Guideline for Good Clinical Practice E6(R2) Flashcards
Good Clinical Practice (GCP)
An international ethical and scientific quality 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 the trial subjects are protected.
What does compliance with GCP provide?
Public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
What is the objective of the ICH GCP Guideline?
To provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
Adverse Drug Reaction (ADR) in the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not yet be established:
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.
Responses to a medicinal product
A causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (the relationship cannot be ruled out)
Adverse Drug Reaction (ADR) in marketed medicinal products:
A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function.
Adverse Event
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 (investigational) product, whether or not related to the medicinal (investigational) product.
Applicable Regulatory Requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products
Approval (in relation to the IRB)
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, GCP, and the applicable regulatory requirements.
Audit
A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
Audit Certificate
A declaration of confirmation by the auditor that an audit has taken place.
Audit Report
A written evaluation by the sponsor’s auditor of the results of the audit.
Audit Trail
Documentation that allows reconstruction of the course of events.
Blinding/Masking
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).
Single-blinding
Usually refers to the subject(s) being unaware of the treatment assignment(s).
Double-blinding
Usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).
Case Report Form (CRF)
A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
Clinical Trial/Study
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.
Clinical Trail/Study Report
A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report.
Comparator (Product)
An investigational or marketed product, or placebo, used as a reference in a clinical trial.
Compliance (in relation to trials)
Adherence to all the trial-related requirements, GCP requirements, and the applicable regulatory requirements.
Confidentiality
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity.
Contract
A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters.
The protocol may serve as the basis of a contract.
Coordinating Committee
A committee that a sponsor may organize to coordinate the conduct of a multicenter trial.
Coordinating Invetsigator
An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial.
Contract Research Organization (CRO)
A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions.
Direct Access
Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial.
What should any party with direct access do?
Take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary information.
Documentation
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.
Essential Documents
Documents which individually or collectively permit evaluation of the conduct of a study and the quality of the data produced.
Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)
An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
Impartial Witness
A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.
Independent Ethics Committee (IEC)
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.
Informed Consent
A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.
How is informed consent documented?
By means of a written, signed and dated informed consent form.
Inspection
The act by a regulatory authority of conducting 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 sponsor’s and/or contract research organization’s facilities, or at other establishments deemed appropriate by the regulatory authority.
Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
Institutional Review Board (IRB)
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 method and material to be used in obtaining and documenting informed consent of the trial subjects.
Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
Investigational Product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled 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.
Investigator
A person responsible for the conduct of the clinical trial at a trial site.
If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.
Investigator/Institution
An expression meaning “the investigator and/or institution, where required by the applicable regulatory requirements”.
Investigator’s Brochure
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.
Legally Acceptable Representative (LAR)
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.
Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable regulatory requirement(s).
Monitoring Report
A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.
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.
Nonclinical Study
Biomedical studies not performed on human subjects.
Opinion (in relation to IEC)
The judgement and/or advice provided by an Independent Ethics Committee (IEC).
Protocol
A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.
The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents.
The term protocol refers to the protocol and protocol amendments.
Protocol Amendment
A written description of a change(s) to or formal clarification of a protocol.
Quality Assurance (QA)
All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented, and reported in compliance with GCP and the applicable regulatory requirement(s).
Quality Control
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.
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.
Regulatory Authorities
Bodies having the power to regulate.
This includes the authorities that review submitted clinical data and those that conduct inspections.
Sometimes referred to as competent authorities.
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
Any untoward medical occurrence that at any dose:
- results in death
- is life-threatening
- requires inpatient hospitalization or prolongation of existing hospitalization
- results in persistent or significant disability/incapacity
or
- is a congenital anomaly/birth defect
Source Data
All information in original records and certified copies of original records of clinical findings, observations, and other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
Where is source data contained?
In source documents
Source Documents
Original documents, data, and records.
What are some examples of source documents?
- Hospital records
- Clinical and office charts
- Laboratory notes
- Memoranda
- Subjects’ diaries or evaluation checklists
- Pharmacy dispensing records
- Recorded data from automated instruments
- Copies of transcriptions certified after verification as being accurate copies
- Microfiches
- Photographic negatives
- Microfilm or magnetic media
- X-rays
- Subject files
- Records kept at the pharmacy, laboratories and medico-technical departments involved in the clinical trial
Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.
Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject.
The term does not include any person other than an individual.
What are the obligations of a sponsor-investigator?
The obligations include both those of a sponsor and those of an investigator.
Standard Operating Procedures (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
Subinvestigator
Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions.
Subject/Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
Subject Identification Code
A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial related data.
Trial Site
The location(s) where trial-related activities are actually conducted.
Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product information.
Vulnerable Subjects
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of retaliatory response from senior members of a hierarchy in case of refusal to participate.
What are examples of vulnerable subjects?
- Members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students
- Subordinate hospital and laboratory personnel
- Employees of the pharmaceutical industry
- Members of the armed forces
- Persons kept in detention
- Patients with incurable diseases
- Persons in nursing homes
- Unemployed or impoverished persons
- Patients in emergency situations
- Ethnic minority groups
- Homeless persons
- Nomads
- Refugees
- Minors
- All those incapable of giving consent
Well-being (of the trial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
Certified Copy
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.
Monitoring Plan
A document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial.
Validation of Computerized Systems
A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system.
What should the approach to validation of a computerized system be based on?
A risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.
What are the 13 principles of ICH GCP?
- 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).
- 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.
- The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
- The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
- Clinical trials should eb scientifically sound and described in a clear, detailed protocol.
- A trial should be conducted in compliance with the protocol that has received prior IRB/IEC approval/favorable opinion.
- 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, or a qualified dentist.
- Each individual involved in conducting a trial should eb qualified by education, training, and experience to perform his or her respective task(s).
- Freely given informed consent should be obtained from every subject prior to clinical trial participation.
