ICH E6R1 Good Clinical Practice Flashcards
(246 cards)
1
Q
Good Clinical Practice (GCP)
An international ethical and scientific quality standard for ____, ____, ____ and ____ trials that involve the participation of human subjects.
A
An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.
2
Q
GCP Compliance Assurance, Aspects (2)
A
- Rights, safety and well-being of trial subjects are protected (DoH Principles)
- Clinical trial data are credible
3
Q
ICH GCP Mutual Acceptance Jurisdictions (3+2)
A
Original Jurisdictions E6(R1):
1. United States
2. European Union
3. Japan
Additional Jurisdictions E6(2):
1. Canada
2. Switzerland
4
Q
E6(R1) vs E6(R2) ICH GCP Guidelines
A
E6(R1): Largely paper-based
E6(R2): Electronic data recording and reporting
5
Q
Applicable Regulatory Requirement(s)
A
Any laws and regulations addressing the conduct of clinical trials of investigational products.
6
Q
IRB Approval, Constrained Criteria (4)
A
The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constrains set forth by:
- the IRB
- the institution,
- GCP, and
- applicable regulatory requirements
7
Q
Audit, Aspects (2)
A
A systematic and independent examination of trial related activities and documents to determine whether
- the conduct of the evaluated trial related activities, and
- the recording, analysis and reporting of data
are in compliance according to the protocol, sponsor’s SOPs, GCP, and the applicable regulatory requirements.
8
Q
Audit Certificate
A
A declaration of confirmation by the auditor that an audit has taken place.
9
Q
Audit Report
A
A written evaluation by the sponsor’s auditor of the results of the audit.
10
Q
Audit Trail
A
Documentation that allows reconstruction of the course of events.
11
Q
Blinding / Masking
A
A procedure in which one or more parties to the trial are kept unaware of the treatment assignments.
Single-blinding: usually refers to the subjects being unaware.
Double-blinding: usually refers to the subjects, investigator, monitor, and in some cases, data analysts being unaware of the treatment assignments.
12
Q
Case Report Form (CRF)
A
A document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
13
Q
Clinical Trial/ Clinical Study, Qualifiers (3)
A
Any investigation in human subjects intended to:
- Discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects,
- Identify any adverse reactions,
- Study absorption, distribution, metabolism and excretion (ADME)
of an object of ascertaining its safety/efficacy.
Note: The terms clinical trial and clinical study are synonymous.
14
Q
Clinical Trial/Study Report
A
A written description of a trial 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.
15
Q
Comparator Product
A
An investigational or marketed product (active control), or placebo, used as a reference in a clinical trial.
16
Q
Trial Compliance
A
Adherence to all the trial-related requirement, GCP requirements, and applicable regulatory requirements.
17
Q
Confidentiality
A
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identify.
18
Q
Contract
A
A written, dated, and signed agreement between two or more involved parties that sets out any arrangement on delegation and distribution of tasks and obligations and, if appropriate, on financial matter.
The protocol may serve as the basis of a contract.
19
Q
Coordinating Committee
A
A committee that a sponsor may organize to coordinate the conduct of a multi-center trial.
20
Q
Coordinating Investigator
A
An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multi-center trial.
21
Q
Contract Research Organization (CRO)
A
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.
22
Q
Direct Access
A
Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial (Essential Documents).
23
Q
Documentation for Clinical Trial, General Content (3)
A
All record, in any form (written, electronic, x-rays, etc) that describe or record
- the methods, conduct, and results of a trial,
- the factors affecting a trial,
- the actions taken from a trial.
24
Q
Essential Documents
A
Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.
25
Independent Data-Monitoring Committee/
Data and Safety Monitoring Board/
Monitoring Committee/
Data Monitoring Committee,
Duties (3)
An independent data-monitoring committee that may be established by the sponsor to assess at intervals:
1. the progress of a clinical trial,
2. the safety data,
3. the critical efficacy endpoints,
to recommend to the sponsor whether to continue, modify, or stop a trial.
26
Impartial Witness
A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial ("impartial"),
who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who read the informed consent form and any other written information supplied to the subject ("witness").
27
Independent Ethics Committee, Reviewing Aspects (4)
An independent body, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial, and provide public assurance of that protection, by reviewing and approving:
1. the trial protocol,
2. the suitability of the investigator(s),
3. facilities, and
4. informed consent process
28
Direct Access, Aspects with Precautions (2)
Any party (i.e., regulatory authorities, sponsor's monitors, and auditors) with direct access should take all reasonable precautions within the constrains of the applicable regulatory requirement to maintain:
1. the confidentiality of subject's identities, and
2. the sponsor proprietary information.
29
Informed Consent
A process by which a subject voluntarily conforms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate.
Informed consent is documented by means of a written, signed, and dated informed consent form.
30
Inspection
The act by a regulatory authority of conducing an official review of
documents, facilities, records, and any other resources that are deemed by the authority to be related to the clinical trial, and
that may be located at the site of the trial, at the sponsors's and CRO facilities, or at other establishments deemed appropriate by the regulatory authority.
31
Medical Institution
Any public or private
entity/agency/facility
where clinical trials are conducted.
32
Institutional Review Board (IRB), Responsibilities (2)
An independent body constituted of medical, scientific and others, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, reviewing and approving
1. the trial protocol and amendments
2. informed consent process.
33
Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
34
Investigational Product, Qualifying Scenarios (4)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including
1. Pre-market approval product
2. Product with a marketing authorization but its assembly (formulation/packaging) is different than the approved form
3. Product with a marketing authorization but its use (indication) is different than the approved form
4. Product with a marketing authorization is used to gain further information about the approved use.
35
Investigator
A person responsible for the conduct of the clinical trial at a trial site.
If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team (Principal Investigator, PI).
36
Investigator's Brochure, Definition
A compilation of the clinical and nonclinical data on the investigational product, relevant to the study in human subjects.
37
Legally Acceptable Representative
An individual, 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.
38
Clinical Trial Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded in accordance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
39
Monitoring Report
A written report from the monitor to the sponsor after each site visit, or other trial-related communication according to the sponsor's SOPs.
40
Multicenter-trial
A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.
41
Nonclinical Study
Biomedical studies not performed on human subjects.
42
Protocol, Sections (5+2)
A document that describes:
1. objective,
2. design,
3. methodology,
4. statistical considerations, and
5. organization of a trial,
also usually gives:
6. background
7. rationale
43
Protocol Amendment
A written description of changes to or formal clarification of a protocol
44
Quality Assurance (QA),
All those planned and systematic actions that are established to ensure that:
1. the performance of the trial, and
2. the generation, documentation, and reporting of data
are in compliance with GCP and applicable regulatory requirements.
45
Quality Control (QC)
The operational techniques and activities undertaken within the quality assurance system,
to verify that the requirements for quality of the trial-related activities have been fulfilled.
46
Randomization
The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
47
Regulatory Authority, Duties (2)
The authorities that
1. review submitted clinical data
2. conduct inspections
48
Source Data
All information in original records (or certified copies) of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
Source data are contained in source documents.
49
Source documents, Examples (7)
1. Hospital records
2. Clinical charts
3. Laboratory notes
4. Subject's diaries
5. Evaluation checklist
6. Pharmacy records
7. Digital records
50
Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and financing of a clinical trial
51
Sponsor-Investigator
An individual (not a company, institution, or organization) who both initiates and conducts a clinical trial.
