Thursday, July 2, 2009


The document of this part is not required for Generic Products, Minor Variation Products and
some Major Variation Products. For ASEAN member countries, the Clinical Study Reports
of this part may not be required for NCE, Biotechnological Products and other Major
Variation Products if the Original Products are already registered and approved for market
authorization in Reference Countries. Therefore, the authority who wishes to obtain such
Clinical Study Reports should request for additional documentation.
The Clinical Summary is intended to provide a detailed, factual summarisation of all of the
clinical information in the ASEAN Common Technical Dossier. This includes information
provided in Clinical Study Reports; information obtained from any meta-analyses or other
cross-study analyses for which full reports have been included in Clinical Study Reports and
post-marketing data for products that have been marketed in other regions. The comparisons
and analyses of results across studies provided in this document should focus on factual
observations. In contrast, the ACTD Clinical Overview document should provide critical
analysis of the clinical study program and its results, including discussion and interpretation
of the clinical findings and discussion of the place of the test drug in the armamentarium.
The length of the Clinical Summary will vary substantially according to the information to be
conveyed, but it is anticipated that (excluding attached tables) the Clinical Summary will usually be in
the range of 50 to 400 pages.

1.1 Background and Overview
This section should provide the reviewer with an overall view of the formulation
development process, the in vitro and in vivo dosage form performance, and the general
approach and rationale used in developing the bioavailability (BA), comparative BA,
bioequivalence (BE), and in vitro dissolution profile database. Reference should be made to
any guidelines or literature used in planning and conducting the studies. This section should
also provide the reviewer with an overview of the analytical methods used, with emphasis on
the performance characteristics of assay validation (e.g., linearity range, sensitivity,
specificity) and quality control (e.g., accuracy and precision). This section should not include
detailed information about individual studies.
1.2 Summary of Results of Individual Studies
A tabular listing of all biopharmaceutic studies should generally be provided (see Appendix
1), together with narrative descriptions of relevant features and outcomes of each of the
individual studies that provided important in vitro or in vivo data and information relevant to
BA and BE. The narrative descriptions should be brief, e.g., similar to an abstract for a
journal article, and should describe critical design features and critical results. Similar
studies may be described together, noting the individual study results and any important
differences among the studies. These narratives may be abstracted from the ICH E3 synopsis.
References or electronic links to the full report of each study should be included in the
1.3 Comparison and Analyses of Results across Studies
This section should provide a factual summary of all in vitro dissolution, BA, and
comparative BA studies carried out with the drug substance or drug product, with particular
attention to differences in results across studies. This overview should typically summarise
the findings in text and tables (see Appendix 1) and should consider the following:
• evidence of the effects of formulation and manufacturing changes on in vitro dissolution
and BA and conclusions regarding BE. When manufacturing or formulation changes are
made for products containing complex drug substances (e.g., a protein), pharmacokinetic
(PK) studies comparing the product before and after the changes may be performed to
ensure that the PK characteristics have not changed as a result of product changes.
Although such studies are sometimes referred to as BE studies, they generally do not
focus on assessing release of drug substance from drug product. Nonetheless, such studies
should be reported in this section. Note also that PK studies alone may not be sufficient
to assure similarity between such drug products. In many situations, pharmacodynamic
(PD) studies or clinical trials may be necessary. Additionally, depending on the
circumstances, antigenicity data may also be needed. Results of these other types of
studies, when they are needed, should be reported in the appropriate places in the dossier.
• evidence of the extent of food effects on BA and conclusions regarding BE with respect
to meal type or timing of the meal (where appropriate).
• evidence of correlations between in vitro dissolution and BA, including the effects of pH
on dissolution, and conclusions regarding dissolution specifications.
• comparative bioavailability, including BE conclusions, for different dosage form
• comparative BA of the clinical study formulations (for clinical studies providing
substantial evidence of efficacy) and the formulations to be marketed.
• the source and magnitude of observed inter- and intra-subject variability for each
formulation in a comparative BA study.
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Appendix 1
Tables and figures should be embedded in the text of the appropriate sections when they
enhance the readability of the document. Lengthy tables can be provided in the appendix at
the end of the Section.
Tables 1.1 and 1.2 are provided as examples of tabular formats for reporting information and
results related to bioavailability and in vitro dissolution studies respectively. These examples
give results as well as identifying the type and design of the study. Tables prepared for
reporting the results of BE studies could also include the mean ratios (test/reference) for
Cmax and AUC and their 90% confidence interval, or the currently recommended metrics for
BE assessments.
These tables are not intended to be templates, but only to illustrate the type of information
that should be considered by an applicant in designing the tables for biopharmaceutic studies.
Applicants should also decide whether information and results from these studies are best
presented in tables, text or figures in order to aid clarity. If, for example, results are best
presented in text and figures, tables might be used simply to list the studies.
2.1 Background and Overview
This section should provide the reviewer with an overall view of the clinical pharmacology
studies. These studies include clinical studies performed to evaluate human pharmacokinetics
(PK), and pharmacodynamics (PD), and in vitro studies performed with human cells, tissues,
or related materials (hereinafter referred to as human biomaterials) that are pertinent to PK
processes. For vaccine products, this section should provide the reviewer with immune
response data that support the selection of dose, dosage schedule, and formulation of the final
product. Where appropriate, relevant data that are summarised in Items 1, 3 and 4 of Section
C can also be referenced to provide a comprehensive view of the approach and rationale for
the development of the pharmacokinetic, pharmacodynamic, PK/PD and human biomaterial
database. This section should not include detailed information about individual studies.
