Guidance for Industry
`E6 Good Clinical Practice:
`Consolidated Guidance
`
`ICH
`April 1996
`
`Sandoz Inc.
`Exhibit 1049-0001
`
`

`
`Guidance for Industry
`E6 Good Clinical Practice:
`Consolidated Guidance
`
`Additional copies are available from:
`the Drug Information Branch (HFD-21
`Center for Drug Evaluation and Research (CDER),
`5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`or
`Office of Communication,
`Training, and Manufacturers Assistance (HFM-40)
`Center for Biologics Evaluation and Research (CBER)
`1401 Rockville Pike, Rockville, MD 20852-1448,
`http ://www. fda.gov/cber/guidelines.htm
`(Fax) 888-CBERFAX or 301-827-3844
`(Voice Information) 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`April 1996
`ICH
`
`Sandoz Inc.
`Exhibit 1049-0002
`
`

`
`Table of Contents
`
`INTRODUCTION .......................................................... 1
`
`1.
`
`2.
`
`GLOSSARY ......................................................... 1
`
`THE PRINCIPLES OF ICH GCP ......................................... 8
`
`INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
`(IRB/IEC) .......................................................... 10
`Responsibilities ................................................. 10
`3.1
`Composition, Functions, and Operations .............................. 11
`3.2
`3.3
`Procedures .................................................... 12
`3.4
`Records ...................................................... 13
`
`INVESTIGATOR .................................................... 13
`Investigator’s Qualifications and Agreements .......................... 13
`4.1
`Adequate Resources ............................................. 14
`4.2
`Medical Care of Trial Subjects ..................................... 14
`4.3
`Communication with IRB/IEC ..................................... 15
`4.4
`Compliance with Protocol ........................................ 15
`4.5
`Investigational Product(s) ......................................... 16
`4.6
`Randomization Procedures and Unblinding ............................ 16
`4.7
`Informed Consent of Trial Subjects .................................. 17
`4.8
`Records and Reports ............................................ 21
`4.9
`4.10
`Progress Reports ............................................... 22
`Safety Reporting ................................................ 22
`4.11
`Premature Termination or Suspension of a Trial ........................ 23
`4.12
`Final Report(s) by Investigator/Institution ............................. 23
`4.13
`
`SPONSOR .......................................................... 24
`Quality Assurance and Quality Control ............................... 24
`5.1
`Contract Research Organization (CRO) .............................. 24
`5.2
`Medical Expertise ............................................... 24
`5.3
`Trial Design ................................................... 25
`5.4
`Trial Management, Data Handling, Recordkeeping, and Independent Data
`5.5
`Monitoring Committee ........................................... 25
`Investigator Selection ............................................ 27
`Allocation of Duties and Functions .................................. 27
`Compensation to Subjects and Investigators ........................... 28
`Financing ..................................................... 28
`Notification/Submission to Regulatory Authority(ies) .................... 28
`
`5.6
`5.7
`5.8
`5.9
`5.10
`
`Sandoz Inc.
`Exhibit 1049-0003
`
`

`
`5.11
`5.12
`5.13
`5.14
`5.15
`5.16
`5.17
`5.18
`5.19
`5.20
`5.21
`5.22
`5.23
`
`Confirmation of Review by IRB/IEC ................................ 28
`Information on Investigational Product(s) ............................. 29
`Manufacturing, Packaging, Labeling, and Coding Investigational ........... 29
`Supplying and Handling Investigational Product(s) ...................... 30
`Record Access ................................................. 31
`Safety Information .............................................. 31
`Adverse Drug Reaction Reporting .................................. 31
`Monitoring .................................................... 32
`Audit ........................................................ 36
`Noncompliance ................................................. 37
`Premature Termination or Suspension of a Trial ........................ 37
`Clinical Trial/Study Reports ....................................... 37
`Multicenter Trials ............................................... 37
`
`CLINICAL TRIAL PROTOCOL AND PROTOCOL ......................... 38
`General Information ............................................. 38
`6.1
`Background Information .......................................... 39
`6.2
`Trial Objectives and Purpose ...................................... 39
`6.3
`Trial Design ................................................... 39
`6.4
`Selection and Withdrawal of Subj ects ................................ 40
`6.5
`Treatment of Subjects ............................................ 40
`6.6
`Assessment of Efficacy ........................................... 41
`6.7
`Assessment of Safety ............................................ 41
`6.8
`Statistics ...................................................... 41
`6.9
`Direct Access to Source Data/Documents ............................. 42
`6.10
`Quality Control and Quality Assurance ............................... 42
`6.11
`Ethics ........................................................ 42
`6.12
`Data Handling and Recordkeeping .................................. 42
`6.13
`Financing and Insurance .......................................... 42
`6.14
`Publication Policy ............................................... 42
`6.15
`Supplements ................................................... 42
`6.16
`
`INVESTIGATOR’S BROCHURE ........................................ 42
`7.1
`Introduction ................................................... 42
`7.2
`General Considerations ........................................... 43
`Contents of the Investigator’s Brochure .............................. 44
`7.3
`Appendix 1 .................................................... 48
`7.4
`Appendix 2 .................................................... 49
`7.5
`
`ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL ..... 50
`8.1
`Introduction ................................................... 50
`8.2
`Before the Clinical Phase of the Trial Commences ...................... 51
`
`Sandoz Inc.
`Exhibit 1049-0004
`
`