52
Standard Operating Procedure (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
53
Sub-Investigator
An individual member of the clinical trial team designated and supervised by the investigator at trial site to perform critical trial-related procedures and to make important trial-related decisions.
Typically include associates, residents, research fellows.
54
Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational products or as a control
55
Subject Identification Code
A unique identifier assigned by the investigator to each trial subject to protect the subject's identify and used in lieu of the subject's name when the investigator report adverse events and other trial related data.
56
Trial Site
The location where trial-related activity are actually conducted.
57
Vulnerable Subjects Unduly Influences (2)
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by:
1. the expectation, whether justified or not, of benefits associated with participation.
2. a retaliatory response from senior members of a hierarchy in case of refusal to participate.
58
Vulnerable Subject Examples (3)
1. Unduly influence by expectation of benefits: members of a disadvantageous status (health, age, financial, emergency, ethnic, political)
2. Unduly influence by retaliatory response: members of a group with a hierarchical structure (students, employees, soldiers, prisoners)
3. Person incapable of giving consent.
59
Well-being of the Trial Subject, Aspects (2)
The physical and mental integrity of the subjects participating in a clinical trial.
60
Certified Copy, Verification Methods (2)
A copy of the original record that has been verified to have the same information, including data that describe the context, content, and structure, as the original, by
1. a dated signature
2. generation through a validated process
61
Monitoring Plan
A document that describes the strategy, methods, responsibility, and requirements for monitoring the trial.
62
Validation of Computerized Systems, Principles (2)
A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration of the system's:
1. intended use
2. potential to affect human subject protection and the reliability of trial results.
63
The Principles of ICH GCP, Clinical Trial Requirement (13)
Subject Protection Principal (5)
Sponsor Principal (3)
Investigator Principal (5)
Clinical trial requires:
Subject protection Principal:
1. DoH, GCP ARR compliance
2. prior IRB/IEC approval
3. Risk vs Benefit justification
4. Prevailing right, safety, and well-being of trial subjects over other interests
5. Quality assurance system for human subject protection and trial reliability
Sponsor
6. Adequate supporting information on the investigational product
7. Scientifically sound and well-written protocol
8. Good manufacture practice (GMP) for investigational products
Investigator
9. Qualified physician for medical care
10. Qualified individual for conducting trial
11. Freely given informed consent
12. Proper data management
13. Subject privacy confidentiality
64
IRB/IEC Responsibilities (9)
Procedures (5)
Consent Ethics (2)
Payment (2)
Procedure
1. Safeguard the right, safety and well-being of trial subjects
2. Obtaining trial related documents
3. Consider qualifications of the investigator
4. Review human subject risk at least once per year
5. Request additional information meaningful to subject protection
Consent Ethics
6. Determine the ethical compliance for trials with consent from legally acceptable representative
7. Determine the ethical compliance for trials without possible consent
Payment
8. Assure payment is free of coercion or undue influence to subject
9. Ensure payment is communicated clearly to the subjects
65
Clinical Trial Related Documents for IRB (9)
1. Protocol (and amendment)
2. Informed consent form (and consent updates)
3. Subject recruitment (procedures and advertisement)
4. written information for subjects
5. Investigators Brochure
6. Safety Information
7. Payment and Compensation
8. Investigator's CV
9. Others
66
Compensation Payment
Payment to a subject should be prorated and not wholly contingent on completion of the trial by the subjects.
67
IRB/IEC Decision, Types (4)
1. Approval
2. Modifications required prior to approval
3. Disapproval
4. Termination
approval = favorable opinion
disapproval = negative opinion
68
Composition of IRB, Minimum Criteria (3)
1. at least 5 members
2. at least one member whose primary area of interest is in a nonscientific area
3. at least one member who is independent of the institution or trial site
May invite nonmembers with expertise in special areas for assistance.
69
IRB Voting Member, Criteria (2)
Voting IRB members on a trial-related matter should:
1. be independent of the investigator and the sponsor of the trial
2. have participated in the IRB review and discussion
Investigators may provide information on any aspect of the trial, but should not participate in the deliberations or voting.
70
IRB Function, Expectations (3)
IRB should:
1. perform its functions according to written operating procedures
3. maintain records of its activities and minutes of meetings.
4. comply with GCP and ARR
71
IRB Decision Quorum
An IRB should make its decisions at announced meetings at which at least a puorum (minimum number), as stipulated in its written operating procedures.
72
IRB Procedures (9)
Review Procedures (5)
Review Specification (4)
Review Procedures:
1. Determining composition (name and qualification)
2. Scheduling and conduct meetings (time and location)
3. Conducting review of trials
4. Determining the frequency of continuing review
5. Providing expedited review and approval of minor changes
Review Specification:
6. Specifying that no subject should be admitted to a trial before approval
7. specifying that no deviation of protocol should be made without approval
8. specifying that investigator should promptly report to IRB when deemed necessary
9. ensuring that IRB promptly notify in writing when deemed necessary
73
Protocol Deviation, Amendment Exemptions (2)
No protocol deviation should be made expect for when,
1. necessary to eliminate immediate hazards to the subjects
2. the changes involves only logistical or administrative aspects of the trial (changes of monitors or phone numbers)
74
Investigator Prompt Notification to IRB (4)
1. Serious and unexpected ADRs
2. Protocol deviation to eliminate immediate hazards to subjects
3. Any adverse effect to protection of the subject
4. Any adverse effect to conduct of the trial
75
IRB Prompt Notification to Investigator (3)
1. Trial-related opinions
2. Reasons for its decision
3. Procedures for appeal
76
IRB Records, Examples (6)
1. written procedures
2. membership lists
3. occupation/affiliation of member
4. submitted documents
5. minutes of meetings,
6. correspondence
All record maintained for at least 3-years after completion of the trial
77
Investigators Qualification, Criteria (3)
1. Qualified by education, training, and experience to assume responsibility for the proper conduct of the trial
2. Meet all the qualifications specified by the applicable regulatory requirements
3. Provide evidence of such qualification through up-to-date CV and other requested documents
78
Investigators Agreement, Aspects (4)
Investigator should
1. be thoroughly familiar with the appropriate use of investigational product provided by the sponsor
2. comply with GCP and ARR
3. permit monitoring and auditing by the sponsor, and inspection by the regulatory authorities.
4. maintain a list of qualified persons for delegation
79
Investigators Adequate Resources (3)
The investigator should:
1. be able to demonstrate a potential for recruiting the required number of suitable subjects (based on retrospective data)
2. have sufficient time to properly conduct and complete the trial
3. have adequate number of qualified staff and facilities
80
Investigator Delegation Responsibilities (3)
1. Ensure all persons assisting the trial have adequate information on the protocol, investigational product, and trial-related duties and functions
2. Supervise any individual or party to whom the investigator delegates
3. Implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated by the retained services
81
Investigator Responsibilities for Medical Care of Trial Subject (4)
1. Ensured all trial-related medical decision made by a qualified physician who is a PI/Sub-I.
2. ensure adequate medical care is provided for any AE related to the trial.
3. inform the subject's primary physician about the subject's participation in the trial upon agreement by the subject.