This section should begin with a brief overview of the human biomaterial studies that were
conducted and that were intended to help in the interpretation of PK or PD data. Studies of
permeability (e.g., intestinal absorption, blood brain barrier passage), protein binding, hepatic
metabolism, and metabolic-based drug-drug interactions are particularly relevant. This should
be followed by a brief overview of the clinical studies that were carried out to characterise
PK and PD of the medicinal product, including studies of PK/PD relationships in healthy
subjects and patients. Critical aspects of study design and data analysis should be noted, e.g.,
the choice of the single or multiple doses used, the study population, the choice of PD
endpoints, and whether a traditional approach or a population approach was used to collect
and analyse data to assess PK or PD.
2.2 Summary of Results of Individual Studies
A tabular listing of all clinical pharmacology studies should generally be provided (see
Appendix 2), together with a narrative description of the relevant features and outcomes of
each of the critical individual studies that provided in vitro or in vivo data and information
relevant to PK, PD and PK/PD relationships. The narrative descriptions should be brief, e.g.,
similar to an abstract for a journal article, and should describe critical design features and
critical results. Similar studies may be described together, noting the individual study results
and any important differences among the studies. References or electronic links to the full
report of each study should be included in the narratives.
Summaries of dose-response or concentration response (PK/PD) studies with
pharmacodynamic endpoints should generally be included in this section. In some cases,
however, when well-controlled dose-response PD or PK/PD studies provide important
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evidence of efficacy or safety, they should be placed in Item 3 or 4 as appropriate and
referenced, but not summarised, here.
2.3 Comparison and Analyses of Results across Studies
This section should use the results of all in vitro human biomaterial studies and PK, PD and
PK/PD studies to characterise the PK, PD and PK/PD relationships of the drug. Results
related to the inter- and intra-individual variability in these data affecting these
pharmacokinetic relationships should be discussed.
This section (typically with the use of text and tables) should provide a factual presentation of
all data across studies pertinent to the following:
• in vitro drug metabolism and in vitro drug-drug interaction studies and their clinical
• human PK studies, including the best estimates of standard parameters and sources of
variability. The focus should be on evidence supporting dose and dose individualisation
in the target patient population and in special populations, e.g., pediatric or geriatric
patients, or patients with renal or hepatic impairment.
• comparison between single and repeated-dose PK
• population PK analyses, such as results based on sparse sampling across studies that
address inter-individual variations in the PK or PD of the active drug substances.
• dose-response or concentration-response relationships. This discussion should highlight
evidence to support the selection of dosages and dose intervals studied in the important
clinical trials. In addition, information that supports the dosage instructions in the
proposed labelling should be discussed in Item 3.4.
• major inconsistencies in the human biomaterial, PK, or PD database.
2.4 Special Studies
This section should include studies that provide special types of data relevant to specific
types of medicinal products. For immunogenicity studies and other studies in which data may
correlate with PK, PD, safety, and/or efficacy data, explanations of such correlations should
be summarised here. Any observed or potential effects on PK, PD, safety and/or efficacy
should be considered in other appropriate sections of the Clinical Summary as well, with
cross-referencing to this section. Human studies that address a specific safety issue should
not be reported here, but instead should be reported in Item 4, Summary of Clinical Safety.
Example 1: Immunogenicity
For protein products and other products to which specific immunological reactions have been
measured, data regarding immunogenicity should be summarised in this section. For vaccines
or other products intended to induce specific immune reactions, immunogenicity data should
be described in the efficacy section. Assays used should be briefly described and information
about their performance (e.g., sensitivity, specificity, reliability, validity) should be
summarised; the location in the application of detailed information should be crossreferenced.
Data regarding the incidence, titre (titer), timing of onset and duration of antibody responses
should be summarised for each type of antibody assay used (e.g., IgG by ELISA,
neutralisation). Relationships of antibody formation to underlying disease, concomitant
medication, dose, duration, regimen, and formulation should be explored and summarised.
For drugs intended to be given as chronic, continuous therapy, any data on the impact of
interruptions of therapy on antigenicity should be analysed and summarised.
It is particularly important to summarise analyses of potential clinically relevant correlates of
immunogenicity, e.g., to determine the extent to which the presence of antibodies of a
particular type or titer appears to correlate with alterations of PK, changes in PD, loss of
efficacy, loss of adverse event profile, or development of adverse events. Particular attention
should be paid to events that might be immunologically mediated (e.g., serum sickness) and
events that might result from binding of cross-reactive endogenous substances by antibodies
to the administered drug.
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Example 2: Clinical microbiology
For antimicrobial or antiviral medicinal products, in vitro studies to characterise the spectrum
of activity are an important part of the programme of studies relevant to clinical efficacy.
Clinical efficacy studies that include characterisation of the susceptibility of the clinical
isolates as a part of the efficacy determination should be included in Item 3, Summary of
Clinical Efficacy. However, studies that evaluate such findings as the pattern of in vitro
susceptibility of strains of bacteria from different parts of the world (not in the context of
clinical efficacy study) would be included here.
Appendix 2
Tables and figures should be embedded in the text of the appropriate sections when that
enhances the readability of the document. Lengthy tables can be provided in the appendix at
the end of the Section.
Table 2.1 is provided as an example of a tabular format for reporting information and results
related to pharmacokinetic drug-drug interaction studies. Similar tables could be prepared for
PK/PD studies, dose-response studies, studies of effects on human biomaterials, and
population PK studies. This table is not intended to be a template, but only to illustrate the
type of information that should be considered by sponsors in designing their own tables.
Applicants should also decide whether information and results from clinical pharmacology
studies are best presented in tables, text or figures in order to aid clarity. If, for example,
results are best presented in text and figures, the tables might simply list the studies.
