ABSTRACT
PharmaceuticalsThe aim of preclinical development is to integrate information obtained from various preclinical studies to help in designing early clinical trials. The information also helps select second-generation compounds, predict drug liability, and define the efficacy-safety relationship. The key components of a preclinical program are safety and pharmacological evaluations. These preclinical studies should seek to clarify the relationship between dose, exposure, toxicity, and pharmacological effects. Specific information regarding the toxicology, pharmacology, and toxicokinetics (TK) should be collected prior to the initiation of the first human trials. From a pharmacokinetic (PK) perspective, focus should be placed on collection the essential information needed for the selection of the first clinical dose: exposure, clearance, bioavailability, and dose-or concentration-effect relationship. The specific goal of preclinical safety evaluation includes suggestion of an initial safe starting dose in humans and dose escalation trial design, identification of potential target organ(s) of toxicity, and identification of safety parameters for clinical monitoring. Accordingly, toxicity studies should be conducted in relevant species to assess a dose-limiting toxicity. Considerations in toxicity study design generally include selection of model (e.g., species or alternative model), dose (e.g., route, frequency, and
duration), and endpoint (e.g., activity, biomarker, and/or toxicity). The approach for the preclinical safety evaluation of biologics has been referred to be the “case-by-case” approach (see a later section). The International Conference on Harmonisation (ICH) (consisting of the United States, the European Union [EU], and Japan) of Technical Requirements for Registration of Pharmaceuticals for Human Use has standardization preclinical safety studies for international marketing approval of pharmaceuticals. For instance, ICH guidance M3 (2000) and M3(R2) (2009) covers single-dose toxicity, repeated-dose toxicity, genotoxicity, reproductive toxicity, PK, safety pharmacology, and special toxicity studies [1, 2]. ICH guidance S6 (1997) is intended to recommend a basic framework of for the preclinical safety evaluation of biotechnology-derived pharmaceuticals [3]. Carcinogenicity may be required depending on the indications and level of concern (e.g., chronically administration and anticipated proliferation of malignancies) [4]. 19.2.1 Outline of Preclinical Safety Assessment (Timing
A preclinical safety program is a staged approach as it is impractical to conduct all toxicity studies required for marketing approval concomitantly because of the required resources. In additionally, most new drugs do not reach late development or market approval. With the staged approach, preclinical toxicity studies supporting the next clinical phase are performed before the initiation of the particular clinical phase. For a first-in-man (FIM) trial, the typical preclinical toxicology package includes single-dose toxicity (two species with one rodent and one nonrodent), repeated-dose toxicity (again one rodent and one nonrodent), local tolerance (could be part of repeated-dose toxicity studies), and genotoxicity studies [1]. The standard genotoxicity battery consists of bacterial mutagenicity assay and in vitro chromosomal damage with mammalian cells (or in vitro mouse lymphoma assay). The aforementioned studies are conducted to provide sufficient information for dose selection in the FIM trial. An exception to the aforementioned approach is for a single-dose clinical trial where only single-dose toxicity studies are needed [5]. In addition, safety pharmacology (see Section 19.4 for
more details) and the exposure data (i.e., PK/TK; see Section 19.5 for more details) are also required for IND submission. Longer-term repeated-dose toxicity, reproductive toxicity, and in vivo genotoxicity studies should be conducted upon the completion of the initial clinical trial. The duration of the repeated-dose studies depend on the duration and phase of the clinical trial(s) [1]. For instance, one-month toxicity studies would support phase I and II trials up to one-month duration worldwide and phase III up to one-month duration in the United States. While the longer-term repeated-dose toxicity studies are being conducted, reproductive toxicity and additional genotoxicity studies are initiated. The types of reproductive toxicity (namely, fertility, embryo-fetal and pre-and postnatal development) studies are essentially the same worldwide. The concerns by regulatory authorities often go by the acronym development and reproductive toxicity (DART) or reproduction, teratogenicity, and fertility (RTF). The timing of conducting reproductive toxicity studies supporting different phases of clinical trials vary by the regions of the world. Generally, segment II (i.e., embryo-fetal toxicity) studies are designed to detect developmental toxicity and performed early and in some regions are required before phase I trials, for example, in China. Many companies actually conduct a segment II teratology study in rats before a segment I (i.e., fertility) study because a segment II study requires less time and resources. A segment I study in rats is generally conducted during phase II trials. One or both studies should be completed prior to including women of child-bearing potential in the clinical studies. The FDA required segment II studies in rodents (rats or mice) and rabbits. The employment of rabbits was due to the finding of thalidomide as the agent was a positive teratogen in rabbits but not in rats. Both segment II studies should be completed before initiation of a phase III trial. A segment III (i.e., pre-and postnatal development) study is usually initiated during phase III and part of the NDA. Provided timing of reproductive studies differs by region, their timing should be assessed on a case-by-case basis. Nevertheless, male and female fertility, embryo-fetal, and pre-and postnatal development studies are required before marketing approval in all regions.