4. Make reasonable effort to ascertain the reasons for subjects to withdraw prematurely from a trial, while respecting their rights
82
Investigator Communication with IRB (3)
1. Before trial initiation, during application, provide IRB with Investigator's Brochure and its updates.
2. Before trial initiation, obtain IRB approval of reviewed trial documents.
3. During the trial, continue to provide IRB all update documents subject to review.
83
Investigator Protocol Compliance Assurance (4)
The investigator should conduct the trial in compliance with the protocol, which need to be:
1. Approved by sponsor, ARR, and IRB
2. free of deviation without IRB approval (with 2 exceptions)
3. documented and explained for any deviation
4. amended and submitted to sponsor, ARR, and IRB for approval.
84
Investigator Investigational Products, Responsibilities (6)
Investigator is responsible for:
1. overall accountability of the investigational product at the trial site.
2. assign some or all of the accountability to an appropriate pharmacist, if allowed/required
3. Maintains record of the investigational products
4. Proper storage as specified by the sponsor or ARR
5. Ensure the investigational products are only used in accordance with the approved protocol
6. Explain and follow up on the correct use of the investigational products to subject
85
Investigational Products, Logistic Records, Examples (4)
Investigator should maintains the following record of the investigational products:
1. Delivery record to trial site
2. inventory at the site
3. use by each subject
4. return to the sponsor or alternative disposition of unused products
All investigational products received from the sponsor should reconcile.
86
Investigators Randomization Responsibilities (2)
The investigator should:
1. follow the trial's randomization procedures, and 2. ensure that the code is broken only in accordance with the protocol.
87
Investigators Unblinding Responsibilities, Scenarios (2)
The investigator should promptly document and explain to the sponsor any premature unblinding of the investigational products for:
1. accidental unblinding
2. unblinding due to a serious adverse events
88
Investigator Responsibilities for Informed Consent of Trial Subjects (15)
General Compliance (2)
Informed Consent Form Language (4)
Informed Consent Discussion (5)
Consent by Representative (4)
General Compliance
1. Obtain informed consent in compliance to ARR, GCP, DoH, and the approval by IRB.
2. Revise informed consent form with relevant and important information, and inform IRB and subject for new approval and consent
Informed Consent Language:
3. Ensure no coercion or unduly influence in trial participation or continuation.
4. Ensure language causes no waiving of any legal rights of subject or releases trial from liability for negligence.
5. Ensure language is as non-technical as practical to be understood by the subjects/representative/ witness.
6. Fully inform all pertinent aspects of the trial.
Informed Consent Discussion:
7. Ensure the information was accurately and effectively explained by impartial witness if needed.
8. Ensure the all components (20) of ICF is explained during the discussion.
9. Provide opportunities to inquire more details and answers to the satisfaction of subject.
10. Ensure that ICF is signed and dated.
11. Ensure copy of the signed and dated written ICF and its updates received by the subjects
Consent by representative:
12. Ensure that subject personally agree and sign if capable the ICF, despite consent from the legally acceptable representative.
13. Non-therapeutic trial with no direct clinical benefit should generally be consented only by subject themselves, not by representatives
14. Non-therapeutic trials may only be consented by legally acceptable representatives under certain conditions.
15. When consent from neither subject or representative is possible, enrollment of the subject will require IRB approval.
89
Components in the Informed Consent Form (20)
Nature of the trial (3)
Study Design (5)
Risk and Benefit (4)
Compensation and expense (3)
Subject Protection (3)
Subject Communication (2)
The ICF should state:
The nature of the trial:
1. the trial involves research
2. the purpose of the trial
3. invasive and non-invasive trial procedures
The Study Design:
4. the experimental aspects of the trial
5. expected duration of the subject participation
6. approximate number of subjects involved
7. the trial treatments and probability for random assignment for each treatment
8. foreseeable circumstances for participation termination
Risk and benefit for subject:
9. responsibilities of the subject
10. reasonably foreseeable risks or inconveniences
11. reasonably expected benefits, or whether benefits exists
12. the risk and benefits of alternative procedures/treatment available
Subject Compensation and expense:
13. compensation and treatment in event of trial-related injury
14. anticipated prorated payments to the subject if any
15. anticipated expense to the subject if any
Subject Protection:
16. the subjects participation and continuation is voluntary without penalty
17. direct access to the subject's original medical records without violating the confidentiality of the subject
18. records identifying the subjects will be kept confidential
Subject Communication:
19. subject will be informed timely if new information affect subject's willingness to continue
20. person(s) to contact for trial related activities, subject rights, and injuries.
90
Direct Access, Parties (4)
1. monitor
2. auditor
3. IRB
4. regulatory authority
91
Legally Acceptable Representative Senarios, Example (2)
1. minors
2. patients with severe dementia
92
Legally Applicable Representative Consent Exception for Non-therapeutic Trials, Requirement (1+3+1)
Non-therapeutic trials must be conducted in subjects with consent from subject themselves, not from a legally acceptable representative unless:
the are required by design (1), poses minimum risk or burden (3), mandated by IRB (1)
1. the objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally
2. the foreseeable risks to the subjects are low
3. the negative impact on the subject's well-being is minimized and low
4. the trial is not prohibited by law
5. the approval of IRB is expressly sought on inclusion of the subject.
93
Investigator Records, Requirements (2)
1. sources documents and trial records are adequate and accurate
2. source data is attributable, legible, contemporaneous, original, accurate, traceable, and complete.
94
Investigator Case Report Form (CRF), Responsibilities (7)
Data (3)
Documents (4)
Data, derived data, changed data:
1. Ensure accuracy, completeness, legibility, and timeliness of all data
2. Ensure consistency or explain discrepancies for data derived data from source documents
3. Date, initial and explain any changes according to sponsor guidance.
Essential Documents:
4. Maintain and safeguard the Essential Documents
5. Retain Essential Documents until at least 2-years after the last approval of a marketing application, or clinical development discontinuation.
6. Document financial aspects in an agreement between sponsor and investigator
7. Make records available for monitor, auditor, IRB, and regulatory authority upon request.
95
Investigator Progress Reports, Requirements (2)
1. submit summary of trial status to IRB at least annually
2. promptly provide written reports to sponsor, IRB, and institution on any changes significantly affecting the conduct of the trial or increasing the risk to subjects.
96
Investigator Safety Reporting (3)
1. Immediately report serious and unexpected AE to sponsor, followed by detailed report.
2. Other AE identified in the protocol as critical to safety evaluations should be reported to sponsor accordingly.
3. Report death event to the sponsor and IRB with any autopsy report, terminal medical report, and other requested information.
97
Investigator Responsibility During Premature Termination or Suspension of a Trial (3)
1. promptly inform the trial subjects
2. assure appropriate therapy and follow-up for the subject
3. inform the regulatory authorities when applicable
98
Investigator Trial Completion Report (3)
Upon completion of the trial, the investigator should
1. inform the institution
2. provide a summary of trial outcome to IRB
3. provide requested report regulatory authorities
99
Investigator Responsibility on Premature Termination or Suspension, Communication Scenarios (3)
