Applied Clinical Research, Clinical Trials and Regulatory Affairs - Volume 3, Issue 2, 2016

Worldwide, every year is described 9 million of new cases of pulmonary tuberculosis (PTB) and this disease is responsible for 1.5 million deaths. The main causative agent of PTB is Mycobacterium tuberculosis (MTB). The bacillus has a cell wall rich in lipids and shows very slow growth, which raises difficulties to the execution of cultivation methods. Although the cases and deaths are still high, progress is being made aiming to reduce the incidence and prevalence of PTB due to new methods of diagnosis and more efficient treatments. One of the main challenges for the control of PTB is the high proportion of false negative results and extended time for obtaining diagnostics, which contributes for the spreading of the disease. The aim of this review was to approach the main methods of laboratory diagnostics for active human pulmonary tuberculosis, focusing on bacteriological, immunological, molecular and imaging methods.

Background: Regulation of drugs across the world has been a crucial component in providing quality products around the globe. Henceforth different drug administrative powers are moving forward for initiating better regulatory framework which will lead to easier differentiation of superior medicinal products to that of sub-standard ones. For this purpose legitimate dossier preparation becomes essential so that a worthy drug gets registered with better evaluation process instead of getting rejected due to various hindrances. The pharmaceutical markets are established all around the world depending upon the qualitative and complexity of the regulations implied and as a result it has been divided into regulated and emerging markets. Amongst the emerging markets, Africa is considered as long term opportunity for pharmaceutical investment, with GDP of $ 2.9 trillion. This article provides a detailed comparative study of the specifications to be noted during generic drug registration documentation in African region emphasizing more on Kenya, Ghana, Botswana, and Nigeria. Hence this article will ultimately lead to a clearer view of dossier registration variations within these regions and will help in systematic acceptance of essential medicines for more prominent purposes in near future. Conclusion: Comparative finding of regulatory requirements in African countries provide with the understanding of variations which are to be considered during drug registration in such countries despite the fact that harmonization is taking place at an extensive pace. It can also be concluded that African countries are rapidly developing their regulatory needs for compliance with stringent authorities with concern of procuring better health products.

Background: Older patients with diabetes require a provider to consider health status and the ability to self-manage with concomitant morbidities. Careful insight into pharmacotherapy regimens that offer the best profile with appropriate efficacy is critical. Diabetes is a common disorder that is often undertreated in the elderly because of the concern for hypoglycemia. A review of the literature and if newer basal insulin formulations cause less hypoglycemia was assessed. Methods: We reviewed published society guidelines for older patients with diabetes targeting specific A1C treatment goals. The pharmacokinetic and pharmacodynamic profiles of two new basal insulin therapies and their use in older populations were also evaluated. The overall experience with hypoglycemia and the action profile of newer basal insulins, including insulin degludec and concentrated insulin glargine, are described. Results: Goals for A1C in older adults should be individualized based on patient characteristics and factors including chronic illnesses, activities of daily living, cognitive impairment and life expectancy. In older patients, intensive insulin dosing may be challenging due to a higher risk of hypoglycemia. Newer basal insulin therapies provide a safe option for daily dosing of insulin and less hypoglycemia compared to traditional insulin choices. Conclusion: Diabetes is a common disorder among the elderly and insulin is a viable therapy that has to be individualized and adequately monitored to prevent untoward risks of hypoglycemia. Newer basal insulins, if affordable for the patient, offer another choice for therapy.

Background: In this era of evolution, quality and safety of pharmaceutical dosage forms have been given a prime importance. In this context, a detailed knowledge about physical and chemical properties of excipients is not sufficient, but information about safety and regulatory status of these materials is now essential to know. The present work will be beneficial to focus more on the safety, quality and stability of pharmaceutical product. Objective: Study of regulatory mechanism for pharmaceutical excipients in US, Europe and Japan. Method: As an initial step, information about the history and general regulatory perspectives of each country was gathered and referred. After that the different regulatory mechanisms for pharmaceutical excipients in regulated market were understood from data obtained from the above sources and conclusion was made from that. Results & Conclusion: Excipients are crucial element of pharmaceutical dosage form so they should be regulated to minimize risk. This article presents a current regulatory mechanism for pharmaceutical excipients in regulated market like US, Europe and Japan. According to the regulative point of view, concern relating to the excipients involves Good Manufacturing Practices, Toxicity, Safety, Quality Assurance, Stability, Labeling and Approval regulations. This article also overviews the guidance documents published by the IPEC for regulating excipients which is helpful to harmonize regulatory standards of excipients & enhance development of excipients with introduction of novel excipients.

Background: In many African countries, cultural practices along with deteriorating economic conditions have resulted increases in the number of cases of domestic violence. Furthermore, high levels of gender equality has contributed to a normative climate of acceptance and justification of domestic violence. The primary purpose of this study is to examine the relationship between women’s autonomy and justification for domestic violence among women in Zambia. Method: The Demographic Health Survey (DHS) data for Zambia (2008) was used. Confirmatory factor analysis (CFA) was conducted to develop a scale of women’s autonomy. Logistic regression was conducted to examine the predictors of justification for domestic violence. Results: Logistic regression results show that two indicators of women’s autonomy, low levels of education and high degree of spouse control significantly increase the odds of justification for domestic violence. Conclusion: The scale developed in this study to measure women’s autonomy in Zambia will have to be validated for several other African countries. The items that constitute the scale suggest directions for interventions to empower women.

