The Predictive Value of Non-Clinical Testing: Timing of non-clinical studies to the clinical trial programme

4. Timing of non-clinical studies to the clinical trial programme

A development candidate must undergo rigorous safety and efficacy testing in non-clinical studies before it is given to humans in Phase I clinical studies (also called first-in-human studies).

The programme and timing of non-clinical studies, to clinical trials, and to marketing authorisation have been harmonised through the ICH (ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals).

The ICH guideline requires the following studies be conducted:

Pharmacology studies.
General toxicity studies.
Toxicokinetic and non-clinical pharmacokinetic studies.
Repeated-dose toxicity studies.

Some further non-clinical studies are done on a case-by-case basis according to specific conditions. These include for instance:

Assessments of carcinogenic potential.
Phototoxicity, immunotoxicity, juvenile animal toxicity, etc.
Biotechnology-derived products (guideline issued under ICH topic S62).
Life-threatening or serious diseases – such as resistant HIV infection or congenital enzyme deficiency diseases that don’t have a current effective therapy.
Medicines that use innovative therapeutic modalities (for example, siRNA or vaccine adjuvants) and where non-clinical studies can be shortened, postponed, left out, or added in the non-clinical programme.

The non-clinical safety assessment programme has more goals. These include:

To characterise toxic effect.
To identify target organs.
To clarify dose dependence.
To understand how toxicities are related to exposure.
To assess potential reversibility.

The table below shows the standard non-clinical programme that must be completed before the clinical programme may begin.

Type of studies	Aim
Safety pharmacology core studies	Assess effects on cardiovascular, respiratory, and central nervous systems (CNS).
Primary pharmacodynamics	In vivo and/or in vitro studies. Assess mode of action/
Pharmacokinetics and toxicokinetics	Data gathered during in vitro studies on metabolic and blood protein binding data for animals and humans. Systemic exposure data from toxicology studies (Area under the curve, (AUC)).
Acute toxicity studies	Single-dose toxicity studies in two mammalian species – but can be completed during studies that define a maximum tolerated dose in the species used for toxicity testing.
Repeated dose toxicity studies	Vary in length according to duration, therapeutic indication and scope of the proposed clinical programme. Minimum duration for two weeks in two species (one of which is not a rodent).
Other studies of concern	For instance, examination of phototoxicity (when the skin reacts when exposed to light)

Table 1: Standard non-clinical study programme before ‘first-in-human’ clinical trials. In this phase, single dose, data on lethality or reproductive studies are not needed. Table adapted from ICH (2009) M3(R2).