M. Sibille

Adverse events in phase one studies: a study in 430 healthy volunteers

SummaryAll the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up.The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events.Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.

Laboratory data in healthy volunteers : reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

AbstractObjective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5–97.5% interval for each laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

Acute, Recurrent Fosfomycin-induced Liver Toxicity in an Adult Patient with Cystic Fibrosis

We report a very unusual adverse effect--fosfomycin-induced repeat liver toxicity--in a female adult with cystic fibrosis (CF).

Laboratory screening method for selection of healthy volunteers

SummaryThe aim of laboratory screening in Phase I is to exclude subjects with subclinical illness, who might be at increased risk in the study, and who might also adversely influence interpretation of the results.A new method for laboratory screening, based on Bayesian probability theory, is proposed, which consists of:1.Drawing up a list of diseases to be excluded.2.Defining for each disease, the maximum acceptable risk that an included subject could be affected by it.3.Identifying one test for each disease.4.Using a contingency table to calculate the specificity of the test and integrating the estimated prevalence of the disease from epidemiological data.5.Applying the percentage obtained by the calculation of specificity to the previously determined distribution of values in the volunteer population to identify the threshold value for inclusion. Use of this deductive method in screening volunteers for Phase I trials affords increased security of selection, while reducing the number of non-pertinent exclusions because of laboratory findings.

Critical limits to define a lab adverse event during phase I studies: a study in 1134 subjects

Objective: The first goal of phase I drug development is the determination of maximal tolerated dose, which must be established by case-by-case analysis, sometimes using a laboratory adverse event. Since no accurate rule defining lab adverse events, has been validated yet, we propose a new “combined method” based on combination of two thresholds: inclusion values and magnitude of variation. Using this combined method, the label “lab adverse event” is applied if any lab value exceeds the inclusion threshold and is associated with a variation from baseline exceeding the variation threshold defined from reference change limit. Thus, this study aimed to test this combined method on a large healthy volunteer population, studied in 19 phase I centres worldwide, and on five lab parameters: alanine amino transferase, aspartate amino transferase, alkaline phosphatases, creatinine and polymorphonuclear leukocytes. Methods: The inclusion threshold from each center was used. Reference change limits were defined from volunteers previously included in comparable studies and were expressed as absolute values: increases of 10 IU · l−1 for alanine amino transferase or aspartate amino transferase, 15 IU · l−1 for alkaline phosphatases, 15 μmol · l−1 for creatinine and a 0.34 109 · l−1 decrease for polymorphonuclear leukocytes. Comparison between the “combined method” and a normal range method was made using positive predictive value and a ratio between relevant and irrelevant results. This application was implemented in all young healthy volunteers (1134) included in 38 phase I studies sponsored by Rhône Poulenc Rorer from 1991 to 1993. Results: Seventy seven subjects (6.7%) were indicated in final study reports as having a lab adverse event (reference group). Of 179 subjects with lab abnormalities defined by the normal range method, 77 belonged to the reference group, inducing a poor 0.43 positive predictive value. Of ninety subjects with lab adverse events defined by the “combined method”, seventy-five belonged to the reference group, inducing a two-fold higher 0.83 positive predictive value. The combined method produced a high ratio of relevant/irrelevant results () compared with the low ratio () achieved using the normal range method. Conclusion: This new “combined method”, leading to a better definition of lab adverse event, seems an accurate and useful tool for routine case-by-case analysis within phase I drug development studies.

Upper limit of plasma alanine amino transferase during Phase I studies

In Phase I clinical studies, the maximum tolerated dose has to be determined by a case by case analysis sometimes using a laboratory adverse effect, e.g. an increase in alanine amino transferase (ALT). For this reason a threshold to discriminate between significant or non significant adverse changes in ALT is required particularly in Phase I studies, in order to deal with the very common “close to the limit values”. Previous methods (limit of normal range or normal range plus an arbitrary margin) do not solve this problem. The authors propose a new method taking into account the threshold used as inclusion criteria for ALT (R) and the range of spontaneous variations measured under identical Phase I study conditions (V). The (R) and (V) thresholds, respectively, are defined as 50 IU·1−1 and a 50% increase, from baseline. Thus an ALT value is recognized as a “significant adverse experience” if it exceeds 50 IU·1−1 above an increase from baseline exceeding 50% of the baseline value.To highlight the value of the method, it was implemented in a one year period including 8 studies and 134 subjects. The sensitivity, specificity and positive predictive value of various methods were compared.The results showed the following: Six out of 134 subjects had significant adverse changes in ALT (4%); and all these 6 subjects were detected by the proposed new method without error. Eight subjects including two false positives, were detected by an use of the normal range limit, and only 4 were detected using, the 10% margin. Thus, use of the new method showed 1. keeping the normal range limit as the detection threshold led to preserved sensitivity; 2. it reduced the background noise of false positive results related to chance variation around the upper limit, mainly in subjects with a baseline value close to the limit; 3. it allowed better judgment of the significance of a value which lay just beyond the limit when variation from the baseline exceeding the normal range. The new method produced the best combination of sensitivity, specificity and positive predictive value. Given the small number of subjects in the study, further evaluation with a larger population is required.Finally, the proposed new method seems to be a tool easy to use determining the significance of adverse changes in ALT when the values are close to the limit that is common in Phase I studies.

Bioequivalence Study of Two Formulations (Sachet and Tablet) of Cefixime after Single Oral Doses of 200mg in Healthy Male Volunteers

ObjectiveThe comparative bioavailability of two oral formulations of cefixime, the Oroken® 200mg tablet (reference formulation) and the novel Oroken® 200mg sachet (test formulation), was investigated in a single-dose crossover study in 18 healthy male volunteers.ResultsThe data obtained in this study demonstrated bioequivalence of the two formulations. No statistical differences were observed for either maximum serum drug concentrations (Cmax) or areas under serum drug concentration versus time curves (AUC). 90% confidence intervals for mean Cmax and mean AUC (logarithmically transformed data) of the sachet as compared with the tablet were within the bioequivalence interval of 0.8 to 1.25. No differences between formulations in time to reach Cmax (tmax) or serum elimination half-life (t00BDβ) were evident. Moreover, after administration of either formulation, comparable amounts of unchanged cefixime were excreted in urine over similar time-frames. Clinical and biological tolerability was excellent for both formulations.ConclusionThe results of the present study show bioequivalence in terms of rate and extent of absorption of the tablet and sachet formulations of cefixime. The novel sachet formulation appears of considerable use for patients who are unable or unwilling to take tablets and for whom therapy with cefixime is recommended.