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December 23, 2002
NOTICE
Our file number: 02-122028-691
Withdrawal of Toxicological Evaluation Guidelines and Re-issuance
of ICH1 Safety Guidances
The Health Canada Toxicological Evaluation guidances (revised
1996) are being withdrawn following an internal review by a Safety Expert
Working Group which concluded that they no longer reflected current toxicological
methodologies. Furthermore, the review revealed substantial areas of overlap
and inconsistency between these guidances and their more recently adopted
ICH counterparts.
The following Health Canada-adopted ICH Safety (Nonclinical)
guidances, previously available as part of the Toxicological Evaluation
guidances, are being re-issued as stand alone documents:
- S1A Need for Carcinogenicity Studies of Pharmaceuticals
- S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests
For Pharmaceuticals
- S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic
Exposure in Toxicity Studies
- S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution
Studies
- S5A Detection of Toxicity to Reproduction for Medicinal Products
These ICH guidances have been developed by the appropriate
ICH Expert Working Group and have been subject to consultation by the
regulatory parties, in accordance with the ICH Process. The ICH Steering
Committee has endorsed the final draft and recommended its adoption by
the regulatory bodies of the European Union, Japan and USA.
In adopting these ICH guidances, Health Canada as observer
to ICH, endorses the principles and practices described therein. These
documents should be read in conjunction with this covering notice and
with the relevant sections of other applicable Health Canada guidances.
These and other guidance documents are currently available on the Therapeutic
Products Directorate / Biologics and Genetic Therapies Directorate Website
(s) (http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/). The availability
of printed copies of guidance documents may be confirmed by consulting
the Guidelines and Publications Order Forms (available on the TPD/BGTD
Website) or by contacting the Publications Coordinator2.
Should you have any questions regarding the content of the
guidance, please contact
Colette F. Strnad, B. Sc., Ph.D.
Title: Senior Scientific Advisor
Office of Science
Therapeutic Products Directorate
Holland Cross, Tower B, 2nd Floor,
A.L. 3102C3 1600 Scott Street
Ottawa, Ontario K1A 1B6
telephone: (613) 941-3693
fax: (613) 941-5035
email: colette_strnad@hc-sc.gc.ca
1 ICH - International Conference on Harmonization
of Technical Requirements for the Registration of Pharmaceuticals for
Human Use
2 Tel: (613) 954-6466; E-mail: publications_coordinator@hc-sc.gc.ca
S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution
Studies
Published by authority of the
Minister of Health
1994
Health Products and Food Branch
Guidance Document
Our mission is to help the people of Canada
maintain and improve their health.
Health Canada |
HPFB's Mandate is to take an integrated approach to the management
of the risks and benefits to health related to health products and
food by:
- Minimizing health risk factors to Canadians while maximizing
the safety provided by the regulatory system for health products
and food; and,
- Promoting conditions that enable Canadians to make healthy choices
and providing information so that they can make informed decisions
about their health.
Health Products and Food Branch
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© Minister of Public Works and Government Services Canada 1994
Available in Canada through
Health Canada - Publications
Brooke Claxton Building,
A.L. #0913A Tunney's Pasture
Ottawa, Ontario K1A 0K9
Tel: (613) 954-5995
Fax: (613) 941-5366
Également disponible en français sous le titre: Pharmacocinétique:
Ligne directrice sur les études de diffusion tissulaire à doses répétées
FOREWORD
This guidance has been developed by the appropriate ICH
Expert Working Group and has been subject to consultation by the regulatory
parties, in accordance with the ICH Process. The ICH Steering Committee
has endorsed the final draft and recommended its adoption by the regulatory
bodies of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses
the principles and practices described therein. This document should
be read in conjunction with the accompanying notice and the relevant
sections of other applicable guidances.
Guidance documents are meant to provide assistance to industry
and health care professionals on how to comply with the policies
and governing statutes and regulations. They also serve to provide review
and compliance guidance to staff, thereby ensuring that mandates are implemented
in a fair, consistent and effective manner.
Guidance documents are administrative instruments not having
force of law and, as such, allow for flexibility in approach. Alternate
approaches to the principles and practices described in this document
may be acceptable provided they are supported by adequate scientific
justification. Alternate approaches should be discussed in advance with
the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.
