E8(R1) GENERAL 
CONSIDERATIONS FOR 
CLINICAL STUDIES 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2022 
ICH 
 
Revision 1 
    
E8(R1) GENERAL 
CONSIDERATIONS FOR 
CLINICAL STUDIES 
Guidance for Industry 
 
 
 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2022 
ICH 
 
Revision 1 
   
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry. 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  OBJECTIVES OF THIS DOCUMENT (1) .................................................................... 1 
II.  GENERAL PRINCIPLES (2) .......................................................................................... 2 
A.  Protection of Clinical Study Participants (2.1) ............................................................................ 2 
B.  Scientific Approach in Clinical Study Design, Planning, Conduct, Analysis, and Reporting 
(2.2)  ................................................................................................................................................. 3 
C.  Participant Input Into Drug Development (2.3) .......................................................................... 4 
III.  DESIGNING QUALITY INTO CLINICAL STUDIES (3) .......................................... 4 
A.  Quality by Design of Clinical Studies (3.1) .................................................................................. 4 
B.  Critical-to-Quality Factors (3.2) ................................................................................................... 5 
C.  Approach to Identifying the Critical-to-Quality Factors (3.3) ................................................... 6 
1. Establishing a Culture That Supports Open Dialogue (3.3.1) ......................................................... 6 
2. Focusing on Activities Essential to the Study (3.3.2) ....................................................................... 7 
3. Engaging Stakeholders in Study Design (3.3.3) .............................................................................. 7 
4. Reviewing Critical-to-Quality Factors (3.3.4) ................................................................................. 7 
5. Critical-to-Quality Factors in Operational Practice (3.3.5) ........................................................... 8 
IV.  DRUG DEVELOPMENT PLANNING (4).................................................................................. 8 
A.  Quality of Investigational Medicinal Product (4.1) ..................................................................... 9 
B.  Nonclinical Studies (4.2) ................................................................................................................ 9 
C.  Clinical Studies (4.3) .................................................................................................................... 10 
1. Human Pharmacology (4.3.1) ........................................................................................................ 10 
2. Exploratory and Confirmatory Safety and Efficacy Studies (4.3.2) ............................................... 11 
3. Special Populations (4.3.3) ............................................................................................................ 12 
4. Postapproval Studies (4.3.4) .......................................................................................................... 13 
D.  Additional Development (4.4) ..................................................................................................... 13 
V.  DESIGN ELEMENTS AND DATA SOURCES FOR CLINICAL STUDIES (5) .... 13 
A.  Study Population (5.1) ................................................................................................................. 15 
B.  Treatment Description (5.2) ........................................................................................................ 15 
C.  Choice of Control Group (5.3) .................................................................................................... 15 
E.  Methods To Reduce Bias (5.5) .................................................................................................... 17 
F.  Statistical Analysis (5.6)............................................................................................................... 18 
G.  Study Data (5.7) ............................................................................................................................ 19 
VI.   CONDUCT, SAFETY MONITORING, AND REPORTING (6) .............................. 20 
A.  Study Conduct (6.1) ..................................................................................................................... 20 
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1. Protocol Adherence (6.1.1) ............................................................................................................ 20 
2. Training (6.1.2) .............................................................................................................................. 20 
3. Data Management (6.1.3) .............................................................................................................. 21 
4. Access to Interim Data (6.1.4) ....................................................................................................... 21 
B.  Participant Safety During Study Conduct (6.2) ........................................................................ 21 
1. Safety Monitoring (6.2.1) ............................................................................................................... 21 
2. Withdrawal Criteria (6.2.2) ........................................................................................................... 22 
3. Data Monitoring Committee (6.2.3) .............................................................................................. 22 
C.  Study Reporting (6.3)................................................................................................................... 22 
VII. CONSIDERATIONS IN IDENTIFYING CRITICAL-TO-QUALITY FACTORS       
(7) .......................................................................................................................................... 23 
ANNEX: TYPES OF CLINICAL STUDIES ........................................................................... 25 
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E8(R1) GENERAL 
CONSIDERATIONS FOR CLINICAL STUDIES 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
This guidance describes internationally accepted principles and practices in the design and 
conduct of clinical studies of drug and biological products. The guidance is intended to assist 
sponsors and other parties that design clinical studies, and to promote the quality of the studies 
submitted to regulatory authorities, while allowing for flexibility. This guidance revises the ICH 
guidance E8 General Considerations for Clinical Trials issued in December 1997. Significant 
changes from the 1997 version include the following: (1) addresses study quality to ensure the 
protection of study participants and the generation of reliable and meaningful results, while 
promoting study efficiency; (2) addresses a broad range of study designs and data sources; and 
(3) provides updated cross-referencing to other relevant ICH guidances that inform the design, 
planning, and conduct of clinical research. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited.  The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
 