`
`8.3
`8.4
`
`During the Cfinical Conduct of the Trial .............................. 55
`After Completion or Termination of the Trial .......................... 58
`
`Sandoz Inc.
`Exhibit 1049-0005
`
`

`
`GUIDANCE FOR INDUSTRY1
`
`E6 Good Clinical Practice: Consolidated Guidance
`
`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
`subj ects. 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 obj ective of this ICH GCP guidance 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 guidance was developed with consideration of the current good clinical practices of the
`European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic
`countries, and the World Health Organization (WHO).
`
`This guidance should be followed when generating clinical trial data that are intended to be
`submitted to regulatory authorities.
`
`The principles established in this guidance may also be applied to other clinical investigations that
`may have an impact on the safety and well-being of human subj ects.
`
`1.
`
`GLOSSARY
`
`1.1 Adverse drug reaction (ADR): In the preapproval clinical experience with a new
`medicinal product or its new usages, particularly as the therapeutic dose(s) may not be
`established, all noxious and unintended responses to a medicinal product related to any
`dose should be considered adverse drug reactions. The phrase "responses to a medicinal
`
`1 This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
`subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed
`by the ICH Steering Committee at Step 4 of the ICH process, April 1996. At Step 4 of the process, the final draft is
`recommended for adoption to the regulatory bodies of the European Union, Japan and the United States. This guidance
`was published in the Federal Registeron May 9, 1997 (62 FR 25692), and is applicable to drug and biological
`products. This guidance represents the Agency’s current thinking on good clinical practices. It does not create or confer
`any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if
`such approach satisfies the requirements of the applicable statute, regulations, or both.
`
`Sandoz Inc.
`Exhibit 1049-0006
`
`

`
`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 guidance 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 subj ect 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 guidance for
`Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
`
`1.3
`
`Amendment (to the protocol): See Protocol Amendment.
`
`1.4 Applicable regulatory requirement(s): Any law(s) and regulation(s) addressing
`the conduct of clinical trials of investigational products of the jurisdiction where trial is
`conducted.
`
`1.5 Approval (in relation to institutional review boards ORBs)): The affirmative
`decision of the IRB that the clinical trial has been reviewed and may be conducted at the
`institution site within the constraints set forth by the IRB, the institution, good clinical
`practice (GCP), and the applicable regulatory requirements.
`
`1.6 Audit: A systematic and independent examination of trial-related activities and
`documents to determine whether the evaluated trial-related activities were conducted, and
`the data were recorded, analyzed, and accurately reported according to the protocol,
`sponsor’s standard operating procedures (SOPs), good clinical practice (GCP), and the
`applicable regulatory requirement(s).
`
`1.7 Audit certificate: A declaration of confirmation by the auditor that an audit has
`taken place.
`
`1.8 Audit report: A written evaluation by the 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)
`
`Sandoz Inc.
`Exhibit 1049-0007
`
`

