Adaptive designs in dermatology clinical trials: Current status and future perspectives.

Current drug development strategies present many challenges that can impede drug approval by regulatory agencies. Alternative study models, such as adaptive trial designs, have recently sparked interest, as they provide a flexible and more efficient approach in conducting clinical trials. Adaptive trial designs offer several potential benefits over traditional randomized controlled trials, which include decrease in costs, reduced clinical development time and limiting exposure of patients to potentially ineffective treatments allowing completion of studies with fewer patients. This article explores the current use of adaptive trial designs in non-oncologic skin diseases and highlights the most common types of adaptive designs used in the field. We also review the operational challenges and statistical considerations associated with such designs and propose clinical development strategies to successfully implement adaptive designs. The article also proposes instances where adaptive trial designs are particularly beneficial, and other situations where they may not be very useful.

Adaptive significance of affiliative behaviour differs between sexes in a wild reptile population.

In recent years, we have begun to appreciate that social behaviours might exhibit repeatable among-individual variation. Such behavioural traits may even covary and have critical evolutionary implications. Importantly, some social behaviours such as aggressiveness have been shown to provide fitness benefits, including higher reproductive success and survival. However, fitness consequences of affiliative behaviours, especially between or among sexes, can be more challenging to establish. Using a longitudinal behavioural dataset (2014-2021) collected on eastern water dragons (Intellagama lesueurii), we investigated whether various aspects of affiliative behaviour (i) were repeatable across years, (ii) covaried with each other at the among-individual level, and (iii) influenced individuals' fitness. In particular, we considered affiliative behaviours towards opposite-sex and same-sex conspecifics separately. We found that social traits were repeatable and covaried with each other similarly for both sexes. More notably, we found that male reproductive success was positively correlated with the number of female associates and the proportion of time spent with females, while females' reproductive success was not correlated with any of the measured social behaviour metrics. Overall, these findings suggest that selection may be acting differently on social behaviour of male and female eastern water dragons.

Production of recycled manure solids for use as bedding in Canadian dairy farms: II. Composting methods.

Recent technological advances in the dairy industry have enabled Canadian farms with liquid manure systems to use mechanical solid-liquid separation paired with composting of the separated solids for on-farm production of low-cost bedding material. However, because several approaches are available, it is difficult for farmers to select the appropriate one to achieve high quality recycled manure solids (RMS). Whereas 3 solid-liquid manure separators were compared in part I of the series (companion paper in this issue), the present study (part II) aims to assess the performance of 4 composting methods (static or turned windrow and drum composter for 24 or 72 h) under laboratory conditions. Parameters evaluated included temperature, physico-chemical characteristics, and bacterial composition of RMS, as well as airborne microorganisms, dust, and gases associated with composting RMS. Because each treatment attained the desired composting temperature range of 40 to 65°C (either in heaps or in the drum composter), reductions in bacteria were a better indicator of the sanitation efficiency. The treatment of fresh RMS in a drum composter for 24 h showed decreased bacterial counts, especially for Escherichia coli (from 1.0 × 105 to 2.0 × 101 cfu/g of dry matter) and Klebsiella spp. (from 3.2 × 104 to 4.0 × 102 cfu/g of dry matter). Increasing the time spent in the rotating vessel to 72 h did not result in further decreases of these pathogens. Composting in a static or turned windrow achieved similar E. coli and Klebsiella spp. reductions as the 24-h drum composting but in 5 or 10 d, and generally showed the lowest occupational exposure risk for dairy farmers regarding concentrations of airborne mesophilic bacteria, mesophilic and thermotolerant fungi, and total dust. Drum-composted RMS stored in piles exhibited intermediate to high risk. Composting approaches did not have a major influence on the physico-chemical characteristics of RMS and gas emissions. Drum composting for 24 h was the best compromise in terms of product quality, temperature reached, decreased bacterial numbers, and emitted airborne contaminants. However, because levels of pathogenic agents rapidly increase once composted RMS are spread in stalls, bacteriological characteristics of RMS along with milk quality and animal health and welfare features should be monitored in Canadian dairy barns applying recommended separation (part I) and composting (part II) systems to evaluate health risk and optimize management practices.

Stress, song and survival in sparrows.

