Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Point and Interval Estimators of the Target Dose in Clinical Dose-Finding Studies with Active Control.

In a clinical dose finding study with active control a new drug with several dose levels is compared with an active comparator drug. The main focus of such studies often lies on the estimation of a target dose that leads to the same efficacy as the control. This article investigates the finite sample properties of the maximum likelihood estimation of the target dose and compares several approaches for constructing corresponding confidence intervals under the assumption of a linear dose-response curve and normal error terms. Furthermore, the impact of deviations from the model assumptions regarding the error distribution is explored.

[The relevance of biomarkers for personalised medicine]. / Die Bedeutung von Biomarkern für eine personalisierte Medizin.

In this paper the relevance of biomarkers for the benefit/risk assessment of pharmaceuticals and the validation of biomarkers within clinical trials is presented. For this purpose the most important study designs for validation are described and discussed. Using the example of the development of rosuvastatin and the validation of hs-CRP (JUPITER study), aspects that are necessary for the planning of a joint development program for a pharmaceutical drug and a biomarker are discussed. In addition, alternatives considering how the validation of the biomarker could be involved in the entire development program of the pharmaceutical drug are presented.

Impaired endothelial function and blood flow in repetitive strain injury.

Repetitive Strain Injury (RSI) is a disabling upper extremity overuse injury that may be associated with pathophysiological changes in the vasculature. In this study we investigated whether RSI is associated with endothelial dysfunction and impaired exercise-induced blood flow in the affected forearm. 10 patients with RSI (age, 40.2 ± 10.3; BMI, 23.8 ± 3.3) and 10 gender- and age-matched control subjects (age, 38.0 ± 12.4; BMI, 22.7 ± 3.4) participated in this study. Brachial artery blood flow was measured at rest and during 3-min periods of isometric handgrip exercise at 15%, 30% and 45% of the individual maximal voluntary contraction. Brachial artery endothelial function was assessed as the flow mediated dilation (FMD), by measuring brachial artery diameter and velocity before and after 5-min ischemic occlusion. We found a lower exercise-induced brachial artery blood flow in patients with RSI than in controls (p=0.04). Brachial artery FMD was significantly lower in patients with RSI than in controls (p<0.01), whilst a lower FMD was also found in patient with unilateral RSI when comparing the affected arm with the non-affected arm (p=0.04). Our results suggest that patients with RSI have an attenuated exercise-induced blood flow and an impaired endothelial function in the affected arm. These findings importantly improve our understanding of the pathophysiological mechanism of RSI.

Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens.

METHOD: A randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of drospirenone (1, 2 or 3 mg) combined with estradiol (1 mg) in the treatment of climacteric symptoms in healthy postmenopausal women. RESULTS: The frequency of hot flushes was significantly decreased in all treatment groups (range 86-90%) in comparison to placebo (45%, p < or = 0.001) and remained suppressed at 16 weeks. Treatment with drospirenone and estradiol also decreased the intensity and severity of sweating, sleep problems, depression, nervousness, and urogenital symptoms. Most adverse events were mild or moderate, with similar rates observed in all groups. No serious adverse events or clinically significant laboratory abnormalities attributed to treatment occurred. CONCLUSION: These results demonstrate that the combinations of 1, 2, and 3 mg drospirenone with 1 mg estradiol are safe and effective for the treatment of climacteric symptoms.

[Chemoembolization of hepatocellular carcinomas: which factors determine therapeutic response and survival?]. / Chemoembolisation des hepatozellulären Karzinoms: Welche Faktoren bestimmen Therapieansprechen und Uberleben?

