E6(R3) GOOD CLINICAL PRACTICE (GCP)  
 
 
 
 
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or 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 staff responsible for this guidance as listed on the title page.  The draft guidance 
has been left in the original International Council for Harmonisation format.  The final guidance will be reformatted and 
edited to conform with FDAs good guidance practice regulation and style. 
 
 
 
 
 
 
 
 
 
 
For questions regarding this draft document, contact (CDER) Amy Chi, Amy.Chi@fda.hhs.gov.  
     
 
 
 
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.   
     
 
 
 
 
 
 
 
 
INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 
 
 
 
 
 
ICH HARMONISED GUIDELINE 
GOOD CLINICAL PRACTICE (GCP) 
E6(R3) 
 
 
Draft version 
Endorsed on 19 May 2023 
Currently under public consultation 
 
 
 
 
 
 
 
 
 
 
 
 
 
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate 
ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities 
of the ICH regions for internal and external consultation, according to national or regional 
procedures.  E6(R3) 
Document History 
 
Code  History  Date 
E6  Approval by the Steering Committee under Step 2  27  April 1995 
and release for public consultation. 
E6  Approval by the Steering Committee under Step 4  1 May 1996 
and recommended for adoption to the three ICH 
regulatory bodies. 
E6(R1)  Approval by the Steering Committee of Post-Step 4  10 June 1996 
editorial corrections. 
E6(R2)  Adoption by the Regulatory Members of the ICH  9 November 2016 
Assembly under Step 4. Integrated Addendum to 
ICH  E6(R1)  document.  Changes  are  integrated 
directly into the following sections of the parental 
Guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13, 
4.2.5,  4.2.6,  4.9.0,  5.0,  5.0.1,  5.0.2,  5.0.3,  5.0.4, 
5.0.5, 5.0.6, 5.0.7, 5.2.2, 5.5.3 (a), 5.5.3 (b), 5.5.3 (h), 
5.18.3, 5.18.6 (e), 5.18.7, 5.20.1, 8.1 
E6(R3)  Endorsement by the Members of the ICH Assembly   19 May 2023 
under Step 2 and release for public consultation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be 
used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a 
public license provided that ICH's copyright in the document is acknowledged at all times. In case of 
any adaption, modification or translation of the document, reasonable steps must be taken to clearly 
label, demarcate or otherwise identify that changes were made to or based on the original document. 
Any impression that the adaption, modification or translation of the original document is endorsed or 
sponsored by the ICH must be avoided. 
The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors 
of the original document be liable for any claim, damages or other liability arising from the use of the 
document. 
The above-mentioned permissions do not apply to content supplied by third parties.  Therefore, for 
documents where the copyright vests in a third party, permission for reproduction must be obtained 
from this copyright holder. 
 
 
 
 
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ICH HARMONISED GUIDELINE 
GOOD CLINICAL PRACTICE (GCP) 
E6(R3) 
ICH Consensus Guideline 
TABLE OF CONTENTS 
I.  INTRODUCTION ........................................................................................................ 1 
Guideline Scope ........................................................................................................................ 1 
Guideline Structure .................................................................................................................. 1 
II.  PRINCIPLES OF ICH GCP ....................................................................................... 2 
III.  ANNEX 1 ....................................................................................................................... 7 
1.  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
(IRB/IEC) ...................................................................................................................... 7 
1.1  Responsibilities ............................................................................................................. 7 
1.2  Composition, Functions and Operations .................................................................... 9 
1.3  Procedures..................................................................................................................... 9 
1.4  Records ........................................................................................................................ 10 
1.5  Submission and Communication ............................................................................... 11 
2.  INVESTIGATOR ....................................................................................................... 11 
2.1  Qualifications and Training ...................................................................................... 11 
2.2  Resources .................................................................................................................... 11 
2.3  Responsibilities ........................................................................................................... 11 
2.4  Communication with IRB/IEC .................................................................................. 12 
2.5  Compliance with Protocol .......................................................................................... 12 
2.6  Premature Termination or Suspension of a Trial ................................................... 13 
2.7  Participant Medical Care and Safety Reporting ..................................................... 13 
2.7.1  Medical Care of Trial Participants ............................................................ 13 
2.7.2  Safety Reporting ......................................................................................... 14 
2.8  Informed Consent of Trial Participants ................................................................... 14 
2.9  End of Participation in a Clinical Trial .................................................................... 18 
2.10  Investigational Product Management ....................................................................... 19 
2.11  Randomisation Procedures and Unblinding ............................................................ 19 
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2.12  Records ........................................................................................................................ 20 
2.13  Clinical Trial/Study Reports ..................................................................................... 21 
3.  SPONSOR ................................................................................................................... 22 
3.1  Trial Design ................................................................................................................. 22 
3.2  Resources .................................................................................................................... 22 
3.3  Allocation of Activities ............................................................................................... 22 
3.4  Qualification and Training ........................................................................................ 22 
3.4.1  Medical Expertise ...................................................................................... 22 
3.5  Financing ..................................................................................................................... 23 
3.6  Agreements ................................................................................................................. 23 
3.7  Investigator Selection ................................................................................................. 24 
3.8  Communication with IRB/IEC and Regulatory Authority(ies) .............................. 24 
3.8.1  Notification/Submission to Regulatory Authority(ies) ............................... 24 
3.8.2  Confirmation of Review by IRB/IEC .......................................................... 25 
3.9  Sponsor Oversight ...................................................................................................... 25 
3.10  Quality Management .................................................................................................. 26 
3.10.1  Risk Management ....................................................................................... 26 
3.11  Quality Assurance and Quality Control ................................................................... 27 
3.11.1  Quality Assurance ...................................................................................... 27 
3.11.2  Audit .......................................................................................................... 27 
3.11.3  Quality Control .......................................................................................... 28 
3.11.4  Monitoring ................................................................................................. 28 
3.12  Noncompliance ........................................................................................................... 33 
3.13  Safety Assessment and Reporting ............................................................................. 33 
3.13.1  Sponsor Review of Safety Information ....................................................... 34 
3.13.2  Safety Reporting ......................................................................................... 34 
3.13.3  Managingan Immediate Hazard ................................................................ 35 
3.14  Insurance/Indemnification/Compensation to Participants and Investigators ....... 35 
3.15  Investigational Product(s) .......................................................................................... 35 
3.15.1  Information on Investigational Product(s) ................................................ 35 
3.15.2  Manufacturing,  Packaging,  Labelling  and  Coding  Investigational 
Product(s) .............................................................................................................. 35 
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3.15.3  Supplying and Handling Investigational Product(s) ................................. 36 
3.16  Data and Records ....................................................................................................... 37 
3.16.1  Data Handling ........................................................................................... 37 
3.16.2  Statistical Programming and Data Analysis .............................................. 41 
3.16.3  Record Keeping and Retention .................................................................. 41 
3.16.4  Record Access ............................................................................................ 42 
3.17  Reports ........................................................................................................................ 42 
3.17.1  Premature Termination or Suspension of a Trial ...................................... 42 
3.17.2  Clinical Trial/Study Reports ...................................................................... 42 
4.  DATA GOVERNANCE  INVESTIGATOR AND SPONSOR ............................. 43 
4.1  Safeguard Blinding in Data Governance .................................................................. 43 
4.2  Data Life Cycle Elements ........................................................................................... 44 
4.2.1  Data Capture ............................................................................................. 44 
4.2.2  Relevant Metadata, Including Audit Trails ............................................... 44 
4.2.3  Review of Data and Metadata ................................................................... 45 
4.2.4  Data Corrections ....................................................................................... 45 
4.2.5  Data Transfer, Exchange and Migration ................................................... 45 
4.2.6  Finalisation of Data Sets Prior to Analysis ............................................... 45 
4.3  Computerised Systems ............................................................................................... 45 
4.3.1  Procedures for the Use of Computerised Systems ..................................... 46 
4.3.2  Training ..................................................................................................... 46 
4.4  Security of Computerised Systems ............................................................................ 46 
4.5  Validation of Computerised Systems ........................................................................ 46 
4.6  System Failure ............................................................................................................ 47 
4.7  Technical Support ...................................................................................................... 47 
4.8  User Management ....................................................................................................... 48 
GLOSSARY ............................................................................................................................ 49 
APPENDICES ........................................................................................................................ 58 
Appendix A. INVESTIGATORS BROCHURE ................................................................. 58 
A.1  Introduction ................................................................................................................ 58 
A.2  General Considerations.............................................................................................. 59 
A.2.1  Title Page ................................................................................................... 59 
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A.2.2  Confidentiality Statement ........................................................................... 59 
A.3  Contents of the Investigators Brochure .................................................................. 59 
A.3.1  Table of Contents ....................................................................................... 59 
A.3.2  Summary .................................................................................................... 59 
A.3.3  Introduction ............................................................................................... 59 
A.3.4  Physical, Chemical and Pharmaceutical Properties and Formulation ..... 59 
A.3.5  Nonclinical Studies .................................................................................... 60 
A.3.6  Effects in Humans ...................................................................................... 61 
A.3.7  Summary of Data and Guidance for the Investigator ................................ 62 
Appendix B. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 
. ..................................................................................................................................... 64 
B.1  General Information .................................................................................................. 64 
B.2  Background Information ........................................................................................... 64 
B.3  Trial Objectives and Purpose .................................................................................... 64 
B.4  Trial Design ................................................................................................................. 65 
B.5  Selection of Participants ............................................................................................ 65 
B.6  Withdrawal of Consent or Discontinuation of Participation .................................. 65 
B.7  Treatment and Interventions for Participants ......................................................... 66 
B.8  Assessment of Efficacy ............................................................................................... 66 
B.9  Assessment of Safety .................................................................................................. 66 
B.10  Statistical Considerations ........................................................................................... 66 
B.11  Direct Access to Source Records ............................................................................... 67 
B.12  Quality Control and Quality Assurance ................................................................... 67 
B.13  Ethics ........................................................................................................................... 67 
B.14  Data Handling and Record Keeping ......................................................................... 67 
B.15  Financing and Insurance ........................................................................................... 67 
B.16  Publication Policy ....................................................................................................... 67 
Appendix C. ESSENTIAL RECORDS FOR THE CONDUCT OF A CLINICAL TRIAL 
. ..................................................................................................................................... 68 
C.1  Introduction ................................................................................................................ 68 
C.2  Management of Essential Records ............................................................................ 68 
C.3  Essentiality of Trial Records ..................................................................................... 69 
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1  I.  INTRODUCTION 
2  Good Clinical Practice (GCP) is an international, ethical, scientific and quality standard for the 
3  conduct of trials that involve human participants. Clinical trials conducted in accordance with 
4  this standard will help to assure that the rights, safety and well-being of trial participants are 
5  protected; that the conduct is consistent with the principles that have their origin in the 
6  Declaration of Helsinki; and that the clinical trial results are reliable. The term trial conduct 
7  in this document includes processes from planning to reporting, including planning, initiating, 
8  performing, recording, oversight, evaluation, analysis and reporting activities as appropriate. 
9  The objective of this ICH GCP Guideline is to provide a unified standard to facilitate the mutual 
10  acceptance of clinical trial data for ICH member countries and regions by applicable regulatory 
11  authorities. 
12  This guideline builds on key concepts outlined in ICH E8(R1) General Considerations for 
13  Clinical Studies. This includes fostering a quality culture and proactively designing quality into 
14  clinical trials and drug development planning, identifying factors critical to trial quality, and 
15  engaging stakeholders, as appropriate, using a proportionate risk-based approach. 
16  Clinical trials vary widely in scale, complexity and cost. Careful evaluation of the priorities 
17  involved in each trial and the risks associated with the priorities will help ensure efficiency by 
18  focusing on activities critical to achieving the trial objectives. 
19  Guideline Scope 
20  This guideline applies to interventional clinical trials of investigational products 1 that are 
21  intended to be submitted to regulatory authorities. This guideline may also be applicable to 
22  other interventional clinical trials of investigational products that are not intended to support 
23  marketing authorisation applications in accordance with local requirements. 
24  Guideline Structure 
25  This ICH GCP Guideline is composed of principles and annexes that expand on the principles, 
26  with specific details for different types of clinical trials. The principles are intended to apply 
27  across  clinical  trial  types  and  settings  and  to  remain  relevant  as  technological  and 
28  methodological advances occur. The principles outlined in this guideline may be satisfied using 
29  differing approaches and should be applied to fit the intended purpose of the clinical trial. 
30  Annex-1 is intended to provide information on how the principles can be appropriately applied 
31  to clinical trials. Additional annexes may be developed to respond to stakeholder needs and to 
32  address emerging innovations in trial design and conduct. This guideline should be read in 
33  conjunction with other ICH guidelines relevant to the design and conduct of clinical trials, 
34  including multiregional trials. 
 
 
 
 
 
 
 
1 For the purpose of this guideline, the term investigational products should be considered synonymous with 
drugs, medicines, medicinal products, vaccines and biological products. 
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ICH E6(R3) Guideline 
 
35  II.  PRINCIPLES OF ICH GCP 
36  Clinical trials are a fundamental part of clinical research that support the development of new 
37  medicines or uses of existing medicines. Well-designed and conducted clinical trials help 
38  answer key questions in healthcare and drug development. Their results are essential for 
39  evidence-based healthcare decisions. Trials with inadequate design and/or poorly conducted 
40  trials may place participant safety at risk and yield inadequate or unreliable evidence and are 
41  unethical. They waste resources and the efforts and time of investigators and participants. 
42  The principles of GCP are designed to be flexible and applicable to a broad range of clinical 
43  trials.  This  guideline,  along with  ICH  E8(R1),  encourages  thoughtful  consideration  and 
44  planning to address specific and potentially unique aspects of an individual clinical trial. This 
45  includes evaluation of trial characteristics, such as the design elements, the investigational 
46  product being evaluated, the medical condition being addressed, the characteristics of the 
47  participants, the setting in which the clinical trial is being conducted, and the type of data being 
48  collected. Careful consideration of factors relevant to ensuring trial quality is needed for each 
49  clinical trial. 
50  The principles are intended to support efficient approaches to trial design and conduct. For 
51  example, innovative digital health technologies, such as wearables and sensors, may expand 
52  the possible approaches to trial conduct. Such technologies can be incorporated into existing 
53  healthcare infrastructures and enable the use of a variety of relevant data sources in clinical 
54  trials. This will aid in keeping clinical trial conduct in line with advancing science and 
55  technological developments. The use of technology in the conduct of clinical trials should be 
56  adapted to fit the participant characteristics and the particular trial design. This guideline is 
57  intended to be media neutral to enable the use of different technologies for the purposes of 
58  documentation. 
59  The use of innovative clinical trial designs and technologies may help include diverse patient 
60  populations, as appropriate, and enable wider participation. The design of the trial, to ensure 
61  appropriate quality and meaningful trial outcomes, may be supported by the perspectives of 
62  stakeholders; for example, patients and/or healthcare providers. Their input can increase the 
63  likelihood of meaningful trial outcomes, which are relevant to both trial participants and future 
64  patients. This input will also guide decisions on the feasibility of data collection and assure that 
65  participation in the trial does not become unduly burdensome for those involved. 
66  Clinical trials should be designed to protect the rights, safety and well-being of participants and 
67  assure the reliability of results. Quality by design should be implemented to identify the factors 
68  (i.e., data and processes) that are critical to ensuring trial quality and the risks that threaten the 
69  integrity of those factors and ultimately the reliability of the trial results. Clinical trial processes 
70  and risk mitigation strategies implemented to support the conduct of the trial should be 
71  proportionate to the importance of the data being collected and the risks to trial participant 
72  safety and data reliability. Trial designs should be operationally feasible and avoid unnecessary 
73  complexities. 
74  The overarching principles provide a flexible framework for clinical trial conduct. They are 
75  structured to provide guidance throughout the life cycle of the clinical trial. These principles 
76  are applicable to trials involving human participants. The principles are interdependent and 
77  should be considered in their totality to assure ethical trial conduct and reliable results. 
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78  1.  Clinical trials should be conducted in accordance with the ethical principles that 
79  have their origin in the Declaration of Helsinki and that are consistent with GCP 
80  and applicable regulatory requirement(s). Clinical trials should be designed and 
81  conducted in ways that ensure the rights, safety and well-being of participants. 
82 
83  1.1  The rights, safety and well-being of the participants are the most important 
84  considerations and should prevail over interests of science and society. 
85  1.2  The safety of the participants should be reviewed periodically as new safety 
86  information becomes available, which could have an impact on the participant 
87  or the conduct of the trial. 
88  1.3  Foreseeable risks and inconveniences should be weighed against the anticipated 
89  benefits for the individual participants and society. A trial should be initiated 
90  and continued only if the anticipated benefits justify the known and anticipated 
91  risks. 
92  1.4  When designing a clinical trial, the scientific goal and purpose should be 
93  carefully considered so as not to unnecessarily exclude particular participant 
94  populations. The participant selection process should be representative of the 
95  anticipated population who is likely to use the medicinal product in future 
96  clinical  practice  to  allow  for  generalising  the  results  across  the  broader 
97  population.  Certain  trials  (e.g.,  early  phase,  proof  of  concept  trials, 
98  bioequivalence studies) may not require a heterogeneous population. 
99  1.5  A  qualified  physician  or,  when  appropriate,  a  qualified  dentist  (or  other 
100  qualified  healthcare  professionals  in  accordance  with  local  regulatory 
101  requirements) should have the overall responsibility for the trial-related medical 
102  care given to, and medical decisions made on behalf of, participants; however, 
103  the practical interactions and the delivery of medical care and decisions can be 
104  carried out by appropriately qualified healthcare professionals in accordance 
105  with applicable regulatory requirements. 
106  1.6  The confidentiality of information that could identify participants should be 
107  protected  in  accordance  with  applicable  privacy  and  data  protection 
108  requirements. 
109 
110  2.  Informed consent is an integral feature of the ethical conduct of a trial. Clinical 
111  trial participation should be voluntary and based on a consent process that 
112  ensures  participants  (or  their  legally  acceptable  representatives,  where 
113  applicable) are well-informed. 
114 
115  2.1  Freely given informed consent should be obtained and documented from every 
116  participant prior to clinical trial participation. For potential participants unable 
117  to provide informed consent, their legally acceptable representative should 
118  provide consent prior to clinical trial participation. 
119  2.2  The process and information provided should be designed to achieve the 
120  primary objective of enabling potential trial participants to evaluate the benefits 
121  and risks of participating in the trial and to make an informed decision on 
122  whether or not to participate in the trial. The information provided during the 
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123    informed consent process should be clear and concise so as to be understandable 
124  by potential participants or legally acceptable representatives. 
125  2.3    The informed consent process should take into consideration relevant aspects of 
126  the trial, such as the characteristics of the participants, the trial design, the 
127  anticipated benefit and risk of medical intervention(s), the setting and context 
128  in which the trial will be conducted (e.g., trials in emergency situations), and 
129  the potential use of technology to inform participants (or their legally acceptable 
130  representatives) and obtain informed consent. 
  131 
132  3.  Clinical trials should be subject to an independent review by an institutional 
133    review board/independent ethics committee (IRB/IEC). 
  134   
135    3.1  A trial should always be conducted in compliance with the protocol that 
136    receives prior IRB/IEC approval/favourable opinion. 
137    3.2  Periodic review of the trial by the IRB/IEC should also be conducted in 
138    accordance with applicable regulatory requirements. 
  139   
140  4.  Clinical trials should be scientifically sound for their intended purpose and based 
141    on robust and current scientific knowledge and approaches. 
  142   
143    4.1  The  available  nonclinical  and  clinical  information  on  an  investigational 
144    product(s) should be adequate to support the proposed clinical trial. 
145    4.2  Clinical trials should be scientifically sound and reflect the state of knowledge 
146    and experience with the investigational product(s), including, if applicable, the 
147    condition to be treated, diagnosed or prevented; the current understanding of 
148    the underlying biological mechanism (of both the condition and the treatment); 
149    and the population for which the investigational product is intended. 
150    4.3  There should be periodic review of current scientific knowledge and approaches 
151    to  determine  whether modifications  to  the  trial  are  needed,  since  new  or 
152    unanticipated information may arise once the trial has begun. 
  153   
154  5.  Clinical trials should be designed and conducted by qualified individuals. 
  155   
156    5.1  Individuals with different expertise and training may be needed across all 
157    phases of a clinical trial, such as physicians, scientists, ethicists, technology 
158    experts,  trial  coordinators,  monitors,  auditors  and  statisticians.  Individuals 
159    involved in a trial should be qualified by education, training and experience to 
160    perform their respective task(s). 
  161   
162  6.  Quality should be built into the scientific and operational design and conduct of 
163    clinical trials. 
  164   
165    6.1  Quality of a clinical trial is considered in this guideline as fit for purpose. The 
166    quality and amount of the information generated during a clinical trial should 
167    support good decision making. 
 
