European Medicines Agency
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`March 1998
`CPMP/ICH/291/95
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`ICH Topic E 8
`General Considerations for Clinical Trials
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`Step 5
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`NOTE FOR GUIDANCE ON GENERAL CONSIDERATIONS FOR CLINICAL
`TRIALS
`(CPMP/ICH/291/95)
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`TRANSMISSION TO CPMP
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`TRANSMISSION TO INTERESTED PARTIES
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`DEADLINE FOR COMMENTS
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`FINAL APPROVAL BY CPMP
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`DATE FOR COMING INTO OPERATION
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`November 1996
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`November 1996
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`May 1997
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`September 1997
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`March 1998
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`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40
`E-mail: mail@emea.eu.int http://www.emea.eu.int
`EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
`
`AVENTIS EXHIBIT 2056
`Mylan v. Aventis, IPR2016-00712
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`1.
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`2.
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`GENERAL CONSIDERATIONS FOR CLINICAL TRIALS
`
`ICH Harmonised Tripartite Guideline
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`
`
`Table of Contents
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`OBJECTIVES OF THIS DOCUMENT.............................................................................3
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`GENERAL PRINCIPLES...................................................................................................3
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`2.1
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`2.2
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`Protection of clinical trial subjects.............................................................................3
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`Scientific approach in design and analysis.................................................................3
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`3.
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`DEVELOPMENT METHODOLOGY...............................................................................6
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`3.1
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`Considerations for the Development Plan..................................................................6
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`3.1.1 Non-Clinical Studies ........................................................................................6
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`3.1.2 Quality of Investigational Medicinal Products.................................................6
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`3.1.3 Phases of Clinical Development ......................................................................6
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`3.1.4 Special Considerations...................................................................................10
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`3.2
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`Considerations for Individual Clinical Trials...........................................................11
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`3.2.1 Objectives.......................................................................................................11
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`3.2.2 Design ............................................................................................................11
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`3.2.3 Conduct ..........................................................................................................13
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`3.2.4 Analysis..........................................................................................................13
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`3.2.5 Reporting........................................................................................................13
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`ANNEX ............................................................................................................................................14
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`1.
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`OBJECTIVES OF THIS DOCUMENT
`
`b)
`
`In the three ICH regions, the evolution of drug development strategies and evaluation
`processes has led to the establishment of regional guidances on general considerations for
`clinical trials and the process of clinical development of pharmaceuticals for human use. This
`harmonised guideline is derived from those regional documents as well as from ICH
`Guidelines.
`The ICH document "General Considerations for Clinical Trials" is intended to:
`a)
`describe internationally accepted principles and practices in the conduct of both
`individual clinical trials and overall development strategy for new medicinal products.
`facilitate the evaluation and acceptance of foreign clinical trial data by promoting
`common understanding of general principles, general approaches and the definition of
`relevant terms.
`present an overview of the ICH clinical safety and efficacy documents and facilitate
`the user's access to guidance pertinent to clinical trials within these documents. The
`relevant ICH documents are listed in Annex 1.
`provide a separate glossary of terms used in the ICH clinical safety and efficacy related
`documents that pertain to clinical trials and indicate which documents contain them.
`For the sake of brevity, the term "drug" has been used in this document. It should be
`considered synonymous with "investigational (medicinal) product", "medicinal product" and
`"pharmaceutical" including vaccines and other biological products. The principles established
`in this guideline may also be applied to other clinical investigations (e.g. radiotherapy,
`psychotherapy, surgery, medical devices and alternative therapies).
`
`c)
`
`d)
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`2.
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`GENERAL PRINCIPLES
`
`Protection of clinical trial subjects
`2.1
`The principles and practices concerning protection of trial subjects are stated in the ICH
`Guideline on Good Clinical Practice (ICH E6). These principles have their origins in The
`Declaration of Helsinki and should be observed in the conduct of all human drug
`investigations.
`Before any clinical trial is carried out, results of non-clinical investigations or previous human
`studies should be sufficient to indicate that the drug is acceptably safe for the proposed
`investigation in humans. The purpose and timing of animal pharmacology and toxicology
`studies intended to support studies of a given duration are discussed in ICH M3. The role of
`such studies for biotechnology products is cited in ICH S6.
