E6(R2) Good Clinical 
Practice: Integrated 
Addendum to ICH E6(R1) 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
March 2018 
Procedural 
 
OMB Control No. 0910-0014 
Current expiration date available at https://www.reginfo.gov 
(Search ICR and enter OMB control number) 
See additional PRA statement in section 9 of this guidance 
 
16676fnlPRAupdate11-3-23   
 
 
 
 
E6(R2) Good Clinical 
Practice: Integrated 
Addendum to ICH E6(R1) 
Guidance for Industry  
 
 
Additional copies are available from:  
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 885-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
 
Office of Communication, Outreach and Development 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
March 2018 
Procedural 
 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
INTRODUCTION ................................................................................................................ 1 
l.  GLOSSARY ...................................................................................................................... 3 
2.  THE PRINCIPLES OF ICH GCP .......................................................................... 11 
3.  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE (IRB/IEC) ........................................................................................ 12 
3.1  Responsibilities ........................................................................................................ 12 
3.2  Composition, Functions, and Operations ........................................................... 13 
3.3  Procedures .................................................................................................................. 14 
3.4  Records ........................................................................................................................ 15 
4.  INVESTIGATOR ........................................................................................................ 15 
4.l  Investigators Qualifications and Agreements .................................................. 15 
4.2  Adequate Resources ................................................................................................. 15 
4.3  Medical Care of Trial Subjects .............................................................................. 16 
4.4  Communication with IRB/IEC .............................................................................. 16 
4.5  Compliance with Protocol ....................................................................................... 17 
4.6  Investigational Product(s) ....................................................................................... 17 
4.7  Randomization Procedures and Unblinding ..................................................... 18 
4.8  Informed Consent of Trial Subjects ..................................................................... 18 
4.9  Records and Reports ............................................................................................... 22 
4.10 Progress Reports ....................................................................................................... 23 
4.11 Safety Reporting ...................................................................................................... 23 
4.12 Premature Termination or Suspension of a Trial ............................................ 23 
4.13 Final Report(s) by Investigator ............................................................................. 24 
5.  SPONSOR ...................................................................................................................... 24 
  5.0   Quality Management ............................................................................................... 24   
   
5.l  Quality Assurance and Quality Control ............................................................. 25 
5.2  Contract Research Organization (CRO) ............................................................ 26 
5.3  Medical Expertise ..................................................................................................... 26 
5.4  Trial Design ................................................................................................................ 26 
5.5  Trial Management, Data Handling, and Recordkeeping ................................ 27 
5.6  Investigator Selection ............................................................................................... 28 
5.7  Allocation of Responsibilities ................................................................................... 29 
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5.8  Compensation to Subjects and Investigators ..................................................... 29 
5.9  Financing .................................................................................................................... 29 
5.10 Notification/Submission to Regulatory Authority(ies) ...................................... 30 
5.11 Confirmation of Review by IRB/IEC ................................................................... 30 
5.12 Information on Investigational Product(s) ......................................................... 30 
5.13 Manufacturing, Packaging, Labeling, and Coding Investigational Product(s)
 ....................................................................................................................................... 30 
5.14 Supplying and Handling Investigational Product(s) ........................................ 31 
5.15 Record Access ............................................................................................................. 32 
5.16 Safety Information.................................................................................................... 32 
5.17 Adverse Drug Reaction Reporting ........................................................................ 33 
5.18 Monitoring................................................................................................................. 33 
5.18.1  Purpose.............................................................................................................. 33 
5.18.2  Selection and Qualifications of Monitors ....................................................... 33 
5.18.3  Extent and Nature of Monitoring ................................................................... 33 
5.18.4  Monitor's Responsibilities .............................................................................. 34 
5.18.5  Monitoring Procedures .................................................................................. 36 
5.18.6  Monitoring Report ......................................................................................... 36 
5.18.7  Monitoring Plan ............................................................................................... 37 
5.19 Audit ............................................................................................................................ 37 
5.19.1  Purpose ........................................................................................................... 37 
5.19.2  Selection and Qualification of Auditors ...................................................... 37 
5.19.3  Auditing Procedures ....................................................................................... 37 
5.20 Noncompliance ........................................................................................................... 38 
5.21 Premature Termination or Suspension of a Trial ............................................ 38 
5.22 Clinical Trial/Study Reports .................................................................................. 38 
5.23 Multicenter Trials .................................................................................................... 38 
6.  CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) ..... 39 
6.l  General Information ............................................................................................... 39 
6.2  Background Information ........................................................................................ 39 
6.3  Trial Objectives and Purpose ................................................................................ 40 
6.4  Trial Design ................................................................................................................ 40 
6.5  Selection and Withdrawal of Subjects ................................................................. 41 
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6.6  Treatment of Subjects ............................................................................................. 41 
6.7  Assessment of Efficacy .............................................................................................. 41 
6.8  Assessment of Safety.................................................................................................. 41 
6.9  Statistics ...................................................................................................................... 42 
6.10 Direct Access to Source Data/Documents ............................................................ 42 
6.11 Quality Control and Quality Assurance ............................................................ 42 
6.12 Ethics ........................................................................................................................... 42 
6.13 Data Handling and Recordkeeping ...................................................................... 42 
6.14 Financing and Insurance ........................................................................................ 42 
6.15 Publication Policy ..................................................................................................... 42 
6.16 Supplements .............................................................................................................. 42 
7.  INVESTIGATOR'S BROCHURE .......................................................................... 43 
7.l  Introduction .............................................................................................................. 43 
7.2  General Considerations........................................................................................... 43 
7.2.1  Title Page ......................................................................................................... 44 
7.2.2  Confidentiality Statement ............................................................................... 45 
7.3  Contents of the Investigator's Brochure ............................................................. 45 
7.3.1  Table of Contents  ............................................................................................ 45 
7.3.2  Summary ........................................................................................................... 45 
7.3.3  Introduction ...................................................................................................... 45 
7.3.4  Physical, Chemical, and Pharmaceutical Properties and Formulation .... 45 
7.3.5  Nonclinical Studies .......................................................................................... 45 
7.3.6  Effects in Humans ........................................................................................... 47 
7.3.7  Summary of Data and Guidance for the Investigator ................................. 48 
7.4  APPENDIX l ................................................................................................................ 49 
7.5  APPENDIX 2 .............................................................................................................. 50 
8.  ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
 .......................................................................................................................................... 51 
8.l  Introduction .............................................................................................................. 51 
8.2  Before the Clinical Phase of the Trial Commences ............................................ 52 
8.3  During the Clinical Conduct of the Trial ............................................................ 56 
8.4  After Completion or Termination of the Trial ......................................................... 61 
9.  PAPERWORK REDUCTION ACT OF 1995 ................................................................ 63 
 
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  Contains Nonbinding Recommendations 
E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1) 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
INTRODUCTION 
 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting trials that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, and 
well-being of trial subjects are protected, consistent with the principles that have their origin 
in the Declaration of Helsinki, and that the clinical trial data are credible. 
 
The objective of this ICH GCP guidance is to provide a unified standard for the European 
Union, Japan, and the United States to facilitate the mutual acceptance of clinical data  by 
the regulatory authorities in these jurisdictions. 
 
The guidance was developed with consideration of the current good clinical practices of the 
European Union, Japan, and the United States, as well as those of Australia, Canada, the 
Nordic countries, and the World Health Organization. 
 
This guidance should be followed when generating clinical trial data that are intended to be 
submitted to regulatory authorities. 
 
The principles established in this guidance may also be applied to other clinical  investigations 
that may have an impact on the safety and well-being of human subjects. 
 
 
1 This guidance was developed within the Expert Working Group (Procedural) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and 
has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has 
been endorsed by the ICH Management Committee at Step 4 of the ICH process, November 2016. At Step 4 of the 
process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the 
United States authorities represented at ICH. 
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  Contains Nonbinding Recommendations 
ADDENDUM 
 
Since the development of the ICH GCP Guidance, the scale, complexity, and cost of clinical 
trials have increased. Evolutions in technology and risk management processes offer new 
opportunities to increase efficiency and focus on relevant activities. When the original ICH 
E6(R1) text was prepared, clinical trials were performed in a largely paper-based process. 
Advances in use of electronic data recording and reporting facilitate implementation of other 
approaches. For example, centralized monitoring can now offer a greater advantage, to a 
broader range of trials than is suggested in the original text. Therefore, this guidance has 
been amended to encourage implementation of improved and more efficient approaches to 
clinical trial design, conduct, oversight, recording, and reporting while continuing to ensure 
human subject protection and reliability of trial results. Standards regarding electronic 
records and essential documents intended to increase clinical trial quality and efficiency have 
also been updated. 
 
This guidance should be read in conjunction with other ICH guidances relevant to the conduct 
of clinical trials (e.g., E2A (clinical safety data management), E3 (clinical study reporting), 
E7 (geriatric populations), E8 (general considerations for clinical trials), E9  (statistical 
principles), and E11 (pediatric populations)). 
 
This ICH GCP Guidance Integrated Addendum provides a unified standard for the European 
Union, Japan, the United States, Canada, and Switzerland to facilitate the mutual acceptance 
of data from clinical trials by the regulatory authorities in these jurisdictions. In the event of 
any conflict between the E6(R1) text and the E6(R2) addendum text, the E6(R2) addendum 
text should take priority. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
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  Contains Nonbinding Recommendations 
l.  GLOSSARY 
 
1.1  Adverse Drug Reaction (ADR) 
In the preapproval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered adverse drug 
reactions. The phrase responses to a medicinal product means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
 
Regarding marketed medicinal products: A response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting). 
 
1.2  Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (see 
the ICH Guidance for Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
 
1.3  Amendment (to the protocol) 
See Protocol Amendment. 
 
1.4  Applicable Regulatory Requirement(s) 
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products. 
 
1.5  Approval (in relation to institutional review boards (IRBs)) 
The affirmative decision of the IRB that the clinical trial has been reviewed and may be 
conducted at the institution site within the constraints set forth by the IRB, the institution, good 
clinical practice (GCP), and the applicable regulatory requirements. 
 
1.6  Audit 
A systematic and independent examination of trial-related activities and documents to determine 
whether the evaluated trial-related activities were conducted, and the data were recorded, 
analyzed, and accurately reported according to the protocol, sponsor's standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s). 
 
1.7  Audit Certificate 
A declaration of confirmation by the auditor that an audit has taken place. 
 
1.8  Audit Report 
A written evaluation by the sponsors auditor of the results of the audit. 
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1.9  Audit Trail 
Documentation that allows reconstruction of the course of events. 
 
1.10  Blinding/Masking 
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double- 
blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data 
analyst(s) being unaware of the treatment assignment(s). 
 
1.11  Case Report Form (CRF) 
A printed, optical, or electronic document designed to record all of the protocol required 
information to be reported to the sponsor on each trial subject. 
 
1.12  Clinical Trial/Study 
Any investigation in human subjects intended to discover or verify the clinical, pharmacological 
and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any 
adverse reactions to an investigational product(s), and/or to study absorption, distribution, 
metabolism, and excretion of an investigational product(s) with the object of ascertaining its 
safety and/or efficacy. The terms clinical trial and clinical study are synonymous. 
 
1.13  Clinical Trial/Study Report 
A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent 
conducted in human subjects, in which the clinical and statistical description, presentations, and 
analyses are fully integrated into a single report (see the ICH Guidance for Structure and Content 
of Clinical Study Reports). 
 
1.14  Comparator (Product) 
An investigational or marketed product (i.e., active control), or placebo, used as a reference in a 
clinical trial. 
 
1.15  Compliance (in relation to trials) 
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, and 
the applicable regulatory requirements. 
 
1.16  Confidentiality 
Prevention of disclosure, to other than authorized individuals, of a sponsors proprietary 
information or of a subjects identity. 
 
1.17  Contract 
A written, dated, and signed agreement between two or more involved parties that sets out any 
arrangements on delegation and distribution of tasks and obligations and, if appropriate, on 
financial matters. The protocol may serve as the basis of a contract. 
 
1.18  Coordinating Committee 
A committee that a sponsor may organize to coordinate the conduct of a multicenter trial. 
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1.19  Coordinating Investigator 
An investigator assigned the responsibility for the coordination of investigators at different 
centers participating in a multicenter trial.  
 
l.20  Contract Research Organization (CRO) 
A person or an organization (commercial, academic, or other) contracted by the sponsor to 
perform one or more of a sponsor's trial-related duties and functions. 
 
l.2l  Direct Access 
Permission to examine, analyze, verify, and reproduce any records and reports that are important 
to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, 
sponsors monitors, and auditors) with direct access should take all reasonable precautions 
within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality 
of subjects identities and sponsors proprietary information. 
 
1.22  Documentation 
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical 
records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, 
and/or results of a trial, the factors affecting a trial, and the actions taken. 
 
1.23  Essential Documents 
Documents that individually and collectively permit evaluation of the conduct of a study and the 
quality of the data produced (see section 8. Essential Documents for the Conduct of a Clinical 
Trial). 
 
1.24  Good Clinical Practice (GCP) 
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and 
reporting of clinical trials that provides assurance that the data and reported results are credible 
and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. 
 
1.25  Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring 
Board, Monitoring Committee, Data Monitoring Committee) 
An independent data monitoring committee that may be established by the sponsor to assess at 
intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to 
recommend to the sponsor whether to continue, modify, or stop a trial. 
 
1.26  Impartial Witness 
A person, who is independent of the trial, who cannot be unfairly influenced by people involved 
with the trial, who attends the informed consent process if the subject or the subjects legally 
acceptable representative cannot read, and who reads the informed consent form and any other 
written information supplied to the subject. 
 
