analysis has greater utility and reliability. Analysis of factorial dose response studies is reviewed only slightly as this is an emerging area of interest, and further development is necessary.

Applicability of teicoplanin dosage adjustment guidelines for renally impaired patients over the range of 3 to 30 mg kg-1.

The pharmacokinetics of teicoplanin were investigated in 13 subjects with various degrees of renal impairment using a randomized two-period crossover design; 11 subjects completed both periods. Doses of 3 and 30 mg kg-1 were administered as single dose, 60-min constant rate intravenous infusions. Blood samples were obtained over 28 days and urine was collected over 48 h. Serum and urine were analyzed using a microbiological assay. As previously observed in studies conducted in renally impaired subjects, teicoplanin total and renal clearance significantly decreased with decreasing creatinine clearance (p < 0.0001). However, for these parameters, no differences between doses were observed. Dosage adjustment guidelines for renally impaired patients are usually developed using the ratio of total clearance in renally impaired patients to the total clearance in patients with normal renal function. Since no dose-related differences existed in the relationship between teicoplanin total clearance and creatinine clearance, initial dosage adjustment guidelines for renally impaired patients developed at 3 or 30 mg kg-1 are applicable over the range of 3 to 30 mg kg-1.

Pharmacokinetics of terfenadine in healthy elderly subjects.

The pharmacokinetics of the terfenadine active metabolite, metabolite I, was examined in ten healthy elderly adults and ten younger adults after single-dose oral administration of 120-mg terfenadine. All subjects successfully completed the study without reporting sedation or other adverse events. Absorption was rapid in both the young and elderly. The mean Cmax was the same for both groups, 501 ng/mL, and occurred at 2.3 hours in the young subjects and 2.5 hours in elderly subjects. However, the apparent clearance was reduced by about 25% in the elderly. After correcting clearance for bodyweight, this difference was not statistically significant.

Pharmacokinetics of teicoplanin upon multiple-dose intravenous administration of 3, 12, and 30 milligrams per kilogram of body weight to healthy male volunteers.

Teicoplanin pharmacokinetics were evaluated after multiple-dose intravenous administration to healthy male volunteers by using a randomized, double-blind, parallel design. Doses of 3, 12, or 30 mg of teicoplanin per kg of body weight were administered every 24 h for 14 days as 60-min constant-rate intravenous infusions. Blood and urine samples were collected over 21 days and analyzed by a microbiological assay. Twenty-three subjects were included in the pharmacokinetic analysis. The median pharmacokinetic parameters upon multiple-dose intravenous administration of 3, 12, and 30 mg/kg included steady-state volumes of distribution of 0.94, 0.77, and 0.68 liter/kg; total clearances of 11.9, 12.0, and 13.2 ml/h/kg; and terminal disposition half-lives of 143, 166, and 96 h, respectively. Renal clearance accounted for approximately 95% of total clearance. No dose-related differences existed for teicoplanin total or renal clearance. The steady-state volume of distribution decreased significantly with increasing doses. As a result of the decrease in the volume of distribution, the terminal disposition half-life at 30 mg/kg was significantly decreased. However, the decreases in the volume of distribution and terminal disposition half-life are of limited clinical importance, since steady-state trough concentrations in serum increase in proportion to dose. Combined results of all multiple-dose studies with similar durations of sample collection indicate no dose-related differences for any pharmacokinetic parameters from 3 to 12 mg/kg. As observed in the present study, no dose-related differences exist for teicoplanin total and renal clearances from 3 to 30 mg/kg. However, at 30 mg/kg, a significant decrease in the steady-state volume of distribution is observed. As a consequence of the reduction in the volume of distribution at 30 mg/kg with no change in clearance, the terminal disposition half-life is decreased.

Pooling data for stability studies: testing the equality of batch degradation slopes.

Pharmaceutical products are routinely monitored for their stability over time. Stability studies generally consist of a random sample of dosage units (e.g., tablets, capsules, vials) from a batch or several batches placed in a storage room and periodically assayed for their drug content. The degradation of the drug product is modeled, and according to the Guideline for Submitting Documentation for Stability Studies of Human Drugs and Biologics (Food and Drug Administration, 1987), the shelf-life is calculated as the time point at which the lower 95% confidence limit about the fitted regression line crosses the lowest acceptable limit for drug content (frequently 90% of the labeled amount). When multiple batches are manufactured, preliminary testing for any batch differences (both slope and intercept) should precede pooling stability data from all batches in the analysis. The Guideline recommends a level of significance of .25 for such preliminary testing based on the work described by Bancroft (1964, Biometrics 20, 427-442). Using such a large significance level helps ensure that the power of the test for the batch differences is sufficiently high. This paper presents an approach whereby the power of the test is fixed and the significance level of the test needed to obtain this power is calculated from the data. If the observed significance level does not achieve the calculated significance level, then the data can be pooled. Examples will illustrate the relative performance of the FDA guideline and the proposed procedure.

Comparison of vancomycin- and teicoplanin-induced histamine release and "red man syndrome".