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168    6.2  Factors critical to the quality of the trial should be identified. These factors are 
169    attributes of a trial that are fundamental to the protection of participants, the 
170    reliability and interpretability of the trial results and the decisions made based 
171    on those trial results. Quality by design involves focusing on the design of all 
172    components of the trial in order to maximise the likelihood of trial success (i.e., 
173    that the trial will answer the research question). 
174    6.3  Strategies should be implemented to avoid, detect and address serious non- 
175    compliance with GCP, the trial protocol and applicable regulatory requirements 
176    to prevent recurrence. 
  177   
178  7.  Clinical trial processes, measures and approaches should be implemented in a 
179    way that is proportionate to the risks to participants and to the importance of 
180    the data collected. 
  181   
182    7.1  Trial processes should be proportionate to the risks inherent in the trial and the 
183    importance of the information collected. Risks in this context include risks to 
184    the rights, safety and well-being of trial participants as well as risks to the 
185    reliability of the trial results. 
186    7.2  The focus should be on the risks to participants beyond those associated with 
187    standard medical care. The risks relating to investigational products that have a 
188    marketing authorisation when used in the clinical trial context may differ from 
189    the routine care of patients and should be taken into consideration. 
190    7.3  Risks  to  critical  to  quality  factors  should  be  managed  prospectively  and 
191    adjusted when new or unanticipated issues arise once the trial has begun. 
  192   
193  8.  Clinical trials should be described in a clear, concise and operationally feasible 
194    protocol. 
  195   
196    8.1  A well-designed trial protocol is fundamental to the protection of participants 
197    and for the generation of reliable results. 
198    8.2  The scientific objectives of any trial should be clear and explicitly stated in the 
199    protocol. 
200    8.3  The clinical trial protocol as well as the plans or documents for the protocol 
201    execution (e.g., statistical analysis plan, data management plan, monitoring 
202    plan) should be clear, concise and operationally feasible. 
  203   
204  9.  Clinical trials should generate reliable results. 
  205   
206    9.1  The quality and amount of the information generated in a clinical trial should 
207    be sufficient to provide confidence in the trials results and support good 
208    decision making. 
209    9.2  Systems and processes that aid in data capture, management and analyses, as 
210    well as those that help ensure the quality of the information generated from the 
211    trial, should be fit for purpose, should capture the data required by the protocol 
212    and should be implemented in a way that is proportionate to the risks to 
213    participants and the importance of acquired data. 
 
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214    9.3  Trial  processes  should  be  operationally  feasible  and  avoid  unnecessary 
215    complexity, procedures and data collection. Trial processes should support the 
216    key trial objectives. 
217    9.4  Computerised systems used in clinical trials should be fit for purpose, and 
218    factors critical to their quality should be addressed in their design or adaptation 
219    for clinical trial purposes. 
220    9.5  Clinical trials should incorporate efficient and well-controlled processes for 
221    managing  records  through  appropriate  management  of  data  integrity, 
222    traceability  and  protection  of  personal  information,  thereby  allowing  the 
223    accurate reporting, interpretation and verification of the clinical trial-related 
224    information. 
225    9.6  Clinical  trial-related  records  should  be  retained  securely  by  sponsors  and 
226    investigators  for  the  required  period  of  time  and  should  be  available  to 
227    regulatory authorities upon request to enable reconstruction of the trial conduct 
228    and results in order to ensure the reliability of trial results. 
229    9.7  The transparency of clinical trials in drug development includes registration on 
230    publicly accessible and recognised databases and the public posting of clinical 
231    trial results. 
  232   
233  10.  Roles and responsibilities in clinical trials should be clear and documented 
234    appropriately. 
  235   
236    10.1  The sponsor may transfer or the investigator may delegate some or all their 
237    tasks, duties or functions (hereafter referred to as activities), but they retain 
238    overall responsibility for their respective activities. 
239    10.2  Agreements should clearly define the roles, activities and responsibilities for 
240    the clinical trial and be documented appropriately. Where activities have been 
241    transferred or delegated to service providers, the responsibility for the conduct 
242    of the trial, including quality and integrity of the trial data, resides with the 
243    sponsor or investigator, respectively. 
244    10.3  The  sponsor  or  investigator  should  maintain  appropriate  oversight  or 
245    supervision of the aforementioned activities, respectively. 
  246   
247  11.  Investigational products used in  a clinical trial should be manufactured  in 
248    accordance with applicable Good Manufacturing Practice (GMP) standards and 
249    be stored, shipped, handled and disposed of in accordance with the product 
250    specifications and the trial protocol. 
  251   
252    11.1  Investigational products used in a clinical trial should be manufactured in 
253    accordance with applicable GMP standards. 
254    11.2  Measures should be in place to ensure that the investigational product provided 
255    to trial participants retains its quality. 
256    11.3  Investigational products should be used in accordance with the protocol and 
257    relevant trial documents. 
 
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258  11.4  Manufacturing, handling and labelling of investigational products should be 
259  undertaken in a manner that aligns with treatment assignment and maintains 
260  blinding, where applicable. 
261  11.5  Investigational  product  labelling  should  follow  applicable  regulatory 
262  requirements. 
263  11.6  Adequate measures to ensure that the investigational product is handled and 
264  shipped appropriately should be implemented. 
265   
266  III.  ANNEX 1 
267  1.  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
268    (IRB/IEC) 
 
269  The IRB/IEC is responsible for the ethical review of the trial. The requirements for 
270    the IRB/IEC in this guideline should be read in conjunction with local regulatory 
271    requirements. 
272  1.1  Responsibilities 
273  1.1.1  The purpose of an IRB/IEC is to safeguard the rights, safety and well-being of all trial 
274    participants. 
275     
276  1.1.2  The IRB/IEC should review the following information, where applicable: 
277     
278    (a)  protocol and any amendments; 
279     
280    (b)  informed consent  material(s),  assent  form(s),  where  applicable,  and  any 
281    updates, including the description of the process for how informed consent is 
282    to be obtained; 
283     
284    (c)  Investigators Brochure or current scientific information, such as a basic 
285    product  information  brochure  (e.g.,  Summary  of  Product  Characteristics 
286    (SmPC), package leaflet or labelling), as appropriate, including their updates; 
287     
288    (d)  any other information to be provided to the trial participant(s), including a 
289    description of the media through which such information will be provided; 
290     
291    (e)  advertisement for participant recruitment (if used) and information on the 
292    recruitment process; 
293     
294    (f)  plans to compensate participants (if any); 
295     
296    (g)  ongoing updates to safety information (dependent on requirements of the 
297    IRB/IEC); 
298     
299    (h)  investigators current curriculum vitae and/or other documentation evidencing 
300    qualifications; 
301     
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302    (i)  any other documents that the IRB/IEC may need to fulfil its responsibilities. 
  303 
304  1.1.3  The IRB/IEC should review a proposed clinical trial within a reasonable time and 
305    document its reviews clearly identifying the trial, the documents reviewed and the 
306    dates for the following: 
  307   
308    (a)  approval/favourable opinion; 
  309   
310    (b)  modifications required prior to its approval/favourable opinion; 
  311   
312    (c)  disapproval/negative opinion; 
  313   
314    (d)  termination/suspension of any prior approval/favourable opinion. 
  315   
316  1.1.4  The IRB/IEC should conduct continuing review of each ongoing trial at intervals 
317    appropriate to the degree of risk to participants. 
  318   
319  1.1.5  The IRB/IEC may request more information than is outlined in section 2.8.11 be given 
320    to participants when, in the judgement of the IRB/IEC, the additional information 
321    would add meaningfully to the protection of the rights, safety and/or well-being of the 
322    participants. 
  323   
324  1.1.6  Where  the  protocol  indicates  that  prior  consent  of  the  trial  participant  or  the 
325    participants legally acceptable representative is not possible (see section 2.8.9), the 
326    IRB/IEC should determine that the proposed protocol and/or other document(s) 
327    adequately  address  relevant  ethical  concerns  and  meet  applicable  regulatory 
328    requirements for such trials (e.g., in emergency situations). 
  329   
330  1.1.7  If  minors  are  to  be  included  in  a  trial,  the  IRB/IEC  should  review  the  assent 
331    information considering the age, maturity and psychological state of the minor, as well 
332    as applicable regulatory requirements. 
  333   
334  1.1.8  If the trial participants are compensated for their participation in the trial, the IRB/IEC 
335    should review both the amount and method of payment to participants to assure that 
336    neither presents problems of coercion or undue influence on the trial participants. 
337    Payments to a participant should be prorated and not wholly contingent on completion 
338    of the trial by the participant. Reasonable reimbursement of participants for travel and 
339    lodging is not typically coercive. 
  340   
341  1.1.9  The IRB/IEC should ensure that information regarding payment to participants, 
342    including the methods, amounts and schedule of payment to trial participants, is set 
343    forth in the informed consent material and any other information to be provided to 
344    participants. 
 
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345  1.2  Composition, Functions and Operations 
346  1.2.1  The IRB/IEC should consist of a reasonable number of members who collectively 
347    have the qualifications and experience to review and evaluate the science, medical 
348    aspects and ethics of the proposed trial. It is recommended that the IRB/IEC should 
349    include: 
  350   
351    (a)  at least five members; 
  352   
353    (b)  at least one member whose primary area of interest is not in medical sciences; 
  354   
355    (c)  at least one member who is independent of the institution/investigator site. 
  356   
357    Only those IRB/IEC members who are independent of the investigator and the sponsor 
358    of the trial should vote/provide an opinion. A list of IRB/IEC members and their 
359    qualifications should be maintained. 
  360   
361  1.2.2  The  IRB/IEC  should  perform  its  functions  according  to  documented  operating 
362    procedures, should maintain records of its activities and minutes of its meetings, and 
363    should comply with GCP and with the applicable regulatory requirement(s). 
  364   
365  1.2.3  An IRB/IEC should make its decisions at announced meetings at which at least a 
366    quorum, as stipulated in its documented operating procedures, is present. 
  367   
368  1.2.4  Only  members  who  participate  in  the  IRB/IEC  review  and  discussion  should 
369    vote/provide their opinion and/or advise. 
  370   
371  1.2.5  The  investigator,  investigator  site  staff  and/or  sponsor,  where  appropriate,  may 
372    provide information on any aspect of the trial but should not participate in the decision 
373    making of the IRB/IEC or in the vote/opinion of the IRB/IEC. 
  374   
375  1.2.6  An IRB/IEC may invite non-members with expertise in special areas for assistance. 
376  1.3  Procedures 
 
377  The IRB/IEC should establish, document in writing or electronically, and follow its procedures, 
378  which should include: 
 
379  1.3.1  Determining its composition (names and qualifications of the members) and the 
380    authority under which it is established; 
381     
382  1.3.2  Scheduling, notifying its members of and conducting its meetings; 
383     
384  1.3.3  Conducting initial and continuing review of trials; 
385     
386  1.3.4  Determining the frequency of continuing review, as appropriate; 
387     
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388  1.3.5  Providing, according to the applicable regulatory requirements, expedited review and 
389    approval/favourable  opinion  of  minor  change(s)  in  ongoing  trials  that  have  the 
390    approval/favourable opinion of the IRB/IEC; 
  391   
392  1.3.6  Specifying that no participant should be admitted to a trial before the IRB/IEC issues 
393    its documented approval/favourable opinion of the trial; 
  394   
395  1.3.7  Specifying that no deviations from the protocol should be initiated without prior 
396    documented  IRB/IEC  approval/favourable  opinion,  except  when  necessary  to 
397    eliminate immediate hazards to the participants; 
  398   
399  1.3.8  Specifying that the investigator/institution should promptly report to the IRB/IEC (see 
400    section 1.5): 
  401   
402    (a)  deviations from the protocol to eliminate immediate hazards to the trial 
403    participants (see sections 1.3.7, 2.5.3 and 2.5.4); 
  404   
405    (b)  changes increasing the risk to participants and/or significantly affecting the 
406    conduct of the trial (see section 2.4.6); 
  407   
408    (c)  all suspected unexpected serious adverse reactions (SUSARs) in line with 
409    applicable regulatory requirements; 
  410   
411    (d)  new information that may affect adversely the safety of the participants or the 
412    conduct of the trial. 
  413   
414  1.3.9  Ensuring  that  the  IRB/IEC  (see  section  1.5)  promptly  notifies  in  writing  or 
415    electronically the investigator/institution or sponsor concerning: 
  416   
417    (a)  its trial-related decisions/opinions; 
  418   
419    (b)  the reasons for its decisions/opinions; 
  420   
421    (c)  procedures for appeal of its decisions/opinions. 
422  1.4  Records 
423  1.4.1  The IRB/IEC should retain all relevant records (e.g., documented procedures, 
424    membership lists, lists of occupations/affiliations of members, submitted documents, 
425    minutes of meetings and correspondence) in accordance with applicable regulatory 
426    requirements and make them available upon request from the regulatory 
427    authority(ies). 
  428   
429  1.4.2  The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to 
430    provide its documented procedures and membership lists. 
 
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431  1.5  Submission and Communication 
432  For the submission to or communication with the IRB/IEC, it is recognised that in most regions, 
433  there is also a requirement to make a submission to the relevant regulatory authority, and these 
434  may be combined, in line with applicable regulatory requirements, in a single submission in 
435  some regions. In addition, applicable regulatory requirements may require that submissions to 
436  the IRB/IEC are made in some regions by the investigator/institution and in others by the 
437  sponsor. 
438 
439  2.  INVESTIGATOR 
440  2.1  Qualifications and Training 
441  2.1.1  The investigator(s) should be qualified by education, training and experience to 
442  assume responsibility for the proper conduct of the trial and should provide evidence 
443  of such qualifications. 
444 
445  2.1.2  The investigator should be familiar with the appropriate use of the investigational 
446  product(s) as described in the protocol, in the current Investigators Brochure, in the 
447  product information and/or in other information sources provided by the sponsor. 
448  2.2  Resources 
449  2.2.1  The investigator should be able to demonstrate (e.g., based on retrospective  or 
450  currently available data) a potential for recruiting the proposed number of eligible 
451  participants within the recruitment period as agreed with the sponsor. 
452 
453  2.2.2  The investigator should have sufficient time, an adequate number of available and 
454  qualified staff, and adequate facilities for the foreseen duration of the trial to conduct 
455  the trial properly and safely. 
456  2.3  Responsibilities 
457  2.3.1  The investigator may delegate trial-specific activities to other persons or parties. 
458  The investigator may be supported by the sponsor to identify a suitable service 
459  provider(s); however, the investigator retains the final decision on whether the service 
460  provider intended to support the investigator is appropriate based on information 
461  provided by the sponsor (see section 3.6.6). 
462  The  investigator  retains  the  ultimate  responsibility  and  maintains  appropriate 
463  supervision of the persons or parties undertaking the activities delegated to ensure the 
464  rights, safety and well-being of the trial participants and data reliability. 
465 
466  2.3.2  The investigator should ensure that persons or parties to whom the investigator has 
467  delegated trial-specific activities are appropriately qualified and supervised and are 
468  adequately informed about the protocol, the investigational product(s) and their 
469  assigned trial activities (including activities conducted by staff provided by other 
470  parties, for example, home nurses arranged by the sponsor). Trial-related training to 
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471  persons assisting in the trial should correspond to what is necessary to enable them to 
472  fulfil their delegated trial activities that go beyond their usual training and experience. 
473 
474  2.3.3  The investigator should ensure a record is maintained of the persons and parties to 
475  whom the investigator has delegated significant trial-related activities. In situations 
476  where the clinical trial activities are performed in accordance with routine clinical 
477  care, delegation documentation may not be required. 
478 
479  2.3.4  Agreements made by the investigator/institution with service providers for trial- 
480  related activities should be documented. 
481 
482  2.3.5  The investigator/institution should permit monitoring and auditing by the sponsor and 
483  inspection by the appropriate regulatory authority(ies). 
484  2.4  Communication with IRB/IEC 
485  2.4.1  Submission to the IRB/IEC may be made by the investigator/institution or sponsor in 
486  accordance with applicable regulatory requirements (see section 1.5). 
487 
488  2.4.2  Before initiating a trial, the investigator/institution should have a documented and 
489  dated approval/favourable opinion from the IRB/IEC for the trial protocol, informed 
490  consent material, participant recruitment procedures (e.g., advertisements) and any 
491  other information to be provided to participants. 
492 
493  2.4.3  As part of the investigators/institutions or sponsors (in accordance with applicable 
494  regulatory  requirements)  submission  to  the  IRB/IEC,  a  current  copy  of  the 
495  Investigators Brochure or basic product information brochure should be provided 
496  (see section A.1.1 of Appendix A. Investigators Brochure). If the Investigators 
497  Brochure is updated during the trial, the IRB/IEC should receive the current version 
498  in accordance with applicable regulatory requirements. 
499 
500  2.4.4  As the trial progresses, the investigator/institution or sponsor should provide any 
501  updates  to  the  participant  information  according  to  applicable  regulatory 
502  requirements. 
503 
504  2.4.5  The investigator or the sponsor should submit documented summaries of the trial 
505  status to the IRB/IEC in accordance with local regulatory requirements or upon 
506  request. 
507 
508  2.4.6  The investigator or the sponsor should promptly communicate to the IRB/IEC (see 
509  section 1.3.8) and, where applicable, the institution about any changes significantly 
510  affecting the conduct of the trial and/or increasing the risk to participants. 
511  2.5  Compliance with Protocol 
512  2.5.1  The investigator should comply with the protocol and GCP and applicable regulatory 
513  requirements. The investigator/institution should sign the protocol or an alternative 
514  contract to confirm agreement with the sponsor. 
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515  2.5.2  The investigator should document all protocol deviations and review deviations 
516    communicated to them by the sponsor. For important deviations, the investigator 
517    should  explain  the  deviation  and  implement  appropriate  measures  to  prevent  a 
518    recurrence, where applicable, see section 3.9.3. 
  519   
520  2.5.3  The investigator should follow the protocol and deviate only where necessary to 
521    eliminate an immediate hazard(s) to trial participants. In case of deviations undertaken 
522    to eliminate immediate hazard to trial participants, the investigator should inform the 
523    sponsor, IRB/IEC and/or regulatory authorities promptly. 
  524   
525  2.5.4  The investigator should report information on the immediate hazard, the implemented 
526    change and the subsequent proposed protocol amendment to the IRB/IEC and/or 
527    regulatory authorities. 
528  2.6  Premature Termination or Suspension of a Trial 
529  2.6.1  If  the  trial  is  prematurely  terminated  or  suspended  for  any  reason,  the 
530    investigator/institution should promptly inform the trial participants and should assure 
531    appropriate therapy and follow-up for the participants. 
  532   
533  2.6.2  Where the investigator terminates or suspends their involvement in a trial without 
534    prior agreement by the sponsor, the investigator should promptly inform the sponsor, 
535    the IRB/IEC and the regulatory authorities in accordance with applicable regulatory 
536    requirements and should provide a detailed explanation of the reasons. 
  537   
538  2.6.3  If  the sponsor  terminates  or  suspends  a  trial,  the  investigator/institution,  or  the 
539    sponsor, in accordance with applicable regulatory requirement(s), should promptly 
540    inform the IRB/IEC and the regulatory authorities. See section 3.17.1. 
  541   
542  2.6.4  If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 
543    sections  1.1.3  and  1.3.9),  the  investigator  should  inform  the  institution,  where 
544    applicable, and the investigator/institution should promptly notify the sponsor. 
545  2.7  Participant Medical Care and Safety Reporting 
546  2.7.1  Medical Care of Trial Participants 
 
547  (a)  A qualified physician or, where appropriate, a qualified dentist (or other 
548    qualified  healthcare  professionals  in  accordance  with  local  regulatory 
549    requirements) who is an investigator or a sub-investigator for the trial should 
550    have the overall responsibility for trial-related medical care and decisions. 
  551   
552    (b)  Other appropriately qualified healthcare professionals may be involved in the 
553    medical care of trial participants, in line with their normal activities and in 
554    accordance with local regulatory requirements. 
  555   
556    (c)  During and following participation in a trial, the investigator/institution should 
557    ensure that adequate medical care is provided to a participant for any adverse 
558    events, including clinically significant laboratory values, related to the trial. 
 
