U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2003
ICH
Guidance for
Industry
M4: The CTD — Safety
Questions and Answers
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2003
ICH
Guidance for Industry
M4: The CTD — Safety
Questions and Answers
This guidance represents the Food and Drug
Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. An alternative
approach may be used if such approach satisfies the requirements
of the applicable statutes and regulations.
This is one in a series of guidances that
provide recommendations for applicants preparing the Common
Technical Document for the Registration of Pharmaceuticals for
Human Use (CTD) for submission to the U.S. Food and Drug
Administration (FDA). This guidance provides answers to questions
that have arisen since the finalization of the harmonized CTD
guidance documents in November 2000. This guidance specifically
addresses questions related to safety. Other question and answer
(Q &A) guidances are under development to address general
questions as well as questions related to quality and efficacy.
The questions and answers provided here reflect the consensus of the ICH
parties.
The guidance for industry issued in November
2000 on preparing the CTD was divided into four separate
documents: (1) M4: Organization of the CTD, (2) M4Q: The CTD —
Quality, (3) M4E: The CTD — Efficacy, and (4) M4S: The CTD —
Safety. Since implementation of these guidances, a number of
questions regarding the various CTD documents have been submitted
to the various ICH regions. The ICH has developed a process for
responding to questions submitted to the ICH Web site.
Q1: Kinetics in Pregnant Animals
and Neonates
Kinetics in
pregnant animals and neonates are included in the pharmacokenetics
(PK) section. Is it expected that these data will come from PK
studies, or can they be from kinetics in the Segment 2 studies?
A1: The CTD — Safety guidance is not intended to indicate
what studies are required. It merely indicates an appropriate
format for the nonclinical data that have been acquired.
Q2: Conduct/Nonconduct of Specific
Studies
If a
particular category of toxicology studies (e.g., carcinogenicity)
is not conducted for a drug because of the nature of the drug
(e.g., oncology agent), should the section heading be maintained
in the CTD document with an explanation provided as to why these
studies were not conducted, or should the heading section be
deleted and subsequent sections renumbered?
A2: Section headings should be maintained in the CTD and a
brief explanation provided as to why these studies were not
conducted.
Q3: Pivotal Studies
Would a
3-month toxicity study that was needed to support clinical studies
of 3-months’ duration, which was later replaced with a 9-month
toxicity study, be considered “pivotal” and tabulated as in Table
2.6.7.7?
A3: Yes. There should be one table for each of the
repeat-dose toxicity studies specified by the ICH guidance M3, as
well as any other repeat dose toxicity studies that could be
considered pivotal.
Q4: Tabulated Summary
Are only
toxicologically significant changes, as considered by applicants,
to be tabulated in CTD?
A4: Only noteworthy findings should be tabulated in the CTD.
These might include statistically significant differences from
controls, as well as noteworthy findings that are not
statistically significant.
Q5: Impurity Data Table in CTD-Safety-1
Generally speaking, it is
unlikely to have the finalized specification for related
substances and their analytical method throughout drug
development. Therefore, direct comparison of related-substance
data between different stages of development would be very
difficult, because of analytical method changes.
A5: One purpose of the “Drug Substance” table is to
facilitate a review of the qualification of the specified
impurities. If the analytical methods have changed, information
on early batches might not be applicable for qualification of
impurities. In this case, it is recommended that you use
footnotes in the “Drug Substance” table to identify the batches
that are relevant to qualification of impurities.
Q6: Impurity Data Table in
CTD-Safety-2
Should impurity-specification
test results of test articles used in early-stage toxicology
studies be included in CTD tables? Do test articles of non-GLP
(good laboratory practice) studies in the CTD need to have
specification test data?
A6: You need not analyze the drug substance used in non-GLP
studies. However, if such analyses have been conducted, the
results should be included in the “Drug Substance” table.
Q7: Nonclinical Tabulated
Summaries Templates
Are the templates for the
nonclinical tabulated summaries (Module 2.6) a suggested or a
required format?
A7: It is recommended that summary tables for the nonclinical
information in the Common Technical Document be provided in the
format outlined. Applicants can modify the format if needed to
provide the best possible presentation of the information and to
facilitate the understanding and evaluation of the results.
Q8: Granularity/Nonclinical
Tabulated Summaries
Is it right
that we need to correct the “Nonclinical Tabulated Summaries –
Word Templates” (in Appendix B) lines “Location in the CTD” with
volume and section instead of volume and
page?
A8: Yes. Applicants should put volume and section
number in the column of “Location in the CTD” within the
Nonclinical Tabulated Summaries.
Q9: List of References
A section for
list of references of the nonclinical summary (2.6.8 or 2.6.2.8
plus 2.6.4.11 plus 2.6.6.11) is not covered in the guidance,
unlike for the clinical summary and both nonclinical and clinical
overview. Could you please provide clarity where in these
summaries lists of references should be included?
A9: Applicants can place the list of references in the most
appropriate location and create new subsection numbers as far as
it facilitates the best possible understanding by the regulatory
reviewers.
This guidance was developed
within the M4 CTD-Safety Implementation Working Group of the
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
(ICH) and has been subject to consultation by the regulatory
parties, in accordance with the ICH process. This document
has been endorsed by the ICH Steering Committee at Step 4
of the ICH process, September 12, 2002. At Step 4 of
the process, the final draft is recommended for adoption to
the regulatory bodies of the European Union, Japan, and the
United States.