- All clinical trial information should be record, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
- 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).
- Investigational products should be manufactured, handled, and stored in accordance with applicable GMP. They should be used in accordance with the approved protocol.
- Systems with procedures that assure the quality of very aspect of the trial should be implemented. Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems.
What should the IRB/IEC safeguard?
The rights, safety, and well-being of all trial subjects, with special attention being paid to trials that may include vulnerable subjects.
What documents should the IRB/IEC obtain?
- Trial protocol(s)/amendments(s)
- Written informed consent form(s)
- 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 (IB)
- Available safety information
- Information about payments and compensation available to subjects
- The investigator’s current curriculum vitae and/or other documentation evidencing qualifications
- Any other documents that the IRB/IEC may need to fulfill its responsibilities
After reviewing a proposed clinical trial within a reasonable time, how should the IRB/IEC document its views?
In writing, clearly identifying the trial, the documents reviewed and the dates for the following:
- Approval/favorable opinion
- Modifications required prior to its approval/favorable opinion
- Disapproval/negative opinion
- Termination/suspension of any prior approval/favorable opinion
How often should the IRB/IEC conduct continuing reviews of each ongoing trial?
At intervals appropriate to the degree of risk to human subjects, but at least once per year.
What should the IRB/IEC determine when a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative?
That the proposed protocol and/or other document(s) adequately address relevant ethical concerns and meet applicable regulatory requirements for such trials.
What should the IRB/IEC determine when the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (emergency situations)?
That the proposed protocol and/or other document(s) adequately address relevant ethical concerns and meet applicable regulatory requirements for such trials.
Why does the IRB need to review both the amount and method of payment to subjects for trials?
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.
Where should information regarding payment to subjects, including methods, amounts, and schedule of payment to trial subjects be found?
In the written informed consent form and any other written information to be provided to the subjects.
This will need to be reviewed by the IRB/IEC.
It is recommended that the IRB/IEC should include:
- At least 5 members
- At least 1 member whose primary area of interest is in a nonscientific area
- At least 1 member who is independent of the institution/trial site
Can IRB/IEC members associated with the investigator or the sponsor of a trial vote/provide opinion on a trial-related matter?
No
True/False:
The IRB/IEC does not need to maintain a list of the IRB/IEC members and their qualifications.
False
The IRB/IEC does need to maintain a list of the IRB/IEC members and their qualifications.
Where should the IRB make its decisions?
At announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.
True/False:
Members who do not participate in the IRB/IEC review and discussion can still vote/provide their opinion and/or advise.
False
Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.
Can the IRB/IEC invite nonmembers with expertise in special areas for assistance?
Yes
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
- Determining its composition and the authority which it is established.
- Scheduling, notifying its members of, and conducting its meetings.
- Conducting initial and continuing review of trials.
- Determining the frequency of continuing review, as appropriate.
- Providing, according to the applicable regulatory requirements, expedited review and approval/favorable opinion of minor change(s) in ongoing trials that have he approval/favorable opinion of the IRB/IEC.
- Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favorable opinion of the trial.
- Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favorable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial.
- Specifying that the investigator should promptly report to the IRB/IEC:
- Deviations from, or changes of, the protocol to eliminate immediate hazards to
the trial subjects
- Changes increasing the risk to subjects and/or affecting significantly the
conduct of the trial
- All adverse drug reactions that are both serious and unexpected
- New information that may affect adversely the safety of the subjects or the
conduct of the trial - Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
- Its trial-related decisions/opinions
- The reasons for its decisions/opinions
- Procedures for appeal of its decisions/opinions
How long should the IRB/IEC retain all relevant records?
At least 3 years after completion of the trial and make them available upon request from the regulatory authorities.
What are the qualifications and agreements are needed from the investigator for them to assume responsibility for the proper conduct of the clinical trial?
- The investigator should be qualified by education, training, and experience.
- The investigator should meet all the qualifications specified by the applicable regulatory requirement(s), and 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 regulatory authorities.
- The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described int he protocol, in the current IB, in the product information and in other information sources provided by the sponsor.
- The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
- The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authorities.
- The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
What are the adequate resources needed by an investigator for them to assume responsibility for the proper conduct of the clinical trial (what is required of them)?
- The ability to demonstrate a potential for recruiting the required number of suitable subjects within the agreed recruitment period.
- The sufficient time to properly conduct and complete the trial within the agreed trial period.
- The available adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
- The oversight to ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and heir trial-related duties and functions.
- The responsibility for supervising any individual or party to whom the investigator delegates trial-related duties and functions conducted at the trial site.
- If the investigator/institution retains the services of any individual or party to perform trial-related duties and functions, the investigator/institution should have the oversight to ensure that this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated.
Who should be responsible for all trial-related medical (or dental) decisions?
A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial.
When should the investigator/institution ensure that adequate medical care is provided to a subject for any adverse events related to the trial?
During and following a subject’s participation in a trial.
Should the investigator/institution inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware?
Yes
Who should the investigator inform about the subject’s participation in the trial if the subject agrees to them being informed?
The subject’s primary physician
A subject is not obligated to give their reason(s) for withdrawing prematurely from a trial, so would it be appropriate for the investigator make a reasonable effort to ascertain the reason(s) while fully respecting the subject’s rights?
Yes, the investigator should.
Before initiating a trial what should the investigator/institution have from the IRB?
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.
True/False:
The investigator/institution needs to provide the IRB/IEC with a current copy of the IB as part of the written application, but if it is updated during the trial they do not need to supply the IRB/IEC with a copy of the updated IB.
False
If the IB is updated during the trial, the investigator/institution should supply a copy of the updated IB to the IRB/IEC.
After initial approval/favorable opinion, does the investigator/institution need to continue to provide the IRB/IEC all documents to review?
Yes, during the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
Who should sign the protocol, or an alternative contract, to confirm agreement that the trial will be conducted in compliance with the protocol?
