Preclinical drug candidate safety

As the drug discovery process increased in intensity in the mid- to late 20th century, primarily as a result of the major screening and chemical synthetic efforts in the pharmaceutical industry in industrialized countries worldwide, but also as a result of the biotechnology revolution, the need for increased sophistication and efficacy in (1) how to discover new drugs, (2) how to reproducibly prepare bulk chemicals, (3) how to determine the activity and safety of new drug candidates in preclinical animal models prior to their... 

Assays provide a means to test the potential drug candidate quickly and in a cost-effective manner. Until such time as the efficacy and safety assays (including preclinicals in animals) are completed and show that the candidate has the potential to become a drug, it should never be tested on humans. 

Undertake preclinical studies (Preclinical Development) this involves many different important steps, of which the most critical is safety evaluation of the efficacious drug candidate in animal models. Before introduction of any new drug in humans it must be shown to be safe in animals. 

To establish safety and efficacy of a bio-pharmaceutical candidate for a defined therapeutic indication, the company or sponsor must provide the FDA with preclinical and clinical data assembled and summarized in the BLA. The preclinical and clinical testing process can vary depending on drug candidate and complexity of the therapeutic indication (Figure 4.18). 

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. 

This section describes some of the biological research experiments that could, and in most cases should, be conducted to evaluate the potential of a lead compound to become a developmental candidate. Figure 3 shows where these developability experiments fit into the drug discovery and development process. These nondefinitive developability studies may also uncover problems that have to be resolved before the definitive preclinical development studies required to support an IND submission are started and before the clinical protocols to evaluate the safety and efficacy of the drug candidate in humans are designed. 

Before entering into a clinical evaluation program, a drug candidate is subjected to a number of preclinical studies to further define and characterize its safety profile. The results from the pharmacology, developability, and preclinical studies are documented in technical reports or scientific publications and used to prepare the IND submission. All of the preclinical studies, described in the section below, and nonclinical studies, discussed in the following section, need to be conducted according to GLP regulations. 

The topic of preclinical assessment of a clinical candidate has been reviewed in Chapter 29. The topic is mentioned here because the decision as to whether it is safe to take a candidate drug into humans is ultimately a medical judgment that can only be made by individuals responsible for clinical drug development. Preclinical safety assessments are designed to provide the knowledge needed to decide whether it is reasonably safe to study a drug candidate in humans. The term reasonably safe is used in this context because that is what an FDA reviewer must answer when reviewing an IND application. 

The paradigm in drug development is sequentially divided into several phases starting with preclinical assessment. After selection of a drug candidate based on preclinical studies, clinical Phase 1 studies are initiated to characterize the safety, tolerability, biomarker, and pharmacokinetic profiles of the candidate, typically in healthy subjects. Phase 2 studies test the drug efficacy hypothesis in patients and explore dose range, and Phase 3 studies aim to demonstrate efficacy in the intended patient population in a statistically robust manner. 

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