1.27  Independent Ethics Committee (IEC) 
An independent body (a review board or a committee, institutional, regional, national, or 
supranational), constituted of medical professionals and non-medical members, whose 
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responsibility it is to ensure the protection of the rights, safety and well-being of human subjects 
involved in a trial and to provide public assurance of that protection, by, among other things, 
reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the 
investigator(s), facilities, and the methods and material to be used in obtaining and documenting 
informed consent of the trial subjects. 
 
The legal status, composition, function, operations and regulatory requirements pertaining to 
Independent Ethics Committees may differ among countries, but should allow the Independent 
Ethics Committee to act in agreement with GCP as described in this guidance. 
 
1.28  Informed Consent 
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
subjects decision to participate. Informed consent is documented by means of a written, signed, 
and dated informed consent form. 
 
1.29  Inspection 
The act by a regulatory authority(ies) of conducting an official review of documents, facilities, 
records, and any other resources that are deemed by the authority(ies) to be related to the clinical 
trial and that may be located at the site of the trial, at the sponsors and/or contract research 
organizations (CROs) facilities, or at other establishments deemed appropriate by the regulatory 
authority(ies). 
 
1.30  Institution (medical) 
Any public or private entity or agency or medical or dental facility where clinical trials are 
conducted. 
 
l.31  Institutional Review Board (IRB) 
An independent body constituted of medical, scientific, and nonscientific members, whose 
responsibility is to ensure the protection of the rights, safety and well-being of human subjects 
involved in a trial by, among other things, reviewing, approving, and providing continuing 
review of trial protocols and amendments and of the methods and material to be used in 
obtaining and documenting informed consent of the trial subjects. 
 
1.32  Interim Clinical Trial/Study Report 
A report of intermediate results and their evaluation based on analyses performed during the 
course of a trial. 
 
1.33  Investigational Product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a 
clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use. 
 
1.34  Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted by a 
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team of individuals at a trial site, the investigator is the responsible leader of the team and may 
be called the principal investigator. (See also Subinvestigator.) 
 
1.35  Investigator/Institution 
An expression meaning the investigator and/or institution, where required by the applicable 
regulatory requirements. 
 
1.36  Investigators Brochure 
A compilation of the clinical and nonclinical data on the investigational product(s) that is 
relevant to the study of the investigational product(s) in human subjects (see section 7. 
Investigators Brochure). 
 
1.37  Legally Acceptable Representative 
An individual or juridical or other body authorized under applicable law to consent, on behalf of 
a prospective subject, to the subjects participation in the clinical trial. 
 
1.38  Monitoring 
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, 
recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), 
GCP, and the applicable regulatory requirement(s). 
 
1.39  Monitoring Report   
A written report from the monitor to the sponsor after each site visit and/or other trial-related 
communication according to the sponsors SOPs. 
 
1.40  Multicenter Trial 
A clinical trial conducted according to a single protocol but at more than one site, and therefore, 
carried out by more than one investigator. 
 
1.41  Nonclinical Study 
Biomedical studies not performed on human subjects. 
 
1.42  Opinion (in relation to Independent Ethics Committee) 
The judgment and/or the advice provided by an Independent Ethics Committee (IEC). 
 
1.43  Original Medical Record 
See Source Documents. 
 
1.44  Protocol 
A document that describes the objective(s), design, methodology, statistical considerations, and 
organization of a trial. The protocol usually also gives the background and rationale for the trial, 
but these could be provided in other protocol referenced documents. Throughout the ICH GCP 
Guidance, the term protocol refers to protocol and protocol amendments. 
 
1.45  Protocol Amendment 
A written description of a change(s) to or formal clarification of a protocol. 
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1.46  Quality Assurance (QA) 
All those planned and systematic actions that are established to ensure that the trial is performed 
and the data are generated, documented (recorded), and reported in compliance with GCP and 
the applicable regulatory requirement(s). 
 
1.47  Quality Control (QC) 
The operational techniques and activities undertaken within the quality assurance system to 
verify that the requirements for quality of the trial-related activities have been fulfilled. 
 
1.48  Randomization 
The process of assigning trial subjects to treatment or control groups using an element of chance 
to determine the assignments in order to reduce bias. 
 
1.49  Regulatory Authorities 
Bodies having the power to regulate.  In the ICH GCP guidance, the expression Regulatory 
Authorities includes the authorities that review submitted clinical data and those that conduct 
inspections (see 1.29).  These bodies are sometimes referred to as competent authorities. 
 
1.50  Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) 
Any untoward medical occurrence that at any dose:  
 
  Results in death,  
-
  Is life-threatening, 
-
  Requires inpatient hospitalization or prolongation of existing hospitalization, 
-
  Results in persistent or significant disability/incapacity, or 
-
  Is a congenital anomaly/birth defect. 
-
 
(See the ICH guidance for Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting.) 
 
1.51  Source Data 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source documents (original records or certified copies). 
 
1.52  Source Document 
Original documents, data, and records (e.g., hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as  being accurate copies, microfiches, photographic negatives, microfilm  or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial). 
 
1.53  Sponsor 
An individual, company, institution, or organization that takes responsibility for the initiation, 
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management, and/or financing of a clinical trial. 
 
1.54  Sponsor-Investigator 
An individual who both initiates and conducts, alone or with others, a clinical trial, and under 
whose immediate direction the investigational product is administered to, dispensed to, or used 
by a subject. The term does not include any person other than an individual (e.g., it does not 
include a corporation or an agency). The obligations of a sponsor-investigator include both those 
of a sponsor and those of an investigator. 
 
1.55  Standard Operating Procedures (SOPs) 
Detailed, written instructions to achieve uniformity of the performance of a specific function. 
 
1.56  Subinvestigator 
Any individual member of the clinical trial team designated and supervised by the investigator at 
a trial site to perform critical trial-related procedures and/or to make important trial-related 
decisions (e.g., associates, residents, research fellows). See also Investigator. 
 
1.57  Subject/Trial Subject 
An individual who participates in a clinical trial, either as a recipient of the investigational 
product(s) or as a control. 
 
1.58  Subject Identification Code 
A unique identifier assigned by the investigator to each trial subject to protect the subjects 
identity and used in lieu of the subjects name when the investigator reports adverse events 
and/or other trial-related data. 
 
1.59  Trial Site 
The location(s) where trial-related activities are actually conducted. 
 
1.60  Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigators Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). (See the ICH Guidance for 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.) 
 
1.61  Vulnerable Subjects 
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the 
expectation, whether justified or not, of benefits associated with participation, or of a retaliatory 
response from senior members of a hierarchy in case of refusal to participate. Examples are 
members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing 
students, subordinate hospital and laboratory personnel, employees of the pharmaceutical 
industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects 
include patients with incurable diseases, persons in nursing homes, unemployed or impoverished 
persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, 
refugees, minors, and those incapable of giving consent. 
 
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1.62  Well-being (of the trial subjects) 
The physical and mental integrity of the subjects participating in a clinical trial. 
 
ADDENDUM 
 
1.63  Certified Copy 
A copy (irrespective of the type of media used) of the original record that has been verified (i.e., 
by a dated signature or by generation through a validated process) to have the same information, 
including data that describe the context, content, and structure, as the original. 
 
1.64  Monitoring Plan 
A document that describes the strategy, methods, responsibilities, and requirements for 
monitoring the trial. 
 
1.65  Validation of Computerized Systems 
A process of establishing and documenting that the specified requirements of a computerized 
system can be consistently fulfilled from design until decommissioning of the system or 
transition to a new system. The approach to validation should be based on a risk assessment that 
takes into consideration the intended use of the system and the potential of the system to affect 
human subject protection and reliability of trial results. 
 
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2.  THE PRINCIPLES OF ICH GCP 
 
2.l  Clinical trials should be conducted in accordance with the ethical principles that 
have  their origin in the Declaration of Helsinki, and that are consistent with GCP 
and the applicable regulatory requirement(s). 
 
2.2  Before a trial is initiated, foreseeable risks and inconveniences should be weighed 
against the anticipated benefit for the individual trial subject and society. A trial should 
be initiated and continued only if the anticipated benefits justify the risks. 
 
2.3  The rights, safety, and well-being of the trial subjects are the most important 
considerations and should prevail over interests of science and society. 
 
2.4  The available nonclinical and clinical information on an investigational product 
should be adequate to support the proposed clinical trial. 
 
2.5  Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 
 
2.6  A trial should be conducted in compliance with the protocol that has received prior 
institutional review board (IRB)/independent ethics committee (IEC) 
approval/favorable opinion. 
 
2.7  The medical care given to, and medical decisions made on behalf of, subjects 
should always be the responsibility of a qualified physician or, when appropriate, of 
a qualified dentist. 
 
2.8  Each individual involved in conducting a trial should be qualified by education, 
training, and experience to perform his or her respective task(s). 
 
2.9  Freely given informed consent should be obtained from every subject prior to 
clinical trial participation. 
 
2.10  All clinical trial information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. 
ADDENDUM 
This principle applies to all records referenced in this guidance, irrespective of the type of 
media used. 
2.11  The confidentiality of records that could identify subjects should be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
 
2.12  Investigational products should be manufactured, handled, and stored in accordance with 
applicable good manufacturing practice (GMP). They should be used in accordance with  the 
approved protocol. 
 
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2.13  Systems with procedures that assure the quality of every aspect of the trial should 
be implemented. 
 
ADDENDUM   
Aspects of the trial that are essential to ensure human subject protection and reliability of trial 
results should be the focus of such systems. 
 
3.  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE (IRB/IEC) 
 
3.1  Responsibilities 
 
3.1.1   An IRB/IEC should safeguard the rights, safety, and well-being of all trial 
subjects. Special attention should be paid to trials that may include vulnerable 
subjects. 
 
3.1.2  The IRB/IEC should obtain the following documents: 
Trial protocol(s)/amendment(s), written informed consent form(s) and consent form 
updates that the investigator proposes for use in the trial, subject recruitment 
procedures (e.g., advertisements), written information to be provided to subjects, 
Investigators Brochure (IB), available safety information, information about 
payments and compensation available to subjects, the investigators current curriculum 
vitae and/or  other documentation evidencing qualifications, and any other 
documents that the IRB/IEC may need to fulfil its responsibilities. 
The IRB/IEC should review a proposed clinical trial within a reasonable time and 
document its views in writing, clearly identifying the trial, the documents reviewed 
and the dates for the following: 
 Approval/favorable opinion; 
-
 Modifications required prior to its approval/favorable opinion; 
-
 Disapproval/negative opinion; and 
-
 Termination/suspension of any prior approval/favorable opinion. 
-
 
3.1.3  The IRB/IEC should consider the qualifications of the investigator for the proposed 
trial, as documented by a current curriculum vitae and/or by any other relevant 
documentation  the IRB/IEC requests. 
 
3.1.4  The IRB/IEC should conduct continuing review of each ongoing trial at intervals 
appropriate to the degree of risk to human subjects, but at least once per year. 
 
3.1.5  The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be 
given to subjects when, in the judgment of the IRB/IEC, the additional information 
would add  meaningfully to the protection of the rights, safety, and/or well-being of 
the subjects. 
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3.1.6  When a nontherapeutic trial is to be carried out with the consent of the subjects 
legally acceptable representative (see sections 4.8.12, 4.8.14), the IRB/IEC should 
determine that the  proposed protocol and/or other document(s) adequately addresses 
relevant ethical concerns and meets applicable regulatory requirements for such trials.  
 
3.1.7  Where the protocol indicates that prior consent of the trial subject or the subjects 
legally acceptable representative is not possible (see section 4.8.15), the IRB/IEC 
should determine that  the proposed protocol and/or other document(s) adequately 
addresses relevant ethical  concerns and meets applicable regulatory requirements for 
such trials (i.e., in emergency situations). 
 
3.1.8  The IRB/IEC should review both the amount and method of payment to subjects to 
assure that neither presents problems of coercion or undue influence on the trial 
subjects.  Payments to a subject should be prorated and not wholly contingent on 
completion of the trial by the subject. 
 
3.1.9  The IRB/IEC should ensure that information regarding payment to subjects, including 
the methods, amounts, and schedule of payment to trial subjects, is set forth in the 
written informed consent form and any other written information to be provided to 
subjects. The way payment will be prorated should be specified. 
 
3.2  Composition, Functions, and Operations 
 
3.2.1  The IRB/IEC should consist of a reasonable number of members, who collectively 
have the qualifications and experience to review and evaluate the science, medical 
aspects, and  ethics of the proposed trial. It is recommended that the IRB/IEC should 
include: 
 
(a) At least five members. 
(b) At least one member whose primary area of interest is in a nonscientific area. 
(c) At least one member who is independent of the institution/trial site. 
 
Only those IRB/IEC members who are independent of the investigator and the sponsor 
of the trial should vote/provide opinion on a trial-related matter. 
 
A list of IRB/IEC members and their qualifications should be maintained. 
 
3.2.2  The IRB/IEC should perform its functions according to written operating procedures, 
should maintain written records of its activities and minutes of its meetings, and 
should comply with GCP and with the applicable regulatory requirement(s). 
 
3.2.3  An IRB/IEC should make its decisions at announced meetings at which at least a 
quorum, as stipulated in its written operating procedures, is present. 
 
3.2.4  Only members who participate in the IRB/IEC review and discussion should 
13 
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vote/provide their opinion and/or advice. 
 
3.2.5  The investigator may provide information on any aspect of the trial, but should not 
participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC. 
 
3.2.6  An IRB/IEC may invite nonmembers with expertise in special areas for assistance. 
 
3.3  Procedures 
The IRB/IEC should establish, document in writing, and follow its procedures, which 
should  include: 
 
3.3.1  Determining its composition (names and qualifications of the members) and the 
authority under which it is established. 
 
