ICH E8

ICH E8(R1) General Considerations for Clinical Studies
中文版 
 ICH E8(R1) 临床试验的一般考虑 
 
 1. OBJECTIVES OF THIS DOCUMENT 
 Clinical studies of medicinal products are conducted to provide information that can ultimately improve access to safe and effective products with meaningful impact on patients, while protecting those participating in the studies. This document provides guidance on the clinical development lifecycle, including designing quality into clinical studies, considering the broad range of clinical study designs and data sources used. 
 The ICH document "General Considerations for Clinical Studies" is intended to: 
 1. Describe internationally accepted principles and practices in the design and conduct of clinical studies that will ensure the protection of study participants and facilitate acceptance of data and results by regulatory authorities 
 2. Provide guidance on the consideration of quality in the design and conduct of clinical studies across the product lifecycle, including the identification, during study planning, of factors that are critical to the quality of the study, and the management of risks to those factors during study conduct 
 3. Provide an overview of the types of clinical studies performed during the product lifecycle, and describe study design elements that support the identification of quality factors critical to ensuring the protection of study participants, the integrity of the data, the reliability of results, and the ability of the studies to meet their objectives 
 4. Provide a guide to the ICH efficacy documents to facilitate user's access 
 General principles are described in Section 2 of this document, followed by a discussion of designing quality into clinical studies in Section 3. A broad overview of drug development planning and the information provided by different types of studies needed to progress development through the lifecycle of the product is given in Section 4. In Section 5, important elements of clinical study design are described that reflect the variety of designs used in drug development as well as the range of data sources available. Section 6 addresses study conduct, ensuring the safety of study participants, and study reporting. Some considerations for identifying factors that are critical to the quality of a study are provided in Section 7. 
 The ICH Efficacy guidelines are an integrated set of guidance covering the planning, design, conduct, safety, analysis, and reporting of clinical studies. ICH E8 provides an overall introduction to clinical development, designing quality into clinical studies and focusing on those factors critical to the quality of the studies. The guidelines should be considered and used in an integrated, holistic way rather than focusing on only one guideline or subsection. 
 For the purposes of this document, a clinical study is meant to refer to a study of one or more medicinal products in humans, conducted at any point in a product’s lifecycle, both prior to and following marketing authorisation. The focus is on clinical studies to support regulatory decisions, recognizing these studies may also inform health policy decisions, clinical practice guidelines, or other actions. The term "drug" should be considered synonymous with therapeutic, preventative, or diagnostic medicinal products. The term “drug approval” refers to obtaining marketing authorisation for the drug. 
 2. GENERAL PRINCIPLES 
 2.1 Protection of Clinical Study Participants 
 Important principles of ethical conduct of clinical studies and the protection of participants, including special populations, have their origins in the Declaration of Helsinki and should be observed in the conduct of all human clinical investigations. These principles are stated in other ICH guidelines, in particular, ICH E6-Good Clinical Practice. 
 As further described in the E6 guideline, the investigator and sponsor have responsibilities for the protection of study participants together with the Institutional Review Board/Independent Ethics Committee. 
 The confidentiality of information that could identify participants should be protected in accordance with the applicable regulatory and legal requirement(s). 
 Before initiating a clinical study, sufficient information should be available to ensure that the drug is acceptably safe for the planned study in humans. Emerging non-clinical, clinical, and pharmaceutical quality data should be reviewed and evaluated, as they become available, by qualified experts to assess the potential implications for the safety of study participants. Ongoing and future studies should be appropriately adjusted as needed, to take new knowledge into consideration and to protect study participants. Throughout drug development, care should be taken to ensure all study procedures and assessments are necessary from a scientific viewpoint and do not place undue burden on study participants. 
 2.2 Scientific Approach in Clinical Study Design, Planning, Conduct, Analysis, and Reporting 
 The essence of clinical research is to ask important questions and answer them with appropriate studies. The primary objectives of any study should reflect the research questions and be clear and explicitly stated. Clinical studies should be designed, planned, conducted, analysed, and reported according to sound scientific principles to achieve their objectives. 
 Quality of a clinical study is considered in this document as fitness for purpose. The purpose of a clinical study is to generate reliable information to answer the research questions and support decision making while protecting study participants. The quality of the information generated should therefore be sufficient to support good decision making. 
 Quality by design in clinical research sets out to ensure that the quality of a study is driven proactively by designing quality into the study protocol and processes. This involves the use of a prospective, multidisciplinary approach to promote the quality of protocol and process design in a manner proportionate to the risks involved, and clear communication of how this will be achieved. 
 Across the product lifecycle, different types of studies will be conducted with different objectives and designs and may involve different data sources. For purposes of this guideline, development planning is considered to cover the entire product lifecycle (Section 4). The Annex provides a broad categorisation of study type by objective within the different stages of drug development. Studies should be rigorously designed to address the study objectives with careful attention to the design elements, such as the choice of study population and response variables and the use of methods to minimize biases in the findings (Section 5). 
 The cardinal logic behind serially conducted studies is that the results of prior studies should inform the plan of later studies. Emerging data will frequently prompt a modification of the development strategy. For example, results of a confirmatory study may suggest a need for additional human pharmacology studies. 
 The availability of multi-regional data as a result of the increased globalisation of drug development programmes, facilitated by the harmonisation of ICH Guidelines, minimises the need to conduct individual studies in different regions. The results of a study are often used in regulatory submissions in multiple regions, and the design should also consider the relevance of the study results for regions other than the one(s) in which the study is conducted. Further guidance is provided by ICH E5 Ethnic Factors, ICH E6, and ICH E17 Multi-Regional Clinical Trials. 
 Early engagement with regulatory authorities to understand local/regional requirements and expectations is encouraged and will facilitate the ability to design quality into the study. 
 2.3 Patient Input into Drug Development 
 Consulting with patients and/or patient organisations during drug development can help to ensure that patients’ perspectives are captured. The views of patients (or of their Caregivers/parents) can be valuable throughout all phases of drug development. Involving patients early in the design of a study is likely to increase trust in the study, facilitate recruitment, and promote adherence. Patients also provide their perspective of living with a condition, which may contribute to the determination, for example, of endpoints that are meaningful to patients, selection of the appropriate population and duration of the study, and use of acceptable comparators. This ultimately supports the development of drugs that are better tailored to patients’ needs. 
 3. DESIGNING QUALITY INTO CLINICAL STUDIES 
 The quality by design approach to clinical research (Section 3.1) involves focusing on critical to quality factors to ensure the protection of the rights, safety, and wellbeing of study participants, the generation of reliable and meaningful results, and the management of risks to those factors using a risk-proportionate approach (Section 3.2). The approach is supported by the establishment of an appropriate framework for the identification and review of critical to quality factors (Section 3.3) at the time of design and planning of the study, and throughout its conduct, analysis, and reporting. 
 3.1 Quality by Design of Clinical Studies 
 Good planning and implementation of a clinical study also derive from attention to the design elements of clinical studies as described in Section 5, such as: 
 
 the need for clear pre-defined study objectives that address the primary scientific question(s); 
 selection of appropriate participants that have the disease, condition, or molecular/genetic profile that is being studied; 
 use of approaches to minimise bias, such as randomisation, blinding or masking, and/or control of confounding; 
 endpoints that are well-defined, measurable, clinically meaningful, and relevant to patients. 
 
