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The central task of the Institutional Review Board (IRB) is to ensure that a project's risks are justified by its benefits.
The IRB reviews a proposal by first assessing the risks and benefits of research participation. After determining that the research benefit outweighs the risks involved, the IRB turns to the consent process to ensure that subjects are fully aware of the risks and the benefits and that they participate in the project voluntarily. The consent form is a key element in this review.
After reviewing the application and its supporting materials, the IRB may require revisions in the protocol. When the investigator revises a project, the IRB reviews the project again to see whether its concerns have been adequately addressed. A project may undergo several reviews.
To fully protect subjects, the IRB must approve a project before investigators start to work on it--even before they begin to recruit subjects, since recruitment strategies are part of the review. Although there are different types of review, many projects require "full" committee review. The initial full review will occur within two weeks of submission if the application is complete. All IRB actions are communicated in writing to the investigator by the IRB staff.
Research projects are reviewed at one of three levels, according to the IRB's determination of the project's potential risk to the human subjects and the federal guidelines that define the categories of review, which are:
The level of review is determined only by the IRB.
Investigators do not have the authority to determine whether research involving human subjects is exempt from full review 45 CFR 46.101(b) and (c) & 21 CFR 56.104(c) and (d). Hence, while research that involves only minimal risk to human subjects is sometimes exempt from full IRB committee review, it is still subject to IRB review. Researchers must file an application requesting that the IRB determine exempt status for a project.
In general, the federal guidelines for research on human subjects allow a project to be exempt from full review only if the research involves no risk to the subject and the procedures are limited to the following criteria:
Projects that involve contact with subjects may still qualify as exempt. Copies of the written consent form should be filed with the application or justification for a waiver of written documentation should be provided. See 45 CFR 46.117.
The application form, titled Exempt Screening Application Form, is available from the Human Research Protection Program office or its Web site.
The IRB administrator decides whether the project qualifies as exempt, and the decision is confirmed in writing, most often within one week. If the project does not qualify as exempt, it is referred back to the investigator with the appropriate application forms.
To qualify for expedited review, a research procedure must be limited to the activities that are federally approved (from 63 FR 60364-60367, November 9, 1998.) for expedited review and incur no more than minimal risk for participants, or be a minor change in previously approved research that involves no additional risk to the research subject.
The activities approved in the federal regulations for expedited review are:
The researcher must demonstrate in the application how the proposed project activities fall into one or more of these categories.
To apply for expedited review, investigators complete complete either the Health & Medical/Biological or the Social & Behavioral Sciences Application Form and indicate that they are requesting expedited review in the appropriate section.
The IRB administrative staff assures that all of the elements essential for review, including consent forms and supporting information, have been submitted. The application is then forwarded to a designated committee member for review and decision. Either the research is approved (perhaps with stipulations) by the committee member or it is forwarded for full review.
A project that involves greater than minimal risk requires approval by an IRB panel composed of members qualified to review research in that field. Research that requires full committee review includes:
Survey research that involves sensitive questions or information about sexual practice or illegal behavior is subject to full review, in keeping with federal guidelines. Any survey or interview that is likely to be stressful for the subject requires full committee review. IRB staff will make this determination.
All applications are screened by the administrative staff before they are assigned to an IRB panel; if the application is incomplete, it is returned to the investigator. After review by the IRB panel, the application will be:
All non-exempt research is subject to continuing review at least annually[see 6.1 Continuing Review]. If research involves significant risk to subjects, the IRB may require more frequent review and may ask to be kept apprised of all research activity. For example, researchers in acute care settings or whose research involves novel therapies are asked to submit their protocols for frequent review.
If the overall objective of a course assignment is to learn about the design and conduct of research projects, and if data will be collected and analyzed for classroom learning only, a request for approval of a Class Protocol should be filed with the IRB office by submitting an application.
If the same Class Protocol will be used in several courses during an academic year, the IRB may be able to approve all uses with a single application. The protocol must be reevaluated annually, however, to ensure that the guidelines are maintained and to bring the protocol up to date with any changes in the federal guidelines.
Very ambitious projects and projects that involve sensitive topics and vulnerable populations are not suited to the Class Protocol process. These must be pursued as individual projects.
An example of an acceptable Class Protocol is a course in psychology taught several times per year by different faculty members. The course involves a cluster of independent projects conducted by the students. In this case, students complete IRB application forms and submit them to their instructors for review and approval. The Course Protocol adheres to the following terms:
Please see section 2.5 to find more about research in classes and research conducted by students.