Twelve healthy adult males participated in a double-blind, randomized, two-way crossover study to determine histamine release and the frequency and severity of "red man syndrome" (RMS) following intravenous administration of vancomycin (15 mg/kg of body weight over 60 min) and teicoplanin (15 mg/kg over 30 min). Concentrations of vancomycin and teicoplanin in serum and concentrations of histamine in plasma were measured at baseline and during and after each infusion. Erythema and pruritus were classified a priori as mild, moderate, or severe. The extent of erythema was determined by the use of a burn chart, and pruritus was assessed by the subject with a rank scale. Global severity of RMS was determined by summation of the individual scores for pruritus and erythema. Baseline areas under the concentration-time curve for histamine were not significantly different for the vancomycin and teicoplanin treatments. Vancomycin caused RMS in 11 of 12 subjects (9 severe and 2 moderate cases) and was associated with a significant increase in plasma histamine (46.7 +/- 31.3 ng.min/ml, P less than 0.05). In contrast, teicoplanin did not cause RMS or elicit significant histamine release (8.7 +/- 13.2 ng.min/ml). Peak concentrations of vancomycin and teicoplanin in serum were 58.8 +/- 8.4 and 148.0 +/- 31.8 micrograms/ml, respectively (P less than 0.05). Assuming equal efficacy, these data suggest that teicoplanin may be a safe alternative agent in subjects experiencing severe RMS due to vancomycin; however, further studies in the clinical setting are needed.

Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure.

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotransformation and pharmacokinetic overview of enoximone and its sulfoxide metabolite.

Enoximone possesses both positive inotropic and vasodilatory activities and may be useful in the treatment of patients with congestive heart failure (CHF). In all animal species investigated (rat, dog, monkey and man), the major urinary metabolite is the sulfide oxidation product (sulfoxide); very little unchanged drug appears in urine. Both in vitro and in vivo animal studies indicate reversibility of the sulfoxidation reaction; therefore, it is presumed that sulfoxidation is reversible in man. In normal healthy subjects, no difference in extent of absorption due to dietary state is observed. In patients with New York Heart Association class III to IV CHF, median terminal disposition half-lives for enoximone and its sulfoxide metabolite are 6.2 to 7.6 hours, respectively. Enoximone and sulfoxide plasma concentrations from high dose intravenous infusion studies in patients with class III to IV CHF were also investigated. The collective data suggest nonlinearity in one or more pharmacokinetic processes, of which one may be saturation of sulfoxidation. No direct relation between enoximone and/or the sulfoxide metabolite plasma concentration and pharmacologic effect has been established.

Effects of enoximone and isobutylmethylxanthine on contractile tension and cyclic nucleotide levels in isolated blood-perfused dog papillary muscle.

The effects of enoximone (MDL 17,043) and 3-isobutyl-1-methylxanthine (IBMX) on developed tension, blood flow, and cyclic nucleotide levels were investigated in the isolated blood-perfused dog papillary muscle preparation. Intraarterial infusion of each agent, over 15 s, in doses ranging from 0.001 to 3 mg, produced a dose-dependent positive inotropic effect accompanied by increases in rate of contraction, rate of relaxation, and blood flow. The dose-response relationships for enoximone were always less steep than those for IBMX. Enoximone did not enhance automaticity at any dose, whereas the higher doses of IBMX (0.3, 1, and 3 mg) enhanced automaticity and produced arrhythmic preparations. Both agents produced increases in cyclic AMP during the peak positive inotropic effect (45 s); however, only IBMX produced an increase in cyclic GMP. The increase in cyclic AMP produced by enoximone lagged behind tension development by at least 15 s, whereas the increases in cyclic nucleotides produced by IBMX occurred concurrently with the development of the positive inotropic effect. The evaluation in cyclic AMP produced by enoximone is consistent with the reported property of this agent to inhibit specifically and selectively the particulate high-affinity cyclic AMP phosphodiesterase from dog heart, and supports a cyclic AMP-dependent mechanism of positive inotropism for enoximone.

Publication rates of pharmaceutical scientists: application of the waring distribution.

The publication frequency characteristics of 1984 Journal of Pharmaceutical Sciences reviewers were investigated to provide a perspective on the state of the pharmaceutical literature, its dynamics and some of its features. The average number of per capita total publications in 1984 was 3.56, with 26.9% of the reviewers not publishing at all during the year. The average number of per capita first-authorship publications in our survey was 1.17; the percentage of reviewers not publishing a paper as senior author increased to 50.4%. The so-called elite group of scientists--that is, the top group of scientists who publish 50% of the papers--consisted of 12.8% and 11.7% of the sample for total and senior-authored papers, respectively. Waring distributions were shown to adequately characterize the data. The conceptual scheme leading to the Waring distribution assumes three fundamental characteristics: (1) a "self-reproducing" property, viz., the rate of new entrants (potential publishing scientists) is proportional to community size; (2) a "cumulative advantage" or "success breeds success" property, viz., more highly published scientists; are more likely to publish their next article than are less-published scientists; and (3) a uniform "leakage" property, viz., all scientists, regardless of publication rates, have equal likelihood of dropping out of the publication community.