Mendelian Randomization Studies Promise to Shorten the Journey to FDA Approval.

There has been a dearth of new drugs approved for cardiovascular disorders. The cost is prohibitive, averaging to $2.5 billion, and requiring 12.5 years. This is in large part due to the high failure rate, with only 5% approval by the Food and Drug Administration. Despite preclinical studies showing potential safety and efficacy, most fail when they go to clinical trials phase I to III. One cause for failure is the drug target, often discovered to be a biomarker rather than causative for the disease. Mendelian randomization (MR) studies would determine whether the drug target is causative and could save millions of dollars and time, and prevent unnecessary exposure to adverse drug effects. This was demonstrated in 3 clinical trials that were negative with 2 drugs, veraspladib and darapladib. MR studies during the trials showed the targets of secretory and lipoprotein-associated phospholipids A2 are not causative for coronary artery disease and predicted negative results. The requirement for MR studies is a genetic risk variant with altered function, randomized at conception that remains fixed throughout one's lifetime. It is not confounded by dietary, lifestyle, or socioeconomic factors. It is more sensitive than randomized controlled trials because exposure to the risk factor is fixed for a lifetime. MR studies showed plasma high-density lipoprotein cholesterol is not a causative target of coronary artery disease, and neither is uric acid, C-reactive protein, and others. MR studies are highly sensitive in determining whether drug targets are causative, and are relatively easy, inexpensive, and not time consuming. It is recommended that drug targets undergo MR studies before proceeding to randomized controlled trials.