PURPOSE: To determine independent prognostic factors influencing the survival of patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: Ninety-one patients with unresectable HCC were treated with 269 repetitive TACE. The dosages of epirubicin (40-60 mg) and ethiodized oil (8-20 ml) were adjusted to tumor size and liver function. The impact of tumor size, macroscopic tumor type, tumor location, portal vein infiltration, capsular infiltration, tumor vascularization, uptake of ethiodized oil within the tumors, Child-Pugh-Class and Okuda-Stage on patient survival were evaluated by means of univariate and multivariate regression analysis. RESULTS: The following independent prognostic factors were found: tumor type (nodular vs. infiltrating, p = 0 008), tumor size (p = 0.01), Child-Pugh-Class (A vs. B; p = 0.02) and grade of tumor vascularization (p = 0.04). In 57 patients with HCC of the nodular type, the median survival time was significant longer than in 32 patients with HCC of the infiltrating type (17.0 months vs. 7.9 months; p < 0.003; 2 tumors could not be classified). The 1-, 2- and 3-year-survival rates were significantly higher in 57 patients with Okuda-Stage I disease, compared to 34 patients with Okuda-Stage II and III disease (73%, 31% and 8% vs. 23%, 6% and 4% p < 0.0001). CONCLUSIONS: Tumor type, tumor size and grade of liver cirrhosis have an independent impact on prognosis of patients with HCC treated by TACE. An appropriate selection of patients is necessary to improve patients survival.

[Did suicidal behavior have relevance for prison suicide?]. / Welche Relevanz hat die dokumentierte Suizidalität in Gefangenensuiziden?

OBJECTIVE: Suicides in correctional institutions occur more frequently than in the general population. Inmate suicide rates have been increasing in many countries during the last decades, possibly reflecting a selection of highly endangered individuals with a high prevalence of mental disorders. This study investigates all suicides in all correctional institutions of Austria during the last 25 years. METHODS: All available personal files of inmates who had committed suicide in the 29 Austrian prisons between January 1st, 1975, and December 31st, 1999, were analysed. Beside personal characteristics and circumstances of custody, information concerning psychiatric disorders and the inmate's history of suicidal behavior was included. RESULTS: 220 personal files of 250 suicides were available and included. Half of all suicides had a history of attempted suicide and 37 % had expressed suicidality. Referral to psychiatric consultants was known in 48.6 % and about 37 % received psychopharmacological treatment. Based on these frequent signs of psychiatric illness and vulnerability, possible implications of these results for psychiatric services of the correctional system to improve suicide prevention are discussed. CONCLUSIONS: Obvious signs of suicidality play an important role in vulnerability profiles for jail and prison suicides. Any signs of suicidality (st. p. attempted suicide, verbal suicide threat, self-harm) should have the consequence of further psychiatric care.

[Diagnosis and differential diagnosis of consciousness disorders from the psychiatric viewpoint]. / Diagnose und Differentialdiagnose der Bewusstseinsstörungen aus psychiatrischer Sicht.

Diagnosis and differential diagnosis of disturbance of consciousness are often difficult, especially when occurring in the course of psychiatric diseases. Apart from discord in defining the term of consciousness it is not always easy to distinguish between qualitative and quantitative alterations of the disorders. The performance of an exact interview and a thorough clinical examination allows an estimation of the degree of dimming of consciousness as well as the possible causes. Disorder of Consciousness is often found in patients carrying out substance abuse but also in the course of other psychiatric diseases such as depression, schizophrenia, personality disorders and dissociative disorders. This article is dealing with the clinical approach towards patients experiencing alterations or disturbances of consciousness and is also trying to communicate innovations in the field of psychiatric diagnostics.

[Society-research-diagnosis: have classification problems in psychiatry been overcome at the beginning of the new millennium?]. / Gesellschaft--Forschung--Diagnosen: Sind Klassifikationsprobleme in der Psychiatrie nach der Jahrtausendwende überwunden?

Although diagnostics of organic psychoses already had been quite well established at the beginning of the last century, no satisfactory results had been achieved in the field of functional psychoses. This led to a return towards the concept of "unitarian psychoses" and thus to a revival of cross-sectional diagnoses. With the development of psychopharmacological compounds the need for exact demarcation of disease grew. Around this time syndromatological classification systems that were supposed to be used internationally have been developed. In the course of the last thirty years the argument about the meaning of psychiatric diagnoses rose anew; the necessity of standardized means of psychiatric diagnoses was contrasted by the fact that there was no way of defining disease entities for clinical research. A polydiagnostic approach as well as clinical diagnose of the illness course--using single symptoms as predictors of the disease's course--could point to a solution.

