Research and Development Strategies Non-clinical Assessment of New Drug Products


Michael R Hamrell MORIAH Consultants, Yorba Linda


Abstract


Multidisciplinary product development programmes use pre-clinical or non-clinical safety evaluation studies to provide sufficient understanding of a product’s pharmacology and toxicological potential prior to the initiation of studies in humans. In addition to providing insights into a product’s pharmacology and safety, non-clinical animal testing helps scientists to determine an optimal initial formulation, select an initial safe starting dose, develop a safe dose-escalation scheme, identify potential target organ(s) of toxicity, recommend appropriate types of clinical monitoring procedures and identify potential at-risk populations. Recent identification of studies to quantify the risk of certain types of toxicity has led to the development and use of new tests for screening potential drug compounds. The number and nature of studies relevant in assessing safety and activity often differs between classes of products and is dependent on the indication.


Keywords Pre-clinical, toxicology, safety assessment, pharmacology


Disclosure: The author has no conflicts of interest to declare. Received: 7 September 2010 Accepted: 17 November 2010 Citation: Drug Development, 2010;5:30–3 Correspondence: Michael R Hamrell, 4481 Paloma Lane, Yorba Linda, CA 92886, US. E: michael@moriahconsultants.com


Pre-clinical Assessment


The regulation of drug products is based on the use of available scientific data, the consideration of theoretical and practical concerns and flexibility in the application of requirements and standards. Due to the pace of scientific and technological advances, policy development has been, by necessity, a dynamic process. Approaches to product safety evaluation have therefore evolved through the application of scientific insight, historical experiences and common sense.


A non-clinical development programme includes studies to assess items such as:


• in vitro and in vivo pharmacological activity; •


pharmacokinetic parameters, including absorption, distribution, metabolism and excretion (ADME); and • in vitro and in vivo toxicity.


The route of administration, dose, frequency and duration utilised in pre-clinical studies are based on the product’s proposed indication(s). The adequacy of the studies will depend on the review and integration of all available data.


A number of non-clinical toxicology guidelines are available that provide both regulatory and industry scientists with a point of reference for determining what is likely to be acceptable. These guidelines promote consistency in testing within and across product classes. Over the past few years, there has been important progress in the harmonisation of toxicity testing guidelines for pharmaceuticals and biopharmaceuticals, particularly through the International Conference on Harmonisation (ICH).1


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Regulatory scientists and sponsors must have a common understanding of potential safety concerns and a basic knowledge of the specific product. The timing of pre-clinical studies is critical in a product’s ‘realtime’ development. Consideration needs to be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include:


• the pharmacodynamic responsiveness of the model;


• the susceptibility, sensitivity and reproducibility of the test system; •


species, strain, gender and age of the experimental animals;


• pharmacokinetic profile; and •


available background data on the substance.


For biotechnology-derived products that achieve highly specific receptor targeting or binding, it may be sufficient to evaluate safety pharmacology end-points as a part of toxicology and/or pharmacodynamic studies.


Information Required to Begin Clinical Studies There are three essential elements of information needed to begin clinical studies.


First, the sponsor must demonstrate that it has sufficient knowledge to manufacture the drug. It must have appropriate considerations for the identity, strength, quality and purity of the molecule. Second, a company has to show that the drug has an adequate safety profile in pre-clinical pharmacology and toxicology studies. The goal of early animal testing is to demonstrate the major safety considerations for the product and to demonstrate that the product is ‘safe enough’ to begin


© TOUCH BRIEFINGS 2010


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