GOOD CLINICAL PRACTICE

Consolidated Guideline

Table of Contents

Introduction

1. Glossary

2. The Principles of ICH GCP

3. Institutional Review Board/Independent Ethics Committee (IRB/IEC)

3.1 Responsibilities

3.2 Composition, Functions, and Operations

3.3 Procedures

3.4 Records

4. Investigator

4.1 Investigator's Qualifications and Agreements

4.2 Adequate Resources

4.3 Medical Care of Trial Subjects

4.4 Communication with IRB/IEC

4.5 Compliance with Protocol

4.6 Investigational Product(s)

4.7 Randomization Procedures and Unblinding

4.8 Informed Consent of Trial Subjects

4.9 Records and Reports

4.10 Progress Reports

4.11 Safety Reporting

4.12 Premature Termination or Suspension of a Trial

4.13 Final Report(s) by Investigator/Institution

5. Sponsor

5.1 Quality Assurance and Quality Control

5.2 Contract Research Organization (CRO)

5.3 Medical Expertise

5.4 Trial Design

5.5 Trial Management, Data Handling, Recordkeeping, and

   Independent Data Monitoring Committee

5.6 Investigator Selection

5.7 Allocation of Duties and Functions

5.8 Compensation to Subjects and Investigators

5.9 Financing

5.10 Notification/Submission to Regulatory Authority(ies)

5.11 Confirmation of Review by IRB/IEC

5.12 Information on Investigational Product(s)

5.13 Manufacturing, Packaging, Labeling, and Coding

   Investigational Product(s)

5.14 Supplying and Handling Investigational Product(s)

5.15 Record Access

5.16 Safety Information

5.17 Adverse Drug Reaction Reporting

5.18 Monitoring

5.18.1 Purpose

5.18.2 Selection and Qualifications of Monitors

5.18.3 Extent and Nature of Monitoring

5.18.4 Monitor's Responsibilities

5.18.5 Monitoring Procedures

5.18.6 Monitoring Report

5.19 Audit

5.19.1 Purpose

5.19.2 Selection and Qualification of Auditors

5.19.3 Auditing Procedures

5.20 Noncompliance

5.21 Premature Termination or Suspension of a Trial

5.22 Clinical Trial/Study Reports

5.23 Multi-center Trials

6. Clinical Trial Protocol and Protocol Amendment(s)

6.1 General Information

6.2 Background Information

6.3 Trial Objectives and Purpose

6.4 Trial Design

6.5 Selection and Withdrawal of Subjects

6.6 Treatment of Subjects

6.7 Assessment of Efficacy

6.8 Assessment of Safety

6.9 Statistics

6.10 Direct Access to Source Data/Documents

6.11 Quality Control and Quality Assurance

6.12 Ethics

6.13 Data Handling and Recordkeeping

6.14 Financing and Insurance

6.15 Publication Policy

6.16 Supplements

7. Investigator's Brochure

7.1 Introduction

7.2 General Considerations

7.2.1 Title Page

7.2.2 Confidentiality Statement

7.3 Contents of the Investigator's Brochure

7.3.1 Table of Contents

7.3.2 Summary

7.3.3 Introduction

7.3.4 Physical, Chemical, and Pharmaceutical Properties and

   Formulation

7.3.5 Nonclinical Studies

7.3.6 Effects in Humans

7.3.7 Summary of Data and Guidance for the Investigator

7.4 Appendix 1

7.5 Appendix 2

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 (International Conference on Harmonisation)GCP Guideline is to provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory

authorities in these jurisdictions.

The guideline 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 (WHO).

This guideline should be followed when generating clinical trial

data that are intended to be submitted to regulatory authorities.

The principles established in this guideline may also be applied to

other clinical investigations that may have an impact on the safety and

well-being of human subjects.

1. Glossary

1.1 Adverse Drug Reaction (ADR)

In the pre-approval 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 that

is noxious and unintended and that 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)

An AE is any untoward medical occurrence in a patient or

clinical investigation subject administered a pharmaceutical product

and that 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 Guideline 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 of the jurisdiction where a trial

is conducted.

1.5 Approval (in relation to Institutional Review Boards (IRB's))

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 (SOP's), 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 sponsor's auditor of the results of the audit.

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

Guideline 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 sponsor's proprietary information or of a subject's 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.

1.19 Coordinating Investigator

An investigator assigned the responsibility for the coordination

of investigators at different centers participating in a multicenter

trial.

1.20 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.

1.21 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 sponsor's 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.

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 subject's 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/scientific professionals and nonmedical/nonscientific

members, whose 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 guideline.

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

subject's 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

sponsor's and/or contract research organization's (CRO's)

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.

1.31 Institutional Review Board (IRB)

An independent body constituted of medical, scientific, and

nonscientific members, whose responsibility it 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 trials, of 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 team of individuals at a

trial site, the investigator is the responsible leader of the team

and may be called the principal investigator.

1.35 Investigator/Institution

An expression meaning ``the investigator and/or institution,

where required by the applicable regulatory requirements.''