In designing tables, if any, for various types of other clinical pharmacology studies such as
those listed below, applicants should consider including the following types of information.
These examples are for illustrative purposes only and the sponsor should decide which
information needs to be presented.
• metabolism studies using human biomaterials: biomaterials used (e.g., microsomes,
hepatocytes), probe drugs, enzymatic pathways and % contribution and relevant kinetic
parameters (e.g., Vmax, Km).
• in vitro studies of drug-drug interactions using human biomaterials: for studies of other
drugs inhibiting the new drug, the metabolite(s) inhibited, enzymatic pathways affected,
range of inhibitor concentrations used, IC50 and Ki values and proposed mechanism of
inhibition should be included. For studies of the new drug inhibiting other drugs, the
drugs and metabolites inhibited should be included, along with the information mentioned
• population PK studies: co-variates studied, number and type of subjects or patients
studied, summary statistical parameters and final estimates of mean (± standard deviation)
PK parameters.
There might be time when a product may be effective for more than one indication, then a
separate Section 3 should be provided for each indication, although closely related
indications can be considered together. When more than one Section 3 is submitted, the
sections should be labelled 3A, 3B, 3C, etc.
3.1 Background and Overview of Clinical Efficacy
This section should describe the program of controlled studies and other pertinent studies in
the application that evaluated efficacy specific to the indication(s) sought. Any results of
these studies that are pertinent to evaluation of safety should be discussed in Item 4,
Summary of Clinical Safety.
The section should begin with a brief overview of the design of the controlled studies that
were conducted to evaluate efficacy. These studies include dose-response, comparative
efficacy, long-term efficacy, and efficacy studies in population subsets. Critical features of
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study design should be discussed, e.g., randomisation, blinding, choices of control treatment,
choice of patient population, unusual design features such as crossover or randomised
withdrawal designs, use of run-in periods, other methods of “enrichment”, study endpoints,
study duration, and prespecified plans for analysis of the study results. Although this section
is intended to focus on clinical investigations, nonclinical data and clinical pharmacology
data may also be referenced as appropriate to provide a comprehensive summary of human
experience related to efficacy. This section should not include detailed information about
individual studies.
3.2 Summary of Results of Individual Studies
A tabular listing of all studies that provided (or were designed to provide) information
relevant to product efficacy should generally be provided (see Appendix 3), together with
narrative descriptions for important studies. The narrative descriptions should be brief, e.g.,
similar to an abstract for a journal article, and should describe critical design features and
critical results. Similar studies may be described together, noting the individual study results
and any important differences among the studies. For studies that also contributed
significantly to the safety analysis, study narratives should include information about the
extent of exposure of study subjects to the test drug or control agent, and how safety data
were collected. These narratives can be abstracted from the synopses of the clinical study
reports (ICH E3). References or electronic links to the full report of each study should be
included in the narratives.
3.3 Comparison and Analyses of Results across Studies
Using text, figures, and tables as appropriate (see Appendix 3), the Item of 3.3 should
summarise all available data that characterise the efficacy of the drug. This summary should
include analyses of all data, irrespective of their support for the overall conclusion and
should, therefore, discuss the extent to which the results of the relevant studies do or do not
reinforce each other. Any major inconsistencies in the data regarding efficacy should be
addressed and any areas needing further exploration should be identified.
The section will generally utilise two kinds of analyses: comparison of results of individual
studies, and analysis of data combined from various studies. Details of analyses that are too
extensive to be reported in a summary document should be presented in a separate report, to
be placed in Clinical Study Reports.
This section should also cross-reference important evidence from Item 2, such as data that
support the dosage and administration section of the labelling. These data include dosage and
dose interval recommended, evidence pertinent to individualisation of dosage and need for
modifications of dosage for specific subgroups (e.g., pediatric or geriatric subjects, or
subjects with hepatic or renal impairment), and data relevant to dose-response or
concentration response (PK/PD) relationships.
3.3.1 Study Populations
The demographic and other baseline characteristics of patients across all efficacy studies
should be described. The following should be included:
• the characteristics of the disease (e.g., severity, duration) and prior treatment in the study
subjects, and study inclusion/exclusion criteria
• differences in baseline characteristics of the study populations in different studies or
groups of studies.
• any differences between populations included in critical efficacy analyses and the overall
patient population that would be expected to receive the drug when it is marketed should
be noted.
• assessment of the number of patients who dropped out of the studies, time of withdrawal
(a defined study day or visit during treatment or follow up period), and reasons for
Tabular presentations that combine and compare study populations across studies may be
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3.3.2 Comparison of Efficacy Results of all Studies
The results from all studies designed to evaluate the drug’s efficacy should be summarised
and compared, including studies with inconclusive or negative results. Important differences
in study design such as endpoints, control group, study duration, statistical methods, patient
population, and dose should be identified.
Comparisons of results across studies should focus on pre-specified primary endpoints.
However, when the primary endpoints involved different variables or time points in different
efficacy studies, it may be useful to provide cross-study comparisons of important data
elements that were obtained in all studies. If results over time are important, results of studies
may be displayed in a figure that illustrates the change over time in each study.
Confidence intervals for treatment effects should be given to aid in the interpretation of point
estimates. If differences are shown between placebo and test drugs in the change from
baseline, the baseline values and the magnitude of effect in all treatment groups, including
placebo and active controls (if used), should generally be presented in the table or in text
accompanying a figure. If the objective of an active control trial was to show equivalence or
non-inferiority, the difference or the ratio of outcomes between treatments should be given
with the confidence interval. The results should be evaluated by using the predefined criteria
for defining equivalence or non-inferiority and the rationale for the criteria and support for
the determination that the study (studies) had assay sensitivity should be provided (see ICH
Important differences in outcomes between studies with a similar design should be delineated
and discussed. Cross-study comparisons of factors that may have contributed to differences in
outcomes should be described.