All forms that an investigator must file with the IRB to apply for review are available, with specific instructions, on the Web at http://www.research.umn.edu/subjects, or from the Human Research Protection Program (HRPP) office. The HRPP staff can help researchers determine which level of review is appropriate for a project. The forms are:
Forms must not be handwritten.
Fill out all of the questions on form completely (If there are questions about using the text form fields or checkboxes with this form, please contact the HRPP office 612-626-5654 or firstname.lastname@example.org).
Make sure to include the e-mail address and UMN employee/student ID numbers of the PI, Co-investigators and all other personnel.
Fill out and attach the appropriate appendices required by responses in this application.
Attach supporting documentation: consent form(s), assent form(s), protocol, survey instruments, interview schedules, solicitation letters, advertisements, letters of permission, etc.
Complete the checklist that accompanies this form to assure all requirements for submission are completed so that review is not delayed.
E-mail a copy of application and any other materials required to the Human Research Protection Program Office: IRB@umn.edu
Electronically submitted protocols must be carbon copied (Cc) to an advisor as secure electronic notification using password protected authentications, which have been deemed by the University of Minnesota to constitute a legal signature.
For help with form and to download additional appendices see the Forms main page or call 612-626-5654
Reminder: Keep a copy for your records
Mail or deliver to:
Human Research Protection Program
420 Delaware St. SE
Minneapolis, MN 55455-0392
Human Research Protection Program
To submit a project to the IRB for review, an investigator must complete the application form according to detailed instructions and enclose supporting material as necessary.
A fully completed application form will include:
The application form alone will be used as background information for all future reviews of the study; therefore, "see protocol" is not an adequate response to any application question.
No form can adequately address the wide diversity of research at such a large institution. Principal investigators should use the form to convey the nature and specifics of the project proposed attaching appendices as necessary.
A research project is headed by a principal investigator (PI). At one time, federal regulations for human subjects research allowed the PI to shoulder most of the responsibility for a project. Recently, though, the regulations have emphasized that the whole research team shares responsibility, even though the PI directs the project and bears ultimate responsibility for its conduct.
The IRB must ensure that PIs have the training and experience that the project requires. Researchers are given considerable latitude, however, in designating the PI. The IRB is most likely to have concerns about projects in which the principal investigator appears to lack training and experience in human subjects research or has a conflict of interest that could make it difficult for him or her to ensure the subjects' well-being. If external funding is being sought, the University's policies on Principal Investigator Eligibility on Sponsored Projects also must be met.
Some research projects include a proposal to delegate much of the recruitment or intervention to research associates. In those instances, an explanation of the training of the associates should accompany the application.
Whenever there is a change in the PI or in the PI's status that affects the project, the IRB must be notified. [See section 6.2 Making changes to research protocols]
The IRB is required to protect subjects from the first contact for possible recruitment. All subjects who go through the recruitment process even if they fail or decline participation screening must be accounted for. When asking for subjects please ask for a number large enough to account for this group.
The application must specify the number of study subjects to be recruited and tested, grouped by age, gender, and population diversity. Exceeding the recruitment limits approved by the IRB is a violation of the protocol. The IRB must give prior written approval for any increase in subjects.
If it is difficult to predict how many subjects will be eligible or be attracted to a study, the optimum number should be specified. Responses such as "don't know" or "as many as we can recruit" to questions about the number of subjects are not acceptable.
Multicenter studies, in which data will be pooled and recruitment may vary, present a special problem for investigators. The application should provide information about the total picture, including both the number of subjects to be studied at the University or by University researchers and information on overall recruitment goals.
Research benefits and burdens should be distributed fairly. If an individual or group is denied access to a clinical trial that might be beneficial or if some people are singled out to bear the burden of risks associated with a study, the requirement for fairness is not met.
In accordance with the policies of the National Institutes of Health, the IRB requires researchers applying for federal funds to give breakdowns of their subject populations by gender and minority group. Studies with the potential to address issues relevant to both sexes must recruit both genders, and minority populations should be included in a study population wherever feasible. Researchers must justify the exclusion of any group of individuals. The IRB makes exceptions if there is adequate scientific justification for exclusion, such as when a disease predominates in one gender or the focus of the research question is on a specific group.
Though the researcher may be careful to avoid potentially coercive behavior, the very nature of the relationship with the subject can create the appearance of coercion. For this reason, researchers should be aware of the potential for coercion that exists when a research subject is also a student, employee, colleague, or subordinate of the researcher. For this reason, researchers should avoid using their own students or employees as research subjects.
If there is a good scientific reason to include their own students, researchers should:
Researchers who include colleagues or subordinates as research subjects, must be able to provide a rationale other than convenience for selecting them and must show that the recruitment method does not lead colleagues to think they will be compromised by not participating. Usually recruitment through bulletin board advertisements or by a third party is preferable.
