Life Cycle: Manage the Study
- Subject Recruitment (including Advertising)
- Subject Selection and Consent
- Study-Specific Screening Procedures
- Subject Enrollment
- For Clinical Studies: Subject Scheduling & Documentation
- For Clinical Studies: Subject Billing & Payment
- Adverse Events & Unanticipated Problems
- Data Safety Reports
- Complaint by a Subject
- Breach of Confidentiality
- Protocol Violations/Deviations
After IRB Approval
Initiation of any subject-related activities prior to IRB approval and consent is a violation of federal regulations and institutional policy. The following activities may not start until the Principal Investigator has received documentation of IRB approval:
Subject Recruitment (including Advertising)
In the process of recruiting subjects, a reasonable effort must be made to implement the ethical principle of justice, that is, an equitable involvement of classes of individuals irrespective of sex, race, and age.
Subject Selection and Consent
At the time individuals are actually selected for study participation, Investigators must be mindful not only of the inclusion/exclusion criteria but ensure that women and racial and ethnic groups are included whenever feasible and appropriate. Because the practice of medicine has shown that advanced age is not necessarily a predictor of clinical outcome, the elderly should not necessarily be excluded from research based solely upon a categorical age limit.
Obtaining consent. Both the informed consent process and consent document shall demonstrate the ethical principle of respect , incorporating the required elements of information, comprehension, and voluntariness. The subject or their representative must be given ample time to read the consent document and contemplate its contents before signing. The role of cultural values and norms of subjects should also be considered. Specific guidance is found in Institutional policy H-30: Informed Consent in Human Subjects Research , and H-30a: Procedures for Informed Consent in Human Subjects Research . To summarize the consent process:
- Discuss inclusion and exclusion criteria.
- Review the Informed Consent Document (ICD).
- Provide an opportunity for subject’s questions to be answered.
- Obtain required signatures, including subject’s (and the parent/s if required), approved study staff, attending physician (if required), and witnesses (if required).
- Obtain assent (if required).
- For clinical studies, document the informed consent process in the medical record.
Documentation. In most cases, informed consent is documented by the use of a written consent form approved by the IRB and signed by the subject or the subject’s legally authorized representative. A copy should be given to the person signing the form, another kept in the investigator’s research records and (if medical research) one in the patient medical record.
Non-English Speaking. The investigator is responsible for determining if the prospective subject is fully capable of understanding and participating in the consent process. To recruit non-English speaking, the investigator should provide the IRB with a plan for conducting informed consent process in a language that they understand, including appropriately translated consent documents.
Protected & Vulnerable Populations. Certain populations may require additional protections because they are economically or educationally disadvantaged. Every subject’s rights and welfare should be safeguarded by making sure that any possible coercion or undue influence is eliminated (e.g., compensation that is not commensurate with risk, discomfort, or inconvenience involved; recruiting in settings where voluntary participation might be compromised).
Study-Specific Screening Procedures
- Can be done only after consent is signed by the subject or their Legally Authorized Representative (unless consent is specifically waived by the IRB)?
- Post-IRB approval screening procedures include all procedures that are not considered standard practice or would not otherwise be done if not for study participation
- For clinical studies:
- Assure that subject completes all required screening tests and procedures and review the results
- Complete eligibility checklist (if required)
Typical considerations for enrolling subjects in clinical studies include:
- Follow sponsor’s protocol guidelines.
- Send notification of new research subject to appropriate registration offices (LLUMC or FPBO as appropriate).
- Immediately following consent, complete Study Authorization Letters.
- Fax Study Authorization Letters to appropriate registration offices.
For Clinical Studies: Subject Billing & Payment
IRB Approval Period
IRB approval is generally valid for, but may not exceed, one year from the date of IRB approval. Before assigning an approval period, the IRB is required to consider such things as the risk/benefit ratio, investigator’s experience, and vulnerability of subjects. Consequently the IRB may require a shorter approval period to reassess the study progress. To prevent expiration of IRB approval, investigators must request extension of IRB approval within 60 days prior to the IRB approval end date.
Renewal of IRB approval is necessary even if recruitment of subjects stops but previously enrolled subjects continue to participate in the research, or if the study is in data analysis. Federal regulations require re-evaluation of approved research at intervals that are appropriate to the degree of risk. All research must be reviewed within the anniversary date of the previous IRB review.
Lapse of IRB Approval. It is the PI’s responsibility to assure that a lapse does not occur. The continuation of research after expiration of IRB approval is a violation of Federal regulations [21 CFR 56.103(a)]. No more research activity can occur and no new subjects may be enrolled. However, if the investigator is actively pursuing renewal with the IRB and the IRB believes that an over-riding safety concern or ethical issue is involved, the IRB may permit the study to continue for the brief time required to complete the review process.
- SOP for Continuing Review (download)
- Institutional Policy for Lapse of IRB Approval
- Research Report Form
Renewal of IRB Approval
Investigators may renew the IRB approval period as many times as required to complete the study. To renew IRB approval, the Principal Investigator must complete and submit a Research Report Form sufficiently prior to expiration to avoid a lapse in IRB approval.
The IRB office sends the PI a study-specific Research Report Form prior to expiration. This information is not sent to students or co-investigators. If a research study has been formally completed or terminated, the PI should notify the IRB in writing by filing a Research Report Form. If the PI does not respond, the IRB office will automatically close the study.
Information requested in the Research Report Form:
- a description of adverse events or unanticipated problems involving risks to subjects,
- number of subjects enrolled during the approval period,
- a summary of any recent literature, findings obtained thus far, reports on multi-center trials,
- amendments or modifications to the protocol,
- verification that the approved consent form was used,
- an indication of the project’s status.