If a meta-analysis of the clinical studies is performed, it should be clear whether this analysis
is conducted according to a predefined protocol or is a post hoc exercise. Any differences in
trial designs or populations, or in efficacy measurements between trials should be described
to allow assessment of the relevance and validity of the results and conclusions (See ICH E9).
A detailed description of the methodology and results of the meta-analysis should generally
be submitted in a separate report (Clinical Study Reports).
3.3.3 Comparison of Results in Sub-populations
The results of individual studies or overview analyses of efficacy in specific populations
should be summarised in this section. The purpose of these comparisons should be to show
whether the claimed treatment effects are observed consistently across all relevant subpopulations,
especially those where there are special reasons for concern. The comparisons
may highlight apparent variations in efficacy that require further investigation and discussion.
The limitations of such analyses, however, should be recognised (ICH E9), and it is important
to note that their purpose is not to provide the basis for specific claims, nor to attempt to
improve the evidence of efficacy in situations where the overall results are disappointing.
Given the limited sample sizes in individual studies, analyses across multiple studies should
be performed to evaluate effects of major demographic factors (age, sex, and race) on
efficacy. Factors of special interest may arise from general concerns (e.g., the elderly) or
from specific issues that are related to the pharmacology of the drug or that have arisen
during earlier drug development. Efficacy in the pediatric population should be routinely
analysed in applications for a proposed indication that occurs in children. Depending on the
data set, if extensive, detailed efficacy analyses are performed, they can be placed in Clinical
Study Reports, with the results of those analyses reported here.
3.4 Analysis of Clinical Information Relevant to Dosing Recommendations
This section should provide an integrated summary and analysis of all data that pertain to the
dose-response or blood level-response relationships of effectiveness (including dose-blood
level relationships), and thus have contributed to dose selection and choice of dose interval.
Relevant data from nonclinical studies may be referenced, and relevant data from
pharmacokinetic studies, other clinical pharmacology studies, and controlled and
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uncontrolled clinical studies should be summarised to illustrate these dose-response or blood
level-response relationships. For pharmacokinetic and pharmacodynamic studies from which
data have been summarised in Item 2.2, it may be appropriate to draw upon those data in this
summary while cross-referencing the summaries in Item 2.2, without repeating those
While the interpretation of how these data support specific dosing recommendations should
be supplied in the Clinical Overview document, the individual study results and any crossstudy
analyses that will be used to support the dosing recommendations (including the
recommended starting and maximal doses, the method of dose titration, and any other
instructions regarding individualisation of dosage) should be summarised here. Any
identified deviations from relatively simple dose-response or blood-level response
relationships due to non-linearity of pharmacokinetics, delayed effects, tolerance, enzyme
induction, etc. should be described.
Any evidence of differences in dose-response relationships that result from a patient’s age,
sex, race, disease, or other factors should be described. Any evidence of different
pharmacokinetic or pharmacodynamic responses should also be discussed, or discussions in
Item 2 can be cross-referenced. The ways in which such differences were looked for, even if
no differences were found, should be described (e.g., specific studies in subpopulations,
analysis of efficacy results by subgroup, or blood level determinations of the test drug).
3.5 Persistence of Efficacy and/or Tolerance Effects
Available information on persistence of efficacy over time should be summarised. The
number of patients for whom long-term efficacy data are available, and the length of
exposure, should be provided. Any evidence of tolerance (loss of therapeutic effects over
time) should be noted. Examination of any apparent relationships between dose changes over
time and long-term efficacy may be useful.
The primary focus should be on controlled studies specifically designed to collect long-term
efficacy data, and such studies should be clearly differentiated from other, less rigorous,
studies such as open extension studies. This distinction also applies to specific studies
designed for evaluation of tolerance and withdrawal effects. Data concerning withdrawal or
rebound effects pertinent to product safety should be presented in the safety section (see Item
In long-term efficacy trials, the effect of premature discontinuation of therapy or switching to
other therapies upon the assessment of the results should be considered. These issues might
also be important for short term trials and should be addressed when discussing the results of
these trials, if appropriate.
Appendix 3
Tables and figures should be embedded in the text of the appropriate sections when that
enhances the readability of the document. Lengthy tables can be provided in the appendix at
the end of the Section.
Tables should identify all studies pertinent to the evaluation of efficacy (including studies
that were terminated or are not yet completed, studies that failed to show effectiveness for
any reason, studies available only as publications, studies reported in full technical reports
(ICH E3), and studies described in abbreviated reports); and should provide the most
important results of those studies. Note, however, that unplanned interim analyses on ongoing
studies are generally not needed or encouraged. When more than one section 3 is provided for
an application with more than one indication, usually each section should have its own
appendix with tables.
Illustrative tables for an antihypertensive drug are provided, but these examples will not be
relevant to every application. In general, applications will require tables and/or figures that
are developed specifically for the particular drug class and the studies that were carried out.
Table 3.1 Description of Clinical Efficacy and Safety Studies
Table 3.2 Results of Efficacy Studies
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This section should be a summary of data relevant to safety in the intended patient
population, integrating the results of individual clinical study reports as well as other relevant
reports, e.g., the integrated analyses of safety that are routinely submitted in some regions.
The display of safety-related data can be considered at three levels (ICH E3):
− The extent of exposure (dose, duration, number of patients, type of patients) should be
examined to determine the degree to which safety can be assessed from the database.
− The more common adverse events and changes in laboratory tests should be identified
and classified, and their occurrence should be summarised.