3.3.2  Scheduling, notifying its members of, and conducting its meetings. 
 
3.3.3  Conducting initial and continuing review of trials. 
 
3.3.4  Determining the frequency of continuing review, as appropriate. 
 
3.3.5  Providing, according to the applicable regulatory requirements, expedited review and 
approval/favorable opinion of minor change(s) in ongoing trials that have the 
approval/favorable opinion of the IRB/IEC. 
 
3.3.6  Specifying that no subject should be admitted to a trial before the IRB/IEC issues 
its written approval/favorable opinion of the trial. 
 
3.3.7  Specifying that no deviations from, or changes of, the protocol should be initiated 
without prior written IRB/IEC approval/favorable opinion of an appropriate 
amendment, except when necessary to eliminate immediate hazards to the subjects 
or  when the change(s) involves only logistical or administrative aspects of the trial 
(e.g., change of monitor(s), telephone number(s)) (see section 4.5.2). 
 
3.3.8  Specifying that the investigator should promptly report to the IRB/IEC: 
 
(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to 
the trial subjects (see sections 3.3.7, 4.5.2, 4.5.4). 
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct 
of the trial (see section 4.10.2). 
(c) All adverse drug reactions (ADRs) that are both serious and unexpected. 
(d) New information that may affect adversely the safety of the subjects or the 
conduct of the trial. 
 
3.3.9  Ensuring that the IRB/IEC promptly notify in writing the investigator/institution 
concerning: 
 
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(a)  Its trial-related decisions/opinions. 
(b) The reasons for its decisions/opinions. 
(c)  Procedures for appeal of its decisions/opinions. 
 
3.4  Records 
 
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, 
lists of occupations/affiliations of members, submitted documents, minutes of meetings, and 
correspondence) for a period of at least 3 years after completion of the trial and make 
them available upon request from the regulatory authority(ies). 
 
The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide 
its written procedures and membership lists. 
 
4.  INVESTIGATOR 
 
4.l  Investigators Qualifications and Agreements 
 
4.1.1  The investigator(s) should be qualified by education, training, and experience to 
assume responsibility for the proper conduct of the trial, should meet all the 
qualifications specified by the applicable regulatory requirement(s), and should 
provide evidence of such qualifications through up-to-date curriculum vitae and/or 
other relevant documentation requested by the sponsor, the IRB/IEC, and/or the 
regulatory authority(ies). 
 
4.l.2  The  investigator  should  be  thoroughly  familiar  with  the appropriate  use  of  the 
investigational product(s), as described in the protocol, in the current Investigators 
Brochure, in the product information, and in other information sources provided by 
the sponsor. 
 
4.l.3  The investigator should be aware of, and should comply with, GCP and the 
applicable regulatory requirements. 
 
4.l.4  The investigator/institution should permit monitoring and auditing by the sponsor, 
and inspection by the appropriate regulatory authority(ies). 
 
4.l.5  The investigator should maintain a list of appropriately qualified persons to whom 
the investigator has delegated significant trial-related duties. 
 
4.2  Adequate Resources 
 
4.2.1  The investigator should be able to demonstrate (e.g., based on retrospective data) a 
potential for recruiting the required number of suitable subjects within the agreed 
recruitment period. 
 
4.2.2  The investigator should have sufficient time to properly conduct and complete the 
trial within the agreed trial period. 
 
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4.2.3  The investigator should have available an adequate number of qualified staff and 
adequate facilities for the foreseen duration of the trial to conduct the trial properly 
and  safely. 
 
4.2.4  The investigator should ensure that all persons assisting with the trial are 
adequately informed about the protocol, the investigational product(s), and their trial-
related duties  and functions. 
 
ADDENDUM 
4.2.5  The investigator is responsible for supervising any individual or party to whom the 
investigator delegates trial-related duties and functions conducted at the trial site. 
 
4.2.6  If the investigator/institution retains the services of any individual or party to 
perform trial-related duties and functions, the investigator/institution should ensure this 
individual  or party is qualified to perform those trial-related duties and functions and 
should implement procedures to ensure the integrity of the trial-related duties and 
functions  performed and any data generated. 
 
4.3  Medical Care of Trial Subjects 
 
4.3.1  A qualified physician (or dentist, when appropriate), who is an investigator or a 
subinvestigator for the trial, should be responsible for all trial-related medical (or 
dental)  decisions. 
 
4.3.2  During and following a subjects participation in a trial, the investigator/institution 
should ensure that adequate medical care is provided to a subject for any adverse 
events, including clinically significant laboratory values, related to the trial. The 
investigator/institution should inform a subject when medical care is needed for 
intercurrent illness(es) of which the investigator becomes aware. 
 
4.3.3  It is recommended that the investigator inform the subjects primary physician about 
the  subjects participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
 
4.3.4  Although a subject is not obliged to give his/her reason(s) for withdrawing 
prematurely from a trial, the investigator should make a reasonable effort to ascertain 
the reason(s),  while fully respecting the subjects rights. 
 
4.4  Communication with IRB/IEC 
 
4.4.1  Before initiating a trial, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the trial protocol, written informed 
consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements), and any other written information to be provided to subjects. 
 
4.4.2  As part of the investigators/institutions written application to the IRB/IEC, the 
investigator/institution should provide the IRB/IEC with a current copy of the 
Investigators Brochure. If the Investigators Brochure is updated during the trial, the 
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  Contains Nonbinding Recommendations 
investigator/institution should supply a copy of the updated Investigators Brochure 
to the IRB/IEC. 
 
4.4.3  During the trial the investigator/institution should provide to the IRB/IEC all 
documents subject to review. 
 
4.5  Compliance with Protocol 
 
4.5.1  The investigator/institution should conduct the trial in compliance with the protocol 
agreed to by the sponsor and, if required, by the regulatory authority(ies), and which 
was given approval/favorable opinion by the IRB/IEC. The investigator/institution 
and the  sponsor should sign the protocol, or an alternative contract, to confirm 
agreement. 
 
4.5.2  The investigator should not implement any deviation from, or changes of, the 
protocol without agreement by the sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where 
necessary to eliminate an immediate hazard(s) to trial subjects, or when the 
change(s) involves only logistical or  administrative aspects of the trial (e.g., change 
in monitor(s), change of telephone number(s)). 
 
4.5.3  The investigator, or person designated by the investigator, should document and 
explain any deviation from the approved protocol. 
 
4.5.4  The investigator may implement a deviation from, or a change in, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC 
approval/favorable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted: 
 
(a) To the IRB/IEC for review and approval/favorable opinion; 
(b) To the sponsor for agreement and, if required; 
(c) To the regulatory authority(ies). 
 
4.6  Investigational Product(s) 
 
4.6.1  Responsibility for investigational product(s) accountability at the trial site(s) rests 
with the investigator/institution. 
 
4.6.2  Where allowed/required, the investigator/institution may/should assign some or all of 
the  investigators/institutions duties for investigational product(s) accountability at 
the trial  site(s) to an appropriate pharmacist or another appropriate individual who 
is under the  supervision of the investigator/institution. 
 
4.6.3  The investigator/institution and/or a pharmacist or other appropriate individual, who 
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  Contains Nonbinding Recommendations 
is designated by the investigator/institution, should maintain records of the products 
delivery to the trial site, the inventory at the site, the use by each subject, and the 
return to the sponsor or alternative disposition of unused product(s). These records 
should include dates, quantities, batch/serial numbers, expiration dates (if 
applicable), and the unique code numbers assigned to the investigational product(s) 
and trial subjects. Investigators should maintain records that document adequately 
that the subjects were  provided the doses specified by the protocol and reconcile all 
investigational product(s) received from the sponsor. 
 
4.6.4  The investigational product(s) should be stored as specified by the sponsor (see 
sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s). 
 
4.6.5  The investigator should ensure that the investigational product(s) are used only in 
accordance with the approved protocol. 
 
4.6.6  The investigator, or a person designated by the investigator/institution, should explain 
the correct use of the investigational product(s) to each subject and should check, at 
intervals appropriate for the trial, that each subject is following the instructions 
properly. 
 
4.7  Randomization Procedures and Unblinding 
The investigator should follow the trials randomization procedures, if any, and should ensure 
that the code is broken only in accordance with the protocol. If the trial is blinded, the 
investigator should promptly document and explain to the sponsor any premature unblinding 
(e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational 
product(s). 
 
4.8  Informed Consent of Trial Subjects 
 
4.8.1  In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. Prior to the beginning 
of  the trial, the investigator should have the IRB/IECs written approval/favorable 
opinion of the written informed consent form and any other written information to be 
provided to subjects. 
 
4.8.2  The written informed consent form and any other written information to be provided 
to subjects should be revised whenever important new information becomes available 
that  may be relevant to the subjects consent. Any revised written informed consent 
form, and  written information should receive the IRB/IECs approval/favorable 
opinion in advance  of use. The subject or the subjects legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the subjects willingness to continue participation 
in the trial. The communication of this  information should be documented. 
 
4.8.3  Neither the investigator, nor the trial staff, should coerce or unduly influence a subject 
to participate or to continue to participate in a trial. 
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4.8.4  None of the oral and written information concerning the trial, including the written 
informed consent form, should contain any language that causes the subject or the 
subjects legally acceptable representative to waive or to appear to waive any legal 
rights,  or that releases or appears to release the investigator, the institution, the 
sponsor, or their agents from liability for negligence. 
 
4.8.5  The investigator, or a person designated by the investigator, should fully inform the 
subject or, if the subject is unable to provide informed consent, the subjects legally 
acceptable representative, of all pertinent aspects of the trial including the written 
information and the approval/ favorable opinion by the IRB/IEC. 
 
4.8.6  The language used in the oral and written information about the trial, including  the 
written informed consent form, should be as non-technical as practical and should 
be understandable to the subject or the subject's legally acceptable representative 
and the  impartial witness, where applicable. 
 
4.8.7  Before informed consent may be obtained, the investigator, or a person designated by 
the investigator, should provide the subject or the subjects legally acceptable 
representative  ample time and opportunity to inquire about details of the trial and to 
decide whether or not to participate in the trial. All questions about the trial should 
be answered to the satisfaction of the subject or the subjects legally acceptable 
representative. 
 
4.8.8  Prior to a subjects participation in the trial, the written informed consent form should 
be  signed and personally dated by the subject or by the subjects legally acceptable 
representative, and by the person who conducted the informed consent discussion. 
 
4.8.9  If a subject is unable to read or if a legally acceptable representative is unable to read, 
an impartial witness should be present during the entire informed consent discussion. 
After the written informed consent form and any other written information to be 
provided to subjects, is read and explained to the subject or the subject's legally 
acceptable representative, and after the subject or the subjects legally acceptable 
representative has  orally consented to the subjects participation in the trial and, if 
capable of doing so, has signed and personally dated the informed consent form, the 
witness should sign and personally date the consent form. By signing the consent form, 
the witness attests that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the subject or 
the subjects legally acceptable representative, and that informed consent was freely 
given by the subject or the subjects  legally acceptable representative. 
 
4.8.10  Both the informed consent discussion and the written informed consent form and 
any other written information to be provided to subjects should include explanations 
of the  following: 
 
(a) That the trial involves research. 
(b) The purpose of the trial. 
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(c) The trial treatment(s) and the probability for random assignment to each treatment. 
(d) The trial procedures to be followed, including all invasive procedures. 
(e) The subjects responsibilities. 
(f)  Those aspects of the trial that are experimental. 
(g) The reasonably foreseeable risks or inconveniences to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
(h) The reasonably expected benefits. When there is no intended clinical benefit to 
the subject, the subject should be made aware of this. 
(i)  The alternative procedure(s) or course(s) of treatment that may be available to 
the subject, and their important potential benefits and risks. 
(j)  The compensation and/or treatment available to the subject in the event of trial- 
related injury. 
(k) The anticipated prorated payment, if any, to the subject for participating in the trial. 
(l)  The anticipated expenses, if any, to the subject for participating in the trial. 
(m) That the subjects participation in the trial is voluntary and that the subject may 
refuse to participate or withdraw from the trial, at any time, without penalty or 
loss of benefits to which the subject is otherwise entitled. 
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory 
authority(ies) will be granted direct access to the subjects original medical records 
for verification  of clinical trial procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written informed consent form, the subject or 
the subjects legally acceptable representative is authorizing such access. 
(o) That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the trial are published, the subjects identity will 
remain confidential. 
(p) That the subject or the subjects legally acceptable representative will be informed 
in  a timely manner if information becomes available that may be relevant to the 
subjects willingness to continue participation in the trial. 
(q) The person(s) to contact for further information regarding the trial and the rights 
of  trial subjects, and whom to contact in the event of trial-related injury. 
(r)  The foreseeable circumstances and/or reasons under which the subjects 
participation in the trial may be terminated. 
(s)  The expected duration of the subjects participation in the trial. 
(t)  The approximate number of subjects involved in the trial. 
 
4.8.11  Prior to participation in the trial, the subject or the subject's legally acceptable 
representative should receive a copy of the signed and dated written informed 
consent  form and any other written information provided to the subjects. During a 
subjects participation in the trial, the subject or the subjects legally acceptable 
20 
  Contains Nonbinding Recommendations 
representative  should receive a copy of the signed and dated consent form updates 
and a copy of any amendments to the written information provided to subjects. 
 
4.8.12  When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only 
be enrolled in the trial with the consent of the subjects legally acceptable 
representative (e.g., minors, or patients with severe dementia), the subject should be 
informed about the trial to the extent compatible with the subjects understanding and, 
if capable, the subject should sign and personally date the written informed consent. 
 
4.8.13  Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is 
no anticipated direct clinical benefit to the subject), should be conducted in subjects 
who personally give consent and who sign and date the written informed consent form. 
 