 Operational criteria are also important, such as ensuring a clear understanding of the feasibility of the study, selection of suitable investigator sites, quality of specialised analytical and testing facilities and procedures, and processes that ensure data integrity. 
 3.2 Critical to Quality Factors 
 A basic set of factors relevant to ensuring study quality should be identified for each study. Emphasis should be given to those factors that stand out as critical to study quality. These critical to quality factors are attributes of a study whose integrity is fundamental to the protection of study participants, the reliability and interpretability of the study results, and the decisions made based on the study results. These quality factors are considered to be critical because, if their integrity were to be undermined by errors of design or conduct, the reliability or ethics of decision-making based on the results of the study would also be undermined. Critical to quality factors should also be considered holistically, so that dependencies among them can be identified. Section 7 of this document provides considerations that can help identify critical to quality factors for a study. 
 The design of a clinical study should reflect the state of knowledge and experience with the drug; the condition to be treated, diagnosed or prevented; the underlying biological mechanism (of both the condition and the treatment); and the population for which the drug is intended. As research progresses, knowledge increases and uncertainties about the pharmacology, safety and efficacy of a drug decrease. Knowledge of the drug at any point in development will continually inform the identification of critical to quality factors and control processes used to manage them. 
 The sponsor and other parties designing quality into a clinical study should identify the critical to quality factors. Having identified those factors, it is important to determine the risks that threaten their integrity and decide whether they can be accepted or should be mitigated, based on their probability, detectability and impact. Where it is decided that risks should be mitigated, the necessary control processes should be put in place and communicated, and the necessary actions taken to mitigate the risks. The term risk is used here in the context of general risk management methodology applicable to all factors of a study. 
 Proactive communication of the critical to quality factors and risk mitigation activities will support understanding of priorities and resource allocation by the sponsor and investigator sites. Proactive support (e.g., training to site staff, relevant to their role, and description of critical to quality factors and potential mitigation measures in the protocol) will enhance correct implementation of study protocol, procedures, and associated operational plans and process design. 
 Perfection in every aspect of an activity is rarely achievable or can only be achieved by use of resources that are out of proportion to the benefit obtained. The quality factors should be prioritised to identify those that are critical to the study, at the time of the study design, and study procedures should be proportionate to the risks inherent in the study and the importance of the information collected. The critical to quality factors should be clear and should not be cluttered with minor issues (e.g., due to extensive secondary objectives or processes/data collection not linked to the proper protection of the study participants and/or primary study objectives). 
 3.3 Approach to Identifying the Critical to Quality Factors 
 A key aspect of a quality approach to study design is to ask whether the objectives being addressed by the study are clearly articulated; whether the study is designed to meet the research question it sets out to address; whether these questions are meaningful to patients; and whether the study hypotheses are specific and scientifically valid. The approach to the identification of the critical to quality factors should consider whether those objectives can be met, well and most efficiently, by the chosen design and data sources. Patient consultation early in the study design process can contribute to this approach and ultimately help to identify the critical to quality factors. Study designs should be operationally feasible and avoid unnecessary complexity. Protocols and case report forms/data collection methods should enable the study to be conducted as designed and avoid unnecessary data collection. 
 Identification of critical to quality factors will be enhanced by approaches that include the following elements: 
 3.3.1 Establishing a Culture that Supports Open Dialogue 
 Creating a culture that values and rewards critical thinking and open, proactive dialogue about what is critical to quality for a particular study or development programme, going beyond sole reliance on tools and checklists, is encouraged. Open dialogue can facilitate the development of innovative methods for ensuring quality. 
 Inflexible, “one size fits all” approaches should be discouraged. Standardised operating procedures are necessary and beneficial for conducting good quality clinical studies, but study specific strategies and actions are also needed to effectively and efficiently support quality in a study. 
 Evidence used to inform the study design should be gathered and reviewed, before and during the study, in a transparent manner, while acknowledging gaps in data and conflicting data, where present and known, and anticipating the possible emergence of such gaps or conflicts. 
 3.3.2 Focusing on Activities Essential to the Study 
 Efforts should be focused on activities that are essential to the reliability and meaningfulness of study outcomes for patients and public health, and the safe, ethical conduct of the study for participants. Consideration should be given to eliminating nonessential activities and data collection from the study to increase quality by simplifying conduct, improving study efficiency, and targeting resources to critical areas. Resources should be deployed to identify and prevent or control errors that matter. 
 3.3.3 Engaging Stakeholders in Study Design 
 Clinical study design is best informed by input from a broad range of stakeholders, including patients and healthcare providers. It should be open to challenge by subject matter experts and stakeholders from outside, as well as within, the sponsor organisation. 
 The process of building quality into the study may be informed by participation of those directly involved in successful completion of the study such as clinical investigators, study coordinators and other site staff, and patients/patient organisations. Clinical investigators and potential study participants have valuable insights into the feasibility of enrolling participants who meet proposed eligibility criteria, whether scheduled study visits and procedures may be overly burdensome and lead to early dropouts, and the general relevance of study endpoints and study settings to the targeted patient population. They may also provide insight into the value of a treatment in the context of ethical issues, culture, region, demographics, and other characteristics of subgroups within a targeted patient population. 
 Early engagement with regulatory authorities is encouraged, particularly when a study has novel elements considered critical to quality (e.g., defining patient populations, procedures, or endpoints). 
 3.3.4 Reviewing Critical to Quality Factors 
 Accumulated experience and knowledge, together with periodic review of critical to quality factors should be used to determine whether adjustments to risk control mechanisms are needed, because new or unanticipated issues may arise once the study has begun. 
 Studies with adaptive features and/or interim decision points need specific attention during proactive planning and ongoing review of critical to quality factors, and risk management (ICH E9 Statistical Principles for Clinical Trials). 
 3.3.5 Critical to Quality Factors in Operational Practice 
 The foundation of a successful study is a protocol that is both scientifically sound and operationally feasible. A feasibility assessment involves consideration of study design and implementation elements that could impact the successful completion of clinical development from an operational perspective. 
 Feasibility considerations also include but are not limited to regional differences in medical practice and patient populations, the availability of qualified investigators/site personnel with experience in conducting a clinical study (ICH E6), availability of equipment and facilities required to successfully conduct the study, availability of the targeted patient population, and ability to enrol a sufficient number of participants to meet the study objectives. The retention and follow up of study participants are also key critical to quality factors. Consideration of these and other critical to quality factors relating to study feasibility can inform study design and enhance quality implementation. 
 4. DRUG DEVELOPMENT PLANNING 
 This section provides general principles to consider in drug development planning. Drug development planning adheres to the principles of scientific research and good study design that ensure the reliability and interpretability of results. Efficient drug development includes appropriately planned interactions with regulatory authorities throughout development to ensure alignment with requirements for product quality and to support approval in the condition or disease, including possible post-approval studies to address remaining questions. Throughout this process there is critical attention to the protection of the rights, safety and wellbeing of study participants. 
 Drug development planning builds on knowledge acquired throughout the investigational process to reduce levels of uncertainty as the process moves from target identification through non-clinical and clinical evaluation. Such planning encompasses quality of medicinal product, including chemistry, manufacturing and controls (CMC), and non-clinical and clinical studies (pre and post-approval). Modelling and simulation may inform drug development throughout the process. Planning may also include regional considerations for product introduction into the market, such as health technology assessments. 
 It is important to ensure that the experiences, perspectives, needs, and priorities of relevant stakeholders relating to the development and evaluation of the drug throughout its lifecycle are captured and meaningfully incorporated into drug development planning. 
 Clinical development may also feature requirements for co-development of validated biomarkers, diagnostic testing, or devices that facilitate the safe and effective use of a drug. 
 The types of studies that may contribute to drug development are described in subsections 4.2 and 4.3 and summarised in the Annex. 
 4.1 Quality of Investigational Medicinal Product 
 Ensuring adequate quality and characterisation of physicochemical properties of investigational medicinal product is an important element in planning a drug development programme and is addressed in ICH and regional quality guidelines. More extensive characterisation may be required for complex or biological products. Formulations should be well characterised in the drug development plan, including information on bioavailability, wherever feasible, and should be appropriate for the stage of drug development and the targeted patient population. Age-appropriate formulation development may be a consideration when clinical studies are planned in paediatric populations (ICH E11- E11A Clinical Trials in Pediatric Population). 
 Evaluation of the quality of a drug may extend to devices required for its administration or a companion diagnostic to identify the targeted population. 
 Changes in a product during development should be supported by comparability data to ensure the ability to interpret study results across the development programme. This includes establishing links between formulations through bioequivalence studies or other means. 
 4.2 Non-Clinical Studies 
 Guidance on non-clinical safety studies is provided in ICH M3 Nonclinical Safety Studies, ICH Safety (S) Guidelines and related Q&A documents, as well as in regional guidance. The nonclinical assessment usually includes toxicology, carcinogenicity, immunogenicity, pharmacology, pharmacokinetics, and other evaluations to support clinical studies (and may encompass evidence generated in in vivo and in vitro models, and by modelling and simulation). The scope of non-clinical studies, and their timing with respect to clinical studies, depend on a variety of factors that inform further development, such as the drug’s chemical or molecular properties; pharmacological basis of principal effects (mechanism of action); route(s) of administration; absorption, distribution, metabolism, and excretion (ADME); physiological effects on organ systems; dose/concentration-response relationships; metabolites; and duration of action and use. Use of the drug in special populations (e.g., pregnant or breast-feeding women, children) may require additional non-clinical assessments. Guidance for non-clinical safety studies to support human clinical studies in special populations should be reviewed (see, e.g., ICH S5 Reproductive Toxicology, S11 Nonclinical Paediatric Safety, and M3). 
 Assessment of the preclinical characteristics, including physiological and toxicological effects of the drug, serve to inform clinical study design and planned use in humans. Before proceeding to studies in humans there should be sufficient non-clinical information to support initial human doses and duration of exposure. 
 4.3 Clinical Studies 
 Clinical drug development, defined as studying the drug in humans, is conducted in a sequence
that builds on knowledge accumulated from non-clinical and previous clinical studies. The structure of the drug development programme will be shaped by many considerations and comprised of studies with different objectives, different designs, and different ependencies. The Annex provides an illustrative list of example studies and their objectives. Although clinical drug development is often described as consisting of four temporal phases (phases 1-4), it is important to appreciate that the phase concept is a description and not a requirement, and that the phases of drug development may overlap or be combined. 
 To develop new drugs efficiently, it is essential to identify their characteristics in the early stages of development and to plan an appropriate development programme based on this profile. Initial clinical studies may be more limited in size and duration to provide an early evaluation of short-term safety and tolerability as well as proof of concept of efficacy. These studies may provide pharmacodynamic, pharmacokinetic, and other information needed to choose a suitable dosage range and/or administration schedule to inform further clinical studies. As more information is known about the drug, clinical studies may expand in size and duration, may include more diverse study populations, and may include more secondary endpoints in addition to the primary measures of efficacy. Throughout development, new data may suggest the need for additional studies. 
 The use of biomarkers has the potential to facilitate the availability of safer and more effective drugs, to guide dose selection, and to enhance a drug’s benefit-risk profile (see ICH E16 Qualification of Genomic Biomarkers) and may be considered throughout drug development. Clinical studies may evaluate the use of biomarkers to better target patients more likely to benefit and less likely to experience adverse reactions, or as intermediate endpoints that could predict clinical response. 
 The following subsections describe the types of studies that typically span clinical development from the first studies in humans through late development and post-approval. 
 4.3.1 Human Pharmacology 
 The protection of study participants should always be the first priority when designing early clinical studies, especially for the initial administration of an investigational product to humans (usually referred to as phase 1). These studies may be conducted in healthy volunteer participants or in a selected population of patients who have the condition or the disease, depending on drug properties and the objectives of the development programme. 
 These studies typically address one or a combination of the following aspects: 
 4.3.1.1 Estimation of Initial Safety and Tolerability 
 The initial and subsequent administration of a drug to humans is usually intended to determine the tolerability of the dose range expected to be evaluated in 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. 
 4.3.1.2 Pharmacokinetics 
 Characterisation of a drug's absorption, distribution, metabolism, and excretion continues throughout the development programme, but the preliminary characterisation is an essential early goal. Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites, interactions with metabolic enzymes and transporters, and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. For orally administered drugs, the study of food effects on bioavailability is important to inform the dosing instructions in relation to food. Obtaining pharmacokinetic information in sub-populations with potentially different metabolism or excretion, such as patients with renal or hepatic impairment, geriatric patients, children, and ethnic subgroups should be considered (ICH E4 Dose-Response Studies, E7 Clinical Trials in Geriatric Population, E11, and E5, respectively). 
 4.3.1.3 Pharmacodynamics & Early Measurement of Drug Activity 
 Depending on the drug and the endpoint of interest, pharmacodynamic studies and studies relating drug levels to response (PK/PD studies) may be conducted in healthy volunteer participants or in patients with the condition or disease. If there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and efficacy and may guide the dosage and dose regimen in later studies. 
 4.3.2 Exploratory and Confirmatory Safety and Efficacy Studies 
 After initial clinical studies provide sufficient information on safety, clinical pharmacology and dose, exploratory and confirmatory studies (usually referred to as phases 2 and 3, respectively) are conducted to further evaluate both the safety and efficacy of the drug. Depending on the nature of the drug and the patient population, this objective may be combined in a single or small number of studies. Exploratory and confirmatory studies may use a variety of study designs depending on the objective of the study. 
 Exploratory studies are designed to investigate safety and efficacy in a selected population of patients for whom the drug is intended. Additionally, these studies aim to refine the effective dose(s) and regimen, refine the definition of the targeted population, provide a more robust safety profile for the drug, and include evaluation of potential study endpoints for subsequent studies. Exploratory studies may provide information on the identification and determination of factors that affect the treatment effect and, possibly combined with modelling and simulation, serve to support the design of later confirmatory studies. 
 Confirmatory studies are designed to confirm the preliminary evidence accumulated in earlier clinical studies that a drug is safe and effective for use for the intended indication and recipient population. These studies are often intended to provide an adequate basis for marketing approval, and to support adequate instructions for use of the drug and official product information. They aim to evaluate the drug in participants with or at risk of the condition or disease who represent those who will receive the drug once approved. This may include investigating subgroups of patients with frequently occurring or potentially relevant comorbidities (e.g., cardiovascular disease, diabetes, hepatic and renal impairment) to characterise the safe and effective use of the drug in patients with these conditions. 
 Confirmatory studies may evaluate the efficacy and safety of more than one dose or the use of the drug in different stages of disease or in combination with one or more other drugs. If the intent is to administer a drug for a long period of time, then studies involving extended exposure to the drug should be conducted (ICH E1 Clinical Safety for Drugs used in Long-Term Treatment). Irrespective of the intended duration of administration, the duration of effect of the drug will also inform the duration of follow-up. 
 Study endpoints selected for confirmatory studies should be clinically relevant and reflect disease burden or be of adequate surrogacy for predicting disease burden or sequelae. 
 4.3.3 Special Populations 
 Some groups in the general population require additional investigation during drug
development because they have unique risk/benefit considerations, or because they can be
anticipated to need modification of the dose or schedule of a drug. ICH E5 and E17 provide a framework for evaluating the impact of ethnic factors on a drug’s effect. Particular attention should be paid to the ethical considerations related to informed consent in vulnerable populations (ICH E6 and E11). Studies in special populations may be conducted during any phase of development to understand the drug effects in these populations. Some considerations of special populations are the following: 
 4.3.3.1 Investigations in pregnant women 
 Investigation of drugs that may be used in pregnancy is important. Where pregnant women volunteer to be enrolled in a clinical study, or a participant becomes pregnant while participating in a clinical study, follow-up evaluation of the pregnancy and its outcome and the reporting of outcomes are necessary. 
 4.3.3.2 Investigations in lactating women 
 Excretion of the drug or its metabolites into human milk should be examined where applicable and feasible. When nursing mothers are enrolled in clinical studies their babies are usually also monitored for the effects of the drug. 
 4.3.3.3 Investigations in children 
 ICH E11 provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of drugs in paediatric populations. 
 4.3.3.4 Investigations in geriatric populations 
 ICH E7 provides an outline of critical issues in developing drugs for use in geriatric populations and approaches to their safe, efficient, and ethical study. 
 4.3.4 Post-Approval Studies 
 After the approval of a drug, additional studies may be conducted to further understand the safety and efficacy of the drug in its approved indication (usually referred to as phase 4). These 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. Post-approval studies may be conducted to address a regulatory requirement. 
 Post-approval studies may be performed to provide additional information on the efficacy, safety, and use of the drug in populations more diverse than included in the studies conducted prior to marketing authorisation. Studies with long-term follow-up or with comparisons to other treatment options or standards of care may provide important information on safety and efficacy. Commonly conducted studies include 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). These studies may explore use of the drug in the real-world setting of clinical practice and may also inform health economics and health technology assessments. 
 4.4 Additional Development 
 After initial approval, drug development may continue with studies of new or modified indications in new patient populations, new dosage regimens, or new routes of administration. If a new dose, formulation, or combination is studied, additional non-clinical and/or human pharmacology studies may be indicated. Data from previous studies or from clinical experience with the approved drug may inform these programmes. 
 5. DESIGN ELEMENTS AND DATA SOURCES FOR CLINICAL STUDIES 
 Study objectives impact the choice of study design and data sources, which in turn impact the strength of a study to support regulatory decisions and clinical practice. As discussed in Section 4, there are a wide variety of study objectives in drug development. Similarly, there is a wide range of study designs and data sources to address these objectives. Sections 5.1 through 5.6 discuss key elements that may be used to define the study design, and Section 5.7 discusses the various data sources that may be used for the study. 
 Clear objectives will help to specify the study design, and conversely, the process of specifying the design may help to further clarify the objectives. At the design stage, the objectives may need to be modified if substantial practical considerations and limitations or other risks to critical to quality factors are identified. The study objectives are further refined through specification of estimands. Estimands, discussed in ICH E9(R1) Addendum: Statistical Principles for Clinical Trials, provide a precise description of the treatment effects reflecting the clinical questions posed by the study objectives. The estimand summarises at a population level what the outcomes would be in the same patients under the different treatment conditions being compared. 
 An important distinction between studies is whether the allocation of individuals to the study drug(s) is controlled by the study procedures or allocation to the drug is not controlled but exposure to the drug(s) is observed in the study. In this document, the former case is referred to as an interventional study and the latter case is referred to as an observational study. 
 Interventional studies, and in particular randomised studies, play a central role in drug development, as they can better control biases. The designs of randomised studies range from simple parallel group designs to more complex variants. For example, adaptive design studies allow prospectively planned modifications to the study, such as changes in the population studied or changes in doses of the drug studied over the course of the study, based on accumulating data. Master protocol studies allow for the investigation of multiple drugs or multiple conditions under a shared framework. Platform studies allow for multiple drugs to be investigated in a continuous manner, with different drugs entering the study at different times and leaving the study based on pre-specified decision rules. 
 Studies without randomisation (whether interventional or observational) can play a role as well in certain settings when randomisation is not feasible. Observational studies are often conducted post-approval but can be of utility as complementary sources of evidence during development and across the life cycle of a drug. 
 Along with the breadth of study designs, there are multiple sources of data that studies may employ. Traditionally, studies have used study-specific data collection processes. Data such as that obtained from electronic medical records or digital health technologies may be leveraged to increase the efficiency of studies or generalisability of study results. 
 This section presents important elements that define the design of a clinical study including population, treatment, control group, response variable, methods to reduce bias, statistical analysis, and data sources. It is intended to assist in identifying the critical to quality factors necessary to achieve the study objectives, while also enabling flexibility in study design and promoting efficiency in study conduct. Although the focus is on interventional studies, the discussion is intended to apply to both interventional and observational studies. The elements outlined here are expected to be relevant to study types and data sources that are used in clinical studies now and that may be developed in the future. 
 5.1 Study Population 
 The population to be studied should be chosen to support the study objectives and is defined through the inclusion and exclusion criteria for the study. The degree to which a study succeeds in enrolling the desired population will impact the ability of the study to meet its objectives. 
 The study population may be narrowly defined to reduce the risk to study participants or to maximise the sensitivity of the study for detecting a certain effect. Conversely, it may be broadly defined to more closely represent the diverse populations for which the drug is intended. In general, studies conducted early in a development programme, when little is known about the safety of the drug, are more homogeneous in study population definitions. Studies conducted in the later phases of drug development or post-approval are often more heterogeneous in study population definitions. Such studies should involve participants who are representative of the diverse populations which will receive the intervention in clinical practice. Available knowledge about participant characteristics that may predict disease outcomes or effects of the intervention can be used to further define the study population. 
 The number of participants (sample size) in a study should be large enough to provide a reliable answer to the questions addressed (see ICH E9). This number is usually determined by the primary objective of the study. If the sample size is determined on some other basis, then this should be made clear and justified. For example, a sample size determined to address safety questions or meet important secondary objectives may need larger numbers of participants than needed for addressing the primary efficacy question (see ICH E1). If study objectives include obtaining information on certain subgroups, then efforts should be made to ensure adequate representation of these subgroups. 
 5.2 Treatment Description 
 The treatment(s), including controls, under study should be described explicitly and specifically. These might be individual treatments (including different doses or regimens), combinations of treatments, or no treatments, and can include specification of background treatments. The definition of treatments should align with the objectives of the study (ICH E9(R1)). For example, if the objective of the study is to understand the effect of the treatment in clinical practice, the study may specify that the background treatment, if any, is up to the discretion of the participants and healthcare providers. If the objectives are to understand the effect of the drug when added to a specific background treatment, the background treatment should be defined explicitly and specifically for all groups including controls. 
 5.3 Choice of Control Group 
 The major purpose of a control group is to separate the effect of the treatment(s) from the effects of other factors such as natural course of the disease, other medical care received, or observer or patient expectations (E10 Choice of Control Group in Clinical Trials). The treatment effect of interest may be the effect relative to not receiving the drug or the effect relative to receiving other therapies. Comparisons may be made with placebo, no treatment, standard of care, other treatments, or different doses of the drug under investigation. 
 The source of control group data may be internal or external to the study. The intent of using an internal control group is to help ensure that the only differences between treatment groups are due to the treatment they receive and not due to differences in the selection of participants, the timing and measurement of study outcomes, or other differences. A special case of an internal control group is when each participant serves as their own internal control by receiving the drug and control at different points of time. With use of an external control group, individuals are selected from an external source, and the individuals may have been treated at an earlier time (historical control group) or during the same time but in another setting than participants in the study. 
 Important limitations of the use of external controls are discussed in ICH E10. Particular care is needed to minimise the likelihood of erroneous inference. The use of an external control requires that the disease course is well known and predictable. External control individuals may differ from study participants with respect to demographic and background characteristics (e.g., medical history, concurrent diseases). In addition, external control individuals may differ from participants in the study with respect to concurrent care and the measurement of study outcomes and other data elements. Because the use of internal controls generally mitigates the potential for bias better than external controls, particularly in conjunction with randomisation, the suitability of the use and choice of external control should be carefully considered and justified. Section 5.5 discusses the sources of bias which can arise in observational studies and is relevant to the use of external controls. 
 Participant level data may not be available for some choices of external control groups.
Summary measures may be available to form the basis of comparisons with treated participants to estimate drug effects and test hypotheses about those effects. There is, however, less ability to control for differences in characteristics between study individuals in the external control group and study participants in the internal treatment groups in making these comparisons or examining the quality and completeness of individual data elements. Additionally, there may not be the ability to examine subgroups or modify the response variable to be consistent with the response variable used in the study. 
 5.4 Response Variables 
 A response variable is an attribute of interest that may be affected by the drug. The response variable may relate to pharmacokinetics, pharmacodynamics, efficacy, or safety of the drug, or to the use of the drug including, for example, in adherence to risk minimisation measures postapproval. Study endpoints are the response variables that are chosen to assess drug effects. 
 The primary endpoint should be capable of providing clinically relevant and convincing evidence related to the primary objective of the study (ICH E9). Secondary endpoints are either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives. Exploratory endpoints are used to further explain or to support study findings or to explore new hypotheses for later research. The choice of endpoints should be meaningful for the intended population and may also take into account the views of patients. The definition of each study endpoint should be specific and include how and at what time points in a participant’s treatment course of the drug and follow-up it is ascertained. 
 Knowledge of the drug, along with the clinical context and purpose of a given study affect what response variables should be collected. For example, a proof-of-concept study of relatively short duration may employ a pharmacodynamic outcome rather than the outcome of primary interest (ICH E9). A larger study of longer duration could then be used to confirm a clinically meaningful effect on the outcome of primary interest. In other cases, such as a study where the safety profile of the drug is well characterised, the extent of safety data collection may be tailored to the objectives of the study. 
 5.5 Methods to Reduce Bias 
 The study design should address potential sources of bias that can undermine the reliability of results. Although different types of studies are subject to different sources of bias, this section addresses some common sources. ICH E9 discusses principles for controlling and reducing bias mainly in the context of interventional studies. 
 In studies with internal control groups, randomisation is used to ensure comparability of treatment groups, thereby minimising the possibility of bias in treatment assignment. 
 Randomisation at the start of the study addresses differences between the groups at the time of randomisation but does not prevent bias due to differences arising during the study. Events after randomisation (particularly intercurrent events (ICH E9(R1)) may affect the validity and interpretation of comparisons between treatment groups. Examples include treatment discontinuation or use of rescue medications. There may also be differences in the follow-up patterns between the groups due to participants in one group discontinuing the study at different rates, because of, for example, adverse events or perceived lack of efficacy. Careful consideration of the potential for intercurrent events to occur during the study and their impact will help with the identification of critical to quality factors, such as reducing study discontinuation, continuing data collection following treatment discontinuation, and retrieving data after study discontinuation, if appropriate. It is important when defining the treatment effect (estimand) to account for the occurrence of intercurrent events. 
 Concealing the treatment assignments (blinding) limits the occurrence of conscious or unconscious bias in the conduct and interpretation of a clinical study that may affect the course of treatment, monitoring, endpoint ascertainment, and participants’ responses. In a single-blind study the investigator is aware of the treatment, but the participant is not. When the investigators who are involved in the treatment or clinical evaluation of the participants are also unaware of the treatment assignments, the study is referred to as double-blind. In an openlabel study, the consequences of the lack of blinding may be reduced through the use of prespecified decision rules for aspects of study conduct, such as recruitment, treatment assignment, participant management, safety reporting, and response variable ascertainment. Blinding for staff at the study sites or sponsor should be implemented where feasible. 
 Knowledge of interim results (whether individual or treatment group level) has the potential to introduce bias or influence the conduct of the study and interpretation of study results. Specific considerations related to information flow and confidentiality are therefore necessary. 
 Observational studies introduce unique challenges to the assessment and control of bias. These include ensuring that the individuals have the condition under study and ensuring comparability between treatment groups, in prognostic factors associated with the choice of therapies, in the ascertainment of response variables, and in post-baseline concomitant patient care. These challenges may also exist with the use of external controls in an interventional study. Methods exist that may mitigate some of these challenges and should be considered during the design phase. 
 5.6 Statistical Analysis 
 The statistical analysis of a study encompasses important elements necessary to achieving the study objectives. The specification and documentation of the statistical analysis are important for ensuring the integrity of the study findings. The principal features of the statistical analysis should be planned during the design of the study and should be clearly specified in a protocol written before the study begins (ICH E9). Full details of the planned statistical analysis should be specified and documented before knowledge of the study results that may reveal the drug effects, which may be accomplished using a separate statistical analysis plan. The protocol should define the estimand(s) following the framework established in ICH E9(R1). 
 Statistical analyses of primary and secondary endpoints that address key study objectives with respect to both efficacy and safety should be described in the protocol, including any interim analyses and/or planned design adaptations. Other statistical aspects of the study that should be described in the protocol include the analytical methods for any planned estimation and tests of hypotheses about the drug effect and a justification of the sample size. 
 The statistical analysis should include pre-specified sensitivity analyses for assessing the impact of the assumptions made for the primary and important secondary analyses on the results of the study (E9(R1)). For example, if the analysis relies on a particular assumption about the reasons for missing data, sensitivity analyses should be planned to assess the impact of that assumption on the study results. In the case of observational studies, sensitivity analyses might, for example, consider additional potential confounders. 
 For double-blind studies, the statistical analysis plan should be finalised before treatment assignments are revealed. Therefore, if a study includes one or more interim analyses, the planned statistical analysis should not be changed after an interim analysis that involves unblinding. For open-label and single-blind studies, details pertaining to the primary and important secondary analyses would ideally be finalised before the first participant is randomised or allocated to study intervention. 
 Pre-specification of the analysis approach is particularly important for studies that make use of existing data sources rather than primary data collection (Section 5.7), not only for the statistical analysis planned for the study but also for any feasibility analysis to assess the applicability of the existing data. For example, for a single-arm interventional study with an external control, the specifics of the external control should be defined prior to the conduct of the interventional aspect of the study. Pre-specification of the analysis should be in place so that any review of the existing data sources prior to the design of the study does not threaten the study integrity. 
 The statistical analysis should be carried out in accordance with the prospectively defined analysis plan, and all deviations from the plan should be indicated in the study report (E3 Clinical Study Reports). 
 5.7 Study Data 
 Study data comprise all information generated, collected, or used in the context of the study ranging from existing source data to study-specific assessments. The study data should contain the necessary information to conduct the statistical analysis specified in the protocol and statistical analysis plan, as well as to monitor for participant safety, protocol adherence, and data integrity. 
 Study data can be broadly classified into two types: (1) data generated specifically for the present study (primary data collection) and (2) data obtained from sources external to the present study (secondary data use). Data generated for the study may be collected via case report forms, laboratory measurements, electronic patient reported outcomes, or mobile health tools. Examples of external sources of data include historical clinical studies, national death databases, disease and drug registries, claims data, and medical and administrative records from routine medical practice. A study may make use of both types of data. 
 For all data sources, procedures to ensure the protection of personal data of the individuals being studied should be implemented. The study protocol, and if applicable the informed consent, should explicitly address the protection of personal data. Regulations related to protection of individuals’ data need to be followed. When considering data from external sources, it is important to ascertain whether the regulatory authorities accept the use of such data for purposes other than the original intent. 
 Study data should be of sufficient quality to address the objectives of the study and, in interventional studies, to monitor participant safety. Data quality attributes include consistency (uniformity of ascertainment over time), accuracy (correctness of collection, transmission, and processing), and completeness (lack of missing information). These aspects should be proactively considered during study planning by identifying the factors, critical to the quality of the study, associated with data sourcing, collection, and processing. 
 The use of standards for data recording and coding (or recoding) is important to support data reliability, facilitate correct analysis and interpretation of results, and promote data sharing. Internationally accepted data standards exist for many sources of study data and should be used where applicable. 
 With primary data collection, the methods and standards established for use at the point of capture and the subsequent processing provide an opportunity to prospectively ensure the quality of the data. 
 With secondary data use, the relevance of the available data should be considered and clearly described in the study protocol. For example, when using existing electronic health record data to ascertain the study endpoint rather than through primary data collection, information in the health record about outcomes may need to be converted to the study endpoint. 
 In some cases, secondary data use may not be sufficient for all aspects of the study and may need to be supplemented by primary data collection. The quality of data collected for a different purpose should be evaluated when re-used in the context of the present study. Careful quality control processes may have been applied during their acquisition; where used, those processes were not necessarily designed with the objectives of the present study in mind. 
 There are several additional considerations with secondary data use. For example, methods to conceal the treatment should be considered when selecting and prior to analysing data from external sources. As another example, absence of affirmative information on a condition or event does not necessarily mean the condition or event is not present. There may also be a delay between the occurrence of events and their appearance in existing data sources. To the extent possible, uncertainties and potential sources of bias should be addressed at the study design stage, during data analysis, and in the interpretation of the study results. 
 6. CONDUCT, SAFETY MONITORING, AND REPORTING 
 6.1 Study Conduct 
 The principles and approaches set out in this guideline, including those of quality by design, should inform the approach taken to the conduct and reporting of clinical studies. Risk proportionate mitigation measures should be employed to ensure the integrity of the critical to quality factors. 
 6.1.1 Protocol Adherence 
 Adherence to the study protocol and other relevant documents is essential, and many aspects of adherence should be considered among the study’s critical to quality factors. Successful application of the quality by design principles may minimise the need for modifications to the protocol and make adherence throughout the study more likely. If modification of the protocol becomes necessary, a clear description of the rationale for the modification should be provided in a protocol amendment, and the impact of the modification on study conduct should be carefully considered. 
 6.1.2 Training 
 Individuals involved in study conduct should receive training commensurate with their role in the study and this training should occur prior to their becoming involved in the study. Updated training or retraining may be needed to address issues related to critical to quality factors observed during the course of the study, and/or implement protocol modifications. 
 6.1.3 Data Management 
 The manner and timelines in which study data are collected and managed are critical contributors to overall study data quality. Operational checks, centralised data monitoring, and statistical surveillance can identify important data quality issues for corrective action. Data management procedures should account for the diversity of data sources in use for clinical studies (Section 5.7). For interventional clinical studies, further guidance on data management is available in ICH E6. 
 6.1.4 Access to Interim Data 
 Inappropriate access to data during the conduct of the study may compromise study integrity (Sections 5.5 and 5.6 and ICH E9). In studies with planned interim analyses, special attention should be given to which individuals have access to the data and results. Even in studies without planned interim analyses, special attention should be paid to any ongoing monitoring of unblinded data to avoid inappropriate access. 
 6.2 Participant Safety during Study Conduct 
 Important standards of ethical conduct and the protection of participants in clinical studies are described in Section 2.1. This section describes safety related considerations during the conduct of the study. 
 6.2.1 Safety Monitoring 
 The goals of safety monitoring are to protect study participants and to characterise the safety profile of the drug. Procedures and systems for the identification, monitoring, and reporting of safety concerns during the study should be clearly specified. The approach should reflect the type and objectives of the study, the risks to the study participants and what is known about the drug and the study population. Guidance is available on reporting of safety data to appropriate authorities and on the content and timing of safety reports (ICH E2-E2F Pharmacovigilance, and, for interventional clinical trials in particular, ICH E6). 
 6.2.2 Withdrawal Criteria 
 Clear criteria for stopping treatment or study procedures for a study participant while remaining in the study are necessary to ensure the protection of the participants but should also minimise loss of critical data. 
 6.2.3 Data Monitoring Committee 
 An important component of safety monitoring in many clinical studies is the use of an independent data monitoring committee. This group monitors accumulating data while the study is being conducted to make recommendations on whether to continue, modify, or terminate a study. 
 During programme planning, the need for an independent data monitoring committee to monitor safety data across studies in a development programme should also be assessed. If a data monitoring committee is needed for either an individual study or across the development programme, procedures governing its operation and, in particular the review of unblinded data in an interventional trial, while preserving study integrity (ICH E9) should be established prior to study start. 
 6.3 Study Reporting 
 Clinical studies and their results should be adequately reported using formats appropriate for the type of study (interventional or observational studies) and information being reported. ICH E3 focuses particularly on the report format for interventional clinical trials, but the basic principles may be applied to other types of clinical studies (ICH E3 Q&A). The design of the study report should be part of the quality by design process. The report should describe the critical to quality factors in the study. The reporting of study results should be comprehensive, accurate, and timely. 
 Consideration should be given to providing a factual summary of the overall study results to study participants in an objective, balanced and nonpromotional manner, including relevant safety information and any limitations of the study. In addition, consideration could be given to providing individual participants with information about their study specific results (e.g., their treatment arm, test results). The information should be conveyed by someone involved in the health management of the participant (e.g., the clinical investigator). Participants should be informed about the information they will receive and when they will receive it at the time of providing informed consent. 
 The transparency of clinical research in drug development includes the registration of clinical studies, before they start, on publicly accessible and recognised databases, and the public posting of clinical study results. Adopting such practices for observational studies also promotes transparency. Making objective and unbiased information publicly available can benefit public health in general, as well as the indicated patient populations, through enhancing clinical research, reducing unnecessary clinical studies, and informing decisions in clinical practice. 
 7. CONSIDERATIONS IN IDENTIFYING CRITICAL TO QUALITY FACTORS 
 The identification of critical to quality factors should be supported by proactive, crossfunctional discussions and decision making at the time of study planning, as described in Section 3. Different factors will stand out as critical for different types of studies, following the concepts introduced in Sections 4 through 6. 
 In designing a study, the following aspects should be considered, where applicable, to support the identification of critical to quality factors: 
 
