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Status of Safety Topics
S1A: Guideline on the Need for
Carcinogenicity Studies of Pharmaceuticals
The tripartite harmonised ICH guideline was finalised (Step 4) in November 1995.
This document provides a consistent definition of the circumstances under
which it is necessary to undertake carcinogenicity studies on new drugs.
These recommendations take into account the known risk factors as well as
the intended indications and duration of exposure. |
S1A |
Implementation (Step 5) :
EU : Adopted by CPMP, December 95, issued as CPMP/ICH/140/95
MHLW : Adopted April 97, PAB/PCD Notification No.315
FDA : Published in the Federal Register, Vol. 61, March 1, 1996,
pages 8153 |
Status : Step 5
November 1995 |
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S1B: Testing for Carcinogenicity of
Pharmaceuticals
The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997.
This document provides guidance on the need to carry out carcinogenicity
studies in both mice and rats, and guidance is also given on alternative
testing procedures which may be applied without jeopardizing safety. |
S1B |
Implementation (Step 5) :
EU : Adopted by CPMP, September 97, issued as CPMP/ICH/299/95
MHLW : Adopted July 1998, PMSB/ELD Notification No.548
FDA : Published in the Federal Register, Vol. 63, February 23,
1998, page 8983 |
Status : Step 5
July 1997 |
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S1C(R2): Dose Selection for Carcinogenicity
Studies of Pharmaceuticals
This second revision has been approved by the ICH
Steering Committee directly under Step 4 without further public
consultation in March 2008. Note 2 of the parent
guideline has been deleted, and the text referring to the Notes has been
revised. The title has been changed by deleting "& Limit
Dose".
The Addendum has been integrated in the text. This document addresses the
criteria for the selection of the high dose to be used in carcinogenicity
studies on new therapeutic agents to harmonise current practices
and improve the design of studies. In this
revision, the pharmacokinetic endpoint of 25 is declared to be applicable
also for pharmaceuticals with positive genotoxicity signals. This change
has implications on "Refinement" (one of the 3R's) in enhancing
the welfare, i.e., reducing the pain or discomfort of the animals at the
MTD.
S1C(R2)
Final Concept Paper, June 2006 (revision of S1C(R1) |
S1C(R2)
|
Implementation (Step 5) : EU : Core
guideline adopted by CPMP (CPMP/ICH/383/95), November 94, Addendum adopted, September 97, issued as
CPMP/ICH/366/96.
Second revision: Final approval by CHMP in April 2008 (CHMP/ICH/383/1995). Date for coming into operation: October 2008.
MHLW : Core guideline adopted August 96, PAB/PCD Notification
No.544, Addendum adopted July 1998, PMSB/ELD Notification No.551.
Second
revision: PFSB/ELD Notification n° 1127001 on November 27, 2008.
FDA : Core guideline published in the Federal Register, Vol. 60, No.40,
March 1, 1995, pages 11278- 11281, Addendum published in the FR, Vol.
62, No. 233, December 4, 1997, page 64260. R2 was posted on the FDA
website on September 17, 2008. |
Status : Step 5
March 2008
|
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S2A: Guidance on Specific Aspects of
Regulatory Genotoxicity Tests for Pharmaceuticals
The tripartite harmonised ICH guideline was
finalised (Step 4) in July 1995. This document provides specific
guidance and recommendations for in vitro and in vivo tests
and on the evaluation of test results. It includes a glossary of
terms related to genotoxicity tests to improve consistency in
applications. |
S2A |
Implementation (Step 5) :
EU : Adopted by CPMP, September 95, issued as CPMP/ICH/141/95
MHLW : Adopted July 96, PAB/PCD Notification No.444
FDA : Published in the Federal Register, Vol. 61, April 24, 1996,
page 18199 |
Status : Step 5
July 1995 |
S2B: Genotoxicity: A Standard Battery for
Genotoxicity Testing for Pharmaceuticals
The tripartite harmonised ICH guideline was
finalised (Step 4) in July 1997. This document addresses two
fundamental areas of genotoxicity testing: the identification of a
standard set of assays to be conducted for registration, and the extent of
confirmatory experimentation in any particular genotoxicity assay in the
standard battery. |
S2B |
Implementation (Step 5) :
EU : Adopted by CPMP, September 97, issued as CPMP/ICH/174/95
MHLW : Adopted July 1998, PMSB/ELD Notification No.554
FDA : Published in the Federal Register 21 November 1997 |
Status : Step 5
July 1997 |
S2(R1): Guidance on Genotoxicity Testing
and Data Interpretation for Pharmaceuticals Intended for Human Use
This guideline has been released for consultation
under Step 2 of the ICH process on 6 March 2008.