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559  The investigator/institution should inform a participant when medical care is 
560  needed for intercurrent illness(es) of which the investigator becomes aware. 
561 
562  (d)  The investigator should inform the participants primary physician about the 
563  participants involvement in the trial if the participant has a primary physician 
564  and agrees to the primary physician being informed. 
565  2.7.2  Safety Reporting 
566  (a)  Adverse events and/or laboratory abnormalities required for safety evaluations 
567  (as outlined in the protocol) should be reported to the sponsor according to the 
568  reporting requirements and within the time periods specified in the protocol. 
569 
570  (b)  All serious adverse events (SAEs) should be reported immediately (after the 
571  investigator  reasonably  becomes  aware  of  the  event)  to  the  sponsor.  In 
572  accordance with applicable regulatory requirements, the protocol may identify 
573  SAEs not requiring immediate reporting, for example, deaths or other events 
574  that are endpoints. Subsequent information should be submitted as a follow- 
575  up report, as necessary. 
576 
577  (c)  For reported deaths, the investigator should supply the sponsor, the IRB/IEC 
578  and, where applicable, the regulatory authority with any additional requested 
579  information (e.g., autopsy reports and terminal medical reports) when they 
580  become available. 
581 
582  (d)  The investigator may delegate  activities for safety reporting to qualified 
583  investigator  site  staff  but  retains  the  overall  responsibility  for  safety  of 
584  participants  under their  responsibility and  compliance  with  the reporting 
585  requirements. 
586  2.8  Informed Consent of Trial Participants 
587  2.8.1  In obtaining and documenting informed consent (paper or electronic format), the 
588  investigator should comply with the applicable regulatory requirement(s) and should 
589  adhere to GCP and to the ethical principles that have their origin in the Declaration of 
590  Helsinki. See the glossary term informed consent. The informed consent process 
591  should include the following: 
592 
593  (a)  Prior to consenting and enrolling participants, the investigator should have the 
594  IRB/IECs documented approval/favourable opinion of the informed consent 
595  materials and process; 
596 
597  (b)  The information should be  as clear  and concise as possible, use simple 
598  language and avoid unnecessary volume and complexity. This is to ensure that 
599  the  trial  participants  or  their  legally  acceptable  representatives  have  an 
600  adequate understanding of the objectives of the trial, alternative treatments, 
601  the potential benefits and risks, burdens and their rights and obligations to be 
602  able to make an informed decision as to their participation in the trial; 
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603    (c)  Varied approaches (e.g., text, images, videos and other interactive methods) may 
604  be used in the informed consent process including for providing information 
605  to  the participant. Obtaining consent  remotely may be considered  where 
606  appropriate. 
  607 
608  2.8.2  The  participant  or  the  participants  legally  acceptable  representative  should  be 
609    informed in a timely manner if new information becomes available that may be 
610    relevant  to  the  participants  willingness  to  continue  trial  participation.  The 
611    communication of this information and confirmation of the willingness to continue 
612    trial participation should be documented. 
  613   
614    New  information  that  could  impact  a  participants  willingness  to  continue 
615    participation should be assessed to determine if re-consent is needed (e.g., depending 
616    on the stage of the trial, consideration should be given to whether the new information 
617    is relevant only to new participants or to existing participants). If re-consent is needed 
618    (e.g., information on emerging safety concerns), new information should be clearly 
619    identified  in  the  revised  informed  consent  materials.  Revised  informed  consent 
620    materials should receive the IRB/IECs approval/favourable opinion in advance of 
621    use. 
  622   
623  2.8.3  Neither  the  investigator  nor  the  investigator  site  staff  should  coerce  or  unduly 
624    influence a participant to participate or to continue their participation in the trial. 
  625   
626  2.8.4  None of the information provided to the participant during the informed consent 
627    process should contain any language that causes the participant or the participants 
628    legally acceptable representative to waive or to appear to waive any legal rights, or 
629    that releases or appears to release the investigator, the institution, the sponsor or their 
630    service providers from liability for negligence. 
  631   
632  2.8.5  The informed consent process should be conducted by the investigator or other 
633    investigator site staff delegated by the investigator, in accordance with applicable 
634    regulatory requirements. If the participant is unable to provide consent themselves, 
635    the participants legally acceptable representative should provide their consent on 
636    behalf of the participant. 
  637   
638  2.8.6  The information provided during the informed consent process and translations should 
639    be  relevant,  clear,  simple,  concise  and  understandable  to  the  participant  or  the 
640    participants  legally  acceptable  representative  and  the  impartial  witness,  where 
641    applicable. 
  642   
643  2.8.7  Before informed consent may be obtained, the investigator or investigator site staff 
644    delegated by the investigator, in accordance with the protocol and conditions of 
645    IRB/IEC  favourable  opinions/approvals,  should  provide  the  participant  or  the 
646    participants legally acceptable representative ample time unless justified (e.g., in an 
647    emergency situation) and opportunity to enquire about trial details and to decide 
648    whether or not to participate in the trial. Questions about the trial should be answered 
 
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649    to  the  satisfaction  of  the  participant  or  the  participants  legally  acceptable 
650    representative. 
  651   
652  2.8.8  Prior to trial participation, the informed consent form should be signed and dated by 
653    the participant or by the participants legally acceptable representative and, where 
654    appropriate, impartial witness and by the investigator or delegated investigator site 
655    staff who conducted the informed consent discussion. The informed consent process 
656    may involve a physical signature or an electronic signature. 
  657   
658  2.8.9  In emergency situations, when prior consent of the participant is not possible, the 
659    consent of the participants legally acceptable representative, if present, should be 
660    requested. When prior consent of the participant is not possible and the participants 
661    legally acceptable representative is not available, enrolment of the participant should 
662    require  measures  described  in  the  protocol  and/or  elsewhere,  with  documented 
663    approval/favourable opinion by the IRB/IEC, to protect the participants rights, safety 
664    and well-being and to ensure compliance with applicable regulatory requirements. 
665    The  participant  or  the  participants  legally  acceptable  representative  should  be 
666    informed about the trial as soon as possible, and consent as appropriate (see section 
667    2.8.10) should be requested. 
  668   
669  2.8.10  If a participant or the legally acceptable representative is unable to read, an impartial 
670    witness should be present (remotely or in-person) during the entire informed consent 
671    discussion. After the informed consent form and any other information is read and 
672    explained to the participant or the participants legally acceptable representative and 
673    they have orally consented to the participants trial participation and, if capable of 
674    doing so, have signed and personally dated the informed consent form, the witness 
675    should contemporaneously sign and personally date the consent form. By signing the 
676    consent  form,  the  witness  attests  that  the  consent  information  was  accurately 
677    explained to and apparently understood by the participant or the participants legally 
678    acceptable  representative  and  that  informed  consent  was  freely  given  by  the 
679    participant or the participants legally acceptable representative. 
  680   
681  2.8.11  The informed consent discussion and the informed consent materials to be provided 
682    to participants should explain the following as applicable: 
  683   
684    (a)  the purpose of the trial; 
  685   
686    (b)  that the trial involves research and summary of the experimental aspects of the 
687    trial; 
  688   
689    (c)  the  trials  investigational  product(s)  and  the  probability  for  random 
690    assignment to the investigational product, if applicable; 
  691   
692    (d)  the trial procedures to be followed including all invasive procedures; 
  693   
694    (e)  the participants obligations; 
 
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695  (f)  the reasonably foreseeable risks or inconveniences to the participant and, when 
696  applicable, the participants partner, to an embryo, foetus or nursing infant; 
697 
698  (g)  the reasonably expected benefits. When there is no intended clinical benefit to 
699  the participant, the participant should be made aware of this; 
700 
701  (h)  the alternative procedure(s) or course(s) of treatment that may be available to 
702  the participant and their important potential benefits and risks; 
703 
704  (i)  the compensation and/or treatment available to the participant in the event of 
705  trial-related injury; 
706 
707  (j)  any anticipated prorated compensation to the participant for trial participation; 
708 
709  (k)  any anticipated expenses to the participant for trial participation; 
710 
711  (l)  that the participants trial participation is voluntary, and the participant may 
712  refuse to participate or may withdraw, at any time, without penalty or loss of 
713  benefits to which the participant is otherwise entitled; 
714 
715  (m)  the process by which the participants data will be handled, including in the 
716  event  of  the  withdrawal  of participation  in accordance  with  regulatory 
717  requirements; 
718 
719  (n)  that by agreeing to participate in the trial, the participant or their legally 
720  acceptable representative allows direct access to original medical records, per 
721  applicable regulatory requirements, while safeguarding the confidentiality of 
722  the participant. This access is limited for the purpose of reviewing trial 
723  activities and/or reviewing or verifying data and records by the IRB/IEC(s), 
724  regulatory  authority(ies)  and  the  sponsors  representatives,  for  example, 
725  monitor(s) or auditor(s); 
726 
727  (o)  that records identifying the participant will be kept confidential and, to the 
728  extent permitted by the applicable regulatory requirements, will not be made 
729  publicly available. If the trial results are published, the participants identity 
730  will remain confidential. The trial may be registered on publicly accessible 
731  and recognised databases, per applicable regulatory requirements; 
732 
733  (p)  that the participant or the participants legally acceptable representative will 
734  be informed in a timely manner if information becomes available that may be 
735  relevant to the participants willingness to continue trial participation; 
736 
737  (q)  the person(s) to contact for further trial information and the trial participants 
738  rights, and whom to contact in the event of suspected trial-related injury; 
739 
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740  (r)  the foreseeable circumstances and/or reasons under which the participants 
741  trial participation may be terminated; 
742 
743  (s)  the expected duration of the participants trial participation; 
744 
745  (t)  the approximate number of participants involved in the trial; 
746 
747  (u)  that trial results and information on the participants actual treatment, if 
748  appropriate, will be made available to them should they desire it. 
749 
750  2.8.12  Prior  to  participation,  the  participant  or  the  participants  legally  acceptable 
751  representative should receive a copy (paper or electronic) of the signed informed 
752  consent form and any other informed consent materials provided to the participants, 
753  or in accordance with applicable regulatory requirements. During trial participation, 
754  the participant or the participants legally acceptable representative should receive a 
755  copy of the consent form updates and any other updated informed consent materials 
756  provided to participants. 
757 
758  2.8.13  Where a minor is to be included as a participant, age-appropriate assent information 
759  should be provided and discussed with the minor as part of the consent process, and 
760  assent from the minor to enrol in the trial should be obtained as appropriate. A process 
761  for re-consent should be considered if, during the course of the trial, the minor reaches 
762  the age of legal consent, in accordance with applicable regulatory requirements. 
763 
764  2.8.14  When a clinical trial includes participants who may only be enrolled in the trial with 
765  the consent of the participants legally acceptable representative (e.g., minors, patients 
766  with severe impaired decision-making capacity), the participant should be informed 
767  about the trial to the extent compatible with the participants understanding and, if 
768  capable, the participant should sign and personally date the informed consent form or 
769  assent form as appropriate. 
770 
771  2.8.15  In  exceptional  circumstances  (e.g.,  public  health  emergencies),  when  the  usual 
772  methods to obtain and document informed consent are not possible, the use of 
773  alternative  measures  and  technologies  in  accordance  with  local  IRBs/IECs  and 
774  applicable regulatory requirements should be considered. 
775  2.9  End of Participation in a Clinical Trial 
776  2.9.1  When a participant decides to stop treatment with the investigational product, stop 
777  trial visits or completely withdraw from a trial; is discontinued from the trial; or 
778  reaches routine end of trial, the investigator should follow the protocol and other 
779  sponsor instructions to determine appropriate follow-up measures. This may include 
780  instructions to avoid unnecessary loss of already collected critical data in accordance 
781  with applicable regulatory requirements. 
782 
783  2.9.2  Although  a  participant  is  not  obliged  to  provide  a  reason(s)  for  withdrawing 
784  prematurely from a trial, the investigator should make a reasonable effort to ascertain 
  18   
ICH E6(R3) Guideline 
 
785  the reason(s), while fully respecting the participants rights. The investigator should 
786  consider  discussing  with  the  participant  or  the  participants  legally  acceptable 
787  representative the reasons for withdrawal to determine if there are ways to address the 
788  concerns. The investigator site staff should make an effort to explain to the participant 
789  the  value  and  importance  of  continuing  their  participation  to  minimise  trial 
790  participants withdrawal. 
791 
792  2.9.3  Where relevant, the investigator should inform the participant about the trial results 
793  and treatment received when this information is available from the sponsor after 
794  unblinding, with due respect to the participants preference to be informed. 
795  2.10  Investigational Product Management 
796  2.10.1  Responsibility  for  investigational  product(s)  accountability  rests  with  the 
797  investigator/institution. The sponsor may facilitate this process. 
798 
799  2.10.2  When  the  investigator/institution  assigns  some  or  all  of  their  activities  for 
800  investigational product(s) accountability to a pharmacist or another individual, they 
801  should be under the supervision of the investigator/institution. 
802 
803  2.10.3  The investigator/institution and/or a pharmacist or other appropriate individual should 
804  maintain records of the products delivery, the inventory, the use by each participant 
805  (including documenting that the participants were provided the doses specified by the 
806  protocol) and the return to the sponsor and destruction or alternative disposition of 
807  unused product(s).  These records should include dates, quantities, batch/serial 
808  numbers, expiration dates (if applicable) and the unique code numbers assigned to the 
809  investigational product(s) and trial participants. For authorised medicinal products, 
810  alternative approaches to the aforementioned may be considered, in accordance with 
811  local regulatory requirements. 
812 
813  2.10.4  The investigational product(s) should be stored as specified by the sponsor and in 
814  accordance with applicable regulatory requirement(s). 
815 
816  2.10.5  The investigator should ensure that the investigational product(s) are used only in 
817  accordance with the approved protocol. 
818 
819  2.10.6  Where  applicable,  the  investigator  or  a  person  designated  by  the 
820  investigator/institution should explain the correct use of the investigational product(s) 
821  to each participant and should check, at intervals appropriate for the trial, that each 
822  participant is following the instructions properly. 
823  2.11  Randomisation Procedures and Unblinding 
824  The investigator should follow the trials randomisation procedures, if any, and, in the case of 
825  an investigator-blinded trial, should ensure that the identification code is broken only in 
826  accordance with the protocol. In the case of an emergency, to protect patient safety, the 
827  investigator should be prepared and capable from the start of the trial to perform unblinding 
828  without undue delay and hinderance. The investigator should promptly document and explain 
  19   
ICH E6(R3) Guideline 
 
829  to the sponsor any premature unblinding (e.g., accidental unblinding, emergency unblinding to 
830  protect trial participant, unblinding due to an SAE) of the investigational product(s). 
831  2.12  Records 
832  2.12.1  In generating, recording and reporting trial data, the investigator should ensure the 
833  integrity of data under their responsibility, irrespective of the media used. 
834 
835  2.12.2  The investigator/institution should maintain adequate source records that include 
836  pertinent observations on each of the trial participants under their responsibility. 
837  Source records should be attributable, legible, contemporaneous, original, accurate 
838  and complete. Changes to source records should be traceable, should not obscure the 
839  original entry  and should be explained if necessary  (via an audit trail). The 
840  investigator should define what is considered to be a source record(s), the methods of 
841  data capture and their location prior to starting the trial and should update this 
842  definition when needed. Unnecessary transcription steps in between the source record 
843  and the data acquisition tool should be avoided. 
844 
845  2.12.3  The investigator should have timely access to and be responsible for the timely review 
846  of data, including relevant data from external sources (e.g., central laboratory data, 
847  centrally read imaging data, other institutions records and, if appropriate, electronic 
848  patient-reported outcome (ePRO) data) which can have an impact on, for example, 
849  participant eligibility, treatment or safety. The protocol may provide exceptions for 
850  access, for instance, to protect blinding. 
851 
852  2.12.4  The investigator should ensure that data acquisition tools and other systems deployed 
853  by the sponsor for clinical trial purposes are used as specified in the protocol or trial- 
854  related instructions. 
855 
856  2.12.5  The investigator should ensure the accuracy, completeness, legibility and timeliness 
857  of the data reported to the sponsor in the data acquisition tools completed by the 
858  investigator site (e.g., case report form (CRF)) and in all required reports. The 
859  investigator should review and endorse the reported data at milestones agreed upon 
860  with the sponsor (e.g., interim analysis). 
861 
862  2.12.6  Data reported to the sponsor should be consistent with the source records or the 
863  discrepancies  explained.  Changes  or  corrections  in  the  reported  data  should  be 
864  traceable, should be explained (if necessary) and should not obscure the original entry. 
865 
866  2.12.7  The investigator/institution should implement appropriate measures to protect the 
867  privacy and confidentiality of personal information of trial participants in accordance 
868  with applicable regulatory requirements on personal data protection. Data reported to 
869  the sponsor should be identified by an unambiguous participant code that can be traced 
870  back to the identity of the participant by the investigator/institution. 
871 
872  2.12.8  For systems deployed by the investigator/institution that maintain and retain trial 
873  data/information,  the  investigator/institution  should  ensure  that  such  data  are 
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ICH E6(R3) Guideline 
 
874    protected from unauthorised access, disclosure, dissemination or alteration and from 
875  inappropriate destruction or accidental loss. 
  876 
877  2.12.9  When using computerised systems in a clinical trial, the investigator/institution should 
878    do the following: 
  879   
880    (a)  for systems deployed by the investigator/institution, ensure that appropriate 
881    individuals have secure and attributable access; 
  882   
883    (b)  for  systems  deployed  by  the  investigator/institution  specifically  for  the 
884    purposes of clinical trials, ensure that the requirements for computerised 
885    systems in section 4 are addressed; 
  886   
887    (c)  where equipment for data acquisition is provided to trial participants by the 
888    investigator,  ensure  that  traceability  is  maintained  and  participants  are 
889    provided with appropriate training; 
  890   
891    (d)  ensure that incidents in the use and operation of computerised systems, which 
892    in their judgement may have a significant and/or persistent impact on the trial 
893    data, are reported to the sponsor and, where applicable, to the IRB/IEC. 
  894   
895  2.12.10  The investigator/institution should maintain the trial records as specified in Appendix 
896    C. Essential Records for the Conduct of a Clinical Trial and as required by the 
897    applicable regulatory requirement(s). The investigator/institution should have control 
898    of all essential records generated by the investigator/institution before, during and 
899    after the trial. The investigator/institution should take measures to prevent accidental 
900    or premature destruction of these records. If the investigator closes a site or leaves a 
901    site during or after the end of the clinical trial, the sponsor should be notified of the 
902    appropriate individual responsible for retention of the sites essential records. 
  903   
904  2.12.11  The  investigator/institution  should  retain  the  essential  records  for  the  required 
905    retention period in accordance with applicable regulatory requirements or until the 
906    sponsor informs the investigator/institution that these records are no longer needed, 
907    whichever is the longer (see Appendix C). 
  908   
909  2.12.12  Upon  request  of  the  monitor,  auditor,  IRB/IEC  or  regulatory  authority,  the 
910    investigator/institution should make available for direct access all requested trial- 
911    related records. 
912  2.13  Clinical Trial/Study Reports 
913  2.13.1  Upon completion of the trial, the investigator, where applicable, should inform the 
914    institution. The investigator/institution should provide the IRB/IEC with a summary 
915    of the trials outcome and, if applicable, the regulatory authority(ies) with any required 
916    reports. 
917   
 
  21   
ICH E6(R3) Guideline 
 
918  2.13.2  Where a coordinating investigator is involved in a trial, consideration should be given 
919  to them being a signatory on the clinical trial report; see ICH E3 Structure and Content 
920  of Clinical Study Reports. 
 
921 
922  3.  SPONSOR 
923  The responsibility of the sponsor entails the implementation of risk-proportionate processes to 
924  ensure the safety of the trial participants and the reliability of the trial results throughout the 
925  clinical trial life cycle. 
926  3.1  Trial Design 
927  3.1.1  When planning trials, the sponsor should ensure that sufficient safety and efficacy 
928  data from nonclinical studies and/or clinical trials and/or real-world data are available 
929  to support human exposure by the route, at the dosages, for the duration and in the 
930  trial population to be studied. 
931 
932  3.1.2  Sponsors should incorporate quality into the design of the clinical trial by identifying 
933  factors that are critical to the quality of the trial and by managing risks to those factors. 
934 
935  3.1.3  Sponsors should consider inputs from a wide variety of stakeholders, for example, 
936  healthcare professionals and patients, to support the development plan and clinical 
937  trial protocols as described in ICH E8(R1) and when developing the informed consent 
938  material and any other participant-facing information. 
939 
940  3.1.4  The sponsor should ensure that all aspects of the trial are operationally feasible and 
941  should avoid unnecessary complexity, procedures and data collection. Protocols, data 
942  acquisition tools and other operational documents should be fit for purpose, clear, 
943  concise and consistent, when applicable. 
944  3.2  Resources 
945  The sponsor should ensure that sufficient resources are available to appropriately conduct the 
946  trial. 
947  3.3  Allocation of Activities 
948  Prior to initiating clinical trial activities, the sponsor should determine the roles and allocate 
949  trial-related activities accordingly. 
950  3.4  Qualification and Training 
951  The sponsor should utilise appropriately qualified individuals for the activities to which they 
952  are assigned (e.g., biostatisticians, clinical pharmacologists, physicians, data scientists/data 
953  managers, auditors and monitors) throughout the trial process. 
954  3.4.1  Medical Expertise 
955  The sponsor should have medical personnel readily available who will be able to 
956  advise on specific trial-related medical questions or problems. 
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ICH E6(R3) Guideline 
 
957  3.5  Financing 
958  The financial aspects of the trial should be documented in an agreement between the sponsor 
959  and the investigator/institution. 
960  3.6  Agreements 
961  3.6.1  Agreements made by the sponsor with the investigator/institution, service providers 
962  and  any  other  parties  (e.g.,  independent  data  monitoring  committee  (IDMC), 
963  adjudication committee) involved with the clinical trial should be documented prior 
964  to initiating the activities. 
965   
966  3.6.2  Agreements should be updated when necessary to reflect significant changes in the 
967  activities delegated. 
968   
969  3.6.3  The sponsor should obtain the investigators/institutions and, where applicable, 
970  service providers agreement: 
971   
972  (a)  to  conduct  the  trial  in  accordance  with  the  approved  protocol  and  in 
973  compliance with GCP and applicable regulatory requirement(s); 
974   
975  (b)  to comply with procedures for data recording/reporting; 
976   
977  (c)  to retain the trial-related essential records for the required retention period in 
978  accordance  with  applicable  regulatory  requirements  or  until  the  sponsor 
979  informs the investigator/institution or, where applicable, the service provider, 
980  that these documents are no longer needed, whichever is longer; 
981   
982  (d)  to permit monitoring, auditing and inspections by sponsors, IRB/IECs and 
983  regulatory authorities (domestic and foreign) including providing direct access 
984  to source records and facilities, including to those of service providers. 
985   
986  3.6.4  The  responsibilities  of  coordinating  investigator(s)  and  the  other  participating 
987  investigators should be documented prior to the start of the trial. 
988   
989  3.6.5  Any of the sponsors trial-related activities that are transferred to and assumed by a 
990  service provider should be documented in an agreement. The sponsors trial-related 
991  activities that are not specifically transferred to and assumed by a service provider are 
992  retained by the sponsor. 
993   
994  3.6.6  The sponsor should provide information to the investigator on any service provider 
995  identified by the sponsor to undertake any activities under the responsibility of the 
996  investigator. The responsibility for such activities remains with the investigator. 
997   
998  3.6.7  A sponsor may transfer any or all of the sponsors trial-related activities to a service 
999  provider; however, the ultimate responsibility for the sponsors trial-related activities, 
1000  including protection of participants rights, safety and well-being and reliability of the 
1001  trial data, resides with the sponsor. Any service provider used for clinical trial 
  23   
ICH E6(R3) Guideline 
 
 
1002    activities should implement appropriate quality management and report to the sponsor 
1003    any incidents that might have an impact on the safety of trial participants or/and trial 
1004    results. 
1005     
1006  3.6.8  The sponsor is responsible for assessing the suitability of and selecting the service 
1007    provider to ensure that they can adequately undertake the activities transferred to 
1008    them. The sponsor should provide the service providers with the protocol where 
1009    necessary as well as any other documents required for them to perform their activities. 
1010     
1011  3.6.9  The sponsor should have access to relevant information (e.g., SOPs and performance 
1012    metrics) for selection and oversight of service providers. 
1013     
1014  3.6.10  The sponsor should ensure appropriate oversight of important trial-related activities 
1015    that are transferred to service providers and further subcontracted. 
1016     
1017  3.6.11  Trial-related  activities  performed  by  service  providers  should  be  conducted  in 
1018    accordance with relevant GCP requirements, which may be fulfilled by a service 
1019    providers existing processes. 
1020     
1021  3.6.12  A clinical trial may have one or several sponsors where permitted under applicable 
1022    regulatory requirements. In trials with more than one sponsor, the sponsors should 
1023    have  a  documented  agreement  that  sets  out  their  respective  responsibilities,  in 
1024    accordance with local regulatory requirements and/or practice. Where the documented 
1025    agreement does not specify to which sponsor a given responsibility is attributed, that 
1026    responsibility lies with all sponsors. 
1027  3.7  Investigator Selection 
1028  3.7.1  The  sponsor  is responsible  for  selecting  the  investigator(s)/institution(s).  Each 
1029    investigator should be qualified by education, training and experience and should 
1030    demonstrate they have adequate resources and facilities to properly conduct the trial. 
1031    If organisation of a coordinating committee and/or selection of coordinating 
1032    investigator(s)  are  to  be  utilised  in  multicentre  trials,  their  organisation  and/or 
1033    selection are the sponsors responsibility, and their roles should be documented prior 
1034    to their involvement in the trial. 
1035     
1036  3.7.2  The sponsor should provide the investigator(s)/institution(s) with the protocol and an 
1037    up-to-date Investigators Brochure as well as sufficient time for the review of the 
1038    protocol and the information provided. 
1039  3.8  Communication with IRB/IEC and Regulatory Authority(ies) 
1040  3.8.1  Notification/Submission to Regulatory Authority(ies) 
 
1041  In accordance with applicable regulatory requirement(s), before initiating the clinical 
1042    trial(s), the sponsor (or the sponsor and the investigator) should submit any required 
1043    application(s) to the appropriate regulatory authority(ies) for review, acceptance 
1044    and/or permission to begin the trial(s). Any notification/submission should be dated 
1045    and contain sufficient information to identify the protocol. 
  24   
ICH E6(R3) Guideline 
 
 
1046  3.8.2  Confirmation of Review by IRB/IEC 
1047  (a)  Where reference is made to a submission to the IRB/IEC, this can be made by 
1048  the investigator/institution or sponsor in accordance with applicable regulatory 
1049  requirements (see section 1.5). 
1050   
1051  (b)  The sponsor should ensure that the following is obtained: 
1052   
1053  (i)  The name and address of the relevant IRB/IEC along with: 
1054   
1055  (aa)  a statement that it is organised and operates according to GCP 
1056  and the applicable regulatory requirements; 
1057   
1058  (bb)  documented  initial  and  subsequent  IRB/IEC 
1059      approval/favourable opinion as well as any termination of the 
1060      trial or the suspension of approval/favourable opinion. 
 
