CITI

Question 1

If a sponsor wants to ensure a reviewing IRB is compliant with the regulations applicable to their role, they have the authority to:

Sponsor does not have the authority to monitor the IRB directly

Interview IRB staff and members via phone or in person

Request that Institutional Official or IRB Chair send copies of specific IRB study files, meeting minutes, and HRPP’s policies and procedures

Conduct an on-site IRB monitoring visit

Answer 1

Sponsor does not have the authority to monitor the IRB directly

The answer is “Sponsor does not have the authority to monitor the IRB directly.” In a FDA-regulated clinical trial, the sponsor does not have the authority to monitor an IRB. It is the investigator’s responsibility to ensure adequate and compliant IRB review. A sponsor may monitor documentation of IRB review in the investigators file, but not through IRB files.

Question 2

After an inspection, the FDA inspector will conduct an exit interview to review all findings and observations. If deficiencies are noted on FDA Form 483 (Inspectional Observations) and provided to most responsible IRB personnel, it is recommended the IRB:

Do not provide any information during the exit interview addressing deficiencies outlined

Wait for the appropriate FDA center to evaluate the inspectors Establishment Inspection Report (EIR)

Wait at least 15 days before responding to FDA Form 483

Address deficiencies noted on FDA Form 483 verbally during exit interview or in writing within 15 days

Answer 2

Address deficiencies noted on FDA Form 483 verbally during exit interview or in writing within 15 days

The answer is “Address deficiencies noted on FDA Form 483 verbally during Exit Interview or in writing within 15 days.” While it is not required that an IRB respond to Form 483, it does provide an opportunity to address them before it goes to the FDA center for evaluation.

Question 3

During a routine monitoring visit, the monitor discovers the investigator failed to report an unanticipated adverse device effect. The monitor reports to the sponsor and the sponsor notifies the FDA and participating investigators. Who is responsible for reporting to reviewing IRBs?

FDA
Sponsor
Monitor
Investigator

Answer 3

Sponsor

The correct answer is “Sponsor.” For device studies, the sponsor is responsible for reporting unanticipated adverse device effect and safety information to FDA, participating investigators and reviewing IRBs.

Question 4

A sponsor reviews the research records from Dr. Smith at your university for his drug research trial after the first five subjects were enrolled. The sponsor planned this visit and will review the research records after every five subjects are enrolled to ensure that only eligible subjects are enrolled in the study. This is an example of which type of external oversight?

Monitoring
Evaluation
Audit
Inspection

Answer 4

Monitoring

The correct response is “Monitoring” because this example describes a sponsor providing ongoing monitoring to a site investigator. This is not an inspection because it is not conducted by regulatory authorities and is ongoing (there will be future monitoring visits after every five subjects enroll). This is not an audit because it is ongoing and conducted by the sponsor. An evaluation is not a term that was covered in this module.

Question 5

During a routine monitoring visit, there are multiple and varying types of data queries noted. The monitor determines the data queries were minor and the result of sloppy data entry. What is the most likely sponsor response?

Resolve data queries and provide staff training
Suspend study site
Amend study SOPs
Notify reviewing IRB

Answer 5

Resolve data queries and provide staff training

The answer is “Resolve data queries and provide staff training.” The objective of monitoring is for a sponsor to ensure ongoing compliance and make corrective actions in real-time. If the site continues to make errors due to sloppy data entry (continued noncompliance), it is the sponsor’s responsibility to resolve the noncompliance.

Question 6

If the FDA investigator issues a Form FDA 483 after an inspection, the clinical investigator should:

Respond in writing to the FDA within fifteen (15) business days
Notify the subjects in the clinical trial
Wait to see if the FDA issues a Warning Letter
Respond in writing to the FDA within thirty (30) business days

Answer 6

Respond in writing to the FDA within fifteen (15) business days

The clinical investigator should respond in writing to the FDA within fifteen (15) business days. The response should include corrective actions that will be taken. Providing a written corrective action plan may decrease the probability that the FDA will issue a Warning Letter. However, the FDA will not consider responses received after fifteen (15) business days when evaluating whether to take additional action such as issuing a Warning Letter. There is no requirement to notify subjects when a clinical investigator receives a Form FDA 483.

