Drug Regulators, EMEA, update ICH M3 (R2) Non-Clinical Safety Guidlines.

The EMEA published new guidance on ICH Topic M 3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

Regulatory Guideline Introduction

The purpose of this document is to recommend international standards for, and promote harmonisation of, the nonclinical safety studies recommended to support human clinical trials of a given scope and duration as well as marketing authorization for pharmaceuticals. This guidance should facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3R (reduce/refine/replace) principles and reduce the use of other drug development resources.

The nonclinical safety assessment for marketing approval of a pharmaceutical usually includes pharmacology studies, general toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies, genotoxicity studies and, for drugs that have special cause for concern or are intended for a long duration of use, an assessment of carcinogenic potential. Other nonclinical studies to assess phototoxicity, immunotoxicity, juvenile animal toxicity and abuse liability should be conducted on a case-by-case basis.

The development of a pharmaceutical is a stepwise process involving an evaluation of both animal and human efficacy and safety information. The goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility.

Pharmacology Studies

Safety pharmacology and pharmacodynamic (PD) studies are defined in ICH S7A (Ref. 5). The core battery of safety pharmacology studies includes the assessment of effects on cardiovascular, central nervous and respiratory systems, and should generally be conducted before human exposure, in accordance with ICH S7A and S7B (Refs. 5 and 6).

Toxicokinetic and Pharmacokinetic Studies

In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials. Further information on pharmacokinetics (PK) (e.g., absorption, distribution, metabolism and excretion), in test species and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before Phase III).

Nonclinical characterization of a human metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity studies.

Acute Toxicity Studies

Historically, acute toxicity information has been obtained from single-dose toxicity studies in two mammalian species using both the clinical and a parenteral route of administration. However, such information can be obtained from appropriately conducted dose-escalation studies or short-duration dose-ranging studies that define an MTD in the general toxicity test species (Refs. 8 and 9). When this acute toxicity information is available from any study, separate single-dose studies are not recommended.

In some specific situations (e.g., microdose trials)  acute toxicity or single-dose studies can be the primary support for studies in humans.

Information on the acute toxicity of pharmaceutical agents could be useful to predict the consequences of human overdose situations and should be available to support Phase III.

Repeated-Dose Toxicity Studies

The recommended duration of the repeated-dose toxicity studies is usually related to the duration, therapeutic indication and scope of the proposed clinical trial. In principle, the duration of the animal toxicity studies conducted in two mammalian species (one non-rodent) should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies.

Estimation of The First Dose in Humans

The estimation of the first dose in humans is an important element to safeguard subjects participating in first-in-human studies. In general, the No Observed Adverse Effect Level (NOAEL) determined in nonclinical safety studies performed in the most appropriate animal species gives the most important information. The proposed clinical starting dose will also depend on various factors, including PD, particular aspects of the molecule, and the design of the clinical trials.

Exploratory Clinical Trials

It is recognized that in some cases earlier access to human data can provide improved insight into human physiology/pharmacology, knowledge of drug candidate characteristics and therapeutic target relevance to disease. Streamlined early exploratory approaches can accomplish this end. Exploratory clinical studies for the purpose of this guidance are those intended to be conducted early in Phase I, involve limited human exposure, have no therapeutic intent, and are not intended to examine clinical tolerability. They can be used to investigate a variety of parameters such as PK, PD and other biomarkers, which could include PET receptor binding and displacement or other diagnostic measures. The subjects included in these studies can be patients from selected populations or healthy individuals. Five different examples of exploratory clinical approaches are summarized below:

Microdose Trials

The first approach would involve not more than a total dose of 100 μg that can be administered as a single dose or divided doses in any subject. This could be useful to investigate target receptor binding or tissue distribution in a PET study.

A second microdose approach is one that involves < 5 administrations of a maximum of 100 μg per administration (a total of 500 μg per subject). This can be useful for applications similar to the first microdose approach described above, but with less active PET ligands.

Single-Dose Trials at Sub-Therapeutic Doses or into the Anticipated Therapeutic Range

The third approach involves a single-dose clinical study typically starting at subtherapeutic doses and possibly escalating into the pharmacological or anticipated therapeutic range.

The maximum allowable dose should be based on the nonclinical data, but could be further limited based on emerging clinical information obtained during the course of the study. This approach could allow, for example, determination of PK parameters with non-radiolabeled drug at or near the predicted pharmacodynamically active dose.