As a corollary to the above, it is equally important to
note that Health Canada reserves the right to request information or
material, or define conditions not specifically described in this guidance,
in order to allow the Department to adequately assess the safety, efficacy
or quality of a therapeutic product. Health Canada is committed to ensuring
that such requests are justifiable and that decisions are clearly documented.
TABLE OF CONTENTS
1. INTRODUCTION
2. CIRCUMSTANCES UNDER
WHICH REPEATED DOSE TISSUE DISTRIBUTION STUDIES SHOULD BE CONSIDERED
3. DESIGN AND CONDUCT
OF REPEATED DOSE TISSUE DISTRIBUTION STUDIES
4. SUMMARY
1. INTRODUCTION
A comprehensive knowledge of the absorption, distribution,
metabolism and elimination of a compound is important for the interpretation
of pharmacology and toxicology studies. Tissue distribution studies
are essential in providing information on distribution and accumulation
of the compound and/or metabolites, especially in relation to potential
sites of action; this information may be useful for designing toxicology
and pharmacology studies and for interpreting the results of these experiments.
In the EC, US and Japan, there has been a general agreement
on the need to conduct single dose tissue distribution studies as part
of the non-clinical programme. These studies often provide sufficient
information about tissue distribution.
There has been no consistent requirement for repeated
dose tissue distribution studies. However, there may be circumstances
when assessments after repeated dosing may yield important information.
This paper provides guidance on circumstances when repeated
dose tissue distribution studies should be considered and on the conduct
of such studies.
2. CIRCUMSTANCES UNDER WHICH REPEATED
DOSE TISSUE DISTRIBUTION STUDIES SHOULD BE CONSIDERED
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When single dose tissue distribution studies suggest
that the apparent half-life of the test compound (and/or metabolites)
in organs or tissues significantly exceeds the apparent half life
of the elimination phase in plasma and is also more than twice the
dosing interval in the toxicity studies, repeated dose tissue distribution
studies may be appropriate.
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When steady-state levels of a compound/metabolite
in the circulation, determined in repeated dose pharmacokinetic or
toxicokinetic studies, are markedly higher than those predicted from
single dose kinetic studies, then repeated dose tissue distribution
studies should be considered.
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When histopathological changes, critical for the
safety evaluation of the test substances, are observed that would
not be predicted from short term toxicity studies, single dose tissue
distribution studies and pharmacological studies, repeated dose tissue
distribution studies may aid in the interpretation of these findings.
Those organs or tissues which were the site of the lesions should
be the focus of such studies.
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When the pharmaceutical is being developed for site-specific
targeted delivery, repeated dose tissue distribution studies may be
appropriate.
3. DESIGN AND CONDUCT OF REPEATED DOSE
TISSUE DISTRIBUTION STUDIES
The objectives of these studies may be achieved using
radiolabelled compounds or alternative methods of sufficient sensitivity
and specificity.
Dose level(s) and species should be chosen to address the problem
that led to the consideration of the repeated dose tissue distribution
study.
Information from previous pharmacokinetic and toxicokinetic studies
should be used in selecting the duration of dosing in repeated dose
tissue distribution studies. One week of dosing is normally considered
to be a minimum period. A longer duration should be selected when
the blood/plasma concentration of the compound and/or its metabolites
does not reach steady state. It is normally considered unnecessary
to dose for longer than three weeks.
Consideration should be given to measuring unchanged compound and/or
metabolites in organs and tissues in which extensive accumulation
occurs or if it is believed that such data may clarify mechanisms
of organ toxicity.
4. SUMMARY
Tissue distribution studies are an important component in the non-clinical
kinetics programme. For most compounds, it is expected that single dose
tissue distribution studies with sufficient sensitivity and specificity
will provide an adequate assessment of tissue distribution and the potential
for accumulation. Thus, repeated dose tissue distribution studies should
not be required uniformly for all compounds and should only be conducted
when appropriate data cannot be derived from other sources. Repeated
dose studies may be appropriate under certain circumstances based on
the data from single dose tissue distribution studies, toxicity and
toxicokinetic studies. The studies may be most appropriate for compounds
which have an apparently long half life, incomplete elimination or unanticipated
organ toxicity. The design and timing of repeated dose tissue distribution
studies should be determined on a case-by-case basis.
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