Repurposing historical control clinical trial data to provide safety context.

Billions of dollars spent, millions of subject-hours of clinical trial experience and an abundance of archived study-level data, yet why are historical data underutilized? We propose that historical data can be aggregated to provide safety, background incidence rate and context to improve the evaluation of new medicinal products. Here, we describe the development and application of the eControls database, which is derived from the control arms of studies of licensed products, and discuss the challenges and potential solutions to the proper application of historical data to help interpret product safety.

Creation and implementation of a historical controls database from randomized clinical trials.

Background: Ethical concerns about randomly assigning patients to suboptimal or placebo arms and the paucity of willing participants for randomization into control and experimental groups have renewed focus on the use of historical controls in clinical trials. Although databases of historical controls have been advocated, no published reports have described the technical and informatics issues involved in their creation.

Objective: To create a historical controls database by leveraging internal clinical trial data at Pfizer, focusing on patients who received only placebo in randomized controlled trials.

Prolonged NO treatment decreases alpha-adrenoreceptor agonist responsiveness in porcine pulmonary artery due to persistent soluble guanylyl cyclase activation.

A cultured porcine pulmonary artery (PA) model was used to examine the effects of prolonged nitric oxide (NO) treatment on the response of this vessel to acutely applied NO and to the alpha-adrenoreceptor agonist phenylephrine. Two-hour treatment with the NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO) decreased both NO and phenylephrine responsiveness. Twenty-four-hour treatment with DETA-NO resulted in a further reduction in NO responsiveness but no further reduction in phenylephrine responsiveness.

The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits.

Introduction: Biological and biophysical factors have been shown to play an important role in the initiation, progression, and rupture of intracranial aneurysms. The purpose of this study was to evaluate the association between hemodynamic forces and markers of vascular remodeling in elastase-induced saccular aneurysms in rabbits.

Methods: Elastase-induced aneurysms were created at the origin of the right common carotid artery in rabbits.

Endovascular treatment of experimental aneurysms by use of fibroblast-coated platinum coils: an angiographic and histopathologic study.

Background And Purpose: The purpose of this study was to determine whether implanting exogenous fibroblasts on platinum coils could enhance intra-aneurysmal fibrosis. Hypotheses included: (1) fibroblast-coated (FBC) platinum coils can improve angiographic results after embolization; and (2) FBC platinum coils can accelerate histological healing of embolized aneurysms.

Methods: Experimental aneurysms in rabbits were embolized with control platinum coils (n=18) or FBC coils (n=18).

Vascular anatomic variation in rabbits.

Purpose: To explore the vascular anatomic variation along the aortic arch in New Zealand White rabbits with the goal of highlighting potential anatomic configurations that might be encountered in the performance of preclinical endovascular research in rabbits.

Materials And Methods: Digital subtraction angiography images of the brachiocephalic artery (BCA) and aortic arch in New Zealand White rabbits were obtained after creation of elastase-induced aneurysms at the origin of the right common carotid artery (RCCA) in 214 animals. The patterns of origin of the RCCA and left common carotid artery (LCCA), right subclavian artery (RSCA) and left subclavian artery (LSCA), and right vertebral artery (RVA) and left vertebral artery (LVA) were analyzed.

Modified technique to create morphologically reproducible elastase-induced aneurysms in rabbits.

Introduction: The purpose of this study was to create morphologically reproducible elastase-induced model aneurysms in rabbits.

Methods: We created 120 elastase-induced aneurysms in rabbits using two different methods: the standard technique (group 1, n=62) and a modified technique (group 2, n=58). In the standard technique a small cutdown with a focal area of exposure of the mid-right common carotid artery (RCCA) was employed, while in the modified technique the RCCA was completely exposed to its origin.

Histopathologic and immunohistochemical comparison of human, rabbit, and swine aneurysms embolized with platinum coils.

Background And Purpose: The purpose of this study was to clarify the cellular mechanisms of aneurysmal healing by comparing histologic and immunohistochemical findings in experimental rabbit and swine aneurysms to a human aneurysm embolized with platinum coils.

Methods: Swine sidewall aneurysms (n = 5, harvested at 12 weeks) and elastase-induced rabbit aneurysms (n = 6, harvested at 24 weeks) were created and embolized. A single human aneurysm, embolized 6 years before death, was harvested following autopsy.

Can neck size in elastase-induced aneurysms be controlled? A prospective study.

Background And Purpose: An earlier retrospective study indicated that the neck size of elastase-induced aneurysms could be controlled by adjusting the position of the inflated balloon. We report the current prospective study to confirm our previous work.

Methods: Ninety elastase-induced aneurysms were created in rabbits.

Modified histologic technique for processing metallic coil-bearing tissue.

We developed a modified paraffin-embedding histologic technique for processing metallic coil-bearing aneurysm tissues. This modified technique was successfully employed for processing platinum coil-bearing tissue for 30 rabbit aneurysms and 6 swine aneurysms. This technique for sectioning coil-bearing aneurysms resulted in little or no tissue distortion and permitted good preservation of morphology and application of multiple advanced staining techniques.

Intra-venous digital subtraction angiography: an alternative method to intra-arterial digital subtraction angiography for experimental aneurysm imaging.

Conventional intra-arterial digital subtraction angiography (IADSA), which necessitates surgical exposure and ligation of the femoral artery, is an invasive and expensive method of evaluation for experimental elastase-induced aneurysms in rabbits. The purpose of this study was to examine and validate intra-venous digital subtraction angiography (IVDSA) as an alternative to IADSA by comparing their diagnostic accuracies. We performed both IVDSA and IADSA for 24 elastase-induced saccular aneurysms in a rabbit model, 1 month following creation.