 Engagement of all relevant stakeholders, including patients, is considered during study planning and design. 
 The prerequisite non-clinical studies, and where applicable, clinical studies, are complete and adequate to support the study being designed. 
 The study objectives address relevant scientific questions appropriate for a given study’s role in the development programme, taking into account the accumulated knowledge about the product. 
 The clinical study design supports a meaningful comparison of the effects of the drug when compared to the chosen control group. 
 Adequate measures are used to protect participants’ rights, safety, and welfare (informed consent process, Institutional Review Board/Ethics Committee review, investigator and clinical study site training, pseudonymisation). 
 Information provided to the study participants should be clear and understandable. 
 Competencies and training required for the study by sponsor and investigator staff, relevant to their role, should be identified. 
 The feasibility of the study should be assessed to ensure the study is operationally viable. 
 The number of participants included, the duration of the study, and the frequency of study visits are sufficient to support the study objective. 
 The eligibility criteria should be reflective of the study objectives and be well documented in the clinical study protocol. 
 The protocol specifies the collection of data needed to meet the study objectives, understand the benefit/risk of the drug, and monitor participant safety. 
 The choice of response variables and the methods to assess them are well-defined and support evaluation of the effects of the drug. 
 Clinical study procedures include adequate measures to minimise bias (e.g., randomisation, blinding). 
 The statistical analysis plan is pre-specified and defines the analysis methods appropriate for the endpoints and the populations of interest. 
 Systems and processes are in place that support the study conduct to ensure the integrity of critical study data. 
 The extent and nature of study monitoring are tailored to the specific study design and objectives and the need to ensure participants’ safety. 
 The need for and appropriate role of a data monitoring committee is assessed. 
 The reporting of the study results is planned, comprehensive, accurate, timely, and publicly accessible. 
 
