A nonparametric method to detect increased frequencies of adverse drug reactions over time.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare. The methods need to be specific and account for multiplicity to avoid false positive signals when the list of known adverse drug reactions is long. To apply them as part of a routine process, the methods also have to cope with very diverse drugs (increasing or decreasing number of cases over time, seasonal patterns, very safe drugs versus drugs for life-threatening diseases). In this paper, we develop new nonparametric signal detection methods, directed at detecting differences between a reporting and a reference period, or trends within a reporting period. These methods are based on bootstrap and permutation distributions, and they combine statistical significance with clinical relevance. We conducted a large simulation study to understand the operating characteristics of the methods. Our simulations show that the new methods have good power and control the family-wise error rate at the specified level. Overall, in all scenarios that we explored, the method performs much better than our current standard in terms of power, and it generates considerably less false positive signals as compared to the current standard.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

BACKGROUND AND OBJECTIVE: Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics. METHODS: The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics. RESULTS AND CONCLUSIONS: In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure-response metrics for pharmacokinetic/pharmacodynamic analyses.

Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children.

Extrapolating from information available on one patient group to support conclusions about another is common in clinical research. For example, the findings of clinical trials, often conducted in highly selective patient cohorts, are routinely extrapolated to wider populations by policy makers. Meanwhile, the results of adult trials may be used to support conclusions about the effects of a medicine in children. For example, if the effective concentration of a drug can be assumed to be similar in adults and children, an appropriate paediatric dosing rule may be found by 'bridging', that is, by matching the adult effective concentration. However, this strategy may result in children receiving an ineffective or hazardous dose if, in fact, effective concentrations differ between adults and children. When there is uncertainty about the equality of effective concentrations, some pharmacokinetic-pharmacodynamic data may be needed in children to verify that differences are small. In this paper, we derive optimal group sequential tests that can be used to verify this assumption efficiently. Asymmetric inner wedge tests are constructed that permit early stopping to accept or reject an assumption of similar effective drug concentrations in adults and children. Asymmetry arises because the consequences of under- and over-dosing may differ. We show how confidence intervals can be obtained on termination of these tests and illustrate the small sample operating characteristics of designs using simulation. Copyright © 2016 John Wiley & Sons, Ltd.

Assessing switchability for biosimilar products: modelling approaches applied to children's growth.

The present paper describes two statistical modelling approaches that have been developed to demonstrate switchability from the original recombinant human growth hormone (rhGH) formulation (Genotropin(®) ) to a biosimilar product (Omnitrope(®) ) in children suffering from growth hormone deficiency. Demonstrating switchability between rhGH products is challenging because the process of growth varies with the age of the child and across children. The first modelling approach aims at predicting individual height measured at several time-points after switching to the biosimilar. The second modelling approach provides an estimate of the deviation from the overall growth rate after switching to the biosimilar, which can be regarded as an estimate of switchability. The results after applying these approaches to data from a randomized clinical trial are presented. The accuracy and precision of the predictions made using the first approach and the small deviation from switchability estimated with the second approach provide sufficient evidence to conclude that switching from Genotropin(®) to Omnitrope(®) has a very small effect on growth, which is neither statistically significant nor clinically relevant.

Bayesian Design of Proof-of-Concept Trials.

The proof-of-concept (PoC) decision is a key milestone in the clinical development of an experimental treatment. A decision is taken on whether the experimental treatment is further developed (GO), whether its development is stopped (NO-GO), or whether further information is needed to make a decision. The PoC decision is typically based on a PoC clinical trial in patients comparing the experimental treatment with a control treatment. It is important that the PoC trial be designed such that a GO/NO-GO decision can be made. The present work develops a generic, Bayesian framework for defining quantitative PoC criteria, against which the PoC trial results can be assessed. It is argued that PoC criteria based solely on significance testing versus the control are not appropriate in this decision context. A dual PoC criterion is proposed that includes assessment of superiority over the control and relevance of the effect size and hence better matches clinical decision making. The approach is illustrated for 2 PoC trials in cystic fibrosis and psoriasis.

Experimental designs for small randomised clinical trials: an algorithm for choice.

BACKGROUND: Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple. METHODS: PubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs. RESULTS: We identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs. CONCLUSIONS: The algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.

Comparison of cyclosporine A with methylprednisolone for treatment of canine atopic dermatitis: a parallel, blinded, randomized controlled trial.

