Frequently Asked Questions
|Adverse Events||IRB Approval Expires|
|Approval||Key Study Personnel|
|Electronic Signatures||Research Subject becomes a Prisoner|
|Exemption||Spanish Speaking Subjects|
|Informed Consent||Subject Recruitment|
- It is the responsibility of the UTHSC IRB, not the investigator, to determine whether research activities qualify for Exemption.
- Enrollment occurs when the consent form is signed, not when the subject is randomized. Therefore, an estimate of screened failures should be incorporated into the target enrollment number submitted to the IRB. Also, the number of subjects who signed the consent form, not just those subjects who were randomized, should be included on the renewal application under the number of subjects accrued.
- The principal investigator or collaborating investigator must sign the consent form within 72 hours of the subject's entry into the study.
- At the time of expiration of IRB approval, all study activities including recruitment, consent, data collection, and data analysis must stop. If you wish to continue any activities that are directly related to subject safety, please contact the IRB office to request permission to continue those activities until IRB approval is reinstated.
- Remember to use the most current version of the consent form template and the UTHSC IRB approved standard language whenever you submit a new or amended consent form. Consent form templates are updated/revised by the IRB often. You can find the most current versions on the UTHSC IRB website, and there is a link to the consent form page from within the "Help" button in iMedRIS. Please do not use old templates that you may have saved on your computer.
- An adverse event (AE) must be reported to the IRB if it is (a) unexpected; (b) serious; and (c) possibly, probably, or clearly related to the research intervention.
- A protocol deviation must be reported to the IRB if it (a) has harmed or has posed a significant risk of substantive harm to the individual research subject; or (b) has compromised the scientific integrity of the data collected for the study; or (c) appears to result from the wiling or knowing misconduct on the part of an investigator or study staff; or (d) appears to involve some other serious or continuing noncompliance with federal, state, or local research regulations.
- When a local investigator receives a protocol waiver from a study sponsor, or the principal investigator of an investigator-initiated study proposes to enroll a subject who does not meet the approved inclusion/exclusion criteria, the details of the proposed waiver, subject identification, and all supporting documentation must be submitted to the UTHSC IRB for review and approval prior to implementation of the protocol waiver.
Q: What are adverse events or other unanticipated problems, and how are they categorized?
A: An adverse event is an untoward medical occurrence that may present itself during the course of a research study. An unanticipated adverse event is a medical occurrence whose nature, severity, or frequency is not consistent with existing information regarding the risk profile of the study procedure or test article. For pharmaceutical studies this usually reflects inconsistency with the information contained in the current Investigator's Brochure. A serious adverse event is a medical occurrence that results in death, is life threatening, requires in-patient hospitalization, creates persistent or significant disability or incapacity, or results in a congenital anomaly or birth defect. An important medical event that may not result in death, be life threatening, or require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, it may require medical or surgical intervention to prevent one of the outcomes noted above. Unanticipated problems other than adverse events include occurrences such as (but not limited to) accidental overdoses of study medications, deviations from study inclusion/exclusion criteria, or failure to follow criteria for subject withdrawal.
Q: What classifications are used for the relation of the adverse event to the study
A: An adverse event may be related to the study intervention if it can be regarded as possibly, probably, or clearly caused by the intervention. Alternatively, the relationship of adverse events to study interventions may be characterized as either "unrelated" or as "unlikely related."
Q: What is the UTHSC IRB policy regarding reporting of adverse events?
A: All adverse events must be reported if the event meets the definition for an unanticipated serious event and is also possibly, probably, or clearly related to the intervention. All deaths, regardless of cause or anticipation, must be reported within 24 hours of such occurrence. All other adverse events must be reported within 5 working days from the date of the occurrence. The relationship of the adverse event to the research intervention must be determined by the investigator.
Q: I'm planning a human subjects research project at a hospital where I have privileges
but which is not affiliated with UT's IRB. The hospital IRB has approved the protocol.
