In Silico Clinical Trials: Is It Possible?

Modeling and simulation (M&S), including in silico (clinical) trials, helps accelerate drug research and development and reduce costs and have coined the term "model-informed drug development (MIDD)." Data-driven, inferential approaches are now becoming increasingly complemented by emerging complex physiologically and knowledge-based disease (and drug) models, but differ in setup, bottlenecks, data requirements, and applications (also reminiscent of the different scientific communities they arose from). At the same time, and within the MIDD landscape, regulators and drug developers start to embrace in silico trials as a potential tool to refine, reduce, and ultimately replace clinical trials.

Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Health technology assessment (HTA) aims to be a systematic, transparent, unbiased synthesis of clinical efficacy, safety, and value of medical products (MPs) to help policymakers, payers, clinicians, and industry to make informed decisions. The evidence available for HTA has gaps-impeding timely prediction of the individual long-term effect in real clinical practice. Also, appraisal of an MP needs cross-stakeholder communication and engagement.

Investigation of mixed model repeated measures analyses and non-linear random coefficient models in the context of long-term efficacy data.

The longitudinal data from 2 published clinical trials in adult subjects with upper limb spasticity (a randomized placebo-controlled study [NCT01313299] and its long-term open-label extension [NCT01313312]) were combined. Their study designs involved repeat intramuscular injections of abobotulinumtoxinA (Dysport®), and efficacy endpoints were collected accordingly. With the objective of characterizing the pattern of response across cycles, Mixed Model Repeated Measures analyses and Non-Linear Random Coefficient (NLRC) analyses were performed and their results compared.

Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial.

Background: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA.

Objectives: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia.

AbobotulinumtoxinA for Equinus Foot Deformity in Cerebral Palsy: A Randomized Controlled Trial.

Background: Although botulinum toxin is a well-established treatment of focal spasticity in cerebral palsy, most trials have been small, and few have simultaneously assessed measures of muscle tone and clinical benefit.

Methods: Global, randomized, controlled study to assess the efficacy and safety of abobotulinumtoxinA versus placebo in cerebral palsy children with dynamic equinus foot deformity. Patients were randomized (1:1:1) to abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injections into the gastrocnemius-soleus complex (1 or both legs injected).

Angiogenic gene therapy does not cause retinal pathology.

Background: The potential negative influence of angiogenic gene therapy on the development or progression of retinal pathologies such as diabetic retinopathy (DR) or age-related macular degeneration (AMD) has led to the systematic exclusion of affected patients from trials. We investigated the role of nonviral fibroblast factor 1 (NV1FGF) in two phase II, multinational, double-blind, randomized, placebo-controlled, gene therapy trials (TALISMAN 201 and 211).

Methods: One hundred and fifty-two subjects with critical limb ischemia or claudication were randomized to receive eight intramuscular injections of 2.

Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study.

Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis.

Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH.

Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer.

Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.

Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases.

Minimal effective dose of dysport and botox in a rat model of neurogenic detrusor overactivity.

Background: Two botulinum toxins A have been evaluated for the treatment of refractory neurogenic detrusor overactivity (NDO) in humans: Dysport (abobotulinumtoxinA) and Botox (onabotulinumtoxinA). However, these two distinct commercialized products have different potency units and are not interchangeable.

Objective: Assessment of the dose response and determination of minimal effective dose (MED) for Dysport and Botox in spinal cord-injured (SCI) rats with NDO.

Therapeutic Angiogenesis With Intramuscular NV1FGF Improves Amputation-free Survival in Patients With Critical Limb Ischemia.

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.

Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia.

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.

Does the prognosis of cardiac arrest differ in trauma patients?

Objective: It is proposed to not resuscitate trauma patients who have a cardiac arrest outside the hospital because they are assumed to have a dismal prognosis. Our aim was to compare the outcome of patients with traumatic or nontraumatic ("medical") out-of-hospital cardiac arrest.

Design: Cohort analysis of patients with out-of-hospital cardiac arrest included in the European Epinephrine Study Group's trial comparing high vs.