Information about how students and colleagues will be recruited and how coercion will be avoided should be included in the information submitted to the IRB.
All research conducted is subject to the application of 45 CFR Subpart D. In all cases, inclusion or exclusion of children is reviewed for appropriateness as defined in the regulation.
In general, if research involves greater than minimal risk, children can be included in the study population only if there is direct personal benefit to the child. This restriction applies to research in both the health sciences and the social sciences. A research protocol that involves anything more than minimal risk and that offers no potential benefit to the subject cannot involve children unless all conditions of 45 CFR 46.406 are met. Investigators claiming this provision in 45 CFR 46.406 should be prepared to provide rigorous justification.
Researchers may pay research subjects for their participation, but payment arrangements must be disclosed to and approved by the IRB and are subject to a stringent review. Subjects are not paid to assume risk, but can be compensated for the time and inconvenience involved in participating. Payment arrangements affect the fairness of recruitment plans, the balance of risks and benefits, and the adequacy of informed consent. Although there are no fixed formulas for determining whether payment plans are acceptable, the IRB restricts payment arrangements that appear to be coercive. Payment should not encourage subjects to participate or continue to participate against their better judgment.
The amount paid to subjects must correspond to the burdens of participation. For example, payment might defray parking charges or transportation costs. Payments may also be scaled to the time that subjects spend in a study or to the biological materials they donate. The minimum wage provides a ready baseline for hourly rates for participation, and the Blood Bank's payment scale for plasma and other blood products offers a guideline for compensating subjects for biological materials.
Researchers are encouraged to offer gift certificates/gift cards or grocery vouchers rather than cash or checks. When children and adolescents are the subjects, researchers are encouraged to reimburse parents for parking or transportation and give a token payment or gift certificate to the child subject. Drawings and raffles are subject to the state laws and regulations governing games of chance and are generally discouraged.
Subjects must receive at least partial payment if they withdraw from a study. Withholding all payment until participation is complete is coercive. A modest lump sum can be paid after the subject's participation is complete if the arrangement is thoroughly documented in the consent form. An end bonus cannot exceed half the total payment provided to subjects.
Advertisements are part of the informed consent process and subject selection process. Samples of all advertisements, such as flyers, newspaper ads, radio and television announcements, URLs, bulletin board tear-offs, and posters, along with an explanation of other methods of recruiting subjects, must be submitted to the IRB.
Advertisements should be submitted with the application or as soon as the principal investigator decides to use them. The content of advertisements should be limited to:
Advertisements should include the word "research" and should not claim, explicitly or implicitly, that the research is treatment or is superior to any current practice. Extravagant attention-getting devices such as extremely large, bold typefaces and dollar signs are prohibited. Statements of payment should not be in larger type than the rest of the ad. Advertisements should not pressure readers into participating.
The IRB's authority for review and approval of advertising is supported specifically by the FDA, 21 CFR 56.111(a) (3): PHS Information Sheet, January 1988.
Some additional requirements for PI designation apply to projects that fall under the guidelines of the Food and Drug Administration. The FDA defines an "investigator" as an individual under whose immediate direction a test drug or device is administered or dispensed to a subject. "Subinvestigators" are team members who may help design and conduct the investigation but are not charged with overseeing the investigation. Some team members such as pharmacists, research coordinators, and others who do not deal directly with subjects would not be listed as investigators.
Investigators involved in drug studies must sign an FDA State of Investigator agreement (Form FDA-1572), which documents the investigator's commitment to supervise the investigation. No standard agreement exists for device studies. Instead, the device study sponsor prepares a draft agreement and negotiates its terms with the investigator, following the FDA's regulations for investigational devices. Principal investigators should provide current copies of 1572 to the IRB.
The University IRB needs to be notified when a U of M faculty/staff member or student is identified on an FDA investigator agreement, so it can make sure that its records agree with the FDA's.
Food and Drug Administration guidelines implemented in 1993 give IRBs broad discretion to encourage the entry of women into the early phases of clinical trials.(see the NIH's Women's Health Initiative for more information)
The guidelines now encourage women with childbearing potential to participate in entry phase 1 and early phase 2 trials. FDA believes that early drug trials can be safely conducted on women, even before all animal studies are completed, through sound protocol design. Studies can include pregnancy monitoring, pregnancy testing, and counseling about contraceptives or abstinence. Participants can also be referred to gynecologic consultants for advice.
The guidelines also direct sponsors to collect gender-related data during research and development and to analyze the data for gender effects. New drug applications must include a characterization of drug effects by gender.