`Throughout drug development, emerging animal toxicological and clinical data should be
`reviewed and evaluated by qualified experts to assess their implications for the safety of the
`trial subjects. In response to such findings, future studies and, when necessary, those in
`progress should be appropriately modified in a timely fashion to maintain the safety of trial
`participants. The investigator and sponsor share responsibility for the protection of clinical
`trial subjects together with the Institutional Review Board/Independent Ethics Committee.
`The responsibilities of these parties are described in ICH E6.
`
`2.2 Scientific approach in design and analysis
`Clinical trials should be designed, conducted and analysed according to sound scientific
`principles to achieve their objectives; and should be reported appropriately. The essence of
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`rational drug development is to ask important questions and answer them with appropriate
`studies. The primary objectives of any study should be clear and explicitly stated.
`Clinical studies can be classified according to when the study occurs during clinical
`development or as shown in Table 1 by their objectives. (The illustrative examples are not
`intended to be exhaustive). The cardinal logic behind serially conducted studies of a
`medicinal product is that the results of prior studies should influence the plan of later studies.
`Emerging data will frequently prompt a modification of the development strategy. For
`example, results of a therapeutic confirmatory study may suggest a need for additional human
`pharmacology studies.
`The availability of foreign clinical data should obviate the need to generate similar data in an
`ICH region if the ICH E5 and ICH E6 guidelines are followed. (see ICH E5).
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`Table 1 - An Approach to Classifying Clinical Studies According to Objective
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`Type of Study
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`Objective of Study
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`Study Examples
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`Human
`Pharmacology
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`Therapeutic
`Exploratory
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`Therapeutic
`Confirmatory
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`Therapeutic Use
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`• Assess tolerance
`• Define/describe PK1and PD2
`• Explore drug metabolism and
`drug interactions
`• Estimate activity
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`• Dose-tolerance studies
`• Single and multiple dose PK
`and/or PD studies
`• Drug interaction studies
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`• Explore use for the targeted
`indication
`• Estimate dosage for subsequent
`studies
`• Provide basis for confirmatory
`study design, endpoints,
`methodologies
`
`• Earliest trials of relatively short
`duration in well- defined
`narrow patient populations,
`using surrogate or
`pharmacological endpoints or
`clinical measures
`• Dose-response exploration
`studies
`
`• Demonstrate/confirm efficacy
`• Establish safety profile
`• Provide an adequate basis for
`assessing the benefit/risk
`relationship to support
`licensing
`• Establish dose-response
`relationship
`
`• Refine understanding of
`benefit/risk relationship in
`general or special populations
`and/or environments
`• Identify less common adverse
`reactions
`• Refine dosing recommendation
`
`• Adequate, and well controlled
`studies to establish efficacy
`• Randomised parallel dose-
`response studies
`• Clinical safety studies
`• Studies of mortality/ morbidity
`outcomes
`• Large simple trials
`• Comparative studies
`
`• Comparative effectiveness
`studies
`• Studies of mortality/morbidity
`outcomes
`• Studies of additional endpoints
`• Large simple trials
`• Pharmacoeconomic studies
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`
`1Pharmacokinetics
`2Pharmacodynamics
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`DEVELOPMENT METHODOLOGY
`3.
`This section covers issues and considerations relating to the development plan and to its
`individual component studies.
`
`3.1 Considerations for the Development Plan
`3.1.1 Non-Clinical Studies
`Important considerations for determining the nature of non-clinical studies and their timing
`with respect to clinical trials include:
`a)
`duration and total exposure proposed in individual patients
`b)
`characteristics of the drug (e.g. long half life, biotechnology products)
`c)
`disease or condition targeted for treatment
`d)
`use in special populations (e.g. women of childbearing potential)
`e)
`route of administration
`toxicology, pharmacology and
`including
`information
`The need
`for non-clinical
`pharmacokinetics to support clinical trials is addressed in the ICH M3 and S6 documents.
`
`3.1.1.1 Safety Studies
`For the first studies in humans, the dose that is administered should be determined by careful
`examination of
`the prerequisite non-clinical pharmacokinetic, pharmacological and
`toxicological evaluations (see ICH M3). Early non-clinical studies should provide sufficient
`information to support selection of the initial human dose and safe duration of exposure, and
`to provide information about physiological and toxicological effects of a new drug.
`
`3.1.1.2 Pharmacological and Pharmacokinetic Studies
`The basis and direction of the clinical exploration and development rests on the non-clinical
`pharmacokinetic and pharmacology profile, which includes information such as:
`a)
`Pharmacological basis of principal effects (mechanism of action).
