IRB Investigator Guidelines

       

FHCRC 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. [pdf]

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), the FHCRC is held accountable to federal agencies that have established guidelines for the use of human subjects in research.

The FHCRC Institutional Review Office (IRO) provides administrative support for three 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 page.

Other Administrative Offices and Committees that Support Investigators with Human Subjects Protection

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The FHCRC 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 the FHCRC 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 FHCRC 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 James Riddle, IRO Assistant Director at (206) 667-6501.

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There are four IRBs at the FHCRC. 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 FHCRC 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 FHCRC 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 at http://extranet.fhcrc.org/EN/sections/iro/irb/meetings.html.  

What requires review?

All research involving human subjects must be reviewed by the IRB if:

Definitions applied to "Research" and "Human Subjects"

Human Subjects Research: Any research activity that either:

Research

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).

Systematic Investigation: Generally, an activity in which data are collected and analyzed in an organized and consistent manner according to a pre-specified plan, in order to produce valid, generalizable knowledge.

Generalizable Knowledge: In general, a set of conclusions, facts or principles that enhances scientific or academic understanding by applying broadly to a whole category such as a population or field of knowledge.

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 FHCRC Research Trials Office. The following activities are FDA-regulated research:

Human Subjects

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]

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   Full Board Review

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:

Approved:

The study satisfies the applicable regulatory, institutional, and IRB requirements for human subjects research.  The study can begin human subject activities.

 

      Approved with Minor modifications (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.

 

      Disapproved (used when major modifications are required).

 

Written minutes of each full board meeting include:

Expedited Review

Federal regulations recognize certain kinds of research that may be reviewed by an IRB through an expedited review procedure (45 CFR 46.110 and 21. CFR 56.110). 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.

  1. Research on drugs or devices for which an investigational new drug exemption or an investigational device exemption is not required.
  2. Collection of blood samples by finger stick, heel stick, ear stick or venipuncture as follows: (a) from healthy, nonpregnant adults, who weigh at least 110 pounds. For these subjects, amounts drawn may not exceed 550 ml in an 8 weeks period and no more than 2 times per week; or (b) from other adults and children, considering age, weight, and health, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml/kg in an 8-week period and no more than 2 times per week.
  3. Prospective collection of biological specimens for research purposes by noninvasive means. Examples: (a) hair and nail clippings, in a nondisfiguring manner; (b) deciduous teeth at the time of exfoliation; (c) permanent teeth if patient care indicates a need for extraction; (d) collection of excreta and external secretions (including sweat); (e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or applying a dilute citric solution to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) collection of both supra- and subgingival dental plaque and calculus, provided the collection procedure is accomplished in accordance with accepted prophylactic techniques; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization.
  4. Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed they must be cleared/approved for marketing. Examples: (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject's privacy; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencelphalography, thermography, detection of naturally occurring radioactivity, electroretinography, echography, ultrasound, infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight and health of the individual.
  5. Research involving materials (data, documents, records or specimens) that have been collected or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis).
  6. Collection of data from voice, video, digital or image recordings made for research purposes.
  7. Research on individual or group characteristics or behavior (including but not limited to research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.
  8. Continuing review of research previously approved by the convened IRB where (1) the research is permanently closed to the enrollment of new subjects, all subjects have completed all research-related interventions, and the research remains active only for long-term follow-up of subjects; (2) where no subjects have been enrolled and no additional risks have been identified; or (3) where the remaining research activities are limited to data analysis.
  9. Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.
Exempt from IRB Review

The FHCRC 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.