 These considerations are not exhaustive and may not apply to all studies. Other aspects may need to be considered to identify the critical to quality factors for each individual study. 
 ANNEX: TYPES OF CLINICAL STUDIES 
 Drug development is ideally a logical, stepwise process in which information from early studies is used to support and plan later studies. The actual sequence of studies conducted in a particular drug development programme, however, may reflect different dependencies and overlapping study types. Studies may also involve adaptive designs (which may bridge or combine different study types as listed below) or designs that are intended to investigate multiple drugs or multiple indications or both (e.g., studies conducted under a master protocol). In the table below, types of clinical studies are categorised by objectives. Illustrative examples, not intended to be exhaustive or exclusive, are provided. Study objectives appearing under one type may also occur under another. 
 
 
 
 Type of Study 
 Objective(s) of Study 
 Study Examples 
 
 
 Human Pharmacology 
 
 
 Assess tolerance and safety 
 Define/describe clinical PK 1 and PD 2 
 Explore drug metabolism and drug interactions 
 Evaluate activity, assess immunogenicity 
 Assess renal/hepatic tolerance 
 Assess cardia toxicity 
 
 
 
 
 BA 3 /BE 4 studies under fasted/fed conditions 
 Dose-tolerance studies 
 Single and multiple-rising dose PK and/or PD studies 
 Drug-drug interaction studies 
 QTc prolongation study 
 Human factor studies for drug delivery devices 
 
 
 
 
 Exploratory 
 
 
 Explore use for the intended indication 
 Estimate dose/dosing regimen for subsequent studies 
 Explore doseresponse/exposure-response relationship 
 Provide basis for confirmatory study design (e.g., targeted population, clinical endpoints, patient reported outcome measures, factors affecting treatment effects) 
 
 
 
 
 Randomised controlled clinical trials of relatively short duration in elldefined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures 
 Dose finding studies 
 Biomarker exploration studies 
 Studies to validate patient reported outcomes 
 Adaptive designs that may combine exploratory and confirmatory objectives 
 
 
 
 
 Confirmatory 
 
 
 Demonstrate/confirm efficacy 
 Establish safety profile in larger, more representative patient populations 
 Provide an adequate basis for assessing the benefit/risk relationship to support licensing 
 Establish doseresponse/exposure-response relationship 
 Establish safety profile and confirm efficacy in specific populations (e.g., paediatrics, elderly) 
 
 
 
 
 Randomised controlled clinical trials to establish efficacy in larger, more representative patient populations 
 Dose-response studies 
 Clinical safety studies 
 Studies of mortality/morbidity outcomes 
 Studies in special populations 
 Studies that seek to demonstrate efficacy for multiple drugs in a single protocol 
 
 
 
 
 Post-Approval 
 
 
 Extend understanding of benefit/risk relationship in general or special populations and/or environments 
 Identify less common adverse reactions 
 Refine dosing recommendations 
 
 
 
 
 Comparative effectiveness studies 
 Long-term follow-up studies 
 Studies of mortality/morbidity or other additional endpoints 
 Large, simple randomised trials 
 Pharmacoeconomic studies 
 Pharmacoepidemiology studies 
 Observational studies of the use of the drug in clinical practice 
 Disease or drug registries 
 