The investigator/institution and the sponsor
True/False:
The investigator can implement a deviation from, or change of the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC on an amendment when it is necessary to eliminate an immediate hazard to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial.
True.
These are the only instances where an investigator may deviate from the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC on an amendment.
Who should document and explain any deviation from the approved protocol?
The investigator or a person designated by the investigator
If the investigator needs to implement a deviation from, or a change of, the protocol to eliminate an immediate hazard to trial subjects without prior IRB/IEC approval/favorable opinion, what should they do as soon as possible?
Submit the implemented deviation or change, the reasons for it, and if appropriate, the proposed protocol amendment(s) to the IRB/IEC for review and approval/favorable opinion, the sponsor for agreement, and, if required, to the regulatory authorities.
Who is responsible for investigational product accountability at the trial site?
The investigator/institution
Where allowed/required who should/may the investigator/institution assign some or all of the investigator’s/institution’s duties for investigational product(s) accountability the the trial site to?
An appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution
What investigational product(s) records should the investigator/institution and/or pharmacist or other appropriate individual maintain?
What should these records include?
Records of:
- The product’s delivery to the trial site
- The inventory at the site
- The use by each subject
- 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)
- The unique code numbers assigned to the investigational product(s) and trial subjects
How should investigational product(s) be stored?
Investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s).
Who should ensure that the investigational product(s) are only used in accordance with the approved protocol?
The investigator
Who should explain the correct use of the investigational product(s) to each subject and check, at intervals appropriate for the trial, that each subject is following the instructions properly?
The investigator or a person designated by the investigator/institution
What should the investigator do if a blinded study is prematurely unblinded?
The investigator should promptly document and explain to the sponsor any premature unblinding.
When should the written informed consent form and any other written information to be provided to subjects be revised?
Whenever important new information becomes available that may be relevant to the subject’s consent.
Who 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?
The investigator or a person designated by the investigator
True/False:
None of the oral and written information concerning the trial, including the written informed consent form, should contain language that causes the subject or the subject’s LAR 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.
True
Why should the language used in the oral and written information about the trial, including the written informed consent form, be as non-technical as practical?
So that it will be understandable to the subject or the subject’s LAR and the impartial witness, where applicable.
Prior to a subject’s participation in the trial, who should sign the written informed consent?
The written informed consent should be signed and personally dated by the subject or by the subject’s LAR, and by the person who conducted the informed consent discussion.
When would an impartial witness need to sign the written informed consent form?
When the subject or the subject’s LAR is unable to read.
By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s LAR, and that informed consent was freely given by the subject or the subject’s LAR.
What twenty explanations should be included in both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects?
- That the trial involves research.
- The purpose of the trial.
- The trial treatment(s) and the probability for random assignment to each treatment.
- The trial procedures to be followed, including all invasive procedures.
- The subject’s responsibilities.
- Those aspects of the trial that are experimental.
- The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
- The reasonably expected benefits.
- The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
- The compensation and/or treatment available to the subject in the event of trial-related injury.
- The anticipated prorated payment, if any, to the subject for participating in the trial.
- That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
- That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authorities will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data , without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s LAR is authorizing such access.
- That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be make publicly available.
- That the subject’s LAR will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.
- The person(s) to contact for further information regarding the trial and the rights of the trial subjects, and whom to contact in the event of trial-related injury.
- The foreseeable circumstances and/or reasons under which the subject’s participation in the trial maybe terminated.
- The expected duration of the subject’s participation in the trial.
- The approximate number of subjects involved in the trial.
If the results of the trial are published, will the identity of the subject(s) be revealed?
No, if the results of the trial are published, the identity of the subject(s) will remain confidential.
When should the subject or the subject’s LAR receive a copy of the signed and dated informed consent form and any other written information provided to the subjects?
Prior to participation in the trial
True/False:
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 LAR, the subject does not need to be informed about the trial.
False.
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.
Typically, non-therapeutic trials should only be conducted in subjects who personally give consent and who sign and date the written informed consent form themselves.
However, non-therapeutic trials may be conducted in subjects with consent of a LAR provided what conditions are fulfilled?
- The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally.
- The foreseeable risks to the subject are lor.
- The negative impact on the subject’s well-being is minimized and low.
- The trial is not prohibited by law.
- The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and written approval/favorable opinion covers this aspect.
When can the subject be enrolled in a trial without prior consent from the subject or the subject’s legally acceptable representative?
Only in emergency situations.
When prior consent of the subject is not possible, the consent of the subject’s LAR, if present, should be requested.
When the prior consent of the subject is not possible, and the subject’s LAR 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 LAR should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested.
What should source data be?
- Attributable
- Legible
- Contemporaneous
- Original
- Accurate
- Complete
When changes need to be made to source data, how should they be done?
Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary.
Who should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports?
The investigator
Who should provide guidance to investigators and/or the investigators’ designated representatives on making corrections to CRFs?
The sponsor.
Sponsors should have written procedures to assure that changes or corrections in CRFs made by the sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator.
Who should retain records of changes and corrections to CRFs?
The investigator
Who should maintain trial documents and take measures to prevent accidental or premature destruction of these documents?
The investigator
How long should essential documents 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 a n 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.
Who is responsible for informing the investigator/institution as to when essential documents no longer need to be retained?
The sponsor
The financial aspects of the trial should be documented in an agreement between who?
The sponsor and the investigator/institution
How often should the investigator submit written summaries of the trial status to the IRB/IEC?
Annually, or more frequently, if requested by the IRB/IEC
Who should the investigator notify in writing of any changes significantly affecting the conduct of the trial and/or increasing the risk to subjects?
The sponsor, IRB/IEC, and where applicable, the institution
When should SAEs be reported to the sponsor? When would be an exception?
Immediately, unless the SAE is identified by the protocol or other document as not needing to reported immediately.
