CCRP Practice Questions

ICH-GCP requires that any materials used to recruit or inform prospective subjects (e.g., advertisements, flyers, web postings) be reviewed and approved by the IRB/IEC before use. Section 3.1.2 states that the IRB/IEC “…should review… especially the written informed-consent form(s) and any subject-recruitment procedure (e.g., advertisements).” Recruitment materials are therefore an obligatory part of the submission package for a Phase III vaccine trial. The other listed documents are either not required for IRB/IEC review or are only filed with the sponsor and investigator.

A. Local laboratory normal ranges (ICH E6 8.2.11) are filed with investigator and sponsor; no IRB/IEC review required.

B. Blank CRFs may accompany the protocol (ICH E6 8.2.3) but are not specifically mandated for IRB/IEC submission and are seldom requested.

D. Investigator CVs (ICH E6 8.2.10) document qualifications for sponsor and site files; ICH does not require them to be sent to the IRB/IEC.

1. International Council for Harmonisation. ICH E6(R2) Good Clinical Practice Guideline. Section 3.1.2, p. 22; Section 4.4.3, p. 27; Section 8.2.7, p. 38.

2. FDA Guidance for IRBs, Clinical Investigators, and Sponsors: “Recruiting Study Subjects,” July 2018, pp. 2-3.

3. University of Michigan IRBMED Policy: “IRB Review of Advertisements and Recruitment Materials,” Rev. 2022, pp. 1-2 (illustrates standard application of ICH 3.1.2 requirements).

According to international and U.S. federal regulations, the sponsor holds the ultimate responsibility for the quality and integrity of trial data. This includes implementing and maintaining quality assurance systems. For electronic data capture (EDC) systems used in a multi-site trial, the sponsor must ensure the system is validated to be accurate, reliable, and perform consistently as intended. The sponsor selects, qualifies, and oversees the EDC vendor and ensures the system complies with regulations like 21 CFR Part 11 and ICH E6(R2) across all participating sites. This centralized responsibility ensures uniformity and control over the data management process for the entire study.

A. Institution: The institution is responsible for trial conduct at its specific location but not for validating a multi-site electronic system provided by the sponsor.

C. Regulatory authority: Regulatory authorities (e.g., FDA) set the compliance requirements and conduct inspections, but they do not actively manage or ensure a specific system's compliance; that is the sponsor's duty.

D. Investigator: The investigator is responsible for the accuracy of the data entered at their site but not for the technical validation and compliance of the overall EDC system itself.

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). Section 5.5.3, "Electronic Trial Data Handling and Remote Electronic Trial Data Systems." This section explicitly details the sponsor's responsibility to ensure and document that electronic data processing systems are validated and conform to established requirements for completeness, accuracy, reliability, and consistent intended performance.

2. U.S. Food and Drug Administration. (2003). Code of Federal Regulations, Title 21, Part 11, Electronic Records; Electronic Signatures. Section 11.10(a), "Controls for closed systems." This regulation requires that persons using closed electronic record systems must "employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records," including the validation of systems to ensure accuracy and reliability. In a sponsored trial, this "person" is the sponsor.

3. Johns Hopkins University. (n.d.). Investigator Responsibilities - FAQs. Johns Hopkins Medicine. Retrieved from the Office of Human Subjects Research Institutional Review Board website. The guidance clarifies that while investigators are responsible for data at their site, the sponsor is responsible for "selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s)... and ensuring that the investigation(s) is conducted in accordance with the general investigational plan." This oversight includes the systems used for data collection.

Federal regulations mandate specific additional protections for children participating in research. A primary protection is the requirement to obtain the child's affirmative agreement, or assent, to participate. The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is responsible for determining whether the children are capable of providing assent and specifying an appropriate procedure for obtaining it, based on their age, maturity, and psychological state. This process respects the child's developing autonomy and is required in addition to obtaining permission from the parent(s) or legal guardian.

A. An impartial advocate is typically only required for specific vulnerable child populations, such as wards of the state, not for all children in research.

C. While often encouraged for support, the constant presence of parents during all research procedures is not a universal regulatory requirement.

D. Research involving children must be reviewed by an IRB with appropriate pediatric expertise, but it does not have to be a central or pediatric-specific IRB.

1. U.S. Department of Health & Human Services. (2018). Code of Federal Regulations, Title 45, Part 46, Subpart D - Additional Protections for Children Involved as Subjects in Research.

§46.408(a): "In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent."

§46.409(b): Specifies the requirement of an advocate for research involving children who are wards of the state, demonstrating this is not a universal requirement.

