The European Agency for the Evaluation of Medicinal Products
Evaluation of Medicines for Human UseLondon, 23 January 2003
CPMP/SWP/2599/02

COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS(CPMP)POSITION PAPER ON NON-CLINICAL SAFETY STUDIES TOSUPPORT CLINICAL TRIALS WITH A SINGLE MICRODOSEDISCUSSION IN THE SAFETY WORKING PARTYJune 2002

TRANSMISSION TO CPMPJune 2002

RELEASE FOR CONSULTATION

June 2002

DEADLINE FOR COMMENTS

September 2002

DISCUSSION OF COMMENTS BY THE SAFETY WORKINGPARTYOctober 2002

ADOPTION BY CPMPJanuary 2003

DATE OF COMING INTO OPERATIONJuly 2003

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POSITION PAPER ON NON-CLINICAL SAFETY STUDIES TO SUPPORT
CLINICAL TRIALS WITH A SINGLE MICRODOSE
1INTRODUCTION

Non-clinical safety studies to support the conduct of human clinical trials for pharmaceuticals has beeninternationally harmonised by the International Conference on Harmonisation as outlined inInternational Conference on Harmonisation (ICH) Topic M3: Note for Guidance on Non-clinical
Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, Topic S7A: Note for
Guidance on Safety Pharmacology Studies for Human Pharmaceuticals and Topic S7B: Note for
Guidance on Safety Pharmacology Studies for assessing the Potential for Delayed VentricularRepolarization (QT Interval Prolongation) by Human Pharmaceuticals. However, different regional
requirements still exist with regard to non-clinical studies to support the first dose to humans.
2SCOPE

This Position Paper defines common standards of the non-clinical safety studies needed to support
human clinical trials of a single dose of a pharmacologically active compound using microdose
techniques.
In the current context, the term “microdose” is defined as less than 1/100th of the dose calculated toyield a pharmacological effect of the test substance based on primary pharmacodynamic data obtainedin vitro and in vivo (typically doses in, or below, the low microgram range) and at a maximum dose of≤ 100 microgram. An example of such a clinical trial is the early characterisation of a substance’s
pharmacokinetic- / distribution properties or receptor selectivity profile using positron emission
tomography (PET) imaging, accelerator mass spectrometry (AMS) or other very sensitive analyticaltechniques.
The clinical trials covered by this Position Paper will be exploratory in nature (pre - phase I) and may
be conducted with a single test substance or with a number of closely related pharmaceuticalcandidates to choose the preferred candidate or formulation for further development. In any case thetotal amount of test compound(s) administered should not exceed 100 micrograms.
The non-clinical safety testing should be sufficient to assess the safety of clinical trial participants andpatients in line with the requirements outlined in the Helsinki Declaration. However, the extent ofrequired studies should be proportionate to the nature and scope of the clinical trial. Therefore theCPMP proposes that certain deviations from the existing CPMP/ICH notes for guidance to support
pre-phase I clinical trials may be scientifically justified.
3OVERVIEW OF EXISTING GUIDANCE FOR NON-CLINICAL SAFETY STUDIESTO SUPPORT SAFETY IN FIRST HUMAN CLINICAL TRIALS OF NEW
PHARMACEUTICAL CANDIDATES

Non-clinical studies to support human clinical trials have been harmonised (see Introduction); regional
differences still exist regarding non-clinical testing to support the first dose to humans. In theEuropean Union, repeated dose toxicity studies in two species (one non-rodent) for a minimum
duration of 2 weeks are required to support a single, first human dose. However, in the United Statesof America, single dose acute toxicity studies are in some cases considered sufficient to support asingle dose human clinical trial.
In 1996, the FDA published a notice on single dose acute toxicity studies for pharmaceuticals thatwould allow for the use of single-dose toxicity studies to support single dose studies in humans.

