ACRP CCRC Study Guide (Latest 2024/ 2025 Update) Questions and Verified Answers| 100% Correct| Grade A
ACRP CCRC Study Guide (Latest 2024/
2025 Update) Questions and Verified
Answers| 100% Correct| Grade A
Q: “Approval” (in relation to Institutional Review Boards)
Answer:
The affirmative de- cision 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.
Q: Audit
Answer:
A systematic and independent examination of trial related activities and documents to determine
whether the evaluated trial related activities were conduct- ed, 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).
Q: Audit Certificate
Answer:
A declaration of confirmation by the auditor that an organiza- tion audit has taken place.
Q: Audit Trail
Answer:
Documentation that allows reconstruction of the course of events.
Q: Blinding/Masking
Answer:
A procedure in which one or more parties to the trial are kept unaware of the treatment
assignment. 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 assign- ment(s). (ICH GCP E6 1.10)
Q: Case Report Form (CRF)
Answer:
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.
Q: Clinical Trial/Study
Answer:
Any investigation in human subjects intended to discover or verify the clinical, pharmacological
and/or other PD effects of an IP(s), and/or to identify any AEs to an IP(s), and/or to study
absorption, distribution, metabolism, and excretion of an IP(s) with the object of ascertaining its
safety and/or efficacy.
Q: Clinical Trial/ Study Report
Answer:
A written description of a trial/study of any thera- peutic, 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.
Q: Comparator (Product)
Answer:
An investigational or marketed product (i.e., active con- trol), or placebo, used as a reference in
a clinical trial.
Q: Compliance (in relation to trials)
Answer:
Adherence to all trial-related requirements, GCP requirement and the applicable regulatory
requirements.
Q: Confidentiality
Answer:
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary
information or of a subject’s identity.
Q: Contract
Answer:
A written, date, and signed agreement between two or more involved parties that sets out any
arrangements on delegation and distribution of task and obligations and, if appropriate, on
financial matters. protocol may serve as the basis of a contract.
Q: Coordinating Committee
Answer:
A committee that a sponsor may organize to coordi- nate the conduct of a multicenter trial.
Q: Coordinating Investigator
Answer:
An investigator assigned the responsibility for the coordination of investigators at different
centers participating in a multicenter trial.
Q: Contract Research Organization (CRO)
Answer:
A person or an organization contract- ed by the sponsor to perform one or more of a sponsor’s
trial-related duties and functions.
Conducts Trials.
Q: Direct Access
Answer:
Permission to examine, analyze, verify, and reproduce any records and reports that are important
to evaluation of a clinical trial.
Q: Documentation
Answer:
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical
records, and scans, x-rays, and electrocardio- grams) that describe or record the methods,
conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.
Q: Essential Documents
Answer:
Documents which individually and collectively permit evaluation of the conduct of a study and
the quality of the data produced.
Q: Good Clinical Practice (GCP)
Answer:
A standard for the design, conduct, perfor- mance, 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.
Q: Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitor- ing Board
Monitoring Committee (DSMB), Data Monitoring Committee)
Answer:
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.
Q: Impartial Witness
Answer:
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All noxious and unintended responses to a medicinal product related to any dose Adverse Drug Reaction (ADR)
Glossary of terms E6(R1) 1
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment–any unfavorable and unintended sign , symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product Adverse Event (AE)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products Applicable Regulatory Requirements
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 Institutional Review Board Approval
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) Audit
A declaration of confirmation by the auditor that an audit has taken place Audit Certificate
A written evaluation by the sponsor’s auditor of the results of the audit Audit Report
Documentation that allows reconstruction of the course of events Audit Trail
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Blinding/Masking
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. Case Report Form (CRF)
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 Clinical Trial/Study
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 Clinical Trial/Study Report
An investigational or marketed product, or placebo, used as a reference in a clinical trial. Comparator (Product)
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements Compliance to Trials
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity. Confidentiality
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. Contract
A committee that a sponsor may organize to coordinate the conduct of a multicenter trial. Coordinating Committee
An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial Coordinating Ivestigator
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. Contract Research Organization (CRO)
Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial Direct Access
All records, in any form that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken Documentation
Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced Essential Documents
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 Good Clinical Practice (GCP)
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 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)
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 Impartial Witness
An independent body constituted of medical professionals and non-medical 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. Independent Ethics Committee (IEC)
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–documented by means of a written, signed and dated informed consent form Informed Consent
The act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authorities 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 authorities Inspection
Any public or private entity or agency or medical or dental facility where clinical trials are conducted Institution (Medical)
An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects Institutional Review Board (IRB)
A report of intermediate results and their evaluation based on analyses performed during the course of a trial Interim Clinical Trial/Study Report
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. Investigational Product
A person responsible for the conduct of the clinical trial at a trial site. Investigator
A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects. Investigator’s Brochure
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. Legally Acceptable Representative
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), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). Monitoring
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. Monitoring Report
A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator Multicenter Trial
Biomedical studies not performed on human subjects Nonclinical Study
The judgement and/or the advice provided by an Independent Ethics Committee (IEC) IEC Opinion
A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. Protocol
A written description of a change to or formal clarification of a protocol. Protocol Amendment
All those planned and systematic actions that are established to ensure that the trial is performed ad the data are generated, documented, and reported in compliance with GCP and the applicable regulatory requirements Quality Assurance (QA)
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 Quality Control (QC)
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. Randomization
Bodies having the power to regulate. Regulatory Authorities
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-is a congenital anomaly/birth defect Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
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
Original documents, data, and records. Source Documents
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial Sponsor
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. Sponsor-Investigator
Detailed, written instructions to achieve uniformity of the performance of a specific function Standard Operating Procedures (SOPs)
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. Subinvestigator
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control Subject/Trial Subject
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 Subject Identification Code
The location(s) where trial-related activities are actually conducted Trial Site
An adverse reaction, the nature or severity of which is not consistent with the applicable product information. Unexpected Adverse Drug Reaction
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, or benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Vulnerable Subject
The physical and mental integrity of the subjects participating in a clinical trial Well-being (of the trial subjects)
The Principles of ICH GCP E6(R1) 2
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) E6(R1) 2.1
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. E6(R1) 2.2
The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. E6(R1) 2.3
The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. E6(R1) 2.4
Clinical trials should be scientifically sound, and described in a clear detailed protocol. E6(R1) 2.5
A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) approval/favorable opinion. E6(R1) 2.6
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. E6(R1) 2.7