`
`being unaware, and double blinding usually refers to the subj ect(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
`subj ect.
`
`1.12 Clinical trial/study: Any investigation in human subjects intended to discover or
`verify the clinical, pharmacological, and/or other pharmacodynamic effects of an
`investigational product(s), and/or to identify any adverse reactions to an investigational
`product(s), and/or to study absorption, distribution, metabolism, and excretion of an
`investigational product(s) with the object of ascertaining its safety and/or efficacy. The
`terms clinical trial and clinical study are synonymous.
`
`1.13 Clinical Trial/Study Report: A written description of a trial/study of any
`therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the
`clinical and statistical description, presentations, and analyses are fully integrated into a
`single report (see the ICH Guidance for Structure and Content of Clinical Study Reports).
`
`1.14 Comparator (Product): An investigational or marketed product (i.e., active
`control), or placebo, used as a reference in a clinical trial.
`
`1.15 Compliance (in relation to trials): Adherence to all the trial-related
`requirements, good clinical practice (GCP) requirements, and the applicable regulatory
`requirements.
`
`1.16 Confidentiality: Prevention of disclosure, to other than authorized individuals, of
`a 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.
`
`Sandoz Inc.
`Exhibit 1049-0008
`
`

`
`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 (see section 8.
`"Essential Documents for the Conduct of a Clinical Trial").
`
`1.24 Good Clinical Practice (GCP): A standard for the design, conduct, performance,
`monitoring, auditing, recording, analyses, and reporting of clinical trials that provides
`assurance that the data and reported results are credible and accurate, and that the rights,
`integrity, and confidentiality of trial subjects are protected.
`
`1.25 Independent Data Monitoring Committee (IDMC) (Data and Safety
`Monitoring Board, Monitoring Committee, Data Monitoring Committee): An
`independent data monitoring committee that may be established by the sponsor to assess
`at intervals the progress of a clinical trial, the safety data, and the critical efficacy
`endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
`
`1.26 Impartial Witness: A person, who is independent of the trial, who cannot be
`unfairly influenced by people involved with the trial, who attends the informed consent
`process if the subject or the subj ect’s legally acceptable representative cannot read, and
`who reads the informed consent form and any other written information supplied to the
`subj ect.
`
`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
`subj ects 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 subj ects.
`
`Sandoz Inc.
`Exhibit 1049-0009
`
`

`
`The legal status, composition, function, operations, and regulatory requirements pertaining
`to Independent Ethics Committees may differ among countries, but should allow the
`Independent Ethics Committee to act in agreement with GCP as described in this
`guidance.
`
`1.28 Informed Consent: A process by which a subject voluntarily confirms his or her
`willingness to participate in a particular trial, after having been informed of all aspects of
`the trial that are relevant to the 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 (CROs) facilities, or at other
`establishments deemed appropriate by the regulatory authority(ies).
`
`Institution (medical): Any public or private entity or agency or medical or dental
`1.30
`facility where clinical trials are conducted.
`
`1.31 Institutional Review Board ORB): 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. See also
`Subinvestigator.
`
`1.35 Investigator/Institution: An expression meaning "the investigator and/or
`institution, where required by the applicable regulatory requirements."
`
`Sandoz Inc.
`Exhibit 1049-0010
`
`

`
`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 subj ects (see section 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 (SOPs), GCP, and the applicable regulatory requirement(s).
`
`1.39 Monitoring Report: A written report from the monitor to the sponsor after each
`site visit and/or other trial-related communication according to the sponsor’s SOPs.
`
`1.40 Multicenter Trial: A clinical trial conducted according to a single protocol but at
`more than one site, and, therefore, carried out by more than one investigator.
`
`1.41 Nonclinical Study: Biomedical studies not performed on human subjects.
`
`1.42 Opinion (in relation to Independent Ethics Committee): The judgment and/or
`the advice provided by an Independent Ethics Committee (IEC).
`
`1.43 Original Medical Record: See Source Documents.
`
`1.44 Protocol: A document that describes the objective(s), design, methodology,
`statistical considerations, and organization of a trial. The protocol usually also gives the
`background and rationale for the trial, but these could be provided in other protocol
`referenced documents. Throughout the ICH GCP Guidance, the term protocol refers to
`protocol and protocol amendments.
`
`1.45 Protocol Amendment: A written description of a change(s) to or formal
`clarification of a protocol.
`
`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.
`
`Sandoz Inc.
`Exhibit 1049-0011
`
`