1061  3.9  Sponsor Oversight 
1062  3.9.1  The sponsor should  ensure that the trial design and trial conduct, the processes 
1063  undertaken, and the information and data generated are of sufficient quality to ensure 
1064  reliable trial results, trial participants safety and appropriate decision making. 
1065   
1066  3.9.2  The sponsor should ensure that trial processes are conducted in compliance with the 
1067  trial  protocol  and  related  documents  as  well  as  with  applicable  regulatory 
1068  requirements and ethical standards. 
1069   
1070  3.9.3  The sponsor should determine necessary trial-specific criteria for classifying protocol 
1071  deviations as important (i.e., those that impact the rights, safety and well-being of trial 
1072  participants and the reliability of results). 
1073   
1074  3.9.4  Decisions related to the trial should be appropriately assessed for their impact on 
1075  participants rights, safety and well-being and the reliability of trial results. Risks 
1076  related to such decisions should be suitably managed throughout the planning, conduct 
1077  and reporting of the trial. 
1078   
1079  3.9.5  The range and extent of oversight measures should be fit for purpose and tailored to 
1080  the complexity of and risks associated with the trial. The selection and oversight of 
1081  investigators and service providers are fundamental features of the oversight process. 
1082  Oversight by the sponsor includes quality assurance and quality control processes 
1083  relating to the trial-related activities of investigators and service providers. 
1084   
1085  3.9.6  The sponsor should ensure appropriate and timely escalation and follow-up of issues 
1086  to allow the implementation of appropriate actions in a timely manner. 
1087   
1088  3.9.7  The sponsor may consider establishing an IDMC to assess the progress of a clinical 
1089  trial including the safety data and the efficacy endpoints at intervals and to recommend 
1090  to the sponsor whether to continue, modify or stop a trial. 
  25   
ICH E6(R3) Guideline 
 
1091  3.9.8  Where appropriate, sponsors may also establish an endpoint assessment/adjudication 
1092  committee in certain trials to review important endpoints reported by investigators to 
1093  determine whether the endpoints meet protocol-specified criteria. Such committees 
1094  should  typically  be  blinded  to  the  assigned  treatments  when  performing  their 
1095  assessments, regardless of whether the trial itself is conducted in a blinded manner, to 
1096  ensure that the data reviewed by committee are as free of bias as possible. 
1097   
1098  3.9.9  Committees established for purposes that could impact participant safety or the 
1099  reliability of trial results should include members with relevant expertise and with 
1100  managed conflicts of interest, have written operating procedures (e.g., charters) and 
1101  document their decisions. 
1102  3.10  Quality Management 
1103  The sponsor should implement an appropriate system to manage quality throughout all stages 
1104  of the trial process. Quality management includes the design and implementation of efficient 
1105  clinical trial protocols including tools and procedures for trial conduct (including for data 
1106  collection and management) in order to support participants rights, safety and well-being and 
1107  the reliability of trial results. The sponsor should adopt a proportionate and risk-based approach 
1108  to quality management, which involves incorporating quality into the design of the clinical trial 
1109  (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact 
1110  on participants rights, safety and well-being and the reliability of the results (i.e., critical to 
1111  quality  factors  as  described  in  ICH  E8(R1)).  The  sponsor  should  describe  the  quality 
1112  management approach implemented in the trial in the clinical trial report (see ICH E3). 
1113  3.10.1  Risk Management 
1114  A proportionate approach to the identification and management of risk is described below: 
1115  3.10.1.1 Risk Identification 
1116  The sponsor should identify risks that may have a meaningful impact on critical to 
1117  quality factors. Risks should be considered across the processes used in the clinical 
1118  trial  (e.g.,  patient  selection,  informed  consent  process,  randomisation  and 
1119  investigational product administration, data handling, and service provider activities). 
1120  3.10.1.2 Risk Evaluation 
1121  The sponsor should evaluate potential risks by considering: 
1122  (a)  the likelihood of harm/hazard occurring; 
1123   
1124  (b)  the extent to which such harm/hazard would be detectable; 
1125   
1126  (c)  the  impact  of  such  harm/hazard  on  trial  participant  protection  and  the 
1127  reliability of trial results. 
1128  3.10.1.3 Risk Control 
1129  (a)  Risk  control  should  be  proportionate  to  the  importance  of  the  risk  to 
1130  participants rights, safety and well-being and the reliability of trial results. 
  26   
ICH E6(R3) Guideline 
 
 
1131    Risk mitigation activities may be incorporated in protocol design and 
1132    implementation, monitoring plans, agreements between parties defining roles 
1133    and responsibilities, systematic safeguards to ensure adherence to SOPs, and 
1134    training in processes and procedures. 
1135     
1136    (b)  The sponsor should set acceptable ranges to support this process within which 
1137    variation can be accepted. Where deviation beyond these ranges is detected, 
1138    an evaluation should be performed to determine if there is a possible systemic 
1139    issue and if action is needed. 
1140  3.10.1.4 Risk Communication 
 
1141  The sponsor should communicate the identified risks and mitigating activities, if 
1142    applicable, to those who are involved in taking action or are affected by such activities. 
1143    Communication also facilitates risk review and continual improvement during clinical 
1144    trial conduct. 
1145  3.10.1.5 Risk Review 
 
1146  The sponsor should periodically review risk control measures to ascertain whether the 
1147    implemented quality management activities remain effective and relevant, taking into 
1148    account emerging knowledge and experience. 
1149  3.10.1.6 Risk Reporting 
 
1150  The sponsor should summarise and report the risks and the remedial actions taken in 
1151    relation to important deviations from the acceptable ranges as detailed in section 
1152    3.10.1.3(b) and document them in the clinical trial report (ICH E3). 
1153  3.11  Quality Assurance and Quality Control 
 
1154  The  sponsor  is  responsible  for  establishing,  implementing  and  maintaining 
1155    appropriate  quality  assurance  and  quality  control  processes  and  documented 
1156    procedures to ensure that trials are conducted and data are generated, recorded and 
1157    reported  in  compliance  with  the  protocol,  GCP  and  the  applicable  regulatory 
1158    requirement(s). 
1159  3.11.1  Quality Assurance 
 
1160  Quality  assurance  should  be  applied  throughout  the  clinical  trial  and  includes 
1161    implementing  strategies to identify  potential or actual causes of serious non- 
1162    compliance with the protocol, GCP and/or applicable regulatory requirements to 
1163    enable their corrective and/or preventive actions. 
1164  3.11.2  Audit 
 
1165  When performed, audits should be conducted in a manner that is proportionate to the 
1166    risks associated with the conduct of the trial. 
 
1167  The purpose of a sponsors audit, which is independent of and separate from routine 
1168    monitoring or quality control functions, is to evaluate whether the processes put in 
1169    place to manage and conduct the trial are effective and compliant. 
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ICH E6(R3) Guideline 
 
 
1170  3.11.2.1 Selection and Qualification of Auditors 
 
1171  (a)  The sponsor should appoint individuals who are independent of the clinical 
1172    trial being audited. 
1173     
1174    (b)  The sponsor should ensure that the auditors are qualified by training and 
1175    experience to conduct audits properly. 
1176  3.11.2.2 Auditing Procedures 
 
1177  (a)  The sponsor should ensure that the auditing of clinical trials/processes is 
1178    conducted in accordance with the sponsors documented procedures on what 
1179    to audit, how to audit (i.e., on-site or remote), the frequency of audits and the 
1180    form and content of audit reports. 
1181     
1182    (b)  The sponsors audit plan, program and procedures for a trial audit should be 
1183    guided by the importance of the trial to submissions to regulatory authorities, 
1184    the number of participants in the trial, the type and complexity of the trial, the 
1185    level of risks to the trial participants and any identified problem(s). 
1186     
1187    (c)  The observations and findings of the auditor(s) should be documented. 
1188     
1189    (d)  To preserve the independence and value of the audit function, the regulatory 
1190    authority(ies)  should  not  routinely  request  the  audit  reports.  Regulatory 
1191    authority(ies) may seek access to an audit report on a case-by-case basis when 
1192    evidence of serious GCP non-compliance exists or in the course of legal 
1193    proceedings. 
1194     
1195    (e)  When required by applicable regulatory requirements, the sponsor should 
1196    provide an audit certificate. 
1197  3.11.3  Quality Control 
 
1198  Quality control should be applied to each stage of the data handling to ensure that data 
1199    are reliable and have been processed correctly. Within clinical trials, monitoring and 
1200    data management processes are the main quality control activities. 
1201     
1202    The quality control of sites (other than investigator sites, such as centralised imaging 
1203    reading facilities), including on site and/or centralised activities, may be undertaken 
1204    and reported using a risk-based approach. 
1205  3.11.4  Monitoring 
 
1206  The aim of monitoring is to ensure the participants rights, safety and well-being and 
1207    the reliability of trial results as the trial progresses. Monitoring is one of the principal 
1208    quality control activities. 
 
1209  Monitoring  involves  a  broad  range  of  activities  including,  but  not  limited  to, 
1210    communication with investigator sites, verification of the investigator and investigator 
1211    site staff qualifications and site resources, training and review of trial documents and 
  28   
ICH E6(R3) Guideline 
 
1212  information using a range of approaches including source data review, source data 
1213  verification, data analytics and visits to institutional facilities undertaking trial-related 
1214  activities. Some of these monitoring activities may be conducted by different methods 
1215  and persons with different roles. However, monitoring should be performed by 
1216  persons  not  involved  in  the  clinical  conduct  of  the  trial  being  monitored.  The 
1217  monitoring approach should consider the activities and services involved, including 
1218  decentralised settings, and be included in the monitoring plan. Monitors and other trial 
1219  staff should adhere to data protection and confidentiality requirements in accordance 
1220  with  applicable  regulatory  requirements,  institution  policy  and  established  data 
1221  security standards. 
1222  Monitoring activities may include site monitoring (performed on-site or remotely) and 
1223  centralised monitoring, depending on the monitoring strategy and the design of the 
1224  clinical trial. 
1225  The sponsor should determine the appropriate extent and nature of monitoring, based 
1226  on  identified  risks.  Factors  such  as  the  objective,  purpose,  design,  complexity, 
1227  blinding, number of trial participants, investigational product, current knowledge of 
1228  the safety profile and endpoints of the trial should be considered. 
1229  3.11.4.1 Investigator Site Monitoring 
1230  (a)  Monitoring may be performed in relation to the clinical trial activities at the 
1231  investigator sites (e.g., including their pharmacies and local laboratories, as 
1232  appropriate). The frequency of monitoring activities should also be determined 
1233  based on identified risks. Monitoring activities and their frequency should be 
1234  modified as appropriate using knowledge gained. 
1235   
1236  (b)  This monitoring activity may be performed on-site or remotely depending on 
1237  the nature of the activity and its objectives. 
1238   
1239  (c)  Monitoring may include secure, remote, direct read-only access to source 
1240  records, other data acquisition tools and essential record retention systems. 
1241  3.11.4.2 Centralised Monitoring 
1242  (a)  Centralised monitoring is an evaluation of accumulated data, performed in a 
1243  timely manner, by the sponsors qualified and trained persons (e.g., medical 
1244  monitor, data scientist/data manager, biostatistician). 
1245   
1246  (b)  Centralised monitoring processes provide additional monitoring capabilities 
1247  that can complement and reduce the extent and/or frequency of site monitoring 
1248  or be used on its own. Use of centralised data analytics can help identify 
1249  systemic  or  site-specific  issues,  including  protocol  non-compliance  and 
1250  potentially unreliable data. 
1251   
1252  (c)  Centralised monitoring may support the selection of sites and/or processes for 
1253  targeted site monitoring. 
  29   
ICH E6(R3) Guideline 
 
1254  3.11.4.3 Monitoring Plan 
1255  The sponsor should develop a monitoring plan that is tailored to the identified 
1256  potential safety risks, the risks to data quality and/or other risks to the reliability of the 
1257  trial results. Particular attention should be given to procedures relevant to participant 
1258  safety and to trial endpoints. The plan should describe the monitoring strategy, the 
1259  monitoring activities of all the parties involved, the various monitoring methods and 
1260  tools to be used, and the rationale for their use. The monitoring strategy should ensure 
1261  appropriate oversight of trial conduct and consider site capabilities and the potential 
1262  burden. The plan should focus on aspects that are critical to quality. The monitoring 
1263  plan should reference the sponsors applicable policies and procedures. 
1264  Monitoring of key data and processes (e.g., those related to primary endpoints and key 
1265  secondary endpoints and processes intended to assure patient safety) performed 
1266  outside the investigator site (e.g., central reading facilities, central laboratories) should 
1267  be addressed in the monitoring plan. 
1268  3.11.4.4 Monitoring Procedures 
1269  Persons performing monitoring should follow the sponsors monitoring plan and 
1270  applicable monitoring procedures. 
1271  3.11.4.5 Monitoring Activities 
1272  Monitoring in accordance with the sponsors requirements and monitoring plan 
1273  should generally include the following activities across the clinical trial life cycle, as 
1274  applicable. 
1275  3.11.4.5.1  Communication with Parties Conducting the Trial 
1276  (a)  Establishing and maintaining a line of communication between the 
1277  sponsor and the investigator and other parties and individuals involved 
1278  in the trial conduct (e.g., centrally performed activities). In general, each 
1279  site should have an assigned monitor as their contact point. 
1280   
1281  (b)  Informing the investigator or other parties and individuals involved in 
1282  the trial conduct of identified deviations from the protocol, GCP and the 
1283  applicable  regulatory  requirements  and  taking  appropriate  action 
1284  designed to prevent recurrence of the detected deviations. Important 
1285  deviations should be highlighted and should be the focus of remediation 
1286  efforts as appropriate. 
1287   
1288  (c)  Informing the investigator or other parties and individuals involved in 
1289  the trial conduct of source record(s) or entry errors or omissions in data 
1290  acquisition tools and ensuring that corrections, additions or deletions are 
1291  made as appropriate, dated, explained (if necessary) and that approval 
1292  of the change is properly documented. 
1293   
1294  (d)  Actions taken in relation to the deviations, errors or omissions should be 
1295  proportionate to their importance. 
  30   
ICH E6(R3) Guideline 
 
1296  3.11.4.5.2  Investigator Site Selection, Initiation, Management and Close-out 
1297  (a)  Selecting the site and confirming that the investigator and individuals or 
1298  parties  involved  in  the  trial  conduct  have  adequate  qualifications, 
1299  resources  (see  sections  3.1,  3.2,  and  4.7)  and  facilities,  including 
1300  laboratories, equipment and investigator site staff, to safely and properly 
1301  conduct the trial. 
1302   
1303  (b)  Confirming that the investigator, investigator site staff and other parties, 
1304  and individuals involved in the trial conduct are adequately informed 
1305  about the trial and follow the current approved protocol and other 
1306  protocol-related documents, such as the current Investigators Brochure 
1307  and  relevant  information  related  to  the  investigational  product  and 
1308  instructions related to their delegated activities. 
1309   
1310  (c)  Confirming that the investigator is maintaining the essential records (see 
1311  Appendix C). 
1312   
1313  (d)  Confirming that informed consent was obtained before participation in 
1314  the trial (see section 2.8) for all enrolled participants at the site. 
1315   
1316  (e)  Determining whether adverse events are appropriately reported within 
1317  the time periods required by the protocol, GCP and the applicable 
1318  regulatory requirement(s). 
1319   
1320  (f)  Clarifying the sponsors protocol requirements for source records and 
1321  the sites location of such data. 
1322   
1323  (g)  Verifying that the blinding is maintained, where applicable. 
1324   
1325  (h)  Reviewing and reporting the participant recruitment and retention rates. 
1326   
1327  (i)  Confirming  that  the  investigator  provides  the  required  reports, 
1328  notifications or other information in accordance with the protocol and 
1329  trial procedures. 
1330   
1331  (j)  Confirming the arrangement for the retention of the essential records and 
1332  the final accountability of the investigational product (e.g., return and 
1333  destruction or alternative disposition, if appropriate) during site close- 
1334  out activity. 
1335  3.11.4.5.3  Monitoring of Investigational Product Management 
 
1336  (a)  Confirming, for the investigational product(s): 
1337     
1338    (i)  that storage conditions are acceptable and in accordance with the 
1339    storage requirement specified in the protocol; 
1340     
  31   
ICH E6(R3) Guideline 
 
1341  (ii)  that supplies are sufficient throughout the trial and are used 
1342  within their shelf-life; 
1343   
1344  (iii)  that the correct investigational product(s) are supplied only to 
1345  participants  who  are  eligible  to  receive  it  at  the  protocol- 
1346  specified dose(s) and, where appropriate, in accordance with the 
1347  randomisation procedures; 
1348   
1349  (iv)  that the participants, investigator, investigator site staff and other 
1350  relevant parties and individuals involved in the trial conduct are 
1351  provided with necessary instruction on properly using, handling, 
1352  storing, returning and destroying, or alternative disposition of the 
1353  investigational product(s); 
1354   
1355  (v)  that  the  receipt,  use,  return  and  destruction,  or  alternative 
1356  disposition of the investigational product(s) are controlled and 
1357  documented adequately; 
1358   
1359  (vi)  that  the  disposition  of  unused  investigational  product(s) 
1360  complies with applicable regulatory requirement(s) and is in 
1361  accordance with the sponsor requirements; 
1362   
1363  (vii)  where product available on the market is dispensed and used in 
1364  accordance with applicable regulatory requirements, some of the 
1365  previously outlined considerations may not be applicable. 
1366  3.11.4.5.4  Monitoring of Clinical Trial Data 
1367  (a)  Verifying that the investigator is enrolling only eligible trial participants. 
1368   
1369  (b)  Checking the accuracy, completeness and consistency of the reported 
1370  trial data against the source records and other trial-related records and 
1371  whether these were reported in a timely manner. This can be done on the 
1372  basis of using samples and supported by data analytics, as appropriate. 
1373  The sample size may need adjustment based on previous monitoring 
1374  results  or  other  indications  of  insufficient  data  quality.  Monitoring 
1375  should: 
1376   
1377  (i)  verify that the data required by the protocol and identified as 
1378  critical in the monitoring plan are consistent with the source; 
1379   
1380  (ii)  identify missing data, inconsistent data, data outliers, unexpected 
1381  lack of variability and protocol deviations; 
1382   
1383  (iii)  examine  data  trends,  such  as  the  range,  consistency  and 
1384  variability of data within and across sites; 
1385 
  32   
ICH E6(R3) Guideline 
 
 
1386    (c)  Identifying significant errors in data collection and reporting at a site or 
1387    across sites, potential data manipulation and data integrity problems. 
1388  3.11.4.6 Monitoring Report 
 
1389  (a)  Reports of monitoring activities should include a summary of what was 
1390    reviewed,  a  description  of  significant  findings,  conclusions  and  actions 
1391    required to resolve them and follow-up on their resolution including those not 
1392    resolved  in  previous  reports.  The  requirements  of  monitoring  reports 
1393    (including their content and frequency) should be described in the sponsors 
1394    procedures. 
1395     
1396    (b)  Reports of investigator site and/or centralised monitoring should be provided 
1397    to the appropriate sponsor staff as described in the sponsors procedures in a 
1398    timely manner for review and follow-up. 
1399     
1400    (c)  When needed, the report should describe findings requiring escalation for 
1401    action and resolution. The sponsor should decide on the appropriate action to 
1402    be taken, and these decisions and the resolution of the actions involved, where 
1403    needed, should be recorded. 
1404  3.12  Noncompliance 
1405  3.12.1  Noncompliance  with  the  protocol,  SOPs,  GCP  and/or  applicable  regulatory 
1406    requirement(s) by an investigator/institution or by member(s) of the sponsors staff 
1407    should  lead  to  appropriate  and  proportionate  action  by  the  sponsor  to  secure 
1408    compliance. 
1409     
1410  3.12.2  If noncompliance that significantly affects or has the potential to significantly affect 
1411    trial participants rights, safety or well-being or the reliability of trial results is 
1412    discovered, the sponsor should perform a root cause analysis, implement appropriate 
1413    corrective  and  preventive  actions  and  confirm  their  adequacy  unless  otherwise 
1414    justified. Where the sponsor identifies  issues  that  could  significantly impact 
1415    participants rights, safety and well-being or the reliability of trial results, the sponsor 
1416    should  notify  the  regulatory  authority  and/or  IRB/IEC  in  line  with  applicable 
1417    regulatory requirements. 
1418     
1419  3.12.3  If the monitoring and/or auditing identifies serious noncompliance on the part of an 
1420    investigator/institution that persists despite efforts at remediation, the sponsor should 
1421    terminate  the  investigators/institutions  participation  in  the  trial.  When  an 
1422    investigators/institutions participation is terminated because of noncompliance, the 
1423    sponsor should promptly notify the regulatory authority(ies) and  IRB/IEC as 
1424    appropriate. 
1425  3.13  Safety Assessment and Reporting 
 
1426  The sponsor is responsible for the ongoing safety evaluation of the investigational product(s). 
  33   
ICH E6(R3) Guideline 
 
 
1427  The Investigators Brochure or, where applicable, the current scientific information such as a 
1428  basic product information brochure, forms the basis of safety assessment and reporting for the 
1429  clinical trial. For further information, see Appendix A. 
1430  3.13.1  Sponsor Review of Safety Information 
 
1431  The sponsor should aggregate, as appropriate, and periodically review relevant safety 
1432    information. This may result in the update of the protocol, Investigators Brochure, 
1433    informed consent materials and related documents. 
 