True/False:
Immediate and follow-up SAE reports to the sponsor should identify subjects by the subject’s name, personal identification number and/or address.
False.
The SAE reports to the sponsor should identify subjects by unique code numbers assigned to the trial subjects.
What adverse events and/or laboratory abnormalities need to be reported to the sponsor and when?
- Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations according to the reporting requirements
- Within the time periods specified by the sponsor in the protocol
For reported deaths, what additional information may the sponsor or IRB/IEC request?
Autopsy reports and terminal medical records
If the investigator terminates or suspends a trial without prior agreement of the sponsor, who should they inform?
The institution, where applicable, the sponsor, and the IRB/IEC.
They should also provide the sponsor and IRB/IEC with a detailed written explanation of the termination or suspension.
If the sponsor terminates or suspends a trial, who should they inform?
The investigator.
The investigator should then inform the institution, where applicable, and the investigator/institution should inform the IRB/IEC.
The investigator/institution should provide the IRB/IEC with a detailed written explanation of the termination or suspension.
If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, who should they inform?
The investigator.
The investigator should inform the institution where applicable ad the investigator/institution should notify the sponsor.
The investigator/institution should provide the sponsor with a detailed written explanation of the termination or suspension.
Upon the completion of the trial, who should provide the IRB/IEC with a s summary of the trial’s outcome, and the regulatory authorities with any reports requires?
The investigator/institution
Who should implement a system to manage quality throughout all stages of the trial process?
The sponsor
What does quality management include?
- The design of efficient clinical trial protocols and tools
- Procedures for data collection and processing
- The collection of information that is essential to decision making
What should the methods used to assure and control the quality of the trial be proportionate to?
The inherent risk in the trial and the importance of the information being collected
When designing the trial, the sponsor should avoid unnecessary what?
- Complexity
- Procedures
- Data collection
During protocol development, the sponsor should identify those procedures and data that are critical to what?
Critical to ensure human subject protection and the reliability of trial results
Who should identify risks to critical trial processes and data at both the system level and clinical trial level?
The sponsor
The sponsor should evaluate the identified risks, against existing risk controls by considering:
- The likelihood of errors occurring
- The extent to which such errors would be detectable
- The impact of such errors on human subjects protection and reliability of trial results
Who should decide which risks to reduce and/or which risks to accept?
The sponsor
The approach used to reduce risk to an acceptable level should be proportionate to what?
The significance of the risk
Risk reduction activities may be incorporated in:
- Protocol design and implementation
- Monitoring plans
- Agreements between parties defining roles and responsibilities
- Systematic safeguards to ensure adherence to standard operating procedures
- Training in processes and procedures
Predefined quality tolerance limits should be established, taking into consideration:
- The medical and statistical characteristics of the variables
- The statistical design of the trial
Detection of deviations from the predefined quality tolerance limits should trigger:
An evaluation to determine if action is needed
Who should document quality management activities?
The sponsor
Who should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution?
The sponsor
Who should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant taking into account emerging knowledge and experience?
The sponsor
The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure what?
That trials are conducted and data are generated, documented, and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s)
The sponsor is responsible for securing agreement from al involved parties to ensure direct access to all trial related sites, source data/documents, and reports for what purpose?
The purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities
A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to who? Who will have the ultimate responsibility for the quality and integrity of the trial data?
- A CRO
- The sponsor
True/False:
The sponsor can utilize outside consultant(s) to advise on trial related medical questions or problems.
True.
What are some examples of qualified individuals that sponsors should utilize 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?
- Biostatisticians
- Clinical pharmacologists
- Physicians
What may the sponsor consider establishing 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?
An independent Data-monitoring committee (IDMC)
When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance
What should the sponsor base their approach to validation of electronic data handling and/or remote electronic trial data systems on?
A risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of the trial results
What should the SOPs for electronic trial data handling and/or remote electronic trial data systems cover?
- System setup
- Installation
- Use
- Describe system validation and functionality testing
- Data collection and handling
- System maintenance
- Contingency planning
- Decommissioning
Do electronic trial data handling and/or remote electronic trial data systems need to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data?
Yes, the audit/data/edit trail needs to be maintained.
If the sponsor discontinues the development of an investigational product, how long should the sponsor should maintain all sponsor-specific essential documents?
At least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).
Who should inform the investigator/institution in writing of the need for record retention and who should notify the investigator/institution in writing when the trial related records are no longer needed?
The sponsor
Who is responsible to selecting the investigator/institution for a clinical trial?
The sponsor
Before entering an agreement with an investigator/institution to conduct a trial, can the sponsor provide the investigator/institution with the protocol and IB for review?
Yes, they should.
The sponsor should obtain the investigator’s/institution’s agreement:
- To conduct the trial in compliance with GCP, with applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IEC
- To comply with procedures for data recording/reporting
- To permit monitoring, auditing and inspection
- To retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed
Prior to initiating a trial, what should the sponsor do in regards to all trial-related duties and fuctions?
- Define
- Establish
- Allocate
True/False:
If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial, even for claims that arise from malpractice and/or negligence.
False.
If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial, EXCEPT for claims that arise from malpractice and/or negligence.
Whose policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s)?
The sponsor’s policies and procedures
When trial subjects receive compensation, the method and manner of compensation should comply with what?
Applicable regulatory requirement(s)
The financial aspects of the trial should be documents in an agreement between who and who?
The sponsor and the investigator/institution
Before initiated the clinical trial(s), who should submit any required application(s) to the appropriate authorities for review, acceptance, and/or permission to begin the trial?
The sponsor
Regarding confirmation of review by IRB/IEC, what should the sponsor obtain from the investigator/institution?
- The name and address of the investigator’s/institution’s IRB/IEC
- A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations
- Documented IRB/IEC approval/favorable opinion and, it requested by the sponsor, a current copy of the protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.
