Non-Clinical Testing Requirements

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Chapter: Pharmacovigilance: Non-Clinical Safety Evaluation and Adverse Events in Phase I Trials

Historically, the regulatory control of clinical research has been different in Europe, the United States and Japan.


Historically, the regulatory control of clinical research has been different in Europe, the United States and Japan. In Europe, the Clinical Trial Directive (Direc-tive 2001/20/EC) came into force on 01 May 2004. Although the Directive has set the same regulatory framework for the control of clinical trials across Europe, there are differences between Member States in their transpositions of the Directive, resulting in some diversity in the regulatory mechanisms and requirements. Similarly, there has been no harmonisa-tion on the precise extent of pre-clinical testing (toxi-cology and pharmacology) required before conducting the first study of a new drug in man. Various offi-cial (FDA, 1968) and unofficial (PMA, 1977; ABPI, 1985) guidelines have provided details of the basic studies that should be conducted in advance of a Phase I study. A partial consensus was reached on the non-clinical testing required with the publishing of the ICH M3 guideline, which came into operation in March 1998 (EMEA, 1998). However, even the latest revi-sion of this guideline (November 2000a) shows areas of non-agreement in the data expectations of the EU, United States and Japan during the various phases of clinical development (e.g. duration of toxicology test-ing and timing of reproduction toxicology studies).

Although certain classes of therapeutic agents and drugs for the treatment of certain types of life-threatening or serious disease may warrant a more flexible approach, the general guidance is that, before initiating studies in humans of a pharmaceutical agent, the following studies should be undertaken:

·    Acute toxicity studies in two mammalian species.

·    Repeat-dose toxicity studies in two mammalian species (one non-rodent), the duration of which should equal or exceed the duration of the proposed human clinical study (see details below).

·    Safety pharmacology studies to include the assess-ment of effects on the cardiovascular, central nervous and respiratory systems.

·    In vitro evaluation of genotoxicity to include eval-uation of mutations and chromosomal damage before Phase I with additional tests required before Phase II.

·     Studies to evaluate the absorption, distribution, metabolism and excretion (ADME) of drugs in animals. Results of these studies should be avail-able by the completion of the Phase I studies and before beginning patient studies.

·    When appropriate, local tolerance studies in animals using the proposed route of administra-tion for human studies. Such evaluations may be included as part of other toxicity studies.

·    Reproduction toxicity studies appropriate for the population to be studied. For example, in the EU, embryofoetal development studies are required before the inclusion of females of childbearing potential in Phase I studies. If a male-only popu-lation is to be studied at Phase I, it is usually sufficient to include appropriate examination of the reproductive organs in the repeated dose toxicol-ogy studies. Studies of fertility, early embryonic development, pre- and post-natal development and development will be required before extending the participant population and the duration of admin-istration in the clinical studies.

·    Carcinogenicity studies are not normally required in advance of the conduct of clinical trials but on occasions may be warranted, for example if genotoxicity studies identify a potential risk.

In addition to describing the type of non-clinical studies that should be performed before administration to humans, the ICH M3 guideline addresses the dura-tion of repeated-dose toxicology studies required to support human administration. Study duration should be based on the intended clinical use and dosage regi-men. The non-clinical data required to support early human studies are of limited duration; in the US, single-dose toxicology studies with extended exami-nations can support single-dose human trials, but in Europe 2 weeks repeated dosing in two species, one rodent and one non-rodent, is required for adminis-tration of a single dose. This will also support up to 14 days repeated administration of a standard new chemical entity. For longer-term human administra-tion, the required duration of non-clinical testing varies somewhat across the ICH regions, as noted in the ICH M3 guideline. For a simple daily-repeated dosing regime, however, 6-month rodent data and 9-month non-rodent data are widely acceptable to support Phase III clinical trials longer than 3 months.

Thus, although a relatively limited package of data on a product may be sufficient to allow the adminis-tration of single doses, a more extensive package of studies will be required subsequently, in order to facil-itate assessment of the safety of longer-term studies in more mixed populations. Progress through the vari-ous stages of drug development will require continued assessment of human safety data with the possibility of further non-clinical studies being required, depend-ing on the information generated.

The basic battery of non-clinical safety studies is intended to be adequate for the identification and char-acterisation of potential toxic effects, which may be relevant during the early phase of clinical develop-ment. For some types of product, however, a ‘stan-dard’ non-clinical programme may not be appropriate; abbreviated or extended testing programmes may be required and must be justified on a case-by-case basis. For example, it is generally not appropriate to perform genotoxicity assays for proteins and peptides unless there are concerns over impurities in the product. It may also be appropriate to reduce the repeated dose toxiciology testing of such products, performing studies only in a single relevant species, rather than using a second animal species that is unresponsive to the test material. Conversely, extension of non-clinical programmes may be appropriate where there are special concerns over issues such as immunotox-icity, when special monitoring of immune responses should be included in the toxicology studies. In any case, the non-clinical programme should be designed and, if necessary, adjusted to provide data that will fulfill the aims of non-clinical testing and allow a reasoned assessment of product safety before admin-istration to humans.

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