1434  The sponsor should review the available emerging safety information to assess 
1435    whether there is any new data that may affect the participants willingness to continue 
1436    in the trial, impact the conduct of the trial, or alter the approval/favourable opinion of 
1437    the IRB/IEC and/or regulatory authority(ies), as applicable. Any information of this 
1438    nature  should  be  communicated  to  the  participants,  investigator,  IRB/IEC  and 
1439    regulatory authorities, as applicable, in a timely manner. 
1440  3.13.2  Safety Reporting 
 
1441  (a)  The sponsor should submit to the regulatory authority(ies) safety updates and 
1442    periodic reports, including changes to the Investigators Brochure, as required 
1443    by applicable regulatory requirements. 
1444     
1445    (b)  The  sponsor  should,  in  accordance  with  the  applicable  regulatory 
1446    requirement(s) and with  ICH  E2A  Clinical  Safety Data Management: 
1447    Definitions and Standards for Expedited Reporting, expedite the reporting to 
1448    the regulatory authority(ies) of all adverse drug reactions (ADRs) that meet 
1449    three criteria: suspected, unexpected and serious (i.e., SUSARs). 
1450     
1451    (c)  Safety reporting to regulatory authorities should be undertaken by assessing 
1452    the expectedness  of the reaction in relation to the applicable product 
1453    information (e.g., the reference safety information (RSI) contained within the 
1454    Investigators  Brochure  or  alternative  documents)  in  accordance  with 
1455    applicable regulatory requirements. Refer to ICH E2F Development Safety 
1456    Update Report for more information about RSI. 
1457     
1458    (d)  The  reporting  of  SUSARs  to  investigator(s)/institutions(s)  and  to  the 
1459    IRB(s)/IEC(s) should be undertaken in a manner that reflects the urgency of 
1460    action required and should take into consideration the evolving knowledge of 
1461    the  safety  profile  of  the  product.  Reporting  of  SUSARs  to  the 
1462    investigators/institutions  should  be  made  in  accordance  with  regulatory 
1463    requirements. In some regions, periodic reporting of line listings with an 
1464    overall safety assessment may be appropriate. 
1465     
1466    (e)  Urgent  safety  issues  requiring  immediate  attention  or  action  should  be 
1467    reported to the IRB/IEC and/or regulatory authority(ies) and investigators 
1468    without undue delay and as specified in regulatory requirements. 
1469     
  34   
ICH E6(R3) Guideline 
 
 
1470    (f)  Alternative arrangements for safety reporting to regulatory authorities, 
1471    IRBs/IECs, and investigators and for reporting by investigators to the sponsor 
1472    should be prospectively agreed upon with the regulatory authority(ies) and the 
1473    IRB/IEC if applicable, and described in the clinical trial protocol, (e.g., SAEs 
1474    considered  efficacy  or  safety endpoints,  which  would  not  be  subject  to 
1475    unblinding and expedited reporting; see ICH E2A). See ICH E19. 
1476  3.13.3  Managing an Immediate Hazard 
 
1477  The sponsor should take prompt action to address immediate hazards to participants. 
1478    The sponsor should determine the causes of the hazard and based on this, take 
1479    appropriate remedial actions. 
 
1480  The sponsor should consider whether the protocol requires amendment in response to 
1481    an immediate hazard. The information on the immediate hazard, if required, and any 
1482    subsequent protocol amendment should be submitted  to the  IRB/IEC  and/or 
1483    regulatory authorities by the investigator/institution or sponsor (in accordance with 
1484    applicable regulatory requirements). 
1485  3.14  Insurance/Indemnification/Compensation to Participants and Investigators 
1486  3.14.1  If required by the applicable regulatory requirement(s), the sponsor should provide 
1487    insurance or should indemnify (legal and financial coverage) the investigator/the 
1488    institution against claims arising from the trial except for claims that arise from 
1489    malpractice and/or negligence. 
1490     
1491  3.14.2  The sponsors policies and procedures should address the costs of treatment of trial 
1492    participants in the event of trial-related injuries in accordance with the applicable 
1493    regulatory requirement(s). 
1494     
1495  3.14.3  The approach  to  compensating  trial  participants  should comply with  applicable 
1496    regulatory requirement(s). 
1497  3.15  Investigational Product(s) 
1498  3.15.1  Information on Investigational Product(s) 
1499     
1500    The sponsor should ensure that an Investigators Brochure is developed and updated 
1501    as significant new information on the investigational product becomes available. 
1502    Alternatively, for authorised medicinal products, the sponsor should identify the basic 
1503    product information to be used in the trial (see Appendix A). 
1504  3.15.2  Manufacturing, Packaging, Labelling and Coding Investigational Product(s) 
 
1505  (a)  The sponsor should ensure that the investigational product(s) (including active 
1506    control(s) and placebo, if applicable) is characterised as appropriate to the 
1507    stage of development of the product(s), is manufactured in accordance with 
1508    any applicable GMP and is coded and labelled in a manner that protects the 
1509    blinding,  if  applicable.  In  addition,  the  labelling  should  comply  with 
1510    applicable regulatory requirement(s). 
1511     
  35   
ICH E6(R3) Guideline 
 
 
1512    (b)  The sponsor should determine acceptable storage temperatures and other 
1513    storage  conditions  (e.g.,  protection  from  light)  for  the  investigational 
1514    product(s), appropriate reconstitution fluids and procedures, and devices for 
1515    product infusion, if any. The sponsor should inform all involved parties (e.g., 
1516    monitors,  investigators,  pharmacists,  storage  managers)  of  these 
1517    determinations. 
1518     
1519    (c)  The investigational product(s) should be packaged to prevent contamination 
1520    and unacceptable deterioration during transport and storage. 
1521     
1522    (d)  In blinded trials, the sponsor should implement: 
1523     
1524    (i)  a process to blind the sponsor staff, trial participant and/or investigator 
1525    as appropriate to the investigational product identity and assignment to 
1526    prevent and detect inappropriate unblinding; 
1527     
1528    (ii)  a procedure and mechanism that permits the investigator to rapidly 
1529    identify the  product(s)  in  case  of  a  medical  emergency  where 
1530    unblinding is considered necessary, while protecting the identity of the 
1531    treatment assignment of the other trial participants; 
1532     
1533    (iii)  a mechanism that protects the blinding of the trial where a participants 
1534    treatment assignment is unblinded for the purpose of safety reporting 
1535    to regulatory authorities and/or IRB/IEC, where appropriate. 
1536     
1537    (e)  If significant formulation changes are made in the investigational product(s) 
1538    (including active control(s) and placebo, if applicable) during the course of 
1539    clinical development, the results of any additional studies of the formulated 
1540    product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess 
1541    whether these changes would significantly alter the pharmacokinetic profile 
1542    of the product should be available prior to the use of the new formulation in 
1543    clinical trials. 
1544  3.15.3  Supplying and Handling Investigational Product(s) 
1545  (a)  The sponsor is responsible for supplying the investigator(s)/institution(s) with 
1546  the  investigational  product(s)  or,  where  appropriate,  supplying  trial 
1547  participants in accordance with applicable regulatory requirements and after 
1548  obtaining the required approval/favourable opinion from the IRB/IEC and the 
1549  regulatory authority(ies) for the trial. 
1550   
1551  (b)  The  sponsor  should  ensure  that  instructions  are  available  for  the 
1552  investigator/institution or trial participants on the handling and storage of 
1553  investigational product(s). The procedures should consider adequate and safe 
1554  receipt,  handling,  storage,  dispensing,  retrieval  of  unused  product  from 
1555  participants and return of unused investigational product(s) to the sponsor (or 
  36   
ICH E6(R3) Guideline 
 
 
1556    alternative disposition if authorised by the sponsor and in compliance with the 
1557    applicable regulatory requirement(s)). 
1558     
1559    (c)  The sponsor should: 
1560     
1561    (i)  ensure  timely  delivery  of  investigational  product(s)  to  the 
1562    investigator(s) or, where appropriate, to trial participants in accordance 
1563    with applicable regulatory requirements to avoid any interruption to 
1564    the trial as well as for the continuation of treatment for participants. 
1565     
1566    (ii)  maintain records that document the identity, shipment, receipt, return 
1567    and  destruction,  or  alternative  disposition  of  the  investigational 
1568    product(s) (see Appendix C); 
1569     
1570    (iii)  maintain  a  system  for  retrieving  investigational  products  and 
1571    documenting this retrieval (e.g., for deficient product recall, return and 
1572    destruction, or alternative disposition after trial completion, or expired 
1573    product reclaim); 
1574     
1575    (iv)  maintain a system for the disposition of unused investigational 
1576    product(s) and for the documentation of this disposition; 
1577     
1578    (v)  take steps to ensure that the investigational product(s) are stable over 
1579    the period of use and only used within the current shelf-life; 
1580     
1581    (vi)  maintain sufficient quantities of the investigational product(s) used in 
1582    the trials to reconfirm specifications should this become necessary and 
1583    maintain records of batch sample analyses and characteristics. The 
1584    samples should be retained either until the analyses of the trial data are 
1585    complete or as required by the applicable regulatory requirement(s), 
1586    whichever represents the longer retention period. The samples do not 
1587    need to be kept by the sponsor in trials where an authorised medicinal 
1588    product is used as an investigational product unmodified from its 
1589    authorised state, since samples are kept by the manufacturer. 
1590  3.16  Data and Records 
1591  3.16.1  Data Handling 
 
1592  (a)  The sponsor should ensure the integrity and confidentiality of data generated 
1593    and managed. 
1594     
1595    (b)  The sponsor should apply quality control to  the relevant stages of data 
1596    handling to ensure that the data are of sufficient quality to generate reliable 
1597    results. The sponsor should focus their quality assurance and quality control 
1598    activities and data review on critical data, including its relevant metadata. 
1599     
  37   
ICH E6(R3) Guideline 
 
1600  (c)  The sponsor should pre-specify data to be collected and the method of its 
1601  collection  in  the  protocol  (see  Appendix  B.  Clinical  Trial  Protocol  and 
1602  Protocol Amendment(s)). Where necessary, additional details, including a data 
1603  flow diagram, should be contained in a protocol-related document (e.g., a data 
1604  management plan). 
1605   
1606  (d)  The sponsor should ensure that data acquisition tools are fit for purpose and 
1607  designed to capture the information required by the protocol. They should be 
1608  validated and ready for use prior to their required use in the trial. 
1609   
1610  (e)  The sponsor should ensure that documented processes are implemented to 
1611  ensure the data integrity for the full data life cycle. 
1612   
1613  (f)  The sponsor should implement measures to ensure the safeguarding of the 
1614  blinding, if any (e.g., maintain the blinding during data entry and processing). 
1615   
1616  (g)  The sponsor should provide guidance to investigators/institutions, service 
1617  providers and trial participants, where relevant, on the expectations for data 
1618  capture, data changes, data retention and data disposal. 
1619   
1620  (h)  The sponsor should not make changes to data entered by the investigator or 
1621  trial participants unless justified and documented by the sponsor and agreed 
1622  upon by the investigator. 
1623   
1624  (i)  The sponsor should allow correction of errors to data, including data entered 
1625  by participants, where requested by the investigators/participants. Such data 
1626  corrections should be justified and supported by source records around the 
1627  time of original entry. 
1628   
1629  (j)  The sponsor should ensure that the investigator has access to data collected in 
1630  accordance with the protocol during the course of the trial including relevant 
1631  data from external sources, for example, central laboratory data, centrally read 
1632  imaging data and, if appropriate, ePRO data that are necessary to enable the 
1633  investigators to make decisions (e.g., on eligibility, treatment, continuing 
1634  participation  in  the  trial  and  care  for  the  safety  of  the  individual  trial 
1635  participants).  The  sponsor  should  pay  special  attention  to  data  that  may 
1636  unblind the investigator and include the appropriate provisions in the protocol. 
1637   
1638  (k)  The  sponsor  should  not  have  exclusive  control  of  data captured  in  data 
1639  acquisition tools. 
1640   
1641  (l)  The sponsor should ensure that the investigator has access to the required data 
1642  for retention purposes. 
1643 
  38   
ICH E6(R3) Guideline 
 
 
1644  (m)  The sponsor should ensure that the investigator receives instructions on how 
1645    to navigate systems, data and relevant metadata for the trial participants under 
1646    their responsibility. 
1647     
1648  (n)  The  sponsor  should  seek  investigator  endorsement  of  their  data  at 
1649    predetermined milestones. 
1650     
1651  (o)  The sponsor should document the data management steps to be undertaken 
1652    prior to data analysis. These steps may vary depending on the purpose of the 
1653    analysis to be conducted (e.g., data for IDMC, for interim analysis or the final 
1654    analysis). 
1655     
1656  (p)  Prior to provision of the data for analysis, edit access to the data acquisition 
1657    tools should be restricted as appropriate to the purpose of the analysis; for 
1658    example,  for  interim  analysis,  the  restriction  may only be  temporary  or 
1659    managed differently compared to the final analysis. 
1660     
1661  (q)  Deviations from the planned statistical analysis or changes made to the data 
1662    analysis set after the trial has been unblinded (where applicable) should be 
1663    clearly  documented  and  justified  and  should  only  occur  in  exceptional 
1664    circumstances (e.g., data discrepancies that must be resolved for the reliability 
1665    of the trial results). Data changes should be authorised by the investigator and 
1666    reflected in an audit trail. Post-unblinding data changes and deviations from 
1667    the planned statistical analyses should be reported in the clinical trial report. 
1668     
1669  (r)  The sponsor should use an unambiguous trial participant identification code 
1670    (see glossary term) that allows identification of all the data reported for each 
1671    participant. 
1672     
1673  (s)  The sponsor should implement appropriate measures to protect the privacy and 
1674    confidentiality of personal information of trial participants, in accordance with 
1675    applicable regulatory requirements on personal data protection. 
1676     
1677  (t)  In accordance with applicable regulatory requirements, the sponsor should 
1678    document what happens to data when a participant withdraws or discontinues 
1679    from the trial. 
1680     
1681  (u)  The sponsor should ensure that trial data are protected from unauthorised 
1682    access,  disclosure,  dissemination  or  alteration  and  from  inappropriate 
1683    destruction or accidental loss. 
1684     
1685  (v)  The sponsor should have processes and procedures in place for reporting 
1686    incidents (including security breaches) that have a significant impact on the 
1687    trial data to relevant parties, including regulatory authorities, where relevant. 
1688     
1689     
  39   
ICH E6(R3) Guideline 
 
 
1690  (w)  When using computerised systems in a clinical trial, the sponsor should: 
1691     
1692    (i)  have a record of the computerised systems used in a clinical trial. This 
1693    should include the use, functionality, interfaces and validation status 
1694    of  each  computerised  system,  and  who  is  responsible  for  its 
1695    management should be described. The record should also include a 
1696    description of implemented access controls and internal and external 
1697    security measures; 
1698     
1699    (ii)  ensure that the requirements for computerised systems deployed by the 
1700    sponsor  (e.g.,  requirements  for  validation,  audit  trails,  user 
1701    management, backup, disaster recovery and IT security) are addressed 
1702    and implemented  and that documented procedures and adequate 
1703    training are in place to ensure the correct development, maintenance 
1704    and use of computerised systems in clinical trials (see section 4). These 
1705    requirements should be proportionate to the importance of the 
1706    computerised system and the data or activities they are expected to 
1707    process; 
1708     
1709    (iii)  maintain a record of the individual users who are authorised to access 
1710    the system, their roles and their access privileges: 
1711     
1712    (iv)  ensure  that  access  rights  granted  to  investigator  site  staff  are  in 
1713    accordance with delegations by the investigator and visible to the 
1714    investigator; 
1715     
1716    (v)  for systems deployed by the investigator/institution, assess whether 
1717    such systems, if identified as containing source records in the trial, 
1718    (e.g., electronic health records and other record keeping systems for 
1719    source data collection and investigator site files) are fit for purpose or 
1720    whether  the  known  issue(s)  can  be  appropriately  mitigated.  This 
1721    assessment should occur during the process of selecting clinical trial 
1722    sites and should be documented; 
1723     
1724    (vi)  ensure that there is  a process  in  place for  service providers  and 
1725    investigators to inform the sponsor of system defects identified or 
1726    incidents that could potentially constitute a serious non-compliance 
1727    with the clinical trial protocol, trial procedures or GCP in accordance 
1728    with section 3.13. 
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ICH E6(R3) Guideline 
 
 
1729  3.16.2  Statistical Programming and Data Analysis 
 
1730  This section concerning  documentation of operational aspects of clinical trial 
1731    statistical activities should be read in conjunction with ICH E9 Statistical Principles 
1732    for Clinical Trials, which provides detailed guidance on statistical principles for 
1733    clinical development, trial design, conduct, analysis and reporting. 
 
1734  (a)  The sponsor should ensure that appropriate and documented quality control of 
1735    statistical programming and data analysis is implemented (e.g., for sample size 
1736    calculations, results for IDMC, outputs for clinical trial report, statistical or 
1737    centralised monitoring). 
1738     
1739    (b)  The  sponsor  should  ensure  the  traceability  of  data  transformations  and 
1740    derivations during data processing and analysis. 
1741     
1742    (c)  The sponsor should ensure that the allocation to or exclusion of each trial 
1743    participant from any analysis set is predefined (e.g., in the protocol or the 
1744    statistical analysis plan). The rationale for inclusion or exclusion for any 
1745    participant  (or  particular  data  point)  should  be  clearly  described  and 
1746    documented. 
1747     
1748    (d)  Procedures should be in place to describe unblinding; these descriptions 
1749    should include: 
1750     
1751    (i)  who was unblinded, at what timepoint and for what purpose they were 
1752    unblinded; 
1753     
1754    (ii)  who should remain blinded; 
1755     
1756    (iii)  the safeguards in place to preserve the blinding. 
1757     
1758    (e)  The sponsor should retain the statistical programming records that relate to the 
1759    output contained or used in reports of the trial results, including quality 
1760    control/validation activities performed. Outputs should be traceable to the 
1761    statistical software programs, and they should be dated and time stamped and 
1762    protected against any changes. 
1763  3.16.3  Record Keeping and Retention 
 
1764  (a)  The sponsor (or subsequent owners of the data) should retain all of the 
1765    sponsor-specific essential records pertaining to the trial in conformance with 
1766    the applicable regulatory requirement(s). 
1767     
1768    (b)  The  sponsor  should  inform  the  investigator(s)/institution(s) and  service 
1769    providers, when appropriate, in writing of the need for essential records 
1770    retention  and  should  notify  the  investigator(s)/institution(s) and  service 
1771    providers, when appropriate, in writing when the trial-related records are no 
1772    longer needed. 
  41   
ICH E6(R3) Guideline 
 
 
1773    (c)  The sponsor should report any transfer of ownership of the essential records 
1774    to the appropriate authority(ies) as required by the applicable regulatory 
1775    requirement(s). 
1776  3.16.4  Record Access 
 
1777  (a)  The  sponsor  should  ensure  that  it  is  specified  in  the  protocol  or  other 
1778    documented agreement that the investigator(s)/institution(s) provide direct 
1779    access to source records for trial-related monitoring, audits, IRB/IEC review 
1780    and regulatory inspection. 
1781     
1782    (b)  The sponsor should ensure that trial participants have consented to direct 
1783    access to their original medical records and other participant-related trial 
1784    documents for trial-related monitoring, audit, IRB/IEC review and regulatory 
1785    inspection as part of the informed consent. 
1786  3.17  Reports 
1787  3.17.1  Premature Termination or Suspension of a Trial 
 
1788  If a trial is prematurely terminated or suspended, the sponsor should promptly inform 
1789    the investigators/institutions and the regulatory authority(ies) of the termination or 
1790    suspension and the reason(s) for the termination or suspension. The IRB/IEC should 
1791    also be informed promptly and provided with the reason(s) for the termination or 
1792    suspension by the sponsor or by the investigator/institution, in accordance with 
1793    applicable regulatory requirement(s). 
1794  3.17.2  Clinical Trial/Study Reports 
 
