Thursday, July 2, 2009


The Clinical Overview is intended to provide a critical analysis of the clinical data in the
ASEAN Common Technical Dossier (ACTD). The Clinical Overview is primarily intended
for use by regulatory agencies in the review of the clinical section of a marketing application.
It should also be a useful reference to the overall clinical findings for regulatory agency staff
involved in the review of other sections of the marketing application. The Clinical Overview
should present the strengths and limitations of the development program and study results,
analyse the benefits and risks of the medicinal product in its intended use, and describe how
the study results support critical parts of the prescribing information.
In order to achieve these objectives the Clinical Overview should:
• describe and explain the overall approach to the clinical development of a medicinal
product, including critical study design decisions.
• assess the quality of the design and performance of the studies, and include a statement
regarding GCP compliance.
• provide a brief overview of the clinical findings, including important limitations (e.g.,
lack of comparisons with an especially relevant active comparator, or absence of
information on some patient populations, on pertinent endpoints, or on use in combination
• provide an evaluation of benefits and risks based upon the conclusions of the relevant
clinical studies, including interpretation of how the efficacy and safety findings support
the proposed dose and target indication and an evaluation of how prescribing information
and other approaches will optimise benefits and manage risks.
• address particular efficacy or safety issues encountered in development, and how they
have been evaluated and resolved.
• explore unresolved issues, explain why they should not be considered as barriers to
approval, and describe plans to resolve them.
• explain the basis for important or unusual aspects of the prescribing information.
The Clinical Overview should generally be a relatively short document (about 30 pages). The
length, however, will depend on the complexity of the application. The use of graphs and
concise tables in the body of the text is encouraged for brevity and to facilitate understanding.
It is not intended that material presented fully elsewhere be repeated in the Clinical
Overview; cross-referencing to more detailed presentations provided in the Clinical Summary
or Clinical Study Reports are encouraged.

