PREAMBLE
For ASEAN member countries, the 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 requires specific Study Reports should ask for the necessary documents. The ICH
E3 provides guidance on the organisation of clinical study reports, other clinical data, and
references within the ASEAN Common Technical Dossier (ACTD) for registration of a
pharmaceutical product for human use. In this case, the applicant will submit Section A, B, C. D
and F.
Guideline on Organisation of Clinical Study Reports and Related Information
This guideline recommends a specific organization for the placement of clinical study reports
and related information to simplify preparation and review of dossiers and to ensure
completeness. The placement of a report should be determined by the primary objective of the
study. Each study report should appear in only one section. Where there are multiple objectives,
the study should be cross-referenced in the various sections.
An explanation such as “not applicable” or “no study conducted” should be provided when no
report or information is available for a section or subsection.
A. TABLE OF CONTENTS FOR STUDY REPORTS
A Table of Contents for the study reports should be provided.
B. TABULAR LISTING OF ALL CLINICAL STUDIES
A tabular listing of all clinical studies and related information should be provided. For each
study, this tabular listing should generally include the type of information identified in Table 1 of
this guideline. Other information can be included in this table if the applicant considers it useful.
The sequence in which the studies are listed should follow the sequence described in Section C
below. Use of a different sequence should be noted and explained in an introduction to the
tabular listing.
C. CLINICAL STUDY REPORTS
1. Reports of Biopharmaceutic Studies
BA studies evaluate the rate and extent of release of the active substance from the medicinal
product. Comparative BA or BE studies may use PK, PD, clinical, or in vitro dissolution
endpoints, and may be either single dose or multiple dose. When the primary purpose of a study
is to assess the PK of a drug, but also includes BA information, the study report should be
submitted in Item 3.1, and referenced in Items 1.1 and/or 1.2.
1.1 Bioavailability (BA) Study Reports
BA studies in this section should include 1) studies comparing the release and systemic
availability of a drug substance from a solid oral dosage form to the systemic availability
of the drug substance given intravenously or as an oral liquid dosage form 2) dosage form
proportionality studies, and 3) food-effect studies.
1.2 Comparative BA and Bioequivalence (BE) Study Reports
Studies in this section compare the rate and extent of release of the drug substance from
similar drug products (e.g., tablet to tablet, tablet to capsule). Comparative BA or BE
studies may include comparisons between 1) the drug product used in clinical studies
supporting effectiveness and the to-be-marketed drug product, 2) the drug product used in
clinical studies supporting effectiveness and the drug product used in stability batches,
and 3) similar drug products from different manufacturers.
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1.3 In Vitro – In Vivo Correlation Study Reports
In vitro dissolution studies that provide BA information, including studies used in
seeking to correlate in vitro data with in vivo correlations, should be placed in Item 1.3.
Reports of in vitro dissolution tests used for batch quality control and/or batch release
should be placed in the Quality section of the ACTD.
1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
Bioanalytical and/or analytical methods for biopharmaceutic studies or in vitro
dissolution studies should ordinarily be provided in individual study reports. Where a
method is used in multiple studies, the method and its validation should be included once
in Item 1.4 and referenced in the appropriate individual study reports.
2. Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials
Human biomaterials is a term used to refer to proteins, cells, tissues and related materials derived
from human sources that are used in vitro or ex vivo to assess PK properties of drug substances.
Examples include cultured human colonic cells that are used to assess permeability through
biological membranes and transport processes, and human albumin that is used to assess plasma
protein binding. Of particular importance is the use of human biomaterials such as hepatocytes
and/or hepatic microsomes to study metabolic pathways and to assess drug-drug interactions
with these pathways.
Studies using biomaterials to address other properties (e.g., sterility or pharmacodynamics)
should not be placed in the Clinical Study Reports Section, but in the Nonclinical Study Section
(Part III ).
2.1 Plasma Protein Binding Study Reports
Ex vivo protein binding study reports should be provided here.
Protein binding data from PK blood and/or plasma studies should be provided in Item 3.
2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
Reports of hepatic metabolism and metabolic drug interaction studies with hepatic tissue
should be placed here.
