Nonclinical safety testing

Although, in the 1950s nonclinical safety testing was limited to rodents, with appropriate testing, malformations could be produced in that species and resorptions were a known indicator of possible teratogenesis. The separation of response in rats and rabbits with thalidomide formed the basis for reproductive toxicology guidelines used today. 

The next step in drug development is the toxicological characterization of the compound. Prior to human exposure to a new drug, it is imperative to characterize the potential adverse effects and safety profile of the investigational new drug. This is accomplished through nonclinical safety testing. 

Walker, D. B. 2006. Serum chemical biomarkers of cardiac injury for nonclinical safety testing. Toxicologic Pathology 34 94-104. 

For both small molecules and biopharmaceuticals, regulatory guidelines state that nonclinical safety testing should be conducted in both a rodent and a nonrodent species (ICH M3R2, 2009 ICH S6R1, 2011). For some... 

Animal models of human disease are commonly utilized in early discovery studies, either in elucidation of the pathogenesis of the disease or the potential for a particular compound to provide a therapeutic benefit. However, animal models of human disease are relatively rarely utilized in nonclinical safety testing instead, conventional (healthy) rodent and nomodent models are typically utilized. This chapter will... 

The conduct of dedicated safety pharmacology studies has not routinely been conducted for biopharmaceuticals, even for those agents that were developed prior to the ICH S9 guidance document. This is because the nonclinical safety testing of biopharmaceuticals differs from that of small molecule pharmaceuticals and is described in the ICH S6 (Rl) guidance document (ICH S6 (Rl) 2011). This guidance document emphasizes the need for a case-by-case approach to the... 

Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals Notice Stability testing of new drug substances and products Stability testing Stability testing... 

Anon., Guideline on the evaluation of control samples in nonclinical safety studies checking for contamination with the test substance, CPMP/SWP/1094/04, London, 17 March 2005. 

The test facilities in India and China have evolved over the years and conduct a range of nonclinical safety assessment studies for in-house drug development, and also provide service as contract research organizations (CROs) for sponsors not only from India and China but also from overseas pharmaceutical and agrochemical companies. 

Nonclinical toxicity testing and safety evaluation data of an IND needed for fhe conduct of different phases of clinical frials... 

The animal species chosen for the later nonclinical safety studies should be responsive to the pharmacodynamic action(s). If the standard laboratory species are not responsive, the applicant should justify the choice of species selected or any supplementary tests if these are deemed appropriate. 

Although the European Paediatric Regulation (14) has mandated pharmaceutical companies to address pediatric safety, many drugs are used off-label in children (15), with no formal safety testing in appropriately aged nonclinical species and there have been recent examples of adverse human effects (16). 

If a sponsor has conducted phase 1 trials outside of the United States and believes that there are adequate human safety studies already available, it may not be necessary to conduct any phase 1 trials in the United States. In such a case, the sponsor would prepare an IND and include in the initial IND submission a clinical protocol for phase 2 or 3. This IND, because it will involve exposure of more patients to the drug for the purposes of safety testing as well as efficacy evaluations, will require a greater level and depth of manufacturing and nonclinical data. The next section will describe the requirements for such an advanced-stage IND. 

The standardized guidelines have been compiled to cover test methods in animal studies and in vitro studies on absorption, distribution, metabolism cind excretion in the Notification No. 496 of the PAB in 1998. The guidelines can be applicable for the drugs to be submitted after October 1999. The following principles should be considered in order to select the most appropriate methods bcised on the characteristics of test substance. It is required that the exposure data related to toxicological studies be obtained before the first human study and other pharmacokinetic data before the completion of Phcise I study in principle in accordance with the guidelines on nonclinical safety studies for conducting clinical trials (Notification No. 1019 of the PAB, 1998). 

In 1981, the OECD Principles of GLP were finalized and led to the OECD Council Decision on the Mutual Acceptance of Data (MAD) which states that Data generated in the testing of chemicals in an OECD member country in accordance with OECD Test Guidelines and OECD principles of Good Laboratory Practice shall be accepted in other member countries for purposes of assessment and other uses relating to the protection of man and the environment . The OECD recommended in 1983 that implementation of GLP compliance should be verified by laboratory inspections and study audits. The EC later ratified the OECD principles and a number of Directives (e.g., 2004/9/EC, 2004/10/EC) indicates that tests must be carried out in compliance with the principles of GLP and that also that EU Member States must incorporate into their laws the requirement for all nonclinical safety studies to be conducted in compliance with GLP, and that premises conducting such studies must be inspected by a national authority. 

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