Am I required to submit to UT's IRB for approval of this project before it can be
A: There are a few points that need to be considered: First, if the individual asking the question is UT faculty, he/she will need to also submit his/her research application to the UTHSC IRB. In addition, if the individual asking the question will be conducting research at Regional One Health, or UT Medical Group, Inc., or Methodist Healthcare-Memphis Hospitals or one of its affiliated entities, he/she will need to also submit his/her research application to the UTHSC IRB. However, another point that needs to be considered when determining whether or not an application needs to be submitted to the UTHSC IRB is which hospital IRB has already approved the study. For example, if St. Jude Children's Research Hospital has approved the study, the individual may invoke the cooperative agreement with St. Jude IRB, and St. Jude will forward a copy of the application and approval to the UTHSC IRB for review. If, however, the hospital IRB that has already approved the application is Baptist Memorial Hospital or the VA Medical Center, then the research project will also need to be submitted to the UTHSC IRB, using the appropriate UTHSC IRB forms, for review and approval.
Q: I am interested in conducting a research study using a commercially available drug
for the approved purpose. Does the UTHSC IRB need to review and approve this research
before my study is initiated?
A: Yes. All clinical investigations (which means any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration (FDA) or is not subject to requirements for prior submission to the FDA but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit) require UTHSC IRB review and approval.
Q: I am planning a research project using purchased human cell lines in an animal
model. Do I need IRB approval?
A: UTHSC investigators using anonymized cell lines from ATCC® do not need to undertake any interaction with the IRB. However, all obligations to interact with the IBC and IACUC remain in place.
Use of anonymized human cell lines from sources other than ATCC® must be registered with the IRB using the cell line registration process, so that the IRB can confirm that the conditions for non-applicability of the regulations are satisfied. The cell line registration form must be submitted for IRB review via the Form 1 Application within iMedRIS, the IRB electronic system. In Section (418) entitled, IRB Submission, the investigator should select the option, I am registering the use of a human cell line purchased or acquired from commercial vendors, IRB approved repositories or government tissue banks to access the cell line registration form. Once the cell line registration form is complete, only the investigator needs to apply his/her electronic signature to the submission and submit the form for IRB review and approval.
Use of human cell lines from identifiable individuals must undergo review and approval using the regular IRB application process and is not eligible for the briefer cell line registration process.
Q: Do I need IRB approval for the creation or use of a database for research purposes?
A: If a databases use is intended entirely for research purposes, then its creation involves the development of a research repository and that should not occur until there is an IRB-approved repository protocol. However, if the database will be used for a variety of QA/QI, educational, clinical, and research purposes, then it is not necessary to submit a protocol for the creation of a research repository. Read further regarding using a clinical database or a research repository for research purposes and the associated IRB requirements.
If you do create a research data repository and secure IRB approval for its operation, the latter approval applies only to the creation and operation of the repository. It does not apply to the conduct of individual studies that utilize data from the repository. Each research study must be approved separately. Other uses of the repository would not require IRB review and approval as explained below.
First, IRB review is necessary when the review of records constitutes research, which is defined in the regulations as a systematic investigation designed to develop generalizable knowledge. A good benchmark for determining whether your activity constitutes research as defined here is whether you intend to publish or present the results in a professional setting. If so, you must have IRB approval before your study is undertaken. In addition, if getting consent is not practical, you must request a waiver of informed consent and a waiver of the HIPAA regulation requiring you to secure the specific authorization of subjects prior to reviewing their records for research purposes.
Second, when you initially query a database or record system to determine whether or not a particular study would be valuable or feasible, this activity is not considered research under human subjects regulations. However, under the HIPAA privacy rules, review of records for purposes other than patient care, billing, or quality assurance/improvement cannot be undertaken without the specific authorization of the patients or a waiver of this requirement by the IRB. As a result, before querying a database or record system to determine the value or feasibility of a research study, you must have the approval of the IRB for what the HIPAA regulations call a review preparatory to research. You must simply confirm in the IRB application that the review is related to and necessary for a possible research study, and that you will not remove data from the facility or system in which it is stored.