 
 
 
 1 PK: Pharmacokinetic 2 PD: Pharmacodynamic 3 BA studies: Bioavailability 4 BE studies: Bioequivalence

ICH E8(R1) 临床试验的一般考虑
English 
 ICH E8(R1) General Considerations for Clinical Studies 
 
 1. 本文件的目的 
 实施药物临床研究是为了获得信息，这些信息最终可使患者获得安全有效的药品，对患者产生有意义的影响，同时保护研究受试者。本文件为临床研发生命周期提供指南，包括临床研究相关质量设计，同时考虑到临床研究设计和使用的数据来源的广泛性。 
 ICH 文件“临床研究的一般考虑”旨在： 
 1. 阐述在临床研究设计和实施中被国际公认的原则和惯例，以确保保护受试者和促进监管机构接受数据和结果。 
 2. 提供在产品生命周期中的临床研究设计和实施方面质量考虑相关的指南，包括在研究计划期间确定研究关键质量因素，以及在研究实施过程中对这些因素的风险管理。 
 3. 提供在产品生命周期中开展临床研究类型的概述，并阐述用于支持关键质量因素识别的研究设计要素，以确保对研究受试者的保护、数据的完整性、结果的可靠性及研究能够实现其目的的能力。 
 4. 提供ICH 有效性文件的指南，以便于使用者查阅。 
 本文件的第2 节阐述了临床研究设计的一般原则，第3节中讨论了临床研究相关质量设计。第4 节提供了药物研发计划的简要概述，以及在整个产品生命周期中通过不同类型的研究获得信息以推进药物研发。第5 节描述了临床研究设计的要素，这些要素反映了药物研发中使用的各种设计以及可用的数据来源范围。第6 节讨论研究实施、确保研究受试者安全和研究报告。第7 节提供了对确定研究中关键质量因素的一些考虑事项。 
 ICH 有效性指导原则是一套涵盖临床研究的计划、设计、实施、安全、分析和报告的完整指南。ICH E8 全面介绍了临床研发，临床研究中的质量设计，并重点关注研究关键质量因素。应以综合、整体的方式考虑和使用指南，而不是仅关注一个指南或子章节。 
 就本文件而言，临床研究是指在产品生命周期的任何阶段，包括上市许可前和上市许可后，在人体中开展的一项或多项药物研究。关注点主要在支持监管决策的临床研究，认识到这些研究也可能为卫生政策决策、临床实践指南或其他行动提供信息。术语“药物”应被视为与治疗用、预防用或诊断用药物同义。术语“药物批准”指获得该药物的上市许
可。 
 2. 一般原则 
 2.1 临床研究受试者的保护 
 临床研究伦理准则和保护受试者（包括特殊人群）的重要原则起源于赫尔辛基宣言，与人体相关临床研究必须遵循这些原则。这些原则在其他ICH 指南中有所阐述，特别是ICH E6 药物临床试验质量管理规范。 
 正如E6 指南所述，机构审查委员会/独立伦理委员会、研究者及申办者共同承担保护研究受试者的责任。 
 应根据适用的法规和法律要求保护可识别受试者身份的机密信息。 
 在开始临床研究之前，应获得足够的信息，以确保该药物在计划的人体研究中具有可接受的安全性。当出现新的非临床、临床、药物质量数据时，应由有资历的专家对这些数据进行审查和评价，以评估对研究受试者安全的潜在影响。应考虑新获得的信息，根据需要适当调整正在进行和将要开展的研究，以保护研究受试者。在整个药物研发过程中，应注意从科学角度出发，以保证所有研究程序及评估的必要性，不会给研究受试者带来过度的负担。 
 2.2 临床研究设计、计划、实施、分析及报告的科学方法 
 临床研究的实质是提出重要问题并通过适当的研究回答问题。任何研究的主要目的都应该反映研究问题，并被清晰明确表述。临床研究应遵循合理的科学原则进行设计、计划、实施、分析和报告，以达到其目的。 
 在本文件中，临床研究的质量应与临床研究目的相符。临床研究目的是生成可靠信息，以回答研究问题并支持决策，同时保护研究受试者。因此，所生成的信息质量应足以支持良好的决策。 
 临床研究中的质量源于设计,旨在确保通过将质量设计到研究方案和过程中来主动推动研究质量。这涉及使用前瞻性、多学科方法，以与涉及的风险相称的方式提高方案和过程设计的质量，并就如何实现这一目标进行明确沟通。 
 在产品生命周期中，不同类型的研究具有不同的目的和设计，并可能会涉及不同数据来源。就本指导原则而言，研发计划被视为涵盖产品整个生命周期（第4 节）。附录提供了药物研发不同阶段根据目的进行的广泛分类。应严格设计研究，以解决研究目的，并注重设计要素，例如：研究人群和反应变量的选择以及使结果偏倚最小化的方法（第5 节）。 
 进行系列研究背后的主要逻辑是，既往研究的结果应该为之后的研究计划提供依据。新获得的数据往往会促使研发策略的调整。例如：确证性研究的结果可能提示需要进行额外的人体药理学研究。 
 由于药物研发计划日益全球化，在ICH 指导原则的协调下，多区域数据的可用性最大限度地减少了在不同区域进行个别研究的需要。一项研究的结果通常用于多个地区的监管申请，设计还应考虑研究结果与进行研究地区以外地区的相关性。ICH E5 种族因素、ICH E6、ICH E17 多区域临床试验提供了进一步的指导。 
 鼓励监管机构早期介入，以了解当地/地区的要求和期望，并有助于促进将质量设计融入研究中的能力。 
 2.3 患者参与药物研发 
 在药物研发过程中，倾听患者和/或患者组织的意见，有助于确保获取来自患者的观点。患者（或其看护人员/父母）的意见在药物研发的所有阶段均有价值。在设计的早期阶段让患者参与研究可能会增加其对研究的信任，促进招募并提高依从性。患者还可提供其对所患疾病的看法，这可能有助于决策，例如：对患者有意义的终点、选择合适的研究人群和研究持续时间，以及使用可接受的对照。从而最终支持研发更适合患者需求的药物。 
 3. 临床研究相关质量设计 
 质量源于设计的临床研究方法（第3.1 节）涉及关注关键质量因素，以确保保护研究受试者的权利、安全以及福祉，生成可靠、有意义的研究结果，以及使用基于风险的方法对这些因素进行风险管理（第3.2 节）。质量源于设计主要依靠在研究设计、计划以及整个研究的实施、分析和报告过程中，通过建立适当的框架来确定和审查关键质量因素（第3.3 节）。 
 3.1 临床研究的质量源于设计 
 质量是临床研究设计、计划、实施、分析和报告的主要考虑因素，也是临床研发计划的必要组成部分。通过对于研究方案、程序、相关实施计划和培训等所有组成部分设计的前瞻性关注，可以显著提高临床研究回答研究问题的可能性，同时防止重要错误的发生。回顾性活动如文件、数据审查和监查是质量保证流程的重要组成部分；但是，即使与稽查相结合，也不足以确保临床研究质量。 
 良好的临床研究规划和实施源于对第5 节中所述的临床研究设计要素的关注，例如： 
 
 需要明确预先确定的以解决主要科学问题的研究目的； 
 选择具有正在研究疾病、状况或分子/基因谱的合适受试者； 
 使用偏倚最小化的方法，例如：随机化、盲法或遮蔽、和/或控制混杂因素； 
 终点明确、可测量、具有临床意义且与患者相关的终点。 
 