1. Investigator termination: investigator notify and explain to sponsor and IRB.
2. Sponsor termination: investigator notify and explain to IRB.
3. IRB termination: investigator notify and explain to sponsor.
100
The Principles of ICH GCP, Clinical Trial Requirement (13)
Subject Protection (5)
Clinical trial requires:
Subject protection Principal:
1. DoH, GCP ARR compliance
2. prior IRB/IEC approval
3. Risk vs Benefit justification
4. Prevailing right, safety, and well-being of trial subjects over other interests
5. Quality assurance system for human subject protection and trial reliability
101
The Principles of ICH GCP, Clinical Trial Requirement (13)
Investigator (5)
Investigator
9. Qualified physician for medical care
10. Qualified individual for conducting trial
11. Freely given informed consent
12. Proper data management
13. Subject privacy confidentiality
102
The Principles of ICH GCP, Clinical Trial Requirement (13)
Sponsor Principal (3)
Sponsor
6. Adequate supporting information on the investigational product
7. Scientifically sound and well-written protocol
8. Good manufacture practice (GMP) for investigational products
103
IRB/IEC Responsibilities (9)
To-do (1+4)
Procedure
1. Safeguard the right, safety and well-being of trial subjects
2. Obtaining trial related documents
3. Consider qualifications of the investigator
4. Review human subject risk at least once per year
5. Request additional information meaningful to subject protection
104
IRB/IEC Responsibilities (9)
Consent Ethics (2)
Consent Ethics
6. Determine the ethical compliance for trials with consent from legally acceptable representative
7. Determine the ethical compliance for trials without possible consent
105
IRB/IEC Responsibilities (9)
Payment (2)
Payment
8. Assure payment is free of coercion or undue influence to subject
9. Ensure payment is communicated clearly to the subjects
106
IRB Procedures (9)
Review Procedures (5)
Review Procedures:
1. Determining composition (name and qualification)
2. Scheduling and conduct meetings (time and location)
3. Conducting review of trials
4. Determining the frequency of continuing review
5. Providing expedited review and approval of minor change
107
IRB Procedures (9)
Review Specification (4)
Review Specification:
6. Specifying that no subject should be admitted to a trial before approval
7. specifying that no deviation of protocol should be made without approval
8. specifying that investigator should promptly report to IRB when deemed necessary
9. ensuring that IRB promptly notify sponsor in writing when deemed necessary
108
Investigator Responsibilities for Informed Consent of Trial Subjects (15)
General Compliance (2)
General Compliance
1. Obtain informed consent in compliance to ARR, GCP, DoH, and the approval by IRB.
2. Revise informed consent form with relevant and important information, and inform IRB and subject for new approval and consent
109
Investigator Responsibilities for Informed Consent of Trial Subjects (15)
Informed Consent Form Language (4)
Informed Consent Language:
3. Ensure no coercion or unduly influence in trial participation or continuation.
4. Ensure language causes no waiving of any legal rights of subject or releases trial from liability for negligence.
5. Ensure language is as non-technical as practical to be understood by the subjects/representative/ witness.
6. Fully inform all pertinent aspects of the trial.
110
Investigator Responsibilities for Informed Consent of Trial Subjects (15)
Informed Consent Discussion (5)
Informed Consent Discussion:
7. Ensure the information was accurately and effectively explained by impartial witness if needed.
8. Ensure the all components (20) of ICF is explained during the discussion.
9. Provide opportunities to inquire more details and answers to the satisfaction of subject.
10. Ensure that ICF is signed and dated.
11. Ensure copy of the signed and dated written ICF and its updates received by the subject.
111
Investigator Responsibilities for Informed Consent of Trial Subjects (15)
Consent by Representative (4)
Consent by representative:
12. Ensure that subject personally agree and sign if capable the ICF, despite consent from the legally acceptable representative.
13. Non-therapeutic trial with no direct clinical benefit should generally be consented only by subject themselves, not by representatives
14. Non-therapeutic trials may only be consented by legally acceptable representatives under certain conditions.
15. When consent from neither subject or representative is possible, enrollment of the subject will require IRB approval.
112
Components in the Informed Consent Form (20)
Nature of the trial (3)
The ICF should state:
The nature of the trial:
1. the trial involves research
2. the purpose of the trial
3. invasive and non-invasive trial procedures
113
Components in the Informed Consent Form (20)
Study Design (5)
The Study Design:
4. the experimental aspects of the trial
5. expected duration of the subject participation
6. approximate number of subjects involved
7. the trial treatments and probability for random assignment for each treatment
8. foreseeable circumstances for participation termination
114
Components in the Informed Consent Form (20)
Risk and Benefit (4)
Risk and benefit for subject:
9. responsibilities of the subject
10. reasonably foreseeable risks or inconveniences
11. reasonably expected benefits, or whether benefits exists
12. the risk and benefits of alternative procedures/treatment available
115
Components in the Informed Consent Form (20)
Compensation and expense (3)
Subject Compensation and expense:
13. compensation and treatment in event of trial-related injury
14. anticipated prorated payments to the subject if any
15. anticipated expense to the subject if any
116
Components in the Informed Consent Form (20)
Subject Protection (3)
Subject Protection:
16. the subjects participation and continuation is voluntary without penalty
17. direct access to the subject's original medical records without violating the confidentiality of the subject
18. records identifying the subjects will be kept confidential
117
Components in the Informed Consent Form (20)
Subject Communication (2)
Subject Communication:
19. subject will be informed timely if new information affect subject's willingness to continue
20. person(s) to contact for trial related activities, subject rights, and injuries.
118
Sponsor Responsibility for Quality Management
Implement a system for quality management to ensure human subject protection and the reliability of trial results.
119
Sponsor Quality Management System, Aspects (3)
Design of QA system requires efficient:
1. protocol for conducting clinical trial
2. tools and procedures for data collection and processing
3. collection of information essential to decision making
120
Sponsor Quality Management, Design Objectives (3)
The method used to assure and control quality should be:
1. proportionate to the risks inherent risk in the trial
2. operationally feasible without unnecessary complexity
3. effective in communication with clear, concise, consistent document
121
Sponsor Risk-based Approach for Quality Management, Steps (7)
1. Critical process and data identification
2. Risk identification
3. Risk evaluation
4. Risk control
5. Risk communication
6. Risk review
7. Risk reporting
122
Risk Identification for Quality Management, Levels (2)
1. System level (SOP, computerized systems, personnel)
2. Clinical trial level (trial design, data collection, informed consent process)
123
Risk Evaluation for Quality Management, Error Assessment Aspects (3)
1. Likelihood of error occurring
2. Extent of errors detection
3. Magnitude of error impact (to subject protection and trial reliability)
124
Risk Control for Quality Management, Types (2)
1. Risk reduction: need to be implemented at a level proportionate to the risk in all process and procedures.
2. Risk tolerance: need to have predefined limit considering medical and statistical variables.
125
Risk Communication for Qualify Management
The sponsor should document and communicate quality management activities to facilitate risk review.
126
Risk Review for Quality Management
The sponsor should periodically review risk control measures to ascertain effectiveness and relevancy.
127
Risk Reporting for Quality Management, Aspect (3)
Sponsor should include
1. description of quality management approach
2. summarize of important deviations from predefined quality tolerance limits
3. summarize remedial actions taken
in the clinical study report
128
Sponsor Quality Assurance and Quality Control, Responsibility (4)
Sponsor is responsible for:
1. Specifying qualify control implementation to trial conduct in SOP
3. Applying quality control to data handling.
2. Ensuring Direct Access in agreement for monitoring, auditing and inspection.
4. Ensuring such agreements are in writing
129
Sponsor Contract Research Organizations (CRO), Transfer of Responsibilities (4)
1. All transfer of duties and functions should be in writing, including all contracts and subcontracts.
2. Duties and functions not transferred are retained by the sponsor
3. All referenced sponsor responsibility also apply to CRO that assumed duties and responsibilities.
4. Ultimate responsibility for reliability of trial data always resides with the sponsor, despite transfer of duties and functions.