Third, the conduct of local quality assurance and quality improvement activities using database and record reviews does not require IRB review of any sort. Even though such activities may be systematic investigations, they are not intended to develop generalizable knowledge and so are not considered research under the IRB regulations. Furthermore, these activities are permitted under HIPAA without any specific authorization on the part of patients. However, if you later determine that the results of a quality assurance/quality improvement project may be worthy of publication or presentation in a professional setting, then the activity becomes research and you should secure IRB approval before developing a publication or presentation.
Q: What do I need to know about humanitarian use devices and IRB approval?
A: First, a few definitions:
- HUD-Humanitarian Use Device is the device corollary to an orphan drug. The device must be indicated for use in a disease or condition that affects fewer than 4,000 US patients per year.
- HDE- Humanitarian Device Exemption is the application that must be submitted to the FDA in order to get approval to get an HUD designation.
- PMA - Pre-Market Approval is the corollary to a New Drug Application.
An FDA-approved HDE is not a research protocol; it is an approval for treatment/diagnostic use of the device. It essentially allows a sponsor to market the "orphan" device without the usual clinical trials to prove its effectiveness.
Q: Why is the IRB involved in overseeing an HUD?
A: Because of the unique situation in which an untested device is being used, the FDA regulations require the added protection that the HUD can only be used if the facility's IRB has approved the use (21 CFR 814.124). In its most recent guidance on the topic, the FDA now recommends that the IRB conduct a full board review at its initial consideration, though expedited review may be appropriate for continuing review.
Q: Is informed consent required for an HUD?
A: Although not required by the FDA regulations, written informed consent is highly advisable and required by the UTHSC IRB, including a statement that the devices effectiveness is unproven.
Q: What else does the IRB need to know about the HUD?
A: Although not required by the FDA regulations, IRB review should include sufficient information to support the use of the HUD such as generic and trade name, six-digit HDE number from the FDA, date of HUD designation, description of the device, contraindications, warnings or precautions, adverse effects on health, alternative practices/procedures, summary of studies using the device, and marketing history.
Q: Must each use of the HUD be approved?
A: No. The IRB may decide if a blanket approval or a case-by-case approval is more appropriate.
Q: May patients be charged for an HUD?
A: Yes. FDA regulations allow patients to be charged so long as the amount charged does not exceed the costs of research and development, fabrication, or distribution. If the amount is $250 or more, the HDE must include verification from a CPA or other appropriate individual that the amount charged does not exceed the allowed costs.
For more how-to information on HUDs and HDEs, see http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm110194.htm
From: Institutional Review Board Management and Function, Bankert Amdur
Q: Can an electronic signature be used to document informed consent instead of a handwritten
A: Yes, a written consent, which may be an electronic version, must be given to and signed by the subjects or the subjects' legally authorized representatives, unless the IRB waives the requirement to obtain informed consent [45 CFR 46.116(d)] or the IRB waives the requirement to obtain a signed consent form [45 CFR 46.117(c)]. In addition, some form of the informed consent document must be made available to the subjects or the subjects’ legally authorized representatives in a format that they can retain. For example, subjects or the subjects’ legally authorized representatives may be provided a hard copy of the signed consent form. Further, a secure system that provides encrypted identifiable signatures must be used when obtaining electronic or digital signatures.
Q: When does the study of medical records that contain patient identifiers qualify
for exempt status?
A: The federal regulations set two conditions for assigning exempt status for this sort of study. First, all the records must be in existence prior to initiation of the study. The application for exempt status should specify the inclusive dates of the records to be reviewed under the description of the subject population. Second, the investigator must record the data from the medical record in a manner that subjects cannot be directly or indirectly identified. In satisfying this condition, it is permissible to retain linkage between individual medical records and entries on a data collection sheet, provided that this linkage is destroyed once the project/study is complete. The intention to follow this procedure should be clearly marked in the exempt application.
Q: My research project has been declared exempt by the IRB, and I have a letter that
I need to include with a grant application indicating the IRB exemption number. Can
I mark "no" to the human subjects question and still include my exemption letter?