Question 7

According to ICH E6, an audit is defined as:

An official review of documents, facilities, records, and any other resources related to a clinical trial.
The act of overseeing the progress of a clinical trial.
A systematic and independent examination of trial-related activities and documents.
An institutional self-assessment.

Answer 7

A systematic and independent examination of trial-related activities and documents.

A systematic and independent examination of trial-related activities and documents is “an audit,” and the act of overseeing the progress of a clinical trial is “monitoring.” An inspection is defined as the act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources related to a clinical trial.

Question 8

The overall goal of monitoring, audits, and inspection activities is to:

Resolve disputes between the sponsor and the investigators.
Ensure the protection of human research subjects and data integrity.
Review research-related publications.
Manage conflict of interest.

Answer 8

Ensure the protection of human research subjects and data integrity.

The overall goal of monitoring, audits, and inspection activities is to ensure the protection of the human research subjects and the integrity of the data. Conflicts of interest management plans are developed prior to the initiation of the trial. Research-related publications may require review by the sponsor. Resolution of disputes between the sponsor and the investigators would not be the focus of routine monitoring, audit, and inspection activities.

Question 9

OHRP is an oversight body primarily concerned with:

Adherence to FDA regulations.
Protection of human research subjects.
Compliance with the ICH E6 guideline.
Approval of new drugs.

Answer 9

Protection of human research subjects.

OHRP is an oversight body primarily concerned with the HHS requirements to protect human research subjects (45 CFR 46).

Question 10

According to ICH E6, an inspection is defined as:

An institutional self-assessment.
An official review of documents, facilities, records, and any other resources related to a clinical trial.
The act of overseeing the progress of a clinical trial.
A systematic and independent examination of trial-related activities and documents.

Answer 10

An official review of documents, facilities, records, and any other resources related to a clinical trial.

An inspection is defined as the act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources related to a clinical trial. A systematic and independent examination of trial-related activities and documents is “an audit” and the act of overseeing the progress of a clinical trial is “monitoring.”

Question 11

When the sponsor-investigator holds the IND for an investigational drug he or she is responsible for annual reporting of which one of the following to FDA?

IND report
Adverse Event Summary Report, but only from unblinded portions of studies ("open-label IND safety report")
IND renewal application
Marketing plan (in other words, annual updated projection of sales and profits)

Answer 11

IND report

The sponsor-investigator is required to keep the FDA updated through IND Safety Reports, IND amendments and annual IND reports. IND Safety Reports are filed throughout the study, not just annually. There is no requirement for an annual submission of an IND renewal application or marketing plan.

Question 12

Which of the following is a criterion for determining if a study of an approved drug is exempt from the requirement of an IND?

The study is not intended to be reported to FDA to support a new indication or support a labeling change.
The study involves a route of administration that significantly increases the risks to the subject.
The study intends to invoke an exception from informed consent.
The study intends to involve more than 100 subjects in a study.

Answer 12

er The study is not intended to be reported to FDA to support a new indication or support a labeling change.

The number of subjects in a study is not a consideration for IND exemption. Any study that significantly increases risk to subjects or invokes an exception from informed consent for emergency research (21 CFR 50.24) does not meet one of the criterion for an IND exemption. Investigations that are not intended to be reported to FDA do qualify as meeting one of the six required conditions for an IND exemption.

Question 13

Which of the following reports must be filed using a Form FDA 1572?

Addition of a new investigator
Annual reports
Protocol amendments
Adverse event reports

Answer 13

Addition of a new investigator

Once an IND is submitted and becomes effective, protocol amendments, information amendments, IND safety reports, and annual reports must be submitted to the FDA. Changes or additions to the investigators at a single research site would be filed using a Form FDA 1572.

Question 14

When evaluating the causality of an adverse event, which of the following should be a consideration?

Whether or not the adverse event qualifies as a serious adverse event
The method used to randomize subjects
The timing of the event in relation to administration of the investigational agent
The number of planned interventions in the protocol

Answer 14

The timing of the event in relation to administration of the investigational agent

Whether or not an event qualifies as serious is a regulatory determination and would not be a consideration in assessing the causality of the event. The timing of the event in relation to the administration of the investigational agent should be considered in determining the causality of the event.