 实施标准也很重要，例如：确保清楚地了解研究的可行性、选择适宜的研究中心、确保专业分析和检测设施及程序的质量以及保证数据完整性的流程。 
 3.2 关键质量因素 
 应为每项研究确定与保证研究质量相关的一系列基本因素。应对那些影响研究质量的重要因素予以重视。这些关键质量因素是一项研究的本质，其完整性是研究受试者保护、研究结果可靠性和可解释性，以及基于研究结果作出决策的基础。这些质量因素至关重要，因为如果它们的完整性因设计或实施差错而破坏，基于研究结果决策的可靠性或伦理原则也会被破坏。还应全面考虑关键质量因素，以便确定它们之间的依赖关系。本文件第7 节提供了有助于确定研究关键质量因素的考虑事项。 
 临床研究设计应反映针对药物的认知和经验状态；治疗、诊断或预防的疾病；潜在的生物学机制（包括疾病和治疗）；以及药物所针对的目标人群。随着研究的进展，对药物的认知不断增加，药理学、安全性和有效性的不确定性随之降低。研发过程中任何阶段，对药物的了解都将持续为关键质量因素的识别和用于管理这些因素的控制过程提供指导信息。 
 申办者和其他各方基于质量源于设计理念设计研究时应确定关键质量因素。在确定了这些因素之后，重要的是确定威胁其完整性的风险，并根据其概率、可检测性和影响来决定是否可以接受或应该降低这些风险。在确定应降低风险的情况下，应制定必要的控制流程并进行沟通，并采取必要措施降低风险。此处使用的术语“风险”在一般风险管理方法背景下，适用于研究的所有因素。 
 积极主动地沟通关键质量因素及采取的风险缓解措施将有助于申办者和研究中心了解优先事项和资源分配情况。积极的支持（例如：对研究中心工作人员进行与其工作职责相关的培训、在研究方案中阐述关键质量因素以及潜在降低风险措施）将促进研究方案、程序以及相关的操作计划和流程设计的正确实施。 
 难以保证一项措施的各个方面都达到完美，或者只能通过使用与获得的利益不成比例的资源来实现。在设计研究时，应优先确定对研究至关重要的质量因素，研究程序应与研究中固有的风险及所收集信息的重要性相匹配。关键质量因素应该明确，且不应被次要问题所混淆（例如：与适当的研究受试者保护和/或主要研究目的无关的大量的次要目的或流程/数据收集）。 
 3.3 确定关键质量因素的方法 
 以质量方法来设计研究的关键方面是询问研究所要解决的目的是否清晰明确；研究设计可否解决其提出的研究问题；这些问题是否对患者有意义；以及研究假设是否具体且科学有效。确定关键质量因素的方法应考虑所选设计和数据来源是否能够很好且最有效地实现这些目的。在研究设计过程中尽早与患者沟通有助于这种方法，并最终有助于确定关键质量因素。研究设计应具有实施可行性，避免不必要的繁复。方案和病例报告表/数据的收集方法应保证研究能够按照设计实施，并避免不必要的数据收集。 
 包含下列因素的方法将有利于确定关键质量因素： 
 3.3.1 建立支持开放式对话的文化 
 鼓励创造一种文化，重视和奖励集思广益，并就某一研究或研发项目的关键质量因素进行开放、积极的对话，而不仅仅依赖工具和清单。开放式对话有利于建立可确保质量的创新方法。 
 不鼓励不灵活的“一刀切”方法。标准化的操作规程对于开展高质量的临床研究是必要和有益的，但也需要研究特定策略和行动来有效和高效地支持研究质量。 
 在研究开始前及研究期间，应以透明的方式收集和审查用于研究设计的证据，同时承认存在和已知的数据中的差距，并预测可能出现的此类差距或冲突。 
 3.3.2 关注对研究至关重要的活动 
 应重点关注对患者和公众健康研究结果的可靠性和意义、受试者安全、受试者研究伦理准则等至关重要的活动。应考虑从研究中删除不必要的活动和数据收集，通过简化流程、提高研究效率和将资源用于关键领域等方式来提高质量。对资源进行部署，以识别和防止或控制重要错误。 
 3.3.3 利益相关者参与研究设计 
 临床研究设计最好参考广泛的利益相关者的意见，包括患者和医疗保健服务提供者。临床研究设计应公开接受来自外部以及申办者组织内部的专家和利益相关者的质疑。 
 可通过直接参与并成功完成研究的人员（例如：临床研究者、研究协调员和其他中心工作人员以及患者/患者组织）为研究质量创建过程提供信息。临床研究者和潜在研究受试者可对招募符合拟定入选标准受试者的可行性、安排的研究访视和程序是否可能过于繁重而导致提前脱落，以及研究终点和研究设置与目标患者人群的一般相关性等提供有价值的见解。他们还可基于目标患者人群中的伦理问题、文化、地区、人口统计学和其他亚组特征的背景提供治疗价值方面的见解。 
 鼓励尽早与监管机构沟通，尤其是当一项研究出现可能影响质量的新关键要素（例如：确定患者人群、程序或终点）时。 
 3.3.4 审查关键质量因素 
 应运用积累的经验和知识，结合关键质量因素的定期审查结果，确定是否需要调整风险控制机制，因为一旦研究开始，可能会出现新发或意想不到的问题。 
 在对关键质量因素和风险管理进行前瞻性规划和持续审查期间，需要特别关注具有适应性特征和/或中期决策点的研究（ICH E9 临床试验的统计学原则）。 
 3.3.5 操作实践中的关键质量因素 
 一项成功研究的基础是具有一个既科学合理又操作可行的方案。从操作角度而言，可行性评估涉及考虑可能影响临床研发成功完成的研究设计和实施要素。 
 研究可行性的考虑事项还包括但不限于：医疗实践和患者人群的地区差异、具有开展临床研究（ICH E6）经验的合格研究者/中心人员的可用性、成功实施研究所需设备和设施的可用性、目标患者人群的可用性，以及招募足够数量的受试者以达到研究目的的能力。研究受试者的保留和随访也是关键质量因素。考虑这些以及其他与研究可行性相关的关键质量因素可为研究设计提供信息，并提高实施质量。 
 4. 药物研发计划 
 本节概述在制定药物研发计划时考虑的一般原则。药物研发计划应遵循科学研究和良好研究设计的原则，从而确保结果的可靠性和可解释性。高效的药物研发包括在整个研发过程中与监管机构进行有适当计划的沟通，以确保符合产品质量要求以及支持药物用于特定状况或疾病的批准，包括为解决遗留问题而开展批准后研究。在整个过程中，应重点关注对研究受试者的权利、安全和福祉的保护。 
 药物研发计划建立在整个研究过程中获取的知识的基础上，以降低从靶标识别到非临床和临床评价过程中的不确定性。该计划包括含化学、生产和控制的药品质量（CMC）、非临床和临床研究（批准前和批准后）。建模与模拟可指导药物研发的全过程。研发计划还可能包括产品进入市场的区域性考虑因素，如卫生技术评估。 
 重要的是，确保贯穿药物整个生命周期来收集与药物研发和评价相关的利益相关者的经验、观点、需求和重要事项，并有的放矢地整合至药物研发计划中。 
 临床研发还可能要求共同研发有利于药物安全有效使用的经过验证的生物标志物、诊断检测或器械。 
 可能有助于药物研发的研究类型在第4.2 节和第4.3 节阐述，并在附录中予以总结。
 4.1 试验用药的质量 
 在制定药物研发计划时，确保试验用药品的质量和理化性质的表征符合要求是重要因素，并在ICH 和区域性质量指导原则中予以阐明。复合物或生物产品可能需要进行更为广泛的表征。应在药物研发计划中充分表征药物处方，包括生物利用度信息（酌情），药物处方还应与药物研发阶段和目标患者人群相匹配。当计划在儿童人群中开展临床研究时，可考虑研发适合相应年龄段的处方（ICH E11-E11A 在儿科人群中开展的临床试验）。 
 药物质量评价可能会延伸至给药所需的器械或用于识别目标人群的伴随诊断。 
 研发过程中产品如发生变更，应提供可比性数据予以支持，以确保研究结果在整个研发计划中自始至终能够解释。其中包括通过生物等效性研究或其他方式确立不同处方之间的关系。 
 4.2 非临床研究 
 非临床安全性研究指导原则参见ICH M3 非临床安全性研究、ICH 安全性（S）指南和相关问答文件以及区域性指导原则。非临床评估通常包括毒理学、致癌性、免疫原性、药理学、药代动力学和其他用于支持临床研究的评估（并且可能包括利用体内和体外模型以及通过建模与模拟）。非临床研究的范围及相对于临床研究的实施时间取决于影响药物进一步研发的各种因素，例如：药物的化学或分子特性；主要作用的药理学基础（作用机制）；给药途径；吸收、分布、代谢和排泄（ADME）；对器官系统产生的生理学效应；剂量/浓度-效应关系；代谢物；以及作用持续时间和使用期限。如药物用于特殊人群（例如：妊娠期或哺乳期女性、儿童），则可能需要额外开展非临床评估。应参阅为支持在特殊人群中开展人体临床研究而实施非临床安全性研究时所遵循的指导原则（例如：ICH S5 生殖毒理学、S11 非临床儿童安全性和M3）。 
 非临床研究的评估，包括药物的药理学和毒理学研究，应服务于临床研究设计和拟定用途。在开展人体研究之前，应获取足够的非临床信息支持初始人体剂量和暴露持续时间的选择。 
 4.3 临床研究 
 临床药物研发是指在人体中研究药物，基于从非临床和既往开展的临床研究积累的知识按一定的顺序实施。药物研发计划的结构受诸多因素的影响，该计划由目的、设计方式和依赖关系各不相同的若干研究组成。关于示例研究及其目的的说明性清单见附录。虽然通常临床药物研发分为四个阶段（1 期-4 期），但需要明确的是，阶段的概念只是便于描述，并非规定，并且药物研发的阶段可能重叠或合并。 
 为了高效地研发新药，必须在研发早期阶段识别药物的特征，并根据其特征制定合理的研发计划。最初开展的临床研究可能在规模和持续时间上受到更多限制，以便就短期用药的安全性和耐受性开展早期评估，并对有效性进行概念验证。早期研究收集药效学、药代动力学以及支持剂量范围和/或给药方案选择所需的其他信息，从而为后续开展的临床研究提供有用的信息。随着获取的药物信息的增加，临床研究的规模得以扩大，持续时间延长，研究人群更加多样化，除主要有效性指标外，还可能纳入更多次要终点。在整个研发过程中，新数据可能提示需要开展额外研究。 
 生物标志物的使用有助于研发出更加安全有效的药物、指导剂量选择，并改善药物的获益-风险特征（参见ICH E16基因组生物标志物的鉴定），可在药物研发的整个过程中予以考虑。在临床研究中可以评价生物标志物的使用，从而更好地遴选出获益概率高且不良反应发生概率低的患者，或作为可预测临床反应的中间终点。 
 下文阐述了从首次人体研究至后期研发和批准后研究的整个临床研发阶段开展的各种类型的研究。 
 4.3.1 人体药理学 
 在设计早期临床研究时，务必将研究受试者的保护视为第一要务，特别是试验药物首次用于人体给药（通常称为1期研究）时。这些研究可在健康志愿者中进行，也可在受累于某种状况或疾病的患者群体中进行，取决于药物特性和研发计划的目的。 
 此类研究通常拟用于解决以下一个或多个方面的问题： 
 4.3.1.1 初步安全性和耐受性评估 
 人体首次和后续给药通常旨在确定药物在后续临床研究中需要进一步评价的剂量范围内的耐受性，亦可确定可能出现的不良反应的性质。通常采用单次给药和多次给药的方式。 
 4.3.1.2 药代动力学 
 虽然药物吸收、分布、代谢和排泄特征研究贯穿于整个研发计划，但初步的特征描述是一个重要的早期目标。药代动力学研究对评估药物的清除、预测原型药物或其代谢物是否蓄积、与代谢酶和转运体的相互作用以及潜在的药物间相互作用等方面尤为重要。部分药代动力学研究通常在后续的研发阶段进行，以回答更加特殊的问题。对于口服药物，评价食物对生物利用度的影响对获取与食物有关的给药说明是重要的。应考虑代谢或排泄能力存在潜在差异的亚组人群的药代动力学信息，例如：肾或肝功能损害的患者、老年患者、儿童和各种种族亚组（分别参见ICH E4 剂量-效应研究、E7 在老年人群中开展的临床试验、E11 以及E5）。 
 4.3.1.3 药效学与药物活性的早期测定 
 基于药物的性质和关注的终点，药效学研究以及与血药浓度-效应相关的研究（PK/PD 研究）可以在健康志愿者或受累于特定状况或疾病的患者中实施。如果有适当的衡量指标，药效学数据可以提供药物活性与有效性的早期评估数据，并为有待在后续研究中评估的给药剂量和给药方案提供参考。 
 4.3.2 探索性与确证性的安全性与有效性研究 
 从初步临床研究充分获取有关安全性、临床药理学和剂量方面的信息后，继续开展探索性研究和确证性研究（通常分别称为2 期和3 期），以进一步评价药物安全性和有效性。该研究目的可在单个或少量研究中同时实现，这取决于药物性质和患者人群。探索性与确证性研究可根据研究目的的不同而采用多种研究设计。 
 探索性研究旨在考察药物在特定患者群体中的安全性和有效性。此外，探索性研究的目的在于提炼有效剂量和治疗方案，细化目标人群的定义，确保药物安全性特征的稳健性，并包括对后续研究中采纳的潜在研究终点的评价。探索性研究可提供有关识别和确定影响治疗效果因素的信息，并结合建模与模拟，有助于支持随后的确证性研究设计。 
 确证性研究旨在确证早期临床研究中积累的关于药物在预期用途和用药人群中的安全性和有效性的初步证据。确证性研究通常旨在为药物上市批准提供充分的依据，并为药物的使用和官方公布的制剂信息提供充分的说明。此外，确证性研究在受累于特定状况或疾病或面临此类风险的受试者（即一旦获得批准后将使用该药物的人群）中评价药物，可能包括在受累于频发或潜在相关合并症（例如：心血管疾病、糖尿病、肝和肾功能损害）的患者亚群中开展研究，以确定药物在这类患者中的安全性和有效性。 
 确证性研究可评价多于一种剂量、或在不同疾病阶段用药、或联合一种或多种其他药物使用时的有效性和安全性。如为拟长期使用的药物，应开展涉及长期暴露的研究（ICH E1长期用药的临床安全性）。随访持续时间取决于药物效应的持续时间，与预期用药持续时间无关。 
 为确证性研究选择的研究终点应具有临床相关性，并反映疾病负担，或在预测疾病负担或后遗症方面具有充分的替代性。 
 4.3.3 特殊人群 
 在药物研发中，针对一般人群中的部分群体需要开展额外研究，因为这部分群体独特的风险/获益考虑，或预期需要调整药物剂量或给药方案。ICH E5 和E17 为评估种族因素对药物效应产生的影响提供了一个框架。在弱势人群中开展研究时，应特别重视与知情同意相关的伦理学考虑（ICH E6 和E11）。可于药物研发的任何阶段在特殊人群中开展研究，以了解药物在该类人群中的作用。以下是针对特殊人群的一些考虑： 
 4.3.3.1 在妊娠女性中开展的研究 
 研究妊娠期女性可能使用的药物具有重要意义。如妊娠期女性志愿者入组临床研究，或受试者在参加临床研究期间妊娠，必须随访妊娠及结局并报告结局。 
 4.3.3.2 在哺乳期女性中开展的研究 
 应酌情检测药物或其代谢物向人乳中的分泌情况。如果哺乳期女性入组临床研究，应同时监测药物对乳儿产生的影响。 
 4.3.3.3 在儿童中开展的研究 
 ICH E11 提供了在儿科人群中研发药物的关键问题纲要，以及在儿科人群中安全有效和符合伦理的研究方法。 
 4.3.3.4 在老年人群中开展的研究 
 ICH E7 提供了在老年人群中研发药物的关键问题纲要，以及在老年人群中安全有效和符合伦理的研究方法。 
 4.3.4 批准后研究 
 药物获批后，可能需要开展额外的研究（通常称为4 期研究），以进一步了解药物在批准适应症中的安全性和有效性。获批后研究并非药物获批所必需，但对优化药物的使用通常具有重要意义。虽然研究的类型不受限制，但应具有合理的科学目的。开展批准后研究可能是解决监管要求。 
 批准后研究可额外收集有效性、安全性和用药数据，而且批准后研究中所纳入人群的多样性高于药物获得上市许可前实施的研究所入组的人群。研究中有长期随访，或有与其他治疗方案或标准治疗的比较，则可能提供有关安全性和有效性的重要信息。常见的研究包括额外的药物相互作用、剂量-效应或安全性研究，以及支持在获批准适应症下使用的研究（例如：死亡率/发病率研究、流行病学研究）。这些研究可用于探索该药物在临床实践真实环境中的使用，也可为卫生经济学和卫生技术评估提供信息。 
 4.4 追加研发 
 在首次获批后，可继续开展在新患者人群中新适应症或修改后的适应症、新剂量方案或新给药途径的研究。如评价新剂量、新处方或联合用药，则可能需要额外开展非临床和/或人体药理学研究。使用来源于获批药物既往研究或临床经验的数据可为这些计划提供参考。 
 5. 临床研究的设计要素和数据来源 
 研究目的影响研究设计和数据来源的选择，进而影响研究支持监管决策和临床实践的力度。正如第4 节所讨论，在药物研发期间会存在多个研究目的。同样，可通过广泛的研究设计和数据来源达到这些目的。第5.1 节至第5.6 节讨论了可用于确定研究设计的关键要素，第5.7 节讨论了可用于研究的各种数据来源。 
 明确的目的将有助于确定研究设计，反之，对设计具体化的过程可能有助于进一步明确目的。在设计阶段，如果确认存在重要实践考虑，以及关键质量因素的局限性或其他风险，则可能需要修订目的。通过指定估计目标，进一步细化研究目的。估计目标（详见ICH E9（R1）增补：临床试验的统计学原则）是对治疗效应的精确描述，反映了针对临床试验目的提出的临床问题。估计目标在群体水平上汇总比较相同患者在不同治疗条件下的结局。 
 各种研究之间的一个重要区别是，为受试者分配研究药物是否受研究程序的控制，或者药物分配不受控制，但在研究中观察药物暴露。在本文件中，前一种情况称为干预性研究，后一种情况称为观察性研究。 
 干预性研究，尤其是随机研究，在药物研发中发挥核心作用，因为此类研究可以更好地控制偏倚。随机研究的设计范围从简单的平行组设计到更复杂的设计。例如：采用适应性设计研究可以根据累积的数据对研究进行前瞻性计划修改，如研究人群的改变或研究过程中研究药物剂量的调整。主方案研究允许在共享框架下研究多种药物或多种病症。平台研究允许以连续的方式研究多种药物，不同药物在不同时间进入研究并根据预先指定的决策规则退出研究。 
 随机化不可行时，无随机化的研究（无论是干预性研究还是观察性研究）也可在某些情况下发挥作用。观察性研究通常在批准后进行，但可作为药物研发过程中和整个生命周期中的补充证据来源。 
 随着研究设计的广度，研究还可使用多种数据来源。传统上，研究使用研究特定的数据收集过程。可利用从电子医疗记录或数字健康技术中获得的数据提高研究效率或研究结果的普遍性。 
 本节介绍确定临床研究设计的重要要素，包括人群、治疗、对照组、反应变量、减少偏倚的方法、统计分析和数据来源。旨在帮助确定达到研究目的所必需的关键质量因素，同时提高研究设计的灵活性及实施研究的效率。尽管重点为干预性研究，但讨论旨在同时适用于干预性研究和观察性研究。本文概述的要素将与目前临床研究中使用并可能会在将来研发的研究类型和数据来源相关。 
 5.1 研究人群 
 应选择支持研究目的的研究人群，并通过研究的入组和排除标准进行定义。研究中成功入组期望人群的程度将影响研究达到研究目标的能力。 
 研究人群可能被狭义地定义，以降低研究受试者的风险，或最大限度地提高研究对检测某种效应的敏感性。相反，它可以被广义地定义为更接近代表拟用药物的不同人群。一般而言，在研发项目早期进行的研究，当对药物的安全性知之甚少时，研究人群的定义往往更为单一化，而在药物研发后期或批准后进行的研究中，研究人群的定义往往更为多样化。此类研究应涉及代表将在临床实践中接受干预的不同人群的受试者。可使用关于可能预测疾病结果或干预效果的受试者特征的现有知识进一步定义研究人群。 
 研究中的受试者数量（样本量）应足够大，以便为所解决的问题提供可靠答案（参见ICH E9）。受试者数量通常取决于研究的主要目的。如果样本量在其他基础上确定，则其依据应明确且合理。例如：与解决主要有效性问题所需的受试者数量相比，为解决安全性问题或满足重要次要目的而确定的样本量可能更大（参见ICH E1）。如果研究目的包括获得某些亚组的信息，则应努力确保这些亚组具有充分的代表性。 
 5.2 治疗描述 
 应对研究的治疗，包括对照，进行明确且具体的阐述。治疗可能为单独治疗（包括不同剂量或方案）、联合治疗或不治疗，并且可能包括指定的背景治疗。治疗定义应与研究目的保持一致（ICH E9（R1））。例如：如果研究目的是了解治疗在临床实践中的效果，则研究可能会指定背景治疗（如果有），这取决于受试者和医疗保健提供者的判断。如果研究目的是了解将药物添加到特定背景治疗时的效果，则应明确且具体地指定所有研究组（包括对照组）的背景治疗。 
 5.3 对照组的选择 
 设置对照组的主要目的是区分治疗效应与其他因素的效应，如疾病的自然病程、接受的其他医疗护理或观察者或患者的期望（ICH E10 临床试验中对照组的选择）。研究的治疗效应可能是与不接受药物治疗或与接受其他疗法治疗相比较的效应。可以与安慰剂、不治疗、标准治疗、其他治疗或不同剂量的研究药物进行比较。 
 对照组的数据可来自研究的内部或外部。使用内部对照组的目的是帮助确保治疗组之间唯一的差异是受试者接受的治疗，而非受试者选择差异、研究结果的时间和测量差异或其他差异。内部对照组的特殊情况为，受试者可以作为他们自己的内部对照，在不同的时间点接受研究药物和对照药物。使用外部对照，受试者从外部来源中选择，对照组受试者可以在更早的时间（历史对照组）或在同一时间但在本研究中的受试者以外的其他研究中接受治疗。 
 ICH E10 讨论了使用外部对照的重要局限性。需特别注意尽量降低错误推断的可能性。使用外部对照要求对病程清晰且可预测。外部对照受试者在人口统计学和背景特征（例如：病史、伴发疾病）方面可能与研究受试者不同。此外，外部对照受试者在同步治疗和研究结果的测量及其他数据因素方面可能与参与研究的受试者有所不同。由于与外部对照相比，使用内部对照通常更能减少偏倚，特别是在与随机化结合的情况下，因此，应仔细考虑使用和选择外部对照的适用性，并证明其合理。第5.5 节讨论了观察性研究中可能出现的偏倚来源，与外部对照的使用有关。 
 对于选择的某些外部对照组，可能无法获得受试者水平的数据。但如果可提供综合测量，则可以使用这些数据来形成与接受治疗的受试者进行比较的基础，以估计药物疗效并检验关于此疗效的假设。然而，在进行这些比较或检查单个数据元素质量和完整性时，难以控制外部对照组中的研究受试者与内部治疗组中的研究受试者之间的特征差异。此外，可能无法检查亚组，或无法修改反应变量以与研究中使用的反应变量保持一致。 
 5.4 反应变量 
 反应变量是一种被关注的可能受药物影响的指标。反应变量可能与药物的药代动力学、药效学、有效性或安全性有关，或与药物的使用有关，例如：依从批准后的风险最小化措施。研究终点是选择用于评估药物效应的反应变量。 
 主要终点应能够提供与研究主要目的相关的具有临床相关性和有说服力的证据（ICH E9）。次要终点是与主要目的相关的支持性测量，或与次要目的相关的效应的测量。探索性终点用于进一步解释或支持研究结果或为以后的研究探索新的假设。终点的选择对于目标人群应该是有意义的，并且应考虑到患者的观点。每个研究终点的定义应该是具体的，包括在受试者药物治疗和随访过程中，研究终点的定义是如何确定的，以及在什么时间点确定的。 
 对药物的了解和特定研究的临床背景和目的都会影响应被收集的反应变量。例如：持续时间相对较短的概念验证研究可能采用药效学结果，而不是主要关注的结果（ICH E9）。然后，可以通过持续时间更长的大规模研究确认是否对主要关注的结果产生具有临床意义的影响。在其他情况下，例如：在药物的安全性特征被明确确认的研究中，安全性数据收集的范围可以根据研究目的进行调整。 
 5.5 减少偏倚的方法 
 研究设计应提出可能破坏结果可靠性的潜在偏倚来源。尽管不同类型的研究受到不同偏倚来源的影响，但本节说明的是一些常见来源。ICH E9 主要在干预性研究的背景下讨论控制和减少偏倚的原则。 
 在有内部对照组的研究中，可采用随机化确保治疗组的可比性，从而将治疗分配中出现偏倚的可能性降至最低。 
 研究开始时的随机化可以解决随机化时各组别之间的差异，但并不能防止研究期间出现差异而导致的偏倚。随机化后的事件（特别是伴发事件（ICH E9（R1））可能会影响治疗组之间进行比较的效力和解释，如治疗终止或使用补救用药。由于一组受试者以不同比率终止研究，如由于不良事件或缺乏疗效，各组之间的随访模式也可能存在差异。仔细考虑研究期间发生伴发事件的可能性及其影响将有助于确定关键质量因素，如降低研究终止率、治疗终止后继续收集数据，以及在研究终止后回收数据（如适当）。在确定治疗疗效（估计目标）时，重要的是要考虑伴发事件的发生。 
 隐藏治疗分配（盲法）减少临床研究的实施和解释过程中有意识或无意识的偏倚的发生，这些偏倚可能影响治疗过程、监测、终点确定和受试者反应。单盲研究中，研究者知道治疗分配情况，但受试者不知。如果参与受试者治疗或临床评价的研究者也不知道治疗分配情况，则该研究称为双盲研究。在开放研究中，可通过对研究实施方面（如招募、治疗分配、受试者管理、安全报告和反应变量确定）使用预先制定的决策规则来减少盲法缺失的后果。在可行的情况下，应对研究中心工作人员或申办者进行设盲。 
 获知中期结果（无论受试者水平还是治疗组水平）有可能引入偏倚，或影响研究的实施和研究结果的解释。因此，需特别考虑与信息流和机密性有关的事项。 
 观察性研究在偏倚评估和控制方面存在独特的挑战，包括确保受试者患有所研究的病症并确保治疗组之间的可比性、与治疗选择相关的预后因素、反应变量的确定以及基线后伴随的患者护理。在干预性研究中使用外部对照也可能存在上述挑战。有些方法可能减轻上述某些挑战，应在设计阶段予以考虑。 
 5.6 统计分析 
 研究的统计分析是试验研究目标所必需的重要因素。统计分析规范和文档对于确保研究结果的完整性十分重要。统计分析的主要特征应在研究设计期间进行规划，并应在研究开始前编写的方案中明确规定（ICH E9）。在了解可能揭示药物疗效的研究结果之前，应详细说明和记录计划的统计分析的全部细节，可使用单独的统计分析计划完成。方案应根据ICH E9（R1）中确立的框架定义估计目标。 
 应在方案中描述以实现有效性和安全性为关键研究目的的主要和次要终点的统计分析，包括任何期中分析和/或计划的设计调整。应在方案中描述研究中的统计方面其他事项，包括对药物疗效假设的评估和检验的分析方法，以及确定样本量的依据。 
 统计分析应包括预先指定的敏感性分析，以评估对主要和重要次要分析做出的假设对研究结果的影响（E9（R1））。例如：如果主要分析依赖于对数据缺失原因的特定假设，则应计划敏感性分析，以评估这些假设对研究结果的影响。在观察性研究中，敏感性分析可能会考虑其他潜在的混杂因素。 
 对于双盲研究，应在披露治疗分配之前确定完成统计分析。因此，如果一项研究包括一项或多项期中分析，则不应在涉及揭盲的期中分析完成后更改所计划的统计分析计划。对于开放研究和单盲研究，理想情况下，将在第一例受试者被随机分配或分配到研究干预组之前，确定有关主要和重要次要分析的详细信息。 
 对于利用现有数据来源而非主要数据收集的研究（第5.7 节），预先规范分析方法尤其重要，不仅应适用于研究计划的统计分析，还应适用于评估现有数据适用性的任何可行性分析。例如：对于具有外部对照的单臂干预研究，在进行研究干预之前，应指定具体的外部对照。应预先规范分析方法，以便即使在设计研究之前对现有数据来源进行任何审查也不会威胁研究的完整性。 
 统计分析应按照前瞻性确定的统计分析计划进行，并且应在临床研究报告（ICH E3 临床研究报告）中注明偏离统计分析计划的所有情况。 
 5.7 研究数据 
 研究数据包括在研究背景下生成、收集或使用的所有信息，范围为从现有源数据到研究特定的评估。研究数据应包含执行方案和统计分析计划中规定的统计分析所需的必要信息，以及监测受试者的安全性、方案依从性和数据完整性所需的必要信息。 
 研究数据可大致分为两类：（1）专门为本研究生成的数据（主要数据收集）和（2）从本研究外部获得的数据（次要数据使用）。为研究生成的数据可通过病例报告表、实验室检测、电子版患者报告结局或移动健康工具收集。以外部数据来源为例，包括历史临床研究、国家死亡数据库、疾病和药物登记处、索赔数据以及常规医疗实践的医疗和行政记录。一项研究可以同时使用以上两种类型的数据。 
 对于所有数据来源，应执行可以确保保护受试者个人数据的程序。研究方案和知情同意书（如适用）应明确解决个人数据保护问题。应遵循与受试者数据保护相关的法规。考虑外部来源的数据时，重要的是确定监管机构是否接受将此类数据用于原始意图以外的目的。 
 研究数据的质量应足以实现研究目的，并在干预性研究中监测受试者安全。数据质量属性包括一致性（随时间变化确认的一致性）、准确性（收集、传输和处理的正确性）和完整性（无缺失信息）。在研究计划期间，应通过识别对研究质量至关重要的因素，以及与数据来源、收集和处理相关的关键质量因素主动考虑这些方面。在研究计划期间应主动考虑这些方面，通过识别与数据来源、收集和处理相关的关键质量因素。 
 使用数据记录和编码（或重新编码）标准对支持数据可靠性、方便结果的正确分析和解释以及促进数据共享十分重要。国际上普遍接受的数据标准适用于许多研究数据来源，并应在适用的情况下使用。 
 对于主要数据收集，在捕获点和后续处理中使用既定方法和标准为前瞻性地确保数据质量提供了机会。 
 对于次要数据使用，应考虑现有数据的相关性，并在研究方案中明确阐述。例如：使用现有电子健康记录数据而非通过主要数据收集来确定研究终点时，健康记录中有关结局的信息可能需要转换为研究终点。 
 在某些情况下，次要数据的使用可能不足以涵盖研究的所有方面，可能需要通过收集主要数据进行补充。在本研究中再次使用时，应评价出于不同目的收集的数据的质量。在其获取过程中可能已经应用了严密的质量控制程序；在使用时，这些程序的设计不一定考虑到当前研究的目的。 
 在使用次要数据时，还有一些额外的注意事项。例如：在选择外部来源数据时和分析外部来源数据之前，应考虑隐藏治疗的方法。另一个示例为，缺乏关于病症或事件的确证信息并不一定意味着该症状或事件不存在。事件的发生与其存在的现有数据来源之间也可能存在延迟。在研究设计阶段、数据分析期间和研究结果的解释中，应尽可能解决不确定性和潜在偏倚来源。 
 6. 实施、安全性监测以及报告 
 6.1 研究实施 
 本指导原则中规定的原则和方法，包括质量源于设计的原则和方法，应为临床研究的实施和报告所采取的方法提供信息。应采用适当的风险缓解措施，以确保关键质量因素的完整性。 
 6.1.1 方案遵守 
 遵守研究方案和其他相关文件是必要的，在研究的关键质量因素中，应考虑遵守多个方面。质量源于设计原则的成功应用可最大限度地减少对方案进行修改，并更有可能在整个研究期间遵守方案。如果必须对方案进行修改，应在方案修订案中明确说明修改的依据，并仔细考虑修改对研究实施的影响。 
 6.1.2 培训 
 参与研究实施的个人应在参与研究之前接受符合其在研究中职责的培训。为解决在研究过程中观察到的与关键质量因素相关的问题，和/或实施方案修改，可能需要进行更新培训或再培训。 
 6.1.3 数据管理 
 收集和管理研究数据的方式和时间线对总体研究数据质量至关重要。操作检查、集中数据监测和统计监督可识别需要采取纠正措施的重要数据质量问题。数据管理程序应考虑到临床研究中使用的数据源的多样性（第5.7 节）。对于干预性临床研究，关于数据管理的进一步指导原则参见ICH E6。 
 6.1.4 访问期中数据 
 在研究实施期间不适当地访问数据可能会损害研究的完整性（第5.5 节、第5.6 节以及ICH E9）。在有计划期中分析的研究中，应特别注意哪些人可以访问数据和结果。即使在没有计划期中分析的研究中，也应特别注意对非盲态数据的任何持续监测，以避免不适当的访问。 
 6.2 研究实施期间的受试者安全 
 第2.1 节描述了临床研究中伦理行为的重要标准和对受试者的保护。本节描述了在研究实施期间的安全性相关考虑因素。 
 6.2.1 安全性监测 
 安全性监测的目的是保护研究受试者和描述药物的安全性特征。研究期间，应明确规定识别、监测和报告安全性问题的程序和系统。该方法应反映研究类型和目的、研究受试者的风险以及对药物和研究人群的了解情况。已有向有关主管部门报告安全性数据以及安全性报告内容和时间的指导原则（ICH E2-E2F 药物警戒，特别是对于干预性临床试验，ICH E6）。 
 6.2.2 退出标准 
 对于保留在研究中的受试者，有必要制定明确的停止治疗或研究程序的标准，以确保受试者受到保护，但也应尽量减少关键数据的丢失。 
 6.2.3 数据监查委员会 
 在许多临床研究中，安全性监测的一个重要组成部分是使用独立的数据监查委员会。数据监查委员会在实施研究时监测累积的数据，以建议是否继续、修改或终止研究。 
 在项目计划期间，还应评估是否需要一个独立的数据监查委员会来监查研发项目各项研究中的安全性数据。如果个别研究或整个研发项目需要一个数据监查委员会，则应在研究开始前建立管理其实施的程序，尤其是在保持研究完整性的同时审查干预性试验中的非盲态数据（ICH E9）。 
 6.3 研究报告 
 应使用适合研究类型（干预性或观察性研究）和报告信息的格式充分报告临床研究及其结果。ICH E3 特别侧重于干预性临床试验的报告格式，但其基本原则可能适用于其他类型的临床研究（ICH E3 问答）。研究报告的设计应为质量源于设计过程的一部分。报告应描述研究中的关键质量因素。报告研究结果应全面、准确和及时。 
 应考虑以客观、平衡和非宣传的方式向研究受试者提供总体研究结果的事实总结，包括相关的安全性信息和研究的任何局限性。此外，可以考虑向个体受试者提供有关其研究特定结果的信息（例如：其治疗组别、检查结果）。该信息应由参与受试者健康管理的人员（例如：临床研究者）传达。在提供知情同意时，应告知受试者其将收到的信息以及何时将收到信息。 
 药物研发临床研究的透明度包括在临床研究开始前，可在公开访问和识别的数据库中注册临床研究，以及公开公布临床研究结果。在观察性研究中采用这种做法也有助于提高透明度。公开客观和无偏倚的信息加强了临床研究、减少了不必要的临床研究，同时为临床实践决策提供了信息，有益于公共卫生以及适用的患者人群。 
 7. 识别关键质量因素的考虑 
 如第3 节所述，在研究规划时，应通过前瞻性、跨职能部门的讨论和决策来支持识别关键质量因素。根据第4 节至第6 节中介绍的概念，不同的因素对不同类型的研究至关重要。 
 在设计研究时，应考虑以下适用的方面，以支持识别关键质量因素： 
 