1795  (a)  Whether the trial is completed or prematurely terminated or an interim analysis 
1796    is undertaken for regulatory submission, the sponsor should ensure that the 
1797    clinical trial reports, including interim reports, are prepared and provided to 
1798    the  regulatory  agency(ies)  as  required  by  the  applicable  regulatory 
1799    requirement(s). The sponsor should also ensure that the clinical trial reports in 
1800    marketing applications meet the standards of ICH E3 or are otherwise in 
1801    accordance with applicable regulatory requirements. (Note: ICH E3 specifies 
1802    that abbreviated study reports may be acceptable in certain cases.) 
1803     
1804    (b)  Investigators should be provided with a summary of the trial results. 
1805     
1806    (c)  Consideration should be given to providing the investigator with information 
1807    about the final treatment taken by their participants for blinded trials and a 
1808    brief summary of the overall outcome of the trial. Where this information is 
1809    provided to participants, the language should be non-technical, understandable 
1810    to a layperson and non-promotional. The sponsor should only supply this 
1811    information  after  the  trial  has  been  unblinded  and  all  relevant 
1812    analyses/conclusions have been completed and finalised. 
  42   
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1813  4.  DATA GOVERNANCE  INVESTIGATOR AND SPONSOR 
1814  This section provides guidance to investigators and sponsors (i.e., the responsible parties) on 
1815  appropriate management of data integrity, traceability and security, thereby allowing the 
1816  accurate reporting, verification and interpretation of the clinical trial-related information. This 
1817  section should be read in conjunction with corresponding responsibilities for the investigator 
1818  and the sponsor as defined in sections 2 and 3, along with ICH E8(R1) and ICH E9. 
1819  The quality and amount of the information generated in a clinical trial should be sufficient to 
1820  address trial objectives, provide confidence in the trials results and support good decision 
1821  making. 
1822  The systems and processes that help ensure this quality should be designed and implemented 
1823  in a way that is proportionate to the risks to participants and the reliability of trial results. 
1824  The following key processes should address the full data life cycle with a focus on the criticality 
1825  of the data and should be implemented proportionately and documented appropriately: 
1826  (a)  processes to ensure data protection of trial participants confidential data; 
1827   
1828  (b)  processes for managing computerised systems to ensure that they are fit for 
1829  purpose and used appropriately; 
1830   
1831  (c)  processes  to  safeguard  essential  elements  of  the  clinical  trial,  such  as 
1832  randomisation, dose escalation and blinding; 
1833   
1834  (d)  processes to support key decision making, such as data finalisation prior to 
1835  analysis, unblinding, allocation to analysis data sets, changes in clinical trial 
1836  design and, where applicable, the activities of, for example, an IDMC. 
1837  4.1  Safeguard Blinding in Data Governance 
1838  4.1.1  Maintaining the integrity of the blinding is important in particular in the design of 
1839  systems, management of users account, delegation of responsibilities with respect to 
1840  data handling and provision of data access at sites, data transfers, database review 
1841  prior to planned unblinding and statistical analysis across all appropriate stages of the 
1842  trial. 
1843   
1844  4.1.2  Roles, responsibilities and procedures for access to unblinded information should be 
1845  defined  and  documented  by  all  relevant  parties  according  to  the  protocol;  this 
1846  information may also be included in the data management plans and statistical analysis 
1847  plans. For example, in blinded trials, sponsor staff or designated third parties who are 
1848  involved  in  operation  of  the  trial  and  directly  or  indirectly  interact  with  site 
1849  investigator staff should not have access to unblinding information. 
1850   
1851  4.1.3  The potential for unblinding should be part of the risk assessment of a blinded trial. 
1852  Any planned or unplanned unblinding, including accidental or emergency unblinding, 
1853  should be documented and assessed for impact to trial results. 
  43   
ICH E6(R3) Guideline 
 
1854  4.2  Data Life Cycle Elements 
1855  Procedures should be in place to cover the full data life cycle. 
1856  4.2.1  Data Capture 
1857  (a)  The requirements for and extent of data verification, when data captured on 
1858  paper  or  in  an  electronic  health  record  are  manually  transcribed  into  a 
1859  computerised system, should take the criticality of the data into account. Refer 
1860  to section 4.2.3 for data entered directly in data acquisition tools. 
1861  (b)  Acquired data from any source should be accompanied by relevant metadata. 
1862  At the point of data capture, automated data validation checks should be 
1863  considered as required based upon risk, and their implementation should be 
1864  controlled and documented. 
1865   
1866  4.2.2  Relevant Metadata, Including Audit Trails 
1867  The approach used by the responsible party for implementing, evaluating, accessing, 
1868  managing and reviewing relevant metadata associated with critical data should entail: 
1869   
1870  (a)  Evaluating the system for the types and content of metadata available to ensure 
1871  that: 
1872  (i)  computerised systems maintain logs of user account creation, changes 
1873  to user roles and permissions and user access; 
1874   
1875  (ii)  systems are designed to permit data changes in such a way that the 
1876  initial  data  entry  and  any  subsequent  changes  or  deletions  are 
1877  documented,  including,  where  appropriate,  using  a  risk-based 
1878  evaluation, the reason for the change if it is not implicit; 
1879   
1880  (iii)  systems record and maintain workflow actions in addition to direct data 
1881  entry/changes into the system. 
1882  (b)  Ensuring that audit trails, reports and logs are not disabled or modified except 
1883  in rare circumstances and only if a log of such action and justification is 
1884  maintained; 
1885   
1886  (c)  Ensuring that audit trails and logs are decipherable and can facilitate analysis; 
1887   
1888  (d)  Ensuring that the automatic capture of date and time of data entries or transfer 
1889  using data acquisition tools are unambiguous (e.g., coordinated universal time 
1890  (UTC)); 
1891   
1892  (e)  Determining which of the identified metadata require review and retention. 
  44   
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1893  4.2.3  Review of Data and Metadata 
1894  Procedures for review of trial-specific data, audit trails and other relevant metadata 
1895  should be in place. It should be a planned activity, and the extent and nature should 
1896  be adapted to the individual trial and adjusted based on experience during the trial. 
1897  4.2.4  Data Corrections 
1898  There should be processes to correct data errors that could impact the reliability of the 
1899  trial results. Corrections should be attributed to the entity making the correction, 
1900  justified and supported by source records around the time of original entry, and 
1901  performed in a timely manner. 
1902  4.2.5  Data Transfer, Exchange and Migration 
1903  Validated processes or other appropriate processes such as reconciliation should be in 
1904  place to ensure that electronic data transferred between computerised systems retains 
1905  its  integrity  and  preserves  its  confidentiality.  The  transfer  process  should  be 
1906  documented to ensure traceability, and data reconciliation should be implemented as 
1907  appropriate. 
1908  4.2.6  Finalisation of Data Sets Prior to Analysis 
1909  (a)  Data of sufficient quality for interim and final analysis are achieved by 
1910  implementing timely and reliable processes for data capture, verification, 
1911  validation,  review  and  rectification  of  errors  and  omissions  that  have  a 
1912  meaningful impact on the safety of trial participants and/or the reliability of 
1913  the trial results. 
1914   
1915  (b)  Activities undertaken to finalise the data sets prior to analysis should be 
1916  confirmed  and  documented  in  accordance  with  pre-specified  procedures. 
1917  These activities may include reconciliation of entered data and data sets or 
1918  reconciliation of relevant databases, correction of data errors and omissions, 
1919  medical coding, compilation and addressing the impact of non-compliance 
1920  including protocol deviations. 
1921   
1922  (c)  Data extraction and determination of data analysis sets should take place in 
1923  accordance with the planned statistical analysis and should be documented. 
1924  4.3  Computerised Systems 
1925  As described in sections 2 and 3, the responsibilities of the sponsor, investigator and 
1926  the activities of other parties with respect to a computerised system used in clinical 
1927  trials should be clear and documented. In summary, the sponsor is responsible for 
1928  ensuring that for computerised systems which they put in place, the expectations for 
1929  computerised systems as described in this section are addressed in a risk proportionate 
1930  manner.  The  sponsor  should  review  whether  the  systems  used  by  the 
1931  investigator/institution  (e.g.,  electronic  health  records  and  other  record  keeping 
1932  systems for source data collection) are fit for purpose in the context of the trial. In the 
1933  event that the investigator/institution deploys systems specifically for the purposes of 
  45   
ICH E6(R3) Guideline 
 
1934  conducting  clinical  trials,  the  investigator/institution  should  ensure  that  the 
1935  expectations are proportionately addressed and implemented. 
1936  The responsible party should ensure that those developing computerised systems for 
1937  clinical trials are aware of the intended purpose and the regulatory requirements that 
1938  apply to them. 
1939  It  is  recommended  that  representatives  of  intended  participant  populations  and 
1940  healthcare professionals are involved in the design of the system, where relevant, to 
1941  ensure that computerised systems are suitable for use by the intended user population. 
1942  4.3.1  Procedures for the Use of Computerised Systems 
1943  Documented  procedures  should  be  in  place  to  ensure  the  appropriate  use  of 
1944  computerised systems in clinical trials for essential activities related to data collection, 
1945  handling and management. 
1946  4.3.2  Training 
1947  The  responsible  party  should  ensure  that  those  using  computerised  systems  are 
1948  appropriately trained in their use. 
1949  4.4  Security of Computerised Systems 
1950  4.4.1  The security of the trial data and records should be managed throughout the data life 
1951  cycle. 
1952   
1953  4.4.2  The  responsible  party  should  ensure  that  security  controls  are  maintained  for 
1954  computerised systems. These controls should include user management and ongoing 
1955  measures to prevent, detect and/or mitigate security breaches. Aspects such as user 
1956  authentication requirements and password management, firewall settings, antivirus 
1957  software, security patching, system monitoring and penetration testing should be 
1958  considered. 
1959   
1960  4.4.3  The responsible party should maintain adequate backup of the data. 
1961   
1962  4.4.4  Procedures should cover the following: system security measures, data backup and 
1963  disaster recovery. 
1964  4.5  Validation of Computerised Systems 
1965  4.5.1  The responsible party is responsible for the validation status of the system throughout 
1966  its life cycle. The approach to validation of computerised systems should be based on 
1967  a risk assessment that considers the intended use of the system; the purpose and 
1968  importance of the data/record that is collected/generated, maintained and retained in 
1969  the system; and the potential of the system to affect the well-being, rights and safety 
1970  of trial participants and the reliability of trial results. 
1971   
1972  4.5.2  Validation  should  demonstrate  that  the  system  conforms  to  the  established 
1973  requirements  for  completeness,  accuracy,  and  reliability  and  is  consistent  with 
1974  intended performance. 
  46   
ICH E6(R3) Guideline 
 
 
1975  4.5.3  Systems should be appropriately validated prior to use with adequate change control 
1976    procedures implemented. 
1977     
1978  4.5.4  Validation of changes should be based on risk and consider both previously collected 
1979    and new data. 
1980     
1981  4.5.5  Both  basic  system  functionality  and  protocol  specific  configurations  and 
1982    customisations, including automated data entry checks and calculations, should be 
1983    validated. Interfaces between systems should also be defined and validated. Different 
1984    degrees of qualification/validation may be needed for bespoke systems, systems 
1985    designed to be configured or systems where no alterations are needed. 
1986     
1987  4.5.6  Where relevant, procedures should cover the following: system design, validation, 
1988    and functionality testing; release; setup; installation and change control until 
1989    decommissioning. 
1990     
1991  4.5.7  The responsible party should ensure that the computerised systems used in clinical 
1992    trial processes are qualified and validated, including those developed by other parties. 
1993    They should ensure that qualification and validation documentation is maintained and 
1994    retained. 
1995     
1996  4.5.8  Validation should generally include defining the requirements and specifications for 
1997    the system and their testing, along with the associated documentation, to ensure the 
1998    system is fit for purpose, especially for critical functionality, such as randomisation, 
1999    dosing and dose titrations and reductions, and collection of endpoint data. 
2000     
2001  4.5.9  Unresolved issues, if any, should be justified and, where relevant, addressed by 
2002    mitigations prior to and/or during the continued use of the system. 
2003     
2004  4.5.10  The trial-specific systems (including updates resulting from protocol amendments) 
2005    should only be implemented to enable the conduct of the trial by the investigator after 
2006    all necessary approvals for the clinical trial have been received. 
2007  4.6  System Failure 
2008  Contingency procedures should be in place to prevent loss or lack of accessibility to data 
2009  essential to participant safety, trial decisions or trial outcomes. 
2010  4.7  Technical Support 
2011  4.7.1  Where appropriate, there should be mechanisms (e.g., help desk support) in place to 
2012  document, evaluate and manage issues with the computerised systems (e.g., raised by 
2013  users), and there should be periodic review of these cumulative issues to identify those 
2014  that are repeated and/or systemic. 
2015   
2016  4.7.2  Defects and issues should be resolved according to their criticality. Issues with high 
2017  criticality should be resolved in a timely manner. 
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ICH E6(R3) Guideline 
 
 
2018  4.8  User Management 
2019  4.8.1  Access controls are integral to computerised systems used in clinical trials to limit 
2020  system access to authorised users and to ensure attributability to an individual. The 
2021  security measures should be selected in such a way that they achieve the intended 
2022  security and do not unduly impact user-friendliness. 
2023  4.8.2  Procedures should be in place to ensure that user access rights are appropriately 
2024  assigned based on a users duties and functions, blinding arrangements and the 
2025  organisation to which users belong. Access rights should be revoked when they are 
2026  no longer needed. 
2027  4.8.3  Authorised users and access privileges should be clearly documented, maintained and 
2028  retained. These records should include any updates to a users roles, access rights and 
2029  permissions, and time of access privileges given (e.g., time stamp). 
  48   
ICH E6(R3) Guideline 
 
2030  GLOSSARY 
2031  Adverse Events and Adverse Reaction-related definitions: 
2032  Adverse Event (AE): Any unfavourable medical occurrence in a trial participant. The 
2033  adverse event does not necessarily have a causal relationship with the treatment. 
2034  Adverse Drug Reaction (ADR): 
2035    in the pre-approval clinical experience with a new investigational product or its new 
2036  usages  (particularly  as  the  therapeutic  dose(s)  may  not  be  established): 
2037  unfavourable and unintended responses, such as a sign (e.g., laboratory results), 
2038  symptoms or disease related to any dose of a medicinal product where a causal 
2039  relationship between a medicinal product and an adverse event is a reasonable 
2040  possibility. The level of certainty about the relatedness of the adverse drug reaction 
2041  to an investigational product will vary. If the ADR is suspected to be medicinal 
2042  product-related with a high level of certainty, it should be included in the reference 
2043  safety information (RSI) and/or the Investigators Brochure (IB). 
2044   
2045    for  marketed  medicinal  products:  a  response  to  a  drug  that  is  noxious  and 
2046  unintended and that occurs at doses normally used in humans for prophylaxis, 
2047  diagnosis or therapy of diseases or for modification of physiological function. 
2048  (See ICH E2A Clinical Safety Data Management: Definitions and Standards for 
2049  Expedited Reporting). 
2050  Serious Adverse Event (SAE): Any unfavourable medical occurrence that is considered 
2051  serious at any dose if it: 
2052    results in death 
2053    is life-threatening 
2054    requires inpatient hospitalisation or prolongation of existing hospitalisation 
2055    results in persistent or significant disability/incapacity 
2056    is a congenital anomaly/birth defect (see ICH E2A) 
2057  Suspected Unexpected Serious Adverse Reaction (SUSAR): an adverse reaction that 
2058  meets three criteria: suspected, unexpected and serious. 
2059    Suspected: There is a reasonable possibility that the drug caused the adverse drug 
2060  reaction. 
2061   
2062    Unexpected: An adverse reaction, the nature or severity of which is not consistent 
2063  with the applicable product information (e.g., the RSI, see glossary term contained 
2064  within the Investigators Brochure or alternative documents according to applicable 
2065  regulatory requirements. Refer to ICH E2F Development Safety Update Report for 
2066  more information about RSI. 
2067   
2068    Serious: See above for SAE. 
2069 
  49   
ICH E6(R3) Guideline 
 
 
2070  Agreement 
2071  A document or set of documents describing the details of any arrangements on delegation or 
2072  transfer, distribution and/or sharing of activities and, if appropriate, on financial matters 
2073  between two or more parties. This could be in the form of a contract. The protocol may serve 
2074  as the basis of an agreement. 
2075  Applicable Regulatory Requirement(s) 
2076  Any law(s)  and  regulation(s)  addressing the  conduct  of clinical  trials  of  investigational 
2077  products. 
2078  Assent 
2079  Affirmative agreement of a minor to participate in clinical trial. The absence of expression of 
2080  agreement or disagreement should not be interpreted as assent. 
2081  Audit 
2082  A systematic and independent examination of trial-related activities and records performed by 
2083  the sponsor, service provider (including contract research organisation (CRO)) or institution to 
2084  determine whether the evaluated trial-related activities were conducted and the data were 
2085  recorded, analysed and accurately reported according to the protocol, applicable standard 
2086  operating procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory 
2087  requirement(s). 
2088  Audit Certificate 
2089  A declaration of confirmation by the auditor that an audit has taken place. 
2090  Audit Report 
2091  A record describing the conduct and outcome of the audit. 
2092  Audit Trail 
2093  Metadata records that allow reconstruction of the course of events by capturing details on 
2094  actions (manual or automated) performed relating to information and data collection and, where 
2095  applicable, to activities in computerised systems. The audit trail should show activities, initial 
2096  entry, and changes to data fields or records, by whom, when and, where applicable, why. In 
2097  computerised systems, the audit trail should be secure, computer generated and timestamped. 
2098  Blinding/Masking 
2099  A procedure in which one or more parties to the trial are kept unaware of the treatment 
2100  assignment(s). Single-blinding usually refers to the participant(s) being unaware, and double- 
2101  blinding usually refers to the participant(s), investigator(s) or other trial staff, as appropriate, 
2102  being unaware of the treatment assignment(s). 
2103  Case Report Form (CRF) 
2104  A tool designed to record protocol-required information to be reported by the investigator to 
2105  the sponsor on each trial participant (see Data Acquisition Tool). 
 
2106 
  50   
ICH E6(R3) Guideline 
 
 
2107  Certified Copy 
2108  A copy (irrespective of the type of media used) of the original record that has been verified 
2109  (i.e., by a dated signature or by generation through a validated process) to have the same 
2110  information as the original, including relevant metadata, where applicable. 
2111  Clinical Trial 
2112  Any interventional investigation in human participants intended to discover or verify the 
2113  clinical,  pharmacological  and/or  other  pharmacodynamic  effects  of  an  investigational 
2114  product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to 
2115  study absorption, distribution, metabolism and excretion of an investigational product(s) with 
2116  the object of ascertaining its safety and/or efficacy. 
2117  Clinical Trial/Study Report (CSR) 
2118  A documented description of a trial of any investigational product conducted in human 
2119  participants, in which the clinical and statistical description, presentations and analyses are 
2120  fully integrated into a single report (see ICH E3 Structure and Content of Clinical Study 
2121  Reports). 
2122  Comparator 
2123  An investigational or authorised medicinal product (i.e., active control), placebo or standard of 
2124  care used as a reference in a clinical trial. 
2125  Compliance (in relation to trials) 
2126  Adherence to the trial-related requirements, GCP requirements and the applicable regulatory 
2127  requirements. 
2128  Confidentiality 
2129  Prevention of disclosure to other than authorised individuals of a sponsors proprietary 
2130  information or of a participants identity or their confidential information. 
2131  Coordinating Investigator 
2132  An investigator assigned the responsibility for the coordination of investigators at different 
2133  investigator sites participating in a multicentre trial (if appropriate). 
2134  Computerised Systems Validation 
2135  A process of establishing and documenting that the specified requirements of a computerised 
2136  system can be consistently fulfilled from design until decommissioning of the system or 
2137  transition to a new system. The approach to validation should be based on a risk assessment 
2138  that takes into consideration the intended use of the system and the potential of the system to 
2139  affect trial participant protection and the reliability of trial results. 
2140  Contract Research Organisation (CRO) 
2141  See Service Provider. 
 
2142 
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2143  Data Acquisition Tool (DAT) 
2144  A paper or electronic tool designed to collect data and associated metadata from a data 
2145  originator in a clinical trial according to the protocol and to report the data to the sponsor. 
2146  The data originator may be a human (e.g., the participant or trial staff), a machine (e.g., 
2147  wearables and sensors) or an electronic transfer of data from one system to another (e.g., 
2148  extraction of data from an electronic health record or laboratory system). 
2149  Examples of DATs include but are not limited to CRFs, interactive response technologies 
2150  (IRTs), patient-reported outcomes (PROs), clinical outcome assessments (COAs) and wearable 
2151  devices, irrespective of the media used. 
2152  Direct Access 
2153  Permission to examine, analyse and verify records that are important to the evaluation of a 
2154  clinical trial and may be performed in person or remotely. Any party (e.g., domestic and foreign 
2155  regulatory  authorities,  sponsors  monitors  and  auditors)  with  direct  access  should  take 
2156  reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
2157  maintain the confidentiality of participants identities and their data and sponsors proprietary 
2158  information. 
2159  Essential Records 
2160  Essential records are the documents and data (and relevant metadata), in any format, associated 
2161  with a clinical trial that facilitate the ongoing management of the trial and collectively allow 
2162  the evaluation of the methods used, the factors affecting a trial and the actions taken during the 
2163  trial conduct to determine the reliability of the trial results produced and the verification that 
2164  the trial was conducted in accordance with GCP and applicable regulatory requirements (see 
2165  Appendix C. Essential Records for the Conduct of a Clinical Trial). 
2166  Good Clinical Practice (GCP) 
2167  A standard for the planning, initiating, performing, recording, oversight, evaluation, analysis 
2168  and reporting of clinical trials that provides assurance that the data and reported results are 
2169  reliable and that the rights, safety and well-being of trial participants are protected. 
2170  Impartial Witness 
2171  A person who is independent of the trial who cannot be unfairly influenced by people involved 
2172  with the trial, who attends the informed consent process if the participant or the participants 
2173  legally acceptable representative cannot read, and who reads the informed consent form and 
2174  any other documented information supplied or read to the participant and/or their legally 
2175  acceptable representative. 
2176  Independent Data Monitoring Committee (IDMC) 
2177  An independent data monitoring committee (e.g., data safety monitoring board) that may be 
2178  established by the sponsor to assess at intervals the progress of a clinical trial, the safety data 
2179  and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, 
2180  modify or stop a trial. 
 
