Drug discovery safety testing

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

Fung, M., Thornton, A., Mybeck, K., Hsiao-Hui, W., Hornbuckle, K. and Muniz, E. (2001) Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets - 1960-1999. Drug Information Journal, 35, 293—317. Dykens, J.A. and Will, Y. (2007) The significance of mitochondrial toxicity testing in drug development. Drug Discovery Today, 12, 777-785. 

In drug discovery, specific enzymes or receptors are first targeted for drug action. The earliest experiments use chemistry to synthesize drugs experimental animals to test the biochemical, behavioral, and toxic actions of the drugs and human subjects, both normal volunteers and patients, to test the safety and efficacy of the drugs... 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

Drug discovery requires a host of inputs, new ideas, design and synthesis of substances, evaluation of preclinical toxicity tests in animals, clinical studies in human volunteers, permission to market the drug, postmarketing studies of safety, and comparison with other medicines. Drug development is highly technical and enormously expensive, with a success rate of 1 in 10,000 compounds. 

There are three types of safety pharmacology studies conducted in the pharmaceutical industry, 1) single dose core portfolio preclinical safety studies conducted to Good Laboratory Practise (GLP) 2) supplemental studies of compound specific effects after chronic dosing that are conducted when results from the core battery of tests raise concern and 3) frontloading safety studies conducted in the drug discovery function with the aim of designing safety liabilities out of the lead compound series. 

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