ICH E8(R1) 临床试验的一般考虑

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 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.