4.8.14  Nontherapeutic trials may be conducted in subjects with consent of a legally 
acceptable  representative provided the following conditions are fulfilled: 
 
(a) The objectives of the trial cannot be met by means of a trial in subjects who can 
give informed consent personally. 
(b) The foreseeable risks to the subjects are low. 
(c) The negative impact on the subjects well-being is minimized and low. 
(d) The trial is not prohibited by law. 
(e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion 
of such subjects, and the written approval/ favorable opinion covers this aspect. 
Such trials, unless an exception is justified, should be conducted in patients having 
a disease or condition for which the investigational product is intended. Subjects in 
these  trials should be particularly closely monitored and should be withdrawn if they 
appear to be unduly distressed. 
 
4.8.15  In emergency situations, when prior consent of the subject is not possible, the consent 
of the subjects legally acceptable representative, if  present, should  be  requested.  
When  prior consent of the subject is not possible, and the subjects legally 
acceptable representative is not available, enrollment of the subject should require 
measures  described in the protocol and/or elsewhere, with documented 
approval/favorable  opinion by the IRB/IEC, to protect the rights, safety and well-being 
of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or the subjects legally acceptable representative should be informed about 
the trial as soon as possible and consent to continue and other consent as appropriate 
(see section 4.8.10) should be requested. 
   
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4.9  Records and Reports  
 
ADDENDUM 
 
4.9.0  The investigator/institution should maintain adequate and accurate source documents and 
trial records that include all pertinent observations on each of the site's trial subjects. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g., via an audit trail). 
 
4.9.1  The investigator should ensure the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor in the CRFs and in all required reports. 
 
4.9.2  Data reported on the CRF, that are derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained. 
 
4.9.3  Any change or correction to a CRF should be dated, initialed, and explained (if 
necessary) and should not obscure the original entry (i.e., an audit trail should be 
maintained); this applies to both written and electronic changes or corrections (see 
5.18.4(n)). Sponsors should provide guidance to investigators and/or the investigators' 
designated representatives on making such corrections. Sponsors should have written 
procedures to assure that changes or corrections in CRFs made by sponsor's 
designated  representatives are documented, are necessary, and are endorsed by the 
investigator. The  investigator should retain records of the changes and corrections. 
 
4.9.4  The investigator/institution should maintain the trial documents as specified in 
Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as 
required by the applicable regulatory requirement(s). The investigator/institution 
should take measures to prevent accidental or premature destruction of these 
documents. 
 
4.9.5  Essential documents should be retained until at least 2-years after the last approval of 
a  marketing application in an ICH region and until there are no pending or 
contemplated  marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as 
to when these documents no longer need to be  retained (see section 5.5.12). 
 
4.9.6  The financial aspects of the trial should be documented in an agreement between 
the sponsor and the investigator/institution. 
 
4.9.7  Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial-
related  records. 
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4.10  Progress Reports 
 
4.10.1  The investigator should submit written summaries of the trials status to the IRB/IEC 
annually, or more frequently, if requested by the IRB/IEC. 
 
4.10.2  The investigator should promptly provide written reports to the sponsor, the IRB/IEC 
(see section 3.3.8) and, where applicable, the institution on any changes significantly 
affecting the conduct of the trial, and/or increasing the risk to subjects. 
 
4.11  Safety Reporting 
 
4.11.1 All SAEs should be reported immediately to the sponsor except  for those SAEs that 
the protocol or other document (e.g., Investigator's Brochure) identifies as not needing 
immediate reporting. The immediate reports should be followed promptly by detailed, 
written reports. The immediate and follow-up reports should identify subjects by 
unique code numbers assigned to the trial subjects rather than by the subjects' names, 
personal identification numbers, and/or addresses. The investigator  should also 
comply with the applicable regulatory requirement(s) related to the reporting of 
unexpected serious adverse drug reactions to the regulatory authority(ies) and the 
IRB/IEC. 
 
4.11.2  Adverse events and/or laboratory abnormalities identified in the protocol as critical 
to safety evaluations should be reported to the sponsor according to the reporting 
requirements and within the time periods specified by the sponsor in the protocol. 
 
4.11.3  For reported deaths, the investigator should supply the sponsor and the IRB/IEC with 
any additional requested information (e.g., autopsy reports and terminal medical 
reports). 
 
4.12  Premature Termination or Suspension of a Trial 
If the trial is prematurely terminated or suspended for any reason, the 
investigator/institution  should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects, and, where required by the applicable regulatory 
requirement(s), should inform the regulatory authority(ies). In addition: 
 
4.12.1  If the investigator terminates or suspends a trial without prior agreement of the 
sponsor, the investigator should inform the institution, where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC, and 
should provide the sponsor and the IRB/IEC a detailed written explanation of the 
termination or suspension. 
 
4.12.2  If the sponsor terminates or suspends a trial (see section 5.21), the investigator should 
promptly inform the institution where applicable and the investigator/institution should 
promptly inform the IRB/IEC, and provide the IRB/IEC a detailed written explanation of 
the termination or suspension. 
 
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4.12.3  If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial (see 
sections 3.1.2 and 3.3.9), the investigator should inform the institution where 
applicable and the investigator/institution should promptly notify the sponsor and 
provide the sponsor with a detailed written explanation of the termination or 
suspension. 
 
4.13  Final Report(s) by Investigator 
Upon completion of the trial, the investigator, where applicable, should inform the 
institution;  the investigator/institution should provide the IRB/IEC with a summary of the 
trial's outcome, and the regulatory authority(ies) with any reports required. 
 
5.  SPONSOR 
 
ADDENDUM 
 
5.0  Quality Management 
The sponsor should implement a system to manage quality throughout all stages of the trial 
process. 
Sponsors should focus on trial activities essential to ensuring human subject protection and 
the reliability of trial results. Quality management includes the design of efficient clinical trial 
protocols, tools, and procedures for data collection and processing, as well as the collection of 
information that is essential to decision making. 
The methods used to assure and control the quality of the trial should be proportionate to the 
risks inherent in the trial and the importance of the information collected. The sponsor should 
ensure that all aspects of the trial are operationally feasible and should avoid unnecessary 
complexity, procedures, and data collection. Protocols, case report forms, and other operational 
documents should be clear, concise, and consistent. 
The quality management system should use a risk-based approach as described below. 
 
5.0.1  Critical Process and Data Identification 
During protocol development, the sponsor should identify those processes and data that 
are critical to ensure human subject protection and the reliability of trial results. 
 
5.0.2  Risk Identification 
The sponsor should identify risks to critical trial processes and data. Risks should be 
considered at both the system level (e.g., standard operating procedures, computerized 
systems, and personnel) and clinical trial level (e.g., trial design, data collection, and 
informed  consent process). 
 
5.0.3  Risk Evaluation 
The sponsor should evaluate the identified risks, against existing risk controls by 
considering: 
 
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(a)  The likelihood of errors occurring. 
(b)  The extent to which such errors would be detectable. 
(c)  The impact of such errors on human subject protection and reliability of trial results. 
5.0.4  Risk Control 
The sponsor should decide which risks to reduce and/or which risks to accept. The 
approach used to reduce risk to an acceptable level should be proportionate to the 
significance of the risk. Risk reduction activities may be incorporated in protocol design 
and implementation, monitoring plans, agreements between parties defining roles and 
responsibilities, systematic safeguards to ensure adherence to standard operating 
procedures, and training in processes and procedures. 
 
Predefined quality tolerance limits should be established, taking into consideration the 
medical and statistical characteristics of the variables as well as the statistical design of 
the trial, to identify systematic issues that can impact subject safety or reliability of trial 
results. Detection of deviations from the predefined quality tolerance limits should 
trigger an evaluation to determine if action is needed. 
5.0.5  Risk Communication 
The sponsor should document quality management activities. The sponsor should 
communicate quality management activities to those who are involved in or affected by 
such activities, to facilitate risk review and continual improvement during clinical trial 
execution. 
5.0.6  Risk Review 
The sponsor should periodically review risk control measures to ascertain whether the 
implemented quality management activities remain effective and relevant, taking into 
account emerging knowledge and experience. 
5.0.7  Risk Reporting 
The sponsor should describe the quality management approach implemented in the trial 
and summarize important deviations from the predefined quality tolerance limits and 
remedial actions taken in the clinical study report (ICH E3, section 9.6 Data Quality 
Assurance). 
 
5.l  Quality Assurance and Quality Control 
 
5.1.1  The sponsor is responsible for implementing and maintaining quality assurance 
and quality control systems with written SOPs to ensure that trials are conducted and 
data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirement(s). 
 
5.1.2  The sponsor is responsible for securing agreement from all involved parties to ensure 
direct access (see section 1.21) to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and 
foreign regulatory authorities. 
   
5.1.3  Quality control should be applied to each stage of data handling to ensure that all data 
are reliable and have been processed correctly. 
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5.1.4  Agreements, made by the sponsor with the investigator/institution and any other 
parties  involved with the clinical trial, should be in writing, as part of the protocol 
or in a separate agreement. 
 
5.2  Contract Research Organization (CRO) 
 
5.2.1  A sponsor may transfer any or all of the sponsor's trial-related duties and functions to 
a CRO, but the ultimate responsibility for the quality and integrity of the trial data 
always resides with the sponsor. The CRO should implement quality assurance and 
quality control. 
 
5.2.2  Any trial-related duty and function that is transferred to and assumed by a CRO should 
be specified in writing. 
 
ADDENDUM 
The sponsor should ensure oversight of any trial-related duties and functions carried out 
on its behalf, including trial-related duties and functions that are subcontracted to 
another party by the sponsor's contracted CRO(s). 
5.2.3  Any trial-related duties and functions not specifically transferred to and assumed by 
a  CRO are retained by the sponsor. 
 
5.2.4  All references to a sponsor in this guidance also apply to a CRO to the extent that a 
CRO has assumed the trial-related duties and functions of a sponsor. 
 
5.3  Medical Expertise 
The sponsor should designate appropriately qualified medical personnel who will be readily 
available to advise on trial-related medical questions or problems. If necessary, outside 
consultant(s) may be appointed for this purpose. 
 
5.4  Trial Design 
 
5.4.1  The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical 
pharmacologists, and physicians) as appropriate, throughout all stages of the trial 
process, from designing the protocol and CRFs and planning the analyses to 
analyzing  and preparing interim and final clinical trial reports. 
 
5.4.2  For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see section 
6), the ICH Guideline for Structure and Content of Clinical Study Reports, and other 
appropriate ICH guidance on trial design, protocol, and conduct. 
   
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5.5  Trial Management, Data Handling, and Recordkeeping 
 
5.5.1  The sponsor should utilize appropriately qualified individuals to supervise the overall 
conduct of the trial, to handle the data, to verify the data, to conduct the statistical 
analyses, and to prepare the trial reports. 
 
5.5.2  The sponsor may consider establishing an independent data monitoring committee 
(IDMC) to assess the progress of a clinical trial, including the safety data and the 
critical efficacy endpoints at intervals, and to recommend to the sponsor whether 
to continue, modify, or stop a trial. The IDMC should have written operating 
procedures and maintain written records of all its meetings. 
 
5.5.3  When using electronic trial data handling and/or remote electronic trial data systems, 
the sponsor should: 
 
(a) Ensure and document that the electronic data processing system(s) conforms to 
the sponsor's established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation). 
 
ADDENDUM 
The sponsor should base their approach to validation of such systems on a risk 
assessment that takes into consideration the intended use of the system and the 
potential of the system to affect human subject protection and reliability of trial results. 
(b) Maintains SOPs for using these systems. 
 
ADDENDUM 
The SOPs should cover system setup, installation, and use. The SOPs should 
describe system validation and functionality testing, data collection and handling, 
system maintenance, system security measures, change control, data backup,  recovery, 
contingency planning, and decommissioning. The responsibilities of the sponsor, 
investigator, and other parties with respect to the use of these computerized systems 
should be clear, and the users should be provided with training in their use. 
 
(c) Ensure that the systems are designed to permit data changes in such a way that 
the data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail). 
(d) Maintain a security system that prevents unauthorized access to the data. 
(e) Maintain a list of the individuals who are authorized to make data changes (see 
sections 4.1.5 and 4.9.3). 
(f)  Maintain adequate backup of the data. 
(g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing). 
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ADDENDUM 
 
(h) Ensure the integrity of the data, including any data that describe the context, 
content, and structure. This is particularly important when making changes to the 
computerized systems, such as software upgrades or migration of data. 
5.5.4  If data are transformed during processing, it should always be possible to compare 
the original data and observations with the processed data. 
 
5.5.5  The sponsor should use an unambiguous subject identification code (see 1.58) that 
allows identification of all the data reported for each subject. 
 
5.5.6  The sponsor, or other owners of the data, should retain all of the sponsor-specific 
essential documents pertaining to the trial (see section 8. Essential Documents for the 
Conduct of a Clinical Trial). 
 
5.5.7  The sponsor should retain all sponsor-specific essential documents in conformance 
with the applicable regulatory requirement(s) of the country(ies) where the product 
is approved, and/or where the sponsor intends to apply for approval(s). 
 
5.5.8  If the sponsor discontinues the clinical development of an investigational product 
(i.e., for any or all indications, routes of administration, or dosage forms), the 
sponsor should maintain all sponsor-specific essential documents for at least 2-years 
after formal discontinuation or in conformance with the applicable regulatory 
requirement(s). 
 
5.5.9  If the sponsor discontinues the clinical development of an investigational product, 
the sponsor should notify all the trial investigators/institutions and all the 
regulatory authorities. 
 
5.5.10  Any transfer of ownership of the data should be reported to the appropriate 
authority(ies), as required by the applicable regulatory requirement(s).  
 
5.5.11  The sponsor specific essential documents should be retained until at least 2 years 
after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have  elapsed since the formal discontinuation of clinical development 
of the investigational  product. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirement(s) or if needed 
by the sponsor. 
 