2. Stanford University. (n.d.). Human Research Protection Program (HRPP) Policy Manual. Chapter 14.3, Research Involving Children. Retrieved from the Stanford Research Compliance Office website.

This policy details the implementation of federal regulations, stating, "The IRB must determine that adequate provisions are made for soliciting the assent of children... Assent is a child's affirmative agreement to participate in research."

3. Kopelman, L. M. (2000). Children as research subjects: A dilemma. Journal of Medicine and Philosophy, 25(6), 745–764.

Page 748: Discusses the ethical evolution from proxy consent to a dual requirement of parental permission and the child's assent, highlighting assent as a critical protection. https://doi.org/10.1076/0360-5310(200012)25:6;1-V;FT745

In the United States, the Institutional Review Board (IRB), also known as an Independent Ethics Committee (IEC), is responsible for protecting the rights and welfare of human research subjects. According to both the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) regulations, the IRB must review and approve all materials used to recruit potential participants. This oversight ensures that recruitment methods are not coercive, do not make unsubstantiated claims, and present information in a non-misleading manner. This requirement applies to all clinical investigations involving human subjects, including medical device studies, regardless of whether the device is used within its approved indication.

A. A scientific review board: A scientific review board evaluates the scientific merit and feasibility of a study protocol, not the ethical aspects of patient-facing materials like recruitment advertisements.

B. The FDA: The FDA sets the regulations that require IRB review of recruitment materials but does not directly approve these materials for most individual studies. This responsibility is delegated to the IRB.

C. The Office for Human Research Protections (OHRP): OHRP provides oversight for federally-funded research and interprets human subject protection regulations, but it does not approve study-specific documents. This is the function of the local or central IRB.

1. U.S. Food and Drug Administration (FDA). Code of Federal Regulations Title 21, Part 56, Section 109 (21 CFR § 56.109(a)). This regulation states, "An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by these regulations." This authority explicitly covers recruitment materials and processes.

2. U.S. Food and Drug Administration (FDA). (2015). Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Recruiting Study Subjects. This guidance document clarifies, "All recruitment materials and advertisements must be reviewed and approved by the IRB. The IRB should review the information contained in the advertisement and the mode of its communication to determine that the procedure for recruiting subjects is not coercive and does not state or imply a certainty of a favorable outcome or other benefits beyond what is outlined in the consent document and the protocol."

3. U.S. Department of Health & Human Services (HHS). Code of Federal Regulations Title 45, Part 46, Section 111 (45 CFR § 46.111(a)(3)). This section of the "Common Rule" requires that for research to be approved, the IRB must determine that the "selection of subjects is equitable." The review of recruitment materials is essential to making this determination.

According to the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6(R2), the sponsor is ultimately responsible for implementing and maintaining quality assurance and quality control systems. This includes defining, establishing, and allocating all trial-related duties and functions prior to the trial's initiation. While a sponsor may transfer any or all of these duties to a Contract Research Organization (CRO), the transfer must be specified in writing. However, the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. This ensures a clear and documented assignment of responsibilities before any trial activities commence.

A. The institutional administrator: Manages institutional resources and provides administrative oversight, but does not define or allocate specific trial-related duties per ICH GCP.

C. The study coordinator: Works under the investigator's supervision to perform delegated tasks at the site level, not to define and allocate all trial functions.

D. The IRB/IEC: Is responsible for the ethical review of the trial and protection of human subjects, not the operational management or allocation of duties.

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). Section 5.7, "Allocation of Duties and Functions," p. 21.

2. Harvard Catalyst | The Harvard Clinical and Translational Science Center. (n.d.). Good Clinical Practice (GCP) Course: Roles and Responsibilities. Module 2, "Sponsor Responsibilities." Retrieved from https://catalyst.harvard.edu/courses/gcp/ (Note: Specific courseware content may require login, but the public-facing curriculum outlines these standard GCP principles).

3. Tenti, E., Simonetti, G., & Tassinari, D. (2021). Good Clinical Practice: The sponsor's and the investigator's point of view. European Journal of Internal Medicine, 89, 1-5. https://doi.org/10.1016/j.ejim.2021.05.020 (This article discusses the distinct responsibilities of the sponsor as outlined in ICH GCP, including the allocation of duties).

Upon completion of a clinical trial at a site, the investigator is required to provide the Institutional Review Board (IRB) with a final report. This report summarizes the trial's outcome, details the number of subjects enrolled, and describes any significant findings or adverse events. This submission formally notifies the IRB that the research activities are complete, allowing the IRB to close its file for the study and terminate its oversight responsibilities. This requirement is explicitly stated in the ICH GCP Guideline and is the established practice for complying with U.S. Code of Federal Regulations (CFR) regarding the conclusion of IRB oversight.

