Guidance for Industry
M4: CTD — Efficacy
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. You can use an alternative approach if that
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
I.
INTRODUCTION
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 efficacy. Other question and
answer (Q &A) guidances are under development to address general
questions as well as questions related to quality and safety.
The
questions and answers provided here reflect the consensus of the
ICH parties.
This guidance is being revised to include
additional questions.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
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) M4: The CTD — Quality, (3)
M4: The CTD — Efficacy, and (4) M4: 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: Clinical study reports contained in Module 5 are
cited in the Clinical Overview and/or the Clinical Summary in
Module 2. Each clinical study report may be given a unique short
name when cited. Does the method of citing and naming have to be
uniform throughout all modules?
A1: We recommend that each study have a unique short
identifier that is used consistently throughout the application.
The applicant can select the identifier. The full title of the
study is provided in the Tabular Listing of All Clinical Studies
(Section 5.2)
Q2: Definitions/Terminology
What is the
definition of Common Adverse Events as used in the CTD?
A2: Guidance is provided by ICH E3
Guideline.
Q3: Section Numbering/Title (in
Module 5)
In Module 5 of the CTD, is it
necessary to have a section number for each clinical study report
in a certain section, or is it enough just to mention the title:
5.3.5 Report of
Efficacy….
5.3.5.1 Study
Reports….
5.3.5.1.1
Placebo Controlled….
Study XXX
A3: See ICH granularity document.
Q4: How many pages should a Clinical Summary be for an
application that contains multiple indications?
A4: The estimated size of this document is 50-400 pages,
assuming one indication. Applications that include multiple
indications will be larger, reflecting the submission of multiple
efficacy sections.
Q5: Section “2.7.3.3” Comparisons
and Analyses of Results Across Studies
The Guideline provides “This section should also cross-reference
important evidence from Section 2, such as data that supports the
dosage and administration section of the labeling.” However, this
Guideline also provides a Section, “2.7.3.4. Analysis of Clinical
Information Relevant to Recommended Dose.” Please specify how to
differentiate the two sections “2.7.3.3” and “2.7.3.4”.
A5: Section 2.7.3.3 summarizes the data across all studies
that characterize efficacy of the drug; Section 2.7.3.4 provides
an integrated summary of the dose-response or blood
concentration-response relationships of effectiveness. In both
cases, supportive data from Section 2.7.2 can also be
incorporated.
Q6: Overall Extent of Exposure
In the
Guideline, a table is required to be generated to present the
overall extent of drug exposure in all phases of the clinical
development. Should the table include “patients alone” or
“patients and healthy subjects”?
A6: That table should refer to all subjects exposed to at
least one dose of the drug product. Appropriate subsets of
subjects relevant to the proposed indications should also be
identified and considered.
Q7: Summary of Clinical Safety
Where should information be described
concerning the validity of extrapolation of foreign clinical
safety data to a new region?
A7: Summaries of any bridging studies using clinical
endpoints (i.e., certain studies intended to evaluate the ability
to extrapolate certain types of foreign clinical data to the new
region (see ICH E5)) should be included in Section 2.7.3.2. Where
appropriate, such information should also be described in the
summarization of safety data as related to intrinsic and extrinsic
ethnic factors (ICH E5), in Sections 2.7.4.5.1 and 2.7.4.5.2.
Finally, some applications might include in Section 5.3.5.3 a
detailed analysis of bridging, considering formal bridging
studies, other relevant clinical studies, and other appropriate
information. Such information should be included in that detailed
analysis of bridging.
Q8: Bioavailability/Bioequivalence
Study Data
Where should
the information on bioequivalence studies for a generic
application be included?
A8: Bioavailability study reports should be included in
Module 5 (Clinical documentation), under section 5.3.1 “Reports of
Biopharmaceutical Studies”. More specifically, reports of
comparative Bioavailability/Bioequivalence studies should go under
section 5.3.1.2.
Q9: Tabular Listing of Clinical
Studies in Paper CTD
In Module 5,
5.2 is denoted as the ‘Tabular Listing of all Clinical Studies’.
Is this section for a summary listing of all clinical studies in
the submission, or it is for the listing of the individual study
reports? In other words, should the listings from the appendices
of the individual study reports be included here, rather than as
an appendix to the CSR, or are these only listings that summarize
all studies?
A9: The tabular listing described in section 5.2 is a
listing of all clinical studies in the submission.
An example of such
a listing is given in Table 5.1.
Q10 Integrated Summary of Safety and Effectiveness
Does the
CTD section on safety in Module 2 replace the section under 21 CFR
314.50(d)(5)(v)-(vi) calling for integrated summary of safety and
effectiveness (ISS/ISE)?
A10: The ISS/ISE are critical components of the safety and
effectiveness submission and are expected to be submitted in the
application in accordance with the regulation. FDA’s guidance
Format and Content of Clinical and Statistical Sections of
Application gives advice on how to construct these summaries.
