Taking a drug from the laboratory and preclinical testing arena into first-in-human studies and clinical trials represents the largest, most costly gamble in the drug discovery pipeline.
During this phase of development patient safety takes center stage and acquires quantifiable parameters, dosing may require some guesswork and trial-and-error, unexpected toxicities and off-target effects may arise, and the first real sense of how a compound will be processed, metabolized, made available to tissues and cells, and affect normal physiology and disease becomes evident.
About one-third of experimental drugs never make it past Phase I trials, and only about 13% of those that enter clinical testing receive market approval. Nearly two-thirds of drugs that make it past Phase II fail in late-stage studies, following a substantial investment of time, dollars, and resources.
De-risking clinical development involves minimizing the guesswork and removing as many unknowns as possible as early as possible. In conventional drug discovery, de-risking strategies typically focus on accumulating as much knowledge about a compound as one can during the discovery and preclinical testing stages.
This typically includes defining and validating a compound’s mechanism of action, validating the role of the intended target in a pathological pathway or disease process, and understanding its potential off-target activity. However, even the most rigorous efforts to thoroughly characterize a compound’s bioavailability, pharmacokinetics, and mechanism of action in even the most robust assays and animal models cannot ensure success or eliminate risk in clinical development.
Proof-of-principle and absence of toxicity in preclinical models do not necessarily translate to efficacy and safety in humans. Most animal models only approximate a disease state in humans, and physiology and pharmacokinetics may differ substantially.
When possible, therefore, the best approach for minimizing risk in clinical development is to select a drug that has a well-documented mechanism of action clearly associated with a positive therapeutic effect in the disease of interest. Potential candidates may be experimental compounds developed for other diseases that failed along the path to regulatory approval, although shown to be safe and to have the intended activity, which can be repurposed for a new indication.
Existing drugs can be tried in different clinical settings or patient populations, administered using alternative delivery methods, or be reformulated, given together with another therapeutic or targeting agent, or be combined with a medical device to improve delivery or dosing.