5.5.12  The sponsor should inform the investigator(s)/institution(s) in writing of the need 
for record retention and should notify the investigator(s)/institution(s) in writing 
when the  trial-related records are no longer needed. 
 
5.6  Investigator Selection 
 
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5.6.1  The sponsor is responsible for selecting the investigator(s)/institution(s). Each 
investigator should be qualified by training and experience and should have 
adequate resources (see sections 4.1, 4.2) to properly conduct the trial for which the 
investigator is selected. If organization of a coordinating committee and/or selection 
of coordinating investigator(s) are to be utilized in multicenter trials, their 
organization and/or selection  are the sponsor's responsibility. 
 
5.6.2  Before entering an agreement with an investigator/institution to conduct a trial, the 
sponsor should provide the investigator(s)/institution(s) with the protocol and an up-
to-  date Investigator's Brochure, and should provide sufficient time for the 
investigator/institution to review the protocol and the information provided. 
 
5.6.3  The sponsor should obtain the investigator's/institution's agreement: 
 
(a) To conduct the trial in compliance with GCP, with the applicable regulatory 
requirement(s) (see section 4.1.3), and with the protocol agreed to by the sponsor 
and given approval/favorable opinion by the IRB/IEC (see section 4.5.1); 
(b) To comply with procedures for data recording/reporting; 
(c) To permit monitoring, auditing, and inspection (see section 4.1.4); and 
(d) To retain the trial-related essential documents until the sponsor informs the 
investigator/institution these documents are no longer needed (see sections 4.9.4 
and 5.5.12). 
The sponsor and the investigator/institution should sign the protocol, or an 
alternative  document, to confirm this agreement. 
 
5.7  Allocation of Responsibilities 
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related 
duties  and functions. 
 
5.8  Compensation to Subjects and Investigators 
 
5.8.1  If required by the applicable regulatory requirement(s), the sponsor should provide 
insurance or should indemnify (legal and financial coverage) the investigator/the 
institution against claims arising from the trial, except for claims that arise from 
malpractice and/or negligence. 
 
5.8.2  The sponsor's policies and procedures should address the costs of treatment of trial 
subjects in the event of trial-related injuries in accordance with the applicable 
regulatory requirement(s). 
 
5.8.3  When trial subjects receive compensation, the method and manner of compensation 
should comply with applicable regulatory requirement(s). 
 
5.9  Financing 
The financial aspects of the trial should be documented in an agreement between the sponsor 
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and the investigator/institution. 
 
5.10  Notification/Submission to Regulatory Authority(ies) 
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if 
required by the applicable regulatory requirement(s)) should submit any required 
application(s) to the  appropriate authority(ies) for review, acceptance, and/or permission (as 
required by the applicable regulatory requirement(s)) to begin the trial(s). Any 
notification/submission should be  dated and contain sufficient information to identify the 
protocol. 
 
5.11  Confirmation of Review by IRB/IEC 
 
5.11.1  The sponsor should obtain from the investigator/institution: 
(a) The name and address of the investigator's/institution's IRB/IEC. 
(b) A statement obtained from the IRB/IEC that it is organized and operates according 
to GCP and the applicable laws and regulations. 
(c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor, 
a current copy of protocol, written informed consent form(s) and any other 
written information to be provided to subjects, subject recruiting procedures, and 
documents  related to payments and compensation available to the subjects, and 
any other  documents that the IRB/IEC may have requested. 
 
5.11.2  If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any 
aspect  of the trial, such as modification(s) of the protocol, written informed consent 
form and any other written information to be provided to subjects, and/or other 
procedures, the sponsor should obtain from the investigator/institution a copy of the 
modification(s)  made and the date approval/favorable opinion was given by the 
IRB/IEC. 
 
5.11.3  The sponsor should obtain from the investigator/institution documentation and dates 
of any IRB/IEC reapprovals/reevaluations with favorable opinion, and of any 
withdrawals  or suspensions of approval/favorable opinion. 
 
5.12  Information on Investigational Product(s) 
 
5.12.1  When planning trials, the sponsor should ensure that sufficient safety and efficacy 
data from nonclinical studies and/or clinical trials are available to support human 
exposure by the route, at the dosages, for the duration, and in the trial population to be 
studied. 
 
The sponsor should update the Investigator's Brochure as significant new information 
becomes available (see section 7. Investigator's Brochure). 
 
5.13  Manufacturing, Packaging, Labeling, and Coding Investigational Product(s) 
 
5.13.1  The sponsor should ensure that the investigational product(s) (including active 
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comparator(s) and placebo, if applicable) is characterized as appropriate to the stage 
of  development of the product(s), is manufactured in accordance with any applicable 
GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In 
addition, the labeling should comply with applicable regulatory requirement(s). 
 
5.13.2  The sponsor should determine, for the investigational product(s), acceptable storage 
temperatures, storage conditions (e.g., protection from light), storage times, 
reconstitution fluids and procedures, and devices for product infusion, if any.  The 
sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, 
storage managers) of these determinations. 
 
5.13.3  The investigational product(s) should be packaged to prevent contamination and 
unacceptable deterioration during transport and storage. 
 
5.13.4  In blinded trials, the coding system for the investigational product(s) should include 
a mechanism that permits rapid identification of the product(s) in case of a medical 
emergency, but does not permit undetectable breaks of the blinding. 
 
5.13.5  If significant formulation changes are made in the investigational or comparator 
product(s) during the course of clinical development, the results of any additional 
studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) 
needed to assess whether these changes would significantly alter the pharmacokinetic 
profile of the  product should be available prior to the use of the new formulation in 
clinical trials. 
 
5.14  Supplying and Handling Investigational Product(s) 
 
5.14.1  The sponsor is responsible for supplying the investigator(s)/institution(s) with the 
investigational product(s). 
 
5.14.2  The sponsor should not supply an investigator/institution with the investigational 
product(s) until the sponsor obtains all required documentation (e.g., 
approval/favorable  opinion from IRB/IEC and regulatory authority(ies)). 
 
5.14.3  The sponsor should ensure that written procedures include instructions that the 
investigator/institution should follow for the handling and storage of investigational 
product(s) for the trial and documentation thereof. The procedures should address 
adequate and safe receipt, handling, storage, dispensing, retrieval of unused product 
from subjects, and return of unused investigational product(s) to the sponsor (or 
alternative disposition if authorized by the sponsor and in compliance with the 
applicable regulatory requirement(s)). 
   
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5.14.4  The sponsor should: 
(a)  Ensure timely delivery of investigational product(s) to the investigator(s). 
(b)  Maintain records that document shipment, receipt, disposition, return, and 
destruction of the investigational product(s) (see section 8. Essential Documents 
for the Conduct of a Clinical Trial).  
(c)  Maintain a system for retrieving investigational products and documenting this 
retrieval (e.g., for deficient product recall, reclaim after trial completion, expired 
product reclaim). 
(d)  Maintain a system for the disposition of unused investigational product(s) and for 
the documentation of this disposition. 
 
5.14.5  The sponsor should: 
(a) Take steps to ensure that the investigational product(s) are stable over the period 
of use. 
(b) Maintain sufficient quantities of the investigational product(s) used in the trials 
to reconfirm specifications, should this become necessary, and maintain records of 
batch sample analyses and characteristics. To the extent stability permits, 
samples should be retained either until the analyses of the trial data are complete or 
as required by the applicable regulatory requirement(s), whichever represents the 
longer retention period. 
 
5.15  Record Access 
 
5.15.1  The sponsor should ensure that it is specified in the protocol or other written 
agreement  that the investigator(s)/institution(s) provide direct access to source 
data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory 
inspection. 
 
5.15.2  The sponsor should verify that each subject has consented, in writing, to direct access 
to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, 
and  regulatory inspection. 
 
5.16  Safety Information 
 
5.16.1  The sponsor is responsible for the ongoing safety evaluation of the investigational 
product(s). 
 
5.16.2  The sponsor should promptly notify all concerned investigator(s)/institution(s) and 
the  regulatory authority(ies) of findings that could affect adversely the safety of 
subjects,  impact the conduct of the trial, or alter the IRB/IEC's approval/favorable 
opinion to continue the trial. 
 
   
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5.17  Adverse Drug Reaction Reporting 
 
5.17.1  The sponsor should expedite the reporting to all concerned 
investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the 
regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and 
unexpected. 
 
5.17.2  Such expedited reports should comply with the applicable regulatory requirement(s) 
and with the ICH Guideline for Clinical Safety Data Management: Definitions and 
Standards  for Expedited Reporting. 
 
5.17.3  The sponsor should submit to the regulatory authority(ies) all safety updates and 
periodic reports, as required by applicable regulatory requirement(s).  
 
5.18  Monitoring 
 
5.18.1 Purpose   
 
The purposes of trial monitoring are to verify that: 
 
(a) The rights and well-being of human subjects are protected. 
(b) The reported trial data are accurate, complete, and verifiable from source documents. 
(c) The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory 
requirement(s). 
   
5.18.2  Selection and Qualifications of Monitors 
 
(a) Monitors should be appointed by the sponsor. 
(b) Monitors should be appropriately trained, and should have the scientific and/or 
clinical knowledge needed to monitor the trial adequately. A monitor's 
qualifications should be documented. 
(c) Monitors should be thoroughly familiar with the investigational product(s), the 
protocol, written informed consent form and any other written information to be 
provided to subjects, the sponsor's SOPs, GCP, and the applicable regulatory 
requirement(s). 
 
5.18.3  Extent and Nature of Monitoring   
 
The sponsor should ensure that the trials are adequately monitored. The sponsor should 
determine the appropriate extent and nature of monitoring.  The determination of the 
extent and nature of monitoring should be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a 
need for on-site monitoring, before, during, and after the trial; however, in exceptional 
circumstances the sponsor may determine that central monitoring in conjunction with 
procedures such as investigators' training and meetings, and extensive written guidance 
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can assure appropriate conduct of the trial in accordance with GCP. Statistically 
controlled sampling may be an acceptable method for selecting the data to be verified. 
 
ADDENDUM 
The sponsor should develop a systematic, prioritized, risk-based approach to 
monitoring clinical trials. The flexibility in the extent and nature of monitoring 
described in this section is intended to permit varied approaches that improve the 
effectiveness and efficiency of monitoring. The sponsor may choose on-site 
monitoring, a combination of on-site and centralized monitoring, or, where justified, 
centralized monitoring.  The  sponsor should document the rationale for the chosen 
monitoring strategy (e.g., in the monitoring plan). 
On-site monitoring is performed at the sites at which the clinical trial is being 
conducted. Centralized monitoring is a remote evaluation of accumulating data, 
performed in a timely manner, supported by appropriately qualified and trained 
persons (e.g., data managers, biostatisticians). 
 
Centralized monitoring processes provide additional monitoring capabilities that can 
complement and reduce the extent and/or frequency of on-site monitoring and help 
distinguish between reliable data and potentially unreliable data. 
Review that may include statistical analyses of accumulating data from centralized 
monitoring can be used to: 
 
(a) Identify missing data, inconsistent data, data outliers, unexpected lack of 
variability and protocol deviations 
(b) Examine data trends such as the range, consistency, and variability of data within 
and across sites 
(c) Evaluate for systematic or significant errors in data collection and reporting at a 
site  or across sites; or potential data manipulation or data integrity problems 
(d) Analyze site characteristics and performance metrics 
(e) Select sites and/or processes for targeted on-site monitoring. 
 
5.18.4  Monitor's Responsibilities 
The monitor(s), in accordance with the sponsor's requirements, should ensure that the 
tri al  is conducted and documented properly by carrying out the following activities 
when  relevant and necessary to the trial and the trial site: 
 
(a) Acting as the main line of communication between the sponsor and the investigator. 
(b) Verifying that the investigator has adequate qualifications and resources (see 
sections 4.1, 4.2, 5.6) and these remain adequate throughout the trial period, that 
facilities including laboratories and equipment, and staff, are adequate to safely and 
properly conduct the trial and remain adequate throughout the trial period. 
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(c) Verifying, for the investigational product(s): 
(i)  That storage times and conditions are acceptable, and that supplies are 
sufficient throughout the trial. 
(ii) That the investigational product(s) are supplied only to subjects who are 
eligible to receive it and at the protocol specified dose(s). 
(iii) That subjects are provided with necessary instruction on properly using, 
handling, storing, and returning the investigational product(s). 
(iv) That the receipt, use, and return of the investigational product(s) at the 
trial sites are controlled and documented adequately. 
(v) That the disposition of unused investigational product(s) at the trial sites 
complies with applicable regulatory requirement(s) and is in accordance 
with the sponsor. 
(d) Verifying that the investigator follows the approved protocol and all approved 
amendment(s), if any. 
(e) Verifying that written informed consent was obtained before each subject's 
participation in the trial. 
(f)  Ensuring that the investigator receives the current Investigator's Brochure, all 
documents, and all trial supplies needed to conduct the trial properly and to 
comply with the applicable regulatory requirement(s). 
(g) Ensuring that the investigator and the investigator's trial staff are adequately 
informed about the trial. 
(h) Verifying that the investigator and the investigator's trial staff are performing 
the specified trial functions, in accordance with the protocol and any other written 
agreement between the sponsor and the investigator/institution, and have not 
delegated these functions to unauthorized individuals. 
(i)  Verifying that the investigator is enrolling only eligible subjects. 
(j)  Reporting the subject recruitment rate. 
(k) Verifying that source documents and other trial records are accurate, complete, 
kept up-to-date, and maintained. 
(l)  Verifying that the investigator provides all the required reports, notifications, 
applications, and submissions, and that these documents are accurate, complete, 
timely, legible, dated, and identify the trial. 
(m) Checking the accuracy and completeness of the CRF entries, source documents 
and other trial-related records against each other. The monitor specifically should 
verify that: 
(i) The data required by the protocol are reported accurately on the CRFs and 
are consistent with the source documents. 
(ii) Any dose and/or therapy modifications are well documented for each of 
the trial subjects. 
(iii) Adverse events, concomitant medications and intercurrent illnesses are 
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reported in accordance with the protocol on the CRFs. 
(iv) Visits that the subjects fail to make, tests that are not conducted, and 
examinations that are not performed are clearly reported as such on the 
CRFs. 
(v) All withdrawals and dropouts of enrolled subjects from the trial are 
reported and explained on the CRFs. 
(n) Informing the investigator of any CRF entry error, omission, or illegibility. The 
monitor should ensure that appropriate corrections, additions, or deletions are 
made, dated, explained (if necessary), and initialed by the investigator or by a 
member of the investigator's trial staff who is authorized to initial CRF changes 
for the investigator. This authorization should be documented. 
(o) Determining whether all adverse events (AEs) are appropriately reported within 
the  time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the 
applicable regulatory requirement(s). 
(p) Determining whether the investigator is maintaining the essential documents (see 
section 8. Essential Documents for the Conduct of a Clinical Trial). 
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable 
regulatory requirements to the investigator and taking appropriate action designed 
to  prevent recurrence of the detected deviations. 
 