− Serious adverse events (defined in ICH E2A) and other significant adverse events
(defined in ICH E3) should be identified and their occurrence should be summarised.
These events should be examined for frequency over time, particularly for drugs that may
be used chronically.
The safety profile of the drug, described on the basis of analysis of all clinical safety data,
should be outlined in a detailed, clear, and objective manner, with use of tables and figures.
4.1 Exposure to the Drug
4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies
The overall safety evaluation plan should be described briefly, including special
considerations and observations concerning the nonclinical data, any relevant
pharmacological class effects, and the sources of the safety data (controlled trials, open
studies, etc). A tabular listing of all clinical studies that provided safety data, grouped
appropriately, should generally be provided (see Appendix 4). In addition to studies that
evaluated efficacy and safety, and uncontrolled studies that generate safety information, this
section includes studies that consider special safety issues. Examples would include studies
to compare particular adverse event rates for two therapies, to assess safety in particular
demographic subsets, to evaluate withdrawal or rebound phenomena, or to evaluate particular
adverse events (e.g., sedation, sexual function, effects on driving, absence of a class adverse
effect). Studies in indications for which approval is not being sought in the current
application and ongoing studies would also be included here if they contribute to the safety
Narrative descriptions of these studies should be provided here, except that narrative
descriptions for studies that contributed both efficacy and safety data should be included in
Item 3.2 and cross-referenced here. The narratives should provide enough detail to allow the
reviewer to understand the exposure of study subjects to the test drug or control agent, and
how safety data were collected (including the methods used and the extent of safety
monitoring of the subjects enrolled in the individual studies). If some studies are not analysed
separately but are grouped for safety analysis, that should be noted, and a single narrative
description can be provided.
4.1.2 Overall Extent of Exposure
A table (see example provided in Appendix 4) and appropriate text should be generated to
summarise the overall extent of drug exposure from all phases of the clinical study
development programme. The table should indicate the numbers of subjects exposed in
studies of different types and at various doses, routes, and durations. If a large number of
different doses and/or durations of exposure were used, these can be grouped in a manner
appropriate for the drug. Thus, for any dose or range of doses, duration of exposure can be
summarised by the number of subjects exposed for specific periods of time, such as 1 day or
less, 2 days to 1 week, 1 week to 1 month, 1 month to 6 months, 6 months to 1 year, more
than 1 year (ICH E3). In some applications it may be important to identify diagnostic
subgroups and/or groups receiving specific concomitant therapies deemed particularly
relevant to safety assessment in the intended use.
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The dose levels used for each subject in this presentation could be the maximum dose
received by that subject, the dose with longest exposure, and/or the mean daily dose, as
appropriate. In some cases, cumulative dose may be pertinent. Dosage may be given as the
actual daily dose or on a mg/kg or mg/m2 basis, as appropriate. If available, drug
concentration data (e.g., concentration at the time of an adverse event, maximum plasma
concentration, area under curve) may be helpful in individual subjects for correlation with
adverse events or changes in laboratory variables.
It is assumed that all subjects who were enrolled and received at least one dose of the
treatment are included in the safety analysis; if that is not so, an explanation should be
4.1.3 Demographic and Other Characteristics of Study Population
A summary table should provide the reader with an overview of the demographic
characteristics (Table 4.2) of the population that was exposed to the therapeutic agent during
its development. Choice of age ranges used should take into account considerations discussed
in ICH E7 [Studies in Support of Special Populations: Geriatrics] and ICH E11 [Clinical
Investigation of Medicinal Products in the Paediatric Population]. If the relative exposure of
demographic groups in the controlled trials differed from overall exposure, it may be useful
to provide separate tables.
In addition, one or more tables should show the relevant characteristics of the study
population, and the numbers of subjects with special characteristics. Such characteristics
could include:
− Severity of disease
− Hospitalisation
− Impaired renal function
− Concomitant illnesses
− Concomitant use of particular medications
− Geographical location
If these characteristics are distributed differently in controlled trials versus the overall
database, it will generally be useful to present tables on both groupings.
The text accompanying the table(s) should mention any imbalance(s) between the drug and
placebo and/or comparator regarding any of the above demographic characteristics,
particularly if they could lead to differences in safety outcomes.
If certain subjects were excluded from studies (concomitant illness, severity of illness,
concomitant medications), this fact should be noted.
Separate demographic tables should be provided for every indication, although closely related
indications can be considered together, if study subject characteristics are such that risks are
believed to be the same.
4.2 Adverse Events
4.2.1 Analysis of Adverse Events
Data on the frequency of adverse events should be described in text and tables. Text should
appear in the appropriate Item 4.2.1 and the tables that are not embedded in the text should be
placed in Appendix 4.
All adverse events occurring or worsening after treatment has begun ("treatment emergent
signs and symptoms," those adverse events not seen at baseline and those that worsened even
if present at baseline) should be summarised in tables listing each event, the number of
subjects in whom the event occurred and the frequency of occurrence in subjects treated with
the drug under investigation, with comparator drugs, and with placebo. Such tables could also
present results for each dose and could be modified to show, e.g., adverse event rates by
severity, by time from onset of therapy, or by assessment of causality.
When most of the relevant safety data are derived from a small number of studies (e.g., one
or two studies), or when very different study subject populations were enrolled in the studies
that were performed, presentation of data by study will often be appropriate. When the
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relevant exposure data is not concentrated in a small number of studies, however, grouping
the studies and pooling the results to improve precision of estimates and sensitivity to
differences should generally be considered.