The guidelines stress that pharmacokinetic data on demographic differences should be collected beginning in phase 1 and 2 studies. When it is feasible, three pharmacokinetic issues should be considered when women subjects are involved:
Consent forms should include a statement that there may be unknown risks to the fetus if a woman becomes pregnant while participating in a clinical trial.
Researchers who employ a test article classified by the Food and Drug Administration as an investigational new drug must assure the IRB that they are complying with the FDA's IND regulations (21 CFR 312). The IND number assigned to the test article must be filed with the IRB when the application for review is submitted.
Experimental drugs require an IND number if they are used to develop information about their safety or efficacy.
Approved, marketed drugs may also require an IND, if proposed use is:
The FDA has published several exemptions to the IND requirements. Roughly, a clinical investigation may be exempted from the IND requirements if the drug is lawfully marketed in the U.S. and all the following apply:
The IRB requires detailed discussion of all these points when an exemption from IND requirements is requested.
Researchers who employ a significant risk device classified by the Food and Drug Administration as an investigational device must assure the IRB that they are complying with the FDA's Investigational Device Exemptions(IDE) regulations (21 CFR 812 or 814). The IDE number assigned to the test article must be filed with the IRB when the application for review is submitted.
Requirements for labeling investigational products are similar to those required for prescription medications. FDA regulations for labeling (21 CFR 312.6) indicate the following:
In addition, state regulations for labeling prescription drugs apply to investigational drugs (see Minnesota Statutes 151.06 subd 1, 151.212 subd 1):
All drugs dispensed to or for a patient (other than an inpatient of a hospital) shall be labeled with the following:
There may be some flexibility allowed for labeling due to the unique nature of investigational studies, particularly studies involving a placebo.
|Univ of MN Clinic Name
Address, Phone number
|Tracking Number (ie visit number)
Subject ID (name or initials)
Drug name and strength or study acronym
|Date of issue:
Prescribing MD, or PI if MD
|Directions for use.|
To facilitate the review of applications for research involving radiation exposure, the IRB and the Human Use Subcommittee of the All University Radiation Protection Advisory Committee (HUS-AURPAC) have revised the applications to both committees.
Projects involving higher levels of radiation exposure, or exposure of vulnerable subjects (e.g. pregnant and/or breast feeding subjects, or minors), and/or subjects who receive a radiation dose above 100 millirem, require full review by the HUS-AURPAC. Projects that involve low-level radiation exposure (100 millirem or less) or routine clinical care and that have been approved by the IRB qualify for expedited review by the HUS-AURPAC chairperson.
IMPORTANT: if the radiation dose received by a subject in a study is a part of their normal medical care, and would be received even if they did not participate in the study, the study does not require review by the HUS-AURPAC.
Radiation exposures which may qualify for expedited review by the HUS-AURPAC chairperson are listed in Section 2. of the HUS application form entitled, "Conditions for Accelerated HUS Review". The HUS application form is available on-line at http://www.dehs.umn.edu/rpd/forms/HUS.pdf Listed below are some examples of ionizing radiation procedures for which accelerated review by the HUS may be authorized:
Research conducted at another site requires review by the radiation review committee at that site. Our University IRB should receive documentation of that review.
Application sheets for HUS-AURPAC review are available on-line (http://www.dehs.umn.edu/rpd/forms/HUS.pdf) or from the HRPP office and from the Radiation Protection Division (612/626-6764). If assistance is needed in completing dose calculations for HUS-AURPAC review, contact a medical physicist in the University's Department of Radiology (612-626-6805).
Physicians sometimes decide they must administer a drug, biologic, or experimental agent that has not yet been approved for marketing by the FDA. In such cases, the IRB can grant a waiver for an "emergency use." "Emergency use" is defined as the use of an experimental device on a human subject in a situation that is life-threatening, in which no standard acceptable treatment is available, and in which there is not enough time to obtain full IRB board approval.
When a physician must employ experimental medicines or devices to care for a patient in a life-threatening situation, neither the IRB nor the clock nor the calendar should interfere.
The IRB trusts physicians to exercise their best clinical judgment, to use experimental medications when necessary, and subsequently to take the appropriate steps to request approval or inform the IRB.
When emergency medical care must be provided without prior IRB review and approval, the patient may not be considered a research subject. The emergency care may not be claimed as research, nor may the outcome be included in any report of research activity.
If the need for emergency use arises during the business day, the procedure to secure a waiver is as follows:
Many drug companies require IRB certification of approval to release drugs or biologics. The investigator is responsible for the paperwork required by sponsors, drug companies, and the FDA.
If the need for emergency use arises when the IRB office is not open, the physician should:
Next Section: 4. The Process of Consent
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