Improving academic leadership and oversight in large industry-sponsored clinical trials: the ARO-CRO model.

Standards for clinical trial design, execution, and publication have increased in recent years. However, the current structure for interaction among the pharmaceutical sponsor funding a drug or device development program, the contract research organization (CRO) that typically assists in executing the trial, regulatory agencies, and academicians, provides inadequate leadership and oversight of the development process. Conventional academic steering committees are not provided with the independent infrastructure by which to verify statistical analyses and conclusions regarding safety and efficacy. We propose an alternative approach centered on partnerships between CROs and university-based academic research organizations (AROs). In this model, the ARO takes responsibility for processes that address journal requirements and regulatory expectations for independent academic oversight (including oversight of Steering Committee and Data and Safety Monitoring Board activities), whereas the CRO provides infrastructure for efficient trial execution, site monitoring, and data management. The ARO engages academic experts throughout the trial process and minimizes conflicts of interest in individual industry relationships via diversification of sponsors, agents, and therapeutic areas. Although numerous models can be entertained, the ARO-CRO model is uniquely structured to meet the demand for greater assurance of integrity in clinical trials and the needs of each stakeholder in the process.

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art.

BACKGROUND: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. METHODS: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including "healthy volunteers", "Phase 1", and "normal volunteers", and also based on the authors' own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. RESULTS: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. CONCLUSION: Phase 1 studies can yield critical insights into the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

Lurasidone in post-menopausal females with major depressive disorder with mixed features: Post-hoc analysis of a placebo-controlled trial.

BACKGROUND: Several studies have found that depressed, post-menopausal females may respond differently to antidepressants compared to pre-menopausal females. The atypical antipsychotic lurasidone, whose mechanism of action differs from SSRIs and other standard antidepressants, was shown in a 6-week randomized, flexible-dose, placebo-controlled study (n=209), to be effective in treating major depressive disorder (MDD) with mixed features (subthreshold hypomanic symptoms). This post-hoc analysis assessed the efficacy of lurasidone in this study by menopausal status. METHODS: The main outcome measure for this post-hoc analysis was change in MADRS score from baseline to week 6 endpoint for two lurasidone-treated subgroups: presumptive pre-menopausal (<52years) and presumptive post-menopausal (≥52years) patients, compared to placebo treatment, using a mixed-model for repeated-measures analysis, and calculation of the effect size for each subgroup. Additional efficacy assessments included the CGI-S, HAM-A and YMRS. An exploratory analysis was also conducted removing presumptive peri-menopausal women (ages 45-51years) to allow for clearer definition of pre- and post-menopausal status. RESULTS: A total of 56 lurasidone-treated and 47 placebo-treated pre-menopausal females, and 17 lurasidone-treated and 25 placebo-treated post-menopausal females were available from the larger study for comparison on key outcome measures. The pre- and post-menopausal subgroups had similar demographic and clinical characteristics at study baseline (other than age), including number of past major depressive episodes as well as depressive and manic symptom severity. Mean daily lurasidone dose was similar for each subgroup during the study. Both the primary and exploratory analyses showed that both lurasidone-treated post-menopausal and pre-menopausal females responded significantly compared to placebo (p=0.016 or less) on the MADRS, and that post-menopausal patients had a numerically larger response (effect size=0.96) than pre-menopausal patients (effect size=0.64). All other secondary outcome measures for lurasidone compared with placebo treatment were significant (p=0.045 or less) for both subgroups. CONCLUSIONS: In this post-hoc analysis, lurasidone was found to be effective in treating post-menopausal MDD patients with mixed features (subthreshold hypomanic symptoms).

Sex differences in the psychopharmacological treatment of depression.

Although a number of studies have observed that females respond better to serotonergic antidepressants than males and that postmenopausal females have a diminished response to antidepressants compared with younger females, there are also studies that conflict with both of these findings, making any generalizations regarding sex differences difficult to make. Sex variance in antidepressant efficacy and pharmacokinetics profiles have been attributed to sex-based physiological differences, behavioral differences, related disorders, and sex-specific conditions, including pregnancy and menopause. This paper will review the history and current research on sex effects of antidepressant treatment.

Aunque varios estudios han mostrado que las mujeres responden mejor a los antidepresivos serotoninérgicos que los hombres y que las mujeres postmenopáusicas tienen una respuesta disminuida a los antidepresivos en comparación con las mujeres más jóvenes, también hay estudios que cuestionan estos hallazgos, con lo que se hace difícil plantear algunas generalizaciones respecto a las diferencias por sexo. Las variaciones por sexo en cuanto a la eficacia antidepresiva y los perfiles farmacocinéticos han sido atribuidas a diferencias fisiológicas basadas en el sexo, diferencias conductuales, trastornos relacionados, y condiciones específicas del sexo incluyendo el embarazo y la menopausia. Este artículo revisará la historia y la investigación actual acerca de los efectos del sexo en el tratamiento antidepresivo.

De nombreuses études ont constaté une meilleure réponse aux antidépresseurs sérotoninergiques chez les femmes que chez les hommes et une réponse diminuée aux antidépresseurs chez les femmes ménopausées comparées aux femmes plus jeunes, . mais dD'autres études contredisent ces résultats, et il il est donc difficile de généraliser sur les différences selon le sexe. La variance bilité deselon le sexe de l'efficacité des antidépresseurs sive et dess profils pharmacocinétiques selon le sexe a été attribuée aux différences physiologiques, et comportementales selon liées aule sexe, aux troubles qui y sont liés et aux à des états spécifiques du sexe comme la grossesse et la ménopause. Nous analysons dans cet article l'historique et la recherche actuelle sur les effets du des traitements antidépresseurs selon le sexe.

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects.

INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Bivariate evaluation of thromboembolism and bleeding in clinical trials of anticoagulants in patients with atrial fibrillation.

Clinical trials of antithrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 71,683 patients for prevention of thromboembolic events (TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing corners of the confidence rectangle (termed "corner distance (CD)"). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI: -0.56 % to -0.05 %) and reduced major bleeding by 0.88 % (95 % CI: -1.26 % to -0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = -0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = -2.07 % to -0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.

Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type.

OBJECTIVE: To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg. DESIGN AND SETTING: Randomised, two-period crossover, single-centre, non-blinded, inpatient study. PATIENTS AND PARTICIPANTS: Eleven patients (five females and six males) with mean age 69.5 years. METHODS: The 6 mg oral dose was compared with a 2 mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method. RESULTS: Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration. CONCLUSION: A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6 mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics..

Generalised anxiety disorder: treatment options.

In recent years generalised anxiety disorder (GAD) has become a much better defined disorder, with specific criteria distinguishing it from the other anxiety disorders; however, it still lacks the same public and scientific interests as some of the other anxiety disorders such as panic and social phobia. Nevertheless, refinement in the treatment of GAD is becoming more evident through the conduct of clinical trials. Up until the mid-1980's, treatment consisted primarily of benzodiazepines. However, as a result of growing characterisation of their abuse potential, other therapeutic options were explored. Benzodiazepines became seen as an effective short-term therapy, and buspirone and some of the newer antidepressants have become the treatment of choice for patients with GAD requiring long-term treatment. Buspirone was the first available alternative to the benzodiazepines in the US; however, the initial excitement over this agent was somewhat dampened because of its mild efficacy combined with a slow onset of action. The antidepressants were seen as beneficial for the treatment of GAD because of the high comorbidity with depression, thus allowing a better outcome for these patients. The antidepressants that offer both a good adverse effect profile and efficacy are the selective serotonin reuptake inhibitors including paroxetine, and the serotonin-norepinephrine reuptake inhibitors such as venlafaxine. Clinicians should also consider the potential benefits of psychotherapy as an adjunct to medication. There are a number of potentially new pharmacotherapies being investigated, including newer serotonin 5-HT1A receptor agonists, cholecystokinin receptor antagonists, neurokinin receptor antagonists, gabapentin and its analogues, and gamma-aminobutyric acid (GABA)A receptor modulators. However, these compounds are all in the early stages of investigation, and there are no new therapies expected to be released in the near future. Nonetheless, in the search for the ideal anxiolytic, a more positive outlook is allowed by imminent future research for new treatment options in patients with GAD.

Galantamine hydrobromide: an agent for Alzheimer's disease.

The pharmacology, dosage, adverse effects, efficacy, and economics of galantamine hydrobromide are discussed. Galantamine hydrobromide is a tertiary alkaloid that has been extracted from plant sources and is now synthesized for use in the treatment of mild to moderate Alzheimer's disease (AD). Galantamine acts both as a reversible competitive inhibitor of acetylcholinesterase (AChE) and as an allosteric modulator of nicotinic acetylcholine receptors. The recommended starting dosage is 4 mg (as the hydrobromide) twice daily. The dosage should be increased in increments of 8 mg/day in two divided doses after four weeks at a given dosage until a maintenance dosage of 16-24 mg/day in two divided doses is reached. Adverse effects are primarily mild and cholinergic and include nausea, vomiting, diarrhea, and dizziness. Five large clinical trials demonstrated that galantamine is more effective than placebo in controlling the symptoms of mild to moderate AD. Optimal therapy appears to require early initiation of the drug and a dosage-adjustment period of eight weeks. In one study, galantamine delayed full-time care by 10% and reduced the overall cost of care by $528. Because galantamine has not yet been compared directly with other AChE inhibitors, cost should be the principal factor weighed during formulary evaluations. Galantamine provides the clinician with another choice of an AChE inhibitor for use in treating AD.

The impact of gender on antidepressants.

There is a large body of literature debating whether and how gender affects the metabolism, side-effect profile, and efficacy of antidepressants. Gender differences in antidepressant pharmacokinetics and efficacy profiles have been attributed to not only anatomic and physiological differences between the sexes, but also behavioral factors, comorbid disorders, and gender-specific conditions, such as pregnancy and menopause. Despite the large body of research on this topic, few definitive conclusions regarding effects of gender on antidepressant treatment exist, and much of this research is incomplete, contradictory, or not fully used to optimize the administration of antidepressants and the response to treatment. This chapter will review the latest research on gender-specific effects of antidepressant treatment, focusing on the overall, gender-related differences in efficacy, metabolism, and side-effect profile of antidepressants, and how these differences can be used to better optimize treatment of depression in a clinical setting.

A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition.

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa.

OBJECTIVE: To investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the dopamine transporter antagonist brasofensine (BMS-204756) in patients with Parkinson's disease receiving levodopa/carbidopa treatment. METHODS: A 4-period crossover study was performed in 8 men (mean age 66 y) with moderate Parkinson's disease (Hoehn-Yahr stage II-IV). A dose escalation study was used in which each patient was given a single oral dose of brasofensine 0.5, 1, 2, or 4 mg, which was coadministered with the patient's usual dose of levodopa/carbidopa. RESULTS: The maximum concentration (Cmax) values of brasofensine observed in plasma after oral administration were 0.35, 0.82, 2.14, and 3.27 ng/mL for the 0.5-, 1-, 2-, and 4-mg doses, respectively; these concentrations occurred 4 hours (time to Cmax) after administration in all cases. Exposure to brasofensine (based on AUC0-infinity) increased at a rate greater than proportional to dose. Based on the motor performance subscale of the Unified Parkinson's Disease Rating Scale, no change in patient disability was observed at any dose level. CONCLUSIONS: Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.