Challenges in Drug Design

Despite massive public and private investment in life sciences and the continual advances of molecular medicine, bringing new therapeutics to market has become an increasingly expensive and time-consuming endeavour. Hotly debated estimates of research and development costs for novel drugs range from 161 million dollar to around 4.5 billion dollars. The cost of developing drugs is largely due to the substantial proportion of failures of drug candidates throughout the development pipeline. Over the past 60 years, the ratio of new FDA approved drugs per billion US dollars spent has steadily declined. Currently, on average, more than twelve years pass between the first inception of a new experimental drug and that compound reaching the patient’s bedside. The lowest probability of success in drug development is seen for psychiatric disorders, likely as a consequence of the complex and only partially understood molecular mechanism underlying these diseases.

The drug discovery pipeline, which encompasses all the stages of drug design, preclinical testing, clinical trials (where the drug is tested on humans), and regulatory approval, is a lengthy and resource-intensive process that demands meticulous scrutiny at each step to identify potential dangerous side-effects and improve the chances of medical success. During the first decades of the twentieth century, chemicals with medicinal potential were discovered haphazardly, synthesised by dye-producing companies, tried out in rudimentary cell and animal experiments, and clinically tested on whichever (often non-suspecting) group of patients was available. Luckily, professionalism took over the field of pharmaceutical research and since the 1980’s and 1990’s drug discovery has relied strongly on lab-based target identification and automated experimental screenings of large, proprietary in-house chemical libraries of potential drug candidates.

Clinical trials are required to strictly follow guidelines from regulatory authorities in countries or regions where the drug candidate is intended to be registered and commercialised. Phase I clinical studies evaluate the basic safety of a drug candidate. Using the dose and method found to be the safest in Phase I studies, a small group of patients are given the new treatment in the Phase II study. Phase III studies enrol a large number of patients in double-blind tests that compare the safety and effectiveness of the new treatment against the current standard treatment or a placebo treatment. Unfortunately, up to 90% of drug candidates fail when they enter clinical studies, most often due to a lack of clinical efficacy, unacceptable toxicity levels, poor absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, or a lack of commercial value.