Each individual involved in conducting a trial should be qualified by eduction, training, and experience to perform his or her respective task(s). E6(R1) 2.8
Freely given informed consent should be obtained from every subject prior to clinical trial participation E6(R1) 2.9
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting interpretation and verification. E6(R1) 2.10
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). E6(R1) 2.11
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. E6(R1) 2.12
Systems with procedures that assure the quality of every aspect of the trial should be implemented. E6(R1) 2.13
Institutional Review Board/Independent Ethics Committee (IRB/IEC)–Responsibilities E6(R1) 3.1
Institutional Review Board/Independent Ethics Committee (IRB/IEC)–Composition, Functions and Operations E6(R1) 3.2
Institutional Review Board/Independent Ethics Committee (IRB/IEC)–Procedures-The IRB/IEC should establish, document in writing, and follow its procedures E6(R1) 3.3
Institutional Review Board/Independent Ethics Committee (IRB/IEC)–Records-The IRB/IEC should retain all relevant records for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authorities E6(R1) 3.4
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 E6(R1) 3.1.1
The IRB/IEC should obtain the following documents: trial protocols/amendments, written informed consent forms and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures, written information to be provided to subjects, Investigator’s Brochure, 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 need to fulfill its responsibilities. E6(R1) 3.1.2
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 E6(R1) 3.1.3
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 E6(R1) 3.1.4
The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects. E6(R1) 3.1.5
When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative, the IRB/IEC should determine that the proposed protocol and/or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials E6(R1) 3.1.6
Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible, the IRB/IEC should determine that the proposed protocol and/or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials E6(R1) 3.1.7
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. E6(R1) 3.1.8
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. E6(R1) 3.1.9
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 membersb) at least one member whose primary area of interest is in a nonscientific areac) 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. E6(R1) 3.2.1
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 requirements E6(R1) 3.2.2
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 E6(R1) 3.2.3
Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise E6(R1) 3.2.4
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 E6(R1) 3.2.5
An IRB/IEC may invite nonmembers with expertise in special areas for assistance E6(R1) 3.2.6
Determining its composition(names and qualifications of the members) and the authority under which it is established E6(R1) 3.3.1
Scheduling, notifying its members of, and conducting its meetings. E6(R1) 3.3.2
Conducting initial and continuing review of trials. E6(R1) 3.3.3
Determining the frequency of continuing review, as appropriate. E6(R1) 3.3.4
Providing, according to the applicable regulatory requirements, expedited review and approval/favorable opinion of minor changes in ongoing trials that have the approval/favorable opinion of the IRB/IEC. E6(R1) 3.3.5
Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favorable opinion of the trial E6(R1) 3.3.6
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 eliminate immediate hazards to the subjects or when the changes involves only logistical or administrative aspects to the trial. E6(R1) 3.3.7
Specifying that the investigator should promptly repot to the IRB/IECa) deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjectsb) changes increasing the risk to subjects and/or affecting significantly the conduct of the trailc) all adverse drug reactions (ADRs) that are both serious ad unexpectedd) new information that may affect adversely the safety of the subjects or the conduct of the trial. E6(R1) 3.3.8
Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:a) its trial-related decisions/opinionsb) the reasons for its decisions/opinionsc) Procedures for appeal of its decisions/opinions. E6(R1) 3.3.9
Investigator E6(R1) 4
Investigator’s Qualifications and Agreements E6(R1) 4.1
The investigator(s) should be qualified by education, training, and experience to assume responsibility of 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 authorities E6(R1) 4.1.1
The investigator should be thoroughly familiar with the appropriate use of the investigational products, as described int he protocol, in the current Investigator’s Brochure, in the product information and in other information sources provided by the sponsor. E6(R1) 4.1.2
The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements. E6(R1) 4.1.3
The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authorities E6(R1) 4.1.4
The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties E6(R1) 4.1.5
Investigator-Adequate Resources E6(R1) 4.2
The investigator should be able to demonstrate a potential for recruiting the required number of suitable subjects within the agreed recruitment period. E6(R1) 4.2.1
The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period. E6(R1) 4.2.2
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. E6(R1) 4.2.3
The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational products, and their trial-related duties and functions. E6(R1) 4.2.4
Investigator-Medical Care of Trial Subjects E6(R1) 4.3
A qualified physician (or dentist when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions. E6(R1) 4.3.1
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 E6(R1) 4.3.2
It is recommended that the investigator inform the subject’s primary physician about the subjects participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed. E6(R1) 4.3.3
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 reasons, while fully respecting the subject’s rights. E6(R1) 4.3.4
Investigator–Communication with IRB/IEC E6(R1) 4.4
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, and any other written information to be provided to subjects E6(R1) 4.4.1
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/institutions should supply a copy of the updated Investigator’s Brochure to the IRB/IEC. E6(R1) 4.4.2
During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review. E6(R1) 4.4.3
Investigator–Compliance with Protocol E6(R1) 4.5
The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by th regulatory authorities and which was given approval/favorable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement E6(R1) 4.5.1
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 eh IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the changes involves only logistical or administrative aspects of the trial. E6(R1) 4.5.2
The investigator, or person designated by the investigator, should document and explain any deviation froth approved protocol. E6(R1) 4.5.3
The investigator may implement a deviation from, or a change of, 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) E6(R1) 4.5.4
Investigational Product(s) E6(R1) 4.6
Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution E6(R1) 4.6.1
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 E6(R1) 4.6.2
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 E6(R1) 4.6.3
The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s) E6(R1) 4.6.4
The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol E6(R1) 4.6.5
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 E6(R1) 4.6.6
Randomization Procedures and Unblinding E6(R1) 4.7
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 of the investigational product(s) Randomization Procedures and Unblinding
Informed Consent of Trial Subjects E6(R1) 4.8
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. E6(R1) 4.8.1
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 E6(R1) 4.8.2
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial E6(R1) 4.8.3
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 E6(R1) 4.8.4
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 and the approval/favorable opinion by the IRB/IEC E6(R1) 4.8.5
The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical adn should be understandable to the subject or the subject’s legally acceptable representative adn the impartial witness, where applicable. E6(R1) 4.8.6
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 E6(R1) 4.8.7
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. E6(R1) 4.8.8
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 th etrial and, if capapble of doing so, has signed adn personally dated the informed cosnent form, the witness should sign adn personally date the consent form. By signing the consent form, the witness attests that the information in th e consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptablerepresentative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative E6(R1) 4.8.9
a) That the trial involves researchb) The purpose of the trialc) The trial treatment(s) and the probability for random assignment to each treatmentd) The trial procedures to be followed, including all invasive procedurese) The subject’s responsibilitiesf) Those aspects of the trial that are experimentalg) The reasonably foreseeable risks or inconveniences to the subject and, when applicable to an embryo, fetus, or nursing infanth) the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this E6(R1) 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. . .Part 1
