Leveraging Bayesian Approach to Predict Drug Manufacturing Performance

Purpose

With increase in competition and regulatory requirements, the pharmaceutical and biotechnology industry has focused more resources on ensuring consistency and quality during manufacturing to minimize process deviations and batch failures. Specifically, computational tools are developed to monitor and predict manufacturing performance. The objective of this paper is to identify a process prediction tool, which can leverage available data to predict the performance of future production batches. Hence, if we suspect a process deviation in future batches, strategies can be developed in advance for risk mitigation.

Method

Critical process and quality attribute values for an upcoming manufacturing batch were predicted using both a conventional and Bayesian approach, by leveraging historical manufacturing data.

Result and Conclusion

Both approaches arrived at a similar prediction when a process performed consistently. However, when there was heterogeneity between the historical and current trends, the Bayesian approach was better at capturing the heterogeneity and thus enabling a more accurate prediction of future batch performance.

     

Comprehensive evaluation of cortical structure abnormalities in drug-naïve, adult patients with obsessive-compulsive disorder: A surface-based morphometry study

The study objective was to comprehensively evaluate drug-naïve, adult patients with Obsessive Compulsive Disorder (OCD) for cortical structure abnormalities in comparison with healthy controls. In this cross-sectional study of case–control design, Magnetic Resonance Imaging (1-mm) was performed in drug-naïve OCD patients (N = 50) &; age- sex-, education- and handedness-matched healthy controls (N = 40). We examined cortical volume, thickness, surface area &; local Gyrification Index (LGI) through a completely automated surface-based morphometric analysis using FreeSurfer software. OCD symptoms and insight were assessed using Yale-Brown Obsessive Compulsive Symptom (Y-BOCS) check-list and severity scale. Illness severity was assessed using Clinical Global Impression Severity (CGI-S) Scale. OCD patients had significantly deficient volume, thickness and surface area of right anterior cingulate gyrus (ACG). Right lingual gyrus surface area was found to be significantly decreased in patients. Y-BOCS obsession score had significant negative correlation with left frontal pole volume. Y-BOCS compulsion score had significant negative correlations with right ACG volume and surface area and right lateral orbitofrontal cortex LGI. CGI-Severity score had significant negative correlations with right lingual gyrus volume, thickness and surface area as well as right lateral orbitofrontal area. Y-BOCS insight score showed a significant negative correlation with LGI of left medial OFC and left rostral ACG. Identification of novel deficits involving occipital brain regions and first-time observations of relevant correlations between various illness characteristics and cortical measures in OCD patients supports a network involving anterior cingulate, orbitofrontal and occipital brain regions in the pathogenesis of OCD.     

Safety and Efficacy of Oral Transmucosal Fentanyl Citrate Compared to Morphine Sulphate Immediate Release Tablet in Management of Breakthrough Cancer Pain

Aim:

To compare the efficacy and safety of oral transmucosal fentanyl citrate (OTFC) and oral morphine in Indian patients with breakthrough episodes of cancer pain.

Materials and Methods:

In this randomized, open label, active controlled, clinical study, total 186 patients who regularly experienced 1-4 episodes of breakthrough cancer pain (BTCP) daily, over the persistent pain controlled by taking oral morphine 60 mg/day or its equivalent were randomized to receive either OTFC 200 mcg or oral morphine 10 mg for the treatment of BTCP for 3 days. Improvement in pain as determined by numerical rating scale (NRS) at 5, 15, 30, and 60 minutes of drug administration and percentage of BTCP episodes showing reduction in pain intensity by >33% at 15 minutes were primary efficacy endpoints. Secondary efficacy endpoints were requirement for rescue analgesia and global assessment by physician and patient. Data of both treatment groups were analysed by appropriate statistical test using software, STATISTICA, version 11.

Results:

Patients treated with OTFC experienced significantly greater improvement in pain intensity of breakthrough episodes compared to those treated with oral morphine at all assessment time points (P < 0.0001). 56% of breakthrough pain episodes treated with OTFC showed a greater than 33% reduction in pain intensity from baseline at 15 minutes compared to 39% episodes treated with oral morphine (P < 0.0001). Patient''s and physician''s global assessment favoured OTFC than oral morphine (P < 0.0001). Requirement of rescue analgesia in both the study groups was similar (P > 0.05). Both study drugs were well tolerated.

Conclusions:

OTFC was found to provide faster onset of analgesic effect than immediate release oral morphine in management of breakthrough cancer pain.     

Tumor vascular signals in renal masses: detection with Doppler US

The vascularity of 49 renal masses (26 malignant and 23 benign lesions) was investigated with duplex Doppler ultrasound. Doppler signals obtained at the margins of renal masses were defined as "tumor signals" when the Doppler-shifted frequency of the lesion exceeded the frequency shift in the ipsilateral main renal artery. These exceeded 2.5 kHz with a 3-MHz insonating frequency. Among the 26 renal masses that subsequently proved to be malignant, tumor signals were obtained in 15 of 18 (83%) untreated renal cell carcinomas, in three of four Wilms tumors, and in two patients with metastases to the kidney, but not in the one patient with lymphoma. None of the 23 benign renal masses demonstrated tumor signals. Tumor vascularity in malignant lesions gives rise to abnormal, high-velocity, Doppler-shifted signals that can help in the differential diagnosis of renal masses.     

Volume-selective water-suppressed proton spectra of human brain and muscle in vivo

Volume-selective water-suppressed proton spectra were recorded from live human brain and muscle at 1.5T by combining a stimulated echo acquisition mode pulse sequence for localization and two saturation pulses for water suppression (Frahm et al., SMRM Abstracts, 1987). Metabolite signals were observed in voxels of size 4-64 cm3. Signals from -CH3 and beta-CH2 of N-acetylaspartate, =N-CH3 and =N-CH2 of phosphocreatine/creatine, -N(CH3)3 of choline and inositol protons were visible in the brain spectra from normal subjects. Differences in metabolite levels were observed between gray and white matters of brain from their water-suppressed spectra. Peaks from =N-CH3 of phosphocreatine/creatine and -N(CH3)3 of choline and carnitine were present in normal muscle spectra along with several resonances from fatty acyl chains.     

Renal failure due to cholesterol embolisation

Five cases of cholesterol crystal embolisation resulting in impaired renal function are reported and their investigation and management discussed.     

A radiation hybrid map of the human genome

We have developed a panel of whole-genome radiation hybrids by fusing irradiated diploid human fibroblasts with recipient hamster cells. This panel of 168 cell lines has been typed with microsatellite markers of known genetic location. Of 711 AFM genetic markers 404 were selected to construct a robust framework map that spans all the autosomes and the X chromosome. To demonstrate the utility of the panel, 374 expressed sequence tags (ESTs) previously assigned to chromosomes 1, 2, 14 and 16 were localized on this map. All of these ESTs could be positioned by pairwise linkage to one of the framework markers with a LOD score of greater than 8. The whole genome radiation hybrid panel described here has been used as the starting material for the Genebridge4 panel that is being made widely available for genome mapping projects.      

Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders

BackgroundTranscranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects.ObjectiveWe convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson’s disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction.MethodsExperts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies.ResultsAlthough most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson’s disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy).ConclusionAll recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.