Regarding the investigational product(s): When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support:
- Human exposure by the route
- At the dosages
- For the duration
- In the trial population to be studied
When should the sponsor update the IB?
When significant new information become available
The sponsor should ensure that the investigational product is characterized as:
- Appropriate to the stage of development of the product(s)
- Is manufactured in accordance with any applicable GMP
- Is coded and labelled in a manner that protects blinding, if applicable
Who should determine, for investigational product(s), acceptable storage temperatures, storage conditions, storage times, reconstitution fluids and procedures, and devices from product infusion, if any?
The sponsor.
The sponsor should also inform all involved parties of these determinations.
The investigational product(s) should be packaged to prevent:
- Contamination
- Unacceptable deterioration during transport and storage
In what kind of trials should the coding system for the investigational product(s) include a mechanism that permits rapid identification in case of a medical emergency, but does not permit undetectable breaks of the blinding?
Blinded trials
If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, what needs to be assessed?
The results of any additional studies of the formulated product(s), to determine whether these changes would significantly alter the pharmacokinetic profile of the product.
Who is responsible for supplying the investigator/institution with the IP?
The sponsor
The sponsor should not supply an investigator/institution with the IP until the sponsor obtains what?
All required documents
The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of IP for the trial and documentation thereof. What should those procedures address?
- Adequate and safe receipt
- Handling
- Storage
- Dispensing
- Retrieval of unused product from subjects
- Return of unused IP to the sponsor (or alternative disposition, if applicable)
Regarding supplying and handling the IP, the sponsor should:
- Ensure timely delivery of IP to investigator(s)
- Maintain records that document shipment, receipt, disposition, return, and destruction of the IP
- Maintain a system for retrieving IP and documenting this retrieval
- Maintain a system for the disposition of unused IP and for the documentation of this disposition.
- Take steps to ensure that the IP is stable over the period of use
- Maintain sufficient quantities of the IP used in trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
Who should verify that each subject has consented, in writing, to direct access to their original medical records for trial-related monitoring, audit, IRBIEC revie, and regulatory inspection?
The sponsor
Who is responsible for the ongoing safety evaluation of the IP?
The sponsor
The sponsor should promptly notify who, of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC’s approval/favorable opinion to continue the trial?
All concerned investigator(s)/institution(s) and the regulatory authorities
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 authorities of all adverse drug reactions that are both what and what?
Both serious and unexpected
The purpose of trial monitoring are to verify that:
- The rights and well-being of human subjects are protected.
- The reported trial data are accurate, complete, and verifiable from source documents.
- The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with the GCP, and with the applicable regulatory requirement(s).
Who should appoint monitors to the clinical trial?
The sponsor
What qualifications should a study monitor possess?
- Appropriate training
- The scientific and/or clinical knowledge needed to monitor the trial adequately
- Familiarity with the IP, protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirements
Who determines the appropriate extent and nature of study monitoring?
The sponsor
The determination of the extent and nature of monitoring should be based on what considerations?
- The objective of the trial
- The purpose of the trial
- Trial design
- Trial complexity
- Blinding
- Size
- Endpoints of the trial
In general, at what timepoints is there a need for on-site monitoring?
Before, during, and after the trial
What are the types of monitoring that the sponsor may choose?
- On-site monitoring
- A combination of on-site and centralized monitoring
- Where justified, centralized monitoring
On-site Monitoring
Performed at the sites at which the clinical trial is being conducted
Centralized Monitoring
Remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons.
What kind of monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-cite monitoring and help distinguish between reliable data and potentially unreliable data?
Centralized monitoring
Review, that may include statistical analyses, of accumulating data from centralized monitoring can be used to:
- Identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.
- Examine data trends such as the range, consistency, and variability of data within and across sites.
- Evaluate for systemic or significant errors in data collection and reporting at a site or across sites; or potential data manipulation or data integrity problems.
- Analyze site characteristics and performance metrics.
- Select sites and/or processes for targeted on-site monitoring.
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:
- Acting as the main line of communication between the sponsor and the investigator.
- 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 to safely and properly conduct the trial and remain adequate throughout the trial period.
- Verifying, for the IP:
- That storage times and conditions are acceptable, and that supplies are
sufficient throughout the trial.
- That the IP are supplied only to subjects who are eligible to receive it and at
the protocol specified dose(s).
- That subjects are provided with necessary instruction on properly using,
handling, storing, and returning the IP.
- That the receipt, se, and return of the IP at the trial sites are controlled and
documented adequately.
- That the disposition of unused IP at the trial sites complies with applicable
regulatory requirement(s) and is in accordance with the sponsor. - Verifying that the investigator follows the approved protocol and all approved amendments, if any.
- Verifying that written informed consent was obtained before each subject’s participation in the trial.
- Ensuring that the investigator receives the current IB, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
- Ensuring that the investigator and the investigator’s trial staff are adequately informed about the trial.
- Verifying that the investigator and the investigator’s trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
- Verifying that the investigator is enrolling only eligible subjects.
- Reporting the subject recruitment rate.
- Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained,
- Verifying that he investigator provides all the required reports, notifications, applications, and submission, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
- Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other.
- Informing the investigator of any CRF entry error, omission, or illegibility. Ensure that appropriate corrections, additions, or deletions are made, dated, explained, and initialed by the investigator or by a member of the investigator’s trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
- Determining whether all AEs are appropriately reported within time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
- Determining whether the investigator is maintain the essential documents.
- 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.
When 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:
- The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents,
- any dose and/or therapy modifications are well documented for each of the trial subjects.
- AEs, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
- Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
- All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.
Monitoring reports should include:
- The date
- Site
- Name of the monitor
- Name of the investigator or other individual(s) contacted
- A summary of what the monitor reviewed and the monitor’s statements concerning the significant findings/facts
- Deviations and deficiencies
- Conclusions
- Actions taken or to be taken and/or actions recommended to secure compliance
When should the monitor submit a written report to the sponsor?