  1. Research conducted in established or commonly accepted education settings, involving normal education practices, such as i) research on regular and special education instructional strategies, or ii) research on the effectiveness of or the comparison among instructional techniques, curricula or classroom management methods. The research is not FDA-regulated and the research does not involve prisoners as subjects.
  2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless: i) information obtained is recorded in such a manner that human participants can be identified, directly or through identifiers linked to the participants; and ii) any disclosure of the human participants' responses outside the research could reasonably place the participants at risk of criminal or civil liability or be damaging to the participants' financial standing, employability or reputation. The research is not FDA-regulated and the research does not involve prisoners as subjects. PLEASE NOTE: This exemption, for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, as defined in Subpart D, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed, and research involving the use of educational tests.
  3. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior that is not exempt under item 2 above, if: i) The human participants are elected or appointed public officials or candidates for public office; or ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. The research is not FDA-regulated and the research does not involve prisoners as subjects.
  4. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects. The materials must exist at the time the research is proposed. The research is not FDA-regulated and does not involve prisoners as subjects.
  5. Research and demonstration projects which are conducted by or subject to the approval of department of agency heads, and which are designed to study, evaluate, or otherwise examine: i) Public benefit or service programs; ii) procedures for obtaining benefits or services under those programs; iii) possible changes in or alternatives to those programs or procedures; or iv) possible changes in methods or levels of payment for benefits or services under those programs. Furthermore, iv) the study has to be conducted pursuant to specific federal statutory authority, v) there is no statutory requirement for IRB review, vi) the study does not involve significant physical invasions or intrusions upon the privacy interests of participants, vii) he research should have authorization or concurrency by the funding agency. The research is not FDA-regulated and the research does not involve prisoners as subjects.
  6. Taste and food quality evaluation and consumer acceptance studies if wholesome foods without additives are consumed; or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the FDA or approved by the EPA or the Food Safety and Inspection Service of the US Department of Agriculture. The research does not involve prisoners as subjects.

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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.

The Process of Consent and Assent

Obtaining informed consent is a basic ethical obligation for researchers. The process of consent should ensure that potential subjects are provided with information about the research project that is understandable and permits the subject to make an informed and voluntary decision about whether or not to participate. The amount of information and the manner of presentation is generally related to the complexity and risk involved in the research study. While the initial process is prospective and takes place prior to any research activity, consent should also be an ongoing educational interaction between the investigator and the research subject that continues throughout the study. It is not an exercise in persuasion. If an investigator has a relationship with potential subjects (physician-patient, instructor-student, employer-employee), care should be taken to avoid recruitment methods that may be seen as coercive due to the special relationship between parties.

Consent is a legal concept. Only legally competent adults can give legally effective informed consent. Legal competency and capacity to consent is determined by the law of the state in which the research is conducted. For research studies approved by the FHCRC IRB the presiding law is the law of the jurisdiction in which the research is conducted. That law will also control when determining who is capable of acting as the legal representative for a research participant.  For assistance in determining who may act as the "legally authorized representative" or "LAR" for a prospective research participant, refer to the IRB Policy 2.25 on the Identification and Use of Legally Authorized Representatives or contact the Institutional Review Office or the Office of the General Counsel.

Children and those individuals who are not competent to provide consent should be given the opportunity to assent to participate in the research project. Assent is a knowledgeable agreement to participate in the project. Adequate provisions should be made for soliciting the independent, non-coerced assent from children or cognitively impaired persons who are capable of a knowledgeable agreement. In general, the IRB recommends that children age seven and older, and most cognitively impaired adults, be given the opportunity to assent.

In cases where assent is obtained from a child or cognitively impaired subject, permission must also be obtained from a legally authorized representative. In studies involving children, the legally authorized representative is generally the parent(s) or court-appointed guardian.

If the person from whom assent is sought refuses, the person should not be enrolled, even if the parent or legally authorized representative gives permission. (The IRB may make an exception to this guideline in studies of children with life-threatening illnesses who are eligible for research treatment protocols.) Alternatively, if the person from whom assent is sought agrees to participate, the person may not be enrolled if the parent or legally authorized representative does not give permission. In rare circumstances, depending on the nature of the study and the age and circumstances of the child, the IRB may waive the requirement for parental or legally authorized representative permission. In cases where questions arise as to who may act as a legally authorized representative, it is recommended that you seek assistance from the FHCRC Office of the General Counsel.