This guidance replaces and combines the ICH S2A and S2B
guidelines:
The
purpose of the revision of this guideline is to optimize the standard genetic toxicology
battery for prediction of potential human risks, and to provide guidance
on interpretation of results, with the ultimate goal of improving risk
characterization for carcinogenic effects that have their basis in changes
in the genetic material. The revised guidance describes internationally
agreed upon standards for follow-up testing and interpretation of positive
results in vitro and in vivo in the standard genetic toxicology battery,
including assessment of non-relevant findings.
S2(R1)
Final Concept Paper, September 2006 (revision of S2A and S2B) |
S2(R1) |
Consultation (Step 3) : EU :
Transmitted to CHMP and Interested Parties in March 2008, issued as EMEA/CHMP/ICH/126642/2008. Deadline for comments : May 2008
MHLW : Released for consultation 1 April 2008, PFSB/ELD, deadline
for comments 30 April 2008.
FDA : Published in the Federal Register, March 26, 2008, Volume
73, Number 59, Page 16024-16025, deadline for comments: May 10, 2008. |
Status : Step 3
March 2008 |
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S3A: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies
The tripartite harmonised ICH guideline was
finalised (Step 4) in October 1994. This document gives guidance on developing test
strategies in toxicokinetics and the need to integrate pharmacokinetics
into toxicity testing, in order to aid in the interpretation of the
toxicology findings and promote rational study design development. |
S3A |
Implementation (Step 5) :
EU : Adopted by CPMP, November 94, issued as CPMP/ICH/384/95
MHLW : Adopted July 96, PAB/PCD Notification No.443
FDA : Published in the Federal Register, Vol. 60, No. 40, March
1, 1995, pages 11264-11268 |
Status : Step 5
October 1994 |
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S3B: Pharmacokinetics: Guidance for
Repeated Dose Tissue Distribution Studies
The tripartite harmonised ICH guideline was
finalised (Step 4) in October 1994. This document gives guidance on circumstances
when repeated dose tissue distribution studies should be considered (i.e.,
when appropriate data cannot be derived from other sources). It also
gives recommendations on the conduct of such studies. |
S3B |
Implementation (Step 5) :
EU : Adopted by CPMP, November 94, issued as CPMP/ICH/385/95
MHLW : Adopted July 96, PAB/PCD Notification No.442
FDA : Published in the Federal Register, Vol. 60, No. 40, March
1, 1995, pages 11274-11275 |
Status : Step 5
October 1994 |
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S4: Single Dose Toxicity
Tests
Agreement was reached, at the time of ICH 1, in
1991, that the LD50 determination should be abandoned for
pharmaceuticals. The recommendation was published in the Proceedings of
the First International Conference on Harmonisation, page 184. |
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S4: Duration of Chronic
Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing)
A tripartite, harmonised ICH guideline was
finalised (Step 4) in September 1998. The recommendations are unchanged
from those in the consultation draft issued in July 1997. The text
incorporates the guidance for repeat-dose toxicity tests that was agreed
at the time of ICH 1, in 1991 (reduction of the duration of repeat dose
toxicity studies in the rat from 12 to 6 months). |
S4 |
Implementation (Step 5) :
EU : Adopted by CPMP, November 98 issued as CPMP/ICH/300/95
MHLW : Adopted on 5 April 1999, lyaku-sin No. 655
FDA : Published in the Federal Register, June 25, 1999 : 64FR
Page 34259 |
Status : Step 5
September 1998 |
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S5(R2): Detection of Toxicity to Reproduction
for Medicinal Products & Toxicity to Male Fertility
The core tripartite harmonised ICH guideline was
finalised (Step 4) in June 1993. This document provides guidance on tests for
reproductive toxicity. It defines the periods of treatment to be used in
animals to better reflect human exposure to medical products and allow
more specific identification of stages at risk. The
addendum to the core ICH guideline above
with respect to male fertility studies was finalised (Step 4) in November