 在研究计划和设计过程中考虑所有利益相关者（包括患者）的参与。 
 作为先决条件的非临床研究以及适用的临床研究完整，并足以支持所设计的研究。 
 研究目的阐述了适用于在研发计划中某个研究要解决的相关科学问题，同时考虑到有关产品的已累积知识。 
 当与选定对照组比较时，临床研究设计支持进行有意义的药物疗效比较。 
 采取适当措施保护受试者的权利、安全和福祉（知情同意程序、机构审查委员会/伦理委员会审查、研究者和临床研究中心培训、匿名）。 
 提供给研究受试者的信息应清晰易懂。 
 应确定申办者和研究者进行研究所需的与其职责相关的能力和培训。 
 应评估研究可行性，以确保研究在实施上可行。 
 入选的受试者数量、研究持续时间和研究访视频率足以支持研究目的。 
 入组标准应反映研究目的，并在临床研究方案中有详细记录。 
 方案规定达到研究目的、了解药物的获益/风险和监测受试者安全所需的数据收集。 
 反应变量的选择和评估方法定义明确，并支持对药物疗效的评估。 
 临床研究程序包括尽量减少偏倚的适当措施（例如：随机分组、盲法）。 
 预先制定统计分析计划，并定义适用于研究终点和获益研究人群的分析方法。 
 已建立支持研究实施的系统和流程，以确保关键研究数据的完整性。 
 研究监查的范围和性质根据具体的研究设计和目的以及确保受试者安全的需要而进行调整。 
 评估数据监查委员会的必要性和适当作用。 
 报告研究结果应有计划、全面、准确、及时和公开。 
 
