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II. Federal and Institutional Requirements for the Protection of Human Research Subjects
III. The IRB's Role and Responsibilities
IV. Methods of Review for New IRB Applications: Full Board, Expedited or Exempt?
V. The Responsibilities of Investigators During the Review and Conduct of Research
VI. Investigator Continuation Review Requirements for Reporting Progress, Modifications, Adverse Events, Unanticipated Problems and Noncompliance
VII. Comparing FDA and DHHS Human Subjects Regulations
VIII. Additional Resources
Fred Hutch operates a centralized program to review and approve all research involving human subjects. For more information, see the Office of the Director Policy on Human Research Protection Program.
Before a research project involving human subjects is initiated, it must be reviewed and approved by an Institutional Review Board (IRB). Through its Federalwide Assurance (FWA), Fred Hutch is held accountable to federal agencies that have established guidelines for the use of human subjects in research.
The Fred Hutch Institutional Review Office (IRO) provides administrative support for the Fred Hutch Institutional Review Boards. The IRO provides assistance to investigators who are preparing IRB applications and maintains records of IRB reviews and approvals.
For IRB and IRO policies and practices, see the IRB Policies and Procedures page.
Fred Hutch has filed an assurance of compliance, called a Federalwide Assurance, with the Office of Human Research Protections (OHRP) at the Department of Health and Human Services (DHHS). The Center is required to enter into this agreement because it receives federal funding for research involving human subjects.
A FWA is a binding written agreement between Fred Hutch and DHHS. It states that the Center is guided by the ethical principles of the Belmont Report, and will comply with federal regulations (45 CFR 46) for all human subjects research as defined by 45 CFR 46.
The DHHS regulations at 45 CFR 46 and the regulations of the United States Food and Drug Administration ("FDA") at 21 CFR Parts 50 and 56 require the establishment of an IRB to review and approve human subjects research prior to its initiation. These regulations also require that specific points of information be included in the informed consent process, and that, in most cases, the consent process itself be documented in writing.
The FWA describes the ethical principles and regulations that guide the IRB, institution and the investigator. All investigators at the Fred Hutch are expected to conduct research in accordance with the provisions of the FWA. Primary responsibility for assuring that the rights and welfare of the research subjects are protected rests with principal investigator conducting the research. Faculty members who assign or supervise research conducted by students have an obligation to consider carefully whether those students are qualified to safeguard adequately the rights and welfare of subjects.
If you would like a copy of our FWA, call the IRO.
There are four IRBs at Fred Hutch. They review and approve research in accordance with Department of Health and Human Services (DHHS) regulations at 45 CFR 46. In addition, for studies involving products regulated by the FDA, the Fred Hutch IRBs comply with the requirements set forth in 21 CFR 50, 21 CFR 56, 21 CFR 312, and 21 CFR 812.
Committee A, B, C, and D review any and all research submitted by Fred Hutch and the Fred Hutchinson/University of Washington Cancer Consortium. Any research project involving research participants, regardless of its source of funding, is reviewed by one of the IRBs.
Submission deadlines and meeting dates for each committee are listed on the IRB Meetings webpage.
ll research involving human subjects must be reviewed by the IRB if:
Any research activity that either:
The DHHS regulations define research as a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research even if they are a component of a larger non-research activity (e.g., instruction, demonstration).
The FDA regulations use the term "clinical investigation" rather than the term "research" as any experiment that involves a test article and one or more human subjects, and that is either is subject to requirements for prior submission to the FDA under section 505(i) or 520(g) of the Federal Food, Drug and Cosmetic Act; or, is not subject to requirements for prior submission to the FDA under these sections of the Act, 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. [21 CFR 50.3(c)]. Additional information regarding FDA clinical investigation definitions for drug or device studies are found at 21 CFR 312.3(b) and 21 CFR 812.3(h) respectively. For study-specific assistance with FDA regulations in the protocol development phase, contact the Fred Hutch Research Trials Office. The following activities are FDA-regulated research:
The DHHS regulations define a human subject as a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (e.g., venipuncture and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact (e.g., questionnaires, interviews) between the investigator and the subject. Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (e.g., medical record information). [45 CFR 46.102]
The FDA regulations define a human subject as an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. For research involving medical devices a human subject is also an individual on whose specimen an investigational device is used. [21 CFR 50.3]
Under Washington State law, the term "human subject(s)" is not defined but the authority of institutional review boards to approve the release of "health care information" of "patients" for research purposes is recognized and confirmed. The Washington Uniform Healthcare Information Act protects the confidentiality of "health care information" of "patients" who are deceased. [RCW Chapter 70.02]
Human subjects research that is not classified as exempt or expedited requires review by the full IRB at a convened meeting. Applications are placed on a meeting's agenda in order of receipt in the IRO. A full board meeting may be canceled or rescheduled due to a) holiday, b) inability to secure a quorum, or c) other reasons as may arise that make a scheduled meeting unnecessary or otherwise inappropriate.