While often useful, pooling of safety data across studies should be approached with caution
because in some cases interpretation can be difficult, and it can obscure real differences. In
cases where differences are apparent, it is more appropriate to present the data by study. The
following issues should be considered:
• it is most appropriate to combine data from studies that are of similar design,
e.g., similar in dose, duration, methods of determining adverse events, and
• if the incidence for a particular adverse event differs substantially across the
individual studies in a pool, the pooled estimate is less informative.
• any study with an unusual adverse event pattern should be presented separately.
• the appropriate extent of analysis depends on the seriousness of the adverse
event and the strength of evidence of drug causation. Differences in rates of
drug-related, serious events or events leading to discontinuation or dosage
change deserve more investigation, whereas rates of other adverse events do not
merit elaborate analysis.
• examination of which subjects experience extreme laboratory value
abnormalities ("outliers") may be useful in identifying subgroups of individuals
who are at particular risk for certain adverse events.
Groups of studies that could be used in pooled safety analyses include:
• all controlled studies or subsets of controlled studies, such as all placebocontrolled
studies, studies with any positive control, studies with a particular
positive control, or studies of particular indications (and thus carried out in
different populations). These groupings are considered the best source of
information about the more common adverse events and can distinguish drugrelated
events from spontaneous events. Rates in control and treatment groups
should be compared.
• all studies, excluding short-term studies in healthy subjects.
This grouping is most useful for evaluating rarer events.
• all studies using a particular dose route or regimen, or a particular concomitant
• studies in which adverse event reports are elicited by checklist or direct
questioning, or studies in which events are volunteered.
• pools of studies by region.
It is almost always useful to carry out the first two groupings; the others chosen would vary
from drug to drug and should be influenced by inspection of individual study results.
Whatever methods are used, it should be recognised that, as for results of single studies, any
numerical rate is often only a rough approximation of reality.
When a decision is made to pool data from several studies, the rationale for selecting the
method used for pooling should be described. It is common to combine the numerator events
and the denominators for the selected studies. Other methods for pooling results across
studies are available, e.g., weighting data from studies on the basis of study size or inversely
to their variance.
If substantial differences are seen between clinical trials in the rates of adverse events, these
differences should be noted and possible reasons should be discussed (e.g., relevant
differences in study populations, in dose administration, or in methods of collecting adverse
event data).
Adverse events should be described as shown in the individual study report (ICH E3). In
combining data from many studies, it is important to use standardised terms to describe
events and collect synonymous terms under a single preferred term. This can be done with
international standard dictionary and terminology should be used and specified. Frequencies
ACTD clinical final Page 18
should be presented for preferred terms and for appropriately defined groupings. Examination
of which adverse events led to change in therapy (discontinuation of drug use, change in
dose, need for added therapy) can help in assessing the clinical importance of adverse events.
These rates can be added to the adverse event rate tables, or can be presented in separate
tables. Overall discontinuation rates by study may be useful but it is also important to specify
the particular adverse events leading to discontinuation in a separate table. The preferred
terms should be grouped by body system and arranged by decreasing frequency. Common Adverse Events
Tabular displays of adverse event rates (see Appendix 4) should be used to compare
rates in treatment and control groups. For this analysis it may be helpful to combine
the event severity categories and the causality categories, if they are used, leading to a
simpler side-by-side comparison of treatment groups. It should be noted that while
causality categories may be reported, if used, the presentation of the data should
include total adverse events (whether deemed related or unrelated to treatment);
evaluations of causality are inherently subjective and may exclude unexpected
adverse events that are in fact treatment related. Additionally, comparisons of rates of
adverse events between treatment and control groups in individual trials should be
summarised here. It is often useful to tabulate rates in selected trials (see example
table 4.4, in Appendix 4).
It is usually useful to examine more closely the more common adverse events that
seem to be drug related (e.g., those that show that a dose response and/or a clear
difference between drug and placebo rates) for relationship to relevant factors,
- dosage;
- mg/kg or mg/m2 dose;
- dose regimen;
- duration of treatment;
- total dose;
- demographic characteristics such as age, sex, race;
- concomitant medication use;
- other baseline features such as renal status;
- efficacy outcomes;
- drug concentration, where available.
It may also be useful to summarise the results of examination of time of onset and
duration for these drug-related events.
Rigorous statistical evaluations of the possible relationship of specific adverse events
to each of the above factors are often unnecessary. It may be apparent from initial
display and inspection of the data that there is no evidence of a significant relationship
to demographic or other baseline features. In that case, no further analysis of these
particular factors is needed. Further, it is not necessary that all such analyses be
presented in this report. When the safety analyses are too extensive to be presented in
detail in this report, they may be presented in a separate report in Clinical Study
Reports, and summarised here.