Standard Informed Consent Document

The purpose of an Informed Consent Document is to provide subjects with a written source of information for future reference and to document the fact that the initial process of informed consent occurred prior to the subject's participation. The form generally serves as a basis for the initial presentation of the study to the potential subject. Typically, informed consent is documented by using the written Informed Consent Document approved by the IRB and signed and dated by the subject or the subject's legally authorized representative at the time of consent. A copy of the Informed Consent Document should be given to the subject. Unless the investigator has been granted a waiver of documentation of consent, the subject's signature on an Informed Consent Document is required prior to beginning any study procedures.

The Informed Consent Document template on the IRO web site contains instructions and examples of text for preparing an Informed Consent Document. By following the template, the investigator ensures that the basic and additional elements of consent as required by the federal regulations are included. The Model Informed Consent Document can be found at: http://extranet.fhcrc.org/EN/sections/iro/irb/consent.html. The UW model consent can be found at: http://www.washington.edu/research/hsd/forms_paper.php#consent.

The basic elements of informed consent are described in 45 CFR 46.116 for federally funded research and 21 CFR 50 for FDA regulated research.

Assent Document

The Assent Document is used when the investigator recruits subjects who, by age or circumstance, are not able to give legally effective informed consent. When legally effective informed consent cannot be obtained, the investigator should obtain the "assent" of the child or cognitively impaired subject. This form documents the child's or cognitively impaired subject's knowledgeable agreement, or assent, to participate in a research project. The investigator should respect the decision of a child or cognitively impaired subject not to participate, even when the parent or legally authorized representative gives permission, unless specifically instructed otherwise by the IRB.

For studies involving children, the IRB recommends that this form be used with children who are in the 7-13 age range, but it may also be used when teenagers are being recruited to enhance their comprehension if the study involves complicated procedures.

When using an Assent form, the child or cognitively impaired adult should sign the Assent to indicate knowledgeable agreement (assent) to participate. In addition, the parent/guardian or legally authorized representative should sign the full Informed Consent Document to document his/her permission for the child or cognitively impaired adult to participate.

A template is available at http://extranet.fhcrc.org/EN/sections/iro/irb/consent.html.

Recruitment

The Investigator and their research staff are responsible for recruiting participants in a fair and equitable manner, weighing the potential benefits of the research to the participants against their vulnerability and the risks to them.

Recruitment materials, including brochures, flyers, advertisements, audio tapes, video tapes, and letters to potential subjects, must not contain coercive language or incentives. For example, if the study involves comparing an investigational drug to a placebo, the advertisement should not mention the study drug only. Rather, it should indicate that some subjects in the study will receive a placebo, or describe the purpose of the study as comparing the investigational drug to a placebo.

Any material (including audio or video) aimed at recruiting potential subjects into a study must be reviewed and approved by the IRB prior to being used. Suggested guidelines for an advertisement or recruitment letter appear below:

Research Participant Compensation

Payment for participation in research may not be offered to the subject as a means of coercive persuasion. Rather, it should be a form of recognition for the investment of the subject's time, loss of wages, or other inconvenience incurred. Accordingly, compensation may not be withheld contingent on the subject's completion of the study. In most cases involving continued participation, compensation should be given on a reasonable prorated basis to avoid the impression that the investigator is coercing the subject to continue in a study or is punishing the subject for non-compliance.

Information regarding how to process payment for research subjects is posted on The FHCRC Accounting Services website: https://centernet.fhcrc.org/CN/depts/finance/accounting/.

Unanticipated Non-English Speaking or Reading Populations Consenting to Research: Use of Short Form Consent

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 at: http://extranet.fhcrc.org/EN/sections/iro/irb/translation.html.  Prior IRB review and approval is required.

Waiver of Documentation of Consent

In some situations, the IRB may waive the requirement for obtaining a signed Informed Consent Document. 45 CFR 46.117(c). The regulations state that a signed consent form may be waived if the IRB determines that:

Examples of types of studies that fall into the first category are survey or interview studies that contain highly sensitive (e.g., criminal behavior, sexual behavior) questions.

Studies that fall into the second category are mailed-out surveys about topics that could not reasonably damage a research participant's reputation or employability or be otherwise stigmatizing.