Note that, despite the name, these are integrated analyses of all
relevant data, not summaries.
The Clinical
Safety sections of the CTD follow approximately the outline of the
sections of the ISS/ISE, although they are somewhat modified by
experience with ICH E-3 (Structure and Content of Clinical
Study Reports). The CTD Clinical Overview and Summary in
Module 2 will not usually contain the level of detail expected for
an ISS. It may contain the level of detail needed for an ISE, but
this would need to be determined on a case-by-case basis.
If the
requirements of 21 CFR 314.50 can be met for a particular
application by what is in the CTD Module 2 summary, the CTD Module
2 section would fulfill the need for an ISS/ISE. In
some cases, it will be convenient to write much of what is needed
in the CTD Module 2 with appropriate appendices in Module 5. In
other cases, the ISS/ISE would be summarized in Module 2, with
detailed reports in Module 5.
Any questions
about these matters can be raised with the reviewing division.
Q11: Microbiology Data
The
microbiology data will include both in vitro and in vivo studies.
Where should the microbiology summary, overview, and study reports
be included?
A11: The microbiology data from both in vitro and in vivo
studies should be included with the Efficacy information. The
summary information should be provided in the appropriate section
2.7 Clinical Summary and the reports should be filed in section
5.3.5.4 Other Study Reports.
In addition, the
microbiology information can be described in the Nonclinical
sections as appropriate.
Q12: Clinical Variation
For a
clinical variation application, is it mandatory to submit a
clinical overview and a clinical summary, or is it acceptable to
submit either only an overview or only a summary? What are the
parameters/conditions to be taken into account for choosing one or
the other approach?
A12: Since variation is a term from the EU regulations, the
answer should be provided by the EMEA.
Q13: Integrated Analysis of Efficacy (ISE) Section 2.7 –
Clinical Summary – Statistical Listings
What
approach should applicants take for the formatting and
presentation of their integrated analyses when they have large
amounts of statistical output to present (several thousands of
pages)?
A13: As stated in section Reports of Analyses From More Than
One Study 5.3.5.3, where the details of the analysis are too
extensive to be reported in a summary document (for example,
section Clinical Summary 2.7), they should be presented in a
separate report. Such report should be placed in section 5.3.5.3.
Q14: Cross References/Cross Strings (in Paper
Submissions)
It is stated
in the CTD that the section should be indicated in cross strings.
What is meant here: The section number, or the section number and
section name? (The section name is in many cases too long to
indicate in a cross string.)
A14: Providing the section header in addition to the section
number improves the clarity of the reference, particularly for the
uninitiated reader. To reduce the length of the cross string while
maintaining the ease of use, it is recommended to include only the
section number in the cross string and write the text so the
reader will also know the section content. For example, “…as seen
in the population PK study 101 (5.3.3.5)” helps the reader to find
the referenced study report under the Population PK Study Reports
section. The text “…no safety problems were noted in the
uncontrolled pneumonia study 101A (5.3.5.2)” helps the reader find
the referenced study report under the section Study Reports of
Uncontrolled Clinical Studies for the Pneumonia indication.
Q15: Limitations of the Safety Database and Potential
Implications
Section 2.5
Clinical Overview and section 2.5.5 Overview of Safety both refer
to an assessment of the limitations of the safety database but
give few details on how to describe them. How should these
limitations be described? In addition, there is no specific
reference to any postmarketing steps the applicant can take to
remedy those limitations. Where should a discussion of any
postmarketing pharmacovigilance and other postmarketing study
plans go?
A15: A fuller discussion of how to describe in the CTD the
limitations of the safety database and the potential implications
for the safety of the drug when marketed is as follows:
·
Nonclinical toxicology and safety pharmacology
concerns, such as those arising from reproductive / developmental
toxicity, carcinogenicity, hepatic injury, central nervous system
injury, or effects on cardiac repolarization that are not fully
resolved by available human data, or that arise from incomplete
testing.
·
Limitations of human safety database, such as:
o
Patient selection criteria that excluded people who
are likely to be candidates for treatment in medical practice.
o
Evaluations that were deficient for certain purposes
(e.g., many drugs with sedative properties are not evaluated for
effects on cognitive function in the elderly).
o
Limited exposure of demographic or other subgroups,
such as children, women, the elderly, or patients with abnormal
hepatic or renal function.
·
Identified adverse events and potential adverse
events that require further characterization or evaluation with
respect to frequency and/or seriousness in the general population
or in specific subgroups.
·
Important potential risks (e.g., known risks of
pharmacologically related drugs) that require further evaluation.
·
Drug-drug interactions that have not been assessed
adequately.
Such
information should be described and discussed in section 2.5.5
Overview of Safety, with appropriate cross references to section
2.7.4 Summary of Clinical Safety and any other relevant sections.
A
discussion of any planned postmarketing activity or study to
address the limitations of the premarketing safety database should
also be included in section 2.5.5 Overview of Safety, with any
protocols for specific studies provided in section5.3.5.4 Other
Clinical Study Reports or other sections as appropriate (e.g.,
module 4 if the study is a nonclinical study).