Question 15

Accurate reporting of adverse events is most important for:

Allowing rechallenge of subjects.
Ensuring correct site reimbursement for work performed.
Ensuring subject safety.
Updating recruitment materials.

Answer 15

Ensuring subject safety.

The sponsor of the research should specify what is appropriate to record for the particular protocol, so that the data are consistent across research sites. Accurate reporting is essential for subject safety. Adverse event reporting might affect the informed consent document, but is unlikely to change recruitment materials.

Question 16

A subject is a passenger in a car involved in a motor vehicle crash. The subject sustained a broken wrist and mild concussion. The subject was treated and released from the emergency department. What should the investigator do when learning of the crash?

No report is needed because these are not serious adverse events.
Report only the concussion because it might become serious.
No report is needed because the subject was a passenger in the vehicle and not driving.
Report adverse events of both a broken wrist and a mild concussion.

Answer 16

Report adverse events of both a broken wrist and a mild concussion.

The broken wrist and mild concussion are changes from the subject’s baseline and are unexpected and untoward medical occurrences and therefore reportable as adverse events. The motor vehicle crash is the cause of the adverse events, not the adverse event itself.

Question 17

A subject presents to the emergency department (ED) with complaints of chest pain and shortness of breath. Blood studies are positive for a heart attack and the subject is hospitalized. The subject has a history of coronary artery disease. The subject reports to the ED nurse that he is currently enrolled in a phase I study of a new lipid lowering agent. Which individual should determine causality of the serious adverse event?

ED nurse
Principal Investigator
Pharmacist
Study Coordinator

Answer 17

Principal Investigator

Determining the relationship of the investigational agent to an adverse event requires medical decision-making and expertise. The person making this determination should be medically qualified to do so. The Principal Investigator of the phase I study is responsible for assessing and reporting adverse events.

Question 18

What is the legal status of ICH E6 in the U.S.?

It is a regulation codified at 21 CFR
It is an FDA guidance
It is a federal statute (law)
It has no status

Answer 18

It is an FDA guidance

After the finalization of the ICH E6 guideline, several countries adopted it as law. In the U.S., however, the FDA adopted the ICH E6(R1) and subsequently the ICH E6(R2) guidelines only as guidance (HHS and FDA 1997; FDA 2018a).

Therefore, ICH E6 does not have the force of law in the U.S. and is not regulation.

In the Federal Register notice, HHS and FDA (1997) stated that ICH E6 “does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both.” Therefore, compliance is voluntary, but as with any published FDA guidance, compliance is part of GCP.

Question 19

In terms of explaining the probability of assignment to trial arms in consent forms, which is true?

The probability of assignment should always be stated as being “like the flip of a coin” because subjects can understand that example.
FDA requires the probability to be expressed as a percentage chance.
ICH notes that it should be included but does not specify how the information should be presented.
Neither FDA nor ICH require statements about the probability for random assignment to each treatment arm or the use of a placebo arm.

Answer 19

ICH notes that it should be included but does not specify how the information should be presented.

ICH E6 (Section 4.8.10(c)) states that “Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include the probability for random assignment to each treatment;” however, it does not specify how the information should be presented. The FDA has no such requirement about including probability for random assignment to each treatment but does require an identification of any procedures which are experimental.

This difference can be addressed by including a description of each arm of the study in the consent form and including a statement about the likelihood of receiving each of the study arms.

Question 20

ICH E6 has broader requirements than FDA or HHS concerning confidentiality of medical records and access by third parties. If investigators are following ICH E6, they must:

Obtain a non-disclosure form before notifying the subject’s primary physician.
Provide a separate form that notes the possibility that the FDA may inspect the records.
Include a statement in the consent form that confidentiality of trial data cannot be guaranteed because of foreign involvement and the possibility of hacking.
Clearly disclose to subjects in the informed consent form that the monitor, auditor, IRB/IEC, and the regulatory authorities may have access to the subject’s medical records.