The objective of this multicentre, parallel, blinded, randomized controlled study was to evaluate the efficacy and the safety of cyclosporine (CsA group, 117 dogs) in comparison with methylprednisolone (MP group, 59 dogs) in the treatment of atopic dermatitis for 4 months. Mean induction dose of both drugs (5 mg/kg CsA, 0.75 mg/kg MP) was tapered over time according to the clinical response. At the end of the study, the mean estimated percentage reduction from baseline (confidence interval) of lesion scores was 52% (44-59) and 45% (35-56), and the reduction in pruritus score was 36% (27-43) and 33% (23-43) in dogs in the CsA and MP groups, respectively. These percentages were not significantly different between groups. A significantly better overall assessment of efficacy was obtained in the CsA-treated dogs (76 vs. 63% responses excellent or good in the CsA compared with MP group). CsA-treated dogs presented a higher frequency of gastrointestinal disorders, mainly vomiting, but MP dogs tended to be more susceptible to infections. There was no remarkable change over baseline of the haematological and biochemical parameters in the two groups.

Résumé Le but de cette étude contrôlée, multicentrique, parallèle, en aveugle et randomisée, était d'évaluer l'efficacité et l'inocuité de la cyclosporine (groupe CsA, 117 chiens) en comparaison de la methylprednisolone (groupe MP, 59 chiens) pour le traitement de la dermatite atopique pendant 4 mois. La dose moyenne d'induction pour les deux molécules (5 mg kg−1 CsA, 0.75 mg kg−1 MP) était progressivement diminuée en fonction de la réponse clinique observée. A la fin de l'étude, le pourcentage moyen de réduction des scores lésionnels et les intervalles de confiance étaient de 52% (44-59) pour le groupe CsA et de 45% (35-56) pour le groupe MP, alors que le pourcentage moyen de réduction du prurit était de 36 % (27-43) pour la CsA et de 33% (23-43) pour la MP. Ces pourcentages ne sont pas significativement différents entre les groupes. L'amélioration a été jugée significativement meilleure dans le groupe CsA (76% vs 63% des réponses étaient cotées excellentes ou bonnes dans le groupe CsA comparé au groupe MP). Les chiens traités par la CsA ont présenté significativement plus de troubles gastro-intestinaux (notamment des vomissements) mais les chiens du groupe MP se sont avérés plus sensibles aux infections. Aucune modification remarquable des paramètres hématologiques ou biochimiques n'a été remarquée dans les deux groupes de chiens.

Resumen El objetivo de este estudio multicéntrico, en paralelo, ciego y al azar controlado fue evaluar la eficacia y seguridad de la ciclosporina (grupo CsA, 117 perros) en comparación con la metilprednisolona (grupo MP, 59 perros) en el tratamiento de dermatitis atópica durante 4 meses. La dosis media de inducción para ambas drogas (5 mg kg−1 CsA, 0.75 mg kg−1 MP) fue disminuida con el tiempo de acuerdo con la respuesta clínica. Al final del estudio, el porcentaje de reducción medio estimado desde la línea basal (intervalo de confianza) de la puntuación de las lesiones fue del 52% (44-59) y 45% (35-56), y la reducción de la puntuación del prurito fue del 36% (27-43) y 33% (23-43) en los perros de los grupos de CsA y MP, respectivamente. La diferencia entre los porcentajes de ambos grupos no fue significativa. En la estimación global, la eficacia fue mejor en el grupo de perros tratados con CsA (76% de respuestas excelentes o buenas en el grupo CsA comparado con el 63% en el grupo MP). Los perros tratados con CsA mostraron una mayor frecuencia de alteraciones gastro-intestinales, principalmente vómitos, mientras que los perros tratados con MP presentaron mayor susceptibilidad a infecciones. No se observaron diferencias remarcables en los niveles basales de los parámetros hematológicos y bioquímicos en ambos grupos.

Randomized controlled trial of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs.

OBJECTIVE: To evaluate efficacy of cyclosporine A, administered at either of 2 dosages, in dogs with atopic dermatitis (AD). DESIGN: Multicenter randomized controlled trial. ANIMALS: 91 dogs with AD. PROCEDURE: Dogs were assigned to receive placebo (30 dogs), cyclosporine at a low dosage (2.5 mg/kg [1.1 mg/lb], PO, q 24 h for 6 weeks; 30 dogs), or cyclosporine at a high dosage (5.0 mg/kg [2.3 mg/lb], PO, q 24 h for 6 weeks; 31 dogs). RESULTS: After 6 weeks, mean percentage reductions, compared with baseline scores, in scores of lesion severity were 34, 41, and 67% for dogs treated with the placebo, cyclosporine at the low dosage, and cyclosporine at the high dosage, respectively. Similarly, mean percentage reductions in pruritus scores were 15, 31, and 45%, respectively. Percentage reductions in skin lesion and pruritus scores were significantly higher for dogs given cyclosporine at the high dosage than for dogs given the placebo. Treatment efficacy was significantly associated with whether dogs had a history of seasonal AD. Percentage reductions in skin lesion and pruritus scores were high for dogs treated with cyclosporine at the highest dosage that had a history of nonseasonal AD. Dogs in all groups with seasonal AD improved during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that oral administration of cyclosporine at a dosage of 5.0 mg/kg once daily is effective in reducing severity of pruritus and skin lesions in dogs with AD, especially those with nonseasonal disease.