1995. The guideline has been amended on November 9, 2000, under the Maintenance
Process. The amendments provide a better description of the testing concept
and recommendations, especially those
addressing flexibility, pre-mating treatment duration, and observations. |
S5(R2) |
Implementation of the core guideline (Step 5) :
EU : Adopted by CPMP, September 93, issued as CPMP/ICH/386/95
MHLW : Adopted July 94, PAB/PCD Notification No.470
FDA : Published in the Federal Register, Vol. 59, No.183,
September 22, 1994, pages 48746-48752 |
Status : Step 5
June 1993 |
(Addendum incorporated in the core
guideline) |
Implementation of the Addendum (Step 5) : EU : Adopted by
CPMP, December 95, issued as CPMP/ICH/136/95 -
Amended guideline : CPMP/ICH136/95 modification
MHLW : Adopted April 97, PAB/PCD Notification No.316 - Amended
guideline : Adopted December 27, 2000, PMSB/ELD Notification No. 1834
FDA : Published in the Federal Register, Vol. 61, No. 67, April
5, 1996, pages 15360 - Amended guideline : To be notified |
Status : Step 5
November 1995 |
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S6: Preclinical Safety Evaluation of
Biotechnology-Derived Pharmaceuticals
The tripartite harmonised ICH guideline was
finalised (Step 4) in July 1997. This document covers the
pre-clinical safety testing requirements for biotechnological products. It
addresses the use of animal models of disease, determination of when
genotoxicity assays and carcinogenicity studies should be performed, and
the impact of antibody formation on duration of toxicology studies.
S6
Final Concept Paper, October 1994 |
S6 |
Implementation (Step 5) :
EU : Adopted by CPMP, September 97, issued as CPMP/ICH/302/95
MHLW : Published, PAB/PCD, Notification n° 326, 22 February
2000
FDA : Published in the Federal Register, Vol. 62, No. 222,
November 18, 1997, pages 61515 |
Status : Step 5
July 1997 |
S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
This guideline has been released for consultation
under Step 2 of the ICH process on 29 October 2009.
The purpose of the addendum is to
provide clarification on S6 and an update of the following topics discussed in the
original
ICH
S6 guidance: species selection, study design, immunogenicity, reproductive and
developmental toxicity and assessment of carcinogenic potential. Scientific
advances and experience gained since publication of the original
ICH
S6 guidance call for this addendum.
This harmonised addendum will provide further complementary guidance to the S6
guideline and will help to define the current recommendations and
reduce the likelihood that substantial differences will exist among regions.
S6(R1)
Concept Paper, June 2008 |
S6(R1) |
Implementation (Step 3) : EU : Transmission
to CHMP and Interested Parties in November 2009. Deadline for comments:
February 2010. Issued as CPMP/ICH/302/95
MHLW : Released for consultation 8 January 2010, deadline
for comments 8 March 2010
FDA : Published in the Federal Register, Vol. 74, No 241, Docket No. FDA-2009-D-0573,
page 66980, 17 December 2009. Deadline for comments by February 1, 2010 |
Status : Step 3
October 2009 |
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S7A: Safety Pharmacology Studies for Human Pharmaceuticals
The ICH guideline reached Step 4 of the ICH process in November 2000. This
document addresses the definition, objectives and scope of safety pharmacology studies.
It also addresses which studies are needed before initiation of Phase 1 clinical
studies as well as information needed for marketing. |
S7A |
Implementation (Step 5) : EU : Adopted by
CPMP, November 2000, issued as CPMP/ICH/539/00 - ICH S7A
MHLW : Adopted on 21 June 2001, PFSB/ELD Notification n°
902
FDA : Published in the Federal Register, Vol. 66, No. 135; July 13, 2001, page
36791-92 |
Status : Step 5
November 2000 |
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S7B : The Nonclinical
Evaluation of the Potential for Delayed Ventricular Repolarization
(QT Interval Prolongation)
By Human Pharmaceuticals
The Guideline reached Step 4 of the ICH process on 12 May 2005. This
guideline describes a non-clinical testing strategy for assessing the
potential of a test substance to delay ventricular repolarization. This
guideline includes information concerning non-clinical assays and
integrated risk assessments.