After each trial-site visit or trial-related communication
Who should document the review and follow-up of the monitoring report with the sponsor?
The sponsor’s designated representative
The monitoring plan should include:
- The monitoring strategy
- The monitoring responsibilities of all parties involved
- The various monitoring methods to be used and the rationale for their use
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
True/False:
The sponsor should appoint individuals, who are associated with the clinical trial/systems, to conduct audits.
False.
The sponsor should appoint individuals, who are INDEPENDENT of the clinical trial/systems, to conduct audits.
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
- The form and content of audit reports
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
- Any identified problem(s)
To preserve the independence and value of the audit function, the regulatory authorities should not routinely request the audit reports. When would it be appropriate for a regulatory authority to request 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 proceedings.
Noncompliance with what by an investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance?
The protocol, SOPs, GCP, and/or applicable regulatory requirement(s)
What would prompt the sponsor to perform a root cause analysis and implement appropriate corrective and preventive actions?
Noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results.
If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, what should the sponsor do?
Terminate the investigator’s/institution’s participation in the trial
When an investigator’s/institution’s participation is terminated because of noncompliance, who should the sponsor notify?
The regulatory authorities
If a trial is prematurely terminated or suspended, who should the sponsor notify?
The investigator/institution, regulatory authorities, and the IRB/IEC.
Depending on the applicable regulatory requirements, it may be the responsibility of the investigator/institution to inform the IRB/IEC
Whether the trial is completed or prematurely terminated, the sponsor should ensure that what is prepared and provided to the regulatory agencies as required by the applicable regulatory requirement(s)?
The clinical trial reports
For multicenter trials, the sponsor should ensure that:
- 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
- The CRFs are designed to capture the required data at all multicenter trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.
- The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.
- Communication between investigators is facilitated.
In general, what topics should be included in the protocol?
- General Information
- Background Information
- Trial Objectives and Purpose
- Trial Design
- Selection and Withdrawal of Subjects
- Treatment of Subjects
- Assessment of Efficacy
- Assessment of Safety
- Statistics
- Direct Access to Source Data/Documents
- Quality Control and Quality Assurance
- Ethics
- Data Handling and Record Keeping
- Financing and Insurance
- Publication Policy
- Supplements
What general information should be included in the protocol?
- Protocol title
- Protocol identifying number
- Date
- Amendment number and date
- Name and address of the sponsor and monitor
- Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor
- Name, title, address, and telephone number(s) of the sponsor’s medical expert (or dentist when appropriate) for the trial
- Name and title of the investigator(s) who is responsible for conducting the trial
- Address and telephone number(s) of the trial site(s)
- Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator)
- Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial
What background information should be included in the protocol?
- Name and description of the investigational product(s)
- A summary of findings from the nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
- Summary of the known and potential risks and benefits, if any, to human subjects.
- Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s)
- A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
- Description of the population to be studied.
- References to literature and data that are relevant to the trial, and that provide background for the trial.
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include:
- A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
- A description of the type/design of the trial to be conducted and a schematic diagram of the trial design, procedures and stages.
- A description of the measures taken to minimize/avoid bias, including randomization and blinding.
- A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
- The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
- A description of the “stopping rules” or “discontinuation criteria” for individual subjects, parts of the trial and the entire trial.
- Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
- Maintenance of trial treatment randomization codes and procedures for breaking codes.
- The identification of any data to be recorded directly on the CRFs and to be considered to be source data.
What should the protocol include regarding the selection and withdrawal of subjects?
- Subject inclusion criteria
- Subject exclusion criteria
- Subject withdrawal criteria and procedures
What should the subject withdrawal section of the protocol specify?
- When and how to withdraw subjects from the trial/investigational product treatment.
- The type and timing of the data to be collected for withdrawn subjects.
- Whether and how subjects are to be replaced.
- The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
What should the protocol include regarding the treatment of subjects?
- The treatment(s) to be administered, including:
- Name of all the product(s)
- Dose(s)
- Dosing schedule(s)
- Route/mode(s) of administration
- Treatment period(s)
- Follow-up period(s) - Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
- Procedures for monitoring subject compliance.
What should the protocol include regarding assessment of efficacy?
- Specification of the efficacy parameters.
- Methods and timing for assessing, recording, and analyzing of efficacy parameters.
What should the protocol include regarding assessment of safety?
- Specification of safety parameters.
- The methods and timing for assessing, recording, and analyzing safety parameters.
- Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
- The type and duration of the follow-up of subjects after adverse events.
What should the protocol include regarding statistics?
- A description of statistical methods to be employed, including timing of any planned interim analysis
- The number of subjects planned to be enrolled. In multicenter trials, the numbers of enrolled subjects projected for each trial site should be specified.
- Reason for choice of the sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
- The level of significance to be used.
- Criteria for the termination of the trial.
- Procedure for accounting for missing, unused, and spurious data.
- Procedures for reporting any deviation(s) from the original statistical plan.
- The selection of subjects to be included in the analyses.
What is the purpose of the Investigator’s Brochure?
To provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures.
How should the information in the IB be presented?
In a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make their own unbiased risk-benefit assessment of the appropriateness of the proposed trial.
True/False:
If an investigational product is marketed and its pharmacology is widely understood by medical practitioners, the IB will be more extensive.
False,
If an investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary.
Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator.
If a marketed product is being studied for a new use, does an IB specific to that new use need to be prepared?
Yes
How often should the IB be reviewed?
How often should it be revised?
- The IB should be reviewed at least annually.
- The IB should be revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information.
Who should provide the IB to the investigator?
Who should provide the IB to the IRB/IEC?
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator and the investigator is responsible for providing the up-to-date IB to the responsible IRB/IEC.
In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure for an investigational product is available from who?
The commercial manufacturer
In cases where preparation of a formal IB is impractical, what should the sponsor-investigator provide as substitute?