2.3 Studies Using Other Human Biomaterials
Reports of studies with other biomaterials should be placed in this section.
3. Reports of Human Pharmacokinetic (PK) Studies
Assessment of the PK of a drug in healthy subjects and/or patients is considered critical to
designing dosing strategies and titration steps, to anticipating the effects of concomitant drug
use, and to interpreting observed pharmacodynamic differences. These assessments should
provide a description of the body’s handling of a drug over time, focusing on maximum plasma
concentrations (peak exposure), area-under-curve (total exposure), clearance, and accumulation
of the parent drug and its metabolite(s), in particular those that have pharmacological activity.
The PK studies whose reports should be included in Item 3.1 and 3.2 are generally designed to
(1) measure plasma drug and metabolite concentrations over time, (2) measure drug and
metabolite concentrations in urine or feces when useful or necessary, and/or (3) measure drug
and metabolite binding to protein or red blood cells.
On occasion, PK studies may include measurement of drug distribution into other body tissues,
body organs, or fluids (e.g., synovial fluid or cerebrospinal fluid), and the results of these tissue
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distribution studies should be included in Item 3.1 to 3.2, as appropriate. These studies should
characterise the drug’s PK and provide information about the absorption, distribution,
metabolism, and excretion of a drug and any active metabolites in healthy subjects and/or
patients. Studies of mass balance and changes in PK related to dose (e.g., determination of dose
proportionality) or time (e.g., due to enzyme induction or formation of antibodies) are of
particular interest and should be included in Item 3.1 and/or 3.2. Apart from describing mean
PK in normal and patient volunteers, PK studies should also describe the range of individual
variability.
3.1 Healthy Subject PK and Initial Tolerability Study Reports
Reports of PK and initial tolerability studies in healthy subjects should be placed in this
section.
3.2 Patient PK and Initial Tolerability Study Reports
Reports of PK and initial tolerability studies in patients should be placed in this section.
3.3 Population PK Study Reports
Reports of population PK studies based on sparse samples obtained in clinical trials
including efficacy and safety trials, should be placed in this section.
4. Reports of Human Pharmacodynamic (PD) Studies
Reports of studies with a primary objective of determining the PD effects of a drug product in
humans should be placed in this section. Reports of studies whose primary objective is to
establish efficacy or to accumulate safety data, however, should be placed in Item 5.
This section should include reports of 1) studies of pharmacologic properties known or thought
to be related to the desired clinical effects (biomarkers), 2) short-term studies of the main clinical
effect, and 3) PD studies of other properties not related to the desired clinical effect. Because a
quantitative relationship of these pharmacological effects to dose and/or plasma drug and
metabolite concentrations is usually of interest, PD information is frequently collected in dose
response studies or together with drug concentration information in PK studies (concentrationresponse
or PK/PD studies). Relationships between PK and PD effects that are not obtained in
well-controlled studies are often evaluated using an appropriate model and used as a basis for
designing further dose-response studies or, in some cases, for interpreting effects of
concentration differences in population subsets.
Dose-finding, PD and/or PK-PD studies can be conducted in healthy subjects and/or patients,
and can also be incorporated into the studies that evaluate safety and efficacy in a clinical
indication. Reports of dose-finding, PD and/or PK/PD studies conducted in healthy subjects
should be placed in Item 4.1, and the reports for those studies conducted in patients should be
placed in Item 4.2.
In some cases, the short-term PD, dose-finding, and/or PK-PD information found in
pharmacodynamic studies conducted in patients will provide data that contribute to assessment
of efficacy, either because they show an effect on an acceptable surrogate marker (e.g., blood
pressure) or on a clinical benefit endpoint (e.g., pain relief). Similarly, a PD study may contain
important clinical safety information. When these studies are part of the efficacy or safety
demonstration, they are considered clinical efficacy and safety studies that should be included in
Item 5, not in Item 4.
4.1 Healthy Subject PD and PK/PD Study Reports
PD and/or PK/PD studies having non-therapeutic objectives in healthy subjects should be
placed in this section
4.2 Patient PD and PK/PD Study Reports
PD and/or PK/PD studies in patients should be submitted in this section.