`b)
`Dose-response or concentration-response relationships and duration of action
`c)
`Study of the potential clinical routes of administration
`d)
`Systemic general pharmacology, including pharmacological effects on major organ
`systems and physiological responses
`Studies of absorption, distribution, metabolism and excretion
`
`e)
`
`3.1.2 Quality of Investigational Medicinal Products
`Formulations used in clinical trials should be well characterised, including information on
`bioavailability wherever feasible. The formulation should be appropriate for the stage of drug
`development. Ideally, the supply of a formulation will be adequate to allow testing in a series
`of studies that examine a range of doses. During drug development different formulations of a
`drug may be tested. Links between formulations, established by bioequivalence studies or
`other means are important in interpreting clinical study results across the development
`program.
`
`3.1.3 Phases of Clinical Development
`Clinical drug development is often described as consisting of four temporal phases (Phase I-
`IV). It is important to recognise that the phase of development provides an inadequate basis
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`for classification of clinical trials because one type of trial may occur in several phases (see
`Fig 1.). A classification system using study objectives as discussed in section 2.2 is
`preferable. It is important to appreciate that the phase concept is a description, not a set of
`requirements. It is also important to realise that the temporal phases do not imply a fixed
`order of studies since for some drugs in a development plan the typical sequence will not be
`appropriate or necessary. For example, although human pharmacology studies are typically
`conducted during Phase I, many such studies are conducted at each of the other three stages,
`but nonetheless sometimes labelled as Phase I studies. Figure 1 demonstrates this close but
`variable correlation between the two classification systems. The distribution of the points of
`the graph shows that the types of study are not synonymous with the phases of development.
`
`Correlation between Development Phases and Types of Study
`
`
`Figure 1 This matrix graph illustrates the relationship between the phases of development
`and types of study by objective that may be conducted during each clinical development of
`a new medicinal product. The shaded circles show the types of study most usually
`conducted in a certain phase of development, the open circles show certain types of study
`that may be conducted in that phase of development but are less usual. Each circle
`represents an individual study. To illustrate the development of a single study, one circle is
`joined by a dotted line to an inset column that depicts the elements and sequence of an
`individual study.
`
`Drug development is ideally a logical, step-wise procedure in which information from small
`early studies is used to support and plan later larger, more definitive studies. To develop new
`drugs efficiently, it is essential to identify characteristics of the investigational medicine in the
`early stages of development and to plan an appropriate development based on this profile.
`Initial trials provide an early evaluation of short-term safety and tolerability and can provide
`pharmacodynamic and pharmacokinetic information needed to choose a suitable dosage range
`and administration schedule for initial exploratory therapeutic trials. Later confirmatory
`studies are generally larger and longer and include a more diverse patient population. Dose-
`response information should be obtained at all stages of development, from early tolerance
`studies, to studies of short-term pharmacodynamic effect, to large efficacy studies (see ICH
`E4). Throughout development, new data may suggest the need for additional studies that are
`typically part of an earlier phase. For example, blood level data in a late trial may suggest a
`need for a drug-drug interaction study, or adverse effects may suggest the need for further
`dose finding and/or additional non-clinical studies. In addition, to support a new marketing
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`application approval for the same drug e.g. for a new indication, pharmacokinetic or
`therapeutic exploratory studies are considered to be in Phase I or Phase II of development.
`
`3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)
`Phase I starts with the initial administration of an investigational new drug into humans.
`Although human pharmacology studies are typically identified with Phase I, they may also be
`indicated at other points in the development sequence. Studies in this phase of development
`usually have non-therapeutic objectives and may be conducted in healthy volunteer subjects
`or certain types of patients, e.g. patients with mild hypertension. Drugs with significant
`potential toxicity, e.g. cytotoxic drugs, are usually studied in patients. Studies in this phase
`can be open, baseline controlled or may use randomisation and blinding, to improve the
`validity of observations.
`Studies conducted in Phase I typically involve one or a combination of the following aspects:
`a)
`Estimation of Initial Safety and Tolerability
`The initial and subsequent administration of an investigational new drug into humans is
`usually intended to determine the tolerability of the dose range expected to be needed for later
`clinical studies and to determine the nature of adverse reactions that can be expected. These
`studies typically include both single and multiple dose administration.
