Why 90% of clinical drug development fails and how to improve it?

Abstract

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

Keywords: Clinical trial; Drug development; Drug optimization; Structure‒tissue exposure/selectivity relationship (STR); Structure‒tissue exposure/selectivity–activity relationship (STAR).

Graphical abstract

Figure 1

The process of drug discovery and development, and the failure rate at each step.

Figure 2

Structure‒tissue selectivity/exposure–activity relationship (STAR) selects better drug candidates and balances clinical dose/efficacy/toxicity to improve drug optimization for successful clinical drug development.

Figure 3

In vitro high-throughput screening tool to study the structure–tissue selectivity/exposure–activity relationship (STR). (A) Tissue diffusion chamber may provide an easy and high throughput screening to study structure‒tissue exposure/selectivity relationship (STR). (B) Single-organ chips, and (C) Body-on-a-Chip integrates multiple organ units to study STR in different organs.

Figure 4

Implementation of structure‒tissue selectivity/exposure–activity relationship (STAR) for lead compound selection in the current drug optimization process.