Multiple Dose Trials

These approaches support up to 14 days of dosing for determination of PK and PD in human in the therapeutic dose range, but are not intended to support the determination of maximum tolerated clinical dose.

Approach 1 involves 2-week repeated-dose toxicity studies in rodents and non-rodents where dose selection in animals is based on exposure multiples of anticipated AUC at the maximum clinical dose.

Approach 2 involves a 2-week toxicity study in a rodent species and a confirmatory non-rodent study that is designed to investigate whether the NOAEL in the rodent is also not a toxic dose in the non-rodent.

A detailed description of the non-clinical requirements for each study is given in the guidleins

Local Tolerance Studies

It is preferable to evaluate local tolerance by the intended therapeutic route as part of the general toxicity studies; stand alone studies are generally not recommended. To support limited human administration by non-therapeutic routes (e.g., a single i.v. dose to assist in the determination of absolute bioavailability of an oral drug), a single dose local tolerance study in a single species is considered appropriate.

Genotoxicity Studies

An assay for gene mutation is generally considered sufficient to support all single dose clinical development trials. To support multiple dose clinical development trials, an additional assessment capable of detecting chromosomal damage in a mammalian system(s) should be completed. A complete battery of tests for genotoxicity should be completed before initiation of Phase II trials.

Carcinogenicity Studies

If carcinogenicity studies are recommended for the clinical indication, they should be conducted to support the marketing application. Only in circumstances where there is a significant cause for concern for carcinogenic risk should the study results be submitted to support clinical trials.

Reproductive Toxicity Studies

Men can be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies. A male fertility study should be completed before the initiation of large scale or long duration clinical trials (e.g., Phase III trials).

Women not of childbearing potential (i.e., permanently sterilised, postmenopausal) can be included in clinical trials without reproduction toxicity studies if the relevant repeated-dose toxicity studies (which include an evaluation of the female reproductive organs) have been conducted. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.

For women of childbearing potential (WOCBP) there is a high level of concern for the unintentional exposure of an embryo or fetus before information is available concerning the potential benefits versus potential risks. The recommendations on timing of reproduction toxicity studies to support the inclusion of WOCBP in clinical trials are similar in all ICH regions.

Before the inclusion of pregnant women in clinical trials, all female reproduction toxicity studies  and the standard battery of genotoxicity tests (Ref. 10) should be conducted. In addition, safety data from previous human exposure should be evaluated.

Clinical Trials In Pediatric Populations

When pediatric patients are included in clinical trials, safety data from previous adult human experience would usually represent the most relevant information and should generally be available before initiation of pediatric clinical trials. The appropriateness and extent of adult human data should be determined on a case-by-case basis. Extensive adult experience might not be available before pediatric exposures (e.g., for pediatric-specific indications).

Immunotoxicity

As stated in the ICH S8 guidance, all new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity using standard toxicity studies and additional immunotoxicity studies conducted as appropriate based on a weight-of-evidence review, including immune-related signals from standard toxicity studies.

Photosafety Testing

The appropriateness or timing of photosafety testing in relation to human exposure should be influenced by: 1) the photochemical properties (e.g., photoabsorption and photostability) of the molecule, 2) information on the phototoxic potential of chemically related compounds, 3) tissue distribution, and 4) clinical or nonclinical findings indicative of phototoxicity.

Non-clinical abuse liability

For drugs that produce central nervous system activity, regardless of therapeutic indication, it should be considered whether or not an evaluation of abuse liability is warranted. Nonclinical studies should support the design of clinical evaluations of abuse potential, classification/scheduling by regulatory agencies, and product information. There are regional guidance documents on the conduct of nonclinical abuse liability assessment that can be helpful in designing specific abuse liability packages.

Other Toxicity Studies

Additional nonclinical studies (e.g., to identify potential biomarkers, to provide mechanistic understanding) can be useful if previous nonclinical or clinical findings with the product or related products have indicated special safety concerns.

Combination Drug Toxicity Testing

Combinations covered might involve: (1) two or more late stage entities (defined as compounds with significant clinical experience (i.e. from Phase III studies and/ or post marketing)); (2) one or more late stage entity(ies) and one or more early stage entities (defined as compounds with limited clinical experience (i.e. Phase II studies or less)); or (3) more than one early stage entity.

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