 
I.  OBJECTIVES OF THIS DOCUMENT (1)2 
 
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 protect-
ing those participating in the studies. This document provides guidance on the clinical develop-
ment lifecycle, including designing quality into clinical studies, considering the broad range of 
clinical study designs and data sources used. 
 
1 This guidance was developed within the Expert Working Group (Efficacy) of the International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process.  This document has been 
endorsed by the regulatory members of the ICH Assembly at Step 4 of the ICH process, October 2021.   
2 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly 
at Step 4 of the ICH process, October 2021.   
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  Contains Nonbinding Recommendations 
 
This E8(R1) guidance 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 ac-
ceptance 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 lifecy-
cle, 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 relia-
bility of results, and the ability of the studies to meet their objectives  
 
(4) Provide references to the ICH efficacy documents to facilitate the user's access to them 
 
General principles are described in section II (2) of this document, followed by a discussion of 
designing quality into clinical studies in section III (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 IV (4). In section V (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 VI (6) addresses 
study conduct, 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 VII (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(R1) provides an overall 
introduction to clinical development and designing quality into clinical studies and focusing on 
those factors critical to the quality of the studies. The guidances should be considered and used 
in an integrated, holistic way rather than focusing on only one guidance 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 products lifecycle, both prior to and 
following marketing authorization. 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 authorization for the drug. 
 
II.  GENERAL PRINCIPLES (2) 
 
A.  Protection of Clinical Study Participants (2.1) 
 
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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 guidances for industry, in particular, E6(R2) Good Clinical Practice: Integrated Addendum 
to ICH E6(R1) (March 2018).3 As further described in the ICH E6(R2) guidance, the investiga-
tor and sponsor have responsibilities for the protection of study participants together with the In-
stitutional 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 nonclinical, 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. 
 
B.  Scientific Approach in Clinical Study Design, Planning, Conduct, Analysis, 
and Reporting (2.2) 
 
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, analyzed, 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 guidance, 
development planning is considered to cover the entire product lifecycle (section IV (4)). The 
Annex provides a broad categorization of study type by objective within the different stages of 
 
3 Guidances are updated periodically. For the most recent version of a guidance, check the FDA guidance web page 
at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
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  Contains Nonbinding Recommendations 
 
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 V (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 globalization of drug 
development programs, facilitated by the harmonization of ICH guidances, minimizes 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 the ICH guidances for industry E5 Ethnic Factors in the Acceptability of 
Foreign Clinical Data (June 1998), E6(R2), and E17 General Principles for Planning and 
Design of Multiregional Clinical Trials (July 2018).  
 
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. 
 
C.  Patient Input into Drug Development (2.3)  
 
Consulting with patients and/or patient organizations 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. 
 
 
III.  DESIGNING QUALITY INTO CLINICAL STUDIES (3) 
 
The quality by design approach to clinical research (section III.A (3.1)) involves focusing on 
critical-to-quality factors to ensure the protection of the rights, safety, and well-being of study 
participants; the generation of reliable and meaningful results; and the management of risks to 
those factors using a risk proportionate approach (section III.B (3.2)). The approach is supported 
by the establishment of an appropriate framework for the identification and review of critical-to-
quality factors (section III.C (3.3)) at the time of design and planning of the study, and 
throughout its conduct, analysis, and reporting. 
 
A.  Quality by Design of Clinical Studies (3.1) 
 
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Quality is a primary consideration in the design, planning, conduct, analysis, and reporting of 
clinical studies and a necessary component of clinical development programs. The likelihood 
that a clinical study will answer the research questions while preventing important errors can be 
dramatically improved through prospective attention to the design of all components of the study 
protocol, procedures, associated operational plans and training. Activities such as document and 
data review and monitoring, where conducted retrospectively, are an important part of a quality 
assurance process; but even when combined with audits, they are not sufficient to ensure the 
quality of a clinical study. 
 