1.36 Investigator's 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 7.

``Investigator's 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 subject's 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 (SOP's), 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

sponsor's SOP's.

1.40 Multi center 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 Guideline, 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.

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 guideline,

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 Guideline 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 Documents

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 and complete,

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, 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 (SOP's)

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 subject's identity and used in lieu of the

subject's 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.,

Investigator's Brochure for an unapproved investigational product or

package insert/summary of product characteristics for an approved

product). (See the ICH Guideline 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.

1.62 Well-being (of the trial subjects)

The physical and mental integrity of the subjects participating

in a clinical trial.

2. The Principles of ICH GCP

2.1 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.

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.

2.13 Systems with procedures that assure the quality of every

aspect of the trial should be implemented.

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, Investigator's

Brochure (IB), available safety information, information about

payments and compensation available to subjects, the investigator's

current curriculum vitae and/or other documentation evidencing

qualifications, and any other documents that the IRB/IEC may require

to fulfill 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.

3.1.6 When a nontherapeutic trial is to be carried out with the

consent of the subject's legally acceptable representative (see

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 subject's legally acceptable representative is not

possible (see 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 vote/provide their opinion and/or advise.

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 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 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 4.10.2).

(c) All adverse drug reactions (ADR's) 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:

(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 copies of its written procedures

and membership lists.

4. Investigator

4.1 Investigator's 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).

4.1.2 The investigator should be thoroughly familiar with the

appropriate use of the investigational product(s), as described in

the protocol, in the current Investigator's Brochure, in the product

information, and in other information sources provided by the

sponsor.

4.1.3 The investigator should be aware of, and should comply with,

GCP and the applicable regulatory requirements.

4.1.4 The investigator/institution should permit monitoring and

auditing by the sponsor, and inspection by the appropriate

regulatory authority(ies).

4.1.5 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.

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.

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 subject's 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 subject's

primary physician about the subject's 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 subject's 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 investigator's/institution's written

application to the IRB/IEC, the investigator/institution should

provide the IRB/IEC with a current copy of the Investigator's

Brochure. If the Investigator's Brochure is updated during the

trial, the investigator/institution should supply a copy of the

updated Investigator's Brochure to the IRB/IEC.

4.4.3 During the trial the investigator/institution should provide

to the IRB/IEC all documents subject to its 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 their 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 of

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 investigator's/institution's 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 is designated by the investigator/

institution, should maintain records of the product's 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 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 trial's 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/IEC's 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 subject's consent. Any revised written informed consent form,

and written information should receive the IRB/IEC's approval/

favorable opinion in advance of use. The subject or the subject's

legally acceptable representative should be informed in a timely

manner if new information becomes available that may be relevant to

the subject's 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.

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 subject's 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 subject's legally acceptable

representative, of all pertinent aspects of the trial including the

written information given 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

nontechnical 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 subject's 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 subject's legally acceptable representative.

4.8.8 Prior to a subject's participation in the trial, the written

informed consent form should be signed and personally dated by the

subject or by the subject's 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 subject's legally acceptable representative has orally

consented to the subject's 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 subject's legally acceptable representative,

and that informed consent was freely given by the subject or the

subject's 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.

(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 subject's 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 subject's 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

subject's 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 subject's 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 subject's identity will

remain confidential.

(p) That the subject or the subject's legally acceptable

representative will be informed in a timely manner if information

becomes available that may be relevant to the subject's 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

subject's participation in the trial may be terminated.

(s) The expected duration of the subject's 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 subject's

participation in the trial, the subject or the subject's legally

acceptable 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 nontherapeutic)

includes subjects who can only be enrolled in the trial with the

consent of the subject's 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 subject's

understanding and, if capable, the subject should assent, sign and

personally date the written informed consent.

4.8.13 Except as described in 4.8.14, a nontherapeutic 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 subject's 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 subject's legally acceptable

representative, if present, should be requested. When prior consent

of the subject is not possible, and the subject's 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 subject's legally acceptable representative should be informed

about the trial as soon as possible and consent to continue and

other consent as appropriate (see 4.8.10) should be requested.

4.9 Records and Reports

4.9.1 The investigator should ensure the accuracy, completeness,

legibility, and timeliness of the data reported to the sponsor in

the CRF's and in all required reports.

4.9.2 Data reported on the CRF, which 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 CRF's 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 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

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.

4.10 Progress Reports

4.10.1 Where required by the applicable regulatory requirements, the

investigator should submit written summaries of the trial's status

to the institution. The investigator/institution should submit

written summaries of the status of the trial 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 3.3.8), and, where required by the

applicable regulatory requirements, 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 serious adverse events (SAE's) should be reported

immediately to the sponsor except for those SAE's 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 terminated prematurely 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 required by the applicable regulatory

requirements, 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 5.21), the

investigator should promptly inform the institution, where required

by the applicable regulatory requirements, and the investigator/

institution should promptly inform the IRB/IEC and provide the IRB/

IEC a detailed written explanation of the termination or suspension.