An ICH guideline
(E2E Pharmacovigilance Planning) is being developed to further
address the question of how to describe the safety data and its
limitations and how to describe planned postmarketing activities
and studies.
Q16: Multiple Indications
When
submitting one dossier for multiple indications, how should the
applicant present them in the clinical part of the registration
dossier, for example sections 2.5 Clinical Overview, 2.7.3 Summary
of Clinical Efficacy, and 5.3.5 Reports of Efficacy and Safety
Studies?
A16: One section 2.5 Clinical Overview is recommended for
multiple indications to be registered
along with development rationale and cross-referencing to the
corresponding 2.7.3 and 5.3.5 sections; the “benefit/risk”
conclusions should support corresponding claimed indications.
For section 2.7.3 Summary of
Clinical Efficacy, in the case of more than one indication, the
following organization is recommended as applicable. The current
CTD numbering should be retained with identification of the
indication, for example:
2.7.3. UTI Summary of
Clinical Efficacy
2.7.3.1. UTI Background
2.7.3.2. UTI Summary of Results of individual studies
2.7.3.3. UTI comparison and analysis
2.7.3.3.1. UTI study population
2.7.3.3.2. UTI Comparison of efficacy results
2.7.3. Pneumonia Summary of Clinical Efficacy
2.7.3.1. Pneumonia Background
Other sections follow the
same organization where applicable.
For section 5.3.5 Reports of
Efficacy and Safety Studies, in case of more than one indication,
the following organization is recommended as applicable. The
current CTD numbering should be retained with identification of
the indications, for example:
5.3.5.UTI
5.3.5.1. UTI Controlled studies
5.3.5.2. UTI Uncontrolled studies
5.3.5. Pneumonia
5.3.5.1. Pneumonia Controlled studies
5.3.5.2. Pneumonia Uncontrolled studies
Other sections follow the same organization, where applicable.
Q17: Narrative Descriptions
The CTD
guidance for Section Overall Safety Evaluation Plan and Narratives
of Safety Studies 2.7.4.1.1 states that narrative descriptions for
studies that contributed both efficacy and safety should be
included in Section Summary of Results of Individual Studies
2.7.3.2 and only referenced in the safety section. Please clarify
whether the narrative to be included in 2.7.3.2 should include the
safety results as well as “enough detail to allow the reviewer to
understand the exposure… and how safety data were collected” or
whether the results should be included in Section 2.7.4.1.1.
A17: In general, safety results should be described in section
2.7.4.1.1, because section Summary of Clinical Efficacy 2.7.3 is
devoted to efficacy. To avoid the need to describe the same study
twice, section 2.7.3.2 asks for a reasonably complete description
of studies pertinent to both safety and efficacy, including, in
study narratives, information about the extent of exposure of
study subjects to the test drug and how safety data were
collected. This approach is confirmed in section 2.7.4.1.1, which
notes that narratives for studies contributing both safety and
efficacy data should be included in section 2.7.3.2. As noted in
section Background and Overview of Clinical Efficacy 2.7.3.1,
however, any results of these studies that are pertinent to
evaluation of safety should be discussed in section Summary of
Clinical Safety 2.7.4.
Q18: According to ICH
E3 Structure and Content of Clinical Study Reports, the
case report forms should be located in Appendix 16.3, the
individual patient data listings in Appendix 16.4, and the
publications and literature references in Appendices 16.1.11 and
16.1.12 respectively. The CTD organization provides locations for
case report forms and individual patient data listings in Module
5.3.7 and for literature references in Module 5.4.
Can clarity be provided as to where
these items should actually be placed in CTD and the eCTD
submissions?
A18: For paper submissions, case report forms and individual
patient data listings should be located in Module 5.3.7,
identified by study.
For eCTD, PDF
files for case report forms and individual patient data listings
should be organized by study in the folder for Module 5.3.7.
However, in the index.xml file, the leaf elements for the
case report forms and individual patient data listings should be
included under the same heading as other study report files with
additional information included with any accompanying study
tagging file. In addition, a repeat of the leaf element can
be placed under the heading 5.3.7 Case Report Forms and Individual
Patient Data Listings. Datasets, if required by the region,
should be organized according to regional guidance.
For paper
submissions, publications and literature references should be
located in Module 5.4.
For eCTD, the
files for publications and literature references should be located
in the folder for Module 5.4. However, in the index.xml
file, the leaf elements for the publications and literature
references should be included under the same heading as other
study report files with additional information included with any
accompanying study tagging file. In addition, a repeat of the
leaf element should be placed under the heading for 5.4
Literature References.
This guidance was developed within
the M4 CTD-Efficacy 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, June 10, 2004. 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.