The stress response--increases in circulating glucocorticoids following a stressor--is typically considered adaptive, but few studies address the fitness consequences of individual variation in stress response. Generally, due to negative consequences of prolonged elevation of glucocorticoids, animals should have a transient stress response just sufficient to cope with the stressor. In rodents, stress responsiveness is affected by early developmental experience, and hyper-responsiveness to stress is linked to morbidity and mortality. We assessed individual variation in stress responses in free-living song sparrows, Melospiza melodia, in relation to fitness-related measures including song and overwinter survival. Birds with greater increases in corticosterone 30 min following restraint stress were less likely to return to breed the following year. Stress responsiveness was also correlated with song complexity: males with fewer syllables in their song repertoires had greater stress reactivity. Our findings support the hypothesis that developmental stressors both impair song development and affect the adult stress response. Thus, individual variation in the stress response may relate to variation in fitness.

Carry-over effects in bioequivalence studies.

Carry-over effects are often considered to be one of the main problems of the cross-over design: should we adjust for carry-over or not? We attempt to answer this question by examining the observed frequency of carry-over effects in actual bioequivalence studies. A total of 96 six-sequence, three-period, three-treatment fed-fasted studies are analyzed for carry-over effects and 324 two-sequence, two-period, two-treatment fasted studies are analyzed indirectly for carry-over effects via sequence effects. Two log-transformed pharmacokinetic variables, Cmax and AUC0-t, are modeled in an analysis of variance. The impact of statistically significant carry-over effects on bioequivalence results is examined and the rationale behind not adjusting for carry-over in bioequivalence studies is discussed.

Numerical methods for the evaluation of individual bioequivalence criteria.

The evaluation of individual bioequivalence (IBE) by bootstrap resampling using common statistical software, for example SAS, is extremely time consuming. In this article, an estimation procedure that can be implemented in a high level language with the same degree of accuracy as SAS is described. The necessary parameter estimating equations under both least square (LSE) and restricted maximum likelihood (REML) methods are given. The algorithms used to numerically compute these values are outlined and tested, in FORTRAN, on several simulated data sets and shown to reproduce SAS results with at least 10(-3) precision. More importantly, the REML bootstrap algorithm reduces the time taken in SAS by a factor of 20. Secondary results indicate that LSE and REML parameter estimates are similar for mild unbalancedness. PROC MIXED, with unstructured (UN) and compound symmetry heterogeneous (CSH) variance structures give the same results except when the subject-by-treatment interaction variance, sigma(2)(D), is 0 in which case CSH significantly overestimates sigma(2)(D) and underestimates the within-treatment variances. It is concluded that bootstrap evaluation of IBE is efficiently done using either the LSE or REML algorithm in FORTRAN.

Comparison of different methods to evaluate population dose-response and relative potency: importance of interoccasion variability.

Different mixed-effects models were compared to evaluate the population dose-response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose-response and relative potency, there are important differences in the assumptions made by each method.

Enabling factors related to prosthetic use by people with transtibial and transfemoral amputation.

OBJECTIVE: To evaluate the frequency and extent of prosthetic use by people with lower limb amputation and identify factors that facilitate prosthetic use. DESIGN AND SETTING: Five-year follow-up survey using the Prosthetic Profile of the Amputee (PPA) questionnaire and Dillman's mailing strategy. SUBJECTS: Adults with unilateral transtibial and transfemoral amputation (n = 396) who had completed a prosthetic training program. MAIN OUTCOME MEASURES: Frequency of prosthetic wear, in hours per week, and active prosthetic use for locomotion indoors and outdoors. RESULTS: Eighty-five percent of the respondents (mean age 62.9+/-15.9yrs) were prosthetic wearers; 53% used their prosthesis for locomotion indoors, and 64% outdoors. Ability to don the prosthesis (p < .001), locomotor capabilities with the prosthesis (p < .001), walking distances (p < .001), automaticity of gait (p < .05), and assistive devices used (p < .001) were the main factors related to the three outcome measures. People with transfemoral amputation reported greater difficulties in donning their prosthesis (p < .01) and a significantly higher rate of falls (p < .001). CONCLUSION: The majority of people with lower limb amputation wear their prosthesis daily. With the exception of resources (prosthetic laboratory and means of transportation), all enabling factors investigated were significantly associated with the outcome measures.

Truncated area under the curve as a measure of relative extent of bioavailability: evaluation using experimental data and Monte Carlo simulations.