5.18.5  Monitoring Procedures   
The monitor(s) should follow the sponsor's established written SOPs as well as those 
procedures that are specified by the sponsor for monitoring a specific trial. 
 
5.18.6 Monitoring Report 
(a) The monitor should submit a written report to the sponsor after each trial-site visit 
or trial-related communication. 
(b) Reports should include the date, site, name of the monitor, and name of the 
investigator or other individual(s) contacted. 
(c) Reports should include a summary of what the monitor reviewed and the 
monitor's statements concerning the significant findings/facts, deviations and 
deficiencies,  conclusions, actions taken or to be taken and/or actions recommended 
to secure  compliance. 
(d) The review and follow-up of the monitoring report with the sponsor should be 
documented by the sponsor's designated representative. 
 
ADDENDUM 
(e) Reports of on-site and/or centralized monitoring should be provided to the 
sponsor (including appropriate management and staff responsible for trial and site 
oversight) in a timely manner for review and follow up. Results of monitoring 
activities should be documented in sufficient detail to allow verification of 
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compliance with the  monitoring plan. Reporting of centralized monitoring 
activities should be regular and may be independent from site visits. 
 
ADDENDUM 
5.18.7 Monitoring Plan 
The sponsor should develop a monitoring plan that is tailored to the specific human 
subject protection and data integrity risks of the trial. The plan should describe the 
monitoring strategy, the monitoring responsibilities of all the parties involved, the  various 
monitoring methods to be used, and the rationale for their use. The plan should also 
emphasize the monitoring of critical data and processes. Particular attention should be 
given to those aspects that are not routine clinical practice and that require additional 
training. The monitoring plan should reference the applicable policies and procedures. 
   
5.19  Audit 
If or when sponsors perform audits, as part of implementing quality assurance, they should 
consider: 
 
5.19.1  Purpose   
The purpose of a sponsor's audit, which is independent of and separate from routine 
monitoring or quality control functions, should be to evaluate trial conduct and 
compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements. 
 
5.19.2  Selection and Qualification of Auditors 
(a) The sponsor should appoint individuals, who are independent of the clinical 
trials/systems, to conduct audits. 
(b) The sponsor should ensure that the auditors are qualified by training and 
experience to conduct audits properly. An auditor's qualifications should be 
documented. 
 
5.19.3  Auditing Procedures 
(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted 
in  accordance with the sponsor's written procedures on what to audit, how to 
audit, the  frequency of audits, and the form and content of audit reports. 
(b) The sponsor's audit plan and procedures for a trial audit should be guided by 
the  importance of the trial to submissions to regulatory authorities, the number of 
subjects in the trial, the type and complexity of the trial, the level of risks to the 
trial subjects, and any identified problem(s). 
(c) The observations and findings of the auditor(s) should be documented. 
(d) To preserve the independence and value of the audit function, the regulatory 
authority(ies) should not routinely request the audit reports. Regulatory 
authority(ies)  may seek access to an audit report on a case-by-case basis when 
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evidence of serious GCP non-compliance exists, or in the course of legal 
proceedings. 
(e) When required by applicable law or regulation, the sponsor should provide an 
audit certificate. 
 
5.20  Noncompliance 
 
5.20.1  Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory 
requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff 
should lead to prompt action by the sponsor to secure compliance. 
 
ADDENDUM 
If noncompliance that significantly affects or has the potential to significantly affect 
human subject protection or reliability of trial results is discovered, the sponsor 
should perform a root cause analysis and implement appropriate corrective and 
preventive actions. 
 
5.20.2  If the monitoring and/or auditing identifies serious and/or persistent noncompliance on 
the part of an investigator/institution, the sponsor should terminate the 
investigator's/institution's participation in the trial. When an investigator's/institution's 
participation is terminated because of noncompliance, the sponsor should notify 
promptly the regulatory authority(ies). 
 
5.21  Premature Termination or Suspension of a Trial 
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension 
and  the reason(s) for the termination or suspension. The IRB/IEC should also be informed 
promptly and provided the reason(s) for the termination or suspension by the sponsor or 
by the investigator/institution, as specified by the applicable regulatory requirement(s). 
 
5.22  Clinical Trial/Study Reports 
Whether the trial is completed or prematurely terminated, the sponsor should ensure that 
the clinical trial reports are prepared and provided to the regulatory agency(ies) as required 
by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical 
trial reports in marketing applications meet the standards of the ICH Guidance for Structure 
and Content of Clinical Study Reports. (NOTE: The ICH Guidance for Structure and Content 
of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain 
cases.) 
 
5.23  Multicenter Trials 
For multicenter trials, the sponsor should ensure that: 
 
5.23.1  All investigators conduct the trial in strict compliance with the protocol agreed to by 
the sponsor and, if required, by the regulatory authority(ies), and given 
38 
  Contains Nonbinding Recommendations 
approval/favorable  opinion by the IRB/IEC. 
 
5.23.2  The CRFs are designed to capture the required data at all multicenter trial sites. For 
those investigators who are collecting additional data, supplemental CRFs should also 
be provided that are designed to capture the additional data. 
 
5.23.3  The responsibilities of coordinating investigator(s) and the other participating 
investigators are documented prior to the start of the trial. 
 
5.23.4  All investigators are given instructions on following the protocol, on complying with 
a uniform set of standards for the assessment of clinical and laboratory findings, 
and on completing the CRFs. 
 
5.23.5  Communication between investigators is facilitated. 
 
6.  CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 
The contents of a trial protocol should generally include the following topics. However, 
site specific information may be provided on separate protocol page(s), or addressed in a 
separate agreement, and some of the information listed below may be contained in other 
protocol referenced documents, such as an Investigator's Brochure. 
 
6.l  General Information 
 
6.1.1  Protocol title, protocol identifying number, and date. Any amendment(s) should also 
bear  the amendment number(s) and date(s). 
 
6.1.2  Name and address of the sponsor and monitor (if other than the sponsor). 
 
6.1.3  Name and title of the person(s) authorized to sign the protocol and the protocol 
amendment(s) for the sponsor. 
 
6.1.4  Name, title, address, and telephone number(s) of the sponsor's medical expert (or 
dentist when appropriate) for the trial. 
 
6.1.5  Name and title of the investigator(s) who is (are) responsible for conducting the trial, 
and the address and telephone number(s) of the trial site(s). 
 
6.1.6  Name, title, address, and telephone number(s) of the qualified physician (or dentist, 
if applicable), who is responsible for all trial-site related medical (or dental) 
decisions (if other than investigator).  
 
6.1.7  Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or 
technical  department(s) and/or institutions involved in the trial. 
 
6.2  Background Information 
 
6.2.1  Name and description of the investigational product(s). 
 
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  Contains Nonbinding Recommendations 
6.2.2  A summary of findings from nonclinical studies that potentially have clinical 
significance and from clinical trials that are relevant to the trial. 
 
6.2.3  Summary of the known and potential risks and benefits, if any, to human subjects. 
 
6.2.4  Description of and justification for the route of administration, dosage, dosage 
regimen,  and treatment period(s). 
 
6.2.5  A statement that the trial will be conducted in compliance with the protocol, GCP, and 
the applicable regulatory requirement(s). 
 
6.2.6  Description of the population to be studied. 
 
6.2.7  References to literature and data that are relevant to the trial and that provide background 
for the trial. 
 
6.3  Trial Objectives and Purpose 
A detailed description of the objectives and the purpose of the trial. 
 
6.4  Trial Design 
The scientific integrity of the trial and the credibility of the data from the trial depend 
substantially on the trial design. A description of the trial design should include: 
 
6.4.1  A specific statement of the primary endpoints and the secondary endpoints, if any, to 
be measured during the trial. 
 
6.4.2  A description of the type/design of trial to be conducted (e.g., double-blind, 
placebo-controlled, parallel design) and a schematic diagram of trial design, procedures, 
and  stages. 
 
6.4.3  A description of the measures taken to minimize/avoid bias, including: 
(a) Randomization 
(b) Blinding. 
 
6.4.4  A description of the trial treatment(s) and the dosage and dosage regimen of the 
investigational product(s). Also include a description of the dosage form, packaging, 
and labelling of the investigational product(s). 
 
6.4.5  The expected duration of subject participation, and a description of the sequence 
and duration of all trial periods, including follow-up, if any. 
 
6.4.6  A description of the "stopping rules" or "discontinuation criteria" for individual 
subjects, parts of trial, and entire trial.  
 
6.4.7  Accountability procedures for the investigational product(s), including the placebo(s) 
and  comparator(s), if any. 
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  Contains Nonbinding Recommendations 
 
6.4.8  Maintenance of trial treatment randomization codes and procedures for breaking codes. 
 
6.4.9  The identification of any data to be recorded directly on the CRFs (i.e., no prior 
written or electronic record of data), and to be considered to be source data. 
 
6.5  Selection and Withdrawal of Subjects 
 
6.5.1  Subject inclusion criteria. 
 
6.5.2  Subject exclusion criteria. 
6.5.3  Subject withdrawal criteria (i.e., terminating investigational product treatment/trial 
treatment) and procedures specifying: 
(a) When and how to withdraw subjects from the trial/investigational product treatment 
(b) The type and timing of the data to be collected for withdrawn subjects 
(c) Whether and how subjects are to be replaced 
(d) The follow-up for subjects withdrawn from investigational product treatment/trial 
treatment. 
 
6.6  Treatment of Subjects 
 
6.6.1  The treatment(s) to be administered, including the name(s) of all the product(s), the 
dose(s), the dosing schedule(s), the route/mode(s) of administration, and the 
treatment  period(s), including the follow-up period(s) for subjects for each 
investigational product treatment/trial treatment group/arm of the trial. 
 
6.6.2  Medication(s)/treatment(s) permitted (including rescue medication) and not permitted 
before and/or during the trial. 
 
6.6.3  Procedures for monitoring subject compliance. 
 
6.7  Assessment of Efficacy 
 
6.7.1  Specification of the efficacy parameters. 
 
6.7.2  Methods and timing for assessing, recording, and analyzing efficacy parameters. 
 
6.8  Assessment of Safety 
 
6.8.1  Specification of safety parameters. 
 
6.8.2  The methods and timing for assessing, recording, and analyzing safety parameters. 
 
6.8.3  Procedures for eliciting reports of and for recording and reporting adverse event 
and intercurrent illnesses. 
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  Contains Nonbinding Recommendations 
 
6.8.4  The type and duration of the follow-up of subjects after adverse events.  
 
6.9  Statistics 
6.9.1  A description of the statistical methods to be employed, including timing of any 
planned interim analysis(ses). 
 
6.9.2  The number of subjects planned to be enrolled.  In multicenter trials, the numbers 
of enrolled subjects projected for each trial site should be specified. Reason for 
choice of sample size, including reflections on (or calculations of) the power of the trial 
and clinical justification. 
 
6.9.3  The level of significance to be used. 
 
6.9.4  Criteria for the termination of the trial. 
 
6.9.5  Procedure for accounting for missing, unused, and spurious data. 
 
6.9.6  Procedures for reporting any deviation(s) from the original statistical plan (any 
deviation(s) from the original statistical plan should be described and justified in 
protocol  and/or in the final report, as appropriate). 
 
6.9.7  The selection of subjects to be included in the analyses (e.g., all randomized subjects, 
all dosed subjects, all eligible subjects, evaluable subjects). 
 
6.10  Direct Access to Source Data/Documents 
The sponsor should ensure that it is specified in the protocol or other written agreement that 
the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and  regulatory inspection(s), providing direct access to source data/documents. 
 
6.11  Quality Control and Quality Assurance 
 
6.12  Ethics 
Description of ethical considerations relating to the trial. 
 
6.13  Data Handling and Recordkeeping  
 
6.14  Financing and Insurance 
Financing and insurance if not addressed in a separate agreement. 
 
6.15  Publication Policy 
Publication policy, if not addressed in a separate agreement. 
 
6.16  Supplements 
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant 
information can be found in the ICH Guidance for Structure and Content of Clinical Study 
42 
  Contains Nonbinding Recommendations 
Reports.)
 
 
7.  INVESTIGATOR'S BROCHURE 
 
7.l  Introduction 
 
The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on 
the investigational product(s) that are relevant to the study of the product(s) in human 
subjects. Its purpose is to provide the investigators and others involved in the trial with the 
information to facilitate their understanding of the rationale for, and their compliance with, 
many key features  of the protocol, such as the dose, dose frequency/interval, methods of 
administration: and safety  monitoring procedures. The IB also provides insight to support the 
clinical management of the  study subjects during the course of the clinical trial. The 
information should be presented in a concise, simple, objective, balanced, and non-
promotional form that enables a clinician, or potential investigator, to understand it and make 
his/her own unbiased risk-benefit assessment of  the appropriateness of the proposed trial. For 
this reason, a medically qualified person should  generally participate in the editing of an IB, 
but the contents of the IB should be approved by the disciplines that generated the described 
data. 
 