An explicit no response instead of time-out in automated visual-field testing.

BACKGROUND: To evaluate the effect of response-acquisition technique on psychometric performance in visual-field testing, the conventional one-button yes/time-out method was compared with a two-button yes/no method for responding whether or not the stimulus was detected. There are a number of situations in which the single-button technique leads to ambiguous results. In this study, we thus expected the yes/no method to reduce tendencies towards habituation and automatic responding. Our hypothesis was that the two-button technique could reduce the rate of erroneous responses. METHODS: Luminance-difference sensitivity for bright stimuli (32') on a photopic background was evaluated at 26 locations within the central visual field (30 degrees) using a specially equalised video display unit and a modified 4/2-dB staircase strategy (six reversals, maximum-likelihood threshold estimation). Sixty-one ophthalmologically normal subjects (aged 20-30 years) were examined twice with each method. RESULTS: Mean sensitivities with the two-button yes/no method were found to be, on average, 0.13 dB above those measured with the one-button yes/time-out technique--a difference without clinical relevance. Within-subject variability did not differ between the two methods. However, the less intuitive two-button yes/no method had a slightly higher number of false responses in catch trials. CONCLUSION: Compared to the conventional one-button yes/time-out method, the two-button yes/no method in normal young subjects thus showed little difference in mean sensitivities and equivalent within-subject variabilities. Concerning our initial hypothesis, the yes/no method is of somewhat higher complexity and is not able to reduce the rate of erroneous responses. The one-button yes/time-out method fared a little better in error rate. In summary, the yes/no method is an alternative and additional possibility of response acquisition in visual-field testing, which is worthy of being tested in a clinical study with elderly subjects.

Cardiac output and central distribution of blood flow in the human fetus.

BACKGROUND: The objectives of this study were to establish reference ranges for left and right cardiac output and to investigate blood flow distribution through the foramen ovale, ductus arteriosus, and pulmonary bed in human fetuses. METHODS AND RESULTS: A prospective study was performed in 222 normal fetuses from 13 to 41 weeks of gestation with high-resolution color Doppler ultrasound. Cardiac output and ductal flow were calculated by use of vessel diameter and the time-velocity integral. Pulmonary blood flow was expressed as the difference between right cardiac output and ductal flow. Foramen ovale flow was estimated as the difference between pulmonary flow and left cardiac output. Gestational age-specific reference ranges are given for left, right, and biventricular output and volume of ductal blood flow, showing an exponential increase with gestational age. Median ratio of right to left cardiac output was 1.42 and was not associated with gestational age. Right cardiac output was 59% and left cardiac output was 41% of biventricular cardiac output. Median biventricular cardiac output was estimated to be 425 mL. min(-1). kg(-1) fetal weight. Ductal blood flow was 46%, estimated pulmonary flow was 11%, and estimated foramen ovale flow was 33% of biventricular output. CONCLUSIONS: The study establishes reference ranges for fetal cardiac output and offers insights into the central blood flow distribution in human fetuses from 13 weeks to term. There is a clear right heart dominance. The estimated ratio of pulmonary blood flow to cardiac output is higher than in fetal lamb studies.

The European acamprosate trials: conclusions for research and therapy.

In an excellent methodological approach, the European acamprosate study project showed that acamprosate increases sobriety times. In one randomized prospective study (n = 260) comparing acamprosate and placebo, with a 1-year treatment phase and 1-year follow-up phase, the authors found that acamprosate is effective only in Lesch type I and type II patients. To investigate the possible influence of diagnostic subgrouping, we applied the Lesch typology in a co-work with the main researchers of the UK study. The UK results concerning acamprosate's effects in the types do not mirror the Vienna results, but the numbers of type I and type II patients, retrospectively found as included in the UK centers, were too small for any conclusions. The distribution of the types points to the fact that too many type III and IV patients had been included to give acamprosate the chance to be effective. Following our typology and also these studies, we developed special treatment approaches. For relapse prevention studies, the cumulative abstinence duration together with the Lesch typology seems to be promising.