130
Sponsor Medical Expertise
Sponsor should designate qualified medical personnel to advise on trial related medical concerns.
131
Sponsor Trial Design Qualified Individual, Example (3)
The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians) as appropriate.
132
Sponsor Trial Management (2)
Sponsor should:
1. utilize appropriately qualified individuals for trial supervision, data handling and collection, statistical analysis, and report preparation
2. establish independent data-monitoring committee (IDMC) to advise on whether to continue, modify or stop a trial
133
Sponsor Electronic Data Handling, Aspects (8)
System Design (5)
System Design:
1. processed electronic data conforming to the established requirements.
2. comprehensive SOP for using the the electronic system.
3. data changes maintains an audit trial
4. blinding during data entry and processing
5. use unambiguous subject identification code (SIC) for each subject
134
Sponsor Electronic Data Handling, Aspects (8)
Data Security and Integrity (4)
Data security and integrity:
5. security system prevents unauthorized access
6. list of individuals authorized to view or change data
7. adequate data backup
8. data integrity during software upgrades and storage migration
135
Sponsor Record Keeping, Essential Documents Management (5)
Sponsor should:
1. ensure essential documents in conformance with ARR
2. retain all essential documents specific to sponsor for at least 2 years after completion (approval or discontinuation)
3. notify investigators and regulatory authorities upon discontinuation of a clinical development for any aspect indication, delivery, or dosage.
4. inform investigators of the need for record retention, and when the records are no longer needed.
5. report transfer of ownership of data per ARR.
136
Sponsor Investigator Selection, Steps (3)
1. Select qualified investigators and organizing coordinating committees.
2. Provide protocol and Investigators Brochure, and allow sufficient time for investigator to review.
3. Obtain investigator agreement in form of a signed protocol, or others.
137
Sponsor Investigators Agreement, Covered Aspect (4)
1. conduct trial in compliance with GCP, ARR, protocol, and IRB.
2. comply to with procedures for data recording and reporting
3. permit monitoring, auditing, and inspection
4. retain the trial related essential documents until notified by sponsor.
138
Sponsor Allocation of Responsibilities
Sponsor should define, establish, and allocate all trial-related duties and functions prior to trial initiation.
139
Sponsor Compensation to Subjects and Investigators (2+1)
1. address costs of treatment of trial subjects in trial-related injuries
2. comply with AAR for compensation for subjects
3. provide legal and financial coverage for the investigator against trial related claims, except for malpractice/negligence.
140
Sponsor Financing
Financial aspect of the trial should be documented in an agreement between the sponsor and investigator.
141
Sponsor Notification / Submission to Regulatory Authorities
Sponsor and/or Investigator should
submit any required applications for review prior to trial initiation.
142
Sponsor Confirmation of Review by IRB, Scenarios (3)
Sponsor should obtain the following IRB approval documents from investigator:
1. IRB approval of the original document
2. IRB approval of the modified documents
3. IRB suspension, withdraw or reapproval
143
Investigator Submitted IRB Approval Documents, Content (3)
1. Name and address of investigators IRB
2. Statement confirming IRB is compliant with GCP and RR
3. IRB approval documents, along with protocol, ICF, subject handouts, recruiting procedures, payment and compensation etc.
144
Sponsor Provided Information on Investigational Products, Responsibilities (2)
1. Ensure sufficient safety and efficacy data are available to support the intended human study.
2. Update Investigator's Brochures as significant new information becomes available
145
Sponsor Investigational Products, Overall Responsibilities (4)
Sponsor should ensure that the investigational products (and controls) is:
1. characterized as appropriate for the clinical trial stage
2. manufactured with GMP
3. coded and labelled with blinding for blind studies
4. with ARR compliant labels
146
Sponsor Investigational Products Storage Specifications (5)
Sponsor should inform monitors, investigators, pharmacists, and storage managers regarding the following aspects of investigational product storage:
1. storage temperature
2. storage conditions (i.e., protection from light)
3. storage time
4. reconstitution (fluids and methods)
5. delivery device (i.e., infusion device)
147
Sponsor Investigational Product Packaging, Requirement (2)
Packaging should
1. prevent contamination
2. unacceptable deterioration during transport and storage
148
Sponsor Investigational Product Blinding with Coding System, Requirement (2)
The blinding coding system must include the mechanism which
1. permits rapid identification in case of medical emergency
2. does not permit undetectable breaks of the blinding (if unblinded, must be noticeable)
149
Sponsor Investigational Product Formulation Modification, Assess Properties Examples (3)
Modified formulation need to be assed for:
1. Stability
2. Dissolution rate
3. Bioavailability
Prior to the use of new formulation in clinical trials.
150
Sponsor Investigational Product Supplying and Handling, Responsibility (2)
The sponsor should
1. supply the investigational products to investigator, but
2. obtain all required approval before supplying.
151
Sponsor Investigational Product, Logistic Instruction for Investigator, Aspects (6)
1. receipt
2. handling
3. storage
4. dispensing
5. retrival of unused product from subject
6. return of unused product to sponsor
152
Sponsor Investigational Product Logistic, Scenario (3)
Sponsor should maintain a system and document for:
1. timely delivery of product to investigator
2. retrieval of product to sponsor (recall/reclaim)
3. disposition of product if applicable
153
Sponsor Investigational Product Provision Responsibilities (3)
1. Ensure product stability for the period of use.
2. Ensure sufficient quantity for the study need.
3. Retain product for as long as required by ARR.
154
Sponsor Direct Access, Responsibility (2)
Sponsor should:
1. ensure investigator provide direct access for monitoring, auditing, review and inspection
2. verify that each subject has consented to direct access original medical records.
155
Sponsor Safety Information, Responsibilities (2)
Sponsor is responsible for
1. ongoing safety evaluation of the investigational products
2. promptly notify investigators and authorities of findings which could affect subject protection, trial conduct, or IRB decisions.
156
Sponsor ADR Reporting, Responsibilities (3)
Sponsor should:
1. Expedite the reporting for ADRs that are both serious and unexpected
2. Ensure expedited reporting in compliance with ARR and ICH guidelines
3. Submit safety updates and periodic reports to authorities as required by the authorities.
157
Sponsor Monitoring General Purpose (3)
The purpose of trial monitoring are to verify that:
1. Rights and well-being of human subject are protected.
2. Trial data are accurate, complete, and verifiable from source documents.
3. Conduct of the trial is in compliance with protocols, GCP, and ARR.
158
Monitors Selection and Qualification, Requirements (3)
Monitors should be:
1. Appointed by the sponsor
2. Educated, trained, and experienced for monitoring.
3. Throughly familiar with the all aspects of the ongoing trial.
159
Extend and Nature of Monitoring, Considerations (5)
The extend and nature of monitoring are determined based on:
1. Objective and purpose
2. Design and complexity
3. Blinding
4. Trial size
5. Endpoints
160
Sponsor On-site vs Centralized Monitoring
On-site: performed at the clinical trial site
Centralized: remote and timely evaluation of accumulating data, supported by data managers and biostatisticians.
On-site and centralized monitoring are often used in combination.