This guidance delineates the minimum information that should be included in an IB and 
provides suggestions for its layout. It is expected that the type and extent of information 
available will vary with the stage of development of the investigational product. If the 
investigational product is marketed and its pharmacology is widely understood by medical 
practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, 
a  basic product information brochure, package leaflet, or labelling may be an appropriate 
alternative, provided that it includes current, comprehensive, and detailed information on all 
aspects of the investigational product that might be of importance to the investigator. If a 
marketed product is being studied for a new use (i.e., a new indication), an IB specific to 
that new use should be prepared. The IB should be reviewed at least annually and revised  as 
necessary in compliance with a sponsor's written procedures. More frequent revision may 
be appropriate depending on the stage of development and the generation of relevant new 
information. However, in accordance with GCP, relevant new information may  be so important 
that it should be communicated to the investigators, and possibly to the Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory  authorities before it is 
included in a revised IB. 
 
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to 
the  investigator(s) and the investigators are responsible for providing the up-to-date IB to the 
responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-
investigator  should determine whether a brochure is available from the commercial 
manufacturer. If the  investigational product is provided by the sponsor-investigator, then he or 
she should provide the  necessary information to the trial personnel. In cases where preparation 
of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an 
expanded background  information section in the trial protocol that contains the minimum 
current information described  in this guidance. 
 
7.2  General Considerations 
The IB should include: 
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  Contains Nonbinding Recommendations 
 
7.2.1  Title Page 
This should provide the sponsor's name, the identity of each investigational product 
(i.e., research number, chemical or approved generic name, and trade name(s) where 
legally permissible and desired by the sponsor), and the release date. It is also 
suggested that an edition number, and a reference to the number and date of the 
edition it supersedes, be provided. An example is given in Appendix 1. 
   
44 
  Contains Nonbinding Recommendations 
7.2.2  Confidentiality Statement 
The sponsor may wish to include a statement instructing the investigator/recipients 
to  treat the IB as a confidential document for the sole information and use of the 
investigator's team and the IRB/IEC. 
 
7.3  Contents of the Investigator's Brochure 
The IB should contain the following sections, each with literature references where appropriate: 
 
7.3.1  Table of Contents   
 
An example of the Table of Contents is given in Appendix 2 
 
7.3.2  Summary 
 
  A brief summary (preferably not exceeding two pages) should be given, highlighting the 
significant physical, chemical, pharmaceutical, pharmacological, toxicological, 
pharmacokinetic, metabolic, and clinical information available that is relevant to the 
stage of clinical development of the investigational product. 
 
7.3.3  Introduction 
 
  A brief introductory statement should be provided that contains the chemical name 
(and  generic and trade name(s) when approved) of the investigational product(s), all 
active  ingredients, the investigational product (s) pharmacological class and its 
expected  position within this class (e.g., advantages), the rationale for performing 
research with  the investigational product(s), and the anticipated prophylactic, 
therapeutic, or diagnostic  indication(s). Finally, the introductory statement should 
provide the general approach to  be followed in evaluating the investigational product. 
 
7.3.4  Physical, Chemical, and Pharmaceutical Properties and Formulation 
  A description should be provided of the investigational product substance(s) 
(including the chemical and/or structural formula(e)), and a brief summary should be 
given of the relevant physical, chemical, and pharmaceutical properties. 
 
To permit appropriate safety measures to be taken in the course of the trial, a 
description of the formulation(s) to be used, including excipients, should be provided 
and justified if clinically relevant. Instructions for the storage and handling of the 
dosage form(s) should also be given. 
 
Any structural similarities to other known compounds should be mentioned. 
 
7.3.5  Nonclinical Studies 
 
Introduction:   
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and 
investigational product metabolism studies should be provided in summary form. This 
summary should address the methodology used, the results, and a discussion of the 
relevance of the findings to the investigated therapeutic and the possible unfavorable 
45 
  Contains Nonbinding Recommendations 
and unintended effects in humans. 
 
The information provided may include the following, as appropriate, if known/available: 
  Species tested; 
  Number and sex of animals in each group; 
  Unit dose (e.g., milligram/kilogram (mg/kg)); 
  Dose interval; 
  Route of administration; 
  Duration of dosing; 
  Information on systemic distribution; 
  Duration of post-exposure follow-up; 
  Results, including the following aspects: 
 Nature and frequency of pharmacological or toxic effects; 
 Severity or intensity of pharmacological or toxic effects; 
 Time to onset of effects; 
 Reversibility of effects; 
 Duration of effects; 
 Dose response. 
 
Tabular format/listings should be used whenever possible to enhance the clarity of 
the presentation. 
The following sections should discuss the most important findings from the studies, 
including the dose response of observed effects, the relevance to humans, and any 
aspects to be studied in humans. If applicable, the effective and nontoxic dose findings 
in  the same animal species should be compared (i.e., the therapeutic index should be 
discussed). The relevance of this information to the proposed human dosing should 
be  addressed. Whenever possible, comparisons should be made in terms of blood/tissue 
levels rather than on an mg/kg basis. 
 
(a) Nonclinical Pharmacology 
A summary of the pharmacological aspects of the investigational product and, 
where  appropriate, its significant metabolites studied in animals, should be 
included. Such a summary should incorporate studies that assess potential 
therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as 
well as those that assess safety (e.g.,  special studies to assess pharmacological 
actions other than the intended therapeutic  effect(s)). 
(b) Pharmacokinetics and Product Metabolism in Animals 
A summary of the pharmacokinetics and biological transformation and disposition 
of the investigational product in all species studied should be given. The discussion 
of the  findings should address the absorption and the local and systemic 
bioavailability of the  investigational product and its metabolites, and their 
relationship to the pharmacological  and toxicological findings in animal species. 
(c) Toxicology 
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  Contains Nonbinding Recommendations 
A summary of the toxicological effects found in relevant studies conducted in 
different animal species should be described under the following headings where 
appropriate: 
 Single dose 
 Repeated dose 
 Carcinogenicity 
 Special studies (e.g., irritancy and sensitization) 
 Reproductive toxicity 
 Genotoxicity (mutagenicity) 
7.3.6  Effects in Humans 
Introduction 
A thorough discussion of the known effects of the investigational product(s) in 
humans should be provided, including information on pharmacokinetics, metabolism, 
pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. 
Where possible, a summary of each completed clinical trial should be provided. 
Information should also be provided regarding results of any use of the 
investigational  product(s) other than from in clinical trials, such as from experience 
during marketing. 
(a) Pharmacokinetics and Product Metabolism in Humans 
A summary of information on the pharmacokinetics of the investigational 
product(s) should be presented, including the following, if available: 
  Pharmacokinetics (including metabolism, as appropriate, and absorption, 
-
plasma  protein binding, distribution, and elimination). 
  Bioavailability of the investigational product (absolute, where possible, 
-
and/or  relative) using a reference dosage form. 
  Population subgroups (e.g., gender, age, and impaired organ function). 
-
  Interactions (e.g., product-product interactions and effects of food). 
-
  Other pharmacokinetic data (e.g., results of population studies performed 
-
within clinical trial(s). 
 
(b) Safety and Efficacy 
A summary of information should be provided about the investigational 
product's/products' (including metabolites, where appropriate) safety, 
pharmacodynamics,  efficacy, and dose response that were obtained from 
preceding trials in humans (healthy volunteers and/or patients). The implications 
of this information should be discussed. In  cases where a number of clinical 
trials have been completed, the use of summaries of safety and efficacy across 
multiple trials by indications in subgroups may provide a clear presentation of the 
data. Tabular summaries of adverse drug reactions for all the clinical  trials 
(including those for all the studied indications) would be useful. Important 
differences in adverse drug reaction patterns/incidences across indications or 
subgroups  should be discussed. 
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The IB should provide a description of the possible risks and adverse drug reactions 
to be  anticipated on the basis of prior experiences with the product under 
investigation and  with related products. A description should also be provided of 
the precautions or special  monitoring to be done as part of the investigational use 
of the product(s). 
(c) Marketing Experience 
The IB should identify countries where the investigational product has been 
marketed or  approved. Any significant information arising from the marketed use 
should be  summarized (e.g., formulations, dosages, routes of administration, and 
adverse product  reactions). The IB should also identify all the countries where the 
investigational product did not receive approval/registration for marketing or was 
withdrawn from  marketing/registration. 
 
7.3.7  Summary of Data and Guidance for the Investigator 
This section should provide an overall discussion of the nonclinical and clinical data, 
and should summarize the information from various sources on different aspects of 
the investigational product(s), wherever possible. In this way, the investigator can 
be provided with the most informative interpretation of the available data and with an 
assessment of the implications of the information for future clinical trials. 
Where appropriate, the published reports on related products should be discussed. 
This  could help the investigator to anticipate adverse drug reactions or other problems 
in clinical trials. 
The overall aim of this section is to provide the investigator with a clear understanding of 
the possible risks and adverse reactions, and of the specific tests, observations, and 
precautions that may be needed for a clinical trial. This understanding should be based 
on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and 
clinical information on the investigational product(s). Guidance should also be provided 
to the clinical investigator on the recognition and treatment of possible overdose and 
adverse drug reactions that are based on previous human experience and on the 
pharmacology of the investigational product. 
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7.4  APPENDIX l  
 
TITLE PAGE (Example)  
SPONSOR'S NAME Product: 
Research Number: 
Name(s):  Chemical, Generic (if approved) 
  Trade Name(s) (if legally permissible and desired by the sponsor) 
 
 
INVESTIGATOR'S BROCHURE 
 
Edition Number:  
Release Date: 
 
 
 
Replaces Previous Edition Number:  
Date: 
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  Contains Nonbinding Recommendations 
 
7.5  APPENDIX 2 
TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example) 
 
 
-  Confidentiality Statement (optional)  
-  Signature Page (optional) 
1.  Table of Contents 
2.  Summary 
3.  Introduction 
4.  Physical, Chemical, and Pharmaceutical Properties and Formulation  
5.  Nonclinical Studies 
5.1  Nonclinical Pharmacology 
5.2  Pharmacokinetics and Product Metabolism in Animals  
5.3  Toxicology  
6.  Effects in Humans. 
6.1  Pharmacokinetics and Product Metabolism in Humans  
6.2  Safety and Efficacy   
6.3  Marketing Experience 
7.  Summary of Data and Guidance for the Investigator  
 
NB: References on  1.  Publications 
2.  Reports 
These references should be found at the end of each chapter. 
Appendices (if any) 
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8.  ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 
 
8.l  Introduction 
Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the  data 
produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with 
all applicable regulatory requirements. 
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites  in 
a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor, and monitor. These documents are also  the 
ones that are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the 
process to confirm the validity of the trial conduct and the integrity of data collected. 
The minimum list of essential documents that has been developed follows. The various documents are grouped in three sections according to  the 
stage of the trial during which they will normally be generated: (1) before the clinical phase of the trial commences, (2) during the clinical 
conduct of the trial, and (3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it 
should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the 
individual elements are readily identifiable. 
Trial master files should be established at the beginning of the trial, both at the investigator/institution's site and at the sponsor's office. A final 
close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all 
necessary documents are in the appropriate files. 
Any or all of the documents addressed in this guidance may be subject to, and should be available for, audit by the sponsor's auditor and 
inspection by the regulatory authority(ies). 
ADDENDUM 
The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source 
documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval. 
Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation), based on the  importance 
and relevance of the specific documents to the trial. 
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The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not 
have exclusive control of those data. 
When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies. 
The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during,  and 
after the trial. 
 
8.2  Before the Clinical Phase of the Trial Commences 
During this planning stage the following documents should be generated and should be on file before the trial formally starts. 
 