Good planning and implementation of a clinical study also derive from attention to the design 
elements of clinical studies as described in section V (5), such as: 
 
  The need for clear, predefined 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 minimize bias, such as randomization, 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 specialized analytical and testing 
facilities and procedures, and processes that ensure data integrity. 
 
B.  Critical-to-Quality Factors (3.2) 
 
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 VII (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 
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  Contains Nonbinding Recommendations 
 
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 
prioritized 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). 
 
C.  Approach to Identifying the Critical-to-Quality Factors (3.3) 
 
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 
questions 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: 
 
1.  Establishing a Culture That Supports Open Dialogue (3.3.1) 
 
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 program, going beyond sole 
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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.  Standardized 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. 
 
2.  Focusing on Activities Essential to the Study (3.3.2) 
 
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.  Engaging Stakeholders in Study Design (3.3.3) 
 
Clinical study design is best informed by input from a broad range of stakeholders, including 
patients and health care providers. It should be open to challenge by subject matter experts and 
stakeholders from outside, as well as within, the sponsor organization. 
 
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 organizations. 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). 
 
4.  Reviewing Critical-to-Quality Factors (3.3.4) 
 
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. 
 
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Studies with adaptive features and/or interim decision points should be given specific attention 
during proactive planning and ongoing review of critical-to-quality factors, and risk management 
(ICH guidance for industry E9 Statistical Principles for Clinical Trials (September 1998)). 
 
5.  Critical-to-Quality Factors in Operational Practice (3.3.5) 
 
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(R2)), availability of equipment and facilities 
required to successfully conduct the study, availability of the targeted patient population, and 
ability to enroll 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. 
 
 
IV.  DRUG DEVELOPMENT PLANNING (4) 
 
This section provides general principles to consider in drug development planning. Drug 
development planning should adhere 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 well-
being 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 
nonclinical and clinical evaluation. Such planning encompasses quality of medicinal product, 
including chemistry, manufacturing, and controls, and nonclinical 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. 
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The types of studies that can contribute to drug development are described in subsections IV.B 
(4.2) and IV.C (4.3) and summarized in the Annex. 
 
A.  Quality of Investigational Medicinal Product (4.1) 
 
Ensuring adequate quality and characterization of physicochemical properties of investigational 
medicinal product is an important element in planning a drug development program and is 
addressed in ICH and regional quality guidances. More extensive characterization may be 
required for complex or biological products. Formulations should be well characterized 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 
pediatric populations (ICH guidances for industry E11 Clinical Investigation of Medicinal 
Products in the Pediatric Population (December 2000) and E11(R1) Addendum: Clinical 
Investigation of Medicinal Products in the Pediatric Population (April 2018)).  
 
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 program. This includes establishing 
links between formulations through bioequivalence studies or other means. 
 
B.  Nonclinical Studies (4.2) 
 
Guidance on nonclinical safety studies is provided in the ICH guidance for industry M3(R2) 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals (January 2010), in ICH Safety (S) Guidances and related 
question-and-answer 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 nonclinical studies, 
and their timing with respect to clinical studies, depend on a variety of factors that inform further 
development, such as the drugs chemical or molecular properties; pharmacological basis of 
principal effects (mechanism of action); route(s) of administration; absorption, distribution, 
metabolism, and excretion; 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 people, children) may require additional nonclinical 
assessments. Guidance for nonclinical safety studies to support human clinical studies in special 
populations should be reviewed (see, e.g., the ICH guidances for industry S5(R3) Detection of 
Reproductive and Developmental Toxicity for Human Pharmaceuticals (May 2021), S11 
Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals (May 2021), 
and M3(R2).   
Assessment of the preclinical characteristics, including physiological and toxicological effects of 
the drug, serves to inform clinical study design and planned use in humans. Before proceeding to 
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studies in humans, there should be sufficient nonclinical information to support initial human 
doses and duration of exposure. 
 
C.  Clinical Studies (4.3) 
 
Clinical drug development, defined as studying the drug in humans, is conducted in a sequence 
that builds on knowledge accumulated from nonclinical and previous clinical studies. The 
structure of the drug development program is shaped by many considerations and comprised of 
studies with different objectives, designs, and dependencies. 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 1through 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 program 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 
pharmacodynamics, pharmacokinetics, 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 drugs benefit-risk profile (see the ICH guidance 
for industry E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, 
Structure, and Format of Qualification Submissions (August 2011)) and can 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. 
 
