Safety assessment preclinical development

Rafael Ponce, PhD, DABT, Director, Safety Assessment, Preclinical Development, ZymoGenetics, Inc., 1201 Eastlake Ave. E., Seattle, WA 98102 poncer zgi.com, reap zgi.com... 

It may seem that the course of preclinical safety assessment (and of other aspects of development) of a pharmaceutical is a relatively linear and well-marked route, within some limits. This is generally the case, but not always. There are a number of special cases where the pattern and phasing of development (and of what is required for safety assessment) do not fit the usual pattern. Four of these cases are... 

The kinds of information described here are found on three types of PC media floppy, CD-ROM, and laser disks. The products run the gamut of allowing one to assess current developments on a weekly basis, as well as to carry out more traditional reviews of historical information. The general types of information one can cover include basic pharmacology, preclinical toxicology, competitive products, and clinical safety. 

The formulations that are developed and used for preclinical studies are sometimes specific for the test species to be employed, but their development always starts with consideration of the route of exposure that is to be used clinically and, if possible, in accordance with a specified regimen of treatment (mirroring the intended clinical protocol, as much as possible). One aspect of both nonclinical and clinical formulation and testing which presents an important but often overlooked aspect of pharmaceutical safety assessment is the special field of excipients. These will be considered at the end of this chapter... 

Frequently, a simple approach of pH adjustment or cosolvent is not enough to achieve the target concentration. Cosolvents are often used in combination with pH adjustment to further enhance the solubility. Using this approach, Lee et al. (2003) observed that nearly 85% of PLzer, Ann Arbor discovery compounds (> 300) submitted for discovery and preclinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. It was also observed that 11% of compounds were not formulatable using this approach, and another32% ofthe formulation used more than 55% cosolvent. The high solvent content can limit the pertinent safety assessment of lead compounds. Therefore, the synergistic combinations of pH adjustment and cosolvent are not sufLcient to develop commercially... 

Cavagnaro JA. Preclinical safety assessment of biological products. In Mathieu M, ed. Biologies Development A Regulatory Overview. Waltham, MA Parexel International, 1993 23 i0. 

Types of Biopharmaceuticals Survey data on preclinical safety assessment programs were analyzed for 34 biopharmaceuticals cases. The numbers of antibodies, human proteins, and human protein analogues either in the development or marketed as of 2001 in Japan were 13,12, and 6, respectively. The remainder were bioconjugates, DNA-derived vaccines, and human T cell epitopes. Thus antibodies and human proteins are the two major biopharmaceuticals. 

The strategies to develop the preclinical safety assessment programs for biotechnology-derived therapeutics have often been characterized as case by... 

Bussiere JL, McCormick GC, Green JD. Preclinical safety assessment considerations in vaccine development. Pharm Biotechnol 1995 6 61-79. 

Knowledge about metabolites and their activity is further an important criteria for the assessment of species-specific effects and differences, e.g. the search for the most human-like test model as the best predictor for human reactions, focuses on such differences. Metabolism can lead to pharmacologically active metabolites such knowledge is desirable early in development. In vitro metabolism studies normally precede in vivo preclinical safety assessments. 

Before human clinical trials are initiated, a number of toxicology studies need to be completed and documented in the IND submission. In addition to the studies listed above for toxicology developability assessment, preclinical toxicology studies include local tolerance, genotoxicity, safety pharmacology, and subchronic tests. 

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. 

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