S7B
Final Concept Paper, May 2001 |
S7B |
Implementation (Step 5) :
EU : Adopted by CHMP May 2005, issued as CHMP/ICH/423/02.
Date for coming into operation : November 2005
MHLW : Adopted 23 October 2009, PFSB/ELD Notification n° 1023-4
FDA : Published in the Federal Register, Vol. 70, N° 202,
pages 61133-61134; October 20, 2005 |
Status : Step 5
May 2005 |
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S8 : Immunotoxicity Studies for
Human Pharmaceuticals
The Guideline reached Step 4 of the ICH process on 15 September 2005. This guideline addresses the
recommendations on nonclinical testing for immunosuppression induced by
low molecular weight drugs (non-biologicals). It applies to new
pharmaceuticals intended for use in humans, as well as to marketed drug
products proposed for different indications or other variations on the
current product label in which the change could result in unaddressed and
relevant toxicologic issues. In addition, the guideline might also apply
to drugs in which clinical signs of immunosuppression are observed during
clinical trials and following approval to market. The term immunotoxicity
in this guideline will primarily refer to immunosuppression, i.e. a state
of increased susceptibility to infections or the development of tumors.
It is beyond the scope of this guideline to provide specific guidance on
how each immunotoxicity study should be performed.
General guidance is provided in Appendix 1.
S8
Final Concept Paper, November 2003 |
S8 |
Implementation (Step 5) : EU : Adopted
by CHMP October 2005, issued as EMEA/CHMP/167235/2004-ICH, Date for coming
into operation: April 2006
MHLW : Adopted 18 April 2006, PFSB/ELD Notification n°
0418001
FDA : Published in the Federal Register, Vol. 71, n° 71,
pages 19193 - 19194; April 13, 2006 |
Status : Step 5
September 2005 |
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S9: Nonclinical Evaluation for Anticancer
Pharmaceuticals
The Guideline reached Step 4 of the ICH process on 29 October 2009.
This guideline provides information for pharmaceuticals that are only
intended to treat cancer in patients with late stage or advanced disease
regardless of the route of administration, including both small molecule
and biotechnology-derived pharmaceuticals. It describes the
type and timing of nonclinical studies in relation to the development of
anticancer pharmaceuticals and references other guidance as appropriate.
S9
Final Concept Paper, April 2007
S9
Final Business Plan, May 2007
|
S9 |
Consultation (Step 5) : EU : Adopted
by CHMP November 2009, issued as CHMP/ICH/646107/2008, Date for coming
into operation: May 2010
MHLW : Adopted 4 June 2010, PFSB/ELD Notification n°0604-1
FDA : Published in the Federal Register, Vol. 75, No 44, Docket
No. FDA?2009?D?0006, page 10487, 8 March 2010 |
Status : Step 5
October 2009 |
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M3(R2): Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical
Trials and Marketing Authorization for Pharmaceuticals
The recommendations of this revised guidance further harmonise the nonclinical
safety studies to support the various stages of clinical development among the
regions of European Union (EU), Japan, and the United States. The present
guidance represents the consensus that exists regarding the type and duration of
nonclinical safety studies and their timing to support the conduct of human
clinical trials and marketing authorization for pharmaceuticals.
M3(R2)
Final Concept Paper, September 2006 (revision of M3(R1))
|
M3(R2)
|
Implementation (Step 5) : EU : Approved
by CHMP June 2009, issued as CPMP/ICH/286/95.
Date for coming into operation: December 2009
MHLW : Adopted on February 19, 2010, PFSB/ELD notification
No. 0219-4
FDA : Published in the Federal Register, Vol. 75, No 13, Docket
No. FDA?2008?D?0470, page 3471, 21 January 2010 |
Status : Step 5
June 2009
|
|
Questions and comments concerning the
implementation of M3(R2) are welcome. Your questions and comments will be discussed at the following working
session of the M3(R2) Implementation Working Group (IWG). A Questions & Answers
document will be developed by the IWG and submitted for adoption by the ICH Steering
Committee. |
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Updated : 13.09.10
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