Animal studies principles

The CWS spent several years doing animal studies to establish the safely of proceeding with such tests in volunteers. Rules governing the use of humans in medical experiments originated during the Nuremberg Military Tribunals. (These principles, in their unabridged form, are in the appendix.) The main points were as follows ... 

The risk assessment comprises an effect assessment (hazard identification and hazard characterization) and an exposure assessment. The principles for the effect assessment of the active substances are in principle similar to those for existing and new chemicals and are addressed in detail in Chapter 4. Based on the outcome of the effect assessment, an Acceptable Daily Intake (ADI) and an Acceptable Operator Exposure Level (AOEL) are derived, usually from the NOAEL by applying an overall assessment factor addressing differences between experimental effect assessment data (usually from animal studies) and the real human exposure situation, taking into account variability and uncertainty for further details the reader is referred to Chapter 5. As a part of the effect assessment, classification and labeling of the active substance according to the criteria laid down in Directive 67/548/EEC (EEC 1967) is also addressed (Section 2.4.1.8). 

Unless a N/LOAEL is available from human data, the N/LOAEL are those derived from the animal studies without any modifications. When a human N/LOAEL is available, the approaches described below can stiU be used in principle but some of the factors which need to be considered when using data from animal studies will obviously not be applied. 

Once the animal studies are completed human studies can commence, moving through phase I (up to 50 naive patients to establish a sufficient immune response) phase (several hundred patients in several locations) to phase III in which expanded studies on as many as thousands of patients. The trials require to be randomized and closely controlled by being blinded to avoid bias in interpretation. The patients all have to provide informed consent and strict adherence to good clinical practices in accordance with ethical principles is required to ensure risk-benefit considerations justify the risks associated with all trials of this type. The safety of the patients is an overall requirement and trials must be supervised by the appropriate independent ethics committee or the local Institutional Review Board. 

In parallel to catheter-based delivery, stent-based approaches, such as passive stent coatings (diamond-like carbon, phosphorylcholine, and silicon carbide coatings) and immobilized drug coatings (heparin-coated stents), were evaluated for their ability to inhibit restenosis. Although animal studies demonstrated some promise, none of these technologies were clinically successful for restenosis prevention. The failure of these surface modification technologies further added to the need for the development of DES based on the principles of sustained CDD,... 

The fundamental principle here is that animals are only used when there is no alternative. Researchers have an ethical duty (and in some countries, a legal one) to check all of the available scientific literature to determine if there is an alternative way of acquiring the information that would be gained from an animal study. Innovation in any field of investigation that allows information to be gained from alternative research methodology not involving animals is welcomed by the pharmaceutical industry. 

In the mechanism-based approach, a model is validated by its ability to reproduce observed temporal behaviors, i.e. wave forms, phase relationships, parameter dependences, and stability properties under many different conditions. For oscillatory phenomena, prediction of amplitudes and frequencies (using independently determined parameters) play a significant role. Further validation of the model is based on its ability to predict the outcome of new experiments, performed under conditions not previously examined. Among the advantages of this approach are that the model can be gradually expanded without changing already consolidated parts and that the model, in principle at least, allows translation by replacement of, e.g. parameters from animal studies by parameters relevant to man. 

The duration for Repeat Dose Toxicity Studies is related to the duration of clinical trials and their therapeutic indication. In principle, the duration of animal studies are equal to or exceed the duration of the human clinical trials. 

The TTC principle has been developed originally for chemicals present in food such as flavouring substances. Its use has been proposed for herbal preparations, personal and household care products, and impurities in pharmaceuticals (Munro et al. 2008). Recently it has been proposed for cosmetic ingredients (Kroes et al. 2007). The TTC principle determines a human exposure value for the daily uptake of a compound, below which there would be no appreciable risk to human health. Depending on the structure of the compound, different values for the daily uptake are applied. It may avoid animal studies for compounds of very low exposure. 

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