Under certain circumstances, life table or similar analyses may be more informative
than reporting of crude adverse event rates. Deaths
A table in Appendix 4 should list all deaths occurring while on study (including
deaths that occurred shortly following treatment termination, e.g., within 30 days or as
specified in the study protocol, as well as all other deaths that occurred later but may
have resulted from a process that began during studies). Only deaths that are clearly
disease-related per protocol definitions and not related to the investigational product,
ACTD clinical final Page 19
either in studies of conditions with high mortality such as advanced cancer or in
studies where mortality from disease is a primary study endpoint, should be excepted
from this listing (it is assumed, however, that these deaths would still be reported in
the individual ICH E3 study reports). Even these deaths should be examined for any
unexpected patterns between study arms, and further analysed if unexplained
differences are observed. Deaths should be examined individually and analysed on the
basis of rates in individual trials and appropriate pools of trials, considering both total
mortality and cause-specific deaths. Potential relationships to the factors listed in Item should also be considered. Although cause-specific mortality can be difficult
to determine, some deaths are relatively easy to interpret. Thus deaths due to causes
expected in the patient population (heart attacks and sudden death in an angina
population) are individually not considered to be informative, but even one death due
to a QT interval prolongation-associated arrhythmia, aplastic anaemia, or liver injury
may be informative. Special caution is appropriate before an unusual death is
attributed to concomitant illness. Other Serious Adverse Events
Summaries of all serious adverse events (other than death but including the serious
adverse events temporally associated with or preceding the deaths) should be
displayed. Serious adverse events that occurred after the drug use was discontinued
should be included in this section. The display should include major laboratory
abnormalities, abnormal vital signs, and abnormal physical observations that are
considered serious adverse events using the ICH E2A definitions. Results of analyses
or assessments of serious adverse events across studies should be presented. Serious
events should be examined for frequency over time, particularly for drugs that may be
used chronically. Potential relationships to the factors listed in Item should
also be considered. Other Significant Adverse Events
Marked haematologic and other laboratory abnormalities (other than those meeting
the definition of serious) and any events that led to a substantial intervention
(premature discontinuation of study drug, dose reduction, or substantial additional
concomitant therapy), other than those reported as serious adverse events, should be
Events that led to premature discontinuation of study drug represent an important
safety concern and deserve particular attention in the analysis of drug safety for two
reasons. First, even for expected events (based on pharmacologic activity), the need to
discontinue (or otherwise alter) treatment reflects the severity and perceived
importance of the event to patient and physician. Second, discontinuation may
represent a drug-related event not yet recognised as drug related. Adverse events
leading to treatment discontinuation should be considered possibly drug-related even
if this was not recognised initially and even if the event was thought to represent
intercurrent illness. Reasons for premature treatment discontinuations should be
discussed and rates of discontinuations should be compared across studies and
compared with those for placebo and/or active control treatment. In addition, the
study data should be examined for any potential relationships to the factors listed in
Item Analysis of Adverse Events by Organ System or Syndrome
Assessment of the causality of, and risk factors for, deaths, other serious events, and
other significant events is often complicated by the fact that they are uncommon. As a
result, consideration of related events as a group, including less important events of
potentially related pathophysiology, may be of critical value in understanding the
safety profile. For example, the relationship to treatment of an isolated sudden death
ACTD clinical final Page 20
may become much clearer when considered in the context of cases of syncope,
palpitations, and asymptomatic arrhythmias.
It is thus generally useful to summarise adverse events by organ system so that they
may be considered in the context of potentially related events including laboratory
abnormalities. Such presentations of adverse events by organ system should be placed
in Item, labelled as,, etc., and titled by the organ system
under consideration. The list of organ systems to be addressed and the approach to
grouping certain events should be selected as appropriate to best present the adverse
event data for the medicinal product. If some adverse events tend to occur in
syndromes (e.g., influenza-like syndrome, cytokine release syndrome), the sponsor
may choose to create some Item for syndromes rather than organ systems.
The same data and summarisations should generally not be repeated in more than one
subsection of Item 4.2.1. Instead, a summary presentation may be placed in one
subsection and cross-referenced as needed in the other.
4.2.2 Narratives
The locations in the application of individual narratives of patient deaths, other serious
adverse events, and other significant adverse events deemed to be of special interest because
of clinical importance (as described in ICH E3 individual study reports) should be referenced
here for the convenience of the reviewer. The narratives themselves should be a part of the
individual study reports, if there is such a report. In cases where there is no individual study
report (e.g., if many open studies are pooled as part of a safety analysis and are not
individually described), narratives can be placed in Clinical Study Reports, Item 5.3.
Narratives should not be included here, unless an abbreviated narrative of particular events is
considered critical to the summary assessment of the drug.
4.3 Clinical Laboratory Evaluations
This section should describe changes in patterns of laboratory tests with drug use. Marked
laboratory abnormalities and those that led to a substantial intervention should be reported in
Item or If these data are also presented in this section, this duplicate reporting
should be made clear for the reviewer. The appropriate evaluations of laboratory values will
in part be determined by the results seen, but, in general, the analyses described below should
be provided. For each analysis, comparison of the treatment and control groups should be
carried out, as appropriate and as compatible with study sizes. In addition, normal laboratory
ranges should be given for each analysis (ICH E3). Where possible, laboratory values should
be provided in standard international units.
A brief overview of the major changes in laboratory values across the clinical studies should
be provided. Laboratory data should include haematology, clinical chemistry, urinalysis and
other data as appropriate. Each parameter at each time over the course of the study (e.g., at
each visit) should be described at the following three levels:
• the central tendency, i.e., the group mean and median values,
• the range of values, and the number of subjects with abnormal values or with abnormal
values of a certain size (e.g. twice the upper limit of normal, 5 times the upper limit;
choices should be explained). When data are pooled from centers with differences in
normal laboratory ranges, the methodology used in pooling should be described. The
analysis of individual subject changes by treatment group can be shown with a variety of
approaches (e.g., shift tables, see ICH E3 for examples).
• individual clinically important abnormalities, including those leading to discontinuations.
The significance of the laboratory changes and the likely relation to the treatment should
be assessed (e.g., by analysis of such features as relationship to dose, relation to drug
concentration, disappearance on continued therapy, positive dechallenge, positive
rechallenge, and the nature of concomitant therapy). Potential relationships to other
factors listed in Item should also be considered.
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4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety
The manner of presenting cross-study observations and comparisons of vital signs (e.g., heart
rate, blood pressure, temperature, respiratory rate), weight and other data (e.g.,
electrocardiograms, X-rays) related to safety should be similar to that for laboratory
variables. If there is evidence of a drug effect, any dose-response or drug concentrationresponse
relationship or relationship to individual variables (e.g., disease, demographics,
concomitant therapy) should be identified and the clinical relevance of the observation
described. Particular attention should be given to changes not evaluated as efficacy variables
and to those considered to be adverse events. Particular attention should be given to studies
that were designed to evaluate specific safety issues, e.g., studies of QT interval prolongation.