Answer 20

Clearly disclose to subjects in the informed consent form that the monitor, auditor, IRB/IEC, and the regulatory authorities may have access to the subject’s medical records.

ICH E6 (Section 4.8.10(n)) states that the informed consent should indicate that “the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality 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 legally acceptable representative is authorizing such access.”
The FDA regulations (21 CFR 50.25(a)(5)) state only that in seeking informed consent, the following information shall be provided to each subject: “A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.”
While it is true that data sent out of the U.S. loses certain federal protections, this statement is not required. The possibility of hacking data is a risk that should be addressed in the study design and conduct.
Non-disclosure forms are not required for communications with primary care providers.

Question 21

The updated ICH E6(R2) requires sponsors to implement systems to manage quality throughout all stages of the trial process. The system should use a risk-based approach including which of the following?

Use of the PDA cycle (Plan, Do, Act) during the annual continuing review.
Mandatory use of ICH E6 template Case Report Forms for all drug studies to be submitted to regulatory authorities.
Identification of study risks to determine which may safely be omitted from continual monitoring.
Complete on-site documentation audits every 3-6 months.

Answer 21

Identification of study risks to determine which may safely be omitted from continual monitoring.

ICH E6 (Section 5.0.4) states that the sponsor should decide which risks to reduce and/or which risks to accept. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk. Risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, and agreements.
Routine scheduled audits of study documentation whether on-site or remote are not considered fully responsive to the need for continuous monitoring of data under a proactive risk-based approach.
While data from Case Report Forms may be selected for ongoing monitoring, there is no ICH template and a “one-size-fits-all” approach is not appropriate for study-specific monitoring.
The use of any specific method of analysis quality improvement is not required and routine annual review may not be sufficient for monitoring the study-specific risks that have been identified.

Question 22

The two exempt research categories that always require limited IRB review as a condition of exemption are: Storage or maintenance for secondary research for which broad consent is required (Category 7) and which of the following?

Secondary research for which broad consent is required (Category 8)
Taste and food quality evaluation and consumer acceptance studies (Category 6)
Benign behavioral interventions (Category 3)
Secondary research for which consent is not required (Category 4)

Answer 22

Secondary research for which broad consent is required (Category 8)

The two exempt research categories that always require limited IRB review as a condition of exemption are: Storage or maintenance for secondary research for which broad consent is required (Category 7) and secondary research for which broad consent is required (Category 8).

Question 23

The Final Rule added the requirement that:

Key information essential to decision making be provided in a one-page handout accompanying the informed consent form.

Key information essential to decision making receive priority by appearing at the beginning of the consent document and being presented first in the consent discussion.

Key information essential to decision making be provided in writing to the subject and subject’s legally authorized representative.

Key information essential to decision making be provided by the principal investigator to the subject at least one week prior to signing the informed consent form.

Answer 23

Key information essential to decision making receive priority by appearing at the beginning of the consent document and being presented first in the consent discussion.

The Final Rule added the requirement that key information essential to decision making receive priority by appearing at the beginning of the consent document and being presented first in the consent discussion.

Question 24

The Final Rule made revisions to the following definition:

Minimal risk
IRB
Certification
Human subject

Answer 24

Human subject

The Final Rule revised the definition of human subject.

Question 25

The compliance date for cooperative review is:

The same compliance date as the entire 2017 Final Rule
Three years from publishing the 2017 Final Rule in the Federal Register
Retroactive; it will apply to research approved from 1 December 2016 forward
Effective immediately on the day the 2017 Final Rule was published in the Federal Register

Answer 25

Three years from publishing the 2017 Final Rule in the Federal Register

Question 26

The Final Rule revised the definition of “written or in writing” to clarify:

That handwritten notes to file are appropriate if initialed and dated
That all documentation must be backed up by paper
That these terms include electronic formats
That consent cannot be presented orally to subjects

Answer 26

That these terms include electronic formats

The definition of “written or in writing” is intended to clarify that these terms include electronic formats.

Question 27

Benign behavioral interventions were not defined, but described as which of the following?

