Core battery

The actual requirements of the November 8, 2000 ICH guidelines are broadly outlined. They call for the conduct of studies in a core battery to assess effects on the cardiovascular (Table 19.1), respiratory (Table 19.2), central nervous system (Table 19.3) and secondary organ system (Table 19.4) effects. Follow-up studies for the care battery are also required on a case-by-case basis for the three main organ systems. 

ECG (QT measurements) in a cardiovascular study which would be covered in the core battery... 

Core Battery, Follow-Up, and Supplemental Studies Definitions and Expectations... 

Safety pharmacology studies have been subdivided into "core battery," "follow-up," and "supplemental" studies.25 The "core battery" studies are aimed to investigate the effects of NCEs on the cardiovascular, respiratory, and central nervous systems that are considered as vital organ systems based on the fact that acute failure of these systems would pose an immediate hazard to human life. In some instances, based on scientific rational, the "core battery" may or may not be supplemented.25 Additionally, ADRs may be either (1) suspected based on the pharmacological class, or the chemical class, or (2) identified... 

The safety pharmacology "core battery" studies should be available prior to first administration in humans. Furthermore, "follow-up" and "supplemental" studies should also be available prior to first administration in humans if there are specific cause for concerns. During clinical development, additional studies may be warranted to clarify observed or suspected adverse effects in animals or humans. Finally, prior to product approval, effects on organ systems that are defined as part of "follow-up" and "supplemental" studies should be assessed, unless not warranted. Available information from toxicology or clinical studies can support this assessment and replace the need for stand-alone safety pharmacology studies. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

An exhaustive review of the theory and mechanistic considerations of a mutagenicity evaluation are too lengthy for this discussion. ICH guidelines are available and include general principles and specifics related to the core battery of studies required.1617 Initial INDs are generally required to have two in vitro assays submitted, with the in vivo assay submitted prior to phase 2. 

Issues of cardiovascular safety have brought safety pharmacology to the forefront, especially with issues like prolongation of the QTc interval. In the United States, IND s must routinely include the core battery of cardiovascular, CNS, and pulmonary function studies. The reader is referred to Chapter 13 for a thorough discussion of this important topic. 

The core battery of studies should be carried out before a substance is administered to humans for the first time. Any follow up or supplementary safety pharmacology studies should be carried out if there is a cause for concern raised from the toxicological battery of tests and / or from studies in humans. 

The application of a core battery of WaterTox Program toxicity tests were applied to different types of samples by three South American laboratories. The core battery included the following tests ... 

Table 6. Point allocation scheme for sample ranking and hazard classification based on a toxicity test core battery [HAS 1].

Table 8. Score allocation based on the toxic effect of each core battery bioassay for class weight calculation [HAS 2J.

The Core Battery Approach for Small-Molecule Safety... 

A core battery is normally hierarchical in structure. Screening tests are suggested in section 2.7 of the guidance for CNS, cardiovascular, and respira-... 

The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous systems are usually considered the vital organ systems that should be studied in the core battery. In some instances, based on scientific rationale, the core battery may need to be supplemented (see also section 2.8) or may not need to be implemented (see also section 2.9). 

Overall the ICH S7A guideline is successfully implemented in the pharmaceutical world. The core battery is in general performed prior to First in Man . The guideline increases the visibility of safety pharmacology within companies and increases focus by regulatory agencies. 

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