B. The monitoring close-out visit report: This is a report from the sponsor's monitor to the sponsor, documenting that site activities are complete and in order. It is not a required submission to the IRB.

C. The data safety monitoring summary: These summaries are typically provided to the IRB during the trial as part of the continuing review process to ensure subject safety, not as a separate, final submission after completion.

D. The final subject enrollment log: The IRB requires the final number of enrolled subjects, which is included in the final report. The entire log itself is a source document and is not typically submitted.

1. International Council for Harmonisation (ICH) Harmonised Guideline, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), Section 4.13, "Final Report(s) by Investigator." This section states, "Upon completion of the trial, the investigator...should provide the IRB/IEC with a summary of the trial’s outcome..."

2. U.S. Food and Drug Administration (FDA), "Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Continuing Review After Study Approval" (February 2012), Section IV.B, "When Continuing Review is No Longer Necessary." This guidance clarifies that once a study is closed and all subject interaction and data analysis are complete, "...the investigator should submit a final report to the IRB."

3. Johns Hopkins University, Institute for Clinical and Translational Research, "Study Close-Out Procedures." The university's official guidance for investigators lists "Submit a Final Report/Study Closure Form to the IRB" as a mandatory step in the study close-out process, demonstrating the implementation of federal regulations in a reputable academic setting.

4. Code of Federal Regulations, Title 21, Part 56.109(f). This regulation mandates continuing IRB review of ongoing research. The universally accepted mechanism to end this requirement is the submission of a final report by the investigator, which allows the IRB to formally close the study.

The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) E6(R2) mandates the minimum frequency for the continuing review of ongoing clinical trials by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Section 3.1.4 specifies that the IRB/IEC must review ongoing trials at intervals appropriate to the level of risk, but at least once per year. This "at least annually" requirement establishes a 12-month interval as the standard maximum period between reviews to ensure the continued protection of human subjects' rights, safety, and well-being.

A. 6 months: While more frequent reviews are permissible and may be appropriate for high-risk studies, 12 months is the standard minimum frequency (maximum interval) explicitly required by ICH GCP.

C. 24 months: This interval exceeds the "at least once per year" mandate and is therefore non-compliant with ICH GCP guidelines for continuing review.

D. 36 months: This interval significantly exceeds the maximum allowable period of one year between reviews and is a clear violation of ICH GCP standards.

1. International Council for Harmonisation (ICH). (2016). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). Section 3.1.4, page 12. "The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year."

2. U.S. Food and Drug Administration (FDA). (2023). Code of Federal Regulations, Title 21, Part 56, Section 109 (21 CFR 56.109(f)). "An IRB shall conduct continuing review of research covered by these regulations at intervals appropriate to the degree of risk, but not less than once per year."

3. University of California, San Francisco (UCSF), Human Research Protection Program. IRB Continuing Review Guidance. "Federal regulations require that the IRB re-approve all non-exempt human research projects at least annually (unless the study qualifies for an exception)." This university guidance reflects the implementation of federal and international standards.

According to U.S. federal regulations and international ethical guidelines, a primary responsibility of an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is to ensure the protection of human research subjects. A core criterion for approving research is upholding the ethical principle of Justice, which is operationalized by requiring that the selection of subjects is equitable. This means the IRB/IEC must determine that the burdens and potential benefits of the research are distributed fairly and that vulnerable populations are not targeted for risky research or unfairly excluded from potentially beneficial research. This is a mandatory determination for protocol approval.

A. A plan for the publication of study results is in place: While ethically encouraged for transparency, a formal publication plan is not a regulatory requirement for IRB/IEC approval of a research protocol.

C. The investigator has adequate access to patients eligible for the trial: This pertains to study feasibility, which is primarily the concern of the sponsor and institution, not a required ethical determination for the IRB/IEC.

D. The sponsor is qualified to provide oversight of the trial: Assessing the sponsor's qualifications is the responsibility of regulatory authorities (e.g., FDA), not the local IRB/IEC, whose focus is on the investigator and the protocol.

1. U.S. Department of Health & Human Services (HHS). Code of Federal Regulations, Title 45, Part 46.111(a)(3). "Criteria for IRB approval of research." This regulation explicitly states: "Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted..."

2. U.S. Food and Drug Administration (FDA). Code of Federal Regulations, Title 21, Part 56.111(a)(3). "Criteria for IRB approval of research." This regulation mirrors the HHS requirement, stating that to approve research, the IRB must determine that: "Selection of subjects is equitable."

3. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Part C: Applications, Section 3 (Justice). The report states, "the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects."

4. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016). Guideline for Good Clinical Practice E6(R2). Section 3.1.2. This guideline requires the IRB/IEC to review "subject recruitment procedures" to ensure they are ethically sound, which inherently includes the principle of equitable selection.

The primary responsibility of an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is to protect the rights and welfare of human research subjects. To fulfill this mandate, the IRB/IEC is granted independent authority to review, approve, require modifications to, or disapprove research. This authority includes determining the adequacy of the informed consent process and document. The IRB/IEC can require that additional information be provided to subjects whenever it judges that such information is necessary for subjects to make a truly informed decision, thereby ensuring their protection. This authority is not contingent upon the agreement of the sponsor or the investigator.

B. The IRB/IEC's authority is independent and its primary obligation is to research subjects, not the sponsor. A sponsor cannot veto an IRB/IEC requirement for subject protection.

C. An investigator must comply with the determinations of the IRB/IEC to gain and maintain approval for the research. The investigator's agreement is not a prerequisite for the IRB/IEC's decision.

D. The IRB/IEC's authority is not conditional on agreement from either the sponsor or the investigator. Its decisions are based on ethical principles and regulations for subject protection.

1. International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) E6(R2), Section 3.4.1: "The IRB/IEC may require that other information, when in the IRB/IEC's judgement the information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects, be given to the subjects."

2. U.S. Code of Federal Regulations, Title 21, Part 56, Section 109(a) (21 CFR 56.109(a)): This regulation grants the IRB the authority to "approve, require modifications in (to secure approval), or disapprove all research activities covered by these regulations." This establishes the IRB's power to mandate changes to the informed consent form.

3. U.S. Code of Federal Regulations, Title 45, Part 46, Section 116(c) (45 CFR 46.116(c)): This section on "Additional elements of informed consent" states, "When appropriate, one or more of the following elements of information must also be provided..." The determination of what is "appropriate" is a core function of the IRB's review and discretion.

4. Stanford University, Human Research Protection Program (HRPP) Policy Manual, Chapter 1, Section 1.2, "Authority of the IRB": "The IRB has the authority to: Approve, require modifications in (to secure approval), or disapprove all research activities overseen and conducted by the organization." This university policy reflects the federally mandated authority of the IRB.

According to the U.S. Code of Federal Regulations (CFR), a protocol amendment is required for changes to the clinical investigation protocol itself. The addition of a new test, even to improve safety monitoring, alters the study procedures detailed in the protocol. Per 21 CFR 312.30(b), any change to a protocol that affects the safety of subjects, the scope of the investigation, or the scientific quality of the study must be submitted to the FDA as a protocol amendment. Adding a new monitoring test directly modifies the study procedures and falls under this requirement.

B. A significant change in an investigator's financial interest is reported under financial disclosure regulations (21 CFR Part 54) and is not submitted as a protocol amendment.

C. The addition of a sub-investigator is a personnel change documented via an updated Form FDA 1572 and is not considered a protocol amendment submitted by the sponsor.

D. A change in the manufacturing site is a Chemistry, Manufacturing, and Controls (CMC) change. This requires an information amendment under 21 CFR 312.31, not a protocol amendment.

1. U.S. Code of Federal Regulations, Title 21, Part 312, Subpart B — Investigational New Drug Application (IND).

§ 312.30 Protocol amendments: This section explicitly defines what constitutes a protocol amendment, including "(a) ...whenever a sponsor intends to conduct a study that is different from the study described in the protocol..." and "(b)(1) ...any change... that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study." This directly supports option A.

§ 312.31 Information amendments: This section defines amendments for information not within the scope of a protocol amendment, specifying "(a)(1) New toxicology, chemistry, or other technical information..." A change in manufacturing site falls under this category, making option D incorrect as a protocol amendment.

2. U.S. Code of Federal Regulations, Title 21, Part 54 — Financial Disclosure by Clinical Investigators.

§ 54.4 Certification and disclosure requirements: This part outlines the sponsor's responsibility to collect and disclose financial interest information, which is a separate process from submitting a protocol amendment. This makes option B incorrect.

3. University of California San Francisco (UCSF), Institutional Review Board. Guidance: INDs, IDEs, and Other FDA Submissions. This document clarifies the different types of IND submissions: "Protocol Amendments (21 CFR 312.30) are submitted when there are changes to the protocol... Examples: changes in... study procedures." and "Information Amendments (21 CFR 312.31) are submitted for... new chemistry, manufacturing, and controls (CMC) information." This academic source reinforces the distinction between protocol and information amendments, supporting the rationale for selecting A and rejecting D.