PURPOSE: The use of truncated areas under the curve (AUCs) could be a significant advantage for bioequivalence studies of drugs with long half-lives. The purpose of this study was to evaluate the performance of truncated AUCs as measures of relative extent of bioavailability using a large database of experimental data and Monte Carlo simulations. METHODS: The experimental data consisted of 123 single-dose, 2-treatment, crossover studies with at least 18 subjects/study. Monte Carlo techniques were also used to simulate studies that reflected a wide variety of experimental conditions. AUCs were calculated over different time intervals and the standard two one-sided t tests procedure was used to assess bioequivalence. RESULTS: The experimental data showed that conclusions concerning bioequivalence were identical between AUCs truncated at four times the time of peak concentration (Tmax) and AUCs extrapolated to infinity (AUC(inf)) in 120/123 or 97.6% of studies. There was little change in the intra-subject CVs for AUCs truncated at 3*Tmax or later. The results of Monte Carlo simulations were generally consistent with the experimental data and showed that AUCs truncated at 72 hours (AUC(0-72)) performed well compared to AUC(inf) as measures of bioequivalence for drugs with long half-lives. CONCLUSIONS: Based on both the experimental and simulated data, AUCs truncated after the absorption phase perform well as measures of relative extent of bioavailability. Truncated AUCs offer a particular advantage for drugs with long half-lives and these results indicate that it would be reasonable to limit the sample collection period to 72 hours in bioequivalence studies of oral formulations.

A parametric confidence interval for a moment-based scaled criterion for individual bioequivalence.

Confidence intervals of proposed individual bioequivalence metrics are difficult to determine in closed form because their stochastic distributions are unknown. In this article, it is shown that, with slightly modified weights, the Relative Individual Risks (RIR) moment-based scaled statistic for individual bioequivalence that was presented by Schall and Williams has an exact noncentral Fisher's F distribution with noncentrality parameter give by a scaled squared difference in formulations means. This can be approximated by a central F with adjusted degrees of freedom from which it follows that an upper (1-alpha) confidence bound for RIR is given by [formula: see text] where [formula: see text] is the least square estimate of RIR; dfER is the degrees of freedom associated with the reference intrasubject variance estimate, v is the subject-by-formulation degrees of freedom adjusted for noncentrality and alpha is the significance level. Individual bioequivalence is concluded if UL does not exceed the regulatory limit. The performance of this confidence interval was investigated by comparing its experimental bioequivalence rate to that of the unweighted metric under known parameter situations through simulations of two formulations in a fully replicated study design. Results showed that the proposed metric is slightly less biased and more precise than the unweighted metric.

Multistage designs for phase II clinical trials: statistical issues in cancer research.

The main objective of phase II clinical trials is to estimate treatment efficacy on a relatively small number of patients in order to decide whether the treatment ought to be studied in large-scale comparative trials. They play a key role in the drug development process, since the results determine whether or not to proceed to phase III trials. Multistage designs for phase II clinical trials proposed by Gehan, Fleming, Simon and Ensign are described and compared. Gehan's and Simon's designs have two stages, Fleming's designs can have two or more stages, and Ensign's three-stage design combines the first stage of Gehan with the two stages of Simon. Phase II clinical trial protocols and reports should include a description of the design selected with a justification for the particular choice. The present practice is very far from this ideal.

[Research design for patient selection in clinical trials phase II]. / Plans expérimentaux pour l'inclusion de patients dans les essais de phase II.

Phase II trials play a key role in the development of a treatment, because they are crucial in deciding whether or not to proceed to phase III. In the event of the evaluation of a new treatment given to only one group of subjects, multi-stage designs were developed to include subjects in phase II trials. Gehan's two stage designs stop inclusion of subjects if no success is observed among the first n1 subjects. They are easy to use, but have the disadvantage of exposing many subjects to an inefficient treatment at the second stage. Fleming's multi-stage designs and Simon's two stage designs permit the early termination of a trial when the intermediate results are extreme, either in favor of the efficiency or in favor of the inefficiency of the treatment. Simon's plans minimize either the average or the maximum number of subjects exposed to ineffective treatment. Ensign's three stage designs combine the first stage of Gehan with the two stages of Simon. These plans are interesting because they can reject a treatment quickly after a long run of failures which minimizes the average number of subjects exposed to an ineffective treatment.

Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group.

OBJECTIVE: Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. METHODS: Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. RESULTS: All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.

Factors associated with length of survival among 1081 terminally ill cancer patients.