An expanded background information section in the trial protocol that contains the minimum current information.
The IB should include:
- Title Page
- Confidentiality Statement
- Table of Contents
- Summary
- Physical, Chemical, and Pharmaceutical Properties and Formulation
- Nonclinical Studies
- Nonclinical Pharmacology
- Pharmacokinetics and Product Metabolism in Animals
- Toxicology
- Effects in Humans
- Pharmacokinetics and Product Metabolism in Humans
- Safety and Efficacy
- Marketing Experience
- Summary of Data and Guidance for the Investigator
What should the title page of the IB include?
- Sponsor’s name
- Identity of each investigational product
- Release date
- Edition number
- Reference to the number and date of the edition it supersedes
What should the introduction section in the IB include?
- Chemical name (and generic and trade name(s) when approved) of the investigational product(s)
- All active ingredients
- The investigational product(s) pharmacological class and its expected position within this class
- Rationale for performing research with the investigational product(s)
- General approach to be followed in evaluating the investigational product
What should the physical, chemical, and pharmaceutical properties and formulation section of the IB include?
- A description of the investigational product substance(s) (including the chemical and/or structural formula), and a brief summary of the relevant physical, chemical, and pharmaceutical properties.
- A description of the formulation(s) to be used, including excipients.
- Instructions for the storage and handling of the dosage form(s)
- Any structural similarities to other known compounds.
The nonclinical studies information provided in the IB may include the following, as appropriate, if known/available:
- Species tested
- Number and sex of animals in each group
- Unit dose
- Dose interval
- Route of administration
- Duration of dosing
- Information on systemic distribution
- Duration of post-exposure follow-up
- Results, including the following aspects:
- Nature and frequency of pharmacological or
toxic effects
- Severity or intensity of pharmacological or toxic
effects
- Time to onset of effects
- Reversibility of effects
- Duration of effects
- Dose response
The nonclinical pharmacology section of the IB should include:
A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included.
The summary should incorporate studies that assess potential therapeutic activity as well as those that assess safety.
The pharmacokinetics and product metabolism in animals section of the IB should include:
A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied.
The summary 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.
The nonclinical toxicology section of the IB should include:
A summary of the toxicological effects found in relevant studies conducted in different animal species.
In the IB, the 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
The pharmacokinetics and product metabolism in humans section in the IB should include:
- A summary of information on the pharmacokinetics of the investigational product(s).
- Pharmacokinetics, including:
- Metabolism
- Absorption
- Plasma protein binding
- Distribution
- Elimination - Bioavailability of the investigational product using a reference dosage form.
- Population subgroups
- Interactions
- Other pharmacokinetic data
The safety and efficacy section of the IB should include:
- A summary of information about the IP’s safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans.
- When applicable, summaries of safety and efficacy across multiple trials by indications in subgroups.
- Tabular summaries of adverse drug reactions for all the clinical trials.
- When applicable, important differences in adverse drug reaction patterns/incidences across indications or subgroups.
- 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 of the precautions or special monitoring to be done as part of the investigational use of the product.
What should the marketing experience section of the IB include?
It should identify countries where the IP has been marketed or approved.
Any significant information arising from the marketed use should be summarized.
It should also identify all the countries where the IP did not receive approval/registration for marketing or was withdrawn from marketing/registration.
What is the overall aim of the summary of data and guidance for the investigator section in the IB?
To provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial.
This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s).
Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the IP.
What documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of GCP and with all applicable regulatory requirements?
Essential Documents
Filing essential documents at the investigator/institution and sponsor sites how can greatly assist in the successful management of a trial by the investigator, sponsor, and monitor?
In a timely manner
Which documents are usually audited by the sponsor’s independent audit function and inspected by the regulatory authorities as part of the process to confirm validity of the trial conduct and integrity of the data collected?
Essential Documents
When should trial master files be established?
At the beginning of the trial
Where should trial master files be established?
At the investigator/institution’s site and at the sponsor’s office
A final close-out of a trial can only be done when the monitor has reviewed whose files and confirmed that all necessary documents are in the appropriate files?
Both the investigator/institution and sponsor files
The essential document storage system used during the trial and for archiving should provide for what?
- Document identification
- Version history
- Search
- Retrieval
When a copy is used to replace an original document, the copy should fulfill the requirements for what?
Certified Copies
True/False:
The sponsor should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.
False.
The INVESTIGATOR should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.