A: No. If you are conducting research that has been declared exempt, you must mark "yes" to the human subjects question on the NIH grant application package, then include UT's FWA#, the IRB exemption #, and the approval date.
Q: What do the signatures on the research informed consent document mean?
- Subject - The subject's signature indicates that the person has voluntarily decided to participate in the study, and to the best of his/her ability, understands the meaning and requirements of the study.
- Legally Authorized Representative (LAR) - Tennessee state law does not address the issue of clinical research participation for a subject either too young or incapacitated to make informed decisions for him/herself. Therefore, we look to policies and procedures for health care decision-making for incompetent patients for guidance. Surrogate consent is authorized in TN utilizing the "legally authorized representative" with following hierarchy: conservator, guardian, attorney in fact, spouse, adult child, parent, adult siblings, other adult relative of the patient, or any other adult who has exhibited special care and concern for the patient, who is familiar with the patient's personal values, who is reasonably available, and who is willing to serve. (NOTE: If you are conducting research in a state other than TN, you must use the surrogate consent/LAR hierarchy from that state.) UTHSC policy requires the signature of the LAR when a subject is less than 18 years old, or when the adult subject cannot make decisions for him/herself at that time. In addition, a line to document the relationship between the subject and the legally authorized representative is required on the informed consent document.
- Person Obtaining Consent - The signature of the person obtaining consent indicates that the study has been explained in detail including, but not limited to the contents of the informed consent, purpose of the study, visits and procedures involved, risks and benefits, alternative treatments, confidentiality, the right to withdraw from the study at any time, treatments provided, arms of the study, and randomization. The subject has had sufficient time to read the informed consent document, ask questions, and thoroughly consider their option to participate or not.
- Principal Investigator - The signature of the principal investigator attests that, to the best of his/her knowledge, the informed consent process has been properly conducted, and that the person who conducted the informed consent interview is knowledgeable about the study and is authorized by the principal investigator to conduct the interview. UTHSC policy requires the principal investigator sign the informed consent document within 72 hours.
- Assent - UTHSC policy requires that each child aged 8 years or older provide assent, as long as the investigator determines that the child is capable of assent by evaluating the child's level of maturity, psychological and emotional capacity, as well as the nature of the study.
Q: What should I do if IRB approval of my research study expires?
A: According to federal regulations, if IRB approval of a specific study expires before continuing review and approval occur, investigators must stop all research activities involving human subjects related to that study (45 CFR 46.103(b)), except where they judge that it is in the best interests of already enrolled subjects to continue to participate. When investigators make this judgment, they must promptly notify the IRB (45 CFR 46.103(b)(5)). When the IRB reviews the investigator's decision, it may decide whether it is in the best interests of already enrolled subjects to continue to participate in the research by considering the best interests of subjects either one at a time or as a group. If an IRB determines that it is not in the best interests of already enrolled subjects to continue to participate, investigators must stop all human subjects research activities, including intervening or interacting with subjects, and obtaining or analyzing identifiable private information about human subjects (45 CFR 46.103(b)). Investigators may resume the human subjects research activity once continuing review and approval by the IRB has occurred.
Q: Who is considered key study personnel (KSP) according to UTHSC?
A: For the purpose of completing section 3.0 of the IRB electronic application, the designation “key study personnel” includes all persons who will have a significant role in the design or conduct of the research, and includes at a minimum all principal investigators and co-investigators, any individuals who are individually named on a grant or contract application, persons who are listed on an FDA form 1572, research coordinators, persons who supervise those who obtain informed consent, individuals who obtain informed consent, and those who are named as contact persons in the informed consent documents or recruitment materials for research.
Q: What do I need to consider when making plans to pay or reimburse subjects?
A: There are a few issues to consider when providing payment/reimbursement to subjects:
- Payments made to subjects can be divided into reimbursements for expenses and participation incentives. Reasonable rates of reimbursement for expenses incurred by subjects are generally acceptable to the IRB. Incentive payments may create special issues if the study involves risky procedures that do not directly benefit subjects.