5. Reports of Efficacy and Safety Studies
This section should include reports of all clinical studies of efficacy and/or safety carried out
with the drug, conducted by the sponsor, or otherwise available, including all completed and all
ongoing studies of the drug in proposed and non-proposed indications. The study reports should
provide the level of detail appropriate to the study and its role in the application. ICH E3
describes the contents of a full report for a study contributing evidence pertinent to both safety
and efficacy. Abbreviated reports can be provided for some studies (see ICH E3 and individual
guidance by region).
Within Item 5, studies should be organised by design (controlled, uncontrolled) and, within
controlled studies, by type of control. Within each section, studies should be categorized further,
ordered by whether the study report is complete or abbreviated (ICH E3), with completely
reported studies presented first. Published reports with limited or no further data available to the
sponsor should be placed last in this section.
In cases where the application includes multiple therapeutic indications, the reports should be
organized in a separate Item 5 for each indication. In such cases, if a clinical efficacy study is
relevant to only one of the indications included in the application, it should be included in the
appropriate Item 5; if a clinical efficacy study is relevant to multiple indications, the study report
should be included in the most appropriate Item 5 and referenced as necessary in other Items 5,
e.g., Item 5A, Item 5B.
5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
The controlled clinical study reports should be sequenced by type of control:
• Placebo control (could include other control groups, such as an active comparator
or other doses)
• No-treatment control
• Dose-response (without placebo)
• Active control (without placebo)
• External (Historical) control, regardless of the control treatment
Within each control type, where relevant to assessment of drug effect, studies should be
organized by treatment duration. Studies of indications other than the one proposed in
the application, but that provide support for efficacy in the proposed use, should be
included in Item 5.1.
Where a pharmacodynamic study contributes to evidence of efficacy, it should be
included in Item 5.1. The sequence in which studies were conducted is not considered
pertinent to their presentation. Thus, placebo-controlled trials, whether early or late,
should be placed in Item 5.1. Controlled safety studies, including studies in conditions
that are not the subject of the application, should also be reported in Item 5.1.
5.2 Study Reports of Uncontrolled Clinical Studies
Study reports of uncontrolled clinical studies (e.g., reports of open label safety studies)
should be included. This includes studies in conditions that are not the subject of the
marketing application.
5.3 Reports of Analyses of Data from More than One Study
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Many clinical issues in an application can be addressed by an analysis considering data
from more than one study. The results of such an analysis should generally be
summarized in the clinical summary documents, but a detailed description and
presentation of the results of such analyses are considered critical to their interpretation.
Where the details of the analysis are too extensive to be reported in a summary document,
they should be presented in a separate report. Such reports should be placed in Item 5.3.
Examples of reports that would be found in this section include: a report of a formal
meta-analysis or extensive exploratory analysis of efficacy to determine an overall
estimate of effect size in all patients and/or in specific subpopulations, and a report of an
integrated analysis of safety that assesses such factors as the adequacy of the safety
database, estimates of event rates, and safety with respect to variables such as dose,
demographics, and concomitant medications.
5.4 Other Clinical Study Reports
This section can include:
− Reports of interim analyses of studies pertinent to the claimed indications
− Reports of controlled safety studies not reported elsewhere
− Reports of controlled or uncontrolled studies not related to the claimed indication
− Published reports of clinical experiences with the medicinal product that are not
included in Item 5.1. However, when literature is important to the demonstration or
substantiation of efficacy, it should be included in Item 5.1
− Reports of ongoing studies
6. Reports of Post-Marketing Experience
For products that are currently marketed, reports that summarize marketing experience
(including all significant safety observations) should be included in Item 6.
7. Case Report Forms and Individual Patient Listings
Case report forms and individual patient data listings that are described as appendices 16.3 and
16.4 in the ICH clinical study report guideline, should be placed in this section when submitted,
in the same order as the clinical study reports and indexed by study.
SECTION F. LIST OF KEY LITERATURE REFERENCES
List of referenced documents, including important published articles, official meeting minutes, or
other regulatory guidance or advice should be provided here. This includes all references cited
in the Clinical Overview, and important references cited in the Clinical Summary or in the
individual technical reports that were provided in Clinical Study Reports. Finally, copies of
referenced documents should be available upon request.
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