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ICH M3 includes a requirement for safety pharmacology studies, which is detailed further in the ICH
S7A guideline and guidance on the assessment of QT interval prolongation by non-cardiovascular
medicinal products is given in the ICH S7B guideline.
For biotechnology-derived medicinal products, the safety assessment should be considered on a caseby-case basis, which would also apply to single microdose human clinical trials. Guidance is given in
ICH Topic S6.
For anticancer medicinal products, guidance for non-clinical evaluation before first human dose isgiven in the CPMP Note for Guidance on the Pre-clinical Evaluation of Anticancer Medicinal
Products.
4RECOMMENDATIONS

4.1

EXTENDED SINGLE-DOSE TOXICITY STUDY AND OTHER EFFECTS ON VITALORGAN FUNCTION

The ICH M3 recommendation is for safety pharmacology, single dose toxicity studies and repeateddose toxicity studies. This set of studies may be replaced by an extended single-dose toxicity study in
only one mammalian species if the choice of species could be justified based on comparative in vitro
metabolism data and by comparative data on in vitro primary pharmacodynamics / biological activity.
The extended single-dose toxicity study should include a control group, and a sufficient number oftreatment groups to allow the establishment of the dose inducing a minimal toxic effect. For
compounds with low toxicity a limit dose approach could be used. Allometric scaling from animal
species to man1 and using a safety factor of 1000 should be used to set the limit dose. If a toxic effectis observed at the limit dose, the non-toxic dose level should be established.
The number of animals should be sufficient to ensure reliable interpretation of the study results. The
use of both genders should be considered. The extended single-dose toxicity study should be designed
to obtain the maximum amount of information from the smallest number of animals. Two routes ofadministration should generally be used, the intravenous as well as the intended clinical route, whichwould also allow assessment of local tolerance. When intravenous dosing is the route ofadministration in humans, this route alone in animal testing would generally be sufficient.
The study period should be 14 days and include an interim sacrifice on Day 2 (day of dosing definedas Day 1). All mortalities should be recorded. Time of onset, duration, and reversibility of toxicity andclinical observations should be recorded. Gross necropsy should be performed on all animals,including those sacrificed moribund, found dead, or terminated at Days 2 and 14. .
The extended single-dose toxicity study should be designed to obtain information on haematology andclinical chemistry at a minimum of two time points (Days 2 and 14) and histopathology.
Information should also be obtained on any other organ system where the test substance localises ande.g., those organ systems intended to be visualised by imaging agents.
In addition, all available background information on the test substance and/or close pharmaceuticals aswell as on the therapeutic class with respect to vital organ function and other safety parameters
obtained in drug screening should be provided. Examples of such data are receptor screening profiles,
activity at HERG and other ion channels, effect on action potentials, behavioural screens etc.
4.2

GENOTOXICITY STUDIESIn vitro genotoxicity studies should be performed as recommended in relevant ICH guidance.

1

See CPMP/ICH/283/95 for factors in allometric scaling

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However, if a test substance belongs to a well-known chemical class for which genotoxicity data are
available on other class representatives, performance of abridged/reduced versions of mutation test inbacteria (Ames test) and chromosome aberration, mouse lymphoma or in vitro micronucleus tests may
be sufficient. If abridged/reduced versions of genotoxicity tests are used, data demonstrating that themodification is scientifically justified and provides valid data should be provided. If an equivocal or
positive finding is obtained, additional testing should be performed.
4.3

LOCAL TOLERANCE STUDIES

Local tolerance studies may not be needed when the clinical route of administration is used in theextended single-dose toxicity study.
5FINAL REMARKSWith respect to radiopharmaceuticals, the corresponding stable isotope test substance should be used
for both the extended single-dose toxicity study and the genotoxicity studies.
Before entry into man, adequate information should be available on the primary pharmacodynamics ofeach test substance in the screening programme, e.g., when a number of structural analogues areincluded in the screening programme.
A sponsor should always ensure that an appropriate safety assessment is performed before entry intohumans. If toxicity is observed, this may need to be clarified by additional investigations before entry
into humans. Margins of safety and type of toxicity observed should be assessed.
All non-clinical safety studies should be conducted in accordance with the principles of Good
Laboratory Practice (GLP).
The reduced/abbreviated testing (as compared to the ICH guidance M3, S7Aand S7B) outlined above
is not sufficient to support clinical trial situations with escalating dose regimes or higher doses /exposures than indicated above. Guidance for such trials is found in the ICH M3, S7A and S7B.
The non-clinical safety assessment of biotechnology-derived products should be considered on a caseby-case basis as outlined in ICH Topic S6. Guidance for non-clinical testing of anti-cancer medicinal
products is given in the CPMP Note for Guidance on the Pre-clinical Evaluation of Anti-cancer
Medicinal Products. The extended single-dose toxicity study approach and the recommendation for
genotoxicity studies given in this Position Paper may not be relevant for these product categories.

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