2181 
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2182  Informed Consent 
2183  A process by which a participant or their legally accepted representative voluntarily confirms 
2184  their willingness to participate in a trial after having been informed and been provided with the 
2185  opportunity to discuss all aspects of the trial that are relevant to the participants decision to 
2186  participate. Varied approaches to the provision of information and the discussion about the trial 
2187  can be used. This can include, for example, providing text in different formats, images and 
2188  videos and using telephone or video conferencing with investigator site staff. Informed consent 
2189  is documented by means of a written or electronic, signed and dated informed consent form. 
2190  Obtaining consent remotely may be considered when appropriate. 
2191  Inspection 
2192  The act by a regulatory authority(ies) of conducting an official review of documents, facilities, 
2193  records and any other resources that are deemed by the authority(ies) to be related to the clinical 
2194  trial and that may be accessed at the investigator site, at the sponsors and/or service providers 
2195  (including CROs) facilities, or at other establishments deemed appropriate by the regulatory 
2196  authority(ies). Some aspects of the inspection may be conducted remotely. 
2197  Institution 
2198  Any public or private entity or agency or medical or dental organisation in whose remit clinical 
2199  trials are conducted. 
2200  Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
2201  An independent body (a review board or a committee, institutional, regional, national or 
2202  supranational)  constituted  of  medical  professionals  and  non-medical  members  whose 
2203  responsibility it is to ensure the protection of the rights, safety and well-being of human 
2204  participants involved in a trial and to provide public assurance of that protection by, among 
2205  other things, reviewing and approving/providing favourable opinion on the trial protocol, the 
2206  suitability of the investigator(s), the facilities, and the methods and material to be used in 
2207  obtaining  and  documenting  informed  consent  of  the  trial  participants.  The  legal  status, 
2208  composition, function, operations and regulatory requirements pertaining to IRBs/IECs may 
2209  differ among countries but should allow the IRB/IEC to act in agreement with GCP as described 
2210  in this guideline. 
2211  Interim Clinical Trial/Study Report 
2212  A report of intermediate results and their evaluation based on analyses performed during the 
2213  course of a trial. 
2214  Investigational Product 
2215  A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in 
2216  a clinical trial, including a product with a marketing authorisation when used or assembled 
2217  (formulated or packaged) in a way different from the approved form, or when used for an 
2218  unapproved indication, or when used to gain further information about an approved use. 
2219 
2220 
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2221  Investigator 
2222  A person responsible for the conduct of the clinical trial, including the trial participants for 
2223  whom that person has responsibility during the conduct of the trial. If a trial is conducted by a 
2224  team of individuals, the investigator is the responsible leader of the team and may be called the 
2225  principal investigator. Where an investigator/institution is referenced in this guideline, it 
2226  describes expectations that may be applicable to the investigator and/or the institution in some 
2227  regions. Where required by the applicable regulatory requirements, the investigator should 
2228  be read as investigator and/or the institution. 
2229  Investigators Brochure (IB) 
2230  A compilation of the clinical and nonclinical data on the investigational product(s) that is 
2231  relevant to the study of the investigational product(s) in human participants (see Appendix A. 
2232  Investigators Brochure). 
2233  Investigator Site 
2234  The  location(s)  at  or  from  where  trial-related  activities  are  conducted  under  the 
2235  investigators/institutions supervision. 
2236  Legally Acceptable Representative 
2237  An individual or juridical or other body authorised under applicable law to consent, on behalf 
2238  of a prospective participant, to the participants participation in the clinical trial. 
2239  Metadata 
2240  The contextual information required to understand a given data element. Metadata is structured 
2241  information that describes, explains or otherwise makes it easier to retrieve, use or manage 
2242  data. For the purpose of this guideline, relevant metadata are those needed to reconstruct the 
2243  trial conduct. 
2244  Monitoring 
2245  The act of overseeing the progress of a clinical trial and of ensuring that the clinical trial is 
2246  conducted, recorded and reported in accordance with the protocol, SOPs, GCP and the 
2247  applicable regulatory requirement(s). 
2248  Monitoring Plan 
2249  A  document  that  describes  the  strategy,  methods,  responsibilities  and  requirements  for 
2250  monitoring the trial. 
2251  Monitoring Report 
2252  A documented report following site and/or centralised monitoring activities. 
2253  Multicentre Trial 
2254  A clinical trial conducted according to a single protocol but at more than one investigator site. 
2255  Nonclinical Study 
2256  Biomedical studies not performed on human participants. 
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2257  Original Medical Record 
2258  See Source Records. 
2259  Protocol 
2260  A document that describes the objective(s), design, methodology, statistical considerations and 
2261  organisation of a trial. The protocol usually also gives the background and rationale for the 
2262  trial, but these could be provided in other protocol referenced documents. Throughout the ICH 
2263  GCP Guideline, the term protocol refers to protocol and protocol amendments. 
2264  Protocol Amendment 
2265  A documented description of a change(s) to a protocol. 
2266  Quality Assurance (QA) 
2267  All those planned and systematic actions that are established to ensure that the trial is performed 
2268  and the data are generated, documented (recorded) and reported in compliance with GCP and 
2269  the applicable regulatory requirement(s). 
2270  Quality Control (QC) 
2271  The operational techniques and activities undertaken to verify that the requirements for quality 
2272  of the trial-related activities have been fulfilled. 
2273  Randomisation 
2274  The process of deliberately including an element of chance when assigning participants to 
2275  groups that receive different treatments in order to reduce bias. 
2276  Reference Safety Information (RSI) 
2277  Contains a cumulative list of ADRs that are expected for the investigational product being 
2278  administered to participants in a clinical trial. The RSI is included in the  Investigators 
2279  Brochure. 
2280  Regulatory Authorities 
2281  Bodies having the power to regulate, including those that review submitted protocols and 
2282  clinical data and those that conduct inspections. These bodies are sometimes referred to as 
2283  competent authorities. 
2284  Service Provider 
2285  A person or organisation (commercial, academic or other) providing a service used during the 
2286  conduct of a clinical trial to either the sponsor or the investigator to fulfil one or more of their 
2287  trial-related activities. 
2288  Signature 
2289  A unique mark, symbol or entry in line with applicable regulatory requirements and/or practice 
2290  to show expression of will and allow authentication of the signatory. 
 
2291 
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ICH E6(R3) Guideline 
 
 
2292  Source Records 
2293  Original documents or data (which includes relevant metadata) or certified copies of the 
2294  original documents or data, irrespective of the media used. This may include trial participants 
2295  medical/health records/notes/charts; data provided/entered by trial participants (e.g., electronic 
2296  patient-reported  outcome  (ePROs));  healthcare  providers  records  from  pharmacies, 
2297  laboratories  and  other  facilities  involved  in  the  clinical  trial;  and  data  from  automated 
2298  instruments, such as wearables and sensors. 
2299  Sponsor 
2300  An individual, company, institution, or organisation that takes responsibility for the initiation, 
2301  management and arrangement of the financing of a clinical trial. A clinical trial may have one 
2302  or several sponsors where permitted under regulatory requirements. All sponsors have the 
2303  responsibilities of a sponsor set out in this guideline. In accordance with regulatory 
2304  requirements, sponsors may decide in a documented agreement setting out their respective 
2305  responsibilities. Where the agreement does not specify to which sponsor a given responsibility 
2306  is attributed, that responsibility lies with all sponsors. 
2307  Sponsor-Investigator 
2308  An individual who both initiates and conducts, alone or with others, a clinical trial, and under 
2309  whose immediate direction the investigational product is administered to, dispensed to or used 
2310  by a participant. The term does not include any person other than an individual (e.g., the term 
2311  does not include a corporation or an agency). The obligations of a sponsor-investigator include 
2312  both those of a sponsor and those of an investigator. 
2313  Standard Operating Procedures (SOPs) 
2314  Detailed, documented instructions to achieve uniformity of the performance of a specific 
2315  activity. 
2316  Sub-investigator 
2317  Any individual member of the clinical trial team designated and supervised by the investigator 
2318  to perform critical trial-related procedures and/or to make important trial-related decisions 
2319  (e.g., associates, residents, research fellows). 
2320  Trial Participant 
2321  An individual who participates in a clinical trial, either as a recipient of the investigational 
2322  product(s) or as a control. 
2323  Trial Participant Identification Code 
2324  A unique identifier assigned to each trial participant to protect the participants identity and 
2325  used in lieu of the participants name when the investigator reports adverse events and/or other 
2326  trial-related data. 
2327  Vulnerable Participants 
2328  Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the 
2329  expectation, whether justified or not, of benefits associated with participation or of a retaliatory 
  56   
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2330  response from senior members of a hierarchy in case of refusal to participate. Examples are 
2331  members of a group with a hierarchical structure, such as medical, pharmacy, dental and 
2332  nursing  students;  subordinate  hospital  and  laboratory  personnel;  employees  of  the 
2333  pharmaceutical industry; members of the armed forces and persons kept in detention. Other 
2334  vulnerable participants may include persons in nursing homes, unemployed or impoverished 
2335  persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, 
2336  refugees, minors and those incapable of giving consent. 
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2337  APPENDICES 
2338  Appendix A. INVESTIGATORS BROCHURE 
2339  A.1  Introduction 
2340  The Investigators Brochure (IB) is a compilation of the clinical and nonclinical data on the 
2341  investigational product(s)1 that are relevant to the study of the product(s) in human participants. 
2342  Its purpose is to provide the investigators and others involved in the trial with the information 
2343  to facilitate their understanding of the rationale for and their compliance with many key features 
2344  of the protocol, such as the dose, dose frequency/interval, methods of administration and safety 
2345  monitoring procedures. 
2346   
2347  A.1.1  Development of the Investigators Brochure 
2348  Generally, the sponsor is responsible for ensuring that an up-to-date IB is developed. 
2349  In the case of an investigator-initiated trial, the sponsor-investigator should determine 
2350  whether a brochure is available from the product license/marketing authorisation 
2351  holder. If the investigational product is provided by the sponsor-investigator, then they 
2352  should  provide  the  necessary  information  to  the  investigator  site  staff.  Where 
2353  permitted by regulatory authorities, the current scientific information such as a basic 
2354  product  information  brochure  (e.g.,  summary  of  product  characteristics  package 
2355  leaflet, or labelling) may be an appropriate alternative, provided that it includes 
2356  current, comprehensive and detailed information on all aspects of the investigational 
2357  product that might be of importance to the investigator. If an authorised medicinal 
2358  product is being studied for a new use (i.e., a new indication), an IB specific to that 
2359  new use should be prepared unless there is a rationale for only one IB. The IB should 
2360  be reviewed at least annually and revised as necessary in compliance with a sponsors 
2361  documented procedures. More frequent revision may be appropriate depending on the 
2362  stage of development and the generation of relevant new information. Relevant new 
2363  information may be so important that it needs to be communicated to the investigators 
2364  and possibly to the IRBs/IECs and/or regulatory authorities before it is included in a 
2365  revised IB. 
2366   
2367  A.1.2  Reference Safety Information and Risk-Benefit Assessment 
2368  The reference safety information (RSI) contained in the IB provides an important 
2369  reference point for expedited reporting of suspected unexpected serious adverse 
2370  reactions (SUSARs) in the clinical trial. The IB also provides insight to support the 
2371  clinical management of the participants during the course of the clinical trial. The 
2372  information should be presented in a concise, simple, objective, balanced and non- 
2373  promotional form that enables a clinician or potential investigator to understand it and 
2374  make  their  own  unbiased  risk-benefit  assessment  of  the  appropriateness  of  the 
2375  proposed trial. For this reason, a medically qualified person should be involved in the 
2376  generation of an IB, but the contents of the IB should be approved by the disciplines 
2377  that generated the described data. 
 
 
 
 
1 For the purpose of this guideline, the term investigational products should be considered synonymous with 
drugs, medicines, medicinal products, vaccines and biological products. 
  58   
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2378  A.2  General Considerations 
 
2379  These considerations delineate the minimum information that should be included in an IB. It is 
2380  expected  that  the  type  and  extent  of  information  available  will  vary  with  the  stage  of 
2381  development of the investigational product. 
2382  The IB should include; 
2383  A.2.1  Title Page 
2384  This should provide the sponsors name, the identity of each investigational product 
2385  (i.e., research number, chemical or approved generic name and trade name(s) where 
2386  legally permissible and desired by the sponsor) and the release date. It is also 
2387  suggested that an edition number and a reference to the number and date of the edition 
2388  it supersedes be provided along with the cut-off date for data inclusion in the version. 
2389  Where appropriate, a signature page may be included. 
2390  A.2.2  Confidentiality Statement 
2391  The sponsor may wish to include a statement instructing the investigator and other 
2392  recipients to treat the IB as a confidential document for the sole information and use 
2393  of the investigator/institution, investigator site staff, regulatory authorities and the 
2394  institutional review board/independent ethics committee (IRB/IEC). 
2395  A.3  Contents of the Investigators Brochure 
2396  The IB should contain the following sections, each with literature references (publications or 
2397  reports) included at the end of each chapter, where appropriate; 
2398  A.3.1  Table of Contents 
2399  A.3.2  Summary 
2400  A brief summary (preferably not exceeding two pages) should be given, highlighting 
2401  the significant physical, chemical, pharmaceutical, pharmacological, toxicological, 
2402  pharmacokinetic, metabolic and clinical information available that is relevant to the 
2403  stage of clinical development of the investigational product. 
2404  A.3.3  Introduction 
2405  A brief introductory statement should be provided that contains the chemical name 
2406  (and generic and trade name(s) when approved) of the investigational product(s); all 
2407  active ingredients; the pharmacological class of the investigational product(s) and its 
2408  expected position within this class (e.g., advantages); the rationale for performing 
2409  research with the investigational product(s);  and the anticipated prophylactic, 
2410  therapeutic or diagnostic indication(s). Finally, the introductory statement should 
2411  provide the general approach to be followed in evaluating the investigational product. 
2412  A.3.4  Physical, Chemical and Pharmaceutical Properties and Formulation 
2413  A description  should be  provided  of  the  investigational  product  substance(s) 
2414  (including the chemical and/or structural formula(e)), and a brief summary should be 
2415  given of the relevant physical, chemical and pharmaceutical properties. 
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2416  To permit appropriate safety measures to be taken in the course of the trial, a 
2417  description of the formulation(s) to be used, including excipients, should be provided 
2418  and justified if clinically relevant. Instructions for the storage and handling of the 
2419  dosage form(s) should also be given. 
2420  Any structural similarities to other known compounds should be mentioned. 
2421  A.3.5  Nonclinical Studies 
2422  Introduction 
2423  The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic and 
2424  investigational product metabolism studies should be provided in summary form. This 
2425  summary should address the methodology used, the results and a discussion of the 
2426  relevance of the findings to the investigated therapeutic and the possible unfavourable 
2427  and unintended effects in humans. 
2428  The  information  provided  may  include  the  following,  as  appropriate,  if 
2429  known/available: 
2430    species tested 
2431    number and sex of animals in each group 
2432    unit dose (e.g., milligram/kilogram (mg/kg)) 
2433    dose interval 
2434    route of administration 
2435    duration of dosing 
2436    information on systemic distribution 
2437    duration of post-exposure follow-up 
2438    results, including the following aspects: 
2439  nature and frequency of pharmacological or toxic effects 
-  
2440  severity or intensity of pharmacological or toxic effects 
-  
2441  time to onset of effects 
-  
2442  reversibility of effects 
-  
2443  duration of effects 
-  
2444  dose response 
-  
2445  Tabular format/listings should be used whenever possible to enhance the clarity of the 
2446  presentation. 
2447  The following sections should discuss the most important findings from the studies, 
2448  including the dose response of observed effects, the relevance to humans and any 
2449  aspects to be studied in humans. If applicable, the effective and nontoxic dose findings 
2450  in the same animal species should be compared (i.e., the therapeutic index should be 
2451  discussed). The relevance of this information to the proposed human dosing should 
2452  be  addressed.  Whenever  possible,  comparisons  should  be  made  in  terms  of 
2453  blood/tissue levels rather than on a mg/kg basis. 
2454  (a)  Nonclinical Pharmacology 
2455  A summary of the pharmacological aspects of the investigational product and, where 
2456  appropriate, its significant metabolites studied in animals should be included. Such a 
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ICH E6(R3) Guideline 
 
 
2457  summary should incorporate studies that assess potential therapeutic activity (e.g., 
2458  efficacy models, receptor binding and specificity) as well as those that assess safety 
2459  (e.g.,  special  studies  to  assess  pharmacological  actions  other  than  the  intended 
2460  therapeutic effect(s)). 
 
2461  (b)  Pharmacokinetics and Product Metabolism in Animals 
 
2462  A summary of the pharmacokinetics and biological transformation and disposition of 
2463  the investigational product in all species studied should be given. The discussion of 
2464  the findings should address the absorption and the local and systemic bioavailability 
2465  of  the  investigational  product  and  its  metabolites  and  their  relationship  to  the 
2466  pharmacological and toxicological findings in animal species. 
2467  (c)  Toxicology 
 
2468  A summary of the  toxicological  effects  found  in  relevant  studies  conducted in 
2469    different animal species should be described under the following headings where 
2470    appropriate: 
 
2471    single dose 
2472      repeated dose 
2473      carcinogenicity 
2474      special studies (e.g., irritancy and sensitisation) 
2475      reproductive toxicity 
2476      genotoxicity (mutagenicity) 
2477  A.3.6  Effects in Humans 
2478  Introduction 
2479  A thorough discussion of the known effects of the investigational product(s) in 
2480  humans should be provided, including information on pharmacokinetics, metabolism, 
2481  pharmacodynamics, dose response, safety, efficacy  and other pharmacological 
2482  activities. Where possible, a summary of each completed clinical trial and ongoing 
2483  trials where interim results are available that may inform the safety evaluation should 
2484  be provided. Information should also be provided regarding results of any use of the 
2485  investigational product(s) other than from in clinical trials, such as from experience 
2486  during marketing. 
 
2487  (a)  Pharmacokinetics and Product Metabolism in Humans 
2488  A summary of information on the pharmacokinetics of the investigational product(s) 
2489  should be presented, including the following, if available: 
2490    pharmacokinetics  (including  metabolism,  as  appropriate,  and  absorption, 
2491  plasma protein binding, distribution and elimination) 
2492    bioavailability of the investigational product (absolute, where possible, and/or 
2493  relative) using a reference dosage form 
2494    population subgroups (e.g., sex, age and impaired organ function) 
2495    interactions (e.g., product-product interactions and effects of food) 
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2496     other pharmacokinetic data (e.g., results of population studies performed within 
2497    clinical trial(s)) 
2498     
2499  (b)  Safety and Efficacy 
 
2500  A  summary  of  information  should  be  provided  about  the  investigational 
2501  products/products  (including  metabolites,  where  appropriate)  safety, 
2502  pharmacodynamics, efficacy and dose response that was obtained from preceding 
2503  trials  in  humans  (healthy  volunteers  and/or  patients).  The  implications  of  this 
2504  information should be discussed. In cases where a number of clinical trials have been 
2505  completed, the use of summaries of safety and efficacy across multiple trials by 
2506  indications in  subgroups  may provide  a clear  presentation  of the data.  Tabular 
2507  summaries of adverse drug reactions for all the clinical trials (including those for all 
2508  the studied indications) would be useful. Important differences in adverse drug 
2509  reaction patterns/incidences across indications or subgroups should be discussed. 
2510  The IB should provide a description of the possible risks and adverse drug reactions 
2511  to be anticipated on the basis of prior experiences with the product under investigation 
2512  and with related products. There should be a list of adverse reactions, clearly identified 
2513  as the reference safety information section, including information on their frequency 
2514  and nature. This list should be used for determining the expectedness of a suspected 
2515  serious adverse reaction and subsequently whether it needs  to  be  expedited in 
2516  accordance with regulatory requirements. A description should also be provided of 
2517  the precautions or special monitoring to be done as part of the investigational use of 
2518  the product(s). 
2519  (c)  Marketing Experience 
2520  The IB should identify countries where the investigational product has been marketed 
2521  or approved. Any significant information arising from the marketed use should be 
2522  summarised (e.g., formulations, dosages, routes of administration, adverse drug 
2523  reactions). The IB should also identify all the countries where the investigational 
2524  product did not receive approval/registration for marketing or was withdrawn from 
2525  marketing/registration. 
2526  A.3.7  Summary of Data and Guidance for the Investigator 
2527  This section should provide an overall discussion of the nonclinical and clinical data 
2528  and should summarise the information from various sources on different aspects of 
2529  the investigational product(s), wherever possible. In this way, the investigator can be 
2530  provided with the most informative interpretation of the available data and with an 
2531  assessment of the implications of the information for future clinical trials. 
2532  Where appropriate, the published reports on related products should be discussed. 
2533  This could help the investigator to anticipate adverse drug reactions or other problems 
2534  in clinical trials. 
2535  The overall aim of this section is to provide the investigator with a clear understanding of the 
2536  possible risks and adverse reactions and of the specific tests, observations and precautions that 
2537  may be needed for a clinical trial. This understanding should be based on the available physical, 
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2538  chemical, pharmaceutical, pharmacological, toxicological and clinical information on the 
2539  investigational product(s). Guidance should also be provided to the clinical investigator on the 
2540  recognition and treatment of possible overdose and adverse drug reactions that is based on 
2541  previous human experience and on the pharmacology of the investigational product. 
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2542  Appendix B. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 
2543  Clinical trials should be described in a clear, concise and operationally feasible protocol. The 
2544  protocol should be designed in such a way as to minimise unnecessary complexity and to 
2545  mitigate or eliminate important risks to the rights, safety, and wellbeing of trial participants 
2546  and the reliability of data. Protocol development processes should incorporate input from 
2547  relevant stakeholders, where appropriate. Building adaptability into the protocol, for example, 
2548  by including acceptable ranges for specific protocol provisions, can reduce the number of 
2549  deviations or in some instances the requirement for a protocol amendment. Such adaptability 
2550  should not adversely affect participant safety or the scientific validity of the trial. For additional 
2551  information, refer to ICH E8(R1) General Considerations for Clinical Studies and ICH E9 
2552  Statistical Principles for Clinical Trials. 
2553  The contents of a trial protocol should generally include the following topics, which may vary 
2554  depending on the trial design. Investigator site-specific information may be provided on 
2555  separate protocol page(s) or addressed in a separate agreement, and some of the information 
2556  listed  below  may be  contained  in  other  protocol  referenced  documents,  such  as  an 
2557  Investigators Brochure. 
2558  B.1  General Information 
2559  B.1.1  Protocol title, unique protocol identifying number, and date. Any amendment(s) 
2560  should also bear the amendment number(s) and date(s). 
2561  B.1.2  Name and address of the sponsor. 
2562  B.1.3  Name and title of the person(s) authorised to sign the protocol and the protocol 
2563  amendment(s) for the sponsor. 
2564  B.2  Background Information 
2565  B.2.1  Name and description of the investigational product(s). 
2566  B.2.2  A  summary  of  findings  from  nonclinical  studies  that  potentially  have  clinical 
2567  significance and from clinical trials that are relevant to the trial. 
2568  B.2.3  Summary of the known and potential risks and benefits, if any, to human participants. 
2569  B.2.4  Description of and justification for the route of administration, dosage, dosage 
2570  regimen and treatment period(s). 
2571  B.2.5  A statement that the trial will be conducted in compliance with the protocol, Good 
2572  Clinical Practice (GCP) and the applicable regulatory requirement(s). 
2573  B.2.6  Description of the population to be studied. 
2574  B.2.7  References to literature and data that are relevant to the trial and that provide 
2575  background for the trial. 
2576  B.3  Trial Objectives and Purpose 
2577  A clear description of the scientific objectives and the purpose of the trial. Information on 
2578  estimands, where appropriate, if not included in any other trial-related document, see ICH 
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2579  E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline 
2580  on Statistical Principles for Clinical Trials. 
2581  B.4  Trial Design 
 
