Therapeutic Products Programme
Holland Cross, Tower "B"
1600 Scott Street
Address Locator # 3102D1
OTTAWA, Ontario
K1A 1B6
March 24, 2000
00-003532
To: Main Trade Associations, Registrars of Medicine, Registrars of Pharmacy
I am pleased to inform you of the release of the International Conference
on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals
for Human Use (ICH)/Therapeutic Products Programme Guidance, Duration
of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity
Testing) ICH Topic S4A.
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, the Therapeutic Products Programme (TPP)
endorses the principles and practices described therein. This document
should be read in conjunction with this covering letter and with the relevant
sections of other applicable Programme guidances.
The Programme recognizes that the scope and subject matter of current
TPP guidances may not be entirely consistent with those of the ICH guidances
that are being introduced as part of the Programme's commitment to international
harmonization and the ICH Process. In such circumstances, the ICH guidances
adopted by the TPP take precedence. In this regard, the TPP will be examining
necessary changes to the Programme's 1990 Toxicological Evaluation
Guideline.
The TPP is committed to eliminating such discrepancies through the implementation
of a phased-in work plan that will examine the impact associated with
the adoption of ICH guidances. This will result in the amendment or, depending
on the extent of revisions required, withdrawal of some TPP guidances.
This and other Guidance documents are available on the Therapeutic Products
Programme (TPP) Website (http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/).
The availability of printed copies of TPP guidances may be confirmed by
consulting the Programme's Guidelines and Publications Order Forms
(available on the TPP Website) or by contacting the Publications Coordinator(1).
Should you have any questions regarding the content of the guidance,
please contact
Dr. Peter Grosser
Clinical Trials & Special Access Programme
Bureau of Pharmaceutical Assessment
Therapeutic Products Programme
Health Canada
A.L. 0202C1
Finance Building, Tunney's Pasture
OTTAWA, Ontario
K1A 1B6
Telephone: (613) 941-2132
Facsimile: (613) 941-2121
(Original signed by)
Dann M. Michols
Director General
Enclosure
1 Tel: (613) 954-6466; E-mail: publications_coordinator@hc-sc-gc.ca
Disclaimer
The material herein was prepared under the direction of the Therapeutic
Products Programme, Health Canada. No changes are permitted.
![redbar](/web/20061214002122im_/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/images/redbar.gif)
GUIDANCE FOR INDUSTRY
Duration of Chronic Toxicity Testing in Animals
(Rodent and Non Rodent Toxicity Testing) ICH Topic S4A
![redbar](/web/20061214002122im_/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/images/redbar.gif)
Published by authority of the Minister of Health
![redbar](/web/20061214002122im_/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/images/redbar.gif)
Date Adopted by the TPP |
1999/12/16 |
Effective Date |
2000/03/24 |
Health Products and Food Branch Guidance Document
Our mission is to help the people of Canada
maintain and improve their health.
Health Canada |
Our mission is to ensure that the drug, medical devices,
and other therapeutic products available in Canada are safe, effective
and of high quality and that narcotic and restricted substances are
not abused or diverted from legitimate uses.
Therapeutic Products Programme |
© Minister of Public Works and Government Services Canada 2000
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 : Durée des
essais de toxicité chronique chez les animaux (essais de toxicité chez
les rongeurs et les autres animaux)
Catalogue No. H42-2/67-17-1999E
ISBN 0-662-28444-5
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, the Therapeutic Products Programme (TPP)
endorses the principles and practices described therein. This document
should be read in conjunction with the accompanying covering letter and
with the relevant sections of other applicable Programme guidances.
Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the TPP policies and governing
statutes and regulations. They also serve to provide review and compliance
guidance to TPP staff, thereby ensuring that the Programme's mandate is
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 Programme
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 the
Programme reserves the right to request information or material, or define
conditions not specifically described in this guidance, in order to allow
the Programme to adequately assess the safety, efficacy or quality of
a therapeutic product. The TPP is committed to ensuring that such requests
are justifiable and that decisions are clearly documented.
1. OBJECTIVE
The objective of this guidance is to set out the considerations that
apply to chronic toxicity testing in rodents and non rodents as part of
the safety evaluation of a medicinal product. Since guidance is not legally
binding, an applicant may submit justification for an alternative approach.
2. SCOPE
This guidance has been prepared for the development of medicinal products
with the exception of those already covered by the ICH Guidance on Safety
Studies for Biotechnological Products, e.g. Monoclonal antibodies, recombinant
DNA proteins.
3. BACKGROUND
During the first International Conference on Harmonisation in 1991, the
practices for the testing of chronic toxicity in the 3 regions (EU, Japan,
and US) had been reviewed. Arising from this it emerged that there was
a scientific consensus on the approach for chronic testing in rodents,
supporting the harmonised duration of testing of 6 months. However, for
chronic toxicity testing in non-rodents, there were different approaches
to the duration of testing.
The lack of harmonised duration led to the need for pharmaceutical companies
to perform partially duplicative studies for both 6 and 12 months duration
when developing new medicinal products. As the objective of ICH is to
reduce or eliminate the need to duplicate testing during development of
medicinal products and to ensure a more economical use of material, animal
and human resources, while at the same time maintaining safeguards to
protect public health, further scientific evaluation was undertaken.
Each of the regulatory authorities in EU, Japan and US undertook a review
to determine whether a single duration for chronic toxicity testing in
non-rodents could be identified. From this analysis it emerged that in
16 cases a more detailed evaluation of 6 versus 12 months data should
be undertaken. This evaluation was conducted as a joint exercise by the
competent authorities in the 3 regions.
In some of the cases analysed at the tripartite meetings, there were
no additional findings at 12 months. For some other cases, there was not
complete agreement among the regulators with respect to the comparability
in study design and conduct to allow assessment of whether there were
differences in the findings at 6 and 12 months due to duration of treatment
alone.
In a number of cases there were findings observed by 12 months, but not
by 6 months. It was concluded that these would, or could have been detected
in a study of nine months duration. Varying degrees of concern for the
differences in findings detected between the studies of different durations
were expressed. An agreement on the clinical relevance of these findings
could not be reached.
Studies of 12 months duration are usually not necessary and studies of
shorter than 9 months duration may be sufficient.
In the EU, studies of 6 months duration in non-rodents are acceptable
according to Council Directive 75/318/EEC, as amended. To avoid duplication,
where studies with a longer duration have been conducted, it would not
be necessary to conduct a study of 6 months.
![Top of Page](/web/20061214002122im_/http://www.hc-sc.gc.ca/images/dhp-mps/arrow_up.gif)
4. GUIDANCE ON DURATION OF CHRONIC TOXICITY TESTING FOR TRIPARTITE
DEVELOPMENT PLAN
Arising from the extensive analysis and review of the above mentioned
data in non-rodents and based upon the achievements of ICH1 for testing
in rodents, and so as to avoid duplication and follow a single development
plan for chronic toxicity testing of new medicinal products, the following
studies are considered acceptable for submission in the 3 Regions:
- Rodents: a study of 6 months duration;
- Non-rodents: a study of nine months duration.
|