i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risksj) The compensation and/or treatment available to the subject in the event of trial-related injuryk) The anticipated prorated payment, if any, to the subject for participating in the triall) The anticipated expenses, if any, to the subject for participating in the trialm) 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 entitledn) 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 fo the subject, to the extent permitted by 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 E6(R1) 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. . .Part 2
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 confidentialp) 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 trialq) 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 injuryr) 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 trialt) The approximate number of subjects involved in the trial E6(R1) 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. . .Part 3
Prior to participation i 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. E6(R1) 4.8.11
When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative, the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent E6(R1) 4.8.12
Except as described in 4.8.14, a non-therapeutic trial, should be conducted in subjects who personally give consent and who sign and date the written informed consent. E6(R1) 4.8.13
a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personallyb) The foreseeable risks to the subjects are lowc) The negative impact on the subject’s well-being is minimized and lowd) The trial is not prohibited by lawe) 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 E6(R1) 4.8.14–Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled. . .Part 1
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. E6(R1) 4.8.14–Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled. . .Part 2
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 should be requested E6(R1) 4.8.15
Records and Reports E6(R1) 4.9
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRF’s and infall required reports. E6(R1) 4.9.1
Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained E6(R1) 4.9.2
Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry; this applies to both written and electronic changes or corrections. Sponsors should provide guidance to investigators and/or the investigators’ designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections. E6(R1) 4.9.3
The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents. E6(R1) 4.9.4
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. E6(R1) 4.9.5
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. E6(R1) 4.9.6
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 E6(R1) 4.9.7
Progress Report E6(R1) 4.10
The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC. E6(R1) 4.10.1
The investigator should promptly provide written reports to the sponsor, the IRB/IEC and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects E6(R1) 4.10.2
Safety Reporting E6(R1) 4.11
All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document 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(its) an the IRB/IEC E6(R1) 4.11.1
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 E6(R1) 4.11.2
For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information E6(R1) 4.11.3
If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies) E6(R1) 4.12–Premature Termination or Suspension of a Trial
If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension E6(R1) 4.12.1
If the sponsor terminates or suspends a trial, the investigator should promptly inform the institutions where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension E6(R1) 4.12.2
If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension. E6(R1) 4.12.3
Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(its) with any reports required E6(R1) 4.13 — Final Report(s) by Investigator
Sponsor E6(R1) 5
Quality Assurance and Quality Control E6(R1) 5.1
The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s) E6(R1) 5.1.1
The sponsor is responsible for securing agreement from all involved parties to ensure direct access 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 E6(R1) 5.1.2
Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. E6(R1) 5.1.3
Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement E6(R1) 5.1.4
Contact Research Organization (CRO) E6(R1) 5.2
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 E6(R1) 5.2.1
Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing E6(R1) 5.2.2
Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. E6(R1) 5.2.3
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 E6(R1) 5.2.4
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. E6(R1) 5.3 — Medical Expertise
Trial Design E6(R1) 5.4
The sponsor should utilize qualified individuals as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports E6(R1) 5.4.1
For further guidance: Clinical Trial Protocol and Protocol Amendment(s), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct E6(R1) 5.4.2
Trial Management, Data Handling, and Record Keeping E6(R1) 5.5
The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the stat, to verify the data, to conduct the statistical analysis, and to prepare the trial reports E6(R1) 5.5.1
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 E6(R1) 5.5.2
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 performanceb) Maintains SOPs for using these systemsc) 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 datad) Maintain a security system that prevents unauthorized access to the datae) Maintain a list of the individuals who are authorized to make data changesf) Maintain adequate backup of the datag) Safeguard the blinding, if any E6(R1) 5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data E6(R1) 5.5.4
The sponsor should use an unambiguous subject identification code that allows identification of all the data reported for each subject E6(R1) 5.5.5
The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial E6(R1) 5.5.6
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) E6(R1) 5.5.7
If the sponsor discontinues the clinical development of an investigational product, 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) E6(R1) 5.5.8
If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities E6(R1) 5.5.9
Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s) E6(R1) 5.5.10
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 E6(R1) 5.5.11
The sponsor should inform the investigator(s)/institution(s) in writing of the need for record attention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed E6(R1) 5.5.12
Investigator Selection E6(R1) 5.6
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 to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multi center trials, their organization and/or selection are the sponsor’s responsibility E6(R1) 5.6.1
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 E6(R1) 5.6.2
a) to conduct the trial in compliance with GCP, with th applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IECb) to comply with procedures for data recording/reportingc) to permit monitoring, auditing and inspection d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed E6(R1) 5.6.3 — The sponsor should obtain the investigator’s/institution’s agreement. . .
The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement E6(R1) 5.6.3 Part 2
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions. E6(R1) 5.7–Allocation of Responsibilities
Compensation to Subjects and Investigators E6(R1) 5.8
If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify the investigator/ the institution against claims arising fro the trial, except for claims that arise from malpractice and/or negligence E6(R1) 5.8.1
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 requirements E6(R1) 5.8.2
The trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s) E6(R1) 5.8.3
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution E6(R1) 5.9 — Financing
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 E6(R1) 5.10 — Notification/Submission to Regulatory Authority(ies)
Confirmation of Review by IRB/IEC E6(R1) 5.11
a) The name and address of the investigator’s/institution’s IRB/IECb) 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 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 E6(R1) 5.11.1–The sponsor should obtain from the investigator/institution
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 bytes IRB/IEC E6(R1) 5.11.2
The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC re-approvals/re-evaluations with favorable opinion, and of any withdrawals or suspensions of approval/favorable opinion E6(R1) 5.11.3
Information on Investigational Product(s) E6(R1) 5.12
When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies an/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 E6(R1) 5.12.1
The sponsor should update the Investigator’s Brochure as significant new information becomes available. E6(R1) 5.12.2
Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) E6(R1) 5.13
The sponsor should ensure that the investigational product(s) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s) E6(R1) 5.13.1
The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions, storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties of these determinations. E6(R1) 5.13.2
The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage E6(R1) 5.13.3
In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the 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 E6(R1) 5.13.4
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) 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 E6(R1) 5.13.5
Supplying and Handling Investigational Product(s) E6(R1) 5.14
The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s) E6(R1) 5.14.1
The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation E6(R1) 5.14.2
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 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)) E6(R1) 5.14.3
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 retrievald) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition E6(R1) 5.14.4 — The sponsor should . . .
