Multiple Endpoints are Used as a Measure While Evaluating Clinical Trials for Cardiovascular Disorders

Monday 20 February 2012, Amsterdam

The report examines different aspects under clinical trial endpoints in cardiovascular disorders such as analysis on major marketed Cardiovascular drugs with an emphasis on safety and efficacy details, Phase II and Phase III clinical trial analysis for both completed and ongoing clinical trials, most promising

Cardiovascular drugs with details on safety, efficacy and clinical trials, and terminated trial analysis. The company profiling highlights the cardiovascular drugs of different companies. Cardiovascular disorders represent a collective group of disorders that affect the functioning of the heart and the blood vessels. These disorders are one the most prevalent group of disorders in the world today, and represent a significant proportion of the total global diseased population. Most of them cause significant morbidity and disability.

The global cardiovascular therapeutics market was valued at $93.5 billion in 2010 and expected to reach revenues of $115.6 billion by 2017, with a CAGR of 3.1%. Approximately 127 million patients received pharmacological treatment for their cardiovascular diseases in 2011 with the average cost of therapy being $596 per year. In addition, the average annual cost of therapy for the cardiovascular diseases therapeutic area appears likely to increase at a gradual rate over the next one to two years with an expected price decline from 2011 onwards.

This report details endpoints in clinical trials for cardiovascular disorders, highlighting the five major cardiovascular disorders, which are atherosclerosis, atrial fibrillation, dyslipidemia, hypertension and venous thromboembolism. The classification of five major cardiovascular diseases is done on the basis of the number of pipeline molecules present in Phase III of development.

The term endpoint refers to an outcome or measure of a clinical trial. Endpoints can include all kinds of aspects, such as those related to the effectiveness of treatment, and others. However, endpoint selection must take into account the need to obtain the highest information of therapeutic interest with the least risk and discomfort for the individual. The endpoints must also be important to the objective of the study and represent the most effective way to assess pharmacological response.

Use of Surrogate Endpoints and Biomarkers for the Assessment of ClinicalTrials Designed for Cardiovascular Disorders

The majority of clinical trials for cardiovascular disorders employ surrogate endpoints and clinical biomarkers as substitutes for clinical outcomes. The selection of such biomarkers is based on the relationship with the clinically relevant endpoint. Most of the biomarkers and surrogate endpoints used in clinical trials for cardiovascular disorders include measurement of lipid level parameters such as changes in Low Density Lipoproteins-Cholesterol (LDL-C), High Density Lipoproteins-Cholesterol (HDL-C), and Total Cholesterol (TC), among others; and changes in blood pressure (both systolic and diastolic) measured in various positions, such as sitting, supine and standing. Regulatory authorities believe that these are very closely linked to the clinical outcome so that these are considered to be valid primary variables in pivotal clinical trials and can act as a substitute for a hard clinical endpoint during the marketing authorization process.

Multiple Endpoints are Used as a Measure While Evaluating Clinical Trials for Cardiovascular Disorders

See figure: Endpoints - Clinical Trials in Cardiovascular Disorders, Number of Trials with Multiple Endpoints as Against Total Number of Trials

Use of multiple endpoints is seen in the five indications studied in the cardiovascular disorder segment. This is due to fact that most of the clinical states are inter-dependent and as a result it becomes important to study more than one or two endpoints. Except for atherosclerosis, which has only about 20% of the trials measured with multiple endpoints, the other four indications have more than 50% of the trials which are measured by multiple endpoints.

Safety and Efficacy Issues, Failure to Meet Primary and Secondary Endpoints Led to Discontinuation of Most of the Drugs

Sanofi was engaged in the development of Acomplia (SR141716). Acomplia was under investigation for the treatment of dyslipidemia, diabetes mellitus type 2, atherosclerosis, coronary disease and smoking cessation. Acomplia was approved in Europe for treating obesity in 2006. In October 23, 2008, the European Medicines Agency (EMEA) recommended to the European Commission (EC) the temporary suspension of the marketing authorization of Acomplia for the approved indication of overweight and obese patients. The marketing authorization for Acomplia has been suspended due to concerns about its psychiatric safety. In November 2008, Sanofi decided to discontinue the ongoing rimonabant clinical development program in all indications. The company decision was taken in light of demands by certain national health authorities. The drug candidate was tested in multiple Phase III and II trials for the treatment of dyslipidemia, nonalcoholic steatohepatitis (NASH), obesity, diabetes mellitus type 2 and smoking cessation.

Penwest Pharmaceuticals Co. terminated the development of PW2101 for the treatment of hypertension and angina. On June 29, 2005 the company announced that the US Food and Drug Administration (FDA issued a non-approvable letter for the company's New Drug Application (NDA) for PW2101, a beta blocker intended for the treatment of hypertension and angina. In its letter, the FDA stated that the NDA was non-approvable due to, among other things, the degree of kinetic variability of PW2101 observed among individuals and because beta blockade as a surrogate for efficacy was not demonstrated across the entire inter-dosing interval on an individual subject basis.