Involving more than one institution
Prospective agreement by the subject to participate in research where the subject is informed that he or she will be unaware of or misled regarding the nature or purposes of the research
Interventions in conjunction with collecting information from an adult subject through oral or written responses (including data entry) or audiovisual recording if the subject prospectively agrees to the intervention and information collection and certain conditions are met
Behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information that has been provided for specific purposes by an individual and that the individual can reasonably expect will not be made public (for example, a medical record)

Answer 27

Interventions in conjunction with collecting information from an adult subject through oral or written responses (including data entry) or audiovisual recording if the subject prospectively agrees to the intervention and information collection and certain conditions are met

Benign behavioral intervention is described in 46.104(d)(3) as “behavioral (not biomedical) interventions in conjunction with collecting information from an adult subject through oral or written responses (including data entry) or audiovisual recording if the subject prospectively agrees to the intervention and information collection and certain conditions are met” (HHS 2017).

Question 28

Identify the new term added by the Final Rule that should be used for determining which studies require posting of the IRB-approved consent form used to enroll subjects:

Human subject
Broad consent
Research
Clinical trial

Answer 28

Clinical trial

“Clinical trial means a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes” (HHS 2017). The Final Rule’s preamble notes that, while not implementing the Notice of Proposed Rulemaking’s (NPRM) proposed extension of the Common Rule to all clinical trials, the definition of clinical trial should be used for determining which studies require posting of the IRB-approved consent form used to enroll subjects (HHS 2017).

Question 29

Which of the following definitions was added by the Final Rule?

Minimal Risk
Institutional Review Board (IRB)
Written or in writing
Research

Answer 29

Written or in writing

Written or in writing was added by the Final Rule. The other terms existed in the pre-2018 Common Rule.

Question 29

Examples of vulnerable populations in the Final Rule no longer include:

Pregnant women
Persons with impaired decision-making capacity
Economically disadvantaged persons
Children

Answer 29

Pregnant women

The Final Rule no longer includes pregnant women or handicapped and physically disabled individuals as examples of populations that are potentially vulnerable to coercion or undue influence. The Final Rule uses the term “individuals with impaired decision-making ability” to replace the term “mentally disabled persons” (HHS 2017).

Question 30

The term “vulnerable” was:

Not included in the definitions section
Added to the definitions section
Removed from the definitions section
Revised in the definitions section

Answer 30

Not included in the definitions section

Vulnerable is not included in the definitions section, but the wording surrounding it has been updated in both 46.107 (IRB membership requirements) and 46.111 (Criteria for approval of research).

Question 31

Why was adding the definition of public health authority important?

Application of the definition helps determine which studies require posting of the IRB-approved consent form used to enroll subjects
It aligns the regulation with the U.S. Food and Drug Administration (FDA) and International Council for Harmonisation (ICH) definitions of public health authority
It clarifies that consent forms could be in media other than paper or electronic formats and still meet the requirements of the Common Rule
Certain public health surveillance activities are now excluded from the definition of research

Answer 31

Certain public health surveillance activities are now excluded from the definition of research

Public health authority means an agency or authority that is responsible for public health matters as part of its official mandate. Adding this definition is important because certain public health surveillance activities are now excluded from the definition of research. The excluded public health activities are limited to activities necessary for a public health authority to “identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products)” (HHS 2017).

Question 32

Which of the following definitions remained unchanged in the Final Rule?

Public health authority
Written or in writing
Institutional Review Board (IRB)
Research

Answer 32

Institutional Review Board (IRB)

Most definitions remain the same, including Institutional Review Board (IRB), IRB approval, and minimal risk. Definitions of public health authority and written or in writing were added, and the definition of research was revised.

Question 33

The three new terms added to the definitions section include:

Legally authorized representative, public health authority, and research
Clinical trial, public health authority, and written or in writing
Clinical trial, research, and human subject
Research, vulnerable, and minimal risk

Answer 33

Clinical trial, public health authority, and written or in writing

“Clinical trial means a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes” (HHS 2017). The Final Rule’s preamble notes that, while not implementing the Notice of Proposed Rulemaking’s (NPRM) proposed extension of the Common Rule to all clinical trials, the definition of clinical trial should be used for determining which studies require posting of the IRB-approved consent form used to enroll subjects (HHS 2017).