a) Take steps to ensure that the investigational product(s) are stable over the period of useb) 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 analysis and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required but he applicable regulatory requirement(s), whichever represents the longer retention period. E6(R1) 5.14.5 — Th sponsor should
Record Access E6(R1) 5.15
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 E6(R1) 5.15.1
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 E6(R1) 5.15.2
Safety Information E6(R1) 5.16
The sponsor is responsible for the ongoing safety evaluation of the investigational product(s) E6(R1) 5.16.1
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 opinions to continue the trial E6(R1) 5.16.2
Adverse Drug Reaction Reporting E6(R1) 5.17
The sponsor should expedite the reporting to all concerned investigator(s)/institution(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected E6(R1) 5.17.1
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 E6(R1) 5.17.2
The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s). E6(R1) 5.17.3
Monitoring E6(R1) 5.18
a) the rights and well-being of human subjects are protectedb) the reported trial data are accurate, complete, and verifiable from source documentsc) the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s) E6(R1) 5.18.1 — Purpose–The purposes of trial monitoring are to verify that
a) monitors should be appointed by the sponsorb) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed dod monitor the trial adequately. A monitor’s qualifications should be documentedc) monitors should be thoroughly familiar with the investigational product(s) the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s) E6(R1) 5.18.2 — Selection and Qualifications of Monitors
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 consideration 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 conjunction with procedures such as investigators’ training and meetings, and excessive 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 E6(R1) 5.18.3 — Extent and Nature of Monitoring
a) Acting as the main line of communication between the sponsor and the investigatorb) Verifying that the investigator has adequate qualifications and resources and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate too sales and properly conduct the trial and remain adequate throughout the trial period. E6(R1) 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: (Part 1)
i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trialii) 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 adequatelyv) that the disposition of unused investigational requirement(s) and is in accordance with the sponsor E6(R1) 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: c) verifying ,for the investigational product(s): (Part 2)
d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if anye) Verifying that written informed consent as obtained before each subject’s participation in the trialf) 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 E6(R1) 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: (Part 3)
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 individualsi) verifying that the investigator is enrolling only eligible subjectsj) reporting the subject recruitment ratek) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintainedl) 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 E6(R1) 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: (Part 4)
i) the data required by the protocol are reported accurately on the CRFs and are consistent with the source documentsii) any dose and/or therapy modifications are well documented for each of the trial subjectsiii) aderse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRF’siv) visits that the subjects fail to make, tests that are not conducted, and examinations that are reported as such on the CRFsv) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs E6(R1) 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: m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that: (Part 5)
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 documentedo) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s)p) determining whether the investigator is maintaining the essential documentsq) communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations E6(R1) 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: (Part 6)
The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial E6(R1) 5.18.5 — Monitoring Procdures
a) the monitor should submit a written report to the sponsor after each trial site visit or trial related communicationb) reports should include the date, site, name of the monitor, and name of the investigator or the other individual(s) contactedc) 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 nations recommended to secure complianced) the review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative E6(R1) 5.18.6 — Monitoring Report
Audit — If or when sponsors perform audits, as part of implanting quality assurance, they should consider the following (5.19.1-5.19.3) E6(R1) 5.19
The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, sops, GCP, and the applicable regulatory requirements E6(R1) 5.19.1 –Purpose
a) the sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct auditsb) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented E6(R1) 5.19.2 — Selection and Qualification of Auditors
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 documentedd) to preserve the independence and value of the audit functions, the regulatory authorities should not routinely request the audit reports. Regulatory authorities may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedingse) when required by applicable law or regulation, the sponsor should provide an audit certificate E6(R1) 5.19.3 — Auditing Procedures
Noncompliance E6(R1) 5.20
Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements by a investigator/institution, or by members of ht sponsor’s staff should lead to prompt action by the sponsor to secure compliance E6(R1) 5.20.1
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/instiution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authorities E6(R1) 5.20.2
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authorities of the termination or suspension and the reasons for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reasons for the determination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirements E6(R1) 5.21 — Premature Termination or Suspension of a Trial
Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agencies as required by the applicable regulatory requirements. The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guidelines for Structure and Content of Clinical Study Report (NOTE: the ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases E6(R1) 5.22 — Clinical Trial/Study Reports
Multicenter Trials E6(R1) 5.23
All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authorities, and given approval/favorable opinion by the IRB/IEC E6(R1) 5.23.1
The CRFs are designed to capture the required data at all multi center trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data E6(R1) 5.23.2
The responsibilities of coordinating investigators and the other participating investigators are documented prior to the start of the trial E6(R1) 5.23.3
All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs E6(R1) 5.23.4
Communication between investigators is facilitated E6(R1) 5.23.5
The contents of a trip protocol should generally include the following topics. However site specific information may be provided on separate protocol pages, 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 E6(R1) 6 — Clinical Trial Protocol and Protocol Amendments
Clinical Trial Protocol and Protocol Amendments E6(R1) 6
General Information E6(R1) 6.1
Protocol title, protocol identifying number, and date. Any amendments should also bear the amendment numbers and dates E6(R1) 6.1.1
Name and address of the sponsor and monitor E6(R1) 6.1.2
Name and title of the persons authorized to sign the protocol and the protocol amendments for the sponsor E6(R1) 6.1.3
Name, title, address, and telephone numbers of the sponsor’s medical expert/dentist for the trial E6(R1) 6.1.4
Name and title of the investigators who are responsible for conducting the trial, and the address and telephone numbers of the trial sites E6(R1) 6.1.5
Name, title, address, and telephone numbers of the qualified physician or dentist who is responsible for all trial-site related medical or dental decisions (if other than investigator) E6(R1) 6.1.6
Names and addresses of the clinical laboratories and other medical and/or technical departments and/or institutions involved in the trial E6(R1) 6.1.7
Background Information E6(R1) 6.2
Name and description of the investigational products E6(R1) 6.2.1
A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial E6(R1) 6.2.2
summary of the known and potential risks and benefits, if any, to human subjects. E6(R1) 6.2.3
Description of and justification for the route of administration, dosage, dosage regimen, and treatment periods E6(R1) 6.2.4
A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirements E6(R1) 6.2.5