1.  Human Pharmacology (4.3.1) 
 
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 program. 
 
These studies typically address one or a combination of the following aspects: 
 
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a.  Estimation of Initial Safety and Tolerability (4.3.1.1) 
 
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. 
 
b.  Pharmacokinetics (4.3.1.2) 
 
Characterization of a drug's absorption, distribution, metabolism, and excretion continues 
throughout the development program, but the preliminary characterization is an essential early 
goal. Pharmacokinetic (PK) 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 PK studies are 
commonly conducted in later phases to answer more specialized questions. For orally 
administered drugs, the study of food effects on bioavailability is important to inform the dosing 
instructions in relation to food. Obtaining PK information in subpopulations with potentially 
different metabolism or excretion, such as patients with renal or hepatic impairment, geriatric 
patients, children, and ethnic subgroups, should be considered (ICH guidances for industry E4 
Dose-Response Information to Support Drug Registration (November 1994), E7 Studies in 
Support of Special Populations: Geriatrics (August 1994), E11 and E11(R1) Addendum, and E5, 
respectively). 
 
c.  Pharmacodynamics and Early Measurement of Drug Activity (4.3.1.3) 
 
Depending on the drug and the endpoint of interest, pharmacodynamic (PD) 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, PD 
data can provide early estimates of activity and efficacy and may guide the dosage and dose 
regimen in later studies. 
 
2.  Exploratory and Confirmatory Safety and Efficacy Studies (4.3.2) 
 
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 
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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 co-morbidities (e.g., cardiovascular 
disease, diabetes, hepatic and renal impairment) to characterize 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 using the ICH guidance for industry E1A The Extent of 
Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of 
Non-Life-Threatening Conditions (March 1995).  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. 
 
3.  Special Populations (4.3.3) 
 
Some groups in the general population may need 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 drugs effect. Particular attention 
should be paid to the ethical considerations related to informed consent in vulnerable populations 
(ICH E6(R2) 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: 
 
 
a.  Investigations in Pregnant People (4.3.3.1)   
 
Investigation of drugs that may be used in pregnancy is important. Where pregnant people 
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 should be done. 
 
b.  Investigations in Lactating People (4.3.3.2) 
 
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Excretion of the drug or its metabolites into human milk should be examined where applicable 
and feasible. When nursing people are enrolled in clinical studies, their babies are usually also 
monitored for the effects of the drug.    
 
c.  Investigations in Children (4.3.3.3) 
 
ICH E11and E11(R1) Addendum provide an outline of critical issues in pediatric drug 
development and approaches to the safe, efficient, and ethical study of drugs in pediatric 
populations. 
 
d.  Investigations in Geriatric Populations (4.3.3.4) 
 
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.  Post-Approval Studies (4.3.4) 
 
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 optimizing 
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. 
 
Postapproval 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 authorization. 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. 
 
D.  Additional Development (4.4) 
 
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 nonclinical and/or human 
pharmacology studies may be indicated. Data from previous studies or from clinical experience 
with the approved drug may inform these programs. 
 
 
V.  DESIGN ELEMENTS AND DATA SOURCES FOR CLINICAL STUDIES (5) 
 
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 
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IV (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 V.A (5.1) 
through V.F (5.6) discuss key elements that can be used to define the study design, and section 
V.G (5.7) discusses the various data sources that can 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 the ICH guidance for industry E9(R1) Statistical Principles 
for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (May 
2021), provide a precise description of the treatment effects reflecting the clinical questions 
posed by the study objectives. The estimand summarizes 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 randomized studies, play a central role in drug 
development, because they can better control biases. The designs of randomized 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 prespecified decision rules. 
 
Studies without randomization (whether interventional or observational) can play a role as well 
in certain settings when randomization 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 lifecycle 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 generalizability 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 
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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. 
 
A.  Study Population (5.1) 
 
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 
maximize 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 program, 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 that 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 E1A). If study objectives include 
obtaining information on certain subgroups, then efforts should be made to ensure adequate 
representation of these subgroups.  
 