161
Sponsor Review and Analysis of Accumulating Data from Centralized Monitoring, Utilizations (5)
1. identify data anomaly (i.e., missing, inconsistent, outlier data, and protocol deviations)
2. examine data trend across trial cites (i.e., range, consistency and variability)
3. evaluate systematic error in data collection and reporting
4. analyze site characteristics and performance metrics
5. select site and process for targeted on-site monitoring
161
Review and Analysis of Accumulating Data from Centralized Monitoring, Utilizations (5)
1. identify data anomaly (i.e., missing, inconsistent, outlier data, and protocol deviations)
2. examine data trend across trial cites (i.e., range, consistency and variability)
3. evaluate systematic error in data collection and reporting
4. analyze site characteristics and performance metrics
5. select site and process for targeted on-site monitoring
162
Monitor Responsibilities (7)
1. Verify and ensure the proper function of investigator
2. Verify and ensure the validity of investigational products handling and use
3. Verify informed consent before subjects participation
4. Report the subject recruitment rate
5. Verify and ensure source document are reliable, current and maintained
6. Determine whether AE are appropriately reported
7. Communicate deviations from protocol, SOP, GCP, and ARR to investigator
163
Monitor Verification of the Investigational Products (5)
Monitor verifies that the investigational products are:
1. properly stored and sufficiently supplied
2. supplied only to indented subjects
3. subjects are provided with necessary instruction for use and handling instruction
4. use and handling are controlled documented
5. disposed and returned properly if applicable
164
Monitor Verification of Investigator general (7)
1. are qualified and equipped with resources
2. follows approved protocol
3. received current Investigator's Brochure
4. adequately informed about the trial
5. only delegate to authorized individuals/organizations
6. only recruit eligible subjects
7. provide all required reports
165
Monitor Verifications of Source Documents Case Report Form (5)
Monitor should verify that CRF clearly reports the following:
1. all data required by protocol
2. dose therapy modifications
3. AE, concomitant medications, and intercurrent illness
4. Missing clinic visit, test, and examines
5. Withdraw and dropouts events
166
Monitor Main Responsibility in Clinical Trial
Acting as the main line of communication between sponsor and investigator
167
Monitoring Procedures SOP
Monitor should follow the the sponsors established SOP and other procedures specific for the trial
168
Monitoring Report, Requirements Aspects (3+2)
Monitor reports should be:
1. submitted to sponsor after each site-visit or communication
2. including date, site, and name of monitor, investigator
3. summarizing review content, significant findings, deviations, conclusion and action recommended
4. followed-up by sponsor with documentation
5. may be combined reporting with centralized monitoring
169
Monitoring Plan, General Aspects (5)
Sponsor should develop a monitoring plan tailored to the specific human subject and data integrity risk of the trial.
The plan should include:
1. the overall monitoring strategy
2. monitoring responsibility of all parties
3. various monitoring methods to be used and rationale
4. emphasis on monitoring for critical data and process
5. emphasis on non-routine clinical practice which requires additional training
Referring to ARR.
170
Sponsor Audit, Purpose
Sponsor's Audit evaluate the trial conduct and compliance with protocol, SOP, GCP, and ARR, independent of a routine monitoring or quality control functions
171
Sponsor Auditor Selection (3)
1. appointed by the sponsor
2. independent of the clinical trial
3. qualified by training and experience
172
Sponsor Auditing, General Aspects (4+1)
Sponsor will ensure that:
1. auditing is conducted in accordance with sponsors procedures (coverage, method, frequency of auditing and form, content of report)
2. audit plan is designed according to trial specific factors (submission importance, trial size, trial complexity)
3. auditing findings are documented
4. audit certificate is provided as required by ARR
***5. Regulatory authorities should NOT routinely request the audit report, to preserve the independence of the audit function, unless in serious GCP non-compliance or legal proceedings.
173
Noncompliance, Action Levels (3)
1. Noncompliance with protocol, SOP, GCP, ARR by investigator or sponsor should lead to prompt action by the sponsor to secure compliance.
3. Significant noncompliance affecting subject protection or trial reliability should lead to root cause analysis, corrective and preventive action by sponsor.
2. Serious and/or persistent noncompliance on investigator should result in termination and authority notification by sponsor.
174
Premature Termination or Suspension of Trial, Sponsor Responsibility
Sponsor should promptly inform investigators, authorities, and IRB of the termination and reasons.
175
Clinical Study Reports (CSR) to Authorities (2)
Clinical study reports to the authorities by the sponsor, for both completed or prematurely terminate trials.
176
Sponsor Multi-center Trials, Responsibility (5)
Sponsor should:
1. ensure all investigators agreed and approved the protocol
2. adopt uniform CRF for all trial sites, with supplemental CRF for site specific data.
3. assign and document responsibilities of coordinating investigator and other investigators
4. provide instruction on following protocol, clinical and laboratory assessment, CRF completion for uniform standards.
5. facilitate communication between investigators.
177
Clinical Trial Protocol and Amendment, General Information Title Page (7)
1. Protocol title and ID
2. Sponsor and monitor
3. Sponsor representative
4. Sponsor medical expert
5. Investigator and trial sites
6. Physicians for all medical-decisions
7. Clinical laboratory and technical department
178
Clinical Trial Protocol and Amendment, Background Information (7)
1. investigational product name and description
2. clinical and non-clinical studies justifying the trial
3. known and potential risk and benefits
4. use justification (delivery, dosage, regimen, duration)
5. statement confirming compliance
6. population to be studied
7. literature reference
179
Clinical Trial Protocol, Trial Objective and Purpose
A detailed description of the objects and purpose of the trial
180
Clinical Trial Protocol, Trial Design (9)
General Designs (6)
Bias Controls (3)
General Design:
1. primary and secondary endpoints to be measured, statement
2. type and design of trial, description and schematic diagram
3. treatment, dosage, regimen of the investigation products (adjusted for trial specific product details)
4. subject participation duration for each trial period (including follow-up)
5. discontinuation criteria for subjects and trial
6. CRF data and other source data recording
Bias Control:
7. bias control (randomization and blinding)
8. controls for investigational products (positive and negative)
9. maintenance and breaking trial treatment randomization codes
181
Clinical Trial Protocol, Trial Design (9)
General Designs (6)
General Design:
1. primary and secondary endpoints to be measured, statement
2. type and design of trial, description and schematic diagram
3. treatment, dosage, regimen of the investigation products (adjusted for trial specific product details)
4. subject participation duration for each trial period (including follow-up)
5. discontinuation criteria for subjects and trial
6. CRF data and other source data recording
182
Clinical Trial Protocol, Trial Design (9)
Bias Controls (3)
Bias Control:
7. bias control (randomization and blinding)
8. controls for investigational products (positive and negative)
9. maintenance and breaking trial treatment randomization codes
183
Clinical Trial Protocol, Subject Participation Criteria Scenarios (3)
1. Inclusion criteria
2. exclusion criteria
3. withdraw criteria
184
Clinical Trial Protocol, Subject Withdraw Criteria Specifications (4)
1. Withdraw procedure (when and how)
2. Withdraw data collection (type and timing)
3. Withdraw replacement, if needed
4. Follow-up for withdrawn subjects
185
Clinical Trial Protocol, Treatment of Subjects (3)
1. treatment details during the trial
2. treatment permitted and not permitted before or during the trial
3. subject compliance monitoring
186
Clinical Trial Protocol, Treatment Details (1+3+1)
1. name of products
2. dosage regimen
3. route of administration
4. treatment duration
5. follow-up duration
187
Clinical Trial Protocol, Efficacy Assessment (2)
1. efficacy parameter specifications (what to assess)
2. timing and methods for assessment (when and how to assess)
188
Clinical Trial Protocol, Safety Assessment (4)
1. safety parameter specification (what to assess)
2. timing and methods for assessment (when and how to assess)
3. reporting procedures for AE and intercurrent illnesses
4. follow-up after AE (type and duration)
189
Clinical Trial Protocol, Statistics (7)
1. statistical methods and timing (final and interim analysis)
2. trial size and justification
3. significance level specification
4. criteria for trial termination
5. procedures for data anomaly (missing, unused, spurious)
6. procedures for reporting of deviation from statical plan
7. selection of subjects for analysis (evaluable from all recruited subjects)
190
Clinical Trial Protocol, Direct Access to Source Data and Document
protocol should specify that
Investigator will permit trial-related monitoring, audit, IRB review, and regulatory inspection, and providing direct access.