2582  The scientific integrity of the trial and the reliability of the results from the trial depend 
2583  substantially on the trial design. A description of the trial design should include: 
2584  B.4.1  A specific statement of the primary endpoints and the secondary endpoints, if any, to 
2585  be measured during the trial. 
2586  B.4.2  A description of the type and design of trial to be conducted (e.g., double-blind, 
2587  placebo-controlled, parallel design, adaptive design, platform/umbrella/basket, trials 
2588  with decentralised elements) and a schematic diagram of trial design, procedures and 
2589  stages. 
2590  B.4.3  A description of the measures taken to minimise/avoid bias, including: 
2591  (a)  Randomisation 
2592  (b)  Blinding 
2593  B.4.4  A description of the trial treatment(s) and the dosage and dosage regimen of the 
2594  investigational product(s), including a description of the dosage form, packaging and 
2595  labelling. 
2596  B.4.5  The expected duration of the participants involvement in the trial and a description 
2597  of the sequence and duration of all trial periods, including follow-up, if any. 
2598  B.4.6  A description of the stopping rules or discontinuation criteria and dose 
2599  adjustment or dose interruption for individual participants, parts of trial and entire 
2600  trial. 
2601  B.4.7  Accountability procedures for the investigational product(s), including the placebo(s) 
2602  and other comparator(s), if any. 
2603  B.4.8  Maintenance of treatment randomisation codes and procedures for breaking codes. 
2604  B.5  Selection of Participants 
2605  B.5.1  Participant inclusion criteria. 
2606  B.5.2  Participant exclusion criteria. 
2607  B.5.3  Mechanism for pre-screening, where appropriate, and screening of participants. 
2608  B.6  Withdrawal of Consent or Discontinuation of Participation 
2609  The investigator may choose to discontinue the participant, or the participant may 
2610  withdraw their consent. The protocol should specify: 
2611  (a)  when and how to discontinue participants from the trial/investigational product 
2612  treatment; 
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2613    (b)  the type and timing of the data to be collected for withdrawn/discontinued 
2614    participants, including the process by which the data are handled, in accordance 
2615    with applicable regulatory requirements; 
 
2616  (c)  whether and how participants are to be replaced; 
 
2617  (d)  the  follow-up  for  participants  who  have  discontinued  the  use  of  the 
2618    investigational product. 
2619  B.7  Treatment and Interventions for Participants 
2620  B.7.1  The treatment(s) to be administered, including the name(s) of all the product(s), the 
2621    dose(s), the dosing schedule(s), the criteria for dose adjustment(s), the route/mode(s) 
2622    of administration and the treatment period(s), including the follow-up period(s) for 
2623    participants for each investigational product treatment/trial treatment group/arm of the 
2624    trial. 
2625  B.7.2  Medication(s)/treatment(s) permitted (including concomitant and rescue medication) 
2626    and not permitted before and/or during the trial. 
2627  B.7.3  Strategies to monitor the participants adherence to treatment. 
2628  B.8  Assessment of Efficacy 
2629  B.8.1  Specification of the efficacy parameters, where applicable. 
2630  B.8.2  Methods and timing for assessing, recording and analysing of efficacy parameters. 
2631    Where any trial-related committees (e.g., independent data monitoring committee 
2632    (IDMC)/adjudication committees) are utilised for the purpose of assessing efficacy 
2633    data, procedures, timing and activities should be described in the protocol or a separate 
2634    document. 
2635  B.9  Assessment of Safety 
2636  B.9.1  Specification of safety parameters. 
2637  B.9.2  The methods, extent and timing for recording and assessing safety parameters. Where 
2638    any trial-related committees (e.g., IDMC) are utilised for the purpose of assessing 
2639    safety data, procedures, timing and activities should be described in the protocol or a 
2640    separate document. 
2641  B.9.3  Procedures for obtaining reports of and for recording and reporting adverse event and 
2642    intercurrent events; see ICH E9(R1). 
2643  B.9.4  The type and duration of the follow-up of participants after adverse events. 
2644  B.10  Statistical Considerations 
2645  B.10.1  A description of the statistical methods to be employed, including timing and purpose 
2646    of any planned interim analysis(ses) and the criteria for the stopping of the trial. 
2647  B.10.2  The number of participants planned to be enrolled and the reason for the choice of 
2648    sample size, including reflections on or calculations of the power of the trial and 
2649    clinical justification. 
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2650  B.10.3  The level of significance to be used or the threshold for success on the posterior 
2651    probability in a Bayesian design. 
2652  B.10.4  The criteria for the termination of the trial and the criteria for the stopping of the trial. 
2653  B.10.5  The  selection  of  participants  to  be  included  in  the  planned  analyses  (e.g.,  all 
2654    randomised participants, all dosed participants, all eligible participants, all evaluable 
2655    participants). 
2656  B.10.6  Procedures for accounting for missing, unused and spurious data. 
2657  B.10.7  Statement that any deviation(s) from the statistical analysis plan will be described and 
2658    justified in the clinical study report. 
2659  B.11  Direct Access to Source Records 
2660  The sponsor should ensure that it is specified in the protocol or other documented agreement 
2661  that the investigator(s)/institution(s)/service provider(s) will permit trial-related monitoring, 
2662  audits, institutional review board/independent  ethics  committee (IRB/IEC) review and 
2663  regulatory inspection(s), providing direct access to source records. 
2664  B.12  Quality Control and Quality Assurance 
2665  B.12.1  Description of identified quality factors  and associated risks in the trial unless 
2666  documented elsewhere. 
2667  B.12.2  Description of the monitoring approaches that are part of the quality control process 
2668  for the clinical trial. 
2669  B.12.3  Description of the process for the handling of non-compliance with the protocol or 
2670  GCP. 
2671  B.13  Ethics 
2672  Description of ethical considerations relating to the trial. 
2673  B.14  Data Handling and Record Keeping 
2674  B.14.1  Specification of data to be collected and the method of its collection. Where necessary, 
2675  additional details should be contained in a clinical trial-related document. 
2676  B.14.2  The identification of records to be recorded directly into the data acquisition tools 
2677  (i.e., no prior written or electronic record of data) and considered to be source data. 
2678  B.14.3  A statement that records should be retained in accordance with applicable regulatory 
2679  requirements. 
2680  B.15  Financing and Insurance 
2681  Financing and insurance, if not addressed in a separate agreement. 
2682  B.16  Publication Policy 
2683  Publication policy, if not addressed in a separate agreement. 
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2684  Appendix C. ESSENTIAL RECORDS FOR THE CONDUCT OF A CLINICAL TRIAL 
2685  C.1  Introduction 
2686  C.1.1  Many records are generated before and during the conduct of a clinical trial. The 
2687  nature and extent of those records generated and maintained are dependent upon the 
2688  trial design, its conduct, application of proportional approaches and the importance 
2689  and relevance of that record to the trial. 
2690   
2691  C.1.2  Determining which records are essential will be based upon consideration of the 
2692  guidance in this appendix. 
2693   
2694  C.1.3  The essential records permit and contribute to the evaluation of the conduct of a trial 
2695  and the reliability of the results produced. They serve to demonstrate the compliance 
2696  of the investigator and sponsor with the standards of Good Clinical Practice (GCP) 
2697  and applicable regulatory requirements. The essential records are used as part of the 
2698  sponsor oversight or investigator supervision of the trial. These records are used by 
2699  the  sponsors  independent  audit  function  and  during  inspections  by  regulatory 
2700  authority(ies) to assess the trial conduct and the reliability of the trial results. The 
2701  investigator/institution should have access to and the ability to maintain and retain the 
2702  essential records generated by the investigator/institution before, during and after the 
2703  trial. 
2704  C.2  Management of Essential Records 
2705  C.2.1  Records should be identifiable and version controlled, and should include authors, 
2706  reviewers and approvers as appropriate, along with date and signature (electronic or 
2707  wet ink), where necessary. 
2708   
2709  C.2.2  For activities that are transferred or delegated to service providers by the sponsor or 
2710  investigator/institution respectively, arrangements should be made for the access and 
2711  management of the essential records throughout the trial and for their retention 
2712  following completion of the trial. 
2713   
2714  C.2.3  These essential records should be maintained in or referred to from repositories, 
2715  including, for example, the trial master file (TMF) or investigator site file (ISF). The 
2716  TMF is held by the sponsor or by the investigator; in the latter case, it is often called 
2717  the ISF. 
2718   
2719  C.2.4  The sponsor and investigator/institution should maintain a record of where essential 
2720  records are located, including source records. The storage system(s) used during the 
2721  trial and for archiving (irrespective of the type of media used) should provide for 
2722  appropriate identification, version history, search and retrieval of trial records. 
2723   
2724  C.2.5  The sponsor and investigator/institution should ensure that the essential records are 
2725  collected and filed in a timely manner, including those required to be in place prior to 
2726  the trial start, which can greatly assist in the successful management of a trial. 
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2727  C.2.6  The sponsor and investigator/institution should retain the essential records in a way 
2728  that ensures that they remain complete, readable and readily available and are directly 
2729  accessible upon request by regulatory authorities. Alteration to the essential records 
2730  should be traceable. 
2731   
2732  C.2.7  The original version of the essential record should be retained by the responsible party 
2733  (sponsor or investigator). When a copy is used to permanently replace the original 
2734  essential record, the copy should fulfil the requirements for certified copies. 
2735   
2736  C.2.8  In order to fulfil their responsibilities in the conduct of the trial, the sponsor and 
2737  investigator/institution  may  need  access  to  or  copies  of  one  anothers  relevant 
2738  essential records before, during and after the trial is completed. This will determine 
2739  whether    the    record    resides    in    the    repositories    of    the    sponsor,    the 
2740  investigator/institution, or both. There should be careful consideration of sharing of 
2741  records subject to data protection legislation and blinding considerations in line with 
2742  applicable regulatory requirements. For the sharing of essential records with service 
2743  providers, see section C.2.2. 
2744   
2745  C.2.9  Certain essential records may not be specific to a trial but may be related to the 
2746  systems and processes involved in running multiple trials and retained outside the 
2747  trial-specific repositories (e.g., standard operating procedures validation records, 
2748  master services agreements). 
2749  C.3  Essentiality of Trial Records 
2750  C.3.1  Whether a specific clinical trial record generated before, during and after the trial is 
2751  essential and needs to be retained should be based on the following criteria: 
2752  (a)  Is a document that is submitted to or issued by the regulatory authority or 
2753  IRB/IEC, including related correspondence and those documenting regulatory 
2754  decisions or approvals/favourable opinions; 
2755  (b)  Is a trial-specific procedure or plan; 
2756  (c)  Is relevant correspondence or documentation of meetings related to important 
2757  discussions and/or trial-related decisions that have been made related to the 
2758  conduct of the trial and the processes being used; 
2759  (d)  Documents the conduct of relevant trial procedures; 
2760  (e)  Documents  the  arrangements  between  parties  and  insurance/indemnity 
2761  arrangements; 
2762  (f)  Documents  the  compliance  with  the  requirements  and  any conditions  of 
2763  approval  from  the  regulatory  authority  or  the  favourable  opinion  of  the 
2764  institutional review board/independent ethics committee (IRB/IEC); 
2765  (g)  Documents  the  composition  and,  where  appropriate,  the  functions, 
2766  correspondence and decisions of any committees involved in the trial approval 
2767  or its conduct. 
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2768  (h)  Demonstrates that a trial-specific computerised system is validated and that 
2769    non-trial-specific  systems  have  been  assessed  as  fit  for  purpose  for  their 
2770    intended use in the trial; 
2771  (i)  Is  a  document  that  has  been  authorised/signed  by  the  sponsor  and/or 
2772    investigator to confirm review or approval; 
2773  (j)  Is, where necessary, documentation that demonstrates signatures/initials of staff 
2774    undertaking trial-specific activities; for example, completing data acquisition 
2775    tools; 
2776  (k)  Documents what information was provided to potential trial participants and 
2777    that participants informed consent was appropriately obtained and maintained; 
2778  (l)  Documents that sponsor personnel involved in the trial conduct and individuals 
2779    performing trial-specific activities on their behalf are qualified by education, 
2780    training and experience to undertake their activities; 
2781  (m)  Documents that the investigator and those individuals delegated trial-specific 
2782    activities by the investigator are qualified by education, training and experience 
2783    to undertake their activities, particularly where the activities are not part of their 
2784    normal role; 
2785  (n)  Contains the data as well as relevant metadata that would be needed to be able 
2786    to reconstruct the trial; 
2787  (o)  Are documents related to the sponsor and investigator oversight of safety of 
2788    trial participants during the trial, including compliance with safety reporting 
2789    requirements between sponsors and investigators, regulatory authorities and 
2790    IRBs/IECs and informing trial participants of safety information as necessary; 
2791  (p)  Documents that service providers are suitably qualified for conducting their 
2792    delegated or transferred activities; 
2793  (q)  Documents that laboratory activities and other tests used in the trial are fit for 
2794    purpose; 
2795  (r)  Documents sponsor oversight of investigator site selection and monitoring and 
2796    audit of the trial, where appropriate, and provides information on arising 
2797    issues/non-compliance  and  deviations  detected  and  implementation  of 
2798    corrective and preventative actions; 
2799  (s)  Documents  the  compliance  with  the  protocol  and/or  procedures  for 
2800    management and statistical analysis of the data and production of any interim 
2801    report and the final report; 
2802  (t)  Documents  the  collection,  chain  of  custody,  analysis  and  retention  or 
2803    destruction of biological samples; 
2804  (u)  Provides relevant information on the investigational product and its labelling; 
2805  (v)  Provides  information  about  the  shipment,  storage,  packaging,  dispensing, 
2806    randomisation and blinding of the investigational product; 
2807  (w)  Provides, where appropriate, traceability and accountability information about 
2808    the investigational product from release from the manufacturer to dispensation, 
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2809    administration to trial participants, and return and destruction, or alternative 
2810    disposition; 
2811  (x)  Provides information on the identity and quality of the investigational product 
2812    used in the trial; 
2813  (y)  Documents processes and activities relating to unblinding; 
2814  (z)  Documents the recruitment, pre-trial screening and consenting process of trial 
2815    participants and their identity and chronological enrolment as appropriate; 
2816  (aa)  Documents the existence of the trial participants and substantiates the integrity 
2817    of trial data collected. Includes source records related to the trial and medical 
2818    treatments and history of the trial participants; 
2819  (bb)  Defines processes/practices in place in the event of a security breach in order to 
2820    protect participants rights, safety and well-being and the integrity of the data. 
 
2821  C.3.2  Applying  the  criteria  in  section  C.3.1,  the  trial  records  for  every  trial  that  are 
2822  considered essential, except in justifiable and documented exceptional circumstances, 
2823  are set out in Table 1, and these should be retained. 
2824   
2825  C.3.3  For other trial records, their presence and nature are dependent upon the trial design, 
2826  its conduct and risk proportional management. Table 2 lists potential trial records that 
2827  when generated, would be considered essential by applying the criteria in section 
2828  C.3.1 and should be retained. This is not an exhaustive list, and other trial records may 
2829  also be considered essential by the sponsor or the investigator. 
2830 
  Table 1  Essential Records for All Trials 
1.1  Investigators Brochure or basic product information brochure (e.g., summary of 
product characteristic, package leaflet or labelling) and relevant updates 
1.2  signed protocol and amendments during the trial 
1.3  dated, documented approval/favourable opinion of IRB/IEC of information provided 
to them before and during the trial 
1.4  IRB/IEC composition 
1.5  regulatory authority(ies) authorisation, approval and/or notification of the protocol 
and subsequent protocol amendments during the trial (where required) 
1.6  completed signed and dated informed consent forms 
1.7  completed participant identification code list and enrolment log 
1.8  - notification by originating investigator to sponsor of serious adverse events (SAEs) 
and related reports, where required 
- notification  by  sponsor  and/or  investigator,  where  required,  to  regulatory 
authority(ies) and IRB(s)/IEC(s) of suspected unexpected serious adverse reactions 
(SUSARs) and of other safety information 
- notification by sponsor to investigators of safety information, where required 
1.9  interim or annual reports to IRB/IEC and regulatory authority(ies) 
1.10  source records 
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  Table 1  Essential Records for All Trials 
1.11  data and relevant metadata (including documentation of data corrections) in the data 
acquisition tools 
1.12  final report by investigator to IRB/IEC and regulatory authority(ies), where required 
1.13  interim (where applicable) and final clinical trial reports 
2831 
 
  Table 2  Potential Essential Records 
2.1  sample of data acquisition tools (e.g., case report forms (CRFs), diaries, clinical 
outcome assessments, patient-reported outcomes) that are provided to the investigator 
and/or IRB/IEC 
  sample of information given to trial participants and revisions during the trial 
2.2  - informed consent materials (including all applicable translations) 
- any other documented information, e.g., instructions for use of an investigational 
product or a device 
- advertisement for participant recruitment 
2.3  financial aspects of the trial 
2.4  insurance statement 
2.5  signed agreement between involved parties, e.g., 
-  investigator/institution and sponsor 
-  investigator/institution and service providers 
-  sponsor and service providers 
-  sponsor and independent data monitoring committee (IDMC) members 
2.6  curriculum  vitae  and/or  other  relevant  documents  evidencing  qualifications  of 
investigator(s) and sub-investigator(s) involved in conducting the trial 
2.7  trial-specific training records 
2.8  documentation of delegation of activities by the investigator to investigator site staff 
2.9  signature sheet documenting signatures and initials of delegated investigator site staff 
2.10  normal value(s)/range(s) for medical/laboratory/technical procedure(s) and/or test(s) 
included in the protocol and updates during the trial conduct 
2.11  certification or accreditation or established quality control and/or external quality 
assessment  or  other  validation  (where  required)  of  medical/laboratory/technical 
procedures/tests used during the trial conduct and any updates 
2.12  documentation of collection, processing and shipment of body fluids/tissue samples 
2.13  documentation of body fluids/tissue samples storage conditions 
2.14  record of retained body fluids/tissue samples at the end of the trial 
2.15  sample of label(s) attached to investigational product container(s) 
2.16  instructions for handling of investigational product(s) and trial-related materials (if 
not included in protocol or Investigators Brochure), for example, pharmacy manual 
2.17  shipping records for investigational product(s) and trial-related materials 
2.18  certificate(s) of analysis of investigational product(s) shipped 
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  Table 2  Potential Essential Records 
2.19  investigational product(s) accountability at investigator site 
2.20  documentation of investigational product storage conditions during shipment and at 
the trial site 
2.21  records of relabelling of investigational product at trial site 
2.22  documentation of investigational product destruction 
2.23  emergency decoding procedures for blinded trials 
2.24  master randomisation list 
2.25  instructions for use for critical trial-specific systems (e.g., interactive response 
technologies (IRT) user manual, electronic CRF (eCRF) manual) 
2.26  maintenance and calibration records for critical trial-specific equipment 
2.27  treatment allocation and decoding documentation 
2.28  completed participants screening log 
2.29  site monitoring reports (including site selection, initiation, routine and close-out) 
2.30  centralised monitoring reports 
2.31  records and reports of protocol and GCP non-compliance/deviations and corrective 
and preventative actions 
2.32  documentation of relevant communications and meetings 
2.33  audit certificate 
2.34  documentation relating to data finalisation for analysis (e.g., query resolutions, SAE 
reconciliation, quality control reports, coding completion, output data sets) 
2.35  documentation of trial-specific computerised system validation (e.g., specifications, 
testing, validation report, change control) 
2.36  documentation relating to the statistical considerations and analysis (e.g., sample size 
calculations, analysis sets decisions, analysis datasets, analysis programs, quality 
control records and output) 
2.37  trial-specific plans (e.g., risk management, monitoring, safety, data management, data 
validation and statistical analysis) and procedures 
2.38  procedures, meeting minutes and submissions to the IDMC 
 
2832 
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