- The acceptable amount of reimbursement/incentive payment varies from study to study based on reimbursement needs (distance driven, child care, etc.) and on research procedures (questionnaire vs. repetitive blood draws solely for research purposes).
- If reimbursements/incentive payments for each visit are held until the end of the study, it can be considered undue inducement for subjects to continue participating when they would not otherwise. Reimbursements/incentive payments should generally be evenly distributed across study visits, although somewhat higher payments are permissible for visits involving additional time or procedures. In addition, it is permissible at the time of the last visit to pay subjects a small bonus for completing all study visits.
- Incentive payments should not be so large that they can be considered undue inducement for subjects to participate when they would not otherwise. This issue becomes especially prominent when the study involves risks related to procedures that do not offer the prospect of direct benefit. The IRB will not allow the use of large incentive payments to induce prospective subjects to undergo risky, non-therapeutic procedures.
Q: What should an investigator do if a subject becomes a prisoner after enrollment
A: The investigator should report this situation to the IRB immediately.
Q: What should be done when a subject becomes a prisoner after enrollment in a study
that was not reviewed and approved by the IRB in accordance with the requirements
of subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research
Involving Prisoners as Subjects?
A: When a previously enrolled research subject becomes a prisoner and the relevant research protocol was NOT reviewed and approved by the IRB in accordance with the requirements of HHS regulations at 45 CFR part 46, subpart C, the principal investigator should promptly notify the IRB of this event and then submit a Form 2 for revision. In the Form 2, change your application to indicate that you will include prisoners as subjects. All research interactions and interventions with, and obtaining identifiable private information about, the now-incarcerated subject must cease until the requirements of subpart C have been satisfied with respect to the relevant protocol.
NOTE: OHRP has allowed one important exception. In special circumstances in which the principal investigator asserts that it is in the best interests of the subject to remain in the research study while incarcerated, the IRB Chairperson may determine that the subject may continue to participate in the research until the requirements of subpart C are satisfied.
Upon receipt of the Form 2 indicating that a previously enrolled research subject has become a prisoner, the IRB will promptly re-review the protocol in accordance with the requirements of subpart C if the principal investigator wishes to have the prisoner subject continue to participate in the research.
Q: Is an adolescent (e.g., age 14) who is detained in a juvenile detention facility
A: "Prisoner" is defined by HHS regulations at 45 CFR part 46.303(c) as "any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute; individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution; and individuals detained pending arraignment, trial, or sentencing." Therefore, an adolescent detained in a juvenile detention facility is classified a prisoner according to the Federal Regulation.
Q: I would like to enroll Spanish-speaking subjects in my IRB approved research study.
As one of the members of my research staff speaks Spanish, may I have him/her verbally
translate the English consent form for the Spanish-speaking subjects when they come
in for a visit?
A: No. Federal Regulations (45 CFR 46.116) require that information that is given to the subject or the representative shall be in a language understandable to the subject or the representative. As such, you will need to submit to the UTHSC IRB office a Form 2 (Application for Revision) to change your application to indicate that you will be recruiting Spanish-speaking subjects. In addition, you will need to submit a copy of the consent form translated in Spanish with a signed copy of the Translator's Declaration that can be found on the UTHSC IRB website at www.uthsc.edu/research/irb. The Translator's Declaration states that the Spanish consent form is a true and accurate translation of the English consent form. You may begin enrolling Spanish-speaking subjects once you have received IRB approval.
Q: Does the IRB need to review an advertisement for my research study?
A: Yes. The FDA requires that an Institutional Review Board (IRB) review and have authority to approve, require modifications in, or disapprove all research activities covered by the IRB regulations [21 CFR 56.109(a)]. An IRB is required to ensure that appropriate safeguards exist to protect the rights and welfare of research subjects [21 CFR 56.107(a) and 56.111]. In fulfilling these responsibilities, an IRB is expected to review all the research documents and activities that bear directly on the rights and welfare of the subjects of proposed research, including the methods and material that investigators propose to use to recruit subjects.