191
Investigator's Brochure (IB), Overall Purpose Aspects (3)
The purpose of IB is to provide the investigators with the information to facilitate understanding of the following aspect of the trial:
1. rational (why)
2. investigator compliance (how)
3. key features of the protocol (what)
192
Investigator's Brochure, Characteristics Principal (5)
1. Concise
2. Simple
3. Objective
4. Balanced
5. Non-promotional
which enable investigators to make unbiased risk-benefit assessment of the trial.
193
IB for Marketed Investigational Product
If the investigational product is marketed, the marketed product information may be used in place of IB, provided that it is current, comprehensive, and detailed.
194
Responsibility for IB Update and Availability among
Sponsor, Investigator and IRB
Sponsor-Investigator
Generally:
Sponsor ensures update-to-date IB is made available to Investigator, and investigator ensures update-to-date IB is made available to IRB
For investigator sponsored trial:
investigator provides up-to-date commercial product information to IRB.
195
IB General Considerations, Title Page Content (3)
1. Sponsor's Name
2. Investigational Product Information (IDs, names, and release date)
3. Document edition number.
196
IB General Considerations, Confidentiality Statement
Sponsor may wish to include a statement instructing that:
The investigator and other document recipients to treat the IB as a confidential document for the sole information and use of the investigator's team and the IRB.
197
Investigator's Brochure, Content Sections (7)
1. Table of Content
2. Summary
3. Introduction
4. Physical, Chemical and Pharmaceutical Properties
5. Nonclinical Studies
6. Effects in Humans
7. Summary of Data and Guidance for Investigator
198
IB Summary, Format Requirements (3)
1. maximum 2-page summary
2. highlight significant drug properties and clinical information
3. focus on the information relevant to the stage of clinical development
199
IB Introduction, General Content (6)
1. name (chemical/generic/trade)
2. all active ingredients
3. pharmacological class and positions
4. rationales for research with this drug
5. anticipated indications (prophylactic/therapeutic/diagnostic)
6. general approach to be followed
200
IB Physical, Chemical, and Pharmaceutical Properties and Formulation, Content (5)
1. chemical and structural formula
2. physical, chemical, and pharmaceutical properties
3. structural similarities to other known compounds
4. formulation and excipients description
5. storage and handling information
201
IB Nonclinical Studies Introduction, Drug Aspects (3)
1. Nonclinical Pharmacology
2. Toxicology
3. Pharmacokinetic and Product Metabolism
202
IB Nonclinical Studies Summary, Content (7)
1. Species and gender tested
2. Sample size
3. Dosage, regiment and duration
4. Delivery and systemic distribution
5. post-exposure follow-up
6. Pharmacological or Toxic results
7. Discussion on Translation
203
IB Nonclinical Studies Summary, Pharmacological or Toxic Effects Result Aspects (7)
1. Nature of effect
2. Frequency of effects
3. Severity and intensity of effects
4. Time to effect onset
5. Reversibility of effects
6. Duration of effect
7. Dose response
204
IB Nonclinical Studies Summary, Discussion on Translation, Precautions (2)
1. Effective and nontoxic dose (therapeutic index) should be compared in the same species
2. Comparisons should be made in terms of blood/tissues levels, rather than on a mg/kg basis
205
IB Nonclinical Studies, Nonclinical Pharmacology Studies, Effects (1+3+1)
Summary of studied nonclinical pharmacological effects on:
1. significant metabolites
2. efficacy models (effect)
3. receptor binding (effect)
4. specificity (effect)
5. pharmacological actions other than the intended therapeutic effects (side effects)
205
IB Nonclinical Studies, Pharmacokinetics and Product Metabolism in Animals, Aspects (3)
Summary of the nonclinical pharmacokinetics, biological transformation and disposition of the drug in all species:
1. absorption
2. biodistribution of drug
3. biodistribution of metabolites
and their relationship to pharmacological and toxicological findings
206
IB Nonclinical Studies, Toxicology Assessment Types (6)
Summary of toxicological effect in different species
1. Single dose
2. Repeated dose
3. Carcinogenicity
4. Mutagenicity
5. Reproductive toxicity
6. Special studies (e.g., irritancy and sensitization)
207
IB Effects in Human, Summary Content (7)
A thorough discussion of the known effects of the investigational products in human should be provided:
1. pharmacokinetics
2. metabolism
3. pharmacodynamics
4. dose response
5. safety
6. efficacy
7. other pharmacological activities
208
IB Effects in Human, Pharmacokinetics and Product Metabolism in Human, General Aspects (5)
1. Pharmacokinetics
2. Bioavailability
3. Population Subgroups
4. Interactions
5. Other pharmacokinetic data (i.e., population studies)
209
IB Effect in Human, Pharmacokinetics Data (5)
1. metabolism
2. absorption
3. plasma protein binding
4. distribution
5. elimination
210
IB Effect in Human, Bioavailability Type (2)
1. Absolute bioavailability
2. Relative Bioavailability
211
IB Effect in Human, Population Subgroups, Examples (3)
1. Gender
2. Age
3. Impaired organ function
212
IB Effect in Human, Interactions, Examples (2)
1. Product-product effect
2. Product-food effect
213
IB Effect in Human, Safety and Efficacy (5)
Summary of the following studies from preceding trials in human:
1. safety
2. pharmacodynamics
3. efficacy
4. dose response
5. subgroup analysis
discussed with implications
214
IB Effect in Human, Anticipated Risk and ADR, Aspects (2)
IB should provide a description of
possible risks and adverse drug reactions to be anticipated based on prior experiences with this or related products,
as well as description for
special monitoring and expedited reporting.
215
IB Effect in Human, Marketing Experience (3)
Summary of the marketing use of the investigational product in countries submitted for approval:
1. current approval or marketing status in the country
2. Significant information from the marketed use
3. current disapproval or withdrawn status in the country
216
IB Effect in Human, Significant Information from the marketed Use in Countries of Approval, Examples (4)
1. Formulations
2. Dosage
3. Routes of Administration
4. Adverse Product Reactions
217
IB Summary of Data and Guidance for Investigator, Purpose (3)
Summary of overall discussion of the nonclinical and clinical data, and other information including published reports, to allow investigator to
1. be provided with most informative interpretation of the available data
2. assess the implications of information for this and future clinical trials.
3. anticipate adverse drug reactions and other problems
218
IB Guidance for Investigator, Overall Aim (2)
1. Provide the investigator with a clear understanding of the possible risk and adverse reactions, and specific tests, observations, and precautions
2. Provide information to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reaction
219
Essential Documents for the Conduct of a Clinical Trial, Functions (3)
1. permit evaluation of trial conduct and data quality
2. demonstrate compliance with the GCP and ARR standards
3. assist in the successful management, auditing and inspection
220
Essential Documents, Grouped by Clinical Trial Stages (3)
1. before the clinical phase of the trial commences
2. during the conduct of the trial
3. after completion or termination of the trial
221
Essential Documents, Final Close-out
Monitor has reviewed both investigator and sponsor files and confirmed that all necessary documents are in the appropriate files
222
Essential Documents, Investigator Control
The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.