`
`1.48 Randomization: The process of assigning trial subjects to treatment or control
`groups using an element of chance to determine the assignments in order to reduce bias.
`
`1.49 Regulatory Authorities: Bodies having the power to regulate. In the ICH GCP
`guidance, the expression "Regulatory Authorities" includes the authorities that review
`submitted clinical data and those that conduct inspections (see section 1.29). These
`bodies are sometimes referred to as competent authorities.
`
`1.50
`ADR):
`
`Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious
`Any untoward medical occurrence that at any dose:
`¯ Results in death,
`¯ Is life-threatening,
`¯ Requires inpatient hospitalization or prolongation of existing
`¯ Results in persistent or significant disability/incapacity, or
`¯ Is a congenital anomaly/birth defect.
`
`hospitalization,
`
`(See the ICH guidance for Clinical Safety Data Management: Definitions and Standards
`for Expedited Reporting.)
`
`1.51 Source Data: All information in original records and certified copies of original
`records of clinical findings, observations, or other activities in a clinical trial necessary for
`the reconstruction and evaluation of the trial. Source data are contained in source
`documents (original records or certified copies).
`
`1.52 Source Documents: Original documents, data, and records (e.g., hospital
`records, clinical and office charts, laboratory notes, memoranda, subj ects’ 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.
`
`Sandoz Inc.
`Exhibit 1049-0012
`
`

`
`1.55 Standard Operating Procedures (SOPs): Detailed, written instructions to
`achieve uniformity of the performance of a specific function.
`
`1.56 Subinvestigator: Any individual member of the clinical trial team designated and
`supervised by the investigator at a trial site to perform critical trial-related procedures
`and/or to make important trial-related decisions (e.g., associates, residents, research
`fellows). See also Investigator.
`
`1.57 Subject/Trial Subject: An individual who participates in a clinical trial, either as
`a recipient of the investigational product(s) or as a control.
`
`1.58 Subject Identification Code: A unique identifier assigned by the investigator to
`each trial subject to protect the 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 Guidance for Clinical
`Safety Data Management: Definitions and Standards for Expedited Reporting.)
`
`1.61 Vulnerable Subjects: Individuals whose willingness to volunteer in a clinical trial
`may be unduly influenced by the expectation, whether justified or not, of benefits
`associated with participation, or of a retaliatory response from senior members of a
`hierarchy in case of refusal to participate. Examples are members of a group with a
`hierarchical structure, such as medical, pharmacy, dental, and nursing students,
`subordinate hospital and laboratory personnel, employees of the pharmaceutical industry,
`members of the armed forces, and persons kept in detention. Other vulnerable subjects
`include patients with incurable diseases, persons in nursing homes, unemployed or
`impoverished persons, patients in emergency situations, ethnic minority groups, homeless
`persons, nomads, refugees, minors, and those incapable of giving consent.
`
`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).
`
`Sandoz Inc.
`Exhibit 1049-0013
`
`

`
`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.
`
`The available nonclinical and clinical information on an investigational product
`2.4
`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).
`
`Freely given informed consent should be obtained from every subject prior to
`2.9
`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 subj ects 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.
`
`Sandoz Inc.
`Exhibit 1049-0014
`
`

`
`o
`
`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
`subj ects.
`
`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, subj ect 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 subj ects, the investigator’s current
`curriculum vitae and/or other documentation evidencing qualifications, and any
`other documents that the IRB/IEC may require to fulfil its responsibilities.
`
`The IRB/IEC should review a proposed clinical trial within a reasonable time and
`document its views in writing, clearly identifying the trial, the documents reviewed,
`and the dates for the following:
`Approval/favorable opinion;
`Modifications required prior to its approval/favorable opinion;
`Disapproval/negative opinion; and
`Termination!suspension of any prior approval/favorable opinion.
`
`3.1.3 The IRB/IEC should consider the qualifications of the investigator for the
`proposed trial, as documented by a current curriculum vitae and/or by any other
`relevant documentation the IRB/IEC requests.
`
`3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at
`intervals appropriate to the degree of risk to human subjects, but at least once per
`year.
`
`3.1.5 The IRB/IEC may request more information than is outlined in paragraph
`4.8.10 be given to subjects when, in the judgment of the IRB/IEC, the additional
`information would add meaningfully to the protection of the rights, safety, and/or
`well-being of the subj ects.
`
`3.1.6 When a nontherapeutic trial is to be carried out with the consent of the
`subject’s legally acceptable representative (see sections 4.8.12, 4.8.14), the
`IRB/IEC should determine that the proposed protocol and/or other document(s)
`
`10
`
`Sandoz Inc.
`Exhibit 1049-0015
`
`

`
`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
`subj ect’s legally acceptable representative is not possible (see section 4.8.15), the
`IRB/IEC should determine that the proposed protocol and/or other document(s)
`adequately addresses relevant ethical concerns and meets applicable regulatory
`requirements for such trials (i.e., in emergency situations).
`
`3.1.8 The IRB/IEC should review both the amount and method of payment to
`subjects to assure that neither p