  Title of Document  Purpose  Located in Files of 
Investigator/Institution  Sponsor 
8.2.1  INVESTIGATORS BROCHURE  To document that relevant and  X  X 
current scientific information about 
the investigational product has been 
provided to the investigator 
8.2.2  SIGNED PROTOCOL AND AMENDMENTS, IF  To document investigator and  X  X 
ANY, AND SAMPLE CASE REPORT FORM  sponsor agreement to the 
(CRF)  protocol/amendment(s) and CRF 
8.2.3  INFORMATION GIVEN TO TRIAL SUBJECT  To document the informed consent  X  X 
  INFORMED CONSENT FORM (including 
-
all applicable translations)   
 
    ANY OTHER WRITTEN INFORMATION  To document that subjects will be  X  X 
-
  given appropriate written 
information (content and wording) 
to support their ability to give fully 
informed consent 
 
    ADVERTISEMENT FOR SUBJECT  To document that recruitment  X   
-
RECRUITMENT (if used)  measures are appropriate and not     
coercive     
   
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8.2.4  FINANCIAL ASPECTS OF THE TRIAL  To document the financial  X  X 
agreement between the 
investigator/institution and the 
sponsor for the trial 
8.2.5  INSURANCE STATEMENT (where required)  To document that compensation to  X  X 
subject(s) for trial-related injury 
will be available 
8.2.6  SIGNED AGREEMENT BETWEEN INVOLVED  To document agreements     
PARTIES, e.g.:     
  Investigator/institution and sponsor  X  X 
-
  Investigator/institution and CRO  X  X 
-
    (where required) 
  Sponsor and CRO     
-
X 
  Investigator/institution and authority(ies)  X 
-
X 
(where required) 
8.2.7  DATED, DOCUMENTED  To document that the trial has been  X  X 
APPROVAL/FAVORABLE OPINION OF  subject to IRB/IEC review and 
INSTITUTIONAL REVIEW BOARD  given approval/favorable opinion.  
(IRB)/INDEPENDENT ETHICS COMMITTEE  To identify the version number and 
(IEC) OF THE FOLLOWING:  date of the document(s) 
  Protocol and any amendments 
  CRF (if applicable) 
  Informed consent form(s) 
  Any other written information to be provided 
to the subject(s) 
  Advertisement for subject recruitment (if used) 
  Subject compensation (if any) 
  Any other documents given approval/favorable 
opinion 
   
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8.2.8  INSTITUTIONAL REVIEW  To document that the IRB/IEC is  X  X 
BOARD/INDEPENDENT ETHICS COMMITTEE  constituted in agreement with GCP  (where required) 
COMPOSITION 
8.2.9  REGULATORY AUTHORITY(IES)  To document appropriate  X  X 
AUTHORIZATION/APPROVAL/NOTIFICATION  authorization/approval/notification  (where required)  (where required) 
OF PROTOCOL (where required)  by the regulatory authority(ies) has 
been obtained prior to initiation of 
the trial in compliance with the 
applicable regulatory requirement(s) 
8.2.10  CURRICULUM VITAE AND/OR OTHER  To document qualifications and  X  X 
RELEVANT DOCUMENTS EVIDENCING  eligibility to conduct trial and/or 
QUALIFICATIONS OF INVESTIGATOR(S) AND  provide medical supervision of 
SUBINVESTIGATOR(S)  subjects 
8.2.11  NORMAL VALUE(S)/RANGE(S) FOR  To document normal values and/or  X  X 
MEDICAL/LABORATORY/TECHNICAL  ranges of the tests 
PROCEDURES(S) AND/OR TEST(S) INCLUDED 
IN THE PROTOCOL 
8.2.12  MEDICAL/LABORATORY/TECHNICAL  To document competence of facility  X  X 
PROCEDURES/TESTS  to perform required test(s), and  (where required) 
  Certification or  support reliability of results 
-
  Accreditation or 
-
  Established quality control and/or external 
-
quality assessment or 
  Other validation (where required) 
-
8.2.13  SAMPLE OF LABEL(S) ATTACHED TO  To document compliance with    X 
INVESTIGATIONAL PRODUCT CONTAINER(S)  applicable labelling regulations and 
appropriateness of instructions 
provided to the subjects 
   
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8.2.14  INSTRUCTIONS FOR HANDLING OF  To document instructions needed to  X  X 
INVESTIGATIONAL PRODUCT(S) AND TRIAL- ensure proper storage, packaging, 
RELATED MATERIALS (if not included in  dispensing, and disposition of 
protocol or Investigators Brochure)  investigational product(s) and trial-
related materials 
8.2.15  SHIPPING RECORDS FOR INVESTIGATIONAL  To document shipment dates, batch  X  X 
PRODUCT(S) AND TRIAL-RELATED  numbers and method of shipment of 
MATERIALS  investigational product(s) and trial-
related materials. Allows tracking of 
product batch, review of shipping 
conditions, and accountability 
8.2.16  CERTIFICATE(S) OF ANALYSIS OF  To document identity, purity, and    X 
INVESTIGATIONAL PRODUCT(S) SHIPPED  strength of investigational 
product(s) to be used in the trial 
8.2.17  DECODING PROCEDURES FOR BLINDED  To document how, in case of an  X  X 
TRIALS  emergency, identity of blinded  (third party if 
investigational product can be  applicable) 
revealed without breaking the blind 
for the remaining subjects 
treatment 
8.2.18  MASTER RANDOMIZATION LIST  To document method for    X 
randomization of trial population  (third party if 
applicable) 
8.2.19  PRE-TRIAL MONITORING REPORT  To document that the site is suitable    X 
for the trial (may be combined with 
8.2.20) 
8.2.20  TRIAL INITIATION MONITORING REPORT  To document that trial procedures  X  X 
were reviewed with the investigator 
and the investigators trial staff 
(may be combined with 8.2.19) 
 
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8.3  During the Clinical Conduct of the Trial 
In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant  information is 
documented as it becomes available. 
 
  Title of Document  Purpose  Located in Files of 
Investigator/Institution  Sponsor 
8.3.1  INVESTIGATORS BROCHURE UPDATES  To document that investigator  X  X 
is informed in a timely manner 
of relevant information as it 
becomes available 
8.3.2  ANY REVISION TO:  To document revisions of these  X  X 
  Protocol/amendment(s) and CRF  trial related documents that 
-
  Informed consent form  take effect during trial 
-
  Any other written information provided to subjects 
-
  Advertisement for subject recruitment (if used) 
-
8.3.3  DATED, DOCUMENTED APPROVAL/FAVORABLE  To document that the  X  X 
OPINION OF INSTITUTIONAL REVIEW BOARD  amendment(s) and/or 
IRB)/INDEPENDENT ETHICS COMMITTEE (IEC)  revision(s) have been subject to 
OF THE FOLLOWING:  IRB/IEC review and were 
given approval/favorable 
  Protocol amendment(s)  opinion.  To identify the 
  Revision(s) of:  version number and date of the 
 Informed consent form  document(s). 
 Any other written information to be 
provided to the subject 
 Advertisement for subject recruitment (if 
used) 
  Any other documents given approval/favorable 
opinion 
  Continuing review of trial (where required) 
   
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8.3.4  REGULATORY AUTHORITY(IES)  To document compliance with  X  X 
AUTHORIZATIONS/APPROVALS/NOTIFICATIONS  applicable regulatory  (where required) 
WHERE REQUIRED FOR:  requirements 
  Protocol amendment(s) and other documents 
8.3.5  CURRICULUM VITAE FOR NEW  (See 8.2.10)  X  X 
INVESTIGATOR(S) AND/OR 
SUBINVESTIGATOR(S) 
8.3.6  UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR  To document normal values  X  X 
MEDICAL/LABORATORY/TECHNICAL  and ranges that are revised 
PROCEDURE(S)/TEST(S) INCLUDED IN THE  during the trial (see 8.2.11) 
PROTOCOL 
8.3.7  UPDATES OF  To document that tests remain  X  X 
MEDICAL/LABORATORY/TECHNICAL  adequate throughout the trial  (where required) 
PROCEDURES/TESTS  period (see 8.2.12) 
  Certification or 
-
  Accreditation or 
-
  Established quality control and/or external quality 
-
assessment or 
  Other validation (where required) 
-
8.3.8  DOCUMENTATION OF INVESTIGATIONAL  (See 8.2.15)  X  X 
PRODUCT(S) AND TRIAL-RELATED MATERIALS 
SHIPMENT 
8.3.9  CERTIFICATE(S) OF ANALYSIS FOR NEW  (See 8.2.16)    X 
BATCHES OF INVESTIGATIONAL PRODUCTS 
8.3.10  MONITORING VISIT REPORTS  To document site visits by, and    X 
findings of, the monitor 
   
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8.3.11  RELEVANT COMMUNICATIONS OTHER THAN  To document any agreements  X  X 
SITE VISITS  or significant discussions 
  Letters  regarding trial administration, 
-
  Meeting notes  protocol violations, trial 
-
  Notes of telephone calls  conduct, adverse event (AE) 
-
reporting 
8.3.12  SIGNED INFORMED CONSENT FORMS  To document that consent is  X   
obtained in accordance with 
GCP and protocol and dated 
prior to participation of each 
subject in trial. Also to 
document direct access 
permission (see 8.2.3) 
8.3.13  SOURCE DOCUMENTS  To document the existence of  X   
the subject and substantiate 
integrity of trial data collected. 
To include original documents 
related to the trial, to medical 
treatment, and history of 
subject 
8.3.14  SIGNED, DATED, AND COMPLETED CASE  To document that the  X  X 
REPORT FORMS (CRF)  investigator or authorized  (copy)  (original) 
member of the investigators 
staff confirms the observations 
recorded 
8.3.15  DOCUMENTATION OF CRF CORRECTIONS  To document all  X  X 
changes/additions or  (copy)  (original) 
corrections made to CRF after 
initial data were recorded 
8.3.16  NOTIFICATION BY ORIGINATING  Notification by originating  X  X 
INVESTIGATOR TO SPONSOR OF SERIOUS  investigator to sponsor of 
ADVERSE EVENTS AND RELATED REPORTS  serious adverse events and 
related reports in accordance 
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with 4.11 
8.3.17  NOTIFICATION BY SPONSOR AND/OR  Notification by sponsor and/or  X  X 
INVESTIGATOR, WHERE APPLICABLE, TO  investigator, where applicable,  (where required) 
REGULATORY AUTHORITY(IES) AND  to regulatory authorities and 
IRB(S)/IEC(S) OF UNEXPECTED SERIOUS  IRB(s)/IEC(s) of unexpected 
ADVERSE DRUG REACTIONS AND OF OTHER  serious adverse drug reactions 
SAFETY INFORMATION  in accordance with 5.17 and 
4.11.1 and of other safety 
information in accordance with 
5.16.2 and 4.11.2 
8.3.18  NOTIFICATION BY SPONSOR TO  Notification by sponsor to  X  X 
INVESTIGATORS OF SAFETY INFORMATION  investigators of safety 
information in accordance with 
5.16.2 
8.3.19  INTERIM OR ANNUAL REPORTS TO IRB/IEC AND  Interim or annual reports  X  X 
AUTHORITY(IES)  provided to IRB/IEC in  (where required) 
accordance with 4.10 and to 
authority(ies) in accordance 
with 5.17.3 
8.3.20  SUBJECT SCREENING LOG  To document identification of  X  X 
subjects who entered pre-trial  (where required) 
screening 
8.3.21  SUBJECT IDENTIFICATION CODE LIST  To document that  X   
investigator/institution keeps a 
confidential list of names of all 
subjects allocated to trial 
numbers on enrolling in the 
trial. Allows 
investigator/institution to reveal 
identity of any subject 
8.3.22  SUBJECT ENROLMENT LOG  To document chronological  X   
enrolment of subjects by trial 
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  Contains Nonbinding Recommendations 
number 
8.3.23  INVESTIGATION PRODUCTS ACCOUNTABILITY  To document that  X  X 
AT THE SITE  investigational product(s) have 
been used according to the 
protocol 
8.3.24  SIGNATURE SHEET  To document signatures and  X  X 
initials of all persons 
authorized to make entries 
and/or corrections on CRFs 
8.3.25  RECORD OF RETAINED BODY FLUIDS/TISSUE  To document location and  X  X 
SAMPLES (IF ANY)  identification of retained 
samples if assays need to be 
repeated 
 
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  Contains Nonbinding Recommendations 
8.4  After Completion or Termination of the Trial 
After completion or termination of the trial, all of the documents identified in Sections 8.2 and 8.3 should be in the file together with the following 
 
  Title of Document  Purpose  Located in Files of 
Investigator/Institution  Sponsor 
8.4.1  INVESTIGATIONAL PRODUCT(S)  To document that the  X  X 
ACCOUNTABILITY AT SITE  investigational product(s) have 
been used according to the 
protocol. To document the final 
accounting of investigational 
product(s) received at the site, 
dispensed to subjects, returned 
by the subjects, and returned to 
sponsor 
8.4.2  DOCUMENTATION OF  To document destruction of  X  X 
INVESTIGATIONAL PRODUCT  unused investigational products  (if destroyed at site) 
DESTRUCTION  by sponsor or at site 
8.4.3  COMPLETED SUBJECT  To permit identification of all  X   
IDENTIFICATION CODE LIST  subjects enrolled in the trial in 
case follow-up is required. List 
should be kept in a confidential 
manner and for agreed upon time 
8.4.4  AUDIT CERTIFICATE (if available)  To document that audit was    X 
performed 
8.4.5  FINAL TRIAL CLOSE-OUT  To document that all activities    X 
MONITORING REPORT  required for trial close-out are 
completed, and copies of 
essential documents are held in 
the appropriate files 
   
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  Contains Nonbinding Recommendations 
8.4.6  TREATMENT ALLOCATION AND  Returned to sponsor to document    X 
DECODING DOCUMENTATION  any decoding that may have 
occurred 
8.4.7  FINAL REPORT BY INVESTIGATOR  To document completion of the  X   
TO IRB/IEC WHERE REQUIRED,  trial 
AND WHERE APPLICABLE, TO THE 
REGULATORY AUTHORITY(IES) 
8.4.8  CLINICAL STUDY REPORT  To document results and  X  X 
interpretation of trial  (if applicable) 
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  Contains Nonbinding Recommendations 
 
9.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office  of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520). 
 
The time required to complete this information collection is estimated to average 60 hours per 
response to develop a quality management system, and 3 hours per response to report to FDA. 
These estimates include the time to review instructions, search existing data sources, gather the  data 
needed, and complete and review the information collection. Send comments regarding this 
burden estimate or suggestions for reducing this burden to: 
 
Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave, Bldg. 51, Rm. 6337, Silver Spring, MD 20993- 
0002. 
 
This guidance also refers to previously approved collections of information found in FDA 
regulations.  The collections of information found in 21 CFR part 11 have been approved under 
OMB control number 0910-0303; the collections of information found in 21 CFR part 56 have been 
approved under OMB control number 0910-07555; the collections of information found in 21 CFR 
part 312 have been approved under OMB control numbers 0910-0014 and 0910-0733; the 
collections of information found in 21 CFR part 314 have been approved under OMB control 
number 0910-0001; and the collections of information found in 21 CFR part 601 have been 
approved under OMB control number 0910-0338. 
 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.  The OMB control number 
for this information collection is 0910-0014.  The current expiration date is available at 
https://www.reginfo.gov (search ICR and enter OMB control number). 
 
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