Applied Clinical Research, Clinical Trials and Regulatory Affairs - Volume 1, Issue 3, 2014

Missing data due to dropout of patients in randomized clinical trials may be potential sources of bias in the efficacy evaluation of investigational drugs. The biases may be severe when the presence of missing data is substantial. Over the last two decades, extensive research works on dealing with missing data in clinical trials were conducted by both the academicians and pharmaceutical industry statisticians. Majority of the research findings supported the use of Mixed Model Repeated Measure (MMRM) and Multiple Imputation (MI) ANCOVA analyses for efficacy evaluation of study drugs instead of using the conventional last observation carried forward (LOCF) approach to deal with missing at random (MAR) data in drug development research. However, there is a little evidence of exploring the impact of increases in the prevalence of missing data on biases in the statistical inferences obtained from MMRM and MI ANCOVA analyses. In this paper, an attempt is made to explore the impact of increases in the prevalence of missing data on the biases drawn from the above two approaches based on an extensive simulation study.

Fluoride use as a chemotherapeutic agent for caries prevention has been well researched and documented. The recommendations for the use of fluoride have evolved through the years as a result of many factors. The change in the prevalence of caries and the advent of different fluoride formulations along with the desire to maximize the benefits and minimize the side effects lead many authorities to set guidelines for the use of different formulations of fluoride. This review attempts to summarize the most current evidence-based guidelines of fluoride therapy put forth by various organizations worldwide. The review includes guidelines on community water fluoridation, fluoride supplements, fluoride toothpaste, professionally applied fluorides and fluoride mouth rinses.

Introduction: Limited data exist about the educational value of students performing a case based discussion (CbD) to a group of their peers. Aim: To evaluate the use of CbDs in a group format as an alternative to one on one CbDs. Methods: Foundation year one (FY1) doctors were invited to present a case that they had been involved in the care of to a group of their peers. The format would involve discussing the case and relating it to current literature followed by questions posed by the lead of the session first to the trainee then to the group. The trainees would then fill in a questionnaire about the process. Results: 13 trainees participated in the exercise. All agreed that this assessment had more educational value than the standard format of CbD. The most beneficial points about the experience were feedback, researching the topic and learning from others’ experiences. All trainees agreed that this assessment should be introduced into the foundation program. Conclusion: Presenting CbDs to a group could be educationally beneficial if added to the current foundation program.

Over the last 30 years – there is enormous expansion of pharmaceutical research and clinical trials in the quest for new and effective drugs [1]. Many advances are taking place in the area of clinical trials. Thousands of compounds undergo extensive clinical testing for every new chemical entity (NCE) that receives marketing approval [2]. Clinical trials are the backbone of human therapeutic development process and require careful planning and control to ensure clinical effectiveness and safety of patients [3]. Clinical trials are gaining high importance due to advancement in technology and invention of new molecules in healthcare sector. Each patient battling with a disease or managing a condition lives in the hope that tomorrow will bring a new medicine that delivers better health. Scientists and research companies all over the world are working relentlessly and untiringly to achieve the same goal of developing new drugs and medical devices that can prevent diseases, improve patients’ health, and save lives. Over the last decade, US - FDA has approved more than 300 new drugs and around 500 new medical devices [4, 5] – all this is possible only with a systematic and scientific approach in conducting the clinical trials.

Pricing is always important, because it facilitates growing of sales, and finally business. There is nothing like a magical pricing strategy. Nevertheless, we can get more money by actually adding some strategy flavor to our pricing. Pricing in the case of pharmaceuticals is unique, since while framing a strategy for it, the industry, the health authorities, pricing authorities, reimbursement authorities, physicians, insurance companies and regulatory government agencies to be considered. That is why always there comes a plethora of strategic questions, because at each stage of the Product lifecycle, roadmap for pricing needs to be strategically architected. The aim of this manuscript is to give the insight regarding the basics of pricing, concepts, uniqueness of pharmaceutical environment and tools which can help in formulating winning & smart pricing strategies. Along with that an attempt has been made to highlight the various life stages of the drug product and their relevance to pricing at each stage and the brief comparison of some drug price regulations among developed, and emerging nations.

Present day the biggest challenge faced by the pharmaceutical manufacturers is experiencing inspectional Food and Drug administration (FDA) 483’s, warning letters, import alerts and notice of violations from the regulatory authorities. The USFDA’s inspectional outcome has uncovered the retesting of drug ingredients that had failed quality testing, failure to establish corrective and preventive action following an investigation, procedural lapses etc. All these regulatory non-compliances triggered the FDA to issue warning letters, with holding of the product approval or plant shut-down because the US regulator has perceived violations to be of serious significance. Most experts warn that quality systems should focus on sustainability issues and assume that quality problems and regulatory non-compliances will be reduced as a result of the organized way of thinking, transparency, documentation and continuous evaluation of Quality Management System (QMS). QMS is a set of coordinated activities to direct and control an organization in order to continually improve the effectiveness and efficiency of its performance. It is designed and implemented to emphasize continuous improvement for state of compliance. QMS starts with recognizing that customers play a significant role in defining requirements as inputs and monitoring of customer satisfaction is necessary to evaluate and validate whether customer requirements have been met. QMS also lives in a dynamic regulatory environment of the registration and compliance requirements of global markets as well as inspections. As QMS is related to regulatory compliance and continuous inspection readiness, it shall maximize benefit to the organization by improving quality, increasing the yield, cutting costs and finally curbing FDA 483’s, warning letters and import alerts. The article details about the significance of QMS and its modules for effective regulatory compliance.

Biobetters are new biological entities, that are related to approved biologics by target or action, but they are intentionally altered to improve disposition, safety, efficacy, or manufacturing attributes. Due to the growing need for lower cost better versions of biological medicines, the markets for biobetters are rising. Regulatory authorities of many countries have precise technical standards and legal pathway for approval of synthetic drugs. The objective of the article is to view the different approaches taken by the ICH countries in regulating biobetters; strictly, there are no specific guidelines for biobetters but biosimilar guidelines are adopted. In March 2010, United States (US) passed the Biologics Price Competition and Innovation Act; but Europe had biologics approval process since 2005, while Japan since 2009. In US, it requires to provide clinical data of the drug for multiple years; same as provided by the innovator drug whereas in Europe it is not required to do so, but safety and efficacy data is required. The critical issue in biological with reference to small molecules (drugs), might be to influence doctors, other healthcare professionals and patients that biobetters have sufficient similarity to risk compared to existing biologics. A full preclinical package may be required unless to prove the differences between the biobetters and the innovator products are petite.

We report two cases of one previously healthy child and another known to have G6PD deficiency, who presented with desaturation despite their stable clinical appearance, which later was attributed to methemoglobinemia (MetHb) that was precipitated by fava beans ingestion. When hemolytic crisis occurs, certain G6PD deficient patients might develop cyanosis and show evidence of concurrent methemoglobinemia. In conclusion, Methemoglobinemia is a rare but important cause of persistently low saturation.