1. Product Development Rationale
The discussion of the rationale for the development of the medicinal product should:
• identify the pharmacological class of the medicinal product.
• describe the particular clinical/pathophysiological condition that the medicinal product is
intended to treat, prevent, or diagnose (the targeted indication).
• briefly summarise the scientific background that supported the investigation of the
medicinal product for the indication(s) that was (were) studied.
• briefly describe the clinical development programme of the medicinal product, including
ongoing and planned clinical studies and the basis for the decision to submit the
application at this point in the programme.
• note and explain concordance or lack of concordance with current standard research
approaches regarding the design, conduct and analysis of the studies. Pertinent published
literature should be referenced
2. Overview of Biopharmaceutics
The purpose of this section is to present a critical analysis of any important issues related to
bioavailability that might affect efficacy and/or safety of the to-be-marketed formulation(s)
(e.g., dosage form/strength proportionality, differences between the to-be-marketed
formulation and the formulation(s) used in clinical trials, and influence of food on exposure).
3. Overview of Clinical Pharmacology
The purpose of this section is to present a critical analysis of the pharmacokinetic (PK),
pharmacodynamic (PD), and related in vitro data in the ACTD. The analysis should consider
all relevant data and explain why and how the data support the conclusions drawn. It should
emphasise unusual results and known or potential problems, or note the lack thereof. This
section should address:
• pharmacokinetics, e.g., comparative PK in healthy subjects, patients, and special
populations; PK related to intrinsic factors (e.g., age, sex, race, renal and hepatic
impairment) and to extrinsic factors (e.g., smoking, concomitant drugs, diet); rate and
extent of absorption; distribution, including binding with plasma proteins; specific
metabolic pathways, including effects of possible genetic polymorphism and the
formation of active and inactive metabolites; excretion; time-dependent changes in
pharmacokinetics; stereochemistry issues; clinically relevant PK interactions with other
medicinal products or other substances.
• pharmacodynamics, e.g., information on mechanism of action, such as receptor binding;
onset and/or offset of action; relationship of favorable and unfavorable pharmacodynamic
effects to dose or plasma concentration (i.e., PK/PD relationships); PD support for the
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proposed dose and dosing interval; clinically relevant PD interactions with other
medicinal products or substances; and possible genetic differences in response.
• interpretation of the results and implications of immunogenicity studies, clinical
microbiology studies, or other drug class specific PD studies.
4. Overview of Efficacy
The purpose of this section is to present a critical analysis of the clinical data pertinent to the
efficacy of the medicinal product in the intended population. The analysis should consider all
relevant data, whether positive or negative, and should explain why and how the data support
the proposed indication and prescribing information. Those studies deemed relevant for
evaluation of efficacy should be identified, and reasons that any apparently adequate and
well-controlled studies are not considered relevant should be provided. Prematurely
terminated studies should be noted and their impact considered.
The following issues should generally be considered:
• relevant features of the patient populations, including demographic features, disease
stage, any other potentially important covariates, any important patient populations
excluded from critical studies, and participation of children and elderly (ICH E11 and
E7). Differences between the studied population(s) and the population that would be
expected to receive the medicinal product after marketing should be discussed.
• implications of the study design(s), including selection of patients, duration of studies and
choice of endpoints and control group(s). Particular attention should be given to
endpoints for which there is limited experience. Use of surrogate endpoints should be
justified. Validation of any scales used should be discussed.
• for non-inferiority trials used to demonstrate efficacy, the evidence supporting a
determination that the trial had assay sensitivity and justifying the choice of noninferiority
margin (ICH E10).
• statistical methods and any issues that could affect the interpretation of the study results
(e.g., important modifications to the study design, including endpoint assessments and
planned analyses, as they were specified in the original protocol; support for any
unplanned analyses; procedures for handling missing data; and corrections for multiple
• similarities and differences in results among studies, or in different patient sub-groups
within studies, and their effect upon the interpretation of the efficacy data.
• observed relationships between efficacy, dose, and dosage regimen for each indication, in
both the overall population and in the different patient subgroups (ICH E4).
• for products intended for long-term use, efficacy findings pertinent to the maintenance of
long-term efficacy and the establishment of long-term dosage. Development of tolerance
should be considered.
• data suggesting that treatment results can be improved through plasma concentration
monitoring, if any, and documentation for an optimal plasma concentration range.
• the clinical relevance of the magnitude of the observed effects.
• if surrogate endpoints are relied upon, the nature and magnitude of expected clinical
benefit and the basis for these expectations.
• efficacy in special populations. If efficacy is claimed with inadequate clinical data in the
population, support should be provided for extrapolating efficacy from effects in the
general population.
5. Overview of Safety
The purpose of this section is to provide a concise critical analysis of the safety data, noting
how results support and justify proposed prescribing information. A critical analysis of safety
should consider:
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• adverse effects characteristic of the pharmacological class. Approaches taken to monitor
for similar effects should be described.
• special approaches to monitoring for particular adverse events (e.g., ophthalmic, QT
interval prolongation).
• relevant animal toxicology and product quality information. Findings that affect or could
affect the evaluation of safety in clinical use should be considered.
• the nature of the patient population and the extent of exposure, both for test drug and
control treatments. Limitations of the safety database, e.g., related to inclusion/exclusion
criteria and study subject demographics, should be considered, and the implications of
such limitations with respect to predicting the safety of the product in the marketplace
should be explicitly discussed.
• common and non-serious adverse events, with reference to the tabular presentations of
events with the test drug and with control agents in the Clinical Summary. The discussion
should be brief, focusing on events of relatively high frequency, those with an incidence
higher than placebo, and those that are known to occur in active controls or other
members of the therapeutic class. Events that are substantially more or less common or
problematic (considering the duration and degree of the observed events) with the test
drug than with active controls are of particular interest.
• serious adverse events (relevant tabulations should be cross-referenced from the Clinical
Summary). This section should discuss the absolute number and frequency of serious
adverse events, including deaths, and other significant adverse events (e.g., events leading
to discontinuation or dose modification), and should discuss the results obtained for test
drug versus control treatments. Any conclusions regarding causal relationship (or lack of
this) to the product should be provided. Laboratory findings reflecting actual or possible
serious medical effects should be considered.
• similarities and differences in results among studies, and their effect upon the
interpretation of the safety data.
• any differences in rates of adverse events in population subgroups, such as those defined
by demographic factors, weight, concomitant illness, concomitant therapy, or
polymorphic metabolism.
• relation of adverse events to dose, dose regimen, and treatment duration.
• long-term safety (E1a).
• methods to prevent, mitigate, or manage adverse events.
• reactions due to overdose; the potential for dependence, rebound phenomena and abuse,
or lack of data on these issues.
• world-wide marketing experience. The following should be briefly discussed:
- the extent of the world-wide experience,
- any new or different safety issues identified,
- any regulatory actions related to safety.
6. Benefits and Risks Conclusions
The purpose of this section is to integrate all of the conclusions reached in the previous
sections about the biopharmaceutics, clinical pharmacology, efficacy and safety of the
medicinal product and to provide an overall appraisal of the benefits and risks of its use in
clinical practice. Also, implications of any deviations from regulatory advice or guidelines
and any important limitations of the available data should be discussed here. This assessment
should address critical aspects of the proposed Prescribing Information. This section should
also consider the risks and benefits of the medicinal product as they compare to available
alternative treatments or to no treatment in illnesses where no treatment may be a medically
acceptable option; and should clarify the expected place of the medicinal product in the
armamentarium of treatments for the proposed indication. If there are risks to individuals
other than those who will receive the drug, these risks should be discussed (e.g., risks of
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emergence of drug-resistant bacterial strains with widespread use of an antibiotic for minor
illnesses). The analyses provided in previous sections should not be reiterated here. This
section often can be quite abbreviated when no special concerns have arisen and the drug is a
member of a familiar pharmacological class.
This analysis of benefits and risks is generally expected to be very brief but it should identify
the most important conclusions and issues concerning each of the following points:
• the efficacy of the medicinal product for each proposed indication.
• significant safety findings and any measures that may enhance safety.
• dose-response and dose-toxicity relationships; optimal dose ranges and dosage regimens.
• efficacy and safety in sub-populations, e.g., those defined by age, sex, ethnicity, organ
function, disease severity, and genetic polymorphisms.
• data in children in different age groups, if applicable, and any plans for a development
programme in children.
• any risks to the patient of known and potential interactions, including food-drug and drugdrug
interactions, and recommendations for product use.
• any potential effect of the medicinal product that might affect ability to drive or operate
heavy machinery.
Examples of issues and concerns that could warrant a more detailed discussion of benefits
and risks might include:
• the drug is for treatment of a non-fatal disease but has known or potential serious toxicity,
such as a strong signal of carcinogenicity, teratogenicity, pro-arrhythmic potential (effect
on QT interval), or suggestion of hepatotoxicity.
• the proposed use is based on a surrogate endpoint and there is a well-documented
important toxicity.
• safe and/or effective use of the drug requires potentially difficult selection or management
approaches that require special physician expertise or patient training.

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