Before the clinical phase of the trial commences, the following essential documents should be generated and should be on file with both the investigator/institution and the sponsor before the trial formally starts:
- Investigator’s Brochure
- Signed Protocol and Amendments, if any, and Sample Case Report Form
- Information given to Trial Subject
- Any other written information
- Financial Aspects of the trial
- Insurance Statement
- Signed Agreement Between Involved Parties
- Investigator/Institution and Sponsor
- Investigator/Institution and CRO
- Investigator/Institution and Authorities (where
required) - Dated, Documented Approval/Favorable Opinion of IRB/IEC of the following:
- Protocol and any amendments
- CRF
- ICF
- Any other written information to be provided to
subjects
- Advertisement for subject recruitment
- Subject compensation
- Any other documents given approval/favorable
opinion - IRB/IEC Composition
- Regulatory Authority Authorization/Approval/Notification of Protocol (where required)
- Curriculum Vitae and/or Other Relevant Documents Evidencing Qualifications of Investigators and Sub-Investigators
- Normal Values/Ranges for Medical/Laboratory/Technical Procedures and/or Tests Included in the Protocol
- Medical/Laboratory/Technical Procedures/Tests
- Instructions for Handling of IP and Trial-Related Materials
- Shipping Records for IP and Trial-Related Materials
- Decoding Procedures for Blinded Trials
- Trial Initiation Monitoring Report
Before the clinical phase of the trial commences, the following essential documents should be generated and should be on file with the sponsor only before the trial formally starts:
- Signed Agreement Between Involved Parties
- Sponsor and CRO - Sample of Label Attached to IP Container
- Certificate of Analysis of IP Shipped
- Master Randomization List
- Pre-Trial Monitoring Report
Before the clinical phase of the trial commences, the following essential documents should be generated and should be on file with the investigator/institution only before the trial formally starts:
- Advertisement for Subject Recruitment
During the clinical conduct of the trial, the following essential documents should be added to the files of both, the investigator/institution and the sponsor, during the trial as evidence that all new relevant information is documented as it becomes available:
- IB Updates
- Any Revision to:
- Protocol/amendments and CRF
- ICF
- Any other written information provided to
subjects
- Advertisement for subject recruitment - Dated, Documented Approval/Favorable Opinion of IRB/IEC of the following:
- Protocol amendments
- Revisions of:
- ICF
- Any other written information to be
provided to the subject
- Advertisement for subject recruitment
- Any other documents given
approval/favorable opinion
- Continuing review of trial - Regulatory Authority Authorizations/Approvals/Notifications Where Required For:
- Protocol amendments and other documents - Curriculum Vitae for New Investigator(s) and/or Sub-Investigator(s)
- Updates to Normal Values/Ranges for Medical/Laboratory/Technical Procedures/Tests Included in the Protocol
- Updates of Medical/Laboratory/Technical Procedures/Tests
- Documentation of IP and Trial-Related Materials Shipment
- Relevant Communications Other Than Site Visits
- Signed, Dated and Completed CRFs
- Documentation of CRF Corrections
- Notification by Originating Investigator to Sponsor of SAEs and Related Reports
- Notification by Sponsor and/or Investigator, where applicable, to Regulatory Authorities and IRB/IEC of Unexpected Serious Adverse Drug Reactions and of Other Safety Information
- Notification by Sponsor to Investigators of Safety Information
- Interim or Annual Reports to IRB/IEC and Authorities
- Subject Screening Log
- IP Accountability at the Site
- Signature Sheet
- Record of Retained Body Fluids/Tissue Samples (if any)
During the clinical conduct of the trial, the following essential documents should be added to the files of the investigator/institution only during the trial as evidence that all new relevant information is documented as it becomes available:
- Signed ICFs
- Source Documents
- Subject Identification Code List
- Subject Enrollment Log
During the clinical conduct of the trial, the following essential documents should be added to the files of the sponsor only during the trial as evidence that all new relevant information is documented as it becomes available:
- Certificate of Analysis for New Batches of IP
- Monitoring Visit Reports
After completion or termination of the trial, all of the essential documents filed before and during the trial should be filed together with the following:
- IP Accountability at Site
- Documentation of IP Destruction
- Completed Subject Identification Code List (Investigator/Institution Only)
- Audit Certificate (Sponsor Only)
- Final Trial Close-Out Monitoring Report (Sponsor Only)
- Treatment Allocation and Decoding Documentation (Sponsor Only)
- Final Report by Investigator to IRB/IEC where required, and where applicable, to the Regulatory Authorities (Investigator/Institution Only)
- Clinical Study Report
Before the clinical phase of the trial commences, where should the IB be filed?
With both the investigator/institution and the sponsor
Before the clinical phase of the trial commences, where should the advertisement for subject recruitment (if used) be filed?
With the investigator/institution only
Before the clinical phase of the trial commences, where should the normal values/ranges for medical/laboratory/technical procedures and/or tests included in the protocol be filed?
With both the investigator/institution and the sponsor
Before the clinical phase of the trial commences, where should the sample of label(s) attached to IP container(s) be filed?
With the sponsor only
Before the clinical phase of the trial commences, where should the certificate(a) of analysis of IP(s) shipped be filed?
With the sponsor only
True/False:
Before the clinical phase of the trial commences, the master randomization list should only be filed with the sponsor.
True
True/False:
Before the clinical phase of the trial commences, the pre-trial monitoring report should be filed with both the investigator/institution and the sponsor.
False.
Before the clinical phase of the trial commences, the pre-trial monitoring report should only be filed with the SPONSOR.
During the clinical conduct of the trial, where should the documentation of IP(s) and trial-related materials shipment be filed?
With both the investigator/institution and the sponsor
During the clinical conduct of the trial, where should the certificate(s) of analysis for new batches of IP(s) be filed?
With the sponsor only
During the clinical conduct of the trial, where should monitoring reports be filed?
With the sponsor only
During the clinical conduct of the trial, where should signed informed consent forms be filed?
With the investigator/institution only
True/False:
During the clinical conduct of the trial, the investigator/institution should have copies of the signed, dated and completes case report forms filed and the sponsor should have the originals on file.
True
True/False:
During the clinical conduct of the trial, the sponsor should have copies of the documentation of CRF corrections on file and the investigator/institution should have the originals on file.
False.
During the clinical conduct of the trial, the investigator/institution should have copies of the documentation of CRF corrections on file and the sponsor should have the originals on file.
During the clinical conduct of the trial, where should the subject identification code list and the subject enrollment log be filed?
With the investigator/institution only
After completion or termination of the trial, where should the completed subject identification code list be filed?
With the investigator/institution only
After completion or termination of the trial, where should the audit certificate(s) be filed?
With the sponsor only
After completion or termination of the trial, where should the final trial close-out monitoring report be filed?
With the sponsor only
True/False:
After completion or termination of the trial, the treatment allocation and decoding documentation should be filed with both the investigator/institution and the sponsor.
False.
After completion or termination of the trial, the treatment allocation and decoding documentation should only be filed with the SPONSOR.
After completion or termination of the trial, where should the final report by the investigator to the IRB/IEC (where required) and regulatory authorities (where applicable) be filed?
With the investigator/institution only
What does ICH stand for?
The International Council of Harmonization of Technical Requirements for Pharmaceuticals for Human Use