`b)
`Pharmacokinetics
`Characterisation of a drug's absorption, distribution, metabolism, and excretion continues
`throughout the development plan. Their preliminary characterisation is an important goal of
`Phase I. Pharmacokinetics may be assessed via separate studies or as a part of efficacy, safety
`and tolerance studies. Pharmacokinetic studies are particularly important to assess the
`clearance of the drug and to anticipate possible accumulation of parent drug or metabolites
`and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted
`in later phases to answer more specialised questions. For many orally administered drugs,
`especially modified release products, the study of food effects on bioavailability is important.
`Obtaining pharmacokinetic information in sub-populations such as patients with impaired
`elimination (renal or hepatic failure), the elderly, children, women and ethnic subgroups
`should be considered. Drug-drug interaction studies are important for many drugs; these are
`generally performed in phases beyond Phase I but studies in animals and in vitro studies of
`metabolism and potential interactions may lead to doing such studies earlier.
`c)
`Assessment of Pharmacodynamics
`Depending on the drug and the endpoint studied, pharmacodynamic studies and studies
`relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer
`subjects or in patients with the target disease. In patients, if there is an appropriate measure,
`pharmacodynamic data can provide early estimates of activity and potential efficacy and may
`guide the dosage and dose regimen in later studies.
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`Early Measurement of Drug Activity
`d)
`Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as
`a secondary objective. Such studies are generally performed in later phases but may be
`appropriate when drug activity is readily measurable with a short duration of drug exposure in
`patients at this early stage.
`
`3.1.3.2 Phase II (Most typical kind of study: Therapeutic Exploratory)
`Phase II is usually considered to start with the initiation of studies in which the primary
`objective is to explore therapeutic efficacy in patients.
`Initial therapeutic exploratory studies may use a variety of study designs, including
`concurrent controls and comparisons with baseline status. Subsequent trials are usually
`randomised and concurrently controlled to evaluate the efficacy of the drug and its safety for
`a particular therapeutic indication. Studies in Phase II are typically conducted in a group of
`patients who are selected by relatively narrow criteria, leading to a relatively homogeneous
`population and are closely monitored.
`An important goal for this phase is to determine the dose(s) and regimen for Phase III trials.
`Early studies in this phase often utilise dose escalation designs (see ICH E4) to give an early
`estimate of dose response and later studies may confirm the dose response relationship for the
`indication in question by using recognised parallel dose-response designs (could also be
`deferred to phase III). Confirmatory dose response studies may be conducted in Phase II or
`left for Phase III. Doses used in Phase II are usually but not always less than the highest doses
`used in Phase†I.
`Additional objectives of clinical trials conducted in Phase II may include evaluation of
`potential study endpoints, therapeutic regimens (including concomitant medications) and
`target populations (e.g. mild versus severe disease) for further study in Phase II or III. These
`objectives may be served by exploratory analyses, examining subsets of data and by including
`multiple endpoints in trials.
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`3.1.3.3 Phase III (Most typical kind of study: Therapeutic Confirmatory)
`Phase III usually is considered to begin with the initiation of studies in which the primary
`objective is to demonstrate, or confirm therapeutic benefit.
`Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II
`that a drug is safe and effective for use in the intended indication and recipient population.
`These studies are intended to provide an adequate basis for marketing approval. Studies in
`Phase III may also further explore the dose-response relationship, or explore the drug's use in
`wider populations, in different stages of disease, or in combination with another drug. For
`drugs intended to be administered for long periods, trials involving extended exposure to the
`drug are ordinarily conducted in Phase III, although they may be started in Phase II (see ICH
`E1). ICH E1 and ICH E7 describe the overall clinical safety database considerations for
`chronically administered drugs and drugs used in the elderly. These studies carried out in
`Phase III complete the information needed to support adequate instructions for use of the drug
`(official product information).
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`3.1.3.4 Phase IV (Variety of Studies: - Therapeutic Use)
`Phase IV begins after drug approval. Therapeutic use studies go beyond the prior
`demonstration of the drugís safety, efficacy and dose definition.
`Studies in Phase IV are all studies (other than routine surveillance) performed after drug
`approval and related to the approved indication. They are studies that were not considered
`necessary for approval but are often important for optimising the drug's use. They may be of
`any type but should have valid scientific objectives. Commonly conducted studies include
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`additional drug-drug interaction, dose-response or safety studies and studies designed to
`support use under the approved indication, e.g. mortality/morbidity studies, epidemiological
`studies.