4.12.3 If the IRB/IEC terminates or suspends its approval/favorable

opinion of a trial (see 3.1.2 and 3.3.9), the investigator should

inform the institution, where required by the applicable regulatory

requirements, 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/Institution

Upon completion of the trial, the investigator should, where

required by the applicable regulatory requirements, inform the

institution, and the investigator/institution should provide the

sponsor with all required reports, the IRB/IEC with a summary of the

trial's outcome, and the regulatory authority(ies) with any

report(s) they require of the investigator/institution.

5. Sponsor

5.1 Quality Assurance and Quality Control

5.1.1 The sponsor is responsible for implementing and maintaining

quality assurance and quality control systems with written SOP's 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 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.

5.1.4 Agreements, made by the sponsor with the investigator/

institution and/or with 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.

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 guideline 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 CRF's and planning the analyses to

analyzing and preparing interim and final clinical trial/study

reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol

Amendment(s) (see 6.), the ICH Guideline for Structure and Content

of Clinical Study Reports, and other appropriate ICH guidance on

trial design, protocol, and conduct.

5.5 Trial Management, Data Handling, Recordkeeping, and Independent

Data Monitoring Committee

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).

(b) Maintain SOP's for using these systems.

(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 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).

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.

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 appropriate 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 (see 4.9.5).

5.6 Investigator Selection

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 4.1, 4.2) to

properly conduct the trial for which the investigator is selected.

If a coordinating committee and/or 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), and with the protocol agreed

to by the sponsor and given approval/favorable opinion by the IRB/

IEC;

(b) To comply with procedures for data recording/reporting: and

(c) To permit monitoring, auditing, and inspection (see 4.1.4).

(d) To retain the essential documents that should be in the

investigator/institution files until the sponsor informs

the investigator/institution these documents are no longer needed

(see 4.9.4, 4.9.5, 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 Duties and Functions

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 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.

5.12.2 The sponsor should update the Investigator's Brochure as

significant new information becomes available. (See 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 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 labeled 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)).

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).

(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.

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 (ADR's) 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 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 SOP's, 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 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.

5.18.4 Monitor's Responsibilities.

The monitor(s), in accordance with the sponsor's requirements,

should ensure that the trial 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 4.1, 4.2, 5.6) and these remain adequate

throughout the trial period, and that the staff and facilities,

including laboratories and equipment, are adequate to safely and

properly conduct the trial and these remain adequate throughout the

trial period.

(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's authorized procedures.

(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 data/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 data/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 CRF's and are consistent with the source data/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 reported in accordance with the protocol on the CRF's.

(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 CRF's.

(v) All withdrawals and dropouts of enrolled subjects from the

trial are reported and explained on the CRF's.

(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 (AE's) are

appropriately reported within the time periods required by GCP, the

protocol, the IRB/IEC, the sponsor, the applicable regulatory

requirement(s), and indicated in the ICH Guideline for Clinical

Safety Data Management: Definitions and Standards for Expedited

Reporting.

(p) Determining whether the investigator is maintaining the

essential documents.

(q) Communicating deviations from the protocol, SOP's, 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

SOP's 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 by the

sponsor should be documented by the sponsor's designated

representative.

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, SOP's, 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 trial/data collection system(s), 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 evidence of serious GCP

noncompliance exists, or in the course of legal proceedings or

investigations.

(e) Where required by applicable law or regulation, the sponsor

should provide an audit certificate.

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOP's, 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.

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 terminated prematurely 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/study 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/study reports in marketing

applications meet the standards of the ICH Guideline for Structure

and Content of Clinical Study Reports. (NOTE: The ICH Guideline 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 approval/favorable opinion by

the IRB/IEC.

5.23.2 The CRF's are designed to capture the required data at all

multicenter trial sites. For those investigators who are collecting

additional data, supplemental CRF's should also be provided that are

designed to capture the additional data.

5.23.3 The responsibilities of the 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 CRF's.

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.

6.1 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).

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 (for example):

(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 labeling 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.

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

CRF's (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.

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(es).

6.9.2 The number of subjects planned to be enrolled. In multicenter

trials, the number 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 the 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, evaluate-able 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) by 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 Guideline for Structure and Content of Clinical Study

Reports.)

7. Investigator's Brochure

7.1 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

nonpromotional 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 guideline 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 labeling 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 (IRB's)/Independent Ethics

Committees (IEC's) 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 IRB's/IEC's. 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

guideline.

7.2 General Considerations

The IB should include:

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.

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 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 a 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

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 from

any use of the investigational product(s) other than 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.

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 is based on previous human

experience and on the pharmacology of the investigational product.

7.4 Appendix 1:

TITLE PAGE OF INVESTIGATOR'S BROCHURE (Example)

Sponsor's Name:

Product:

Research Number:

Name(s): Chemical, Generic (if approved)

Trade Name(s) (if legally permissible and desired by the

sponsor)

Edition Number:

Release Date:

Replaces Previous Edition Number:

Date:

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)