Description of the population to be studied E6(R1) 6.2.6
References to literature and data that are relevant to the trial, and that provide background for the trial E6(R1) 6.2.7
A detailed description of the objectives and the purpose of the trial E6(R1) 6.3 — Trial Objectives and Purpose
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design E6(R1) 6.4 –Trial Design
A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial E6(R1) 6.4.1
A description of the type/design of trial to be conducted and a schematic diagram of trial design, procedures and stages E6(R1) 6.4.2
A description of the measures taken to minimize/avoid bias, including a) Randomization b) Blinding E6(R1) 6.4.3
A description of the trial treatments and the dosage and dosage regimen of the investigational products. Also include a description of the dosage form, packaging, and labelling of the investigational products E6(R1) 6.4.4
The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up if any E6(R1) 6.4.5
“A description of the “”stopping rules”” or “”discontinuation criteria”” for individual subjects, parts of trial and entire trial” E6(R1) 6.4.6
Accountability procedures for the investigational products, including the placebos and comparators, if any E6(R1) 6.4.7
Maintenance of trial treatment randomization codes and procedures for breaking codes E6(R1) 6.4.8
The identification of any data to be recorded directly on the CRFs and to be considered to be source data E6(R1) 6.4.9
Selection and Withdrawal of Subjects E6(R1) 6.5
Subject inclusion criteria E6(R1) 6.5.1
Subject exclusion criteria E6(R1) 6.5.2
Subject withdrawal criteria and procedure specifying a) when and how to withdraw subjects from the trial/investigational product treatmentb) the type and timing of the data to be collected for withdrawn subjectsc) whether and how subjects are to be replacedd) the follow-up for subjects withdrawn from investigational product treatment/trial treatment E6(R1) 6.5.3
Treatment of Subjects E6(R1) 6.6
the treatments to be administered, including the names of all the products, the doses, the dosing schedules, the route/modes of administration, and the treatment periods, including the follow-up periods for subjects for each investigational product treatment/trial treatment group/arm of the trial E6(R1) 6.6.1
Medications/treatments permitted (including rescue medication) and not permitted before and/or during the trial E6(R1) 6.6.2
Procedures for monitoring subject compliance E6(R1) 6.6.3
Assessment of Efficacy E6(R1) 6.7
Specifications of the efficacy parameters E6(R1) 6.7.1
Methods and timing for assessing, recording, and analyzing of efficacy parameters E6(R1) 6.7.2
Assessment of Safety E6(R1) 6.8
Specification of safety parameters E6(R1) 6.8.1
The methods and timing for assessing, recording, and analyzing safety parameters E6(R1) 6.8.2
Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses E6(R1) 6.8.3
The type and duration of the follow-up of subjects after adverse events E6(R1) 6.8.4
Statistics E6(R1) 6.9
A description of the statistical methods to be employed, including timing of any planned interim analysis E6(R1) 6.9.1
The number of subjects planned to be enrolled. In multimeter trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification E6(R1) 6.9.2
The level of significance to be used E6(R1) 6.9.3
Criteria for the termination of the trial E6(R1) 6.9.4
Procedure for accounting for missing, unused, and spurious data E6(R1) 6.9.5
Procedures for reporting any deviations from the original statistical plan (any deviations from the original statistical plan should be described and justified in protocol and/or in the final report as appropriate E6(R1) 6.9.6
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigators/institutions will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspections, providing direct access to source data/documents E6(R1) 6.10 — Direct Access to Source Data/Documents
Quality Control and Quality Assurance E6(R1) 6.11
Ethics –Description of ethical considerations relating to the trial E6(R1) 6.12
Data Handling and Record Keeping E6(R1) 6.13
Financing and Insurance — if not addressed in a separate agreement E6(R1) 6.14
Publication Policy — if not addressed in a separate agreement E6(R1) 6.15
Supplements E6(R1) 6.16
Investigator Brochure E6(R1) 7
The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational products that are relevant to the study of the products in human subjects. Its purpose is to proved the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate int he editing of an IB, but the contents o the IB should be approved by the disciplines that generated the described data. E6(R1) 7.1 — Introduction
General Considerations E6(R1) 7.2
This should proved the sponsor’s name, the identity of each investigational product (research number, chemical or approved generic name, the trade names 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. E6(R1) 7.2.1 — Title Page
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 E6(R1) 7.2.2 — Confidentiality Statement
Contents of the Investigator’s Brochure E6(R1) 7.3
Table of Contents E6(R1) 7.3.1
Summary — a brief summary 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 E6(R1) 7.3.2
Introduction — A brief introductory statement should be provided that contains the chemical name of the investigational products, all active ingredients, the investigational products pharmacological class and its expected position within their class, the rationale for performing research with the investigational products, and the anticipated prophylactic, therapeutic, or diagnostic indications. Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product E6(R1) 7.3.3
Physical, Chemical, and Pharmaceutical Properties and Formulation — A description should be provided of the investigational product substances , 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 formulations to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage forms should also be given. Any structural similarities to other known compounds should be mentioned E6(R1) 7.3.4
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. E6(R1) 7.3.5 — Nonclinical studies: Introduction
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 as well as those that assess safety E6(R1) 7.3.5 — Nonclinical studies: Introduction — Nonclinical Pharmacology
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 E6(R1) 7.3.5 — Nonclinical studies: Introduction — Pharmacokinetics and Product Metabolism in Animals
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- Reproductive toxicity- Genotoxicity (mutagenicity) E6(R1) 7.3.5 — Nonclinical studies: Introduction — Toxicology
A thorough discussion of the known effects of the investigational products in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use o fate investigational products other than from in clinical trials, such as from experience during marketing E6(R1) 7.3.6 — Effects in Humans: Introduction
A summary of information on the pharmacokinetics of the investigational products should be presented, including the following, if available:- Pharmacokinetics- Bioavailability of the investigational product- Population subgroups- Interactions- Other pharmacokinetic data E6(R1) 7.3.6 — Effects in Humans: Introduction — Pharmacokinetic and Product Metabolism in Humans
A summary of information should be provided about the investigational products safety, pharmacodynamics, efficacy,a dn dose response that were obtained fro preceding trials in humans. 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 would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed E6(R1) 7.3.6 — Effects in Humans: Introduction — Safety and Efficacy (Part 1)
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 products E6(R1) 7.3.6 — Effects in Humans: Introduction — Safety and Efficacy (Part 2)
The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from eh marketed use should be summarized. 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 E6(R1) 7.3.6 — Effects in Humans: Introduction — Marketing Experience
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 products, 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 E6(R1) 7.3.7 — Summary of Data and Guidance for the Investigator
Essential Documents for the Conduct of a Clinical Trial E6(R1) 8
Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standard of Good Clinical Practice and with all applicable regulatory requirements E6(R1) 8.1 — Introduction
Before the Clinical Phase of the Trial Commences E6(R1) 8.2.
To document that relevant and current scientific information about the investigational product has been provided to the investigatorLOCATION: -Investigator/institution -Sponsor E6(R1) 8.2.1 — Investigator’s Brochure
To document investigator and sponsor agreement to the protocol/amendments and CRFLOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.2 — Signed Protocol and Amendments if any, and Sample Case Report Form (CRF)
to document the informed consentLOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.3 — Information Given to Trial Subject –Informed Consent Form