 这些考虑并不详尽，可能不适用于所有研究。在识别每项单独研究的关键质量因素时，可能需要考虑其他方面。 
 附录：临床研究类型 
 药物研发理论上是一个合乎逻辑、循序渐进的过程，在此过程中，来自早期研究的信息可用来支持和计划随后的研究。然而，在特定药物研发项目中进行的实际研究顺序可能反映了不同的依赖性和重叠的研究类型。研究还可能涉及适应性设计（可以桥接或结合下文列出的不同研究类型）或旨在研究多种药物或多个适应症或两者兼具的设计（例如：根据主方案进行的多个研究）。下表对临床研究的类型按研究目的进行分类。列举的研究示例，并非详尽或唯一。出现在某一类型下的研究目的也可能出现在另一类型下。 
 
 
 
 研究类型 
 研究目的 
 研究示例 
 
 
 人体药理学 
 
 
 评估耐受性和安全性 
 阐明/ 描述临床PK 1 和PD 2 
 探索药物代谢和药物相互作用 
 评价活性，评估免疫原性 
 评估肾/ 肝耐受性 
 评估心脏毒性 
 
 
 
 
 空腹/餐后条件下的BA 3 /BE 4 研究 
 剂量-耐受性研究 
 单次和多次递增剂量的PK 和/或PD 研究 
 药物-药物相互作用研究 
 QTc 延长研究 
 给药装置的人为因素研究 
 
 
 
 
 探索性 
 
 
 探索用于目标适应症 
 评估后续研究的剂量/给药方案 
 探索剂量-效应/暴露量- 效应关 
 提供确证性研究设计的依据（例如：目标人群、临床终点、患者报告结局指标、影响治疗效果的因素） 
 
 
 
 
 采用替代终点或药理学终点或临床指标，在明确的狭义患者人群中进行的持续时间相对较短的随机对照临床试验 
 剂量范围探索研究 
 生物标志物探索研究 
 验证患者报告结局的研究 
 可结合探索性和确证性目的的适应性设计 
 
 
 
 
 确证性 
 
 
 证明/ 确证有效性 
 在更大、更具代表性的患者人群中确定安全性特征 
 为评估获益/ 风险关系提供足够依据以支持上市许可 
 确定剂量-效应/暴露量- 效应关系 
 确定安全性特征并确认在特殊人群（如儿童，老年人）中的有效性 
 
 
 
 
 在更大、更具代表性的患者人群中确定有效性的随机对照临床试验 
 剂量-效应研究 
 临床安全性研究 
 死亡率/发病率结局研究 
 特殊人群中的研究 
 在单一方案中证明多种药物有效性的研究 
 
 
 
 
 批准后 
 
 
 扩展对药物在普通人群、特殊人群和/ 或环境中的获益/ 风险关系的认识 
 识别较少见的不良反应 
 优化给药建议 
 
 
 
 
 有效性对照研究 
 长期随访研究 
 死亡率/发病率或其他额外终点研究 
 大规模、简单随机试验 
 药物经济学研究 
 药物流行病学研究 
 临床实践中药物使用的观察性研究 
 疾病或药物登记研究 
 
 
 
 
 1 PK: 药代动力学 2 PD: 药效学 3 BA研究：生物利用度 4 BE研究：生物等效性