Options for continuing review on the research report form:
- There is no further research activity, other than analysis of de-identified data.
- All subject-related activities are completed.
- No study recruitment began, including retrospective chart review.
- Never Initiated
- Study was approved by the IRB, but subjects were not enrolled. For example, a site initiation visit may have been conducted (including drug shipment), but subjects were never recruited or consented.
- No study recruitment began, including retrospective chart review.
- Permanent cessation of all research activities. Continuing review is no longer required.
- IRB may terminate previously approved research that is not being conducted in accordance with the IRB’s requirements.
- Study has been stopped because of lack of funding, recruitment problems, or administrative issues involving the investigator or sponsor.
- Extension requested for follow-up
- All subject interventions are complete (Only data analysis or follow-up without treatment.) No additional subjects will be enrolled in the study. No new consent documents will be authorized.
- No further enrollment, but existing subject(s) are still active in study. Research activity may include intervention or interaction with subjects and/or continued use of a drug or device.
- Enrollment of new subjects is on-going and there is study intervention.
Amendments to IRB Approval
Since the official IRB record must always be accurate and IRB must approve any changes prior to initiation (except in emergencies where subjects' safety is at stake), PI’s must complete and submit a Change Request Form for any change that affects the study. Examples of changes include but are not limited to:
Addition of study sites
Change in number of subjects to be recruited
Addition or deletion of study staff
Change or addition of a sponsor
Revisions/corrections to consent documents or recruiting materials
Addition of translated consent documents
Any change to the protocol (including protocol deviations)
Change or transfer of a PI
Contact the IRB office for guidance.
Interim Reports to the IRB
Unanticipated Problems and Adverse Events
The IRB provides the Principal Investigator with a study-specific matrix (download) of reporting requirements for Adverse Events and Unanticipated Problems . This matrix specifies what is to be reported, the time frame for reporting, and to whom such events are reported. This will vary depending on the risk, the level of sponsor oversight, sponsor and funding source requirements (such as NIH), whether the study has a Data Safety Monitoring Board or Committee, and regulatory requirements.
Helpful Links for UP/AE:
- Adverse Event (AE) Reporting Tool
- Adverse Event Matrices (download)
- Unanticipated Problems Matrices (download)
- Institutional policy H-43: Adverse Event / Unanticipated Problem Reporting & Reviewing
- Institutional procedure H-43a: Adverse Event / Unanticipated Problem Reporting & Reviewing
- Instituional guidance document H-43b: Examples of Unanticipated Problems
Data Safety Reports
PIs shall submit any interim analysis, whether conducted by investigator or by independent data safety monitoring indicating that participants have a side effect more severe or more frequent than initially expected or that response to treatment is lower than initially expected. This would include action to withdraw a drug, device, or biologic used in a research protocol from marketing for safety reasons.
Complaint by a Subject
Receipt of a formal complaint should be reported to the IRB within 10 days when the complaint indicates unexpected risks or the complaint cannot be resolved by the team. Such complaints may be received by either the research team or by Patient Relations.
Breach of Confidentiality
Breaches involving disclosure of Protected Health Information are subject to reporting rules per the Health Insurance Portability and Accountability Act (HIPAA) and California state requirements. The institution must report breaches to the California Department of Public Health within 5 days of knowledge of a breach, so they must be reported to the institution as soon as a breach is discovered. Report to Research Integrity at ext. 88166 or 49408.
Protocol Violation Report Form (To be printed for submission)
Research Affairs - Research Integrity periodically audits research studies to help ensure compliance with federal and state regulations as well as institutional policies and procedures. Audits are performed to ensure subject safety and confidentiality, verify accurate data collection and reporting, identify risk areas and recommend corrective action to the Vice President for Research Affairs when necessary. Research Integrity works closely with our research community to improve the overall quality of human subject research.
In the Event of Noncompliance or Other Concerns
Failure to obtain IRB approval prior to the involvement of human subjects constitutes violation of University policy, which is subject to disciplinary action and/or legal action by the University in accord with standard academic practice.
Other concerns regarding research: Employees may report concerns regarding the conduct of research on the Compliance Hotline. These reports are forwarded to Research Integrity for follow up, including reporting to the IRB as necessary.
What if the IRB Suspends/Terminates the Study?
The IRB has the authority to suspend or terminate previously approved research that is not being conducted in accordance with the IRB’s requirements or that has been associated with unexpected serious harm to subjects [21 CFR 56.113 , 45 CFR 46.103(a), 45 CFR 46.103(b)(5)].
The IRB may suspend or terminate approval for any of the following reasons:
- The investigator fails to:
- obtain informed consent
- retain completed consent form(s)
- make required revisions prior to starting the study
- make requested changes in the study
- provide accurate progress reports regarding the conduct of the study, i.e., number of subjects, adverse reactions, etc.
- inform the IRB that the sponsoring agency has discontinued the study for reasons of safety
- The investigator shows lack of propriety or deceit through:
- evidence the original study has been altered
- unauthorized modification of the study or consent form
- scientific misconduct involving risks to human subject or others
- evidence that the rights of subjects have been violated
Careful review of reports of adverse events show that unexpected or serious harm occurred to subjects.
Significant new findings developed during the course of the research which alter the feasibility of the study.
This suspension or termination may occur during the progress of a study or prior to the onset of a study. Any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported in writing promptly to the investigator, appropriate institutional officials at Loma Linda University and affiliated institutions, the sponsor, and Office of Human Research Protections and/or the Food and Drug Administration, as appropriate.
When the PI Leaves the Institution
Please see the following policies and guidelines:
- Ownership of data (see p.134, section 3.4.11c(1) of the Faculty Handbook)
- Integrity, Storage, and Retention of Research Data