B.  Treatment Description (5.2) 
 
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 health care 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. 
 
C.  Choice of Control Group (5.3) 
 
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 (ICH guidance for industry E10 Choice of Control Group and Related 
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  Contains Nonbinding Recommendations 
 
Issues in Clinical Trials (May 2001)). 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 minimize 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 randomization, the suitability 
of the use and choice of external control should be carefully considered and justified. Section 
V.E (5.5) discusses the sources of bias that 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. 
 
 
D.  Response Variables (5.4) 
 
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 minimization measures post- 
approval. 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 
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  Contains Nonbinding Recommendations 
 
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 
participants 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 could employ a pharmacodynamic outcome rather than the outcome of primary interest. 
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 characterized, the extent of safety data collection can be tailored to the objectives of 
the study. 
 
E.  Methods to Reduce Bias (5.5) 
 
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, randomization is used to ensure comparability of 
treatment groups, thereby minimizing the possibility of bias in treatment assignment. 
 
Randomization at the start of the study addresses differences between the groups at the time of 
randomization but does not prevent bias because of differences arising during the study. Events 
after randomization (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 open-label 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 
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  Contains Nonbinding Recommendations 
 
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 important. 
 
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. 
 
F.  Statistical Analysis (5.6) 
 
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 prespecified sensitivity analyses for assessing the impact 
of the assumptions made for the primary and important secondary analyses on the results of the 
study (ICH 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 finalized 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 finalized before the first participant is 
randomized or allocated to study intervention. 
 
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Prespecification of the analysis approach is particularly important for studies that use existing 
data sources rather than primary data collection (section V.G (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 before conducting the interventional aspect of 
the study. Prespecification of the analysis should be in place so that any review of the existing 
data sources before 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 (ICH 
guidance for industry E3 Structure and Content of Clinical Reports (July 1996)). 
 
G.  Study Data (5.7) 
 
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. 
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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 reused 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 analyzing, 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. 
 
 
VI.   CONDUCT, SAFETY MONITORING, AND REPORTING (6)   
 
A.  Study Conduct (6.1) 
 
The principles and approaches set out in this guidance, 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. 
 
1.  Protocol Adherence (6.1.1) 
 
Adherence to the study protocol and other relevant documents is important, and many aspects of 
adherence should be considered among the studys critical-to-quality factors. Successful 
application of the quality by design principles may minimize 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. 
 
2.  Training (6.1.2) 
 
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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 to implement protocol modifications. 
 
3.  Data Management (6.1.3) 
 
The manner and timelines in which study data are collected and managed are critical contributors 
to overall study data quality. Operational checks, centralized 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 
V.G (5.7)). For interventional clinical studies, further guidance on data management is available 
in ICH E6(R2). 
 
4.  Access to Interim Data (6.1.4) 
 
Inappropriate access to data during the conduct of the study may compromise study integrity 
(sections V.E (5.5) and V.F (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. 
 
B.  Participant Safety During Study Conduct (6.2) 
 
Important standards of ethical conduct and the protection of participants in clinical studies are 
described in section II.A (2.1). This section describes safety-related considerations during the 
conduct of the study. 
 
1.  Safety Monitoring (6.2.1) 
 
The goals of safety monitoring are to protect study participants and to characterize 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. See the following ICH Efficacy 
Guidelines guidances for industry and, for interventional clinical trials in particular, ICH E6(R2): 
 
  E2A Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting (March 1995) 
 
  E2B(R3) Electronic Transmission of Individual Case Safety Reports (ICSRs) 
Implementation Guide  Data Elements and Message Specification (February 2014) 
 
  E2B(R3) Appendix I (B) to the ICH E2B(R3) ICSRs Implementation Guide  Backwards 
and Forwards Compatibility (February 2014) 
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  E2B(R3) FDA Regional Implementation Specifications for ICH E2B(R3) Implementation 
 Postmarket Submission of Individual Case Safety Reports for Drugs and Biologics, 
Excluding Vaccines  Technical Specifications Document (June 2016)  
 
  E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER) (July 2016) 
 
  E2C(R2) Periodic Benefit-Risk Evaluation Report  Questions and Answers (July 2016) 
 
  E2D Postapproval Safety Data Management: Definitions and Standards for Expedited 
Reporting (September 2003) 
 
  E2E Pharmacovigilance Planning (April 2005) 
 
  E2F Development Safety Update Report (August 2011) 
 
 
2.  Withdrawal Criteria (6.2.2) 
 
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 minimize 
loss of critical data. 
 