Waiver of documentation of consent may mean that no written document is provided to the subject at all, for example, in a random-dial telephone survey study. In this type of study, the telephone interview would begin with a script that includes all of the required elements of consent, but the study subjects would receive no written information about the study, either before or after the interview. The telephone script containing the elements of consent must be included in the New Project Application Form.

On the other hand, the waiver of documentation of consent may mean only that the subject's signature does not have to be obtained. The regulations stipulate that the IRB chair may still require that the investigator provide the subject with a written statement about the research when granting a waiver of documentation. For example, in a mailed-out survey study, the chair may determine that it is reasonable for the investigator to provide the subjects with a cover letter containing all of the basic elements of consent. The letter would simply conclude with a statement that returning the survey or questionnaire would be considered agreement to participate.

Waiver of Consent

Some research projects would not be possible if informed consent from research participants were required. The IRB may consider waiving the requirement for some or all of the elements of informed consent. 45 CFR 46.116(d).

The regulations state that informed consent may be waived in full or in part if the IRB determines that:

Note: Waiver of consent is not allowed for FDA-regulated research. See IRB Policy 1.14 Engagement in Research: Determining when Activities are Research Involving Human Research Participants [pdf] for more details.

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Responding to Participant Complaints or Requests for Information

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.

   Progress Report for Continuation Review

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 Continuing Review Report, and return it to the IRB in a timely manner 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.

Amendments and Modifications

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.

Reports of Unanticipated Problems / Adverse Events / Noncompliance to the IRB

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.

Reporting requirements for the FHCRC IRB can be found at: http://extranet.fhcrc.org/EN/sections/iro/irb/ae.html.  

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.

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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.

Comparison of Regulations

IRB Regulations

312.120 (FDA)
46.101(h) (DHHS)
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.]
56.102 (FDA)
46.102 (DHHS)
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)].
46.103 (DHHS)
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.
56.104 (FDA)
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).
56.105 (FDA)
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.
56.108 (FDA)
46.108 (DHHS)
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.
56.109 (FDA)
46.109 (DHHS)
46.117(c) (DHHS)
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.)
56.110 (FDA)
46.110 (DHHS)
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.
56.114 (FDA)
46.114 (DHHS)
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.)
56.115 (FDA)
46.115 (DHHS)
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.
56.115(c)(FDA)
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.
56.120, 56.121, 56.122, 56.123, and 56.124 (FDA)
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.

Informed Consent Regulations

50.3(l)
FDA 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)].

50.23 (FDA)

FDA, but not DHHS, provides explicit guidance for an exemption from the informed consent requirements in emergency situations. The provision is based on a statutory requirement in the Medical Device Amendments of 1976, and may be used in investigations involving drugs, devices, and other FDA-regulated products in situations described in 50.23.
46.116(c) and (d)(DHHS)
DHHS provides for waiving or altering elements of informed consent under certain conditions. FDA has no such provision because the types of studies that would qualify for waiver or alteration are either not regulated by FDA or are covered by the emergency treatment provisions of 50.23.
50.25(a)(5) (FDA)
46.116(a)(5) (DHHS)
FDA explicitly requires that subjects be informed that FDA may inspect the records of the study because FDA may occasionally examine a subject's medical records as they pertain to the study. While DHHS has the right to inspect records of studies it funds, it does not impose the same informed consent requirement because of the infrequency with which the Department actually inspects subject records.

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Consent and Assent: Relevant Examples and Forms: https://centernet.fhcrc.org/CN/depts/iro/irb/consent/

Requesting FHCRC's OHRP-Approved Assurance: Contact the IRO

HHS Human Subjects Regulations (45 CFR Part 46): http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

The Belmont Report: http://www.fda.gov/oc/ohrt/IRBS/belmont.html

FDA Information Sheets for IRBs and Investigators: http://www.fda.gov/oc/ohrt/irbs/default.htm

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This content was prepared by the IRO using resources found on the OHRP, FDA; CITI Training Program, University of Iowa, and University of Washington websites.

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