To document the subjects will be given appropriate written information to support their ability to give fully informed consent LOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.3 — Information Given to Trial Subject –Any Other Written Information
To document that recruitment measures are appropriate and not coerciveLOCATION:-Investigator/institution E6(R1) 8.2.3 — Advertisement for Subject Recruitment
To document the financial agreement between the investigator/institution and the sponsor for the trialLOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.4 –Financial Aspects of the Trial
To document that compensation to subjects for trial-related injury will be availableLOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.5 — Insurance Statement
To document agreementsLOCATION:-Sponsor-Investigator/Institution when involved E6(R1) 8.2.6 — Signed Agreement Between Involved Parties
To document that the trial has been subject to IRB/IEC review and given approval/favorable opinion. To identify the version number and date of documentsLOCATION:-Investigator/institution-Sponsor E6(R1) 8.2.7 — Dated, Documented Approval/Favorable Opinion of IRB/IEC
To document that the IRB/IEC is constituted in agreement with GCPLOCATION:-Investigator/institution-sponsor -where required E6(R1) 8.2.8 — IRB/IEC Composition
To document appropriate authorization/approval/notification by the regulatory authorities has been obtained prior to initiation of regulatory requirementsLOCATION:-Investigator/Institution -where required-Sponsor -where required E6(R1) 8.2.9 — Regulatory Authorities Authorization/Approval/Notification of Protocol
To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjectsLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.2.10 — Curriculum Vitae and/or Other Relevant Documents Evidencing Qualifications of Investigators and Sub-Investigators
To document normal values and/or ranges of testsLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.2.11 — Normal Values/Ranges for Medical/Laboratory/Technical Procedures and/or Tests Included in the Protocol
To document compétence of facility to perform required tests, and support reliability of resultsLOCATION:-Investigator/Institution -where required-Sponsor E6(R1) 8.2.12 — Medical/Laboratory/Technical Procedures/Tests
To document compliance with applicable labeling regulations and appropriateness of instructions provided to the subjectsLOCATION:-Sponsor E6(R1) 8.2.13 — Sample of Labels Attached to Investigational Product Containers
To document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products and trial related materialsLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.2.14 — Instructions for Handling of Investigational Products and Trial-Related Materials
To document shipment dates, batch numbers and method of shipment of investigational products and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountabilityLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.2.15 — Shippng Records for Investigational Products and Trial-Related Materials
To document identity, purity, and strength of investigational products to be used in the trialLOCATION:-Sponsor E6(R1) 8.2.16 — Certificates of Analysis of Investigational Products Shipped
To document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects’ treatmentLOCATION:-Investigator/Institution-Sponsor-Third Party -if applicable E6(R1) 8.2.17 — Decoding Procedures for Blinded Trials
To document method for randomization of trial populationLOCATION:-Sponsor-Third Party -if applicable E6(R1) 8.2.18 — Master Randomization List
To document that the site is suitable for the trialLOCATION:-Sponsor E6(R1) 8.2.19 — Pre-Trial Monitoring Report
To document that trial procedures were reviewed with the investigator and the investigator’s trial staffLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.2.20 — Trial Initiation Monitoring Report
During the Clinical Conduct of the Trial — all documents in 8.2 plus the following E6(R1) 8.3
To document that investigator is informed in a timely manner of relevant information as it becomes availableLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.1 — Investigator’s Brochure Updates
To document revisions of these trial related documents that take effect during trial LOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.2 — Any Revision to Trial Documents
To document that the amendments and/or revisions have been subject to IRB/IEC review and were given approval/favorable opinion. To identify the version number and date of the documentsLOCATION: -Investigator/Institution-Sponsor E6(R1) 8.3.3 — Dated, Documented Approval/Favorable Opinion of IRB/IEC of Trial Related Documents
To document compliance with applicable regulatory requirementsLOCATION:-Investigator/Institution -where required-Sponsor E6(R1) 8.3.4 — Regulatory Authorities Authorization/Approvals/Notifications Where Required for Protocol Amendments and Other Documents
To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjectsLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.5 — Curriculum Vitae For New Investigators and/or Sub Investigators
To document normal values and ranges that are revised during the trialLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.6 — Updates to Normal Values/Ranges for Medical/Laboratory/Technical Procedures/Tests Included in the Protocol
To document that test remain adequate throughout the trial periodLOCATION:-Investigator/Institution -where required-Sponsor E6(R1) 8.3.7 — Updates of Medical/Laboratory/Technical Procedures/Tests Certification, Accreditation, Established QC and/or External QA, or Other Validation
To document shipment dates, batch numbers and method of shipment of investigational products and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountabilityLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.8 — Documentation of Investigational Products and Trial-Related Materials Shipment
To document identity, purity, and strength of investigational products to be used in the trialLOCATION:-Sponsor E6(R1) 8.3.9 — Certificates of Analysis for New Batches of Investigational Products
To document site visits by, and findings of, the monitorLOCATION:-Sponsor E6(R1) 8.3.10 — Monitoring Visit Reports
To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AD) reportingLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.11 — Relevant Communications Other than Site Visits: letters, meeting notes, notes of telephone calls
To document that consent is obtained in accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permissionLOCATION:-Investigator/Institution E6(R1) 8.3.12 — Signed Informed Consent Forms
To document the existence of the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subjectLOCATION:-Investigator/Institution E6(R1) 8.3.13 — Source Documents
To document that the investigator or authorized member of the investigator’s staff confirms the observations recordedLOCATION:-Investigator/Institution -copy-Sponsor -original E6(R1) 8.3.14 — Signed, Dated and Completed Case Report Forms (CRF)
To document all changes/additions or corrections made to CRF after initial data were recordedLOCATION:-Investigator/Institution -copy-Sponsor -original E6(R1) 8.3.15 — Documentations of CRF Corrections
Notification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11LOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.16 — Notification by Originating Investigator to Sponsor of Serious Adverse Events and Related Reports
Notification by sponsor and/or investigator where applicable, to regulatory authorities and IRB/IECs of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2LOCATION:-Investigator/Institution -where required-Sponsor E6(R1) 8.3.17 — Notification by Sponsor and/or Investigator, Where Applicable, to Regulatory Authorities and IRB/IECs of Unexpected Serious Adverse Drug Reactions and of Other Safety Information
Notification by sponsor to investigators of safety information in accordance with 5.16.2LOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.18 — Notification by Sponsor to Investigators of Safety Information
Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authorities in accordance with 5.17.3LOCATION:-Investigator/Institution-Sponsor -where required E6(R1) 8.3.19 — Interim or Annual Reports to IRB/IEC and Authorities
To document identification of subjects who entered pre-trial screeningLOCATION:-Investigator/Institution-Sponsor -where required E6(R1) 8.3.20 — Subject Screening Log
To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subjectLOCATION:-Investigator/Institution E6(R1) 8.3.21 — Subject Identification Code List
To document chronological enrollment of subjects by trial numberLOCATION:-Investigator/Institution E6(R1) 8.3.22 — Subject Enrollment Log
To document that investigational products have been used according to the protocolLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.23 — Investigational Products Accountability at the Site
To document signatures and initials of all persons authorized to make entries and/or corrections on CRFsLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.24 — Signature Sheet
To document location and identification of retained samples if assays need to be repeatedLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.3.25 — Record of Retained body Fluids/Tissue Samples (If Any)