`
`3.1.3.5 Development of an application unrelated to original approved use
`After initial approval, drug development may continue with studies of new or modified
`indications, new dosage regimens, new routes of administration or additional patient
`populations. If a new dose, formulation or combination is studied, additional human
`pharmacology studies may be indicated, necessitating a new development plan.
`The need for some studies may be obviated by the availability of data from the original
`development plan or from therapeutic use.
`
`3.1.4 Special Considerations
`A number of special circumstances and populations require consideration on their own when
`they are part of the development plan.
`
`3.1.4.1 Studies of Drug Metabolites
`Major active metabolite(s) should be identified and deserve detailed pharmacokinetic study.
`Timing of the metabolic assessment studies within the development plan depends on the
`characteristics of the individual drug.
`
`3.1.4.2 Drug-Drug Interactions
`If a potential for drug-drug interaction is suggested by metabolic profile, by the results of non-
`clinical studies or by information on similar drugs, studies on drug interaction during clinical
`development are highly recommended. For drugs that are frequently co-administered it is
`usually important that drug-drug interaction studies be performed in non-clinical and, if
`appropriate in human studies. This is particularly true for drugs that are known to alter the
`absorption or metabolism of other drugs (see ICH E7), or whose metabolism or excretion can
`be altered by effects by other drugs.
`
`3.1.4.3 Special Populations
`Some groups in the general population may require special study because they have unique
`risk/benefit considerations that need to be taken into account during drug development, or
`because they can be anticipated to need modification of use of the dose or schedule of a drug
`compared to general adult use. Pharmacokinetic studies in patients with renal and hepatic
`dysfunction are important to assess the impact of potentially altered drug metabolism or
`excretion. Other ICH documents address such issues for geriatric patients (ICH E7) and
`patients from different ethnic groups (ICH E5). The need for non-clinical safety studies to
`support human clinical trials in special populations is addressed in the ICH M3 document.
`Particular attention should be paid to the ethical considerations related to informed consent
`from vulnerable populations and the procedures scrupulously followed.(see ICH E6)
`
`Investigations in pregnant women
`a)
`In general, pregnant women should be excluded from clinical trials where the drug is not
`intended for use in pregnancy. If a patient becomes pregnant during administration of the
`drug, treatment should generally be discontinued if this can be done safely. Follow-up
`evaluation of the pregnancy, foetus, and child is very important . Similarly, for clinical trials
`that include pregnant women because the medicinal product is intended for use during
`pregnancy, follow-up of the pregnancy, foetus, and child is very important.
`
`b)
`Investigations in nursing women
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`Excretion of the drug or its metabolites into human milk should be examined where
`applicable. When nursing mothers are enrolled in clinical studies their babies should be
`monitored for the effects of the drug.
`
`Investigations in children.
`c)
`The extent of the studies needed depends on the current knowledge of the drug and the
`possibility of extrapolation from adults and children of other age groups. Some drugs may be
`used in children from the early stages of drug development (see ICH M3).
`For a drug expected to be used in children, evaluation should be made in the appropriate age
`group. When clinical development is to include studies in children, it is usually appropriate to
`begin with older children before extending the trial to younger children and then infants.
`
`3.2 Considerations for Individual Clinical Trials
`The following important principles should be followed in planning the objectives, design,
`conduct, analysis and reporting of a clinical trial (see ICH guidelines in Annex 1). Each part
`should be defined in a written protocol before the study starts (see ICH E6).
`
`3.2.1 Objectives
`The objective(s) of the study should be clearly stated and may include exploratory or
`confirmatory characterisation of safety and/or efficacy and/or assessment of pharmacokinetic
`parameters and pharmacological, physiological, biochemical effects.
`
`3.2.2 Design
`The appropriate study design should be chosen to provide the desired information. Examples
`of study design include parallel group, cross-over, factorial, dose escalation, and fixed dose-
`dose response. (See ICH E4, E6, E9 and E10). Appropriate comparators should be utilised
`and adequate numbers of subjects included to achieve the study objectives. Primary and
`secondary endpoints and plans for their analyses should be clearly stated (see ICH E9). The
`methods of monitoring adverse events by changes in clinical signs and symptoms and
`laboratory studies should be described (see ICH E3). The protocol should specify procedures
`for the follow-up of patients who stop treatment prematurely.