The FDA considers direct advertising for study subjects to be the start of the informed consent and subject selection process. Advertisements and other recruitment materials must receive approval by the IRB prior to the use of such materials. Advertisements and other recruitment materials refer to but are not limited to: materials to be published in local newspapers, broadcast on television or radio networks, placed on the internet, or posted or distributed in pamphlets, posters, signs, brochures, announcements, or promotional materials; descriptions of financial rewards, enrollment fees, and payment to subjects for participation; and any other plans, procedures, or materials designed to solicit the participation of subjects in research.
The content of advertisements, solicitations, and/or recruitment materials must observe the following guidelines:
- No claims should be made, either explicitly or implicitly, that the drug, biologic, or device is safe or effective for the purposes under investigation, or that the test article is known to be equivalent or superior to any other drug, biologic, or device.
- Advertising for recruitment into investigational drug, biologic, or device studies should not use terms such as "new treatment," "new medication," or "new drug" without explaining that the test article is investigational.
- Advertisements should not promise "free medical treatment" when the intent is only to say subjects will not be charged for taking part in the investigation. Advertisements may state that subjects will be paid, but should not emphasize the payment or the amount to be paid, by such means as larger or bold type.
- Advertisements should not state, suggest, or imply that all subjects will receive treatment for their condition if the study involves a placebo-control group.
Should you decide to revise any advertisements or recruitment materials that have already been approved by the IRB or the venue in which the materials will be used, these revised materials must receive prior approval of the IRB before you use them.
Q: Can subjects be recruited via email?
A: Yes. However, it is important to state, in your protocol, how the email addresses were obtained (e.g., you will be using the University listserv, or the PI is a professor and has email addresses of his students in a distribution list, or the potential subjects have agreed to be contacted for research by signing up for a registry online).
TIP: When contacting subjects directly (via mailed letter or email message), the introductory paragraph should include a general statement regarding how the investigator obtained the subjects' contact information (e.g., "We are contacting members of the XXX Association regarding..." or "You are receiving this questionnaire because you are a patient of the investigator, Dr. John Doe").
Q: When may a principal investigator delegate study tasks?
A: The principal investigator may delegate many study tasks to site staff - provided that they are qualified to perform the tasks and it is within the scope of their professional licensure if the task requires a license. Such determinations must be based on FDA requirements, as well as local laws and regulations. For example, the principal investigator may delegate performance of physical exams to a nurse practitioner, advanced practice nurse, or PA. Most state Nurse Practice Acts do not permit an RN without an advanced practice certification to perform physical exams (not to be confused with physical assessments, which RNs routinely perform). In the same manner, a principal investigator may delegate administration of an intravenous study drug to an RN, but not to a medical assistant. Likewise, the informed consent of subjects should be obtained by staff who are qualified by education and background to adequately explain the details of the study.
However, there are some tasks that the principal investigator cannot delegate. For example, the principal investigator or another study physician is responsible for determining if a subject must be withdrawn from a study due to an adverse event. In all cases, the principal investigator has final responsibility for the general conduct of the study at his or her site including, but not limited to, ensuring that all study-related processes and procedures are conducted in accord with the protocol and in compliance with local IRB policy and federal regulations for the protection of human subjects.
Q: In documenting a patient's eligibility for a study, must the investigator obtain the prospective subject's previous medical records, or are history forms completed at the beginning of a study considered adequate?
A: Some studies are so complex, and have so many complicated inclusion/exclusion criteria, that a review of previous medical records is a necessity. A well-written clinical summary prepared by the subject's primary physician, along with relevant lab reports and related documents, will usually suffice. Photocopies of prior medical records are not required. In more straightforward studies that have few inclusion/exclusion criteria, the completion of a history form alone may be adequate (i.e., without the need to obtain prior medical records). The caveat here is that the history taker must be clinically knowledgeable in order to ask the appropriate questions and adequately probe the study candidate for additional information when needed.