To improve their ability to estimate the survival of terminally ill cancer patients, palliative care physicians require accurate information on prognostic factors. The objective of this study was to assess the extent to which variables such as patient characteristics and primary tumor site affect the length of survival of terminally ill cancer patients. The study population consisted of 1081 cancer patients admitted for terminal care to a 15-bed palliative care unit from 1985 to 1991. Univariate Kaplan-Meier survival analysis and multivariate Cox regression analyses were used to examine the relationship between patient characteristics at admission and survival time. The factor most strongly associated with shorter survival was poor performance status; this strong relationship was not altered by taking into account sex and primary cancer site in the multivariate analysis. For patients who were bedridden at admission, the death rate was 5.5 times higher (95% confidence interval (Cl) 3.4-9.0) than that for ambulatory patients during the first four days of stay, and it was 2.8 times higher (95% Cl 2.0-3.9) subsequently (up to 19 days). The other prognostic factors significantly but slightly associated with poorer survival in the univariate analysis were primary lung cancer, male sex, and living with a spouse. These findings indicate that performance status is the main prognostic factor for accurately estimating the survival time of terminally ill cancer patients.

Prognostic significance of cathepsin-D expression in node-positive breast carcinoma: an immunohistochemical study.

The prognostic significance of cathepsin-D expression was evaluated by immunohistochemistry in 638 node-positive breast carcinomas diagnosed between 1980 and 1986. A minimum of 2.5 years of follow-up was available for each patient (maximum: 9.5 years). Cathepsin-D expression was assessed separately both in cancer and in stromal cells using a commercially available polyclonal antibody. While cancer-cell immunostaining was not associated with prognosis, positive staining of stromal elements was related to shorter metastasis-free survival. The difference in distant metastasis-free survival between positive and negative expressors was greatest in the sub-group of patients submitted to adjuvant chemotherapy, with a hazard ratio for occurrence of distant metastasis of 1.76 by multivariate analysis, but was lowest for those receiving hormone therapy. Cathepsin-D expression by stromal cells was related to HER-2/neu oncoprotein expression, HSP-27 expression, poor nuclear grade, aneuploidy, and absence of estrogen and progesterone receptors. No association was found with the number of involved lymph nodes, tumor size, age, histologic grade, S-phase fraction, or vascular invasion. Our study suggests that cathepsin-D expression by stromal cells (and not by cancer cells) affects the prognosis of breast cancer, that stromal cells probably play a key role in local invasion and metastatic dissemination of the tumor, and that the prognostic significance of cathepsin-D expression may vary according to the type of adjuvant therapy.

The use of morphologic tissue examinations as novel technique for estimation of drug adverse reactions in hospitalized patients.

Morphologic evaluation of tissue specimens from a hospital population was used to identify and classify adverse reactions to drugs. With the use of this novel technique, the incidence of adverse tissue reactions was found to be 3.6% out of which 1.5% were found to be definitely caused by a specific pharmacological agent. Adverse tissue reactions were both sex- and age-related occurring more often in women and more frequently between the ages of 51-60 years. Although adverse tissue reactions were noted less frequently in males, a definite causative agent was identified in over 50% of males in which a tissue reaction was observed. Endometrium and liver were the predominant tissues altered morphologically in our hospital population. Estrogenic preparations and alcohol were found to be most frequently implicated in the observed adverse tissue reactions. In comparison to the observation of symptoms associated with drug use, our study provides an alternate means of relating an adverse reaction to pharmacological agent employed in that subjective bias can successfully be removed. Although the present system described appears to be more rigorous in identification of adverse reactions, evidence indicates that tissue adverse reaction technique may be advantageous in determination of an unwanted response in patients under 60 years of age. It is hoped that the tissue adverse reaction evaluation may provide a more accurate prediction of possible adverse effects and perhaps may be a more reliable, sensitive system for estimation of adverse effects in hospitalized patients.

Autopsy tissue examination: a novel method to estimate adverse reactions to pharmacological agents.

Autopsy tissue examination was employed as a measure to remove subjective bias observation in the identification and numerical computation of adverse reactions to drugs. With the the use of this novel technique, the incidence of adverse reactions was 26%, of which 82% were produced by a specific causative agent. Adverse reactions occurred most frequently in autopsied tissues taken from patients who were male and in the 61 and over age group. Further the predominant tissue altered morphologically in autopsied specimens examined was liver. The most common causative agent associated with an adverse tissue reaction was identified as alcohol. In light of the difference between evaluation by physicians of drug adverse reactions and the technique of autopsy tissue examination, our findings provide a more accurate measure of adverse reactions to non-prescription pharmacological agents.