After Completion or Termination of the Trial –all documents in sections 8.2 and 8.3 plus these E6(R1) 8.4
to document that the investigational products have been used according to the protocol. To document the final accounting of investigational products received at the site, dispensed to subjects, returned by the subjects, and returned to sponsorLOCATION:-Investigator/Institution-Sponsor E6(R1) 8.4.1 — Investigational Products Accountability at Site
To document destruction of unused investigational products by sponsor or at siteLOCATION:-Investigator/Institution -if destroyed at site-Sponsor E6(R1) 8.4.2 — Documentation of Investigational Product Destruction
To permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon timeLOCATION:-Investigator/Institution E6(R1) 8.4.3 — Completed Subject Identification Code List
To document that audit was performed LOCATION:-Sponsor E6(R1) 8.4.4 — Audit Certificate (if available)
To document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate filesLOCATION:-Sponsor E6(R1) 8.4.5 — Final Trial Close-Out Monitoring Report
Returned to sponsor to document any decoding that may have occurredLOCATION:-Sponsor E6(R1) 8.4.6 — Treatment Allocation and Decoding Documentations
To document completion of the trialLOCATION:-Investigator/Institution E6(R1) 8.4.7 — Final Report by Investigator to IRB/IEC Where Required, and Where Applicable, to the Regulatory Authorities
To document results and interpretations of trialLOCATION:-Investigator/Institution -if applicable-Sponsor E6(R1) 8.4.8 — Clinical Study Report
Definitions and Standards for Expedited Reporting E2A
Introduction E2A I
Definitions and Terminology Associated with Clinical Safety Experience E2A II
Basic Terms E2A II.A
Adverse Event (or Adverse Experience) E2A II.A.1
Adverse Drug Reaction (ADR) E2A II.A.2
Unexpected Adverse Drug Reaction E2A II.A.3
Serious Adverse Event or Adverse Drug Reaction E2A II.B
Expectedness of an Adverse Drug Reaction E2A II.C
Standards for Expedited Reporting E2A III
What Should be Reported? E2A III.A
Single Cases of Serious, Unexpected ADRs –All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting–source should always be specified, causality assessment required E2A III.A.1
“Other Observations –a) for an “”expected,”” serious ADR, an increase in the rate of occurrence which is judged to be clinically importantb) a significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening diseasec) a major safety finding from a newly comleted animal study” E2A III.A.2
Reporting Time Frames E2A III.B
Fatal or Life-Threatening Unexpected ADRs- Fatal or life-threatening, unexpected ADRsoccurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8additional calendar days. – This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products. E2A III.B.1
All Other Serious, Unexpected ADRs-Serious, unexpected reactions (ADRs) that are not fatal or life threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting E2A III.B.2
Minimum Criteria for Reporting-Information for final description and evaluation of a case report may not be available within the required time frames for reporting outlinedabove. – for regulatory purposes, initial reports should be submitted within the prescribed time as long as the following minimum criteria are met: a) an identifiable patient; b) suspect medicinal product; c) identifiable reporting source; d) event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. -Follow-up information should be actively sought andsubmitted as it becomes available. E2A III.B.3
How to Report E2A III.C
Managing Blinded Therapy Cases E2A III.D
Miscellaneous Issues E2A III.E
Reactions Associated with Active Comparator or Placebo Treatment-Sponsor’s responsibility to decide whether reaction to be reported to manufacturer or to appropriate regulatory agenicies E2A III.E.1
Products with More than one Presentation or Use E2A III.E.2
Post-study events-serious adverse events that occurred after the patient had completed a clinical study will possibly be reported by an investigator to the sponsor E2A III.E.3
Informing Investigators and Ethics Committees/Institutional Review Boards of New Safety Information E2A III.F
- Patient Details Initials2. Suspected Medicinal Products3. Other Treatments4. Details of Suspected Adverse Drug Reactions5. Details on Reporter of Event (Suspected ADR)6. Administrative and Sponsor/Company Details E2A Attachment 1 — Key Data Elements for Inclusion in Expedited Reports of Serious Adverse Drug Reactions
General Considerations for Clinical Trials E8
Objectives of this document E8 1
a) describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal productsb) facilitate the evaluation and acceptance of foreign clinical trial data by promoting common understanding of general principles, general approaches and the definition of relevant termsc) Present an overview of the ICH clinical safety and efficacy documents and facilitate the user’s access to guidance pertinent to clinical trials within these documentsd) provide a separate glossary of terms used in the ICH clinical safety and efficacy related documents that pertain to clinical trials and indicate which documents contain them E8 1 — Objecties of this Document
General Principles E8 2.
Protection of clinical trial subjects E8 2.1
Scientific approach in design analysis E8 2.2
-assess tolerance -describe PK and PD-Explore drug metabolism and drug interactions-estimate activity E8 2.2 Type of Study: Human Pharmacology
-explore use for the targeted indication-estimate dosage for subsequent studies-provide basis for confirmatory study design, endpoints, methodologies E8 2.2 Type of Study: Therapeutic Exploratory
-demonstrate/confirm efficacy-establish safety profileprovide an adequate basis for assessing the benefit/risk relationship to support licensing-establish dose-response relationship E8 2.2 Type of Study: Therapeutic Confirmatory
-refine understanding of benefit/risk relationship in general or special populations and/or environments-identify less common adverse reactions-refine dosing recommendation E8 2.2 Type of Study: Therapeutic Use
Development Methodology –covers issues and considerations related to the development plan and to its individual component studies E8 3
Considerations for the Development Plan E8 3.1
NonClinical Studies E8 3.1.1
Safety Studies — early non-clinical studies should provide sufficient information to support selection of the initial human dose and safe duration of exposure and to provide information about physiological and toxicological effects of a new drug E8 3.1.1.1
Pharmacological and Pharmacokinetic Studies — includes information such as:a) pharmacological basis of principal effectsb) dose-response or concentration-response relationships and duration of actionc) study of the potential clinical routes of administrationd) systemic general pharmacology, including pharmacological effects on major organ systems and physiological responsese) studies of absorption, distribution, metabolism and excretion E8 3.1.1.2
Quality of Investigational medicinal Products — formulations used in clinical trials should be well characterized, including information on bioavailability wherever feasible E8 3.1.2
Phases of Clinical Development E8 3.1.3
Phase I (Most typical kind of study: Human Pharmacology) E8 3.1.3.1
intended to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected–typically include both single and multiple dose administration E8 3.1.3.1.a — Estimation of initial safety and tolerability
-may be assessed via separate studies or as a part of efficacy, safety and tolerance studies-important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions E8 3.1.3.1.b –Pharmacokinetics
-depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease-can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies E8 3.1.3.1.c — Assessment of Pharmacodynamics
-preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective E8 3.1.3.1.d — Early Measurement of Drug Activity
Phase II (Most typical kind of study: Therapeutic Exploratory)-usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients-goal is to determine the doses and regimen for Phase III trials-evaluation of potential study endpoints, therapeutic regimens and target populations for further study E8 3.1.3.2
Phase III (Most typical kind of study: Therapeutic Confirmatory)-primary objective is to demonstrate, or confirm therapeutic benefit-intended to provide an adequate basis for marketing approval-further explore the dose-response relationship or explore the drug’s use in wider populations, in different stages of disease, or in combination with another drug-complete the information needed to support adequate instructions for use of the drug E8 3.1.3.3
Phase IV (Variety of Studies: Therapeutic Use)-begins after drug approval-all studies performed after drug approval and related to the approved indication-important for optimizing the drug’s use E8 3.1.3.4
development of an application unrelated to original approved use after initial approval-new or modified indications-new dosage regimens-new routes of administration-additional patient populations E8 3.1.3.1.5
