Nonclinical testing

The ICH S7B guideline [117] describes a nonclinical testing strategy to identify the potential of a test substance and its metabolites to delay ventricular repolarization and to relate the extent of delayed ventricular repolarization to the concentrations of a test substance and its metabolites. 

The sensitivity of nonclinical tests (i.e. their ability to label as positive those drugs with a real risk of inducing QTprolongation in humans) is sufficiently good [132-137] but their specificity (i.e. their ability to label as negative those drugs carrying no... 

A second approach would have been to shift responsibility for nonclinical testing of regulated products to... 

In the absence of existing human exposure data or other review of the excipient, FDA recommends in its guidance on Pharmaceutical Excipients (2) that the excipient be evaluated using a battery of standard nonclinical tests (7). Which tests are appropriate depends upon the likely patient exposure given the intended use of the drug if approved. Table 1 provides a summary of the necessary tests. This test paradigm will likely be considered as setting the standard for data requirements for any new excipients, whether or not approved by the FDA in an NDA or ANDA, or reviewed by some future alternative review/approval mechanism. 

Evaluate regulatory compliance status of all facilities providing clinical and nonclinical testing as well as manufacturing facilities... 

Nonclinical tests Brief discussion of nonclinical tests submitted, referenced, or relied on... 

Nonclinical research provides very useful information and plays a considerable role in the successful development of a new drug. It is also required by current regulatory statutes. Nonetheless, no matter how meticulously, rigorously, and comprehensively nonclinical testing is conducted, no animal model is a perfect model of the drug s actions and effects in humans. Therefore, in addition to an appreciation of the usefulness of nonclinical data, it is valuable to have an appreciation of their limitations and of statistical considerations of particular pertinence to toxicological data. 

Approval Approval process for biological medicinal products is the same as other chemically synthesized small molecules. The legal test is firmly based upon an assessment of risk-benefit balance. However, in assessing risk-benefit balance of a biological medicinal product, EU law requires the applicant to provide certain additional information. If the medicinal product contains a new biological active substance, the applicant must comply with the requirements set out in article 8(3) of Directive 2001/83/EC by providing results of the pharmaceutical and nonclinical testing, and clinical trials. 

Gene therapy, DNA vaccines, genetically modified tissue or cell-based products. EMEA/273974/05 Draft Annex on nonclinical testing for inadvertent germline transmission of gene transfer vectors [36] 2005... 

Guideline for the Need for Nonclinical Testing in Juvenile Animals on Human Pharmaceuticals for Pediatric Indications (EMEA/CHMP/S WP/169215/2005)... 

At present, the aim is to ensure that a humoral response is generated. For mucosal vaccines, IgA may be more appropriate.21516 T cell-mediated responses may also be considered, and advances in knowledge and the development of different types of vaccines and/or adjuvants suggest that cell-mediated responses may be just as or more important than the humoral response, when considering the selection of species. Adjuvants can selectively switch the T helper cell response, which may influence a protection or pathology dependent response (see Section 19.2.5). However, the current understanding and interpretation of such data are limited in terms of predicitivity, and there are also limitations in the immunoassays developed for species routinely used in nonclinical testing. This is a key area where further development is required. 

A second approach would have been to shift responsibility for nonclinical testing of regulated products to the FDA. Such a shift would have required congressional authorization, because the FFDCA clearly places this responsibility on the sponsor of the product. In addition, the costs of such a shift would have been prohibitive. 

Similar to the requirements for a study director, a nonclinical testing laboratory must designate a single individual to be alternate archivist to serve in the absence of the designated archivist. 

If a facility conducting nonclinical testing goes out of business, are all raw data, documentation, and other material specified in this section transferred to the archives of the sponsor of the study ... 

Overview of the nonclinical testing strategy or nonclinical drug development logic plan. 

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