Does psychiatric comorbidity increase the length of stay in general hospitals?

Several studies reported that in non-psychiatric hospital departments mentally ill patients have a longer length of hospital stay than mentally well. But their methods are often limited because other predictors of length of stay were excluded from statistical analyses. Using the Clinical Interview Schedule, research psychiatrists interviewed 993 patients of medical, surgical, gynecological, and rehabilitation departments in Austria. Using several multiple regression analyses, the influence of psychiatric comorbidity and other variables on length of stay was analyzed. 32.2% of all patients suffered from psychiatric morbidity. Of all psychiatric cases, 6.2% received more than one psychiatric diagnosis. Presence of psychiatric disorders, age, a diagnosis of neoplasms, number of all somatic diagnoses, and the number of previous non-psychiatric hospital admissions predicted length of stay. Patients with dementia, with substance abuse disorders, and with alcohol- and drug-related psychiatric disorders showed a significantly increased length of stay, while other psychiatric diagnoses did not differ from the mentally well. Even after controlling for confounding variables, dementia and substance related diagnoses increase the length of hospital stay. It is important to investigate interventions for early recognition and treatment of these disorders.

30-item General Health Questionnaire in general hospitals: selecting items using a stepwise hierarchical procedure.

An attempt was made to improve the validity of the 30-item General Health Questionnaire by excluding items. This exclusion was performed by using correlations of sum-scores with an external case criterion. This hierarchical approach based on subsets of items (stepwise hierarchical variable selection) resulted in a 9-item questionnaire whose discriminating performance was significantly better than that of the original version.

Sensitivity and specificity of carbohydrate-deficient transferrin in drinking experiments and different patients.

Information provided by patients about the amounts of alcohol they drink may often be too subjective and therefore unreliable. Because of the possible serious consequences of interactions between alcohol and medication, reliable laboratory test markers for alcohol consumption are needed. Carbohydrate-deficient transferrin (CDT) is at present the best available objective measure of drinking behavior. During a withdrawal trial, 92 alcohol-dependent patients who had been admitted to a hospital in an ethanol-intoxicated state were monitored over the following 28 days by using the percent carbohydrate-deficient transferrin (%CDT of total transferrin) (%CDT) method. At the time of admission, 63% showed elevated %CDT levels. After a subsequent period of abstinence, a decrease in %CDT levels was apparent in four different groups of patients, whereas in two groups, comprising the greatest number of patients, normal %CDT levels were evident after 14 days of abstinence. In patients whose CDT levels were very high at study initiation, it took at least 21 to 28 days--and sometimes longer--for CDT to decrease to the radioimmunoassay (RIA) %CDT test cutoff point of 2.5. In a further study of 56 male alcohol-dependent patients, we measured liver enzyme concentrations, mean corpuscular volume (MCV), and four CDT variants on the first day of evidence of withdrawal syndrome. We found a significant correlation between results on the Munich Alcoholism Test (MALT) and MCV levels; among gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels; and among all four CDT variants. A cluster analysis yielded three clusters: (1) GGT, AST, and ALT levels; (2) MCV levels and MALT results; and (3) all CDT measurement variants. We conclude that these three clusters measure different detriments to the patient and that all available CDT variants are commensurate.

Blood flow velocity waveforms of the fetal pulmonary artery and the ductus arteriosus: reference ranges from 13 weeks to term.

OBJECTIVE: To establish reference ranges for blood flow velocity waveforms of the fetal main pulmonary artery and the ductus arteriosus during the second and third trimesters of pregnancy. METHODS: A prospective cross-sectional echocardiographic study was performed in 222 normal fetuses from 13 to 41 weeks of gestation using high resolution/color Doppler ultrasound equipment. RESULTS: Gestational age-specific reference ranges are given for peak velocity across the pulmonary valve, velocities in the ductus arteriosus, peak systolic velocity in the ductus arteriosus-to-peak velocity across the pulmonary valve ratio, ductal systolic velocity-to-diastolic velocity ratio, ductal resistance index and ductal pulsatility index. In the ductus arteriosus, increasing fetal heart rate was significantly associated with increasing end-diastolic velocity and decreasing systolic-to-diastolic ratio, decreasing resistance index, and decreasing pulsatility index. CONCLUSIONS: Based on a prospective study in more than 200 normal fetuses, the data provide gestational age specific reference ranges for blood flow velocity waveforms of the fetal pulmonary artery and the ductus arteriosus. The reference ranges may be helpful in prenatal diagnosis of cardiac malformations and ductal obstruction from 13 to 41 weeks of gestation.