Special Considerations E8 3.1.4
Studies of Drug Metabolites E8 3.1.4.1
Drug-Drug Interactions E8 3.1.4.2
Special Populationsa) investigations in pregnant womenb) investigations in nursing womenc) investigations in children E8 3.1.4.3
Considerations for Individual Clinical Trials E8 3.2
Objectives-should be clearly stated and may include exploratory or confirmatory characterization of safety and/or efficacy and/or assessment of pharmacokinetic parameters and pharmacological, physiological, biochemical effects E8 3.2.1
Design-should be chosen to provide the desired information-appropriate comparators-primary and secondary endpoints and plans for analysis-methods of monitoring adverse events-procedures for the follow-up of patients who stop treatment prematurely E8 3.2.2
Selection of subjects-stage of development and indication to be studied should be taken into account in selecting the subject population- prior non-clinical and clinical knowledge-stage of development and level of concern for safety E8 3.2.2.1
Selection of Control Group-comparison may be made with placebo, no treatment, active controls or of different doses of the drug under investigation E8 3.2.2.2
Number of Subjects-size of trial is influenced by the disease to be investigated, the object of the study and the study endpoints E8 3.2.2.3
Response Variables-should be defined prospectively, giving descriptions of methods of observation and quantification-study endpoints are the response variables that are chosen to assess drug effects that are related to pharmacokinetic parameters, pharmacodynamic measures, efficacy and safety E8 3.2.2.4
Methods to Minimize or Assess Bias-protocol should specify methods of allocation to treatment groups and blinding E8 3.2.2.5
Randomization-preferred means of assuring comparability of test groups and minimizing the possibility of selection bias E8 3.2.2.5.a
Blinding-an important means of reducing or minimizing the risk of biased study outcomes E8 3.2.2.5.b
Compliance-methods used to evaluate patient usage of the test drug should be specified in the protocol and the actual usage documented E8 3.2.2.5.c
Conduct-adherence to the study protocol is essential-if modification of the protocol becomes necessary a clear description of the rationale for the modification should be provided in a protocol amendment E8 3.2.3
Analysis-protocol should have a specified analysis plan that is appropriate for the objectives and design of the study, taking into account the method of subject allocation, the measurement methods of response variables, specific hypotheses to be tested, and analytical approaches to common problems including early study withdrawal and protocol violations E8 3.2.4
Reporting-clinical study reports should be adequately documented following the approaches outlined in other ICH guidelines E8 3.2.5
Statistical Principles for Clinical Trials E9
Introduction E9 1
Background and Purpose E9 1.1
Scope and Direction-For each clinical trial contributing to a marketing application, all-important details of its design and conduct and the principal features of its proposed statistical analysis should be clearly specified in a protocol written before the trial begins E9 1.2
Considerations for Overall Clinical Development E9 2
Trial Context E9 2.1
Development Plan-The broad aim of the process of clinical development of a new drug is to find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable E9 2.1.1
Confirmatory Trial-and adequately controlled trial in which the hypotheses are stated in advance and evaluated-necessary to provide firm evidence of efficacy or safety E9 2.1.2
Exploratory Trial-rationale and design nearly always rests on earlier work carried out in a series of exploratory studies-should have clear and precise objectives-objectives may not always lead to simple tests of pre-defined hypotheses E9 2.1.3
Scope of Trials E9 2.2
Population E9 2.2.1
Primary and Secondary Variables-the primary variable should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary variable-should be specified in the protocol, along with the rationale for its selection E9 2.2.2
Composite Variables-if a single primary variable cannot be selected from multiple measurements associated with the primary objective, another useful strategy is to integrate or combine the multiple measurements into a single or ‘composite’ variable, using a pre-defined algorithm E9 2.2.3
Global Assessment Variables-developed to measure the overall safety, overall efficacy, and/or overall usefulness of a treatment-integrates objective variables and the investigator’s overall impression about the state or change in the state of the subject, and is usually a scale of ordered categorical ratings E9 2.2.4
Multiple Primary Variables-may be desirable to use more than one primary variable, each of which could be sufficient to cover the range of effects of the therapies E9 2.2.5
Surrogate Variables-used in a number of indications where they are believed to be reliable predictors of clinical benefit E9 2.2.6
Categorized Variables-dichotomization or other categorization of continuous or ordinal variables may sometimes be desirable E9 2.2.7
Design Techniques to Avoid Bias-the most important design techniques for avoiding bias in clinical trials are blinding and randomization, and thee should be normal features of most controlled clinical trials intended to be included in a marketing application E9 2.3
Blinding-blinding or making is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from analysis, and so on E9 2.3.1
Randomization-provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects E9 2.3.2
Trial Design Considerations E9 3
Design Configuration E9 3.1
Parallel Group Design-subjects are randomized to one of two or more arms, each arm being allocated a different treatment E9 3.1.1
Crossover Design-each subject is randomized to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons E9 3.1.2
Factorial Designs-two or more treatments are evaluated simultaneously through the use of varying combinations of treatments E9 3.1.3
Multicenter Trials E9 3.2
Type of Comparison E9 3.3
Trials to Show Superiority-Efficacy is most convincingly established by demonstrating superiority to placebo in a placebo-controlled trial, by showing superiority to an active control treatment or by demonstrating a dose-response relationship E9 3.3.1
Trials to Show Equivalence or Non-inferiority-and investigational product is compared to a reference treatment without the objective of showing superiority-divided by two major categories according to its objective; one is an ‘equivalence’ trial and the other is a ‘non-inferiority’ trial E9 3.3.2
Trials to Show Dose-response Relationship-how response is related to the dose of a new investigational product is a question to which answers may be obtained in all phases of development, and by a variety of approaches E9 3.3.3
Group Sequential Designs-used to facilitate the conduct of interim analysis E9 3.4
Sample Size-the number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed-number is usually determined by the primary objective of the trial E9 3.5
Data Capture and Processing-collection of data and transfer of data from the investigator to the sponsor can take place through a variety of media, including paper case record forms, remote site monitoring systems, medical computer systems and electronic transfer E9 3.6
Trial Conduct Considerations E9 4
Trial Monitoring and Interim Analysis E9 4.1
Changes in Inclusion and Exclusion Criteria-should remain constant, as specified in the protocol, throughout the period of subject recruitment E9 4.2
Accrual Rates E9 4.3
Sample Size Adjustment E9 4.4
Interim Analysis and Early Stopping-an analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial E9 4.5
Role of Independent Data Monitoring Committee (IDMC) -may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial E9 4.6
Data Analysis Considerations E9 5
Pre specification of the Analysis E9 5.1
Analysis Sets-set of subjects whose data are to be included in the main analyses should be defined in the statistical section of the protocol-documentation for all subjects for whom trial procedures were initiated may be useful E9 5.2
Full Analysis Set-the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomized subjects E9 5.2.1
Per Protocol Set-valid cases-efficacy sample-evaluable subjects E9 5.2.2
Roles of the Different Analysis Sets-advantageous to demonstrate a lack of sensitivity of the principal trial results to alternative choices of the set of subjects analyzed E9 5.2.3
Missing Values and Outliers E9 5.3
Data Transformation E9 5.4
Estimation, Confidence Intervals and Hypothesis Testing E9 5.5
Adjustment of Significance and Confidence Levels E9 5.6
Subgroups, Interactions and Covariates E9 5.7
Integrity of Data and Computer Software Validity E9 5.8
Evaluation of Safety and Tolerability E9 6
Scope of Evaluation E9 6.1
Choice of Variables and Data Collection E9 6.2
Set of Subjects to be Evaluated and Presentation of Data E9 6.3
Statistical Evaluation E9 6.4
Integrated Summary E9 6.5
Reporting E9 7
Evaluation and Reporting E9 7.1
Summarizing the Clinical Database E9 7.2
Efficacy Data E9 7.2.1
Safety Data E9 7.2.2