The IRBs use a primary and secondary reviewer system for full board reviews. All study documents are made available to all IRB members one week in advance of the meeting. IRO staff determines who the primary and secondary reviewers will be for each study. In addition to reviewing all documents the primary reviewer will be responsible for reviewing the grant application and the Investigator's Brochure when appropriate. For all New Applications the investigator is invited to be available (by phone or in person) for the meeting for the purpose of additional clarification or discussion. The investigator will not be in the room for subsequent discussion and voting.
The IRB Chair leads the discussion of each project at the full board meeting. The IRB determines whether the project meets the criteria for approval or whether revisions to the study design are required. The Informed Consent Document is reviewed for accuracy, clarity, and inclusion of required and optional elements of consent. Voting is done by a show of hands and a majority of those present at the meeting. Possible votes are:Written minutes of each full board meeting include:
The study satisfies the applicable regulatory, institutional, and IRB requirements for human subjects research. The study can begin human subject activities.
Used when minor modifications are required. The study satisfies the applicable regulatory, institutional, and IRB requirements for human subjects research; however there are minor unresolved issues such that final approved documents can not be released. The minor modifications cannot be substantive clarifications or modifications regarding the protocol or informed consent process/documents that are directly relevant to the determinations required by the IRB under HHS regulations at 45 CFR 46.111. A study that is approved with minor modifications cannot begin human subject activities.
An example of approved with minor modification: Simple language changes to consent and other subject materials; clarification of issues on IRB forms; if review by external departments or committees other than the IRB is pending (e.g., Radiation Safety Committee [RSC], Institutional Biosafety Committee [IBC] or Industry Sponsored Contract), status of application is approved, however no study documents (i.e., protocol, consent forms, questionnaire) are released to the investigator.
Used when major modificatiions are required.
Written minutes of each full board meeting include:
Federal regulations recognize certain kinds of research that may be reviewed by an IRB through an expedited review procedure (45 CFR 46.110). Expedited review means that the IRB chair alone (or his/her designee) is responsible for the review and approval. Expedited review does not mean that the review has less depth than a review by the convened IRB, but it does mean that the review might occur more quickly than review by a convened IRB.
The chair or his/her designee is the sole authority for determining whether the research meets the expedited criteria, based on review and approval of the investigator's New Project application to the IRB. The chair retains the discretionary right to require full board review, even when the project appears to meet the criteria for expedited review.
The criteria and categories for expedited review apply to both initial and continuing review of research. Modifications may be reviewed using the expedited procedure when those modifications are minor. Minor modifications include:
The expedited review procedure may not be used where identification of the subjects or their responses would reasonably place them at risk of criminal or civil liability; or be damaging to the subjects' financial standing, employability, insurability, or reputation; or be stigmatizing, unless the investigator has documented that reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.
The expedited review procedure may not be used for classified research involving human subjects.
Expedited review is limited to research involving no more than minimal risk and the only involvement of human subjects is in one or more of the following categories. The activities listed are not deemed to be of minimal risk simply because they are included on the list. Inclusion on the list merely means that the activity is eligible for expedited review when the specific circumstances of the proposed research involve no more than minimal risk to human subjects. If the research project as a whole involves more than minimal risk, it must be reviewed by the full board even if the activities are limited to those listed.
The Fred Hutch policy requires that all human subjects research proposals be submitted for review. However, certain types of human subjects research may be classified as exempt from the federal regulations (45 CFR 46.101(b) and 21 CFR 56.104). The chair or his/her designee is the sole authority for determining whether the research meets the exempt criteria, based on review and approval of the investigator's New Application.
Exempt research projects are re-reviewed every five years. Exempt research is limited to research involving no more than minimal risk and the only involvement of human subjects is in one or more of the following categories.
As the Principal Investigator of a study you must maintain appropriate oversight of your research protocols and your research staff including recruitment, selection of research participants, study conduct, and appropriately delegate research responsibilities.
Please see Informed Consent for information and guidance.
Please see Recruitment of Subjects for information and guidance.
If the investigator encounters one research participant who does not speak or read English, the short form consent document and process can be used (e.g. clinical setting). The short form is a written document that is translated into the subject's parent language and includes the basic elements of informed consent. An interpreter is utilized in these situations and they assist with the oral presentation to the research participant. Specific instructions for use of short forms and interpreters are found in Policies and Procedures. Prior IRB review and approval is required.
Please refer to Consent Waivers for information and guidance.
Investigators and research staff should be open to participants' complaints or requests for information. Investigators and research staff should respond appropriately to such complaints or questions, and report complaints to the IRB.
The IRB must do substantive continuing review and must consider the same issues as during initial review. Specifically:
Typically, continuing review will occur once a year. However, the IRB may direct more frequent review. It is an investigator's responsibility to know when IRB approval will expire. However, as a courtesy to investigators, the FHCRC IRO sends out reminders that IRB approval is about to expire. It is an investigator's responsibility to complete the Continuation Review Report, and return it to the IRB in a timely manner to assure approval of an activity does not lapse.
If a protocol is not granted approval by the end of the approval period granted by the IRB, approval expires and all research activities must cease, including recruitment (all media advertisement must be stopped), enrollment, interventions and interactions that are not needed to ensure the health and safety of the research subjects, and collection of private identifiable data. This has to occur regardless of whether the investigator turned in the review request on time.