4.5 Safety in Special Groups and Situations
4.5.1 Patient Groups
This section should summarise safety data pertinent to individualising therapy or patient
management on the basis of demographic, age, sex, height, weight, lean body mass, genetic
polymorphism, body composition, other illness and organ dysfunction. Safety in the pediatric
population should be routinely analysed in applications for a proposed indication that occurs
in children. Analysis of the impact on safety outcomes should have been presented in other
sections but should be summarised here, together with pertinent PK or other information, e.g.,
in patients with renal or hepatic disease, the medical environment, use of other drugs (see
4.5.2, Drug Interactions), use of tobacco, use of alcohol, and food habits. For example, if a
potential interaction with alcohol is suggested by the metabolic profile, by the results of
studies, by post-marketing experience, or by information on similar drugs, information should
be provided here. If a sufficiently large number of subjects with a given co-morbid condition
such as hypertension, heart disease, or diabetes, was enrolled, analyses should be carried out
to assess whether the co-morbid condition affected the safety of the drug under study. Cross
reference should be made to the tables or description of adverse events when analyses of such
sub-groups has been carried out.
4.5.2 Drug Interactions
Studies on potential drug-drug or drug-food interactions should be summarised in the
Summary of Clinical Pharmacology Studies section of the ACTD. The potential impact on
safety of such interactions should be summarised here, based on PK, PD, or clinical
observations. Any observed changes in the adverse event profile, changes in blood levels
thought to be associated with risk, or changes in drug effects associated with other therapy
should be presented here.
4.5.3 Use in Pregnancy and Lactation
Any information on safety of use during pregnancy or breast-feeding that becomes available
during clinical development or from other sources should be summarised here.
4.5.4 Overdose
All available clinical information relevant to overdose, including signs/symptoms, laboratory
findings, and therapeutic measures/treatments and antidotes (if available) should be
summarised and discussed. Information on the efficacy of specific antidotes and dialysis
should be provided if available.
4.5.5 Drug Abuse
Any relevant studies/information regarding the investigation of the dependence potential of a
new therapeutic agent in animals and in humans should be summarised and cross-referenced
to the nonclinical summary. Particularly susceptible patient populations should be identified.
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4.5.6 Withdrawal and Rebound
Any information or study results pertinent to rebound effects should be summarised. Events
that occur, or increase in severity, after discontinuation of double-blind or active study
medication should be examined to see if they are the result of withdrawal of the study
medication. Particular emphasis should be given to studies designed to evaluate withdrawal
and/or rebound.
Data concerning tolerance should be summarised under Item 3.5 in the Summary of Clinical
4.5.7 Effects on Ability to Drive or Operate Machinery or Impairment of Mental
Safety data related to any impairment in the senses, co-ordination, or other factor that would
result in diminished ability to drive a vehicle or operate machinery or that would impair
mental ability should be summarised. This includes relevant adverse effects reported in
safety monitoring (e.g., drowsiness) and specific studies concerning effects on ability to drive
or operate machinery or impairment of mental ability.
4.6 Post-marketing Data
If the drug has already been marketed, all relevant post-marketing data available to the
applicant (published and unpublished, including periodic safety update reports if available)
should be summarised. The periodic safety update reports can be included in Clinical Study
Reports. Details of the number of subjects estimated to have been exposed should be
provided and categorised, as appropriate, by indication, dosage, route, treatment duration, and
geographic location. The methodology used to estimate the number of subjects exposed
should be described. If estimates of the demographic details are available from any source,
these should be provided.
A tabulation of serious events reported after the drug is marketed should be provided,
including any potentially serious drug interactions.
Any post-marketing findings in subgroups should be described.
Appendix 4
Tabular presentations should be provided that summarise the important results from all
studies pertinent to the evaluation of safety and particularly to support product labelling.
Tables and figures should be embedded in the text of the appropriate sections when that
enhances the readability of the document. Lengthy tables can be provided in the appendix at
the end of the section.
A few illustrative tables are provided, but a clinical summary will routinely need tables and
figures that have been developed for the particular drug, drug class, and clinical indication(s).
See Items 4.2.1,, and 4.3 of this guidance for additional discussion regarding the
content of section 4 tables.
Table 4.1 Study Subject Drug Exposure by Mean Daily Dose and Duration of Exposure
Table 4.2 Demographic Profile of Patients in Controlled Trials
Table 4.3 Incidence of Adverse Events in Pooled Placebo and Active Controlled Trials
Table 4.4 Incidence of Adverse Events in the Largest Trials
Table 4.5 Patient Withdrawals by Study: Controlled Trials
Table 4.6 Listing of Deaths
The ICH E3 guideline (Structure and Content of Clinical Study Reports) suggests inclusion
of a study synopsis with each clinical study report, and provides one example of a format for
such synopses.
ACTD clinical final Page 23
This section should include the table entitled Listing of Clinical Studies, described in
guidance for Clinical Study Reports, followed by all individual study synopses organised in
the same sequence as the study reports in Clinical Study Reports.
It is expected that one synopsis will be prepared per study for use in all regions, and that the
same synopsis will be included in this section and as part of the clinical study report . The
length of a synopsis will usually be up to 3 pages, but a synopsis for a more complex and
important study may be longer, e.g. 10 pages. Within the individual synopsis, tables and
figures should be used as appropriate to aid clarity.


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