***The sponsor should not have exclusive control of those data.
223
Essential Documents, Before Clinical Phase of the Trial Commences, General (7)
1. Investigator's Brochure
2. Signed protocol (and amendments) and CRF
3. Information to trial subjects (ICF, handouts, ads)
4. Financial aspects of the trial
5. Insurance statement if required
6. Signed agreement between involved parties
7. IRB approval for above and other documents
224
Essential Documents, Before Clinical Phase of the Trial Commences, Committees and Authorities (3)
8. IRB committee composition
9. Regulatory authority approval/notification
10. CV of PI and sub-PI
225
Essential Documents, Before Clinical Phase of the Trial Commences, Technical (2)
11. Normal values/ranges for procedures and test included in protocol
12. Medical/lab/technical/procedure/test certifications
226
Essential Documents, Before Clinical Phase of the Trial Commences, Investigational Products (5)
13. Investigational product container sample labels
14. Material handling instructions
15. Material shipping records
16. Certificate of analysis of the shipped batch
17. Decoding procedures for blinded trials
227
Essential Documents, Before Clinical Phase of the Trial Commences, Trial Monitoring (3)
18. Master randomization list
19. Pre-trial monitoring report (site-suitability)
20. Trial initiation monitoring report (investigator confirmation)
228
Essential Documents, During the Clinical Conduct of a Trial, General (3)
1. Investigator's Brochure Updates
2. Revision of protocol or subject information if any
3. IRB approval of amendment and revision
229
Essential Documents, During the Clinical Conduct of a Trial, Authorities (2)
4. Regulatory authority approvals of amendments
5. CV for new PI/Sub-I
230
Essential Documents, During the Clinical Conduct of a Trial, Technical (2)
6. Updates to normal values/ranges for procedures and test included in protocol
7. Updates to Medical/lab/technical/procedures/test certifications
231
Essential Documents, During the Clinical Conduct of a Trial, Investigational Product (2)
8. Documentation of shipment
9. Certification of analysis of new shipped batch
232
Essential Documents, During the Clinical Conduct of a Trial, Monitoring (2)
10. Monitoring visit report
11. Relevant communications for monitoring (letters, in-person and virtual meeting notes)
233
Essential Documents, During the Clinical Conduct of a Trial, Source Documents (4)
12. Signed Informed Consent Forms
13. Other Source Documents
14. Completed Case Report Forms
15. Documentation of CRF corrections
234
Essential Documents, During the Clinical Conduct of a Trial, Safety Reporting (4)
16. Notification to Sponsor of serious ADRs by Investigator
17. Notification to IRB and authorities serious ADRs by Sponsor and Investigator
18. Notification to Investigator of Safety Information by Sponsor
19. Interim or annual reports to IRB and authorities by Sponsor and Investigator
235
Essential Documents, During the Clinical Conduct of a Trial, Trial Subject (3)
20. Subject screening log (ID all subjects who entered pre-trial screening)
21. Subject identification code list
22. Subject enrollment log (chronological enrollment by trial number)
236
Essential Documents, During the Clinical Conduct of a Trial, Ongoing Record (3)
1. Investigational product accountability at the site (use according to protocol)
2. Signature Sheet (of all authorized to make CRF entries and corrections)
3. Record of Retained Biopsy, if any
237
Essential Documents, After Completion or Termination of the Trial, Investigational Product Accountability (2)
1. Investigational product accountability at site (used or returned according to protocol)
2. Documentation of investigational product destruction
238
Essential Documents, After Completion or Termination of the Trial, Final Close-out (6)
3. Completed subject ID code list (for follow-up)
4. Audit certificate
5. Final trial close-out monitoring report
6. Treatment allocation and decoding documentation
7. Final report by investigator to IRB and authority
8. Clinical Study Report
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# Delegation of Investigator Responsibilities
1. Manage ____/EC communications & submissions
2. Maintain ____ documents
3. Receive/access ____ notifications
4. Screen/recruit study ____
5. Obtain informed ____
6. Perform physical ____
7. Obtain medical/medication ____
8. Confirm ____ criteria (inclusion/exclusion)
9. Perform basic ____ (e.g. vital signs, weight, ECG)
10. Make study related medical ____
11. Evaluate study related ____ results
12. Assess AE/SAE ____
13. Report ____
14. Collect/process/ship biological ____
15. Make (e)____ entries, corrections and queries
16. Sign off on (e)____ visit data
17. Use ____/IVRS
18. ____ IP receipt, storage, & temperature monitor
19. Prepare and ____ IP
20. Performs IP ____
21. ____ IP
1. Manage **IRB**/EC communications & submissions
2. Maintain **essential** documents
3. Receive/access **safety** notifications
4. Screen/recruit study **subjects**
5. Obtain informed **consent**
6. Perform physical **exam**
7. Obtain medical/medication **history**
8. Confirm **eligibility** criteria (inclusion/exclusion)
9. Perform basic **assessments** (e.g. vital signs, weight, ECG)
10. Make study related medical **decisions**
11. Evaluate study related test **results**
12. Assess AE/SAE **causality**
13. Report **SAEs**
14. Collect/process/ship biological **samples**
15. Make (e)**CRF** entries, corrections and queries
16. Sign off on (e)CRF visit data
17. Use **IWRS**/IVRS
18. **Manage** IP receipt, storage, & temperature monitor
19. Prepare and **dispense** IP
20. Performs IP **accountability**
21. **Administer** IP
240
# Essential Documents
Investigator Specific Files
| (7)
1. Advertisement for Subject Recruitment
2. Signed Informed Consent Forms
3. Source Documents
4. Subject Identfication Code List
5. Subject Enrolment Log
6. Completed Subject Identification Code List
7. Final Report by Investigator to IRB/FDA where required
241
# Essential Documents
Sponsor Specific Files
| (10)
1. Medical Lab Technical Procedure Test
2. Sample of Label Attached to IP Containers
3. Certificate of Analysis of IP shipped
4. Pre-trial Monitoring Report
5. Regulatory Authorities Authrizatioins
6. Certificate of Analyis of IP, New Batches
7. Monitoring Visit Report
8. Audit Certificates
9. Final Trial Close-out monitoring report
10. Treatmetn allocation and decoding documentatioin
242
# Subject Screening Log vs ID Code List vs Enrollment Log
Subject Screening Log: To document identification of subjects who entered ____
Subject ID Code List: 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 ____ of any subject
Subject Enrollment Log: To document ____ enrolment of subjects by trial number
Subject Screening Log: To document identification of subjects who entered **pre-trial screening**
Subject ID Code List: 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 subject
Subject Enrollment Log: To document **chronological** enrolment of subjects by trial number
## Footnote
Subject Information are typically managed solely by investigator, except for Subject Screening Log which sometimes are required to be filed at Sponsor.
243
# COMPLETED SUBJECT IDENTIFICATION CODE LIST
To permit identification of all subjects ____ in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time.
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 time
244
# Treatment Allocation and Decoding Documentation
Returned to sponsor to document any ____ that may have occurred
Returned to sponsor to document any **decoding** that may have occurred