Reference ranges for two-dimensional echocardiographic examination of the fetal ductus arteriosus.

OBJECTIVES: To establish reference ranges for 2D-echocardiographic examination of the fetal ductus arteriosus and its relationship to the main pulmonary artery and the aorta. METHODS: A prospective cross-sectional echocardiographic study was performed in 222 normal fetuses from 13 to 41 weeks of gestation using high resolution/color Doppler ultrasound equipment. RESULTS: Gestational age-specific reference ranges are given for the diameter of the pulmonary valve anulus, diameter of the ductus arteriosus at its beginning, middle, and end, ductal length, ductal diameter-to-pulmonary valve anulus diameter ratio, and the spatial relationship of the ductus arteriosus to the main pulmonary artery and to the aorta. CONCLUSIONS: The presented data derived from a study group of 222 normal fetuses provide in-vivo insights into the morphology of the ductus arteriosus and its relationship to the adjacent vessels. The reference ranges may be helpful in prenatal diagnosis of cardiac malformations and abnormalities of the ductus arteriosus, such as obstruction or aneurysm from 13 to 41 weeks of gestation.

[Does psychiatric comorbidity increase length of stay in medical, surgical and gynecological departments?]. / Sind die Aufenthaltsdauern von psychisch Kranken an internen, chirurgischen und gynäkologischen Abteilungen länger?

Several studies from Anglo-American countries indicate that in non-psychiatric hospital departments mentally ill patients have a longer length of hospital stay than mentally well, while in Austria and Germany, until now, no studies concerning this question exist. Therefore, we investigated the influence of psychiatric comorbidity on the length of stay in 608 patients of medical, surgical and gynecological departments in Vienna and Tyrol. Based on the Clinical Interview Schedule, 28.1% of the patients in this sample suffered from psychiatric disorders. The presence of psychiatric disorders, as well as type of hospital department (medical department), higher age, more previous non-psychiatric treatment periods, and more somatic diagnoses predicted a longer duration of inpatient treatment. To avoid the influence of cofounding variables, psychiatric cases were matched with psychiatric non-cases. The mentally ill group was treated for a markedly longer period as inpatients than the mentally well. Patients with a diagnosis of dementia or of substance abuse showed a significantly increased length of stay, while we could not confirm this for other psychiatric diagnoses.

[Uncomplicated obstetric injury as a risk factor for anal incontinence? Objective assessment of manometric measurements]. / Die unkomplizierte Geburtsverletzung als Risikofaktor analer Inkontinenz? Objektivierung durch manometrische Messungen.

The proximity of the anorectal sphincter apparatus and the vagina is a risk factor for faecal incontinence in women. To study the impact of the first delivery on anorectal continence, we evaluated 74 primiparae (41 women with midline episiotomy and 33 women with either intact perineum or Grade I tear only) and compared them to a control group of 18 nulliparous women. All subjects were examined by anorectal manometry and asked to complete a standardized questionnaire. Fourteen women of the primiparae group (eight patients with episiotomy, six pats. with intact perineum) had experienced incontinence of flatus, and 6 patients (8%, one pat. (3%) with intact perineum) had occasional incontinence of liquid or solid stool in the first weeks following delivery. We detected amongst those women who underwent episiotomy a significantly decreased maximum squeeze pressure and in women with an intact perineum a significantly decreased resting anal pressure. In all primiparae the anal canal length was significantly less when compared with control group. Even when the anal sphincter appears intact, the trauma of delivery causes detectable changes in the results of anorectal manometry, indicating a need for evaluation of the continence status at postpartum examination.