All amendments and modifications to a study need IRB approval before they are implemented. If the investigator wants to change anything in the research that would impact the subjects, such as recruitment procedures, key personnel, inclusion/exclusion criteria, research procedures, the informed consent document or process, or data elements collected, the investigator must obtain IRB review and approval prior to implementation of the changes. The only exception are changes necessary to immediately protect subjects' safety, as noted in 21 CFR 56.108(a)(4) and 56.115(a)(1). If an investigator is unsure about reporting changes to the IRB, he/she should call the IRO and ask for guidance. The IRO can also provide investigators instructions for submitting a request to modify an IRB approved research.
DHHS and FDA regulations require that the IRB have written policies to ensure prompt reporting of unanticipated problems involving risks to human research subjects or others to the appropriate IRB, regulatory agencies, and institutional officials (Policy 2.6). As part of these procedures, the IRB has published a list of problems that investigators are required to report to the IRB. FDA regulations also specify reporting requirements for investigators to report adverse events to sponsors.
Sponsors, cooperative groups, government agencies or other entities charged with oversight of specific protocols may have reporting requirements that are more stringent than those established by these guidelines. The Principal Investigator is responsible for ensuring compliance with all adverse event reporting requirements relating to each protocol, including those of the IRB, any external third-party sponsor, and regulatory agencies with oversight responsibilities. For example, the FDA has oversight responsibilities in certain studies involving investigational drugs, biologics and devices, and the NIH Office of Biotechnology Activities (OBA) has oversight responsibilities in certain studies involving recombinant DNA. Please note that compliance with the FHCRC guidelines does not necessarily constitute compliance with FDA or OBA requirements for reporting adverse events or other problems.
The DHHS regulations (45 CFR 46) apply to research involving human subjects conducted by DHHS or supported in whole or in part by DHHS. The FDA regulations (21 CFR 50 and 56) apply to all research involving products regulated by the FDA, including research and marketing permits for drugs, biological products, or medical devices for human use, food and color additives, or electronic products. Federal funds do not need to be involved. When research involving products regulated by the FDA is funded by DHHS, both DHHS and FDA regulations apply. This Section describes significant differences between FDA and DHHS regulations, including departures from the new Federal Policy.
The FDA regulations provide criteria for accepting foreign clinical studies not conducted under an Investigational New Drug Application (IND). The DHHS regulations allow a department or agency head to determine that if procedures prescribed by a foreign institution afford protections at least equivalent to DHHS regulations, the department or agency head may approve the substitution of foreign procedures. [See also 21 CFR 812.1.]
FDA definitions are included for terms specific to the type of research covered by the FDA regulations (test article, application for research or marketing permit, clinical investigation). A definition for emergency use is provided. The definition of "IRB approval," added as a result of the Federal Policy, substitutes the term "clinical investigation" for the term "research" used in the Federal Policy [§56.102(m)]. FDA also adopted the Federal Policy's new wording for the definition of "minimal risk" ("the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests") [§56.102(i)].
DHHS requires that institutions provide an Assurance of Compliance with human subjects regulations, which is negotiated with OPRR. FDA does not require Assurances of Compliance, but does require that IRBs have written policies and procedures.
Unlike DHHS, FDA exempts from prospective IRB review the "emergency use" of a test article in specific situations. FDA added the Federal Policy's new "taste testing" exemption at §56.104(d).
FDA provides for sponsors and sponsor-investigators to request a waiver of IRB review requirements (not informed consent requirements). DHHS regulations do not have a similar provision.
DHHS requires prompt reporting of unanticipated problems to the Secretary. FDA does not specify that a similar report be made by the IRB to the FDA Commissioner, but that the IRB have and follow written procedures to ensure that such reporting is done by the sponsor and clinical investigator.
Unlike DHHS, FDA does not provide that an IRB may waive the requirement for signed consent when the principal risk is a breach of confidentiality because FDA does not regulate studies that would fall into that category of research. (Both regulations allow for IRB waiver of documentation of informed consent in instances of minimal risk.)
FDA does not include research on behavior or characteristics of groups or individuals such as studies of perception, cognition, game theory, or test development (DHHS activity #9) in its list of research activities that may be reviewed through expedited review procedures, because those types of studies are not regulated by FDA.
FDA regulations do not discuss administrative matters dealing with grants and contracts because they are irrelevant to the scope of the Agency's regulation. (Both regulations make allowances for review of multi-institutional studies.)
DHHS, but not FDA, requires the IRB or institution to report changes in membership. FDA has neither an assurance mechanism nor files of IRB membership; there is therefore no reason for FDA to be informed about changes in membership.
FDA may refuse to consider a study in support of a research or marketing permit if the IRB or the institution refuses to allow FDA to inspect IRB records. DHHS has no such provision because it does not issue research or marketing permits.
FDA regulations provide sanctions for noncompliance with regulations. There is no parallel DHHS regulation, other than §46.123, which permits early termination of research support and evaluation of applications and proposals in light of prior noncompliance.