3.  Data Monitoring Committee (6.2.3) 
 
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 program planning, the need for an independent data monitoring committee to monitor 
safety data across studies in a development program should also be assessed. If a data monitoring 
committee is needed for either an individual study or across the development program, 
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 before the 
study starts. 
 
C.  Study Reporting (6.3) 
 
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 
can be applied to other types of clinical studies (ICH guidance for industry E3 Structure and 
Content of Clinical Study Reports-Questions and Answers (R1) (January 2013). The design of the 
study report should be part of the quality by design process. The report should describe the 
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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 recognized 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. 
 
 
VII. CONSIDERATIONS IN IDENTIFYING CRITICAL-TO-QUALITY FACTORS (7) 
 
The identification of critical-to-quality factors should be supported by proactive, cross-functional 
discussions and decision-making at the time of study planning, as described in section III (3). 
Different factors will stand out as critical for different types of studies, following the concepts 
introduced in sections IV (4) through VI (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 nonclinical 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 
studys role in the development program, 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, pseudonymization). 
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  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 minimize bias (e.g., 
randomization, blinding). 
 
  The statistical analysis plan is prespecified 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. 
 
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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 program, 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 Table 1 below, types of 
clinical studies are categorized by objectives. Illustrative examples, not intended to be exhaustive 
or exclusive, are provided. Study objectives appearing under one type may also occur under 
another. 
 
Table 1.  Clinical Studies Categorized by Objectives 
 
Type of Study  Objectives of Study  Study Examples 
Human Phar-   Assess tolerance and safety    BA3/BE4 studies under fasted/fed 
macology    Define/describe clinical PK1  conditions 
and PD2    Dose-tolerance studies 
  Explore drug metabolism and    Single and multiple-rising dose PK 
drug interactions  and/or PD studies 
  Evaluate activity, assess    Drug-drug interaction studies 
immunogenicity    QTc prolongation study 
  Assess renal/hepatic    Human factor studies for drug 
tolerance  delivery devices 
  Assess cardiac toxicity 
Exploratory    Explore use for the intended    Randomized, controlled clinical tri-
indication  als of relatively short duration in 
  Estimate dose/dosing  well-defined narrow patient popula-
regimen for subsequent  tions, using surrogate or pharmaco-
studies  logical endpoints or clinical 
  Explore dose-response/ex- measures 
posure-response relation-   Dose-finding studies 
ship    Biomarker exploration studies 
  Provide basis for confirma-   Studies to validate patient-reported 
tory study design (e.g., tar- outcomes 
geted population, clinical    Adaptive designs that may combine 
endpoints, patient-reported  exploratory and confirmatory ob-
outcome measures, factors  jectives 
affecting treatment effects) 
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Type of Study  Objectives of Study  Study Examples 
Confirmatory    Demonstrate/confirm    Randomized, controlled clinical tri-
efficacy  als to establish efficacy in larger, 
  Establish safety profile in  more representative patient popula-
larger, more representative  tions 
patient populations    Dose-response studies 
  Provide an adequate basis for    Clinical safety studies 
assessing the benefit/risk re-   Studies of mortality/morbidity 
lationship to support licens- outcomes 
ing    Studies in special populations 
  Establish dose-response/ex-   Studies that seek to demonstrate 
posure-response relation- efficacy for multiple drugs in a single 
ship  protocol 
  Establish safety profile and 
confirm efficacy in specific 
populations (e.g., pediatric, 
elderly) 
Postapproval    Extend understanding of ben-   Comparative effectiveness studies 
efit/risk relationship in gen-   Long-term follow-up studies 
eral or special populations    Studies of mortality/morbidity or other 
and/or environments  additional endpoints 
  Identify less common adverse    Large, simple randomized trials 
reactions    Pharmacoeconomic studies 
  Refine dosing    Pharmacoepidemiology studies 
recommendations    Observational studies of the use of the 
drug in clinical practice 
  Disease or drug registries 
1PK -Pharmacokinetic 
 
2PD - Pharmacodynamic 
 
3BA - Bioavailability 
 
4 BE  Bioequivalence 
  
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