Background: Drug eluting stents (DES) are the most frequently used devices during coronary interventions. Bioresorbable vascular scaffold (BVS) were developed to circumvent some of the limitations of DES. Worldwide, there is very limited experience with this device. The aim of our study was to see the initial challenges encountered by a single center while using this new device. Methods: We implanted a total of 24 BVS in 17 patients. These patients were followed for a two-year period. All patients received similar, standard of care adjunctive medical therapy. Clinical conditions that necessitated BVS usage were ST elevation myocardial infarction (STEMI), Non STEMI and acute coronary syndromes (ACS). Results: We encountered a high complication rate. Acute and late scaffold thrombosis was seen in four patients. Death or major bleeding was not seen. Patients with and without complications were compared for their coronary artery disease (CAD) risk factors, angiographic characteristics and laboratory data. No difference was detected in their CAD risk factors or metabolic investigations. In all patients post dilation after scaffold deployment was not performed as per industry recommendation at that time. Conclusion: This small study gives insights into potential challenges that centers may face adapting this new technology. Larger randomized trials with long-term follow-up are needed.

Background: Negative bionmial regression is a common statistical model for analyzing count data. For example, hypoglycemic events occurred in clinical trials studying anti-diabetes therapies are often analyzed using negative binomial regression. Recently, methods have been developed for calculating statistical power and sample size needed for negative binomial regression with a common shape parameter across treatment groups. Real data examples suggest that the shape parameters are often distinct when the hypoglycemia event rates between two treatment groups are different. This article extended the existing method of negative binomial regression for distinct shape parameters. Methods: Three new methods are proposed for sample size calculation based on estimating the variance under null hypothesis: (1). Using the true rate and shape parameter based on the reference group; (2) Using the true rates and shape parameters under the alternative hypothesis; (3). Using the true shape parameters under alternative hypothesis and maximum likelihood estmator for the rate under the null hypothesis. Results: Simulations were performed for various mean and shape parameters based on previous publications and based on hypoglycemic events data from clinical trials in diabetes. Results show that Methods (2) and (3) provided satisfactory estimation of sample size in which the simulated statistical power approximated the desired statistical power. In each case, the analysed sample size based on Method 2 was not smaller than the sample size based on Method 1. Conclusion: Two methods for estimating the statistical power using negative binomial regression with distinct shape parameters are proposed and simulations show that they had satistifactory performance.

Background: Joint hypermobility syndrome (JHS) is one of the most common heritable genetic disorders of connective tissue, characterised by excessive joint range of motion and the presence of musculoskeletal symptoms. Prevalence estimates of JHS range from 5% to 18% and vary with gender, age and ethnicity. JHS is associated with generalised joint laxity, joint instability, motion incoordination, decreased joint position sense, and musculoskeletal pain. The research evidence-base for treating lower limb symptoms in JHS is increasing. This paper outlines a protocol for a systematic review of the evidence for physical and mechanical treatments for lower limb problems in children with JHS. Methods/Design: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PUBMED and CINAHL will be searched for randomised controlled trials and quasirandomised controlled trials investigating physical and mechanical interventions for lower limb problems in children with JHS. Two authors will independently screen studies for eligibility for inclusion and will assess risk of bias of included studies. One author will extract and analyse statistical data, which will be checked by the second author. Discussion: The systematic review aims to establish the best-practice use of physical and mechanical interventions for lower limb complications of JHS in children and to highlight the areas of greatest need for future research.

Background: In situ gel is a type of floating polymeric formulation that is in solution form before administration, but undergoes gelation in situ to form a gel upon contact with physiological fluids. Objective: The objective of present study was to design and evaluate sustained release in situ gel suspension of Glimepiride (GLP) and compare it with marketed formulation. Method: Different formulations of GLP were prepared using different concentration of gelling agents, like sodium alginate and calcium carbonate. Polysorbate 80 was used as wetting agent and sodium citrate was included to prevent gelation outside the gastric environment. Optimization was done using ‘32’ randomized full factorial designs. The formulation was evaluated for different parameters including rheological parameter, Particle size, sedimentation rate, in vitro gelling ability, in vitro drug release study and floating ability. Pharmacokinetic study was conducted on Wistar rats for testing of bioequivalance. A single blind study was performed for taste test in human volunteers. Result: The suspension demonstrated a pseudo-plastic behavior with instant gelation. The in situ gelling suspension showed drug release of 99.85% in 12 h. Formulations were floating for more than 12 h. Conclusion: Thus, sustained release floating drug delivery system (FDDS) of in situ gelling suspension of GLP was formulated having sustained drug action for 12 h. Inferences drawn from in vitro and preliminary in vivo studies suggest that in situ gel is a potential delivery system for GLP for improving bioavailability in comparison with marketed formulation.

The present investigation aims at development of spray-dried microspheres for formulation of roxithromycin dispersible tablets. The spray drying process was optimized using a central composite design to study the effect of two critical variables - amount of polymer Eudargit EPO® (X1) and inlet temperature (X2) on entrapment efficiency of drug and percentage cumulative drug release (% CDR). The maximum entrapment efficiency and % CDR was found at high values of inlet temperature and high level of polymer concentration. A drug entrapment efficiency of about 58.48 % (w/w), loading capacity of 64.22% (w/w), 94.26% CDR and particle size of 615 nm were achieved for the optimized batch RMS-3 of roxithromycin microspheres. ANOVA was applied to entrapment effeciency and % CDR to study the fitting and the significance of the model. The model estimated using present study has utility as response surface for cumulative percent of drug release from microspheres. The spray dried optimized microspheres were further formulated into dispersible tablets using direct compression method. The prepared tablets were evaluated for different parameters and the results obtained were found to be within the pharmacopoeial limits. The developed dispersible tablets showed better taste profile when compared with the marketed formulation and were found to be stable.