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`3.2.2.1 Selection of subjects
`The stage of development and the indication to be studied and should be taken into account in
`selecting the subject population (e.g. normal healthy subjects, cancer patients or other special
`populations in early phase development) as should prior non-clinical and clinical knowledge.
`The variability of groups of patients or healthy volunteers studied in early trials may be
`limited to a narrow range by strict selection criteria, but as drug development proceeds, the
`populations tested should be broadened to reflect the target population.
`Depending on the stage of development and level of concern for safety, it may be necessary to
`conduct studies in a closely monitored (i.e., inpatient) environment.
`As a general principle trial subjects should not participate concurrently in more than one
`clinical trial but there can be justified exceptions. Subjects should not be enrolled repetitively
`in clinical trials without time off treatment adequate to protect safety and exclude carry-over
`effects.
`In general, women of childbearing potential should be using highly effective contraception to
`participate in clinical trials (see ICH M3).
`For male subjects, potential hazards of drug exposure in the trial to their sexual partners or
`resulting progeny should be considered. When indicated (e.g. trials involving drugs which are
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`potentially mutagenic, or toxic to the reproductive system), an appropriate contraception
`provision should be included in the trial.
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`3.2.2.2 Selection of Control Group
`Trials should have an adequate control group. Comparisons may be made with placebo, no
`treatment, active controls or of different doses of the drug under investigation. The choice of
`the comparator depends, among other things, on the objective of the trial (see ICH E9 and
`E10). Historical (external) controls can be justified in some cases but particular care is
`important to minimise the likelihood of erroneous inference.
`
`3.2.2.3 Number of subjects
`The size of a trial is influenced by the disease to be investigated, the objective of the study
`and the study endpoints. Statistical assessments of sample size should be based on the
`expected magnitude of the treatment effect, the variability of the data, the specified (small)
`probability of error (see ICH E9) and the desire for information or subsets of the population or
`secondary endpoints.. In some circumstances a larger database may be needed to establish the
`safety of a drug. ICH E1 and ICH E7 suggest a minimum experience to assess safety for a
`registrational database for a new indication. These numbers should not be considered as
`absolute and may be insufficient in some cases ( e.g. where long-term use in healthy
`individuals is expected).
`
`3.2.2.4 Response Variables
`Response variables should be defined prospectively, giving descriptions of methods of
`observation and quantification. Objective methods of observation should be used where
`possible and when appropriate (see ICH E9).
`Study endpoints are the response variables that are chosen to assess drug effects that are
`related to pharmacokinetic parameters, pharmacodynamic measures, efficacy and safety. A
`primary endpoint(s) should reflect clinically relevant effects and is typically selected based on
`the principal objective of the study. Secondary endpoints assess other drug effects that may or
`may not be related to the primary endpoint. Endpoints and the plan for their analysis should
`be prospectively specified in the protocol.
`A surrogate endpoint is an endpoint that is intended to relate to a clinically important outcome
`but does not in itself measure a clinical benefit. Surrogate endpoints may be used as primary
`endpoints when appropriate (when the surrogate is reasonably likely or well known to predict
`clinical outcome).
`The methods used to make the measurements of the endpoints, both subjective and objective,
`should be validated and meet appropriate standards for accuracy, precision, reproducibility,
`reliability, and responsiveness (sensitivity to change over time).
`
`3.2.2.5 Methods to Minimise or Assess Bias
`The protocol should specify methods of allocation to treatment groups and blinding (see ICH
`E9 and E10).
`
`Randomisation
`a)
`In conducting a controlled trial, randomised allocation is the preferred means of assuring
`comparability of test groups and minimising the possibility of selection bias.
`
`Blinding
`b)
`Blinding is an important means of reducing or minimising the risk of biased study outcomes.
`A trial where the treatment assignment is not known by the study participant because of the
`use of placebo or other methods of masking the intervention, is referred to as a single blind
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`study. When the investigator and sponsor staff who are involved in the treatment or clinical
`evaluation of the subjects and analysis of data are also unaware of the treatment assignments,
`the study is double blind.
`
`Compliance
`c)
`Methods used to evaluate patient usage of the test drug should be specified in the protocol and
`the actual usage documented.
`
`3.2.3 Conduct
`The study should be conducted according to the principles described in this guideline and in
`accordance with other pertinent elements outlined in ICH E6 and other relevant ICH
`guidelines (see Annex 1). Adherence to the study protocol is