Non-clinical Assessment of New Drug Products


trials in humans. That is not to imply that the product is completely safe or that all of the toxicological considerations are known at this point. Finally, a company needs to include a rationale for early clinical development in humans. Development plans are sometimes drafted years before and modified continuously in the time before the initial investigational new drug submission to address each of the requirements in order to begin clinical trials. This can be of tremendous value in moving forward, analogous to having a road map before one embarks on an unfamiliar journey. Typically, scientists in each of the key disciplines – manufacturing, pharmacology/toxicology and clinical research – write these development plans.


The Use of In Vitro and Animal Studies The sponsor needs to develop information to demonstrate that the safety of the drug is sufficient to justify the risk of humans being exposed to it. This information is derived from the non-clinical pharmacology and toxicology studies in vitro and in animals. The extent of information required to justify study in humans depends on the duration of the planned clinical study, the mode of administration of the drug, the pharmacokinetics of the drug and its relative safety.


The results of longer chronic toxicity testing are typically not needed until later stages of development, e.g. to support longer-duration studies in humans. The results of special toxicology studies, such as genotoxicity, reproductive studies and carcinogenicity studies are usually generated later in development.


Timing and Availability of Information


The timing and availability of the information will depend on the therapeutic area, the disease being studied and the target population for the clinical studies.3


These studies are lengthy and have long lead


times for the active ingredient being tested (referred to as the active pharmaceutical ingredient [API]). As such, trials must be planned for and started relatively early in any development programme with a compressed clinical development timeline.


Routes of Drug Administration


For non-clinical studies, in general, the expected clinical route of administration should be used when feasible. The development programme will probably also include the assessment of toxicity and risk by the most available route (i.e. intravenous or oral) as well as the primary intended route.


Regardless of the route of administration, exposure to the parent substance and its major metabolites should be similar to or greater than that achieved in humans. Assessment of effects by more than one route may be appropriate if the test substance is intended for clinical use by more than one route of administration (e.g. oral and parenteral) or where there are observed or anticipated significant qualitative and quantitative differences in systemic or local exposure.


Types of Non-clinical Assessments Toxicity and Core Studies


A primary goal in conducting pre-clinical studies is to obtain the data necessary to initiate clinical trials. The data derived from these


DRUG DEVELOPMENT • the safety pharmacology core battery;


• prior clinical trials; • post-approval pharmacovigilance; • experimental in vitro or in vivo studies; and • literature reports.


It is important initially to consider adverse effects that may be predicted or expected depending on the class of the molecule, based on prior experience by other companies with similar products. When such potential adverse effects raise concern for human safety, they should be explored in follow-up or supplemental safety pharmacology studies, as appropriate.


The in vivo safety pharmacology studies should be designed to define the dose-response relationship of any adverse effect observed. The time course (e.g. onset and duration of response) of the adverse effect should be investigated, when feasible. Generally, doses eliciting the adverse effect should be compared with doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans.


It is recognised that there are species differences in pharmacodynamic sensitivity and toxicology profiles. Doses should therefore include and exceed the primary pharmacodynamic or therapeutic range in humans.


In the absence of an adverse effect on the safety pharmacology parameters evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this or other studies


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Human safety studies are derived from toxicology studies conducted in animals with a time of exposure that is at least as long as the proposed duration in humans, usually with multiples of the proposed dose. This includes the general safety of the proposed drug in all organ systems.2


pre-clinical studies provide the scientific basis for the development of clinical monitoring parameters. They also provide the rationale for selection of an initial safe starting dose, a dose-escalation scheme, duration of use, a route of administration and potential target organs to be monitored for toxicity.


Pre-clinical studies should be designed to answer specific toxicity questions. These answers should provide an understanding of:


• the dose/activity relationship; •


the relationship of route and scheduling to activity/toxicity;


• the dose/toxicity relationship; and • the risks of toxicity.


Often, additional studies are designed to help discern a product’s mechanism of action, to facilitate future clinical development (i.e. to help ensure that clinical trials are not needlessly interrupted) and to satisfy liability and/or labelling concerns (i.e. to establish or promote a marketing advantage in some cases). This will include an assessment of certain core studies to investigate the safety of the drug in essential body systems. The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous systems are usually considered the vital organ systems that should be studied in the core battery.


Adverse Effects


Adverse effects may be suspected or predicted based on a number of sources of information. They can be based on the pharmacological properties or chemical class of the test substance. Additionally, concerns may arise from:


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